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

• ClinicalTrials.gov Identifier: NCT00864253
• Recruitment Status: Completed
• First Posted: March 18, 2009
• Results First Posted: June 5, 2014
• Last Update Posted: October 30, 2019
• Sponsor: Celgene
• Collaborator: University of Arizona
• Information provided by (Responsible Party): Celgene

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Malignant Melanoma
• Interventions: Drug: ABI-007; Drug: Dacarbazine
• Enrollment: 529

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 Details	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 [1]	207 [1]
Not Completed	99	58
Reason Not Completed
Adverse Event	56	11
Unrelated Adverse Event	3	1
Physician Decision	11	15
Protocol Violation	0	2
Lost to Follow-up	1	1
Withdrawal by Subject	18	18
Death	1	0
Ongoing	2	3
Untreated	7	7
[1] Completed = defined as discontinuation due to progressive disease

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 Number of Baseline Participants		264	265	529
Baseline Analysis Population Description		Intent-to-Treat (ITT) Population: The ITT population consisted of all randomized participants regardless of whether the participant received any study drug or had any efficacy assessments collected.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	264 participants	265 participants	529 participants
		62.0; (21 to 85)	64.0; (28 to 87)	63.0; (21 to 87)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	264 participants	265 participants	529 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 [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	264 participants	265 participants	529 participants
0 = Fully Active		195	181	376
1= Restrictive but Ambulatory		68	82	150
2 = Ambulatory but Unable to Work		1	2	3
3 = Limited Self-Care		0	0	0
4 = Completely Disabled		0	0	0
		[1] Measure Description: ECOG-Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
Baseline Lactate Dehydrogenase value [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	264 participants	265 participants	529 participants
<0.8 * Upper Limit of Normal (ULN)		138	139	277
0.8-1.1 * ULN		72	69	141
>1.1-2 * ULN		51	56	107
>2 * ULN		3	1	4
		[1] Measure Description: The serum level of Lactate Dehydrogenase (LDH) is considered a risk factor for overall survival in participants with metastatic melanoma. LDH is a blood test used as a general indicator of the existence and severity of acute or chronic tissue damage and used to monitor cancers such as metastatic melanoma. The baseline LDH value was considered to be the last central laboratory LDH value before randomization. If the central laboratory data was not available, the last non-missing local laboratory value before randomization was used.
Metastatic Stage [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	264 participants	265 participants	529 participants
M1a		27	21	48
M1b		66	69	135
M1c		171	175	346
		[1] Measure Description: Distant Metastatic (M) Stages: MX: Distant metastasis cannot be assessed; M0: No distant metastasis; M1= Distant metastasis; M1a: Metastasis to skin, subcutaneous tissues or distant lymph nodes; M1b: metastasis to lung; M1c: metastasis to all other visceral sites or distant metastasis at any site associated with an elevated serum lactic dehyrogenase
BRAF Status [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	264 participants	265 participants	529 participants
V 600 E		65	67	132
Wild Type (mutation negative)		116	108	224
unknown		83	90	173
		[1] Measure Description: BRAF is a mutation biomarker for melanoma, a human gene that makes the protein B-Raf. The gene is referred to as a protoco-oncogene B Raf and vRaf murine sarcoma viral oncogene homolog B1, while the protein is known as serine/threonine-protein kinase B-Raf. The protein is involved in sending signals inside cells and in directing cell growth. These BRAF mutations were associated with features of high risk melanoma, including truncal primary, earlier age of onset, lack of chronic skin damage and shortened survival. The BRAF statuses included: Wild type and V600E mutation.

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.
Overall Number of Participants Analyzed	264	265
Median (95% Confidence Interval); Unit of Measure: months
	4.8; (3.7 to 5.5)	2.5; (2.0 to 3.6)

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	[Not Specified]
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
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	264	265
Median (95% Confidence Interval); Unit of Measure: months
	12.8; (11.3 to 14.6)	10.7; (9.6 to 12.5)

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	[Not Specified]
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
	Estimation Comments	[Not Specified]

