MDX-010 Antibody, MDX-1379 Melanoma Vaccine, or MDX-010/MDX-1379 Combination Treatment for Patients With Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of MDX-010 (ipilimumab, BMS-734016) (anti-CTLA4) in combination with MDX-1379 (gp100, BMS-734019) in patients with previously treated, unresectable Stage III or IV melanoma. Survival time will be evaluated, as well as patient responses and time to disease progression. Eligible patients are those who in response to a single regimen containing interleukin-2 (IL-2), dacarbazine, and/or temozolomide, have 1) relapsed following an objective response (partial response/complete response [PR/CR]); 2) failed to demonstrate an objective response (PR/CR); or 3) could not tolerate such a regimen due to unacceptable toxicity. Patients will be randomized into one of three groups, and will receive one of the following treatments: MDX-010 alone, MDX-1379 alone, or MDX-010 in combination with MDX-1379.

Detailed Description
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Melanoma accounts for approximately 5% of all skin cancers in the United States, but it accounts for about 75% of all skin cancer deaths. In 2004, the expected prevalence of melanoma is 627,252, with about 119,178 of these cases being Stage III or IV (metastatic melanoma). First line treatments for metastatic melanoma, usually IL-2, dacarbazine and/or temozolomide, are associated with significant toxicities. MDX-010 (anti-CTLA4) antibodies are designed to keep the immune system running by blocking CTLA-4 from down-regulating T cell activation. MDX-1379 is made up of two peptides that are pieces of a bigger melanoma protein (gp100). These peptides bind to HLA-A2 which is then recognized by T cells.

Official Title
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A Randomized, Double-Blind, Multicenter Study Comparing MDX-010 Monotherapy, MDX-010 in Combination With a Melanoma Peptide Vaccine, and Melanoma Vaccine Monotherapy in HLA-A2*0201-Positive Patients With Previously Treated Unresectable Stage III or IV Melanoma

Conditions
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Melanoma, Metastases

Intervention / Treatment
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* Drug: MDX-010 (anti-CTLA4) monoclonal antibody
* Biological: MDX-1379 (gp100) Melanoma Peptide Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with malignant melanoma Measurable unresectable Stage III or IV melanoma HLA-A*0201 positive Previous treatment with & failure/relapse/inability to tolerate IL-2, dacarbazine and/or temozolomide At least 4 weeks since prior treatment Negative pregnancy Life expectancy greater than 4 months Eastern Cooperative Oncology Group (ECOG) performance of 0 or 1 Required lab values Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) negative Exclusion Criteria: Prior malignancies which the patient has not been disease free for over 5 years, except treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer Ocular melanoma Active, untreated central nervous system (CNS) metastasis Prior treatment with MDX-010 (anti-CTLA4) antibody Prior treatment with any cancer therapeutic vaccine Active autoimmune disease or history of autoimmune disease Pregnancy or nursing Hypersensitivity to Incomplete Freund's Adjuvant (IFA) (Montanide ISA-51) Underlying medical conditions deemed hazardous if treated with study drug Concomitant therapy with anti-melanoma drugs, chemotherapies, other investigational therapies, chronic use of systemic corticosteroids Unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Melanoma Peptide Vaccine (MDX-1379) (gp100) + Placebo | Biological: MDX-1379 (gp100) Melanoma Peptide Vaccine<br>* 2mL (2 subcutaneous injections of 2 mL each, 1 to each thigh), every 3 weeks for 4 doses.<br>* Other names: melanoma peptide vaccine;|
| Experimental: 2<br>MDX-010 (ipilimumab) + MDX-1379 (gp100) (Melanoma Peptide Vaccine) | Drug: MDX-010 (anti-CTLA4) monoclonal antibody<br>* 3mg/kg (intravenous [iv] infusion over 90 minutes), every 3 weeks for 4 doses<br>* Other names: ipilimumab;Biological: MDX-1379 (gp100) Melanoma Peptide Vaccine<br>* 2mL (2 subcutaneous injections of 2 mL each, 1 to each thigh), every 3 weeks for 4 doses.<br>* Other names: melanoma peptide vaccine;|
| Active Comparator: 3<br>MDX-010 (ipilimumab) + Placebo | Drug: MDX-010 (anti-CTLA4) monoclonal antibody<br>* 3mg/kg (intravenous [iv] infusion over 90 minutes), every 3 weeks for 4 doses<br>* Other names: ipilimumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) (Time-to-Death) Difference Between MDX-010 in Combination With gp 100 Melanoma Peptide Vaccine Versus gp 100 Melanoma Peptide Vaccine Alone | OS was defined as the time from randomization until death from any cause. If a participant did not expire, the subject was censored at the time of last contact (last known alive date). 95% confidence intervals (CI) for median were computed using Brookmeyer and Crowley method. | From randomization until the end of the study, which was defined as the time at which 481 deaths were observed (264 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) (Time-to-Death) Difference Between MDX-010 Monotherapy Versus gp100 Melanoma Peptide Vaccine Alone and MDX-010 in Combination With gp100 Melanoma Peptide Vaccine Versus MDX-010 Monotherapy | OS was defined as the time from randomization until death from any cause. If a participant did not expire, the subject was censored at the time of last contact (last known alive date). 95% confidence intervals (CI) for median were computed using Brookmeyer and Crowley method. | From randomization until the end of the study, which was defined as the time at which 481 deaths were observed (264 weeks) | 
