Phase II Trial of Pimasertib Versus Dacarbazine in N-Ras Mutated Cutaneous Melanoma

• Sponsor: EMD Serono (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01693068
• Collaborator: Merck KGaA, Darmstadt, Germany (Industry)
• Enrollment: 194
• Locations: 102
• Arms: 2
• Actual Duration (Months): 46.6
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a Phase 2, multicenter, randomized, controlled, open-label trial of pimasertib versus dacarbazine aimed to confirm the activity of pimasertib in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma by comparing the progression-free survival (PFS) of subjects treated with either pimasertib or dacarbazine and by getting a better understanding of the efficacy, safety, pharmacogenomics (PGx) and their relationship with pimasertib exposure.

Condition or Disease	Intervention/Treatment	Phase
N-Ras Mutated Locally Advanced or Metastasis Malignant Cutaneous Melanoma	Drug: Pimasertib; Drug: Dacarbazine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open Label, Randomized Phase II Trial of the MEK Inhibitor Pimasertib or Dacarbazine in Previously Untreated Subjects With N-Ras Mutated Locally Advanced or Metastatic Malignant Cutaneous Melanoma
• Actual Study Start Date: Dec 5, 2012
• Actual Primary Completion Date: Jul 4, 2015
• Actual Study Completion Date: Oct 24, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pimasertib	Drug: Pimasertib; Subjects will receive pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment will consist of repeated 21-day cycles which will continue until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first.; Other Names: MSC1936369B AS703026
Active Comparator: Dacarbazine	Drug: Dacarbazine; Subjects will receive dacarbazine intravenously at dose of 1000 milligram per square meter (mg/m^2) of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. Eligible subjects with documented tumor progression on dacarbazine will offer to switch to pimasertib treatment.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)]

   PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment (otherwise censored), whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

1. Objective Response Rate (ORR) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)]

   ORR was defined as the percentage of subjects with complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions.

2. Disease Control Rate (DCR) [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)]

   DCR was defined as the percentage of subjects with CR, PR, or stable disease (SD) for greater than (>) 3 months assessed by investigator according to RECIST version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

3. Percentage of Subjects With Progression-free Survival (PFS) at 6 Months [6 months]

   PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of Subjects with PFS at 6 Months were reported.

4. Overall Survival (OS) [From date of randomization until date of death from any cause, assessed up to cut-off date (04-Jul-2015)]

   OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date.

5. Percentage of Subjects With Overall Survival (OS) at 12 Months [12 months]

   OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date. Percentage of Subjects with OS at 12 months were reported.

6. Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M TS) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT) [Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])]

   QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes 27-item FACT-General (FACT-G) questionnaire which consists of 24 questions;7 relating to physical well-being (PWB),7 relating to social/family well-being (SWB),6 relating to emotional well-being (EWB) and 7 relating to functional well-being (FWB). Also, it includes melanoma-specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.

7. Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Trial Outcome Index (FACT-M TOI) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT) [Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])]

   QoL assessed using FACT-M assessment tool. This includes 27-item FACT-G questionnaire which consists of 24 questions; 7 relating to PWB, 7 relating to SWB, 6 relating to EWB and 7 relating to FWB. Also, it includes melanoma-specific subscale consists of 16 questions for MS and 8 questions for the MSS. Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Trial Outcome Index (FACT-M TOI) ranges from 0 to a high of 120 and is derived as: FACT-M TOI = PWB Score + FWB Score +MS Score. Higher scores represent a better quality of life.

8. Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death [Baseline up to cut-off date (04-Jul-2015)]

   AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 33 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs. TEAEs were to be reported separately for dacarbazine, pimasertib and pimasertib (crossover) reporting arms.

9. Number of Subjects With Adverse Events (AEs) of Special Interest [Baseline up to cut-off date (04-Jul-2015)]

   Adverse events of special interest included ocular retinal vein occlusion, serious retinal detachment or similar retinal abnormality characterized by accumulation of serous fluid in the retina, creatine phosphokinase (CPK) elevation and isoenzyme TEAE of Special Interest (Grade >=2) and acute renal failure (Grade >=2). Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.

10. Number of Subjects With Clinically Significant Change From Baseline in Laboratory Parameter, Vital Signs, Electrocardiogram (ECG) and Ophthalmologic Findings [Baseline up to cut-off date (04-Jul-2015)]

    Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with measurable, histologically or cytologically confirmed, locally advanced or metastatic cutaneous melanoma (stage III c or M1ac) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutational status is already known before screening, it must be retrospectively confirmed after inclusion by the sponsor.

• Tumor lesions amenable to biopsy or available tumor tissue as archival samples.

• Age greater than or equal to (>=) 18 years.

• Has read and understood the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.

• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: "All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile".

• Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose of trial medication. Effective contraception is defined as the method of contraception with a failure rate of less than 1% per year. Adequate contraception is defined as follows: two barrier methods or one barrier method with a spermicidal or intrauterine device or oral contraception for female partners of male subjects.

Exclusion Criteria:

• Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment).

• Has non-measurable lesions, disease not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1

• Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.

• Has bone marrow impairment as evidenced by Hemoglobin <10.0 g/dL, Neutrophil count <1.5 * 10^{9/L, platelets <100 * 10}9/L.

• Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min (according to the Cockcroft-Gault formula).

• Has liver function abnormality as defined by total bilirubin >1.5 * Upper Limit of Normal (ULN), or aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5

• ULN, for subjects with liver involvement AST/ALT >5 * ULN.

• Has significant cardiac conduction abnormalities, including QTc prolongation of >480 milliseconds and/or pacemaker or clinically relevant impaired cardiovascular function.

• Has hypertension uncontrolled by medication

• Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension).

• Has known active central nervous system (CNS) metastases unless previously radiotherapy treated, stable by CT scan for at least 3 months without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.

• History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease, or conditions that may hamper compliance and/or absorption of the tested product.

• Known human immunodeficiency virus (HIV) positivity, active hepatitis C, or active hepatitis B.

• Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment.

• Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial drug treatment.

• Has history of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject well-being or preclude full participation in the trial.

• Has known hypersensitivity to dacarbazine.

• Is a pregnant or nursing female.

• Participated in another clinical trial within the past 28 days.

• Has creatine phosphokinase (CPK) level at baseline National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade >=2 (i.e > 2.5 * ULN), and/or has a previous history of myositis or rhabdomyolysis.

