Trial Outcomes & Findings for Evaluate Safety, Efficacy and Pharmacokinetics (NCT NCT01084863)

Last Updated: 2025-01-24

Results Overview

Area under the concentration time curve at steady state (AUCss), defined as area under the concentration-time curve between Cycle 8 to Cycle 9. The primary endpoint was reached at 6 months (8 treatment cycle; Main Study Treatment Period).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

143 participants

Primary outcome timeframe

3, 6, 12, 24, 72, 168, 336, 504 hours predose

Results posted on

2025-01-24

Participant Flow

Participant milestones

Participant milestones
Measure	CT-P6 & Paclitaxel CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 body surface area (BSA) as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 body surface area (BSA) as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Main Study Treatment Period STARTED	76	67
Main Study Treatment Period COMPLETED	60	56
Main Study Treatment Period NOT COMPLETED	16	11
Treatment Period Beyond Cycle 8 STARTED	60	56
Treatment Period Beyond Cycle 8 COMPLETED	0	0
Treatment Period Beyond Cycle 8 NOT COMPLETED	60	56

Reasons for withdrawal

Reasons for withdrawal
Measure	CT-P6 & Paclitaxel CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 body surface area (BSA) as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 body surface area (BSA) as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Main Study Treatment Period Disease progression	11	7
Main Study Treatment Period Adverse Event	5	3
Main Study Treatment Period Other Reason	0	1
Treatment Period Beyond Cycle 8 Withdrawal by Subject	4	4
Treatment Period Beyond Cycle 8 Physician Decision	2	4
Treatment Period Beyond Cycle 8 Disease progression	51	45
Treatment Period Beyond Cycle 8 Adverse Event	1	0
Treatment Period Beyond Cycle 8 Other	0	1
Treatment Period Beyond Cycle 8 Other reason	2	2

Baseline Characteristics

Evaluate Safety, Efficacy and Pharmacokinetics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CT-P6 & Paclitaxel n=76 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Total n=143 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	63 Participants n=5 Participants	59 Participants n=7 Participants	122 Participants n=5 Participants
Age, Categorical >=65 years	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Age, Continuous	55.1 years STANDARD_DEVIATION 10.26 • n=5 Participants	53.6 years STANDARD_DEVIATION 10.47 • n=7 Participants	54.4 years STANDARD_DEVIATION 10.35 • n=5 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	67 Participants n=7 Participants	143 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	45 Participants n=5 Participants	35 Participants n=7 Participants	80 Participants n=5 Participants
Race/Ethnicity, Customized Asian	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Region of Enrollment Bulgaria	6 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment South Korea	31 Participants n=5 Participants	32 Participants n=7 Participants	63 Participants n=5 Participants
Region of Enrollment Latvia	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Region of Enrollment Russia	19 Participants n=5 Participants	16 Participants n=7 Participants	35 Participants n=5 Participants
Region of Enrollment Serbia	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Region of Enrollment Ukraine	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Childbearing potential Yes	18 Participants n=5 Participants	24 Participants n=7 Participants	42 Participants n=5 Participants
Childbearing potential No	58 Participants n=5 Participants	43 Participants n=7 Participants	101 Participants n=5 Participants
Height at Screening	158.9 cm STANDARD_DEVIATION 6.70 • n=5 Participants	160.3 cm STANDARD_DEVIATION 7.20 • n=7 Participants	159.6 cm STANDARD_DEVIATION 6.95 • n=5 Participants
Weight at Screening	66.0 kg STANDARD_DEVIATION 16.64 • n=5 Participants	67.6 kg STANDARD_DEVIATION 15.71 • n=7 Participants	66.7 kg STANDARD_DEVIATION 16.17 • n=5 Participants
BSA at Screening	1.70 m2 STANDARD_DEVIATION 0.22 • n=5 Participants	1.73 m2 STANDARD_DEVIATION 0.22 • n=7 Participants	1.71 m2 STANDARD_DEVIATION 0.22 • n=5 Participants
Prior chemotherapy Yes	29 Participants n=5 Participants	26 Participants n=7 Participants	55 Participants n=5 Participants
Prior chemotherapy No	47 Participants n=5 Participants	41 Participants n=7 Participants	88 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 0	35 Participants n=5 Participants	25 Participants n=7 Participants	60 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status 1	41 Participants n=5 Participants	42 Participants n=7 Participants	83 Participants n=5 Participants
Karnofsky performance status Category 1	72 Participants n=5 Participants	62 Participants n=7 Participants	134 Participants n=5 Participants
Karnofsky performance status Category 2	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Karnofsky performance status Category 3	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Karnofsky performance status Not reported	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 3, 6, 12, 24, 72, 168, 336, 504 hours predose

