Trial Outcomes & Findings for Phase III Study of ABI-007(Albumin-bound Paclitaxel) Plus Gemcitabine Versus Gemcitabine in Metastatic Adenocarcinoma of the Pancreas (NCT NCT00844649)

Last Updated: 2019-11-25

Results Overview

Overall survival was defined as the time from the date of randomization to the date of death from all causes. Participants who did not die were censored at the last known time the participant was alive. Patient survival was summarized using Kaplan-Meier methods.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

861 participants

Primary outcome timeframe

From randomization to death; until the data cut off 17 Sept 2012. The maximum time in follow up was 37 months.

Results posted on

2019-11-25

Participant Flow

Participants were randomized in a 1:1 ratio and the randomization was stratified by geographic region (Australia versus Eastern Europe versus Western Europe versus North America), Karnofsky performance status (70 to 80 versus 90 to 100), and by the presence of liver metastases (yes versus no)

38 participants were randomized but not treated due to the participants request to withdraw after the randomization results became known. 1 participant was randomized to Gemcitabine and was treated with Albumin-bound paclitaxel ABI-007/Gemcitabine in error and analyzed as treated and included in the intent to treat population (ITT)

Participant milestones

Participant milestones
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine (Gem) Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine (Gem) Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Overall Study STARTED	431	430
Overall Study Treated Population	421	402
Overall Study COMPLETED	26	12
Overall Study NOT COMPLETED	405	418

Reasons for withdrawal

Reasons for withdrawal
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine (Gem) Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine (Gem) Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Overall Study Progressive Disease	196	245
Overall Study Adverse Event	128	73
Overall Study Physician Decision	25	18
Overall Study Protocol Violation	10	6
Overall Study Withdrawal by Subject	28	39
Overall Study Other	7	10
Overall Study Withdrew prior to starting treatment	11	27

Baseline Characteristics

Phase III Study of ABI-007(Albumin-bound Paclitaxel) Plus Gemcitabine Versus Gemcitabine in Metastatic Adenocarcinoma of the Pancreas

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=431 Participants ABI-007 125 mg/m\^2 administered in combination with gemcitabine 1000 mg/m\^2 weekly for 3 weeks followed by one week of rest. Albumin-bound paclitaxel (ABI-007)/Gemcitabine : ABI-007 125 mg/m\^2 administered in combination with Gemcitabine 1000 mg/m\^2 weekly for 3 weeks, Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=430 Participants Gemcitabine, 1000 mg/m\^2 administered weekly for 7 weeks followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks followed by a week of rest (Cycle 2 onward). Gemcitabine : Gemcitabine, 1000 mg/m2 administered weekly for 7 weeks, Day 1 through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks, Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward).	Total n=861 Participants Total of all reporting groups
Age, Continuous	61.4 years STANDARD_DEVIATION 10.70 • n=5 Participants	63.0 years STANDARD_DEVIATION 9.27 • n=7 Participants	62.2 years STANDARD_DEVIATION 10.04 • n=5 Participants
Sex: Female, Male Female	186 Participants n=5 Participants	173 Participants n=7 Participants	359 Participants n=5 Participants
Sex: Female, Male Male	245 Participants n=5 Participants	257 Participants n=7 Participants	502 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) White	378 Participants n=5 Participants	375 Participants n=7 Participants	753 Participants n=5 Participants
Race (NIH/OMB) More than one race	25 Participants n=5 Participants	26 Participants n=7 Participants	51 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Karnofsky Performance Status (KPS) 100% = normal, no complaints, no signs of disease	69 participants n=5 Participants	69 participants n=7 Participants	138 participants n=5 Participants
Karnofsky Performance Status (KPS) 90% = normal activity, few symptoms of disease	179 participants n=5 Participants	199 participants n=7 Participants	378 participants n=5 Participants
Karnofsky Performance Status (KPS) 80% = normal activity, some symptoms of disease	149 participants n=5 Participants	128 participants n=7 Participants	277 participants n=5 Participants
Karnofsky Performance Status (KPS) 70% = caring for self, unable to work	30 participants n=5 Participants	33 participants n=7 Participants	63 participants n=5 Participants
Karnofsky Performance Status (KPS) 60% = needs help, can manage most tasks	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants
Karnofsky Performance Status (KPS) 50% = needs help often and medical care	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Status (KPS) 40% = disabled; requires special care & assistance	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Status (KPS) 30% = severely disabled; death is imminent	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Status (KPS) 20% = hospitalized; requires supportive treatment	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Status (KPS) 10% = Moribund, fatal processes progressing fast	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Karnofsky Performance Status (KPS) 0% = Dead	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Pancreatic Primary Tumor Location Head	191 participants n=5 Participants	180 participants n=7 Participants	371 participants n=5 Participants
Pancreatic Primary Tumor Location Body	132 participants n=5 Participants	136 participants n=7 Participants	268 participants n=5 Participants
Pancreatic Primary Tumor Location Tail	105 participants n=5 Participants	110 participants n=7 Participants	215 participants n=5 Participants
Pancreatic Primary Tumor Location Unknown = not specified	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) 1	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) 2	32 participants n=5 Participants	25 participants n=7 Participants	57 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) 3	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) 4	37 participants n=5 Participants	43 participants n=7 Participants	80 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) 5	8 participants n=5 Participants	8 participants n=7 Participants	16 participants n=5 Participants
Number of Baseline Lesions (Target + Non-Target) >5	276 participants n=5 Participants	262 participants n=7 Participants	538 participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to death; until the data cut off 17 Sept 2012. The maximum time in follow up was 37 months.