3. 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.
Overall Number of Participants Analyzed	257	258
Measure Type: Number; Unit of Measure: participants
≥1 TEAE	255	239
≥1 TEAE related to study drug	250	212
≥1 NCI CTCAE Grade (GR) 3 or above	167	117
≥1 NCI CTCAE GR 3 or above TEAE to study drug	129	71
≥1 TEAE with outcome of death	8	1
≥1 drug related TEAE with outcome of death	2	1
≥1 serious TEAE	62	54
≥1 serious TEAE related to study drug	23	17
≥1 TEAE leading to a dose reduction of study drug	81	51
≥1 related TEAE leading to dose reduction	80	49
≥1 TEAE leading to drug interruption	4	16
≥1 drug related TEAE leading to drug interruption	3	15
≥1 TEAE leading to dose delay of study drug	124	84
≥1 drug related TEAE leading to dose delay	106	77
≥1 TEAE leading to drug discontinuation	59	12
≥1 drug related TEAE leading to drug discontinuing	56	11

4. 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.
Overall Number of Participants Analyzed	257	258
Measure Type: Number; Unit of Measure: participants
Dose Reductions	81	51
Dose Interruptions	6	17
Dose Delay	145	105

5. 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.
Overall Number of Participants Analyzed	253	246
Median (Full Range); Unit of Measure: 10^9/L
	1.50; (0.1 to 20.0)	2.40; (0.0 to 13.2)

6. 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.
Overall Number of Participants Analyzed	253	246
Median (Full Range); Unit of Measure: 10^9/L
	3.00; (0.6 to 22.8)	4.10; (0.5 to 14.7)

7. 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.
Overall Number of Participants Analyzed	252	246
Median (Full Range); Unit of Measure: 10^9/L
	228.5; (112 to 437)	153; (9 to 723)

8. 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.
Overall Number of Participants Analyzed	253	246
Median (Full Range); Unit of Measure: g/L
	109.0; (65.0 to 137)	122.0; (65 to 161)

9. Secondary Outcome

Title	Pharmacokinetic Parameters
Description	[Not Specified]
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.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

10. 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.
Overall Number of Participants Analyzed	264	265
Median (95% Confidence Interval); Unit of Measure: months
	3.7; (3.1 to 3.9)	2.1; (1.9 to 2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.086
	Comments	[Not Specified]
	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
	Estimation Comments	[Not Specified]

11. 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.
Overall Number of Participants Analyzed	264	265
Measure Type: Number; Unit of Measure: percentage of participants
Complete Response (CR)	0	0
Partial Response (PR)	15	11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.239
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Response Rate Ratio
	Estimated Value	1.305
	Confidence Interval	(2-Sided) 95%; 0.837 to 2.035
	Estimation Comments	[Not Specified]

12. 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.
Overall Number of Participants Analyzed	264	265
Measure Type: Number; Unit of Measure: percent of participants
	39	27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.004
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Response Rate Ratio
	Estimated Value	1.442
	Confidence Interval	(2-Sided) 95%; 1.123 to 1.582
	Estimation Comments	[Not Specified]

13. 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.
Overall Number of Participants Analyzed	39	30
Median (95% Confidence Interval); Unit of Measure: months
	11.1 [1]; (7.3 to NA)	16.4; (11.0 to 21.8)

[1]

NA = not estimable (ie., the upper bound of survival curve lies above 0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ABI-007 150mg/m^2, Dacarbazine 1000mg/m^2
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.057
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.201
	Confidence Interval	(2-Sided) 95%; 0.959 to 5.053
	Estimation Comments	[Not Specified]

