Trial Outcomes & Findings for MEtronomic TrEatment Option in Advanced bReast cAncer (NCT NCT02954055)

NCT ID: NCT02954055

Last Updated: 2024-02-26

Results Overview

Efficacy and tolerability, measured by time to treatment failure, of metronomic oral vinorelbine plus cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel, using an intent-to-treat analysis approach.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 140 participants
• Primary outcome timeframe: Assessed at the start of every 4-week (28-day) treatment cycle from randomization to the end of treatment date or discontinuation; median follow-up was 29 months, with a minimum of 0.2 months and maximum of 48.5 months.
• Results posted on: 2024-02-26

Participant Flow

Participant milestones

Measure	Arm A Paclitaxel 90 mg/m2 days 1, 8, 15 q4weeks. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Overall Study STARTED	69	71
Overall Study COMPLETED	63	70
Overall Study NOT COMPLETED	6	1

Reasons for withdrawal

Measure	Arm A Paclitaxel 90 mg/m2 days 1, 8, 15 q4weeks. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Overall Study Did not initiate therapy	6	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Arm A n=63 Participants Paclitaxel 90 mg/m2 days 1, 8, 15 q4weeks. Patients continued to receive assigned treatment until objective progressive disease (PD), symptomatic deterioration, unacceptable toxicity, death, or refusal to continue treatment, whichever occurred first. Paclitaxel: Arm A	Arm B n=70 Participants Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients continued to receive assigned treatment until objective progressive disease (PD), symptomatic deterioration, unacceptable toxicity, death, or refusal to continue treatment, whichever occurred first. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B	Total n=133 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=63 Participants	0 Participants n=70 Participants	0 Participants n=133 Participants
Age, Categorical Between 18 and 65 years	41 Participants n=63 Participants	47 Participants n=70 Participants	88 Participants n=133 Participants
Age, Categorical >=65 years	22 Participants n=63 Participants	23 Participants n=70 Participants	45 Participants n=133 Participants
Sex: Female, Male Female	63 Participants n=63 Participants	70 Participants n=70 Participants	133 Participants n=133 Participants
Sex: Female, Male Male	0 Participants n=63 Participants	0 Participants n=70 Participants	0 Participants n=133 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Italy	63 participants n=63 Participants	70 participants n=70 Participants	133 participants n=133 Participants

PRIMARY outcome

Timeframe: Assessed at the start of every 4-week (28-day) treatment cycle from randomization to the end of treatment date or discontinuation; median follow-up was 29 months, with a minimum of 0.2 months and maximum of 48.5 months.

Efficacy and tolerability, measured by time to treatment failure, of metronomic oral vinorelbine plus cyclophosphamide and capecitabine (VEX) versus weekly paclitaxel, using an intent-to-treat analysis approach.

Outcome measures

Measure	Arm A n=63 Participants Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 Participants Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Time to Treatment Failure (TTF) Compared Between Treatment Groups.	5.7 months Standard Error 0.06	8.3 months Standard Error 0.06

SECONDARY outcome

Timeframe: Time from day 1 of cycle 1 until 28 days after stopping trial treatment.

Frequency of adverse events by type and worst grade experienced.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.

Defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) (or non-CR/non-PD in the case of non-measurable disease only) lasting for at least 24 weeks (at least 2 scans), measured from randomization until first documentation of progressive disease. Best overall response was defined as best response recorded from randomization across all time points until disease progression. Confirmation of partial or complete response by an additional scan was not requested in this trial. Disease response and progression were assessed according to the revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

Outcome measures

Measure	Arm A n=63 Participants Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 Participants Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Disease Control Not evaluable (NE)	1 participants	4 participants
Disease Control Complete response (CR)	1 participants	1 participants
Disease Control Partial response (PR)	18 participants	22 participants
Disease Control Stable disease (SD)/non-complete response (CR)/non-progressive disease (PD)	25 participants	32 participants
Disease Control Progressive disease (PD)	18 participants	11 participants

SECONDARY outcome

Timeframe: Tumor measurements were assessed at baseline, and every 12 weeks (± 2 weeks) from randomization until first disease progression on the basis of clinical and radiological tumor assessments, on average approximately 9 months.

PFS was defined as time from randomization until documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria or death, whichever occurred first; the death must have occurred within an interval of time corresponding to the interval of tumor re-evaluations. For patients without progression, follow-up was censored at the date of last disease assessment.

Outcome measures

Measure	Arm A n=63 Participants Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 Participants Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Progression Free Survival (PFS)	6.9 months Standard Error 0.06	11.1 months Standard Error 0.05

SECONDARY outcome

Timeframe: From day 1 of cycle 1 until death from any cause (censored at date of last assessment of vital status for patients lost to follow up), assessed up to 36 months from the enrollment of the first patient.

Overall survival from time of randomisation will be summarised for each treatment group.

