Trial Outcomes & Findings for Neoadjuvant Accelerated Short Course Radiation Therapy With Proton Beam and Capecitabine for Resectable Pancreatic Cancer (NCT NCT00438256)

Last Updated: 2019-01-23

Results Overview

The number of participants that experienced a dose limiting toxicity in the arm where radiation was administered over 5 consecutive for a total dose of 25 Gray Equivalents (GyE) (Group 4). Participants were monitored for potential Dose Limiting Toxicities (DLT) for three weeks after the start of radiation. DLTs included: 1. Any grade 3 non-hematologic or hematologic toxicity requiring a greater than 7 day interruption in therapy (excluding alopecia and nausea/vomiting not controlled by optimal supportive care or 2. Any grade 4 non-hematologic toxicity or 3. Any grade 4 neutropenia or thrombocytopenia as defined by Common Terminology Criteria for Adverse Events (CTCAE v3.0)

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

50 participants

Primary outcome timeframe

3 Weeks

Results posted on

2019-01-23

Participant Flow

Participant milestones

Participant milestones
Measure	Proton Beam Radiation/ Capecitabine Dose Level 1 Procedure/Surgery: Proton Beam Radiation: Given over 10 Radiation Sessions over 2 weeks Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Overall Study STARTED	3	3	3	41
Overall Study Surgical Resection	1	2	2	34
Overall Study COMPLETED	1	2	2	32
Overall Study NOT COMPLETED	2	1	1	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Proton Beam Radiation/ Capecitabine Dose Level 1 Procedure/Surgery: Proton Beam Radiation: Given over 10 Radiation Sessions over 2 weeks Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Overall Study Ineligible for Resection	2	1	1	7
Overall Study Excluded final Diagnosis	0	0	0	2

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Proton Beam Radiation/ Capecitabine n=50 Participants Procedure/Surgery: Proton Beam Radiation: Given over different schedules and duration Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Age, Continuous	65 years n=50 Participants
Sex: Female, Male Female	23 Participants n=50 Participants
Sex: Female, Male Male	27 Participants n=50 Participants
Region of Enrollment United States	50 Participants n=50 Participants
CA19-9 level at baseline	136.5 units per milliliter n=50 Participants
Tumor size on CT	2.9 Centimeters n=50 Participants

PRIMARY outcome

Timeframe: 3 Weeks

Population: The participants treated with radiation therapy at the 5 fractions over 5 consecutive days

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=6 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Number of Participants With Dose Limiting Toxicities in the 5 Radiation Sessions in One Week Arm	0 Participants	—	—	—

PRIMARY outcome

Timeframe: 30 days after the end of treatment, up to approximately 6 months total

Population: Participants in the Phase II portion of the trial

Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3). The regimen was considered to be tolerated if less than 20% of participants experienced a grade 3 or greater toxicity.

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=35 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Number of Participants With Grade 3 or Greater Toxicity in Phase II	2 Participants	—	—	—

SECONDARY outcome

Timeframe: at the time of surgery (28-42 days after start of treatment)

Population: The eligible participants who underwent surgical resection. The phase I arms and Phase II group were combined together for analysis.

All patients that received surgery underwent a full pathological review of their pancreaticoduodenectomy specimen according to the American Joint Committee on Cancer (AJCC) Staging Classification, 6th. Initial gross evaluation and identification of resection margins was performed jointly by the surgeon and the pathologist. Pathological complete response will be defined as the absence of any viable tumor cells within the pathologic specimen.

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=37 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Number of Participants With a Pathological Complete Response	0 Participants	—	—	—

SECONDARY outcome

Timeframe: from the start of treatment until death or progression, median duration of 10.4 months

Population: Two participants were excluded from the analysis because of ineligible final diagnoses (cholangiocarcinoma and autoimmune pancreatitis)

The median amount of time from the start of treatment until death or disease progression, whichever occurs first. Progressive Disease (PD): A 20% or greater increase in the sum of Longest Diameter (LD) of all target lesions, taking as reference the smallest sum LD recorded since baseline.

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=48 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Median Progression Free Survival	10.4 Months Interval 7.5 to 17.1	—	—	—

SECONDARY outcome

Timeframe: 30 days post surgery (surgery was 28-42 days after the start of treatment)

Population: The eligible participants who underwent surgical resections. The phase I arms and Phase II group were combined together for analysis.