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
Adverse Event Reporting Description	[Not Specified]
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 (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	ABI-007 Arm A	Dacarbazine Arm B
	Affected / at Risk (%)	Affected / at Risk (%)
Total	62/257 (24.12%)	54/258 (20.93%)
Blood and lymphatic system disorders
Febrile neutropenia † 1	3/257 (1.17%)	1/258 (0.39%)
Anaemia † 1	1/257 (0.39%)	2/258 (0.78%)
Neutropenia † 1	0/257 (0.00%)	1/258 (0.39%)
Pancytopenia † 1	0/257 (0.00%)	1/258 (0.39%)
Cardiac disorders
Angina pectoris † 1	1/257 (0.39%)	2/258 (0.78%)
Atrial fibrillation † 1	1/257 (0.39%)	2/258 (0.78%)
Atrial flutter † 1	1/257 (0.39%)	0/258 (0.00%)
Cardio-respiratory arrest † 1	1/257 (0.39%)	0/258 (0.00%)
Acute myocardial infarction † 1	0/257 (0.00%)	2/258 (0.78%)
Palpitations † 1	0/257 (0.00%)	1/258 (0.39%)
Eye disorders
Maculopathy † 1	1/257 (0.39%)	0/258 (0.00%)
Diplopia † 1	0/257 (0.00%)	1/258 (0.39%)
Gastrointestinal disorders
Small intestinal obstruction † 1	3/257 (1.17%)	1/258 (0.39%)
Vomiting † 1	2/257 (0.78%)	2/258 (0.78%)
Nausea † 1	2/257 (0.78%)	1/258 (0.39%)
Diarrhoea † 1	1/257 (0.39%)	1/258 (0.39%)
Abdominal pain lower † 1	1/257 (0.39%)	0/258 (0.00%)
Abdominal pain upper † 1	1/257 (0.39%)	0/258 (0.00%)
Ascites † 1	1/257 (0.39%)	0/258 (0.00%)
Ileus † 1	1/257 (0.39%)	0/258 (0.00%)
Colitis † 1	0/257 (0.00%)	1/258 (0.39%)
Pancreatitis † 1	0/257 (0.00%)	1/258 (0.39%)
General disorders
Pyrexia † 1	2/257 (0.78%)	5/258 (1.94%)
General physical health deterioration † 1	1/257 (0.39%)	1/258 (0.39%)
Death † 1	1/257 (0.39%)	0/258 (0.00%)
Extravasation † 1	1/257 (0.39%)	0/258 (0.00%)
Fatigue † 1	1/257 (0.39%)	0/258 (0.00%)
Implant site thrombosis † 1	1/257 (0.39%)	0/258 (0.00%)
Oedema † 1	1/257 (0.39%)	0/258 (0.00%)
Asthenia † 1	0/257 (0.00%)	1/258 (0.39%)
Non-cardiac chest pain 0 1 † 1	0/257 (0.00%)	1/258 (0.39%)
Hepatobiliary disorders
Cholelithiasis † 1	1/257 (0.39%)	0/258 (0.00%)
Hepatic function abnormal † 1	1/257 (0.39%)	0/258 (0.00%)
Bile duct obstruction † 1	0/257 (0.00%)	1/258 (0.39%)
Immune system disorders
Hypersensitivity † 1	0/257 (0.00%)	2/258 (0.78%)
Infections and infestations
Pneumonia † 1	4/257 (1.56%)	1/258 (0.39%)
Cellulitis † 1	3/257 (1.17%)	4/258 (1.55%)
Erysipelas † 1	3/257 (1.17%)	0/258 (0.00%)
Urinary tract infection † 1	3/257 (1.17%)	0/258 (0.00%)
Device related infection † 1	1/257 (0.39%)	1/258 (0.39%)
Neutropenic sepsis † 1	1/257 (0.39%)	1/258 (0.39%)
Sepsis † 1	1/257 (0.39%)	1/258 (0.39%)
Anal abscess † 1	1/257 (0.39%)	0/258 (0.00%)
Bronchitis † 1	1/257 (0.39%)	0/258 (0.00%)
Respiratory tract infection † 1	1/257 (0.39%)	0/258 (0.00%)
Septic shock † 1	1/257 (0.39%)	0/258 (0.00%)
Skin infection † 1	1/257 (0.39%)	0/258 (0.00%)
Streptococcal bacteraemia † 1	1/257 (0.39%)	0/258 (0.00%)
Swine influenza † 1	1/257 (0.39%)	0/258 (0.00%)
Wound infection † 1	1/257 (0.39%)	0/258 (0.00%)
Catheter related infection † 1	0/257 (0.00%)	1/258 (0.39%)
Clostridium difficile colitis † 1	0/257 (0.00%)	1/258 (0.39%)
Escherichia bacteraemia † 1	0/257 (0.00%)	1/258 (0.39%)
Infected skin ulcer † 1	0/257 (0.00%)	1/258 (0.39%)
