A Trial of ABI-007 Versus Dacarbazine in Previously Untreated Patients With Metastatic Malignant Melanoma

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00864253
• Collaborator: University of Arizona (Other)
• Enrollment: 529
• Locations: 112
• Arms: 2
• Actual Duration (Months): 57.7
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The main purpose of this research study is to compare the safety, tolerability, and anti tumor activity of an investigational drug, ABI-007 versus Dacarbazine in patients with metastatic melanoma who have not previously received chemotherapy. ABI-007 is a new preparation of the active drug paclitaxel. It contains the same medication as the prescription chemotherapy drug Abraxane®. Abraxane® is approved by the FDA for the treatment of metastatic breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Dacarbazine is approved by the FDA for the treatment of melanoma. In this study, ABI-007 and Dacarbazine will be tested as therapy for people who have not yet had any cancer treatment for the diagnosis of metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: ABI-007; Drug: Dacarbazine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 529 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Phase III Trial of ABI-007 vs Dacarbazine in Previously Untreated Patients With Metastatic Malignant Melanoma
• Actual Study Start Date: Apr 23, 2009
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Feb 12, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ABI-007 Treatment Arm A (ABI-007): Patients who receive ABI-007 will be dosed intravenously over approximately 30 minutes without steroid pre-medication and without G-CSF prophylaxis (unless modified as described below). ABI-007 150 mg/m2 will be administered on Days 1, 8, and 15 every 4 weeks.	Drug: ABI-007; Patients who receive ABI-007 will be dosed intravenously over approximately 30 minutes without steroid pre-medication and without G-CSF prophylaxis (unless modified as described below). ABI-007 150 mg/m2 will be administered on Days 1, 8, and 15 every 4 weeks.; Other Names: Abraxane
Active Comparator: Dacarbazine Treatment Arm B (dacarbazine): Patients who receive dacarbazine will be dosed intravenously at 1000 mg/m2 on Day 1 with steroid and antiemetic pre-medication. Treatment will be repeated every 21 days.	Drug: Dacarbazine; Patients who receive dacarbazine will be dosed intravenously at 1000 mg/m2 on Day 1 with steroid and antiemetic pre-medication. Treatment will be repeated every 21 days.; Other Names: Dtic-Dome, DTIC-Dome

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Based on a Blinded Radiology Assessment of Response Using Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines [Response assessment completed every 8 weeks until disease progression for up to 106 weeks; data cut off 30 June 2012]

   PFS was defined as the time from the randomization date to the start of disease progression or patient death, whichever occurred first. Participants who did not have disease progression or had not died were censored at the last known time that the patient was progression free. In the event of palliative radiotherapy or surgery, they were censored at the last assessment where they were documented to be progression-free prior to the date of radiotherapy or surgery. In follow up, participants who began new anticancer therapy prior to documented progression were censored at the last assessment where they were documented as progression free. Those with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where they were documented to be progression free. RECIST defines progressive disease as a ≥ 20% increase taking as reference the smallest sum of the longest diameters recorded since the treatment began.

Secondary Outcome Measures

1. Participant Survival [Up to 38 months; Up to data cut off of 30 June 2012]

   Survival was defined as the time from the date of randomization to the date of death (any cause). Participants were censored at the last known time that they were alive.

2. Summary of Treatment-emergent Adverse Events (AEs) [Maximum exposure to study drug was 106 weeks; up to data cut off of 30 June 2012]

   A Treatment Emergent AE (TEAE) was any AE that began or worsened after the start of the study drug through 30 days after the last dose of study drug or end of study whichever is later. A treatment related toxicity was one considered by the investigator to be possibly, probably or definitely related to study drug. AE's were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V 3.0 criteria and the following scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life threatening, and Grade 5 = Death A SAE is any untoward medical occurrence at any dose that is fatal or life threatening, results in persistent or significant disability or incapacity; requires prolonged hospitalizations; is a congenital anomaly birth defect in the offspring of a patient, and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.

3. Number of Participants Experiencing Dose Reductions, or Dose Interruptions, or Dose Delays of Study Drug [Maximum study drug exposure 106 weeks; data cut off 30 June 2012]

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

4. Nadir for the Absolute Neutrophil Count (ANC) Measurements [Day 1 up to 106 weeks; up to data cut off 30 June 2012]

   Maximal degree of myelosuppression during study drug dosing was represented by the nadir in ANC measurements over all treatment cycles.

5. Nadir for White Blood Cells (WBCs) Measurements [Day 1 up to 106 weeks; up to data cut off 30 June 2012]

   Maximal degree of myelosuppression was represented by the nadir in white blood cells (WBCs) count measurements over all treatment cycles.

6. Nadir for Platelet Count Measurements. [Day 1 up to 106 weeks; up to data cut off 30 June 2012]

   Maximal degree of myelosuppression was represented by the nadir in platelet count measurements over all treatment cycles.

7. Nadir for the Hemoglobin Count Measurements [Day 1 up to 106 weeks; up to data cut off 30 June 2012]

   Maximal degree of myelosuppression during study drug dosing was represented by the nadir in hemoglobin count measurements over all treatment cycles.

8. Pharmacokinetic Parameters [On Cycle 1, Day 1 blood samples were taken at 0.25, 3.5, and 24 hr post-infusion end of the initial dose]

Other Outcome Measures

1. Progression-free Survival (PFS) Based on Investigator Assessment Using RECIST Response Guidelines [Response assessments completed every 8 weeks until disease progression; up to data cut off 30 June 2012; 38 months]

   PFS was defined as the time from the randomization date to the start of disease progression or patient death, whichever occurred first. Participants who did not have disease progression or had not died were censored at the last known time that the patient was progression free. In the event of palliative radiotherapy or surgery, they were censored at the last assessment where they were documented to be progression-free prior to the date of radiotherapy or surgery. In follow up, patients who began new anticancer therapy prior to documented progression were censored at the last assessment where they were documented as progression free. Those with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where they were documented to be progression free.