Number of participants with pancreatic or any other anastomotic leakage within 30 days of surgery

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=37 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Number of Participants With Surgical Morbidity	0 Participants	—	—	—

SECONDARY outcome

Timeframe: 30 days after the time of surgery (Surgery is 28-42 days after start of treatment)

Population: The eligible participants who underwent surgical resection. The phase I arms and Phase II group were combined together for analysis.

The number of participants that died within 30 days of undergoing a pancreaticoduodenectomy.

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=37 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
30-Day Post Operative Mortality	0 Participants	—	—	—

SECONDARY outcome

Timeframe: From the start of treatment until 30 days after the end of treatment, up to approximately 5 months

The number of participants that had treatment related serious adverse events. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3). Adverse events were considered to be serious adverse events if they were grade 3 or greater and were considered to be possibly, probably, or definitely related to treatment.

Outcome measures

Outcome measures
Measure	Proton Beam Radiation/ Capecitabine n=3 Participants Procedure/Surgery: Proton Beam Radiation: 5 fractions over 5 consecutive days for a total of 25 Gray Equivalents (GyE) Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 n=3 Participants Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 n=3 Participants Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 n=41 Participants Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Number of Participants With Treatment Related Serious Adverse Events	0 Participants	0 Participants	0 Participants	2 Participants

Adverse Events

Proton Beam Radiation/ Capecitabine Dose Level 1

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Proton Beam Radiation/ Capecitabine Dose Level 2

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Proton Beam Radiation/ Capecitabine Dose Level 3

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Proton Beam Radiation/ Capecitabine Dose Level 4

Serious events: 2 serious events

Other events: 41 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Proton Beam Radiation/ Capecitabine Dose Level 1 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 10 Radiation Sessions over 2 weeks Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 n=41 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Gastrointestinal disorders Colitis	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	2.4% 1/41 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Musculoskeletal and connective tissue disorders Pain - Chest Wall	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	2.4% 1/41 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months

Other adverse events

Additional Information

Theodore Hong, MD

Massachusetts General Hospital

Phone: 617-724-1159

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Proton Beam Radiation/ Capecitabine Dose Level 1 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 10 Radiation Sessions over 2 weeks Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 2 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 3 in week 1 and 2 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 3 n=3 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation sessions: 4 in week 1 and 1 in week 2 Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks	Proton Beam Radiation/ Capecitabine Dose Level 4 n=41 participants at risk Procedure/Surgery: Proton Beam Radiation: Given over 5 Radiation Sessions in one week Drug: Capecitabine: Given orally starting on day one of radiation therapy for 2 weeks
Musculoskeletal and connective tissue disorders Abdomen- pain	66.7% 2/3 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	22.0% 9/41 • Number of events 12 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Investigations ALT- SGPT	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	9.8% 4/41 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Metabolism and nutrition disorders Anorexia	33.3% 1/3 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	66.7% 2/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	66.7% 2/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	17.1% 7/41 • Number of events 10 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Psychiatric disorders Anxiety	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	9.8% 4/41 • Number of events 7 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Investigations AST- SGOT	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	7.3% 3/41 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Musculoskeletal and connective tissue disorders Back- pain	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	7.3% 3/41 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Investigations Bilirubin	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	4.9% 2/41 • Number of events 2 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Gastrointestinal disorders Constipation	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	36.6% 15/41 • Number of events 23 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Metabolism and nutrition disorders Dehydration	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	4.9% 2/41 • Number of events 2 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Gastrointestinal disorders Diarrhea w/o prior colostomy	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	9.8% 4/41 • Number of events 6 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Gastrointestinal disorders Dyspepsia	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	4.9% 2/41 • Number of events 2 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Musculoskeletal and connective tissue disorders Extremity-limb- pain	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	4.9% 2/41 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
General disorders Fatigue	100.0% 3/3 • Number of events 6 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	66.7% 2/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	100.0% 3/3 • Number of events 5 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	51.2% 21/41 • Number of events 33 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
General disorders Fever w/o neutropenia	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	7.3% 3/41 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	24.4% 10/41 • Number of events 20 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Gastrointestinal disorders Nausea	100.0% 3/3 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	100.0% 3/3 • Number of events 4 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	100.0% 3/3 • Number of events 5 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	70.7% 29/41 • Number of events 43 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Gastrointestinal disorders Vomiting	66.7% 2/3 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 1 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	33.3% 1/3 • Number of events 2 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	17.1% 7/41 • Number of events 8 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months
Investigations Weight loss	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	0.00% 0/3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months	7.3% 3/41 • Number of events 3 • From the start of treatment until 30 days after the end of treatment, up to approximately approximately 5 months