Osteomyelitis † 1	0/257 (0.00%)	1/258 (0.39%)
Injury, poisoning and procedural complications
Fall † 1	1/257 (0.39%)	0/258 (0.00%)
Muscle strain † 1	0/257 (0.00%)	1/258 (0.39%)
Traumatic brain injury † 1	0/257 (0.00%)	1/258 (0.39%)
Metabolism and nutrition disorders
Dehydration † 1	1/257 (0.39%)	0/258 (0.00%)
Hypocalcaemia † 1	1/257 (0.39%)	0/258 (0.00%)
Hypokalaemia † 1	1/257 (0.39%)	0/258 (0.00%)
Hypomagnesaemia † 1	1/257 (0.39%)	0/258 (0.00%)
Musculoskeletal and connective tissue disorders
Pathological fracture † 1	1/257 (0.39%)	1/258 (0.39%)
Lumbar spinal stenosis † 1	1/257 (0.39%)	0/258 (0.00%)
Pain in extremity † 1	1/257 (0.39%)	0/258 (0.00%)
Arthralgia † 1	0/257 (0.00%)	1/258 (0.39%)
Back pain † 1	0/257 (0.00%)	1/258 (0.39%)
Osteoporotic fracture † 1	0/257 (0.00%)	1/258 (0.39%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemorrhagic tumour necrosis † 1	1/257 (0.39%)	0/258 (0.00%)
Tumour pain † 1	0/257 (0.00%)	2/258 (0.78%)
Nervous system disorders
Peripheral motor neuropathy † 1	2/257 (0.78%)	0/258 (0.00%)
Peripheral sensory neuropathy † 1	2/257 (0.78%)	0/258 (0.00%)
Cerebrovascular accident † 1	1/257 (0.39%)	1/258 (0.39%)
Syncope † 1	1/257 (0.39%)	1/258 (0.39%)
Aphasia † 1	1/257 (0.39%)	0/258 (0.00%)
Cerebral haematoma † 1	1/257 (0.39%)	0/258 (0.00%)
Dizziness † 1	1/257 (0.39%)	0/258 (0.00%)
Haemorrhage intracranial † 1	1/257 (0.39%)	0/258 (0.00%)
Neuropathy peripheral † 1	1/257 (0.39%)	0/258 (0.00%)
Subarachnoid haemorrhage † 1	1/257 (0.39%)	0/258 (0.00%)
Transient ischaemic attack † 1	1/257 (0.39%)	0/258 (0.00%)
Ataxia † 1	0/257 (0.00%)	1/258 (0.39%)
Cerebrovascular stenosis † 1	0/257 (0.00%)	1/258 (0.39%)
Haemorrhagic stroke † 1	0/257 (0.00%)	1/258 (0.39%)
Hemiparesis † 1	0/257 (0.00%)	1/258 (0.39%)
Monoplegia † 1	0/257 (0.00%)	1/258 (0.39%)
Presyncope † 1	0/257 (0.00%)	1/258 (0.39%)
Spinal cord compression † 1	0/257 (0.00%)	1/258 (0.39%)
Psychiatric disorders
Anxiety † 1	1/257 (0.39%)	0/258 (0.00%)
Completed suicide † 1	1/257 (0.39%)	0/258 (0.00%)
Renal and urinary disorders
Haematuria † 1	1/257 (0.39%)	0/258 (0.00%)
Renal failure acute † 1	1/257 (0.39%)	0/258 (0.00%)
Urinary retention † 1	1/257 (0.39%)	0/258 (0.00%)
Renal pain † 1	0/257 (0.00%)	1/258 (0.39%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	1/257 (0.39%)	1/258 (0.39%)
Pulmonary embolism † 1	1/257 (0.39%)	1/258 (0.39%)
Haemoptysis † 1	0/257 (0.00%)	2/258 (0.78%)
Skin and subcutaneous tissue disorders
Urticaria † 1	0/257 (0.00%)	1/258 (0.39%)
Vascular disorders
Deep vein thrombosis † 1	1/257 (0.39%)	0/258 (0.00%)
Hypotension † 1	1/257 (0.39%)	0/258 (0.00%)
Orthostatic hypotension † 1	1/257 (0.39%)	0/258 (0.00%)
Venous thrombosis † 1	0/257 (0.00%)	1/258 (0.39%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 12.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	ABI-007 Arm A	Dacarbazine Arm B
	Affected / at Risk (%)	Affected / at Risk (%)
Total	253/257 (98.44%)	232/258 (89.92%)
Blood and lymphatic system disorders
Neutropenia † 1	66/257 (25.68%)	63/258 (24.42%)
Anaemia † 1	39/257 (15.18%)	28/258 (10.85%)
Leukopenia † 1	31/257 (12.06%)	23/258 (8.91%)
Thrombocytopenia † 1	1/257 (0.39%)	43/258 (16.67%)
Eye disorders
Vision blurred † 1	19/257 (7.39%)	6/258 (2.33%)