• Is suitable for treatment with an approved B-Raf inhibitor (exclusion criteria implemented in German amendment only).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Tucson	Arizona	United States
3	Research Site	San Francisco	California	United States
4	Research Site	Miami Beach	Florida	United States
5	Research Site	Orlando	Florida	United States
6	Research Site	Maywood	Illinois	United States
7	Research Site	Indianapolis	Indiana	United States
8	Research Site	Boston	Massachusetts	United States
9	Please contact the US Medical Information in	Rockland	Massachusetts	United States
10	Research Site	Saint Louis	Missouri	United States
11	Research Site	Morristown	New Jersey	United States
12	Research Site	New York	New York	United States
13	Research Site	Columbus	Ohio	United States
14	Research Site	Dallas	Texas	United States
15	Research Site	Madison	Wisconsin	United States
16	Research Site	Adelaide, SA		Australia
17	Research Site	Albury/Wodonga		Australia
18	Research Site	Auchenflower		Australia
19	Research Site	Box Hill		Australia
20	Research Site	Greenslopes		Australia
21	Research Site	Herston		Australia
22	Research Site	Malvern		Australia
23	Research Site	North Sydney		Australia
24	Research Site	Prahran		Australia
25	Research Site	Wendouree		Australia
26	Research Site	Woodville South		Australia
27	Research site	Woolloongabba		Australia
28	Research Site	Brussel		Belgium
29	Research Site	Bruxelles		Belgium
30	Research Site	Edegem		Belgium
31	Research Site	Bordeaux		France
32	Research Site	Brest		France
33	Research Site	Dijon		France
34	Research Site	Lille		France
35	Research Site	Lyon		France
36	Research Site	Marseille		France
37	Research Site	Montpellier		France
38	Research Site	Nantes		France
39	Research Site	Paris		France
40	Research Site	Pierre Benite		France
41	Research Site	Rennes		France
42	Research Site	Toulouse		France
43	Research Site	Villejuif		France
44	Research Site	Augsburg		Germany
45	Research Site	Berlin		Germany
46	Research Site	Bonn		Germany
47	Research Site	Buxtehude		Germany
48	Research site	Düsseldorf		Germany
49	Research Site	Erlangen		Germany
50	Research Site	Essen		Germany
51	Research Site	Frankfurt am Main		Germany
52	Research Site	Hamburg		Germany
53	Research Site	Hannover		Germany
54	Research Site	Kiel		Germany
55	Research Site	Köln		Germany
56	Research Site	Leipzig		Germany
57	Research Site	Magdeburg		Germany
58	Research Site	Mainz		Germany
59	Research site	München		Germany
60	Research Site	Münster		Germany
61	Research Site	Plauen		Germany
62	Research Site	Tübingen		Germany
63	Research Site	Würzburg		Germany
64	Research Site	Jerusalem		Israel
65	Research Site	Ramat-Gan		Israel
66	Research Site	Tel-Aviv		Israel
67	Research Site	Bari		Italy
68	Research Site	Genova		Italy
69	Research Site	Meldola - FC		Italy
70	Research Site	Milano		Italy
71	Research Site	Napoli		Italy
72	Research Site	Padova		Italy
73	Research Site	Roma		Italy
74	Research Site	Siena		Italy
75	Research Site	Groningen		Netherlands
76	Research Site	Rotterdam		Netherlands
77	Research Site	Utrecht		Netherlands
78	Research Site	Christchurch		New Zealand
79	Research Site	Hamilton		New Zealand
80	Research Site	Palmerston North		New Zealand
81	Research Site	Tauranga		New Zealand
82	Research Site	Durban		South Africa
83	Research Site	Johannesburg		South Africa
84	Research Site	Pietermaritzburg		South Africa
85	Research Site	Pretoria		South Africa
86	Research Site	Badalona		Spain
87	Research Site	Barcelona		Spain
88	Research Site	l'Hospitalet de Llobregat		Spain
89	Research Site	Madrid		Spain
90	Research Site	Majadahonda		Spain
91	Research Site	Málaga		Spain
92	Research Site	Pamplona		Spain
93	Research Site	Sevilla		Spain
94	Research Site	Göteborg		Sweden
95	Research Site	Stockholm		Sweden
96	Research Site	Basel		Switzerland
97	Research Site	Zürich		Switzerland
98	Research Site	Cambridge		United Kingdom
99	Research Site	London		United Kingdom
100	Research Site	Manchester		United Kingdom
101	Research Site	Newcastle upon Tyne		United Kingdom
102	Research Site	Southampton		United Kingdom

Sponsors and Collaborators

• EMD Serono
• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Study Director, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT01693068
• Other Study ID Numbers: EMR 200066-007; 2012-002669-37
• First Posted: Sep 26, 2012
• Last Update Posted: Jan 5, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by EMD Serono: Cutaneous Melanoma; Dacarbazine; Pimasertib; N-Ras
• Additional relevant MeSH terms: Melanoma; Skin Neoplasms; Dacarbazine

Study Results

Participant Flow

Recruitment Details	First/last subject (informed consent): 05 December 2012/04 June 2014. Cut-off date: 04 July 2015. Last subject last visit: 24 October 2016.
Pre-assignment Detail	A total of 194 subjects were randomized in trial. Data presented based on the cut-off date of 04 July 2015.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Period Title: Randomization Period
STARTED	64	130	0
Treated	61	130	0
COMPLETED	62	125	0
NOT COMPLETED	2	5	0
Period Title: Randomization Period
STARTED	0	0	41
Treated	0	0	41
COMPLETED	0	0	40
NOT COMPLETED	0	0	1

Baseline Characteristics

Arm/Group Title	Dacarbazine	Pimasertib	Total
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Total of all reporting groups
Overall Participants	64	130	194
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	36 56.3%	65 50%	101 52.1%
>=65 years	28 43.8%	65 50%	93 47.9%
Sex: Female, Male (Count of Participants)
Female	28 43.8%	62 47.7%	90 46.4%
Male	36 56.3%	68 52.3%	104 53.6%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment (otherwise censored), whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Median (95% Confidence Interval) [weeks]	6.86	13.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dacarbazine, Pimasertib
	Comments
	Type of Statistical Test	Other
	Comments	A log-rank test stratified by baseline Eastern Cooperative Oncology Group performance status (ECOG PS) (using the interactive voice response system [IVRS] value) will tested the null hypothesis of no difference between the Pimasertib (first line) and the Dacarbazine treatment groups at the 5% level.
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	Stratified Log Rank Test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Hazard Ratio is obtained from the Cox Proportional Hazards model based on dacarbazine and pimasertib only stratified by baseline ECOG Performance Status.