2. Percent of Participants Who Achieve an Objective Confirmed Complete or Partial Response Based on Blinded Radiology Assessment of Response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 [every 8 weeks; up to data cut off 30 June 2012]

   RECIST defines complete response (CR): The disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. Disappearance of all non-target lesions. The normalization of tumor marker level confirmed at least 4 weeks after initial documentation. Partial response (PR): At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits.

3. Percent of Participants With Stable Disease (SD) for ≥ 16 Weeks, or Confirmed Complete or Partial Response (i.e., Disease Control) Based on a Blinded Radiology Assessment of Response [Response assessment completed every 8 weeks until disease progression; up to data cut-off 30 June 2012]

   Disease control is stable disease (SD) for >=16 weeks + complete response (CR) + partial response (PR). See Outcome #4 for definitions of CR and PR. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions.

4. Duration of Response (DOR) in Responding Participants [up to data cut off 30 June 2012]

   Duration of response (DOR) as measured by PFS based on radiological review for participants who achieved an objective confirmed response of CR or PR. DOR was defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or participants death from any cause, whichever occurred first. Participants that did not have progression or had not died were censored at the last known time the participant was progression free. Participants that had initiated other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Complete response (CR) and partial response (PR) are defined in outcome #4. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed cutaneous malignant melanoma with evidence of metastasis (Stage IV).

• No prior cytotoxic chemotherapy for metastatic malignant melanoma is permitted. Prior treatment with kinase inhibitors or cytokines is permitted.

• No prior adjuvant cytotoxic chemotherapy is permitted. Prior adjuvant therapy with interferon, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or vaccines is permitted.

• Male or non-pregnant and non-lactating female, and ≥ 18 years of age. If a female patient is of child-bearing potential, as evidenced by regular menstrual periods, she must have a negative serum pregnancy test Beta human chorionic gonadotropin (ß-hCG) within 72 hours prior to first study drug administration. If sexually active, the patient must agree to utilize contraception considered adequate and appropriate by the investigator.

• No other current active malignancy within the past 3 years.

• Radiographically-documented measurable disease (defined by the presence of at least 1 radiographically documented measurable lesion

• Patient has the following blood counts at Baseline:

• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 cells/L;

• platelets ≥ 100 x 10^9 cells/L;

• Hemoglobin (Hgb) ≥ 9 g/dL.

• Patient has the following blood chemistry levels at Baseline:

• Aspartate aminotransferase(AST) glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≤ 2.5x upper limit of normal range (ULN); ≤ 5.0 xULN if hepatic metastases present;

• total bilirubin ≤ ULN;

• creatinine ≤ 1.5 mg/dL.

• Lactate Dehydrogenase (LDH) ≤ 2.0 x ULNa

• Expected survival of > 12 weeks.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

• Patient or his/her legally authorized representative or guardian has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent form prior to participation in any study-related activities.

Exclusion Criteria:

• History of or current evidence of brain metastases, including leptomeningeal involvement.

• Patient has pre-existing peripheral neuropathy of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Scale of Grade ≥ 2.

• Prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed.

• Patient has a clinically significant concurrent illness.

• Patient is, in the investigator's opinion, unlikely to be able to complete the study through the End of Study (EOS) visit.

• Patient is currently enrolled, or will enroll in a different clinical study in which investigational therapeutic procedures are performed or investigational therapies are administered while participating in this study. Marker studies or studies evaluating biological correlates are permitted.

• Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35243
2	AZ Cancer Ctr	Scottsdale	Arizona	United States	85258
3	Arizona Cancer Center	Tucson	Arizona	United States	85724
4	Genesis Cancer Ctr - Hot Springs	Hot Springs	Arkansas	United States	71913
5	University of Arkansa for Medical Sciences	Little Rock	Arkansas	United States	72205
6	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
7	San Diego Pacific Oncology and Hematology Associates	Encinitas	California	United States	92024
8	Loma Linda University Cancer Center	Loma Linda	California	United States	92354
9	University of Southern California/Norris Cancer Center	Los Angeles	California	United States	90033
10	University of CA Los Angeles	Los Angeles	California	United States	90095
11	St. Mary's Medical Center	San Francisco	California	United States	94117
12	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
13	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
14	Lakeland Regional Cancer Center	Lakeland	Florida	United States	33805
15	University of Miami Hospital and Clincs/SCCC	Miami	Florida	United States	33136
16	Waren Billhartz Cancer Center	Maryville	Illinois	United States	62062
17	Indiana University	Indianapolis	Indiana	United States	46202
18	IA Blood and Cancer Care, PLC	Cedar Rapids	Iowa	United States	52402
19	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
20	Wayne State University	Detroit	Michigan	United States	48201
21	University of Minnesota	Minneapolis	Minnesota	United States	55455
22	Saint Louis University	Saint Louis	Missouri	United States	63110
23	St. John's Medical Research	Springfield	Missouri	United States	65807
24	Nevada Cancer Institute	Las Vegas	Nevada	United States	89135
25	Atlantic Melanoma Center	Morristown	New Jersey	United States	07962
26	Piedmont Hematology	Winston-Salem	North Carolina	United States	27103
27	OH State University Arthur G. James Cancer Hospital	Columbus	Ohio	United States	43210
28	Integris Cancer Institute of OK	Oklahoma City	Oklahoma	United States	73142
29	St. Luke's Hospital & Health Network	Bethlehem	Pennsylvania	United States	18015
30	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19131
31	Mary Crowley Research Center	Dallas	Texas	United States	75246
32	Univ of TX MD Anderson Cancer Ctr	Houston	Texas	United States	77030
33	Univ of TX Med School at Houston	Houston	Texas	United States	77030
34	Covenant Health System DBA Joe Arrington Cancer Research and Treatment Center	Lubbock	Texas	United States	79410
35	Hope Oncology	Richardson	Texas	United States	75080
36	Utah Cancer Specialist	Salt Lake City	Utah	United States	84106
37	Univ. of Washington Medical Center/Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
38	Evergreen Hematology & Oncology	Spokane	Washington	United States	99218
39	Port Macquarie Base Hospital	Port Macquarie	New South Wales	Australia	2444
40	Royal North Shore Hospital	Sydney	New South Wales	Australia	2065
41	Sydney West Cancer Trials Centre/Westmead Hospital	Westmead	New South Wales	Australia	2145
42	Royal Adelaide Hospital, Department of Medical Oncology	Adelaide	South Australia	Australia	5000
43	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
44	Alfred Hospital	Melbourne	Victoria	Australia	3004
45	Sir Charles Gairdner Hospital	Nedlands Perth	Western Australia	Australia
46	Royal Perth Hospital	Perth	Western Australia	Australia	6000
47	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
48	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
49	BCCA Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
50	BCCA, Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
51	BC Cancer Agency-Fraser Valley Ctr.	Surrey	British Columbia	Canada	V3V 1Z2
52	BC Cancer Agency-Vancouver	Vancouver	British Columbia	Canada	V5Z4E6
53	BC Cancer Agency-Vancouver Island Ctr.	Victoria	British Columbia	Canada	V8R 6V5
54	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
55	Credit Valley Hospital	Missiauga	Ontario	Canada	L5M 2N1
56	The Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
57	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
58	McGill University Dept. of Oncology Clinical Research Program	Montreal	Quebec	Canada	H2W 1S6
59	Hopital Saint Andre' CHU de Bordeaux	Bordeaux		France	33075
60	Centre Hospitaller Universitaire de Grenoble	Grenoble Cedex 09		France	38043
61	CHRU Hopital Claude Huriez	Lile Cedax		France
62	Hopital Dypuytren-CHU de Limoges	Limoges cedex		France
63	Centre Leon Berad	Lyon		France
64	Hopital Sainte Marguerite	Marseille Cedex 9		France
65	CHU Hopital Saint Eloi	Montepellier Cedex 5		France
66	Centre Regional Val d' Aurelle Paul Lamarque	Montpellier		France	34298
67	Hopital de 1 Archet 2	Nice Cedex 3		France	06200
68	Hopital Saint-Louis	Paris Cedex		France
69	Hopital Bichat	Paris		France	75018
70	Groupe hospitalier Cochin-St. Vincent de Paul	Paris		France
71	Institut Gustave Roussy (IGR) Centre de Lutte Contre le Canc	Villejuif Cedex		France	94805
72	Charite Universitaetsmedizin Berlin	Berlin	BE	Germany	10117
73	Universitaetsklinkum Heidelberg	Heidelberg	BW	Germany
74	Universitaetsklinkum Heidelberg	Heidelber	BW	Germany
75	Universitaetsklinkum Tuebingen	Tuebingen	BW	Germany	72076
76	Universitaetsklinkum Wuerzburg PS	Wuerzburg	BY	Germany	97080
77	Universitaetsklinkum Hamburg-Eppendorf	Hamburg	HH	Germany
78	Univeritaetsklinkum Goettingen	Gottington	NI	Germany
79	Medizinische Hochschuke Hannover	Hannover	NI	Germany	30625
80	St. Josef-Hospital	Bochum	Northwest	Germany	44791
81	Universitaetsklinkum Essen	Essen	Northwest	Germany
82	Universitaetklinkum Koeln	Koln	Northwest	Germany
83	Universitaetsklinkum Schegwig-Holstein	Keil	SH	Germany	24105
84	Universitaetsklinkum Dresden	Dresden	SN	Germany
85	UniversitawtsklinKum Jena	Jena	Strasse 35	Germany	07743
86	Universitaesklinkum Leipzig	Leipzig		Germany
87	Universitaetsklinkum Mainz	Mainz		Germany
88	Istituto Tumori "Giovanni Paolo II"	Bari	BA	Italy
89	Istituto Scientifico Romagnolo per lo Studio e la Cura dei T	Meldola	FC	Italy	47014
90	IST-Istituto Nazionale per la Ricera sul Cancro	Genova	GE	Italy	16132
91	Istituto Europeo di Oncologia	Milano	MI	Italy	20141
92	Istituto Nazionale Tumori	Milano	MI	Italy
93	IOV-Instituto Oncologico IRCCS	Padova	PD	Italy	35128
94	Azienda Ospedaliera Universitaria Sense	Siena	SI	Italy	53100
95	Ist. Naz. per lo studio e la cura dei tumori G. Pascale	Napoli		Italy	80131
96	Ospedale S. Chiara	Pisa		Italy	56100
97	Medisch Centrum Alkmaar	Alkmaar		Netherlands	1815
98	Rijnstate ziekenhuis Arnhem	Amhem		Netherlands	6800TA
99	Erasmus MC ae" Daniel den Hoed	Rotterdam		Netherlands
100	H Clinic i Provincial	Barcelona		Spain	08036
101	H CLINIC I Provincial	Barcelona		Spain
102	H Clinico San Carlos	Madrid		Spain
103	Corporacion Sanitaria Parc Tauli	Sabadell		Spain	08208
104	Broomfield Hospital	Chelmsford	Essex	United Kingdom	CM1 7ET
105	Velindre Hospital	Cardiff	Glam	United Kingdom	CF14 2TL
106	St. George's Hospital	London	GT Lon	United Kingdom	SW12 ORE
107	Nottingham University Hospitals NHS Trust	Nottingham	Nott	United Kingdom	NG5 1PB
108	Singleton Hospital, Sothwest Wales Inst.	Swansea	S Glam	United Kingdom	SA28QA
109	Univ Hospital of North Staffordshire	Stroke On Kent	Staffs	United Kingdom	ST4 6QB
110	Weston Park Hospital	Sheffield	Syorks	United Kingdom	S10 2SJ
111	Newcross Hospital	Wolverhampton	Wstmid	United Kingdom	SV10 0QP
112	Royal Marsden Hospital London	London		United Kingdom	SW3 6JJ