Population: Intent to Treat population (ITT population) consisted of all randomized participants.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=431 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=430 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Overall Survival (OS)	8.5 months Interval 7.89 to 9.53	6.7 months Interval 6.01 to 7.23

SECONDARY outcome

Timeframe: Randomization until disease progression or death from any cause; Until the data cut off of 17 Sept 2012. The maximum time in follow up was 37 months.

Population: Intent to Treat population (ITT population) consisted of all randomized participants.

Progression-free survival was defined as the time from the date of randomization to the date of disease progression, or death (any cause) on or prior to the clinical cutoff date, whichever occurred earlier. Participants who did not have disease progression or had not died were censored at the date of the last tumor assessment, on or prior to the clinical cutoff, and the patient was progression free. If a patient began a new anti-cancer treatment prior to documented disease progression (or death), the patient was censored at the date of last assessment when the patient was documented as progression free prior to the intervention. Patients with two or more consecutive missing response assessments prior to a visit with documented progression (or death) were censored at the last date of tumor assessment when the patient was documented to be progression free. PFS was summarized using Kaplan-Meier methods.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=431 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=430 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Progression-free Survival (PFS) by Independent Radiological Review (IRR)	5.5 months Interval 4.47 to 5.95	3.7 months Interval 3.61 to 4.04

SECONDARY outcome

Timeframe: Assessment every 4 weeks after initial response; Day 1 to data cut off of 17 Sept 2013; maximum time on study 37 months

Population: Intent to Treat population (ITT population) consisted of all randomized participants.

Objective tumor response was summarized as the percentage of participants who achieved a confirmed complete (CR) or partial response (PR) based on an independent blinded radiology assessment of response using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Using RECIST Version 1.0, participants were to achieve either a complete response (CR) defined as the disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation or partial response (PR) defined as at least a 30% decrease in the sum of the longest diameters of target lesions and no progression in non-target lesions based on confirmed responses from the investigator assessment of best overall response during study treatment.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=431 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=430 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Percentage of Participants Who Achieved an Objective Confirmed Overall Response by Independent Radiological Review (IRR)	23 percentage of participants Interval 19.1 to 27.2	7 percentage of participants Interval 5.0 to 10.1