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the percentage of subjects with complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Number (95% Confidence Interval) [percentage of subjects]	14.1	26.9

3. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of subjects with CR, PR, or stable disease (SD) for greater than (>) 3 months assessed by investigator according to RECIST version 1.1. CR: defined as disappearance of all target and all non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions. SD: defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Number (95% Confidence Interval) [percentage of subjects]	15.6	33.1

4. Secondary Outcome

Title	Percentage of Subjects With Progression-free Survival (PFS) at 6 Months
Description	PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions. Percentage of Subjects with PFS at 6 Months were reported.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Number (95% Confidence Interval) [percentage of subjects]	9.4	17.3

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date.
Time Frame	From date of randomization until date of death from any cause, assessed up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Median (95% Confidence Interval) [months]	10.61	8.87

6. Secondary Outcome

Title	Percentage of Subjects With Overall Survival (OS) at 12 Months
Description	OS was defined as the time (in months) from randomization to death due to any cause. Subjects without a death date were to be censored at the minimum of last known date alive, defined as the latest date available on the electronic case report form, and cut-off date. Percentage of Subjects with OS at 12 months were reported.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

ITT analysis set included all subjects who were randomized to trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	64	130
Number (95% Confidence Interval) [percentage of subjects]	44.5	43.3

7. Secondary Outcome

Title	Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M TS) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT)
Description	QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes 27-item FACT-General (FACT-G) questionnaire which consists of 24 questions;7 relating to physical well-being (PWB),7 relating to social/family well-being (SWB),6 relating to emotional well-being (EWB) and 7 relating to functional well-being (FWB). Also, it includes melanoma-specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.
Time Frame	Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])

Outcome Measure Data

Analysis Population Description

ITT analysis set. Here "Number of Subjects Analyzed" = subjects evaluable for this outcome and "Number Analyzed" = subjects evaluable at specified time points for each arm, respectively. There were no subjects analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	58	126
Baseline	126.20 (23.828)	132.24 (22.179)
Change at Day 1 Cycle 2	-3.05 (14.815)	-3.06 (18.492)
Change at Day 1 Cycle 3	0.60 (19.965)	-6.77 (21.716)
Change at Day 1 Cycle 4	4.11 (14.746)	-6.54 (19.919)
Change at Day 1 Cycle 5	0.62 (11.810)	-2.81 (17.202)
Change at Day 1 Cycle 6	-3.71 (15.674)	-8.45 (20.939)
Change at Day 1 Cycle 7	-1.10 (13.318)	-8.84 (19.128)
Change at Day 1 Cycle 8	1.28 (12.928)	-14.67 (18.508)
Change at Day 1 Cycle 9	2.21 (16.224)	-13.67 (21.388)
Change at Day 1 Cycle 10	4.40 (14.818)	-13.26 (20.716)
Change at Day 1 Cycle 11	1.02 (19.161)	-14.10 (21.157)
Change at Day 1 Cycle 12	1.56 (19.932)	-10.52 (18.895)
Change at Day 1 Cycle 13	5.51 (20.191)	-13.38 (23.690)
Change at Day 1 Cycle 14	11.50 (21.920)	-18.24 (22.998)
Change at Day 1 Cycle 15	9.60 (15.345)	-11.33 (19.787)
Change at Day 1 Cycle 16	10.56 (14.935)	-11.18 (23.680)
Change at Day 1 Cycle 17	3.00 (5.657)	-9.18 (24.166)
Change at Day 1 Cycle 18	27.00 (NA)	-3.92 (9.640)
Change at Day 1 Cycle 19	16.50 (14.849)	-1.15 (8.147)
Change at Day 1 Cycle 20	16.00 (15.556)	1.17 (5.947)
Change at Day 1 Cycle 21	17.00 (14.142)	4.17 (8.918)
Change at Day 1 Cycle 22	18.00 (12.728)	1.32 (11.163)
Change at Day 1 Cycle 23	27.00 (NA)	-13.69 (15.354)
Change at Day 1 Cycle 24	13.50 (19.092)	-3.83 (NA)
Change at Day 1 Cycle 25	14.50 (17.678)	-3.83 (NA)
Change at Day 1 Cycle 26	27.00 (NA)	-2.83 (NA)
Change at Day 1 Cycle 27	27.00 (NA)
Change at Day 1 Cycle 28	27.00 (NA)	-0.83 (NA)
Change at Day 1 Cycle 30	-1.83 (NA)
Change at Day 1 Cycle 31	-7.83 (NA)
Change at Day 1 Cycle 32	-7.83 (NA)
Change at Day 1 Cycle 33	-8.83 (NA)
Change at Day 1 Cycle 35	-1.83 (NA)
Change at Day 1 Cycle 36	-3.83 (NA)
Change at Day 1 Cycle 37	-4.83 (NA)
Change at EOT	-7.91 (23.119)	-9.98 (20.560)

8. Secondary Outcome

Title	Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Trial Outcome Index (FACT-M TOI) at Day 1 of Pre-Specified Cycles and End of Treatment (EOT)
Description	QoL assessed using FACT-M assessment tool. This includes 27-item FACT-G questionnaire which consists of 24 questions; 7 relating to PWB, 7 relating to SWB, 6 relating to EWB and 7 relating to FWB. Also, it includes melanoma-specific subscale consists of 16 questions for MS and 8 questions for the MSS. Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Trial Outcome Index (FACT-M TOI) ranges from 0 to a high of 120 and is derived as: FACT-M TOI = PWB Score + FWB Score +MS Score. Higher scores represent a better quality of life.
Time Frame	Baseline, Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 35, 36, 37 and EOT (up to cut-off date [04-Jul-2015])

Outcome Measure Data

Analysis Population Description

ITT analysis set. Here "Number of Subjects Analyzed" = subjects evaluable for this outcome and "Number Analyzed" = subjects evaluable at specified time points for each arm, respectively. There were no subjects analyzed at certain time points (that is, Number Analyzed = 0) because there was no data collected for respective arms at those time points.