Lacrimation increased † 1	17/257 (6.61%)	4/258 (1.55%)
Gastrointestinal disorders
Nausea † 1	104/257 (40.47%)	130/258 (50.39%)
Diarrhoea † 1	103/257 (40.08%)	45/258 (17.44%)
Constipation † 1	83/257 (32.30%)	89/258 (34.50%)
Vomiting † 1	53/257 (20.62%)	56/258 (21.71%)
Abdominal pain † 1	34/257 (13.23%)	28/258 (10.85%)
Dyspepsia † 1	24/257 (9.34%)	20/258 (7.75%)
Stomatitis † 1	18/257 (7.00%)	8/258 (3.10%)
Abdominal pain upper † 1	17/257 (6.61%)	14/258 (5.43%)
General disorders
Fatigue † 1	134/257 (52.14%)	110/258 (42.64%)
Oedema peripheral † 1	54/257 (21.01%)	24/258 (9.30%)
Asthenia † 1	39/257 (15.18%)	28/258 (10.85%)
Pyrexia † 1	32/257 (12.45%)	30/258 (11.63%)
Mucosal inflammation † 1	20/257 (7.78%)	13/258 (5.04%)
Pain † 1	20/257 (7.78%)	10/258 (3.88%)
Chills † 1	12/257 (4.67%)	15/258 (5.81%)
Infusion site pain † 1	2/257 (0.78%)	13/258 (5.04%)
Infections and infestations
Upper respiratory tract infection † 1	18/257 (7.00%)	13/258 (5.04%)
Nasopharyngitis † 1	14/257 (5.45%)	10/258 (3.88%)
Investigations
Weight decreased † 1	16/257 (6.23%)	10/258 (3.88%)
Metabolism and nutrition disorders
Decreased appetite † 1	68/257 (26.46%)	52/258 (20.16%)
Hypokalaemia † 1	13/257 (5.06%)	10/258 (3.88%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	48/257 (18.68%)	24/258 (9.30%)
Myalgia † 1	44/257 (17.12%)	10/258 (3.88%)
Pain in extremity † 1	33/257 (12.84%)	20/258 (7.75%)
Back pain † 1	24/257 (9.34%)	26/258 (10.08%)
Muscular weakness † 1	16/257 (6.23%)	5/258 (1.94%)
Musculoskeletal pain † 1	16/257 (6.23%)	16/258 (6.20%)
Nervous system disorders
Neuropathy peripheral † 1	98/257 (38.13%)	6/258 (2.33%)
Dysgeusia † 1	62/257 (24.12%)	24/258 (9.30%)
Peripheral sensory neuropathy † 1	52/257 (20.23%)	9/258 (3.49%)
Headache † 1	42/257 (16.34%)	38/258 (14.73%)
Paraesthesia † 1	41/257 (15.95%)	8/258 (3.10%)
Dizziness † 1	32/257 (12.45%)	30/258 (11.63%)
Psychiatric disorders
Insomnia † 1	42/257 (16.34%)	31/258 (12.02%)
Anxiety † 1	16/257 (6.23%)	19/258 (7.36%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	59/257 (22.96%)	33/258 (12.79%)
Dyspnoea † 1	39/257 (15.18%)	38/258 (14.73%)
Epistaxis † 1	34/257 (13.23%)	5/258 (1.94%)
Oropharyngeal pain † 1	17/257 (6.61%)	9/258 (3.49%)
Skin and subcutaneous tissue disorders
Alopecia † 1	177/257 (68.87%)	9/258 (3.49%)
Rash † 1	72/257 (28.02%)	18/258 (6.98%)
Nail disorder † 1	52/257 (20.23%)	2/258 (0.78%)
Pruritus † 1	31/257 (12.06%)	17/258 (6.59%)
Dry skin † 1	24/257 (9.34%)	5/258 (1.94%)
Erythema † 1	16/257 (6.23%)	5/258 (1.94%)
Photosensitivity reaction † 1	3/257 (1.17%)	13/258 (5.04%)
Vascular disorders
Flushing † 1	8/257 (3.11%)	16/258 (6.20%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 12.1

Limitations and 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

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Anne McClain
• Organization: Celgene Corporation
• Phone: 888-260-1599
• EMail: clinicaltrialdisclosure@celgene.com

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 Submitted: March 16, 2009
• First Posted: March 18, 2009
• Results First Submitted: April 16, 2014
• Results First Posted: June 5, 2014
• Last Update Posted: October 30, 2019