Sponsors and Collaborators

• Celgene
• University of Arizona

Investigators

• Principal Investigator: Evan Hersh, MD, University of Arizona
• Study Director: Ileana Elias, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

• Hersh EM, Del Vecchio M, Brown MP, Kefford R, Loquai C, Testori A, Bhatia S, Gutzmer R, Conry R, Haydon A, Robert C, Ernst S, Homsi J, Grob JJ, Kendra K, Agarwala SS, Li M, Clawson A, Brachmann C, Karnoub M, Elias I, Renschler MF, Hauschild A. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol. 2015 Nov;26(11):2267-74. doi: 10.1093/annonc/mdv324. Epub 2015 Sep 26.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00864253
• Other Study ID Numbers: CA033
• First Posted: Mar 18, 2009
• Last Update Posted: Oct 30, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Celgene: Melanoma; Malignant; Abraxane; ABI-007; Dacarbazine; Dtic-Dome
• Additional relevant MeSH terms: Melanoma; Albumin-Bound Paclitaxel; Dacarbazine

Study Results

Participant Flow

Recruitment Details	This multicenter study was conducted by investigators in 9 countries: Australia, Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom and the United States (US) and treatment was given on an outpatient basis. First participant enrolled 30 April 2011, last participant enrolled June 2011..
Pre-assignment Detail	Participants were randomized in a 1:1 ratio. Randomization was stratified based on metastatic stage (M1a, M1b, and M1c), region (North America, Western Europe and Australia), and baseline lactate dehydrogenase (LDH) (< 0.8 * ULN, 0.8-1.1 * ULN, >1.1-2 * ULN).

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Period Title: Overall Study
STARTED	264	265
Treated	257	258
COMPLETED	165	207
NOT COMPLETED	99	58

Baseline Characteristics

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine Arm B 1000mg/m^2	Total
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.	Total of all reporting groups
Overall Participants	264	265	529
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62.0 (13.44)	64.0 (12.06)	63.0 (12.85)
Sex: Female, Male (Count of Participants)
Female	91 34.5%	91 34.3%	182 34.4%
Male	173 65.5%	174 65.7%	347 65.6%
Eastern Cooperative Oncology Group Performance Status (participants) [Number]
0 = Fully Active	195 73.9%	181 68.3%	376 71.1%
1= Restrictive but Ambulatory	68 25.8%	82 30.9%	150 28.4%
2 = Ambulatory but Unable to Work	1 0.4%	2 0.8%	3 0.6%
3 = Limited Self-Care	0 0%	0 0%	0 0%
4 = Completely Disabled	0 0%	0 0%	0 0%
Baseline Lactate Dehydrogenase value (participants) [Number]
<0.8 * Upper Limit of Normal (ULN)	138 52.3%	139 52.5%	277 52.4%
0.8-1.1 * ULN	72 27.3%	69 26%	141 26.7%
>1.1-2 * ULN	51 19.3%	56 21.1%	107 20.2%
>2 * ULN	3 1.1%	1 0.4%	4 0.8%
Metastatic Stage (participants) [Number]
M1a	27 10.2%	21 7.9%	48 9.1%
M1b	66 25%	69 26%	135 25.5%
M1c	171 64.8%	175 66%	346 65.4%
BRAF Status (participants) [Number]
V 600 E	65 24.6%	67 25.3%	132 25%
Wild Type (mutation negative)	116 43.9%	108 40.8%	224 42.3%
unknown	83 31.4%	90 34%	173 32.7%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) Based on a Blinded Radiology Assessment of Response Using Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines
Description	PFS was defined as the time from the randomization date to the start of disease progression or patient death, whichever occurred first. Participants who did not have disease progression or had not died were censored at the last known time that the patient was progression free. In the event of palliative radiotherapy or surgery, they were censored at the last assessment where they were documented to be progression-free prior to the date of radiotherapy or surgery. In follow up, participants who began new anticancer therapy prior to documented progression were censored at the last assessment where they were documented as progression free. Those with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where they were documented to be progression free. RECIST defines progressive disease as a ≥ 20% increase taking as reference the smallest sum of the longest diameters recorded since the treatment began.
Time Frame	Response assessment completed every 8 weeks until disease progression for up to 106 weeks; data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Intent to treat population = The ITT population consisted of all randomized participants regardless of whether the participant received any study drug or had any efficacy assessments collected.

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 every 4 weeks	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	264	265
Median (95% Confidence Interval) [months]	4.8	2.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	Two hundred fifty-seven (257) patients were to be randomized to each treatment group for a total of 514 patients. This sample size was chosen to provide at least 80% power for the final analysis (with a two-sided type I error of 0.049) to reject the null hypothesis that the ABI 007/dacarbazine hazard ratio (HR) for PFS is equal to 1.0. This sample size calculation was based on estimates of HR = 0.750. Proportional hazards were assumed.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	An interim safety review was performed by DMC. An alpha spending function was utilized to preserve the overall Type 1 error at 0.050. The spending function allocated alpha of 0.001 and 0.049 to the interim and final analyses of PFS, respectively.
	Method	Log Rank
	Comments	The treatment difference was tested using the stratified log-rank test, stratified by metastatic stage, region, and baseline LDH.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.792
	Confidence Interval	(2-Sided) 95.1%; 0.631 to 0.992
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Participant Survival
Description	Survival was defined as the time from the date of randomization to the date of death (any cause). Participants were censored at the last known time that they were alive.
Time Frame	Up to 38 months; Up to data cut off of 30 June 2012