Outcome measures

Measure	Arm A n=63 Participants Paclitaxel 90 mg/m2 days 1, 8, 15 q4w. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 Participants Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, Capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, Vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Overall Survival	33.7 months Standard Error 0.03	29.5 months Standard Error 0.03

Adverse Events

Arm A

Serious events: 18 serious events

Other events: 63 other events

Deaths: 1 deaths

Arm B

Serious events: 31 serious events

Other events: 70 other events

Deaths: 3 deaths

Serious adverse events

Measure	Arm A n=63 participants at risk Paclitaxel 90 mg/m2 days 1, 8, 15 q4weeks. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 participants at risk Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Blood and lymphatic system disorders Anemia	3.2% 2/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	7.1% 5/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	5.7% 4/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Anaphylaxis	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Allergic reaction	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Metabolism and nutrition disorders Anorexia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Diarrhea	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Constipation	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Mucositis oral	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Nausea	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Vomiting	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Peripheral sensory neuropathy	9.5% 6/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Infections and infestations Infection	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Musculoskeletal and connective tissue disorders Arthralgia and/or myalgia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
General disorders Injection site reaction	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
General disorders Fatigue	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	5.7% 4/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Acute coronary syndrome	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Left ventricular systolic dysfunction	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Sinus brachycardia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Ventricular arrhythmia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Optic nerve disorder	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Blood and lymphatic system disorders Neutrophil count decreased	12.7% 8/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	28.6% 20/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Aspartate aminotransferase increased	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	4.3% 3/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Pulmonary valve disease	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Supraventricular tachycardia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Abdominal pain	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations Alanine aminotransferase increased	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations Alkaline phosphatase increased	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations Lymphocyte count decreased	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations White blood cell count decreased	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	17.1% 12/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Hyperhidrosis	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Nail discoloration	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.

Other adverse events

Measure	Arm A n=63 participants at risk Paclitaxel 90 mg/m2 days 1, 8, 15 q4weeks. Patients will continue to receive assigned treatment until progression or lack of tolerability. Paclitaxel: Arm A	Arm B n=70 participants at risk Metronomic VEX: Cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week continuously. Patients will continue to receive assigned treatment until progression or lack of tolerability. Cyclophosphamide: Arm B Capecitabine: Arm B Vinorelbine: Arm B
Blood and lymphatic system disorders Anemia	65.1% 41/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	37.1% 26/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Alopecia	33.3% 21/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome	7.9% 5/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	7.1% 5/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Anaphylaxis	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Allergic reaction	9.5% 6/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Metabolism and nutrition disorders Anorexia	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	7.1% 5/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Diarrhea	19.0% 12/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	31.4% 22/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Constipation	20.6% 13/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	8.6% 6/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Mucositis oral	11.1% 7/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	7.1% 5/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders nausea	27.0% 17/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	42.9% 30/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Vomiting	14.3% 9/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	11.4% 8/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Peripheral sensory neuropathy	47.6% 30/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	7.1% 5/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Infections and infestations Infection	31.7% 20/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	20.0% 14/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Musculoskeletal and connective tissue disorders Arthralgia and/or myalgia	34.9% 22/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	28.6% 20/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
General disorders Injection site reaction	3.2% 2/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
General disorders Fatigue	57.1% 36/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	44.3% 31/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Acute coronary syndrome	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Left ventricular systolic dysfunction	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Sinus brachycardia	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Supraventricular tachycardia	4.8% 3/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	5.7% 4/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Ventricular arrhythmia	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Optic nerve disorder	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Blood and lymphatic system disorders Thrombocytopenia	3.2% 2/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	14.3% 10/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Blood and lymphatic system disorders Neutrophil count decreased	20.6% 13/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	15.7% 11/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Immune system disorders Asparate aminotransferase increased	30.2% 19/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	20.0% 14/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Aortic valve disease	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Cardiac disorders Atrial flutter	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Eye disorders Cataract	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Gastrointestinal disorders Ascites	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
General disorders Sudden death, not otherwise specified	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Injury, poisoning and procedural complications Fracture	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Injury, poisoning and procedural complications Hip fracture	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations Alkaline phosphatase increased	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations Blood bilirubin increased	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Investigations GGT increased	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Metabolism and nutrition disorders Hyperglycemia	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Metabolism and nutrition disorders Hyponatremia	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Depressed level of consciousness	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Nervous system disorders Facial nerve disorder	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	2.9% 2/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	0.00% 0/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	1.4% 1/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.
Vascular disorders Hypotension	1.6% 1/63 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.	0.00% 0/70 • Adverse Events (AEs) were collected from the first dose of trial medication, at day 1 of every treatment cycle, until 28 days after all treatment discontinuation (end of treatment visit), regardless of whether it is considered related to a medication. In the absence of tumor progression, the patient continued to be followed for SAE reporting according and for documented disease progression or a maximum of 12 months after treatment stop, up to approximately 49 months. AEs were collected from the first dose of trial medication until 28 days after all treatment discontinuation (EOT visit), regardless of whether it is considered related to a medication. The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity and causality classified according to the NCI CTCAE Version 4.0.

Additional Information

Dr. Heidi Roschitzki, PhD

ETOP IBCSG Partners Foundation

Phone: +41 31 511 94 00

Email: heidi.roschitzki@etop.ibcsg.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place