Arm/Group Title	Dacarbazine	Pimasertib
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.
Measure Participants	58	126
Baseline	90.35 (19.348)	94.07 (17.534)
Change at Day 1 Cycle 2	-3.33 (12.015)	-4.40 (14.286)
Change at Day 1 Cycle 3	-0.69 (15.974)	-7.99 (17.089)
Change at Day 1 Cycle 4	1.54 (10.304)	-7.97 (16.741)
Change at Day 1 Cycle 5	-0.86 (5.405)	-4.37 (14.084)
Change at Day 1 Cycle 6	-3.29 (7.752)	-9.15 (18.813)
Change at Day 1 Cycle 7	-2.07 (6.859)	-8.99 (14.783)
Change at Day 1 Cycle 8	0.83 (5.161)	-15.09 (14.458)
Change at Day 1 Cycle 9	-1.93 (6.300)	-13.79 (17.198)
Change at Day 1 Cycle 10	-1.10 (5.654)	-12.37 (17.058)
Change at Day 1 Cycle 11	-2.90 (7.722)	-13.95 (17.006)
Change at Day 1 Cycle 12	-2.40 (7.408)	-11.95 (17.311)
Change at Day 1 Cycle 13	0.80 (7.697)	-13.57 (21.699)
Change at Day 1 Cycle 14	0.00 (4.243)	-18.55 (19.880)
Change at Day 1 Cycle 15	1.60 (4.084)	-13.59 (15.747)
Change at Day 1 Cycle 16	0.61 (3.994)	-13.15 (19.130)
Change at Day 1 Cycle 17	2.50 (0.707)	-10.66 (20.007)
Change at Day 1 Cycle 18	3.00 (NA)	-5.72 (4.614)
Change at Day 1 Cycle 19	2.50 (0.707)	-4.94 (5.238)
Change at Day 1 Cycle 20	4.00 (1.414)	-2.33 (1.155)
Change at Day 1 Cycle 21	3.50 (0.707)	0.00 (2.000)
Change at Day 1 Cycle 22	4.00 (1.414)	-1.40 (3.831)
Change at Day 1 Cycle 23	3.00 (NA)	-13.36 (16.061)
Change at Day 1 Cycle 24	2.50 (0.707)	-2.00 (NA)
Change at Day 1 Cycle 25	3.50 (0.707)	-1.00 (NA)
Change at Day 1 Cycle 26	3.00 (NA)	0.00 (NA)
Change at Day 1 Cycle 27	3.00 (NA)
Change at Day 1 Cycle 28	3.00 (NA)	1.00 (NA)
Change at Day 1 Cycle 30	1.00 (NA)
Change at Day 1 Cycle 31	-3.00 (NA)
Change at Day 1 Cycle 32	-4.00 (NA)
Change at Day 1 Cycle 33	-3.00 (NA)
Change at Day 1 Cycle 35	0.00 (NA)
Change at Day 1 Cycle 36	0.00 (NA)
Change at Day 1 Cycle 37	-3.00 (NA)
Change at EOT	-8.18 (16.410)	-10.42 (16.256)

9. Secondary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
Description	AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 33 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. TEAEs include both Serious TEAEs and non-serious TEAEs. TEAEs were to be reported separately for dacarbazine, pimasertib and pimasertib (crossover) reporting arms.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Measure Participants	61	130	41
TEAEs	60	130	41
Serious TEAEs	12	74	26
TEAEs Leading to Discontinuation	3	61	16
TEAEs Leading To Death	4	6	6

10. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs) of Special Interest
Description	Adverse events of special interest included ocular retinal vein occlusion, serious retinal detachment or similar retinal abnormality characterized by accumulation of serous fluid in the retina, creatine phosphokinase (CPK) elevation and isoenzyme TEAE of Special Interest (Grade >=2) and acute renal failure (Grade >=2). Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Measure Participants	61	130	41
Retinal vein occlusion	0	5	2
Serious retinal detachment	0	76	21
CPK/Isoenzyme TEAE of Special Interest (>=Grade 2)	0	74	24
Acute renal failure (Grade >= 2)	1	9	2

11. Secondary Outcome

Title	Number of Subjects With Clinically Significant Change From Baseline in Laboratory Parameter, Vital Signs, Electrocardiogram (ECG) and Ophthalmologic Findings
Description	Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Time Frame	Baseline up to cut-off date (04-Jul-2015)

Outcome Measure Data

Analysis Population Description

Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment.

Arm/Group Title	Dacarbazine	Pimasertib	Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.	Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.	Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
Measure Participants	61	130	41
Laboratory Parameter	0	0	0
Vital Signs	0	0	0
ECG	0	0	0
Ophthalmologic Findings	0	0	0

