Dacarbazine and Ipilimumab vs. Dacarbazine With Placebo in Untreated Unresectable Stage III or IV Melanoma

Melanoma Clinical Trial

Official title:

A Multi-center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients With Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg Ipilimumab (MDX-010) vs. Dacarbazine With Placebo

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00324155
• Other study ID #: CA184-024
• Status: Completed
• Phase: Phase 3
• First received: May 8, 2006
• Last updated: October 24, 2014
• Start date: August 2006
• Est. completion date: October 2013

Study information

• Verified date: October 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this clinical research study is to examine the safety and effectiveness (how well the drug works) of two different treatments for patients with melanoma. One treatment is an investigational compound (a drug that is not currently approved by the United States Food and Drug Administration [FDA]), know as Ipilimumab (also known as MDX-010 or BMS-734016) together with an approved chemotherapy drug called Dacarbazine

Description:

For the extension phase:

Allocation: single arm study; Masking: open label; Intervention Model: Single Group

Recruitment information / eligibility

• Status: Completed
• Enrollment: 681
• Est. completion date: October 2013
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Informed Consent

• Measurable Disease

• Eastern Cooperative Oncology Group (ECOG) 0 or 1

• Lab / imaging requirements

• Neg for Human Immunodeficiency Virus (HIV), Hepatitis B (HepB), C

• Men and Women > 18 years (16 were allowable)

• Prior therapy restriction (adjuvant only)

Exclusion:

• Pregnant / nursing

• Inadequate contraception

• Brain metastasis

• Primary ocular or mucosal melanoma

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Ipilimumab
Intravenous solution; intravenous; 10mg/kg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24, until disease progression, unacceptable toxicity or withdrawal of consent In Maintenance phase: Only Ipilimumab: 10mg/kg, every 12 weeks will be continued until disease progression
• Placebo
Intravenous solution; intravenous; 0 mg; one dose every 3 weeks for 10 weeks then one dose every 12 weeks starting at Week 24; until disease progression, unacceptable toxicity or withdrawal of consent
• Dacarbazine
Intravenous solution; intravenous; 850 mg/m^2; one dose every 3 weeks for 22 weeks, until disease progression, unacceptable toxicity or withdrawal of consent