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	264	265
Median (95% Confidence Interval) [months]	12.8	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	For the participant survival, at the time at least 417 events are recorded, this sample size provides at least 80% power with a two-sided Type 1 error of 0.049 to reject the null hypothesis that the ABI-007/dacarbazine hazard ratio is equal to 1.0. This was based on a HR = 0.760. Proportional hazards were assumed.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.094
	Comments	At the time of the final PFS analysis, an interim analysis of survival was reported. The spending function allocated an alpha of 0.001 and 0.049 for the interim and final analysis, respectively, to preserve the overall Type I error at 0.050.
	Method	Log Rank
	Comments	The treatment difference was tested using the stratified log-rank test, stratified by metastatic stage, region, and baseline LDH.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.831
	Confidence Interval	(2-Sided) 99.9%; 0.578 to 1.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Other Pre-specified Outcome

Title	Progression-free Survival (PFS) Based on Investigator Assessment Using RECIST Response Guidelines
Description	PFS was defined as the time from the randomization date to the start of disease progression or patient death, whichever occurred first. Participants who did not have disease progression or had not died were censored at the last known time that the patient was progression free. In the event of palliative radiotherapy or surgery, they were censored at the last assessment where they were documented to be progression-free prior to the date of radiotherapy or surgery. In follow up, patients who began new anticancer therapy prior to documented progression were censored at the last assessment where they were documented as progression free. Those with two or more missing response assessments prior to a visit with documented disease progression (or death) were censored at the last visit where they were documented to be progression free.
Time Frame	Response assessments completed every 8 weeks until disease progression; up to data cut off 30 June 2012; 38 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	264	265
Median (95% Confidence Interval) [months]	3.7	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments
	Method	Log Rank
	Comments	The treatment difference was tested using the stratified log-rank test, stratified by metastatic stage, region, and baseline LDH.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.845
	Confidence Interval	(2-Sided) 95%; 0.696 to 1.025
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Other Pre-specified Outcome

Title	Percent of Participants Who Achieve an Objective Confirmed Complete or Partial Response Based on Blinded Radiology Assessment of Response by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0
Description	RECIST defines complete response (CR): The disappearance of all known disease and no new sites or disease related symptoms confirmed at least 4 weeks after initial documentation. All sites must be assessed, including non-measurable sites, such as effusions, or markers. Disappearance of all non-target lesions. The normalization of tumor marker level confirmed at least 4 weeks after initial documentation. Partial response (PR): At least a 30% decrease in the sum of the longest diameters of target lesions, taking as a reference the baseline sum of the longest diameters confirmed at least 4 weeks after initial documentation. PR is also recorded when all measurable disease has completely disappeared, but a non-measurable component (i.e., ascites) is still present but not progressing. As well as persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits.
Time Frame	every 8 weeks; up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	264	265
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	15 5.7%	11 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Response Rate Ratio
	Estimated Value	1.305
	Confidence Interval	(2-Sided) 95%; 0.837 to 2.035
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Percent of Participants With Stable Disease (SD) for ≥ 16 Weeks, or Confirmed Complete or Partial Response (i.e., Disease Control) Based on a Blinded Radiology Assessment of Response
Description	Disease control is stable disease (SD) for >=16 weeks + complete response (CR) + partial response (PR). See Outcome #4 for definitions of CR and PR. RECIST defines SD for target lesions as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, no occurrence of progression disease for non-target lesions, and no new lesions.
Time Frame	Response assessment completed every 8 weeks until disease progression; up to data cut-off 30 June 2012

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	264	265
Number [percent of participants]	39 14.8%	27 10.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Response Rate Ratio
	Estimated Value	1.442
	Confidence Interval	(2-Sided) 95%; 1.123 to 1.582
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Duration of Response (DOR) in Responding Participants
Description	Duration of response (DOR) as measured by PFS based on radiological review for participants who achieved an objective confirmed response of CR or PR. DOR was defined as progression-free survival in responders, i.e. as the time between the start of a complete response (CR) or partial response (PR) and the start of progressive disease (PD) or participants death from any cause, whichever occurred first. Participants that did not have progression or had not died were censored at the last known time the participant was progression free. Participants that had initiated other anticancer therapy prior to progression were censored at the time when new anticancer therapy was initiated. Complete response (CR) and partial response (PR) are defined in outcome #4. Progressive disease was defined as at least a 20% increase in the sum of the longest diameters of target lesions; or the appearance of one or more new lesions; or the unequivocal progression of a non-target lesion.
Time Frame	up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

ITT of participants with a confirmed complete or partial overall response

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	39	30
Median (95% Confidence Interval) [months]	11.1	16.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.057
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.201
	Confidence Interval	(2-Sided) 95%; 0.959 to 5.053
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Summary of Treatment-emergent Adverse Events (AEs)
Description	A Treatment Emergent AE (TEAE) was any AE that began or worsened after the start of the study drug through 30 days after the last dose of study drug or end of study whichever is later. A treatment related toxicity was one considered by the investigator to be possibly, probably or definitely related to study drug. AE's were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V 3.0 criteria and the following scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life threatening, and Grade 5 = Death A SAE is any untoward medical occurrence at any dose that is fatal or life threatening, results in persistent or significant disability or incapacity; requires prolonged hospitalizations; is a congenital anomaly birth defect in the offspring of a patient, and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.
Time Frame	Maximum exposure to study drug was 106 weeks; up to data cut off of 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated Population = The Treated population consisted of all randomized participants who received at least one dose of study drug