Adverse Events

Time Frame	Baseline up to cut-off date (04-Jul-2015)
Adverse Event Reporting Description	Safety analysis set (SAF) consisted of all subjects who received at least 1 dose of any trial treatment. Subjects were presented under 3 reporting groups: Dacarbazine group: for subjects who received at least 1 dose of dacarbazine; Pimasertib group: for subjects who received at least 1 dose of pimasertib; Pimasertib (Crossover) group: for subjects who were initially randomized and received dacarbazine, but crossed over to pimasertib treatment on progression of their disease.
Arm/Group Title	Dacarbazine		Pimasertib		Pimasertib (Crossover)
Arm/Group Description	Subjects received dacarbazine intravenously at dose of 1000 mg/m^2 of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first. Eligible subjects with documented tumor progression on dacarbazine were offered to switch to pimasertib treatment.		Subjects received pimasertib orally as monotherapy at a dose of 60 mg twice daily continuously. Treatment consisted of repeated 21-day cycles which was continued until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurred first.		Subjects who were randomized and received dacarbazine and were allowed to crossover to pimasertib treatment on progression of their disease.
All Cause Mortality
	Dacarbazine		Pimasertib		Pimasertib (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dacarbazine		Pimasertib		Pimasertib (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/61 (19.7%)		74/130 (56.9%)		26/41 (63.4%)
Blood and lymphatic system disorders
Anaemia	1/61 (1.6%)		0/130 (0%)		2/41 (4.9%)
Iron deficiency anaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Leukocytosis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Lymphopenia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Thrombocytopenia	3/61 (4.9%)		0/130 (0%)		0/41 (0%)
Cardiac disorders
Acute coronary syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Acute myocardial infarction	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Atrial fibrillation	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Cardiac failure	0/61 (0%)		3/130 (2.3%)		1/41 (2.4%)
Cor pulmonale acute	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Left ventricular dysfunction	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Myocardial ischaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pericarditis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Eye disorders
Chorioretinopathy	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Cystoid macular oedema	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Macular detachment	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Macular oedema	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Retinal detachment	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Retinal vein occlusion	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Ulcerative keratitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Gastrointestinal disorders
Abdominal pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Constipation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Diarrhoea	1/61 (1.6%)		6/130 (4.6%)		1/41 (2.4%)
Duodenal obstruction	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Mouth ulceration	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Nausea	1/61 (1.6%)		3/130 (2.3%)		0/41 (0%)
Small intestinal obstruction	0/61 (0%)		0/130 (0%)		2/41 (4.9%)
Vomiting	1/61 (1.6%)		3/130 (2.3%)		1/41 (2.4%)
General disorders
Chest pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Chills	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cyst rupture	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Death	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Disease progression	1/61 (1.6%)		2/130 (1.5%)		1/41 (2.4%)
Fatigue	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
General physical health deterioration	1/61 (1.6%)		2/130 (1.5%)		4/41 (9.8%)
Impaired healing	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Malaise	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Necrosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oedema peripheral	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pyrexia	1/61 (1.6%)		4/130 (3.1%)		0/41 (0%)
Sudden death	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Hepatobiliary disorders
Cholangitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hepatotoxicity	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Infections and infestations
Bacteraemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Candida infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Catheter site infection	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Cellulitis	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Device related infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Erysipelas	0/61 (0%)		7/130 (5.4%)		1/41 (2.4%)
Infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Localised infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lower respiratory tract infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pharyngitis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Pyelonephritis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Respiratory tract infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Sepsis	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Septic shock	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Skin infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Staphylococcal sepsis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Streptococcal sepsis	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Urinary tract infection	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Injury, poisoning and procedural complications
Subdural haematoma	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Investigations
Alanine aminotransferase increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Blood creatine phosphokinase increased	0/61 (0%)		26/130 (20%)		8/41 (19.5%)
Blood creatinine increased	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Ejection fraction decreased	0/61 (0%)		5/130 (3.8%)		1/41 (2.4%)
Lipase increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Troponin increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Hypokalaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyponatraemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tumour lysis syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Inguinal mass	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Muscular weakness	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Pain in extremity	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pathological fracture	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Spinal column stenosis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Nervous system disorders
Ataxia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Epilepsy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Headache	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Metabolic encephalopathy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Neuralgia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Neuropathy peripheral	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Presyncope	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Transient ischaemic attack	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Psychiatric disorders
Confusional state	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Renal and urinary disorders
Urinary retention	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Reproductive system and breast disorders
Breast haematoma	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/61 (0%)		5/130 (3.8%)		0/41 (0%)
Haemoptysis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pleural effusion	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Pulmonary embolism	1/61 (1.6%)		3/130 (2.3%)		2/41 (4.9%)
Respiratory distress	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Drug eruption	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Rash	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rash macular	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rash maculo-papular	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Skin toxicity	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Vascular disorders
Deep vein thrombosis	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Hypertension	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypotension	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Venous thrombosis limb	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Other (Not Including Serious) Adverse Events
	Dacarbazine		Pimasertib		Pimasertib (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/61 (96.7%)		130/130 (100%)		41/41 (100%)
Blood and lymphatic system disorders
Anaemia	8/61 (13.1%)		13/130 (10%)		3/41 (7.3%)
Thrombocytopenia	12/61 (19.7%)		8/130 (6.2%)		3/41 (7.3%)
Neutropenia	13/61 (21.3%)		1/130 (0.8%)		0/41 (0%)
Lymphopenia	1/61 (1.6%)		9/130 (6.9%)		2/41 (4.9%)
Leukopenia	6/61 (9.8%)		1/130 (0.8%)		0/41 (0%)
Anaemia of chronic disease	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Eosinophilia	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Hypochromic anaemia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Increased tendency to bruise	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Leukocytosis	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Lymph node pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Lymphadenitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lymphadenopathy	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Lymphocytosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Normochromic normocytic anaemia	2/61 (3.3%)		2/130 (1.5%)		1/41 (2.4%)
Thrombocytosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cardiac disorders
Angina pectoris	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Aortic valve disease	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Aortic valve incompetence	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Aortic valve stenosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Atrial fibrillation	2/61 (3.3%)		2/130 (1.5%)		0/41 (0%)
Atrioventricular block	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Atrioventricular block first degree	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Atrioventricular block second degree	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Bradycardia	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Bundle branch block	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Bundle branch block right	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Diastolic dysfunction	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Left ventricular dysfunction	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Left ventricular hypertrophy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Mitral valve incompetence	0/61 (0%)		4/130 (3.1%)		2/41 (4.9%)
Mitral valve sclerosis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Palpitations	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Pericardial effusion	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Pulmonary valve incompetence	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Sinus bradycardia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Sinus tachycardia	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Supraventricular tachycardia	0/61 (0%)		0/130 (0%)		2/41 (4.9%)
Tachycardia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tricuspid valve incompetence	0/61 (0%)		5/130 (3.8%)		4/41 (9.8%)
Ventricular hypokinesia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Congenital, familial and genetic disorders