| 12-, 18-, and 24-Month Survival Rates | The probability that a subject is alive at 12 months, 18 months, and 24 months following randomization, estimated via the non-parametric method (Kaplan-Meier method). For calculating 95% CI, bootstrap method was used with 20000 simulated trials. | Month 12, Month 18, Month 24 | 
| Progression Free Survival (PFS) | PFS was defined as the number of days between the date of randomization and the date of the progression or the date of death. A subject who died without prior progression was considered to have progressed on the date of death. PFS was determined by investigator. 95% confidence intervals (CI) for median were computed using Brookmeyer and Crowley method. | From randomization until the end of the study, which was defined as the time at which 481 deaths were observed (264 weeks) | 
| Percentage of Participants With Progression Free Survival (PFS) at Week 12 and Week 24 | PFS at Week 12 was defined as the probability that the subject was progression-free at 12 weeks and 24 weeks following the start of randomization. It was computed via Kaplan-Meier method, truncated at Week 12 and Week 24. PFS was determined by investigator. 95% confidence intervals (CI) for median were computed using Brookmeyer and Crowley method. | Week 12, Week 24 | 
| Time to Progression (TTP) | TTP was defined as the number of days between the date of the randomization and date of PD or death due to PD. For subjects who had not progression and remained alive, TTP was censored on the date of last assessment; those who remained alive and had no recorded post-baseline assessment, TTP was censored on the date of randomization; those who remained alive and had randomized but were not treated, TTP was censored at the date of randomization; for those who died without reported disease progression, TTP was censored on the date of death. | from time of randomization to date of PD or death due to PD (end of the study was defined as the time at which 481 deaths were observed [264 weeks]) | 
| Best Overall Response (BOR): Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressed Disease (PD) | Investigator's assessment, modified World Health Organization criteria. CR: disappearance of all lesions by 2 consecutive observations >=4 weeks apart, no evidence of PD. PR: >=50% ↓ in sum of products of longest diameter & greatest perpendicular diameter of all target lesions compared to baseline by 2 observations >=4 weeks apart. SD: Neither sufficient ↓ to qualify for PR nor sufficient ↑ to qualify for PD. PD: ↑ >=25% in sum of products of longest diameter & greatest perpendicular diameter of target lesions compared to smallest recorded sum during study, or appearance of >= 1 new lesion. | BOR was determined between Weeks 12 and Week 24 confirmation at least 4 weeks later at Cycle 1. | 
| Determination of Best Overall Response Rate (BORR) | Response was based on the investigators' assessment using modified WHO criteria. BORR is defined as the number of subjects whose BOR is complete or partial response (CR or PR) divided by the total number of subjects in the group. BORR was comprised of responder and non-responder. The definition of a responder in BORR was either confirmed CR or PR, and a non-responder was defined as stable disease (SD), progressed disease (PD), unconfirmed CR (uCR), unconfirmed PR (uPR), and not evaluated. | Up to week 24 | 
| Time to Response | Time to response was defined as the number of days from the date of randomization to the date when measurement criteria are met for BOR of CR or PR, as determined by investigator. | From randomization until the end of the study, which was defined as the time at which 481 deaths were observed (264 weeks) | 
| Duration of Response | Kaplan-Meier medians along with Brookmeyer and Crowley 95% confidence intervals (CI) for were computed. Duration of response was defined in subjects whose BOR was CR or PR as the number of days between the date of response (CR or PR) and the date of PD or the date of death (whichever occurs first). | from time of initial drug administration to date of PD or death due to PD (the end of the study was defined as the time at which 481 deaths were observed [264 weeks]) | 