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	257	258
≥1 TEAE	255 96.6%	239 90.2%
≥1 TEAE related to study drug	250 94.7%	212 80%
≥1 NCI CTCAE Grade (GR) 3 or above	167 63.3%	117 44.2%
≥1 NCI CTCAE GR 3 or above TEAE to study drug	129 48.9%	71 26.8%
≥1 TEAE with outcome of death	8 3%	1 0.4%
≥1 drug related TEAE with outcome of death	2 0.8%	1 0.4%
≥1 serious TEAE	62 23.5%	54 20.4%
≥1 serious TEAE related to study drug	23 8.7%	17 6.4%
≥1 TEAE leading to a dose reduction of study drug	81 30.7%	51 19.2%
≥1 related TEAE leading to dose reduction	80 30.3%	49 18.5%
≥1 TEAE leading to drug interruption	4 1.5%	16 6%
≥1 drug related TEAE leading to drug interruption	3 1.1%	15 5.7%
≥1 TEAE leading to dose delay of study drug	124 47%	84 31.7%
≥1 drug related TEAE leading to dose delay	106 40.2%	77 29.1%
≥1 TEAE leading to drug discontinuation	59 22.3%	12 4.5%
≥1 drug related TEAE leading to drug discontinuing	56 21.2%	11 4.2%

8. Secondary Outcome

Title	Number of Participants Experiencing Dose Reductions, or Dose Interruptions, or Dose Delays of Study Drug
Description	The number of participants with dose reductions, dose interruptions and dose delays that occurred during the treatment period. Dose reductions, interruptions and delays are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.
Time Frame	Maximum study drug exposure 106 weeks; data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated population

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	257	258
Dose Reductions	81 30.7%	51 19.2%
Dose Interruptions	6 2.3%	17 6.4%
Dose Delay	145 54.9%	105 39.6%

9. Secondary Outcome

Title	Nadir for the Absolute Neutrophil Count (ANC) Measurements
Description	Maximal degree of myelosuppression during study drug dosing was represented by the nadir in ANC measurements over all treatment cycles.
Time Frame	Day 1 up to 106 weeks; up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated Population = consisted of all randomized participants who received at least one dose of study drug and with at least one post-baseline central laboratory result were included

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	253	246
Median (Full Range) [10^9/L]	1.50 (1.591)	2.40 (1.694)

10. Secondary Outcome

Title	Nadir for White Blood Cells (WBCs) Measurements
Description	Maximal degree of myelosuppression was represented by the nadir in white blood cells (WBCs) count measurements over all treatment cycles.
Time Frame	Day 1 up to 106 weeks; up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated population = consisted of all randomized participants who received at least one dose of study drug and with at least one post-baseline central laboratory result were included

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	253	246
Median (Full Range) [10^9/L]	3.00 (1.934)	4.10 (1.968)

11. Secondary Outcome

Title	Nadir for Platelet Count Measurements.
Description	Maximal degree of myelosuppression was represented by the nadir in platelet count measurements over all treatment cycles.
Time Frame	Day 1 up to 106 weeks; up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated population = consisted of all randomized participants who received at least one dose of study drug and with at least one post-baseline central laboratory result were included

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine Arm B
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	252	246
Median (Full Range) [10^9/L]	228.5 (71.40)	153 (92.01)

12. Secondary Outcome

Title	Nadir for the Hemoglobin Count Measurements
Description	Maximal degree of myelosuppression during study drug dosing was represented by the nadir in hemoglobin count measurements over all treatment cycles.
Time Frame	Day 1 up to 106 weeks; up to data cut off 30 June 2012

Outcome Measure Data

Analysis Population Description

Treated population = consisted of all randomized participants who received at least one dose of study drug and with at least one post-baseline central laboratory result were included.

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	253	246
Median (Full Range) [g/L]	109.0	122.0

13. Secondary Outcome

Title	Pharmacokinetic Parameters
Time Frame	On Cycle 1, Day 1 blood samples were taken at 0.25, 3.5, and 24 hr post-infusion end of the initial dose

Outcome Measure Data

Analysis Population Description

Patients randomized to receive ABI-007 treatment in Australia, Canada, Europe, United Kingdom and United States had the option to participate in sparse PK sampling in this study. Only 44 participants consented to participate, an insufficient number to support the planned population PK analysis hence these analyses were not performed

Arm/Group Title	ABI-007 150mg/m^2	Dacarbazine 1000mg/m^2
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle	Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
Measure Participants	0	0

