Trial Outcomes & Findings for A Biomarker Identification Trial of Tarceva (Erlotinib) in Patients With Advanced Pancreatic Cancer (NCT NCT00674973)

Last Updated: 2016-06-17

Results Overview

Progression-free survival (PFS) was defined as the time from the date of randomization to the date of the first occurrence of PD or death whichever occurred first. Participants without event were censored at the date of last tumor assessment where non-progression was documented. Analysis was performed using Kaplan-Meier method.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

207 participants

Primary outcome timeframe

From the time of randomization until progression of disease or death (up to 30 months)

Results posted on

2016-06-17

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Overall Study STARTED	103	104
Overall Study Switch to Open-Label Erlotinib	57	0
Overall Study COMPLETED	3	2
Overall Study NOT COMPLETED	100	102

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Overall Study Insufficient Therapeutic Response	77	72
Overall Study Refused Treatment	1	5
Overall Study Failure to Return	1	0
Overall Study Adverse Event	2	9
Overall Study Death	19	15
Overall Study Protocol Violation	0	1

Baseline Characteristics

A Biomarker Identification Trial of Tarceva (Erlotinib) in Patients With Advanced Pancreatic Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.	Total n=207 Participants Total of all reporting groups
Age, Customized Less than (<) 65 years	72 participants n=99 Participants	62 participants n=107 Participants	134 participants n=206 Participants
Age, Customized Greater than (>) 65 years	31 participants n=99 Participants	42 participants n=107 Participants	73 participants n=206 Participants
Sex: Female, Male Female	44 Participants n=99 Participants	45 Participants n=107 Participants	89 Participants n=206 Participants
Sex: Female, Male Male	59 Participants n=99 Participants	59 Participants n=107 Participants	118 Participants n=206 Participants

PRIMARY outcome

Timeframe: From the time of randomization until progression of disease or death (up to 30 months)

Population: The Full-Analysis Set (FAS) was defined as all randomized patients. Participants were presented according to the therapy that they were randomized to receive.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Progression-Free Survival	5.9 weeks Interval 5.4 to 6.1	6.1 weeks Interval 5.9 to 6.4

SECONDARY outcome

Timeframe: From the time of randomization until progression of disease or death (up to 30 months)

Population: The FAS was defined as all randomized patients. Participants were presented according to the therapy that they were randomized to receive.

Response rate was defined as Complete Response (CR) or Partial Response (PR), according to response evaluation criteria in solid tumors (RECIST) Version 1.0 criteria, for at least 4 weeks at any time during randomized treatment (confirmed response). CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameters of target lesions.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Percentage of Participants With Best Overall Response Rate CR	0 percentage of participants Interval 0.0 to 3.5	0 percentage of participants Interval 0.0 to 3.5
Percentage of Participants With Best Overall Response Rate PR	4 percentage of participants Interval 1.1 to 9.6	1 percentage of participants Interval 0.0 to 5.2

SECONDARY outcome

Timeframe: Randomization to Clinical Cutoff: 20 December 2010 (up to 30 months)

Population: The FAS was defined as all randomized patients. Participants were presented according to the therapy that they were randomized to receive.

Disease control rates (DCR) were measured according to RECIST Version 1.0 criteria. Disease control was defined as being a responder or as having stable disease for at least 6 weeks post-randomization. Stable disease was defined as having neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Percentage of Participants With Disease Control Rate (DCR)	19 percentage of participants Interval 11.5 to 27.3	29 percentage of participants Interval 19.5 to 37.5

SECONDARY outcome

Timeframe: From the time of randomization until or death (up to 30 months)

Population: The FAS was defined as all randomized patients. Participants were presented according to the therapy that they were randomized to receive.

Overall survival was defined as the time from the date of randomization to the date of death, regardless of the cause of death.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Overall Survival	3.1 months Interval 2.1 to 4.3	4.0 months Interval 2.8 to 4.8

SECONDARY outcome

Timeframe: Up to 28 days after discontinuation of study drug (up to 30 months)

Population: Safety population included all participants who received at least 1 dose of study medication and had a safety follow-up, whether withdrawn prematurely or not, were included in the safety population.

An adverse event (AE) was defined as any untoward medical occurrence in a participant who was administered a study treatment, regardless of whether or not the event had a causal relationship with the treatment. An AE, therefore, could be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the study treatment, whether or not related to the treatment.