Locations

Country	Name	City	State
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Buenos Aires
Argentina	Local Institution	Cordoba
Argentina	Local Institution	Santa Fe
Australia	Local Institution	Box Hill	Victoria
Australia	Local Institution	Coffs Harbour	New South Wales
Australia	Local Institution	Newcastle	New South Wales
Australia	Local Institution	Port Macquarie	New South Wales
Australia	Local Institution	South Brisbane	Queensland
Austria	Local Institution	Vienna
Belgium	Local Institution	Brasschaat
Belgium	Local Institution	Brussels
Belgium	Local Institution	Edegem
Belgium	Local Institution	Gent
Brazil	Local Institution	Fortaleza	Ceara
Brazil	Local Institution	Porto Alegre	Rio Grande Do Sul
Brazil	Local Institution	Porto Alegre, Rs	Rio Grande Do Sul
Brazil	Local Institution	Sao Paulo
Canada	Local Institution	Edmonton	Alberta
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Saskatoon	Saskatchewan
Chile	Local Institution	Santiago
Czech Republic	Local Institution	Olomouc
Czech Republic	Local Institution	Praha
France	Local Institution	Bordeaux
France	Local Institution	Brest	Cedex
France	Local Institution	Marseille
France	Local Institution	Nantes	Cedex 1
France	Local Institution	Paris
France	Local Institution	Pierre Benite
France	Local Institution	Saint Etienne	Cedex 2
France	Local Institution	Villejuif
Germany	Local Institution	Berlin
Germany	Local Institution	Heidelberg
Germany	Local Institution	Jena
Germany	Local Institution	Kiel
Germany	Local Institution	Mannheim
Germany	Local Institution	Muenchen
Germany	Local Institution	Tubingen
Hungary	Local Institution	Kaposyar
Ireland	Local Institution	Cork
Ireland	Local Institution	Dublin	Dublin 4
Ireland	Local Institution	Galway
Israel	Local Institution	Jerusalem
Israel	Local Institution	Tel Aviv
Italy	Local Institution	Genova
Italy	Local Institution	Milano
Italy	Local Institution	Napoli
Italy	Local Institution	Padova
Italy	Local Institution	Ragusa
Italy	Local Institution	Rome
Italy	Local Institution	Siena
Netherlands	Local Institution	Eindhoven
Netherlands	Local Institution	Hv Amsterdam
Netherlands	Local Institution	Wurzburg
Norway	Local Institution	Montebello	Oslo
Poland	Local Institution	Gdansk
Poland	Local Institution	Lodz
Poland	Local Institution	Lublin
Poland	Local Institution	Poznan
Poland	Local Institution	Wroclaw
Portugal	Local Institution	Lisboa
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Murmansk
Russian Federation	Local Institution	Pyatigorsk	Stavropol
Russian Federation	Local Institution	Ryazan
Russian Federation	Local Institution	Samara
Russian Federation	Local Institution	St Petersburg
Russian Federation	Local Institution	St.-Petersburg
Russian Federation	Local Institution	Stavropol
South Africa	Local Institution	Cape Town	Western Cape
South Africa	Local Institution	Groenkloof	Gauteng
South Africa	Local Institution	Johannesburg
South Africa	Local Institution	Port Elizabeth	Eastern Cape
South Africa	Local Institution	Pretoria	Gauteng
South Africa	Local Institution	Saxonworld	Gauteng
Spain	Local Institution	Barcelona
Spain	Local Institution	Canarias
Spain	Local Institution	Valencia
Spain	Local Institution	Zaragoza
Switzerland	Local Institution	Basel
Switzerland	Local Institution	Geneva
Ukraine	Local Institution	Cherkassy
Ukraine	Local Institution	Dnepropetrovsk
Ukraine	Local Institution	Lviv
Ukraine	Local Institution	Uzhgorod
United Kingdom	Local Institution	Bristol	Avon
United Kingdom	Local Institution	Chelmsford	Essex
United Kingdom	Local Institution	Guildford	Surrey
United Kingdom	Local Institution	London	Greater London
United Kingdom	Local Institution	Poole	Dorset
United Kingdom	Local Institution	Wirral	Merseyside
United States	University Of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Pacific Cancer Medical Center	Anaheim	California
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Sinai Hospital Of Baltimore	Baltimore	Maryland
United States	St. Luke'S Hospital & Health Network	Bethlehem	Pennsylvania
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Blumenthal Cancer Center	Charlotte	North Carolina
United States	University Of Chicago	Chicago	Illinois
United States	Ellis Fischel Cancer Center	Columbia	Missouri
United States	Central Indiana Cancer Centers	Fishers	Indiana
United States	Saint Francis Hospital And Medical Center	Hartford	Connecticut
United States	Kentucky Cancer Clinic	Hazard	Kentucky
United States	Hutchinson Clinic, Pa	Hutchinson	Kansas
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Cancer Specialists Of North Florida Beaches	Jacksonville	Florida
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Wilshire Oncology Medical Group Inc	La Verne	California
United States	The Angeles Clinic And Research Institute	Los Angeles	California
United States	Joe Arrington Cancer Research And Treatment Center	Lubbock	Texas
United States	Lowcountry Hematology & Oncology, Pa	Mount Pleasant	South Carolina
United States	Vanderbilt-Ingram Cancer Ctr	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mid-Illinois Hematology/Oncology Associates, Ltd.	Normal	Illinois
United States	Orlando Health, Inc. M.D. Anderson Cancer Center Orlando	Orlando	Florida
United States	Comprehensive Cancer Center	Palm Springs	California
United States	Oncology Specialists, Sc	Park Ridge	Illinois
United States	Hematology Oncology Associates Of The Treasure Coast	Port Saint Lucie	Florida
United States	Providence Portland Medical Center	Portland	Oregon
United States	Virginia Cancer Institute	Richmond	Virginia
United States	St Joseph Oncology Inc	Saint Joseph	Missouri
United States	Sharp Clinical Oncology Research	San Diego	California
United States	Hematology Oncology, P.C.	Stamford	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Bristol-Myers Squibb	Medarex