Optic nerve hypoplasia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Ventricular septal defect	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Ear congestion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Ear pain	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Hypoacusis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Middle ear inflammation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tinnitus	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Vertigo	2/61 (3.3%)		3/130 (2.3%)		0/41 (0%)
Endocrine disorders
Adrenal insufficiency	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperthyroidism	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Eye disorders
Retinal detachment	0/61 (0%)		56/130 (43.1%)		15/41 (36.6%)
Vision blurred	0/61 (0%)		29/130 (22.3%)		9/41 (22%)
Eyelid oedema	1/61 (1.6%)		18/130 (13.8%)		2/41 (4.9%)
Visual impairment	0/61 (0%)		12/130 (9.2%)		2/41 (4.9%)
Periorbital oedema	0/61 (0%)		12/130 (9.2%)		1/41 (2.4%)
Macular detachment	0/61 (0%)		10/130 (7.7%)		2/41 (4.9%)
Blepharitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Blindness	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Cataract	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Chalazion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Chorioretinopathy	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Chromatopsia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Colour blindness acquired	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Conjunctival haemorrhage	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Conjunctival oedema	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Cystoid macular oedema	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Deposit eye	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Detachment of retinal pigment epithelium	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Diplopia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Dry eye	1/61 (1.6%)		5/130 (3.8%)		0/41 (0%)
Erythema of eyelid	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eye discharge	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eye disorder	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Eye haemorrhage	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eye inflammation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eye oedema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eye pain	1/61 (1.6%)		3/130 (2.3%)		0/41 (0%)
Eye pruritus	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Eye swelling	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Eyelid haematoma	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Eyelid ptosis	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Glaucoma	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lacrimation increased	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Macular cyst	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Macular degeneration	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Macular fibrosis	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Macular oedema	0/61 (0%)		6/130 (4.6%)		1/41 (2.4%)
Myopia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Ocular hyperaemia	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Ocular hypertension	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Optic disc haemorrhage	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Photophobia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Photopsia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Presbyopia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Retinal deposits	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Retinal disorder	0/61 (0%)		0/130 (0%)		2/41 (4.9%)
Retinal haemorrhage	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Retinal oedema	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Retinal pigment epitheliopathy	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Retinal vein occlusion	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Retinopathy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Subretinal fluid	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Visual acuity reduced	0/61 (0%)		5/130 (3.8%)		0/41 (0%)
Vitreous detachment	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Vitreous floaters	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Xerophthalmia	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Gastrointestinal disorders
Diarrhoea	10/61 (16.4%)		106/130 (81.5%)		31/41 (75.6%)
Nausea	25/61 (41%)		47/130 (36.2%)		17/41 (41.5%)
Vomiting	14/61 (23%)		30/130 (23.1%)		16/41 (39%)
Constipation	21/61 (34.4%)		24/130 (18.5%)		7/41 (17.1%)
Abdominal pain	10/61 (16.4%)		31/130 (23.8%)		7/41 (17.1%)
Dry mouth	2/61 (3.3%)		20/130 (15.4%)		8/41 (19.5%)
Stomatitis	3/61 (4.9%)		21/130 (16.2%)		4/41 (9.8%)
Dyspepsia	0/61 (0%)		11/130 (8.5%)		3/41 (7.3%)
Gastrooesophageal reflux disease	2/61 (3.3%)		5/130 (3.8%)		2/41 (4.9%)
Rectal haemorrhage	0/61 (0%)		8/130 (6.2%)		1/41 (2.4%)
Mouth ulceration	0/61 (0%)		7/130 (5.4%)		1/41 (2.4%)
Abdominal distension	1/61 (1.6%)		4/130 (3.1%)		2/41 (4.9%)
Abdominal pain lower	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Abdominal pain upper	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Anal polyp	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Aphthous stomatitis	0/61 (0%)		4/130 (3.1%)		2/41 (4.9%)
Aptyalism	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Ascites	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Cheilitis	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Colitis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Duodenal ulcer	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Dysphagia	1/61 (1.6%)		5/130 (3.8%)		2/41 (4.9%)
Epigastric discomfort	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Faeces discoloured	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Flatulence	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Gastric ulcer	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Gastritis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Gastritis erosive	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Glossitis	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Glossodynia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Haematemesis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Haematochezia	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Haemorrhoidal haemorrhage	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Haemorrhoids	1/61 (1.6%)		4/130 (3.1%)		1/41 (2.4%)
Hyperchlorhydria	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Intestinal obstruction	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lip dry	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lip oedema	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Lip pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Melaena	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Mesenteric vein thrombosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Mouth swelling	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Odynophagia	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Oesophagitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral discomfort	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral dysaesthesia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral mucosal eruption	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral mucosal erythema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral pruritus	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oral toxicity	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Paraesthesia oral	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Regurgitation	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Salivary hypersecretion	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Subileus	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tongue disorder	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Tongue oedema	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Tongue ulceration	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Toothache	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Umbilical hernia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
General disorders
Oedema peripheral	6/61 (9.8%)		59/130 (45.4%)		18/41 (43.9%)
Fatigue	23/61 (37.7%)		39/130 (30%)		11/41 (26.8%)
Asthenia	13/61 (21.3%)		39/130 (30%)		10/41 (24.4%)
Pyrexia	5/61 (8.2%)		27/130 (20.8%)		10/41 (24.4%)
Chills	3/61 (4.9%)		11/130 (8.5%)		3/41 (7.3%)
Axillary pain	1/61 (1.6%)		1/130 (0.8%)		1/41 (2.4%)
Catheter site pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Chest discomfort	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Chest pain	3/61 (4.9%)		2/130 (1.5%)		1/41 (2.4%)
Crying	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Disease progression	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Drug intolerance	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Enanthema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Face oedema	0/61 (0%)		12/130 (9.2%)		9/41 (22%)
Facial pain	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Feeling cold	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Gait disturbance	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
General physical health deterioration	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Generalised oedema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperpyrexia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperthermia	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Hypothermia	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Inflammation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Influenza like illness	1/61 (1.6%)		3/130 (2.3%)		0/41 (0%)
Injection site haematoma	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Localised oedema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Malaise	2/61 (3.3%)		5/130 (3.8%)		2/41 (4.9%)
Mucosal dryness	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Non-cardiac chest pain	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Oedema	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Papillitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Peripheral swelling	0/61 (0%)		5/130 (3.8%)		2/41 (4.9%)
Secretion discharge	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Sensation of foreign body	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Temperature intolerance	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Vessel puncture site haematoma	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Vessel puncture site inflammation	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Vessel puncture site pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Xerosis	0/61 (0%)		1/130 (0.8%)		2/41 (4.9%)
Hepatobiliary disorders
Cholestasis	1/61 (1.6%)		4/130 (3.1%)		0/41 (0%)
Hepatic pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hepatocellular injury	0/61 (0%)		7/130 (5.4%)		0/41 (0%)
Hepatomegaly	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Immune system disorders
Sarcoidosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Infections and infestations
Abdominal wall abscess	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Abscess limb	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Acute sinusitis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Acute tonsillitis	0/61 (0%)		3/130 (2.3%)		1/41 (2.4%)
Bacterial infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Bronchitis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Cellulitis	0/61 (0%)		2/130 (1.5%)		2/41 (4.9%)
Cholangitis infective	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Conjunctivitis	0/61 (0%)		8/130 (6.2%)		0/41 (0%)