Population: PK Analysis Set - Global (PKASg) was defined as all FAS patients who had achieved steady state by the 8th cycle, which required three consecutive similar trough concentrations.

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=51 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=49 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Area Under the Concentration Time Curve at Steady State (AUCss)	34400 ug*h/mL Standard Deviation 15000	31800 ug*h/mL Standard Deviation 9820	—	—

SECONDARY outcome

Timeframe: 3, 6, 12, 24, 72, 168, 336, 504 hours predose

Population: PK Analysis Set - Global (PKASg) was defined as all FAS patients who had achieved steady state by the 8th cycle, which required three consecutive similar trough concentrations.

Trough concentration at steady state (CtroughSS), defined as trough concentration at steady state. The secondary endpoint was reached at 6 months (8 treatment cycle; Main Study Treatment Period).

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=51 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=49 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Trough Concentration at Steady State (CtroughSS)	21.1 ug/mL Standard Deviation 7.83	20.8 ug/mL Standard Deviation 8.26	—	—

SECONDARY outcome

Timeframe: Up to approximately 1 year

Population: Safety Analysis Set (SAF) was defined as all patients in the FAS. All patients receiving at least one dose of CT-P6 were analyzed under the CT-P6 treatment group. All other patients were analyzed under the Herceptin treatment group.

Cardiac Ejection Fraction Assessment, defined as Mean change from baseline to endpoint assessment in left ventricular ejection fraction (LVEF, Unit: %) from the independent tumor review committee (ITRC).

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=62 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=53 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Cardiotoxicity	-5.49 %; percentage of LVEF Standard Deviation 6.543	-6.43 %; percentage of LVEF Standard Deviation 5.622	—	—

SECONDARY outcome

Timeframe: every 4 cycles (each cycle is 3 weeks), Up to approximately 5.5 years

Immunogenicity, defined as proportion of patients with antibodies to study drug (positive for antidrug antibody \[ADA\] result after the first study infusion).

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=76 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Immunogenicity	2 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: every 6 weeks (up to cycle 4) or 12 weeks (after cycle 4) (every cycle is 3 weeks), up to 6 months in Main treatment period and up to 1 year

Population: Full Analysis Set (FAS) was defined as all randomized patients who received any study drug (CT-P6 or Herceptin) and had at least one post-baseline assessment, with the exception of the patients who violated against Herceptin indication.

Overall response rate (ORR) based on best overall response (BOR) during the Main Study Treatment Period and up to 1-year treatment from the independent tumor review committee (ITRC) and Investigator. ORR (complete response \[CR\] plus partial response \[PR\]), as assessed by Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 To be assigned a best ORR of PR or CR, changes in tumour assessments must be confirmed no less than 4 weeks after the criteria for response were met.

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=76 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator n=76 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator n=67 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Overall Response Rate (ORR; Complete Response [CR] Plus Partial Response [PR]) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Main Study Treatment Period	61.8 percentage of responder	76.1 percentage of responder	68.4 percentage of responder	80.6 percentage of responder
Overall Response Rate (ORR; Complete Response [CR] Plus Partial Response [PR]) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 1 Year	65.8 percentage of responder	77.6 percentage of responder	72.4 percentage of responder	80.6 percentage of responder

SECONDARY outcome

Timeframe: day 1 of each cycle (every cycle is 3 weeks), Up to approximately 5.5 years

Serum Human epidermal growth factor receptor-2 (HER-2) shed antigen values at baseline (Cycle 1, Day 1) and the last assessments.

