Monoclonal Antibody Therapy and Vaccine Therapy in Treating Patients With Resected Stage III or Stage IV Melanoma

An Extended Dosing, Two-phase Study of MDX-010 as Monotherapy or in Combination With Tyrosinase/gp100/MART-1 Peptides Emulsified With Montanide ISA 51 VG in the Treatment of Subjects With Resected Stage III or Stage IV Melanoma

RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Vaccines may make the body build an immune response to kill tumor cells. Combining the vaccines with Montanide ISA-51 may cause a stronger immune response and kill more tumor cells. Giving monoclonal antibody therapy together with vaccine therapy may be an effective treatment for stage III or stage IV melanoma.

PURPOSE: This phase II trial is studying how well giving monoclonal antibody therapy together with vaccine therapy works in treating patients with resected stage III or stage IV melanoma.

Study Overview

• Status: Completed
• Conditions: Intraocular Melanoma; Melanoma (Skin)
• Intervention / Treatment: Biological: ipilimumab; Biological: Tyrosinase/gp100/MART-1 Peptides

Detailed Description

OBJECTIVES:

Primary

• Achieve at least a 40% autoimmune breakthrough event rate, as defined by the induction of grade 1, grade 2, or acceptable grade 3 drug-related autoimmune adverse events, in patients with resected stage III or IV melanoma treated with anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen emulsified in Montanide ISA-51.

Secondary

• Determine the incidence of drug-related autoimmune adverse events of any grade in patients treated with this regimen.
• Determine the time to disease relapse in patients treated with this regimen.
• Determine the immunologic response in patients treated with this regimen.

OUTLINE: This is an open-label study.

Patients receive anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010) IV over 90 minutes on day 1 of weeks 1, 9, 17, 25, 33, 41, and 53 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen emulsified in Montanide ISA-51 subcutaneously on day 1 of weeks 1, 3, 5, 7, 9, 11, 17, 21, 25, 33, 41, and 53.

Patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed melanoma

  • Stage III (≥ 3 positive lymph nodes) or stage IV disease
  • Mucosal or ocular melanoma allowed
• Completely resected within the past 6 months
• Patients with stage III resected melanoma rendered free of disease may have failed, been ineligible for, or refused prior treatment with interferon alfa

• Positive staining of tumor tissue for at least one of the following:

  • Antibody HMB-45 for gp100
  • Antibody HMB-45 for tyrosinase
  • Antibody HMB-45 for MART-1
• HLA-A*0201 positive by DNA allele-specific polymerase chain reaction assay

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• At least 6 months

Hematopoietic

• WBC ≥ 2,500/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hematocrit ≥ 30%
• Hemoglobin ≥ 10 g/dL

Hepatic

• AST ≤ 3 times upper limit of normal (ULN)*
• Bilirubin ≤ ULN* (< 3.0 mg/dL for patients with Gilbert's syndrome)
• No significant hepatic disease that would preclude study participation
• Hepatitis B surface antigen negative
• Hepatitis C antibody negative NOTE: * Unless attributable to disease

Renal

• Creatinine ≤ 2.0 mg/dL
• No significant renal disease that would preclude study participation

Cardiovascular

• No significant cardiac disease that would preclude study participation

Pulmonary

• No significant pulmonary disease that would preclude study participation

Immunologic

• No history of any of the following:

  • Inflammatory bowel disease or any other autoimmune bowel disease
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Autoimmune ocular disease
• No systemic hypersensitivity to Montanide ISA-51 or any vaccine component
• No active infection requiring therapy
• HIV negative

Other

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix
• No significant gastrointestinal disease that would preclude study participation
• No significant psychiatric disease that would preclude study participation
• No other medical condition that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 4 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No prior anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-010)
• No prior gp100 antigen, MART-1 antigen, or tyrosinase peptide
• At least 4 weeks since prior immunotherapy for melanoma and recovered
• No other concurrent immunotherapy

Chemotherapy

• At least 4 weeks since prior chemotherapy for melanoma (6 weeks for nitrosoureas) and recovered
• No concurrent chemotherapy

Endocrine therapy

• At least 4 weeks since prior hormonal therapy for melanoma and recovered
• At least 4 weeks since prior systemic, inhaled, or topical corticosteroids
• No concurrent systemic, inhaled, or topical corticosteroids

Radiotherapy

• At least 4 weeks since prior radiotherapy for melanoma and recovered

Surgery

• See Disease Characteristics
• At least 4 weeks since prior surgery for melanoma and recovered