OTHER_PRE_SPECIFIED outcome

Timeframe: Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 696 days

Population: Treated patient population

A Treatment Emergent Adverse Event (TEAE) is as any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=421 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=402 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Participants With Treatment Emergent Adverse Events (AE) At least 1 AE	417 participants	395 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 Treatment related AE (TEAE)	403 participants	371 participants
Participants With Treatment Emergent Adverse Events (AE) At least 1 Serious Adverse Event (SAE)	212 participants	172 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 treatment related SAE	121 participants	53 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 Grade (GR) 3/4 AE	370 participants	298 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 Grade 3 or higher AE	374 participants	303 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 AE leading to stopping treatment	149 participants	95 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 AE leading to death	18 participants	18 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 AE leading to dose reduction of ABI-007 or Gem	209 participants	125 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 AE related dose interruption of ABI-007 or Gem	11 participants	10 participants
Participants With Treatment Emergent Adverse Events (AE) ≥ 1 AE related dose delay of ABI-007 or Gem	276 participants	192 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Maximum time on treatment was 666 days

Population: Treated Population

The number of participants with dose reductions occurring during the treatment period. Dose reductions are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=421 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=402 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Number of Participants With Dose Reductions At least 1 alumbin bound paclitaxel dose reduction	172 participants	0 participants
Number of Participants With Dose Reductions At least 1 Gemcitabine dose reduction	198 participants	132 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Maximum time on treatment was 666 days

Population: Safety population, includes participants who received at least one study treatment

The number of participants with dose interruptions experienced by participants that occurred during the treatment period. Dose interruptions are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=421 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=402 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Number of Participants With Dose Interruptions ≥ 1 Albumin-bound paclitaxel dose interruption	2 participants	0 participants
Number of Participants With Dose Interruptions At least 1 Gemcitabine dose interruption	8 participants	9 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 666 days

Population: Treated Population

The number of dose delays or doses not given experienced by participants during the treatment period. Dose delays are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities. Treatment delays of no longer than 21 days allowed participants to recover from acute toxicity, otherwise participants were discontinued from further treatment except in the event of peripheral neuropathy.

Outcome measures

Outcome measures
Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=421 Participants Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=402 Participants Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
Number of Participants With Dose Delays/Doses Not Given At least 1 ABI-007 dose delay/Not given	300 number of dose delays	0 number of dose delays
Number of Participants With Dose Delays/Doses Not Given At least ≥ 1 Gem dose delay/Not given	295 number of dose delays	230 number of dose delays

Adverse Events

Albumin-bound Paclitaxel (ABI-007)/Gemcitabine

Serious events: 212 serious events

Other events: 412 other events

Deaths: 0 deaths

Gemcitabine

Serious events: 172 serious events

Other events: 392 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Anne McClain

Celgene Corporation

Phone: 1-888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Authorship/contents of any publication is determined by site and provides sponsor a publication prior to submission. Sponsor has 60 days to review and avoid editorial changes but may request site delete confidential data. If publication contains patentable matter, site agrees to delay publication for 60 days. If study is part of multicenter protocol, site agrees not to independently publish. If multicenter publication is not forthcoming in 18 months after study end, site may proceed accordingly.
Publication restrictions are in place