Conjunctivitis viral	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cystitis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Enterobacter infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Erysipelas	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Folliculitis	1/61 (1.6%)		17/130 (13.1%)		7/41 (17.1%)
Fungal oesophagitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Fungal skin infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Furuncle	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Gastroenteritis	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Helicobacter infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Herpes simplex	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Herpes virus infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Herpes zoster	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Impetigo	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Infected bites	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Influenza	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Klebsiella infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Laryngitis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Localised infection	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Lower respiratory tract infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Lung infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Lymph gland infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Nasopharyngitis	3/61 (4.9%)		8/130 (6.2%)		2/41 (4.9%)
Oral candidiasis	0/61 (0%)		5/130 (3.8%)		1/41 (2.4%)
Oral fungal infection	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Oral herpes	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Paronychia	0/61 (0%)		9/130 (6.9%)		3/41 (7.3%)
Pharyngitis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Pneumonia escherichia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pseudomonas infection	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Pulpitis dental	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rash pustular	1/61 (1.6%)		16/130 (12.3%)		3/41 (7.3%)
Rhinitis	1/61 (1.6%)		1/130 (0.8%)		2/41 (4.9%)
Sinusitis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Skin candida	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Skin infection	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Staphylococcal bacteraemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Staphylococcal skin infection	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Superinfection viral	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tinea cruris	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Tinea pedis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tinea versicolour	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Tonsillitis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Tooth abscess	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Trichophytosis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Upper respiratory tract infection	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Urinary tract infection	1/61 (1.6%)		7/130 (5.4%)		0/41 (0%)
Vaginal infection	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Viral infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Vulvovaginal mycotic infection	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Wound infection	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Injury, poisoning and procedural complications
Chest injury	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Clavicle fracture	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Concussion	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Excoriation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Fall	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Lip injury	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Muscle strain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Optic nerve injury	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Procedural pain	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Rib fracture	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Scratch	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Spinal compression fracture	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Sunburn	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Tendon rupture	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Traumatic shock	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Wound	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Wound complication	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Investigations
Blood creatine phosphokinase increased	3/61 (4.9%)		86/130 (66.2%)		28/41 (68.3%)
Aspartate aminotransferase increased	3/61 (4.9%)		17/130 (13.1%)		4/41 (9.8%)
Ejection fraction decreased	0/61 (0%)		13/130 (10%)		3/41 (7.3%)
Weight decreased	2/61 (3.3%)		8/130 (6.2%)		3/41 (7.3%)
Alanine aminotransferase increased	4/61 (6.6%)		6/130 (4.6%)		1/41 (2.4%)
Weight increased	0/61 (0%)		9/130 (6.9%)		2/41 (4.9%)
Blood alkaline phosphatase increased	2/61 (3.3%)		5/130 (3.8%)		3/41 (7.3%)
Gamma-glutamyltransferase increased	2/61 (3.3%)		4/130 (3.1%)		3/41 (7.3%)
Amylase increased	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Blood albumin decreased	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Blood bicarbonate decreased	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Blood bilirubin increased	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Blood creatinine increased	2/61 (3.3%)		2/130 (1.5%)		1/41 (2.4%)
Blood fibrinogen decreased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Blood lactate dehydrogenase increased	1/61 (1.6%)		3/130 (2.3%)		1/41 (2.4%)
Blood phosphorus increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Blood potassium increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Blood pressure increased	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Blood urea increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Body temperature increased	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Breath sounds abnormal	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
C-reactive protein increased	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Creatinine renal clearance decreased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Electrocardiogram PR prolongation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Electrocardiogram QRS complex prolonged	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Electrocardiogram QT prolonged	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Electrocardiogram repolarisation abnormality	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Glomerular filtration rate decreased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Haemoglobin decreased	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Hepatic enzyme increased	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
International normalised ratio increased	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Intraocular pressure increased	0/61 (0%)		3/130 (2.3%)		1/41 (2.4%)
Lipase increased	1/61 (1.6%)		2/130 (1.5%)		2/41 (4.9%)
Lymphocyte count decreased	0/61 (0%)		5/130 (3.8%)		0/41 (0%)
Neutrophil count decreased	1/61 (1.6%)		3/130 (2.3%)		0/41 (0%)
Oxygen saturation decreased	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Platelet count decreased	1/61 (1.6%)		6/130 (4.6%)		1/41 (2.4%)
Protein total decreased	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Protein total increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pupillary light reflex tests abnormal	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Troponin increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
White blood cell count decreased	2/61 (3.3%)		2/130 (1.5%)		0/41 (0%)
White blood cell count increased	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Metabolism and nutrition disorders
Decreased appetite	8/61 (13.1%)		22/130 (16.9%)		7/41 (17.1%)
Hypokalaemia	3/61 (4.9%)		13/130 (10%)		5/41 (12.2%)
Hypoalbuminaemia	0/61 (0%)		10/130 (7.7%)		2/41 (4.9%)
Hypomagnesaemia	0/61 (0%)		4/130 (3.1%)		3/41 (7.3%)
Hyponatraemia	0/61 (0%)		7/130 (5.4%)		0/41 (0%)
Cell death	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Dehydration	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Diabetes mellitus	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Electrolyte imbalance	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Fluid retention	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Gout	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Hyperamylasaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperglycaemia	1/61 (1.6%)		3/130 (2.3%)		0/41 (0%)
Hyperkalaemia	0/61 (0%)		5/130 (3.8%)		0/41 (0%)
Hyperlipasaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperphosphataemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypertriglyceridaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypocalcaemia	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Hypoglycaemia	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Hypophosphataemia	1/61 (1.6%)		3/130 (2.3%)		2/41 (4.9%)
Hypoproteinaemia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Increased appetite	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Iron deficiency	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Malnutrition	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Oligodipsia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	4/61 (6.6%)		18/130 (13.8%)		4/41 (9.8%)
Arthralgia	3/61 (4.9%)		9/130 (6.9%)		7/41 (17.1%)
Back pain	3/61 (4.9%)		8/130 (6.2%)		8/41 (19.5%)
Pain in extremity	3/61 (4.9%)		9/130 (6.9%)		6/41 (14.6%)
Muscular weakness	1/61 (1.6%)		8/130 (6.2%)		1/41 (2.4%)
Groin pain	3/61 (4.9%)		3/130 (2.3%)		1/41 (2.4%)
Musculoskeletal pain	2/61 (3.3%)		2/130 (1.5%)		4/41 (9.8%)
Arthritis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Bone pain	0/61 (0%)		0/130 (0%)		2/41 (4.9%)
Chondrocalcinosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Haemarthrosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Joint swelling	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Mobility decreased	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Muscle contracture	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Muscle spasms	1/61 (1.6%)		1/130 (0.8%)		1/41 (2.4%)
Muscle twitching	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Musculoskeletal chest pain	1/61 (1.6%)		1/130 (0.8%)		1/41 (2.4%)
Musculoskeletal discomfort	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Musculoskeletal disorder	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Musculoskeletal stiffness	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Neck mass	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Neck pain	2/61 (3.3%)		5/130 (3.8%)		1/41 (2.4%)
Pain in jaw	2/61 (3.3%)		1/130 (0.8%)		0/41 (0%)
Rhabdomyolysis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Spinal osteoarthritis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Spinal pain	2/61 (3.3%)		0/130 (0%)		1/41 (2.4%)
Tendonitis	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Trismus	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Blepharal papilloma	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Breast neoplasm	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Cancer pain	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Malignant melanoma	2/61 (3.3%)		0/130 (0%)		1/41 (2.4%)
Metastatic pain	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Monoclonal gammopathy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pyogenic granuloma	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Skin cancer	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Skin papilloma	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Squamous cell carcinoma	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Tumour haemorrhage	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Tumour pain	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Nervous system disorders