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  Czech Republic,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Russian Federation,  South Africa,  Spain,  Switzerland,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS was defined as the time from the date of randomization until the date of death. Analysis of OS was to be done once 416 deaths had occurred (primary endpoint). However, analysis occurred at 414 deaths (February 7, 2011), due to operational timing of the study. Median number of months of OS and associated confidence interval calculated using the method of Brookmeyer and Crowley.	Date of randomization to 37 months through 5-year follow-up and up to approximately 76 months
Secondary	Survival Rate at 1 Year, 18 Months, 2 Years, and 3 Years	The survival rate (percentage of participants alive) was defined as the probability that a participant is alive at 1 year (or 18 months, 2 years, or 3 years) following randomization and was estimated via the Kaplan-Meier method.	Date of randomization to 3 years following randomization
Secondary	Disease Control Rate (DCR)	DCR=number whose best overall response (BOR) was partial response (PR), complete response (CR) or stable disease (SD), divided by all randomized participants (unevaluable participants included). Independent review committee assessment. BOR=date of first dose to last tumor assessment prior to subsequent cancer therapy (including tumor resection, excluding palliative local radiotherapy). Modified World Health Organization criteria: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline; SD=neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD; PD=at least 25% increase in sum of products of all index lesions and/or appearance of any new lesions; nonindex lesions: appearance of any new lesions and/or unequivocal progression of nonindex lesions.	First dose to last tumor assessment prior to subsequent therapy at data cutoff for Primary Endpoint (approximately 5 years)
Secondary	Median Number of Months of Progression-free Survival (PFS)	PFS=time between randomization and date of progression or death, whichever occurs first. Participants who died without reported prior progression were considered to have progressed on date of death. For those alive and not progressed, PFS was censored on date of last evaluable tumor assessment (TA). Those who have not died and have no recorded postbaseline TA were censored at randomization. Those who died without any recorded postbaseline TA were considered to have progressed on date of death. Evaluation was conducted by both investigator and an independent review committee (IRC), who assessed radiologic imaging studies, photographs of skin lesions, and clinical data. Progressive disease defined using modified criteria of the World Health Organization: demonstration of at least a 25% increase in the sum of products of all index lesions or the appearance of any new lesions. For nonindex lesions: appearance of any new lesions or unequivocal progression of nonindex lesions.	Randomization to date of progression or death to approximately 5 years
Secondary	Progression-free Survival (PFS) Rate Truncated at Week 12	PFS rate=probability patient was progression-free at Day 78, calculated as total patients receiving treatment and with an overall response of stable disease (SD), partial response (PR), or complete response (CR) at Week 12, divided by total patients. For those alive and not progressed at or before Week 12, PFS censored on date of last evaluable tumor assessment (TA) at or before Week 12. Those with an assessment of PD prior to Week 12 and subsequent assessment of SD, PR, or CR at Week 12 were called progression-free at Week 12. Those with no recorded postbaseline TA dated on or before Day 109, and who had not died on or before Day 109, were censored at randomization. PD=at least 25% increase in sum of products of all index lesions or appearance of any new lesions. Both an investigator and independent review committee (IRC) assessed radiologic imaging studies, photographs of skin lesions, and clinical data. IRC assessment was considered primary over that of the investigators.	Day 78
Secondary	Best Overall Response Rate (BORR)	BORR=number with Best Overall Response (BOR) of complete response (CR) or partial response (PR), divided by total number of randomized patients. BOR=date of first dose to the last tumor assessment prior to subsequent cancer therapy (including tumor resection surgery but excluding palliative local radiotherapy for bone lesions). Independent review committee assessment. Modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions; no evidence of progressive disease; PR=50% or greater decrease in the sum of products of the longest diameter and greatest perpendicular diameter of all index lesions compared with baseline. Immune-related (ir) response criteria (irRC) assess tumor response in patients on immunotherapy: irCR=disappearance of all lesions in 2 consecutive observations at least 4 weeks apart; irPR=50% or greater decrease in total measureable tumor burden compared with peak in 2 observations at least 4 weeks apart.	First dose to last tumor assessment at data cutoff for primary endpoint (approximately 5 years)