Adverse Events

Time Frame	Any adverse event (AE) that started at any time from the time the signing of the informed consent to 30 days after the last dose of study drug or End of Study was followed and reported; maximum drug exposure 106 weeks
Arm/Group Title	ABI-007 Arm A		Dacarbazine Arm B
Arm/Group Description	ABI-007 150mg/m^2 intravenously over approximately 30 minutes on Days 1, 8 and 15 of each 28 day cycle		Dacarbazine 1000mg/m^2 intravenously over approximately 30-60 minutes on Day 1 of each 21 day cycle.
All Cause Mortality
	ABI-007 Arm A		Dacarbazine Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ABI-007 Arm A		Dacarbazine Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/257 (24.1%)		54/258 (20.9%)
Blood and lymphatic system disorders
Febrile neutropenia	3/257 (1.2%)		1/258 (0.4%)
Anaemia	1/257 (0.4%)		2/258 (0.8%)
Neutropenia	0/257 (0%)		1/258 (0.4%)
Pancytopenia	0/257 (0%)		1/258 (0.4%)
Cardiac disorders
Angina pectoris	1/257 (0.4%)		2/258 (0.8%)
Atrial fibrillation	1/257 (0.4%)		2/258 (0.8%)
Atrial flutter	1/257 (0.4%)		0/258 (0%)
Cardio-respiratory arrest	1/257 (0.4%)		0/258 (0%)
Acute myocardial infarction	0/257 (0%)		2/258 (0.8%)
Palpitations	0/257 (0%)		1/258 (0.4%)
Eye disorders
Maculopathy	1/257 (0.4%)		0/258 (0%)
Diplopia	0/257 (0%)		1/258 (0.4%)
Gastrointestinal disorders
Small intestinal obstruction	3/257 (1.2%)		1/258 (0.4%)
Vomiting	2/257 (0.8%)		2/258 (0.8%)
Nausea	2/257 (0.8%)		1/258 (0.4%)
Diarrhoea	1/257 (0.4%)		1/258 (0.4%)
Abdominal pain lower	1/257 (0.4%)		0/258 (0%)
Abdominal pain upper	1/257 (0.4%)		0/258 (0%)
Ascites	1/257 (0.4%)		0/258 (0%)
Ileus	1/257 (0.4%)		0/258 (0%)
Colitis	0/257 (0%)		1/258 (0.4%)
Pancreatitis	0/257 (0%)		1/258 (0.4%)
General disorders
Pyrexia	2/257 (0.8%)		5/258 (1.9%)
General physical health deterioration	1/257 (0.4%)		1/258 (0.4%)
Death	1/257 (0.4%)		0/258 (0%)
Extravasation	1/257 (0.4%)		0/258 (0%)
Fatigue	1/257 (0.4%)		0/258 (0%)
Implant site thrombosis	1/257 (0.4%)		0/258 (0%)
Oedema	1/257 (0.4%)		0/258 (0%)
Asthenia	0/257 (0%)		1/258 (0.4%)
Non-cardiac chest pain 0 1	0/257 (0%)		1/258 (0.4%)
Hepatobiliary disorders
Cholelithiasis	1/257 (0.4%)		0/258 (0%)
Hepatic function abnormal	1/257 (0.4%)		0/258 (0%)
Bile duct obstruction	0/257 (0%)		1/258 (0.4%)
Immune system disorders
Hypersensitivity	0/257 (0%)		2/258 (0.8%)
Infections and infestations
Pneumonia	4/257 (1.6%)		1/258 (0.4%)
Cellulitis	3/257 (1.2%)		4/258 (1.6%)
Erysipelas	3/257 (1.2%)		0/258 (0%)
Urinary tract infection	3/257 (1.2%)		0/258 (0%)
Device related infection	1/257 (0.4%)		1/258 (0.4%)
Neutropenic sepsis	1/257 (0.4%)		1/258 (0.4%)
Sepsis	1/257 (0.4%)		1/258 (0.4%)
Anal abscess	1/257 (0.4%)		0/258 (0%)
Bronchitis	1/257 (0.4%)		0/258 (0%)
Respiratory tract infection	1/257 (0.4%)		0/258 (0%)
Septic shock	1/257 (0.4%)		0/258 (0%)
Skin infection	1/257 (0.4%)		0/258 (0%)
Streptococcal bacteraemia	1/257 (0.4%)		0/258 (0%)
Swine influenza	1/257 (0.4%)		0/258 (0%)
Wound infection	1/257 (0.4%)		0/258 (0%)
Catheter related infection	0/257 (0%)		1/258 (0.4%)
Clostridium difficile colitis	0/257 (0%)		1/258 (0.4%)
Escherichia bacteraemia	0/257 (0%)		1/258 (0.4%)
Infected skin ulcer	0/257 (0%)		1/258 (0.4%)
Osteomyelitis	0/257 (0%)		1/258 (0.4%)
Injury, poisoning and procedural complications
Fall	1/257 (0.4%)		0/258 (0%)
Muscle strain	0/257 (0%)		1/258 (0.4%)
Traumatic brain injury	0/257 (0%)		1/258 (0.4%)
Metabolism and nutrition disorders
Dehydration	1/257 (0.4%)		0/258 (0%)
Hypocalcaemia	1/257 (0.4%)		0/258 (0%)
Hypokalaemia	1/257 (0.4%)		0/258 (0%)
Hypomagnesaemia	1/257 (0.4%)		0/258 (0%)
Musculoskeletal and connective tissue disorders
Pathological fracture	1/257 (0.4%)		1/258 (0.4%)
Lumbar spinal stenosis	1/257 (0.4%)		0/258 (0%)
Pain in extremity	1/257 (0.4%)		0/258 (0%)
Arthralgia	0/257 (0%)		1/258 (0.4%)
Back pain	0/257 (0%)		1/258 (0.4%)
Osteoporotic fracture	0/257 (0%)		1/258 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemorrhagic tumour necrosis	1/257 (0.4%)		0/258 (0%)
Tumour pain	0/257 (0%)		2/258 (0.8%)
Nervous system disorders
Peripheral motor neuropathy	2/257 (0.8%)		0/258 (0%)
Peripheral sensory neuropathy	2/257 (0.8%)		0/258 (0%)
Cerebrovascular accident	1/257 (0.4%)		1/258 (0.4%)
Syncope	1/257 (0.4%)		1/258 (0.4%)
Aphasia	1/257 (0.4%)		0/258 (0%)
Cerebral haematoma	1/257 (0.4%)		0/258 (0%)
Dizziness	1/257 (0.4%)		0/258 (0%)
Haemorrhage intracranial	1/257 (0.4%)		0/258 (0%)
Neuropathy peripheral	1/257 (0.4%)		0/258 (0%)
Subarachnoid haemorrhage	1/257 (0.4%)		0/258 (0%)
Transient ischaemic attack	1/257 (0.4%)		0/258 (0%)