Dizziness	3/61 (4.9%)		17/130 (13.1%)		5/41 (12.2%)
Headache	8/61 (13.1%)		16/130 (12.3%)		0/41 (0%)
Dysgeusia	6/61 (9.8%)		11/130 (8.5%)		4/41 (9.8%)
Paraesthesia	9/61 (14.8%)		4/130 (3.1%)		2/41 (4.9%)
Sciatica	3/61 (4.9%)		5/130 (3.8%)		3/41 (7.3%)
Dysaesthesia	4/61 (6.6%)		1/130 (0.8%)		0/41 (0%)
Ageusia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Altered state of consciousness	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Amnesia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Aphasia	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Ataxia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Autonomic nervous system imbalance	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Balance disorder	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cervicobrachial syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cognitive disorder	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Depressed level of consciousness	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Dizziness postural	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Dysarthria	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Hyperaesthesia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypoaesthesia	1/61 (1.6%)		1/130 (0.8%)		2/41 (4.9%)
Lethargy	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Loss of consciousness	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Memory impairment	0/61 (0%)		5/130 (3.8%)		1/41 (2.4%)
Migraine	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Motor dysfunction	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Muscle contractions involuntary	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Myasthenic syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Neuropathy peripheral	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Neurotoxicity	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Peripheral motor neuropathy	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Peripheral sensory neuropathy	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Presyncope	0/61 (0%)		3/130 (2.3%)		2/41 (4.9%)
Sensorimotor disorder	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Sensory disturbance	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Somnolence	0/61 (0%)		6/130 (4.6%)		1/41 (2.4%)
Syncope	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Tremor	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Visual field defect	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Psychiatric disorders
Agitation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Anxiety	6/61 (9.8%)		3/130 (2.3%)		2/41 (4.9%)
Confusional state	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Depressed mood	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Depression	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Dyssomnia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Euphoric mood	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hallucination	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hallucination, visual	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Insomnia	4/61 (6.6%)		7/130 (5.4%)		1/41 (2.4%)
Irritability	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Mood altered	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Nervousness	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Nightmare	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Persecutory delusion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Psychomotor retardation	0/61 (0%)		0/130 (0%)		2/41 (4.9%)
Renal and urinary disorders
Acute kidney injury	0/61 (0%)		4/130 (3.1%)		1/41 (2.4%)
Cystitis noninfective	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Dysuria	0/61 (0%)		8/130 (6.2%)		1/41 (2.4%)
Haematuria	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Micturition urgency	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Oliguria	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Proteinuria	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Renal injury	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Renal vein occlusion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Urinary incontinence	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Urinary retention	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Reproductive system and breast disorders
Amenorrhoea	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Breast pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Genital discomfort	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Genital erythema	1/61 (1.6%)		0/130 (0%)		1/41 (2.4%)
Haematospermia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pelvic pain	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Scrotal haematocoele	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Scrotal oedema	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Asthma	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Atelectasis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Bronchospasm	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Cough	5/61 (8.2%)		9/130 (6.9%)		3/41 (7.3%)
Dry throat	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Dysphonia	1/61 (1.6%)		5/130 (3.8%)		1/41 (2.4%)
Dyspnoea	4/61 (6.6%)		26/130 (20%)		6/41 (14.6%)
Dyspnoea exertional	1/61 (1.6%)		4/130 (3.1%)		1/41 (2.4%)
Epistaxis	2/61 (3.3%)		8/130 (6.2%)		2/41 (4.9%)
Hiccups	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypoventilation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hypoxia	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Lung disorder	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Nasal disorder	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Nasal oedema	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Nocturnal dyspnoea	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Oropharyngeal pain	1/61 (1.6%)		4/130 (3.1%)		3/41 (7.3%)
Orthopnoea	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pharyngeal inflammation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pharyngeal ulceration	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pleural effusion	1/61 (1.6%)		4/130 (3.1%)		0/41 (0%)
Pneumonitis	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Productive cough	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pulmonary embolism	1/61 (1.6%)		2/130 (1.5%)		2/41 (4.9%)
Rales	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Respiratory disorder	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Respiratory failure	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Rhinalgia	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rhinitis allergic	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Rhinorrhoea	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Throat irritation	1/61 (1.6%)		1/130 (0.8%)		0/41 (0%)
Wheezing	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Skin and subcutaneous tissue disorders
Rash	5/61 (8.2%)		46/130 (35.4%)		18/41 (43.9%)
Dermatitis acneiform	0/61 (0%)		47/130 (36.2%)		9/41 (22%)
Pruritus	1/61 (1.6%)		17/130 (13.1%)		7/41 (17.1%)
Erythema	2/61 (3.3%)		14/130 (10.8%)		4/41 (9.8%)
Skin fissures	0/61 (0%)		17/130 (13.1%)		2/41 (4.9%)
Alopecia	2/61 (3.3%)		13/130 (10%)		4/41 (9.8%)
Rash maculo-papular	0/61 (0%)		12/130 (9.2%)		6/41 (14.6%)
Dry skin	1/61 (1.6%)		11/130 (8.5%)		3/41 (7.3%)
Eczema	0/61 (0%)		8/130 (6.2%)		1/41 (2.4%)
Acne	0/61 (0%)		4/130 (3.1%)		3/41 (7.3%)
Decubitus ulcer	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Dermatitis	0/61 (0%)		3/130 (2.3%)		1/41 (2.4%)
Dermatitis exfoliative	0/61 (0%)		2/130 (1.5%)		2/41 (4.9%)
Diffuse alopecia	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Drug eruption	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Erythrosis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Haemorrhage subcutaneous	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Hair growth abnormal	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hirsutism	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Hyperhidrosis	2/61 (3.3%)		2/130 (1.5%)		0/41 (0%)
Hyperkeratosis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Ingrowing nail	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Intertrigo	1/61 (1.6%)		4/130 (3.1%)		0/41 (0%)
Nail bed inflammation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Nail discolouration	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Nail disorder	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Night sweats	2/61 (3.3%)		0/130 (0%)		0/41 (0%)
Onycholysis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pain of skin	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/61 (0%)		6/130 (4.6%)		0/41 (0%)
Papule	0/61 (0%)		3/130 (2.3%)		0/41 (0%)
Petechiae	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Photosensitivity reaction	2/61 (3.3%)		3/130 (2.3%)		0/41 (0%)
Pigmentation disorder	0/61 (0%)		1/130 (0.8%)		1/41 (2.4%)
Prurigo	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Pruritus generalised	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Psoriasis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rash erythematous	0/61 (0%)		4/130 (3.1%)		2/41 (4.9%)
Rash generalised	0/61 (0%)		5/130 (3.8%)		1/41 (2.4%)
Rash macular	0/61 (0%)		2/130 (1.5%)		1/41 (2.4%)
Rash morbilliform	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rash papular	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Rash pruritic	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Rosacea	1/61 (1.6%)		2/130 (1.5%)		1/41 (2.4%)
Scab	1/61 (1.6%)		2/130 (1.5%)		0/41 (0%)
Seborrhoeic dermatitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Skin burning sensation	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Skin erosion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Skin exfoliation	1/61 (1.6%)		4/130 (3.1%)		1/41 (2.4%)
Skin irritation	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Skin lesion	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Skin mass	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Skin reaction	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Skin ulcer	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Solar dermatitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Stasis dermatitis	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Swelling face	0/61 (0%)		4/130 (3.1%)		0/41 (0%)
Toxic skin eruption	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Urticaria	0/61 (0%)		2/130 (1.5%)		0/41 (0%)
Vascular disorders
Capillary leak syndrome	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Deep vein thrombosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Diastolic hypertension	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Flushing	2/61 (3.3%)		1/130 (0.8%)		1/41 (2.4%)
Haematoma	2/61 (3.3%)		1/130 (0.8%)		0/41 (0%)
Hot flush	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Hypertension	2/61 (3.3%)		21/130 (16.2%)		6/41 (14.6%)
Hypotension	3/61 (4.9%)		4/130 (3.1%)		2/41 (4.9%)
Lymphoedema	2/61 (3.3%)		11/130 (8.5%)		3/41 (7.3%)
Pelvic venous thrombosis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Peripheral coldness	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Peripheral ischaemia	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Peripheral venous disease	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Phlebitis	0/61 (0%)		0/130 (0%)		1/41 (2.4%)
Thrombophlebitis	0/61 (0%)		1/130 (0.8%)		0/41 (0%)
Vascular compression	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Vena cava thrombosis	1/61 (1.6%)		0/130 (0%)		0/41 (0%)
Venous thrombosis limb	0/61 (0%)		1/130 (0.8%)		0/41 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.