Restriction type: OTHER

Measure	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine n=421 participants at risk Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m\^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m\^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest	Gemcitabine n=402 participants at risk Gemcitabine 1000 mg/m\^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)
General disorders Fatigue	58.7% 247/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	45.5% 183/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Oedema peripheral	46.1% 194/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	30.6% 123/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Pyrexia	38.0% 160/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	27.6% 111/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Asthenia	18.3% 77/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	12.7% 51/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Chills	11.4% 48/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	8.5% 34/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Mucosal inflammation	10.0% 42/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.0% 16/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
General disorders Pain	5.7% 24/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	2.0% 8/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Nausea	53.0% 223/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	47.0% 189/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Diarrhoea	43.2% 182/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	23.4% 94/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Vomiting	34.4% 145/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	26.6% 107/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Constipation	29.0% 122/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	27.6% 111/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Abdominal Pain	21.9% 92/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	21.6% 87/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Abdominal pain upper	10.0% 42/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.0% 28/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Dyspepsia	8.1% 34/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.0% 28/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Stomatitis	7.4% 31/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.5% 14/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Abdominal distension	3.8% 16/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.2% 29/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Gastrointestinal disorders Ascites	3.6% 15/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	6.5% 26/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Skin and subcutaneous tissue disorders Alopecia	50.4% 212/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	5.2% 21/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Skin and subcutaneous tissue disorders Rash	27.8% 117/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	9.7% 39/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Skin and subcutaneous tissue disorders Pruritis	8.1% 34/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	5.0% 20/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Skin and subcutaneous tissue disorders Dry Skin	5.7% 24/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	2.2% 9/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Skin and subcutaneous tissue disorders Erythema	5.7% 24/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.2% 13/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Blood and lymphatic system disorders Anaemia	41.6% 175/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	32.6% 131/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Blood and lymphatic system disorders Neutropenia	40.9% 172/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	30.3% 122/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Blood and lymphatic system disorders Thrombocytopenia	30.2% 127/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	28.6% 115/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Blood and lymphatic system disorders Leukopenia	13.8% 58/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	9.7% 39/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Nervous system disorders Neuropathy peripheral	27.6% 116/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	2.7% 11/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Nervous system disorders Peripheral sensory neuropathy	25.4% 107/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.2% 17/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Nervous system disorders Dysgeusia	16.2% 68/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	8.2% 33/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Nervous system disorders Headache	14.3% 60/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	9.5% 38/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Nervous system disorders Dizziness	11.2% 47/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	8.5% 34/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Metabolism and nutrition disorders Decreased appetite	35.4% 149/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	25.9% 104/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Metabolism and nutrition disorders Dehydration	17.8% 75/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	8.2% 33/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Metabolism and nutrition disorders Hypokalemia	11.9% 50/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.0% 28/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Metabolism and nutrition disorders Hypoalbuminaemia	5.9% 25/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.5% 18/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Metabolism and nutrition disorders Hyperglycaemia	5.2% 22/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.5% 18/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Respiratory, thoracic and mediastinal disorders Cough	17.1% 72/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.5% 30/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.9% 71/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	15.2% 61/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Respiratory, thoracic and mediastinal disorders Epistaxis	15.2% 64/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.5% 14/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	5.7% 24/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.2% 13/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Infections and infestations Urinary tract infection	8.8% 37/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.5% 14/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Infections and infestations Oral candidiasis	7.8% 33/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.7% 15/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Infections and infestations Cellulitis	5.9% 25/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.0% 16/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Weight decreased	13.5% 57/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	11.7% 47/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Alanine aminotransferase increased	10.7% 45/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	9.0% 36/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Haemoglobin decreased	9.7% 41/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.2% 29/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Aspartate aminotransferase increased	9.0% 38/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	8.7% 35/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Platelet count decreased	7.8% 33/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	6.2% 25/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Neutrophil count decreased	6.2% 26/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	4.7% 19/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Investigations Blood alkaline phosphatase increased	5.0% 21/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	7.5% 30/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Musculoskeletal and connective tissue disorders Pain in extremity	11.4% 48/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	6.0% 24/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Musculoskeletal and connective tissue disorders Arthralgia	10.9% 46/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.2% 13/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Musculoskeletal and connective tissue disorders Myalgia	10.5% 44/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	3.7% 15/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Musculoskeletal and connective tissue disorders Back Pain	9.7% 41/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	10.0% 40/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Musculoskeletal and connective tissue disorders Bone pain	5.7% 24/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	2.0% 8/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Psychiatric disorders Insomnia	15.2% 64/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	11.4% 46/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Psychiatric disorders Depression	11.9% 50/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	6.0% 24/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Psychiatric disorders Anxiety	8.3% 35/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	10.7% 43/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Vascular disorders Hypotension	9.0% 38/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	6.5% 26/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)
Vascular disorders Deep vein thrombosis	7.1% 30/421 • Day 1 up to 30 days after the last dose (a maximum of 666 days)	5.5% 22/402 • Day 1 up to 30 days after the last dose (a maximum of 666 days)