Secondary	Duration of Response (DOR): Randomized Participants With Response of Complete Response (CR) or Partial Response (PR)	DOR defined in those with Best Overall Response (BOR)=CR or PR per independent review committee (IRC) as time between date of response of confirmed CR or PR, whichever occurred first, and date of PD or death. If PR assessed before CR, DOR confirmed at earlier time-point showing PR. Modified criteria of the World Health Organization (mWHO): CR=disappearance of all lesions;no evidence of PD; PR=50% or greater decrease in the sum of products of longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline. PD=an increase of 25% or greater in SPD of index lesions compared with the smallest recorded sum, or appearance of 1 or more new lesions. Immune-related response criteria (irRC): SD=50% decrease in total measurable tumor burden compared with peak cannot be established nor 25% increase compared with nadir, in absence of unequivocal progression of nonindex lesions. Unconfirmed immune-related (ir) CR, irPR, or irPD=irSD.	Day of CR or PR to day of PD or death up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Time to Response: All Randomized Participants With Response to Treatment	Time to response was defined as the time between the first dose of study therapy and the date when measurement criteria were met for Best Overall Response (BOR) of partial response (PR) or complete response (CR), whichever occurred first, per independent review committee. Note that if an overall response of PR occurred before confirmation of CR, the time to response endpoint was not determined by the time that the BOR of CR was shown but rather by the earlier time point showing PR. Modified criteria of the World Health Organization: CR=disappearance of all lesions; no evidence of progressive disease (PD); PR=50% or more decrease in the sum of products of the longest and greatest perpendicular diameters (SPD) of all index lesions compared with baseline; PD=an increase of 25% or greater in the SPD of index lesions compared with the smallest recorded sum, or the appearance of 1 or more new lesions.	First dose to date of BOR up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Duration of Stable Disease (SD): Randomized Participants With Stable Disease	Duration of SD was defined in those whose Best Overall Response (BOR) was SD, per independent review committee (IRC) as the time between Week 12 and date of progressive disease (PD) or death , whichever occurs first. For those who underwent tumor resection following Week 12 but prior to PD, duration of SD was censored on date of last evaluable tumor assessment (TA) prior to resection. For those with BOR of SD at Week 12, date of PD was used in analysis of duration of SD. For those with BOR=SD who have not subsequently progressed and who remain alive, duration of SD censored on date of last evaluable TA. Modified criteria of the World Health Organization (mWHO): SD=insufficient decrease to qualify for partial response or sufficient increase to qualify for PD; PD=an increase of 25% or more in sum of products of longest diameter and greatest perpendicular diameter of index lesions compared with smallest recorded sum, or appearance of 1 or more new lesions.	Week 12 to date of disease progression or death up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Percentage of Participants With Brain Metastasis-Free Survival at Time of Data Cutoff	Brain metastasis-free survival was defined as the time from randomization to the date of progression with a new lesion located in the brain. New brain lesions prior to Week 12 constituted a progression event (unlike main progression-free survival analysis). A participant who dies without documentation of a brain lesion was considered to have progressed with brain metastasis on the date of death. Participants who are free of brain metastasis were censored on the date of their last tumor assessment. An independent review committee evaluated images of participants with clinical symptoms to determine the number of those free of brain metastasis. The brain metastasis-free status was reported as a percent of participants (n/N), where n= participants with metastasis-free brains at data cutoff for the Primary Endpoint and N= randomized participants. A 2-sided Clopper and Pearson confidence interval was performed.	Date of randomization up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Number of Participants With Adverse Events (AEs), Drug-related AEs, AEs Leading to Discontinuation, Serious Adverse Events (SAEs), Drug-related SAEs, Drug-related Hypersensitivity, Immune-related AEs/SAEs, and Inflammatory AEs/SAEs	AE=any new undesirable symptom, sign, clinically significant laboratory abnormality, or medical condition occurring after starting study treatment, even if the event was not considered to be drug-related. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Randomization=Day 1; start of treatment (first dose)=Week 1. Summarization time frame is from first dose to 70 days after last dose of study at time of 414 deaths.	Week 1 (First Dose) to 70 days after last dose of study up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Number of Participants With Grade 2-3 and Grade 3-4 Immune-related Adverse Events (irAEs) With Resolution Resolved	irAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=moderate adverse events (AEs); minimal, local, or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment).	Week 1 (first dose) to 70 days after last dose up to data cutoff for primary endpoint (approximately 5 years)
Secondary	Time to Resolution of Grade 2-3, Grade 3-4 Immune-related Adverse Events (irAEs)	irAEs included the categories: gastrointestinal (GI), diarrhea, liver, endocrine, and skin. Grade 2=Moderate adverse events (AEs); minimal, local or noninvasive intervention indicated. Grade 3=severe AEs, medically significant but not immediately life-threatening. Grade 4=life-threatening consequences; urgent intervention indicated. Time to resolution is defined as improvement to Grade 1 or less or to the Grade at baseline (prior to treatment).	Week 1 (first dose) to 70 days after last dose up to database lock for primary endpoint (approximately 5 years)

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