Outcome measures

Outcome measures
Measure	Placebo n=103 Participants Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 Participants Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Number of Participants With Adverse Events (AEs)	71 participants	90 participants

Adverse Events

Placebo

Serious events: 11 serious events

Other events: 70 other events

Deaths: 0 deaths

Erlotinib

Serious events: 21 serious events

Other events: 81 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=103 participants at risk Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 participants at risk Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
General disorders PYREXIA	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	1.9% 2/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders DEVICE OCCLUSION	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders DRUG INTOLERANCE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders FATIGUE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders MUCOSAL INFLAMMATION	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders BILE DUCT OBSTRUCTION	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders BILIARY DILATATION	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders CHOLANGITIS	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders CHOLANGITIS ACUTE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders HEPATIC FAILURE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Hepatobiliary disorders JAUNDICE CHOLESTATIC	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	1.9% 2/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Respiratory, thoracic and mediastinal disorders DYSPNOEA	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Respiratory, thoracic and mediastinal disorders HYDROPNEUMOTHORAX	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Respiratory, thoracic and mediastinal disorders PULMONARY EMBOLISM	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders ABDOMINAL PAIN LOWER	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders DIARRHOEA	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders DYSPHAGIA	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders GASTROINTESTINAL HAEMORRHAGE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders HAEMATEMESIS	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders LOWER GASTROINTESTINAL HAEMORRHAGE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders UPPER GASTROINTESTINAL HAEMORRHAGE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Infections and infestations BILIARY SEPSIS	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	1.9% 2/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Infections and infestations MORGANELLA INFECTION	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Infections and infestations SEPSIS	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Infections and infestations SEPTIC SHOCK	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Metabolism and nutrition disorders DECREASED APPETITE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Metabolism and nutrition disorders DEHYDRATION	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Metabolism and nutrition disorders HYPERCALCAEMIA	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Metabolism and nutrition disorders HYPOGLYCAEMIA	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Blood and lymphatic system disorders ANAEMIA	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	1.9% 2/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Blood and lymphatic system disorders HAEMORRHAGIC ANAEMIA	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Injury, poisoning and procedural complications ANASTOMOTIC ULCER	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Injury, poisoning and procedural complications CONCUSSION	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Injury, poisoning and procedural complications PROCEDURAL PAIN	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Nervous system disorders CEREBROVASCULAR ACCIDENT	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Nervous system disorders ISCHAEMIC STROKE	0.00% 0/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Renal and urinary disorders HAEMATURIA	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Renal and urinary disorders RENAL FAILURE	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Psychiatric disorders ANXIETY	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Vascular disorders VENOUS THROMBOSIS	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.00% 0/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)

Measure	Placebo n=103 participants at risk Participants with advanced pancreatic carcinoma with Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received placebo matching to erlotinib 150 mg tablet orally once daily until disease progression (PD), unacceptable toxicity, withdrawal, or death.	Erlotinib n=104 participants at risk Participants with advanced pancreatic carcinoma with ECOG PS score of 0 to 2, who had failed 1 prior regimen of chemotherapy or who were considered unsuitable for chemotherapy, received erlotinib 150 mg orally once daily until PD, unacceptable toxicity, withdrawal, or death.
Gastrointestinal disorders DIARRHOEA	22.3% 23/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	24.0% 25/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders VOMITING	20.4% 21/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	12.5% 13/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders NAUSEA	9.7% 10/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	21.2% 22/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders ABDOMINAL PAIN	14.6% 15/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	15.4% 16/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders CONSTIPATION	16.5% 17/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	7.7% 8/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders ABDOMINAL PAIN UPPER	11.7% 12/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	9.6% 10/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Gastrointestinal disorders ASCITES	8.7% 9/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	0.96% 1/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Skin and subcutaneous tissue disorders RASH	18.4% 19/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	46.2% 48/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Skin and subcutaneous tissue disorders DERMATITIS ACNEIFORM	1.9% 2/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	6.7% 7/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders FATIGUE	11.7% 12/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	14.4% 15/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders ASTHENIA	6.8% 7/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	11.5% 12/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders PYREXIA	6.8% 7/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	11.5% 12/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
General disorders MUCOSAL INFLAMMATION	0.97% 1/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	5.8% 6/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Metabolism and nutrition disorders DECREASED APPETITE	12.6% 13/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	17.3% 18/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Blood and lymphatic system disorders ANAEMIA	7.8% 8/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	10.6% 11/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Investigations WEIGHT DECREASED	4.9% 5/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	10.6% 11/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Respiratory, thoracic and mediastinal disorders DYSPNOEA	8.7% 9/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	3.8% 4/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Musculoskeletal and connective tissue disorders BACK PAIN	5.8% 6/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	2.9% 3/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)
Psychiatric disorders INSOMNIA	6.8% 7/103 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)	1.9% 2/104 • Adverse events were assessed from baseline up to 28 days after discontinuation of study drug (up to 30 months)