| Disease Control Rate (DCR) | Response was based on the investigators' assessment using modified WHO criteria. DCR is defined as the number of subjects whose BOR is CR, PR, or SD divided by the total number of subjects in the group. | Up to week 24 | 
| Delayed Response (Response Beyond Week 24) | Response was based on the investigators' assessment using modified World Health Organization (WHO) criteria. Delayed response is defined as post Week 24 overall response for the subjects who have PD before or at Week 24. Evaluation of delayed overall response is compared to baseline assessment. Delayed response includes delayed late CR, delayed late PR, delayed late SD, continued PD, unknown, and missing after Week 24. The delayed response of CR and PR also must have been confirmed. | from Week 24 to end of study (the end of the study was defined as the time at which 481 deaths were observed [264 weeks]) | 
| Change From Baseline in Health-Related Quality of Life (QOL) as Measured by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Instrument at Week 12 | The 30 items were grouped into the following: 1 global QOL scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). All scores were linearly transformed to a 0 to 100 scale. For global QOL and functional items, a higher score represents a better level of functioning (100=best/0=worst). For symptom items, a higher score represents a higher level of symptoms (0=no symptom at all/100=very much severe). | Baseline (Day 1, Cycle1), Week 12 | 
| Percentage of Participants With On-Study Adverse Events (AEs) and AEs With an Outcome of Death | An AE was defined as any undesirable sign, symptom, clinically significant laboratory abnormality, or medical condition occurring after starting study treatment, even if the event was not considered to be treatment-related. Adverse events are graded using the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. If CTCAE grading does not exist for an adverse event, the intensity of mild (1), moderate (2), severe (3), and life-threatening (4) were used. | On-study adverse events include all AEs reported between the first dose and 70 days after the last dose of study therapy (end of the study was defined as the time at which 481 deaths were observed [264 weeks]). | 
| Percentage of Participants With Immune-Related Adverse Events (irAEs) | An immune related adverse event (irAE) was defined as an adverse event of unknown etiology, associated with study drug exposure and consistent with an immune phenomenon. The irAEs were programmatically determined from a predefined list of MedDRA version 12.0 high-level group terms, high-level terms and preferred terms of all ipilimumab related adverse event. The category of Other irAEs includes blood, eye, immune, infections, renal, and respiratory systems. | On-study adverse events include all AEs reported between the first dose and 70 days after the last dose of study therapy (end of the study was defined as the time at which 481 deaths were observed [264 weeks]). | 
| Percentage of Participants With Worst On-Study Hematological Abnormalities | ANC=Absolute Neutrophil Count. CTCAE v3.0 Grades 0 through 4 of severity for each AE based on this general guideline: Grade 0=Normal, Grade 1=Mild AE, Grade 2=Moderate AE, Grade 3=Severe AE, Grade 4=Life-threatening or disabling AE. | On-study laboratory results are results reported after the first dose date and within 70 days of last dose of study therapy (end of the study was defined as the time at which 481 deaths were observed [264 weeks]). | 
| Percentage of Participants With Worst On-Study Liver Abnormalities | ALT=alanine aminotransferase; AST=aspartate aminotransferase. CTCAE v3.0 Grades 0 through 4 of severity for each AE based on this general guideline: Grade 0=Normal, Grade 1=Mild AE, Grade 2=Moderate AE, Grade 3=Severe AE, Grade 4=Life-threatening or disabling AE. | On-study adverse events include all AEs reported between the first dose and 70 days after the last dose of study therapy (end of the study was defined as the time at which 481 deaths were observed [264 weeks]). | 
| Percentage of Participants With Worst On-Study Renal Abnormalities | CTCAE v3.0 Grades 0 through 4 of severity for each AE based on this general guideline: Grade 0=Normal, Grade 1=Mild AE, Grade 2=Moderate AE, Grade 3=Severe AE, Grade 4=Life-threatening or disabling AE. | On-study adverse events include all AEs reported between the first dose and 70 days after the last dose of study therapy (end of the study was defined as the time at which 481 deaths were observed [264 weeks]). | 
| Clinically Meaningful Changes in Vital Signs and Physical Examinations | Clinically meaningful changes were according to investigator. Vital sign measurements include height, weight, temperature, pulse, and resting systolic and diastolic blood pressure. | vital signs and physical examination were evaluated at screening and at Weeks 1, 4, 7, 10, 12, 16, 20, 24, 28, 36, and every 3 months thereafter | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, metastatic melanoma, skin cancer