Other

• No concurrent immunosuppressive agents (e.g., cyclosporine and its analog)
• Concurrent analgesic therapy allowed provided the dose is stable for the past 14 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1	Biological: ipilimumab; IV over 90 mins on day 1, wks 1,9,17,25,33,41,53 Dose: 3 mg/kg (Part I), 10 mg/kg (Part II); Biological: Tyrosinase/gp100/MART-1 Peptides; (All subjects in Part I and HLA-A*0201 positive subjects only in Part II): SC, day 1 of wks 1,3,5,7,9,11,17, 21,25,33,41,53 Dose: 1 mg peptide emulsified in 1 mL Montanide ISA 51 VG.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Immune-related Adverse Events (irAEs)	Percentage of participants who experienced an irAE during the course of the study defined by the induction of Grade 1, Grade 2, or acceptable Grade 3 drug-related irAEs. For the purposes of this trial, acceptable drug-related irAEs are skin-related immune-mediated adverse events < or = Grade 3 (potentially reversible inflammation < Grade 4 that can be attributable to a local antitumor reaction that could potentially be a therapeutic response will also be considered an acceptable irAE). Note: The confidence interval was calculated using the Clopper Pearson method	Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase)
Time to Disease Relapse	To determine the time (months) from first dose to disease relapse. Time to disease relapse is defined from the start of treatment to the first occurrence of any new lesion (reported by the investigator on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma) or death. Participants who neither relapse nor died will be censored on the date of their last tumor evaluation. Median estimated using Kaplan-Meier method; A two-sided 95% CI for median in each treatment group was computed via the log-log transformation method.	up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Disease Relapse	To determine the time (months) from first dose to disease relapse. Time to disease relapse is defined from the start of treatment to the first occurrence of any new lesion (reported by the investigator on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma) or death. Participants who neither relapse nor died will be censored on the date of their last tumor evaluation. Median estimated using Kaplan-Meier method; A two-sided 95% CI for median in each treatment group was computed via the log-log transformation method.	up to 3 years
Number of Participants With Drug-related irAEs of Any Grade	The number of participants who experienced a drug-related irAE of any grade over the course of the study. Note: The confidence interval was calculated using the Clopper Pearson method	Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase)
Immunologic Response to the Dose Regimen	The secondary objective was to determine the immunologic response to the dosing regimen, via Human Anti-Human Antibody (HAHA) Assessment, displayed by number of participants observed as HAHA positive or negative. Note: If participant had at least one post-baseline HAHA result with increase in titer over pre-study, the participant is counted as HAHA Positive. A participant with all negative post-baseline results is counted as HAHA negative.	up to 3 years
Number of Participants Experiencing Hematology-related Lab Abnormalities	The number of participants who experienced a Hematology-related laboratory abnormality (grade 1-4 and grade 3-4 categories, grade 4 being the worst) during the course of the study. Laboratory tests were graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.	Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase)
Number of Participants Experiencing Serum Chemistry-related Lab Abnormalities	The number of participants who experienced a Serum Chemistry-related laboratory abnormality (grade 1-4 and grade 3-4 categories, grade 4 being the worst) during the course of the study. Laboratory tests were graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.	Between first dose and 70 days after last dose of study therapy (up to 3 years including maintenance phase)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Garg SK, Ott MJ, Mostofa AGM, Chen Z, Chen YA, Kroeger J, Cao B, Mailloux AW, Agrawal A, Schaible BJ, Sarnaik A, Weber JS, Berglund AE, Mule JJ, Markowitz J. Multi-Dimensional Flow Cytometry Analyses Reveal a Dichotomous Role for Nitric Oxide in Melanoma Patients Receiving Immunotherapy. Front Immunol. 2020 Feb 25;11:164. doi: 10.3389/fimmu.2020.00164. eCollection 2020.
• Sarnaik AA, Yu B, Yu D, Morelli D, Hall M, Bogle D, Yan L, Targan S, Solomon J, Nichol G, Yellin M, Weber JS. Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res. 2011 Feb 15;17(4):896-906. doi: 10.1158/1078-0432.CCR-10-2463. Epub 2010 Nov 24.

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2004
• Primary Completion (Actual): October 31, 2009
• Study Completion (Actual): October 31, 2009

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Actual): April 14, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: recurrent melanoma; stage IV melanoma; ciliary body and choroid melanoma, medium/large size; extraocular extension melanoma; iris melanoma; recurrent intraocular melanoma; metastatic intraocular melanoma; stage III melanoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Ipilimumab
• Other Study ID Numbers: CDR0000365467; P30CA014089 (U.S. NIH Grant/Contract); P30CA076292 (U.S. NIH Grant/Contract); MCC-15241 (Other Identifier: Moffitt Cancer Center); MDX010-16 (Other Identifier: Medarex); NCI-6446 (Other Identifier: National Cancer Institute); CA184-016 (Other Identifier: BMS)