Ataxia	0/257 (0%)		1/258 (0.4%)
Cerebrovascular stenosis	0/257 (0%)		1/258 (0.4%)
Haemorrhagic stroke	0/257 (0%)		1/258 (0.4%)
Hemiparesis	0/257 (0%)		1/258 (0.4%)
Monoplegia	0/257 (0%)		1/258 (0.4%)
Presyncope	0/257 (0%)		1/258 (0.4%)
Spinal cord compression	0/257 (0%)		1/258 (0.4%)
Psychiatric disorders
Anxiety	1/257 (0.4%)		0/258 (0%)
Completed suicide	1/257 (0.4%)		0/258 (0%)
Renal and urinary disorders
Haematuria	1/257 (0.4%)		0/258 (0%)
Renal failure acute	1/257 (0.4%)		0/258 (0%)
Urinary retention	1/257 (0.4%)		0/258 (0%)
Renal pain	0/257 (0%)		1/258 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/257 (0.4%)		1/258 (0.4%)
Pulmonary embolism	1/257 (0.4%)		1/258 (0.4%)
Haemoptysis	0/257 (0%)		2/258 (0.8%)
Skin and subcutaneous tissue disorders
Urticaria	0/257 (0%)		1/258 (0.4%)
Vascular disorders
Deep vein thrombosis	1/257 (0.4%)		0/258 (0%)
Hypotension	1/257 (0.4%)		0/258 (0%)
Orthostatic hypotension	1/257 (0.4%)		0/258 (0%)
Venous thrombosis	0/257 (0%)		1/258 (0.4%)
Other (Not Including Serious) Adverse Events
	ABI-007 Arm A		Dacarbazine Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	253/257 (98.4%)		232/258 (89.9%)
Blood and lymphatic system disorders
Neutropenia	66/257 (25.7%)		63/258 (24.4%)
Anaemia	39/257 (15.2%)		28/258 (10.9%)
Leukopenia	31/257 (12.1%)		23/258 (8.9%)
Thrombocytopenia	1/257 (0.4%)		43/258 (16.7%)
Eye disorders
Vision blurred	19/257 (7.4%)		6/258 (2.3%)
Lacrimation increased	17/257 (6.6%)		4/258 (1.6%)
Gastrointestinal disorders
Nausea	104/257 (40.5%)		130/258 (50.4%)
Diarrhoea	103/257 (40.1%)		45/258 (17.4%)
Constipation	83/257 (32.3%)		89/258 (34.5%)
Vomiting	53/257 (20.6%)		56/258 (21.7%)
Abdominal pain	34/257 (13.2%)		28/258 (10.9%)
Dyspepsia	24/257 (9.3%)		20/258 (7.8%)
Stomatitis	18/257 (7%)		8/258 (3.1%)
Abdominal pain upper	17/257 (6.6%)		14/258 (5.4%)
General disorders
Fatigue	134/257 (52.1%)		110/258 (42.6%)
Oedema peripheral	54/257 (21%)		24/258 (9.3%)
Asthenia	39/257 (15.2%)		28/258 (10.9%)
Pyrexia	32/257 (12.5%)		30/258 (11.6%)
Mucosal inflammation	20/257 (7.8%)		13/258 (5%)
Pain	20/257 (7.8%)		10/258 (3.9%)
Chills	12/257 (4.7%)		15/258 (5.8%)
Infusion site pain	2/257 (0.8%)		13/258 (5%)
Infections and infestations
Upper respiratory tract infection	18/257 (7%)		13/258 (5%)
Nasopharyngitis	14/257 (5.4%)		10/258 (3.9%)
Investigations
Weight decreased	16/257 (6.2%)		10/258 (3.9%)
Metabolism and nutrition disorders
Decreased appetite	68/257 (26.5%)		52/258 (20.2%)
Hypokalaemia	13/257 (5.1%)		10/258 (3.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	48/257 (18.7%)		24/258 (9.3%)
Myalgia	44/257 (17.1%)		10/258 (3.9%)
Pain in extremity	33/257 (12.8%)		20/258 (7.8%)
Back pain	24/257 (9.3%)		26/258 (10.1%)
Muscular weakness	16/257 (6.2%)		5/258 (1.9%)
Musculoskeletal pain	16/257 (6.2%)		16/258 (6.2%)
Nervous system disorders
Neuropathy peripheral	98/257 (38.1%)		6/258 (2.3%)
Dysgeusia	62/257 (24.1%)		24/258 (9.3%)
Peripheral sensory neuropathy	52/257 (20.2%)		9/258 (3.5%)
Headache	42/257 (16.3%)		38/258 (14.7%)
Paraesthesia	41/257 (16%)		8/258 (3.1%)
Dizziness	32/257 (12.5%)		30/258 (11.6%)
Psychiatric disorders
Insomnia	42/257 (16.3%)		31/258 (12%)
Anxiety	16/257 (6.2%)		19/258 (7.4%)
Respiratory, thoracic and mediastinal disorders
Cough	59/257 (23%)		33/258 (12.8%)
Dyspnoea	39/257 (15.2%)		38/258 (14.7%)
Epistaxis	34/257 (13.2%)		5/258 (1.9%)
Oropharyngeal pain	17/257 (6.6%)		9/258 (3.5%)
Skin and subcutaneous tissue disorders
Alopecia	177/257 (68.9%)		9/258 (3.5%)
Rash	72/257 (28%)		18/258 (7%)
Nail disorder	52/257 (20.2%)		2/258 (0.8%)
Pruritus	31/257 (12.1%)		17/258 (6.6%)
Dry skin	24/257 (9.3%)		5/258 (1.9%)
Erythema	16/257 (6.2%)		5/258 (1.9%)
Photosensitivity reaction	3/257 (1.2%)		13/258 (5%)
Vascular disorders
Flushing	8/257 (3.1%)		16/258 (6.2%)

Limitations/Caveats

Participation in the PK sampling for participants randomized to the ABI-007 arm was optional; too few samples were available to support the analysis

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Certain Agreements

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

Institution may publish the results of its findings if a multicenter publication is not forthcoming within 18 months after study completion. Institution shall provide Celgene with a copy of the papers prior to submission; Celgene shall complete its review within 60 days. Institution shall review comments from Celgene. Upon Celgene's request, proposed publication will be delayed up to 60 additional days to allow Celgene to secure adequate intellectual property protection of patentable material.