Outcome measures

Outcome measures
Measure	CT-P6 & Paclitaxel n=76 Participants CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 Participants Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	CT-P6 & Paclitaxel Investigator CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel Investigator Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Serum Human Epidermal Growth Factor Receptor-2 (HER-2) Shed Antigen Value Baseline (Cycle 1, Day 1)	85.20 ng/mL Standard Deviation 195.10	77.87 ng/mL Standard Deviation 169.14	—	—
Serum Human Epidermal Growth Factor Receptor-2 (HER-2) Shed Antigen Value Last assessment	49.68 ng/mL Standard Deviation 162.10	8.82 ng/mL Standard Deviation 19.97	—	—

Adverse Events

CT-P6 & Paclitaxel

Serious events: 12 serious events

Other events: 74 other events

Deaths: 2 deaths

Herceptin & Paclitaxel

Serious events: 19 serious events

Other events: 64 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Head of Clinical Planning Department

Celltrion

Phone: 82328505000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	CT-P6 & Paclitaxel n=76 participants at risk CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 participants at risk Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Infections and infestations Acute tonsillitis	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Bacteraemia	2.6% 2/76 • Number of events 2 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Surgical and medical procedures Biliary drainage	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 4 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Brain oedema	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Cardiac disorders Cardiac failure acute	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Cerebrovascular accident	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Hepatobiliary disorders Cholangitis	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Colitis	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Disease progression	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 5 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Endoscopic retrograde cholangiopancreatography	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Blood and lymphatic system disorders Febrile neutropenia	2.6% 2/76 • Number of events 2 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Gangrene	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Hepatic enzyme increased	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Hepatobiliary disorders Hepatitis cholestatic	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Vascular disorders Hypertension	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Infusion related reaction	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Nausea	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Blood and lymphatic system disorders Neutropenia	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Neutropenic infection	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Pneumonia	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Pyrexia	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 2 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Sepsis	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Urinary tract infection	1.3% 1/76 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	0.00% 0/67 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Vomiting	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)

Measure	CT-P6 & Paclitaxel n=76 participants at risk CT-P6 was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (CT-P6). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.	Herceptin & Paclitaxel n=67 participants at risk Herceptin was administered at a loading dose of 8 mg/kg body weight by IV infusion over 90 minutes on Day 1, Cycle 1, then at 6 mg/kg repeated at 3-weekly intervals until disease progression, death, or discontinuation. Paclitaxel was administered at a dose of 175 mg/m2 BSA as a continuous 3-hour IV infusion on the day following the first dose of study drug (Herceptin). If the first dose of study drug was well tolerated, subsequent doses of paclitaxel were given immediately after the next dose of study drug. Paclitaxel cycles were repeated every 3 weeks until disease progression, death, intolerable toxicity, or discontinuation.
Gastrointestinal disorders Abdominal pain	5.3% 4/76 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Abdominal pain upper	5.3% 4/76 • Number of events 4 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	11.9% 8/67 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Alanine aminotransferase increased	9.2% 7/76 • Number of events 12 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	11.9% 8/67 • Number of events 19 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Skin and subcutaneous tissue disorders Alopecia	61.8% 47/76 • Number of events 59 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	65.7% 44/67 • Number of events 50 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Blood and lymphatic system disorders Anaemia	11.8% 9/76 • Number of events 19 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 9 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Arthralgia	13.2% 10/76 • Number of events 33 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	22.4% 15/67 • Number of events 29 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Aspartate aminotransferase increased	7.9% 6/76 • Number of events 8 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	10.4% 7/67 • Number of events 16 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Asthenia	31.6% 24/76 • Number of events 52 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	14.9% 10/67 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Back pain	6.6% 5/76 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	16.4% 11/67 • Number of events 19 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Blood alkaline phosphatase increased	6.6% 5/76 • Number of events 9 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	1.5% 1/67 • Number of events 1 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Bone pain	17.1% 13/76 • Number of events 22 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	9.0% 6/67 • Number of events 10 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Reproductive system and breast disorders Breast pain	5.3% 4/76 • Number of events 5 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	3.0% 2/67 • Number of events 2 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Chills	7.9% 6/76 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	10.4% 7/67 • Number of events 8 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Constipation	5.3% 4/76 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	14.9% 10/67 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Respiratory, thoracic and mediastinal disorders Cough	14.5% 11/76 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	11.9% 8/67 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Metabolism and nutrition disorders Decreased appetite	9.2% 7/76 • Number of events 12 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	11.9% 8/67 • Number of events 22 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Diarrhoea	17.1% 13/76 • Number of events 23 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	26.9% 18/67 • Number of events 38 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Dizziness	7.9% 6/76 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	19.4% 13/67 • Number of events 23 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Dyspepsia	6.6% 5/76 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.5% 8/76 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Face oedema	2.6% 2/76 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	6.0% 4/67 • Number of events 5 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Fatigue	13.2% 10/76 • Number of events 27 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	14.9% 10/67 • Number of events 31 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Investigations Gamma-glutamyltransferase increased	6.6% 5/76 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	3.0% 2/67 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Headache	14.5% 11/76 • Number of events 16 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	19.4% 13/67 • Number of events 18 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Metabolism and nutrition disorders Hyperglycaemia	5.3% 4/76 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Vascular disorders Hypertension	6.6% 5/76 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	6.0% 4/67 • Number of events 9 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Psychiatric disorders Insomnia	9.2% 7/76 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	19.4% 13/67 • Number of events 16 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Cardiac disorders Left ventricular dysfunction	2.6% 2/76 • Number of events 2 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Blood and lymphatic system disorders Leukopenia	10.5% 8/76 • Number of events 10 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	17.9% 12/67 • Number of events 28 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Mucosal inflammation	5.3% 4/76 • Number of events 5 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.9% 6/76 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	10.4% 7/67 • Number of events 9 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Myalgia	40.8% 31/76 • Number of events 134 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	46.3% 31/67 • Number of events 127 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Skin and subcutaneous tissue disorders Nail disorder	2.6% 2/76 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	6.0% 4/67 • Number of events 4 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Nasopharyngitis	9.2% 7/76 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	4.5% 3/67 • Number of events 9 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Nausea	25.0% 19/76 • Number of events 51 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	25.4% 17/67 • Number of events 41 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Neuropathy peripheral	30.3% 23/76 • Number of events 46 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	31.3% 21/67 • Number of events 54 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Blood and lymphatic system disorders Neutropenia	42.1% 32/76 • Number of events 59 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	49.3% 33/67 • Number of events 85 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Oedema peripheral	10.5% 8/76 • Number of events 10 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	11.9% 8/67 • Number of events 12 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.9% 3/76 • Number of events 4 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	7.5% 5/67 • Number of events 6 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Musculoskeletal and connective tissue disorders Pain in extremity	13.2% 10/76 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	25.4% 17/67 • Number of events 32 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Paraesthesia	5.3% 4/76 • Number of events 4 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	3.0% 2/67 • Number of events 5 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Nervous system disorders Peripheral sensory neuropathy	27.6% 21/76 • Number of events 79 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	40.3% 27/67 • Number of events 50 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Skin and subcutaneous tissue disorders Pruritus	9.2% 7/76 • Number of events 11 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	17.9% 12/67 • Number of events 18 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
General disorders Pyrexia	13.2% 10/76 • Number of events 18 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	14.9% 10/67 • Number of events 18 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Skin and subcutaneous tissue disorders Rash	13.2% 10/76 • Number of events 16 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	17.9% 12/67 • Number of events 29 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Stomatitis	7.9% 6/76 • Number of events 13 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	16.4% 11/67 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Infections and infestations Upper respiratory tract infection	3.9% 3/76 • Number of events 3 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	9.0% 6/67 • Number of events 10 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/76 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	9.0% 6/67 • Number of events 7 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)
Gastrointestinal disorders Vomiting	6.6% 5/76 • Number of events 10 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)	13.4% 9/67 • Number of events 14 • Adverse event (AE) reporting extended from the date of informed consent until completion of the final visit. (Up to approximately 170 months)