A Phase II/III Trial of Nivolumab, Ipilimumab, and GM-CSF in Patients With Advanced Melanoma

• ClinicalTrials.gov Identifier: NCT02339571
• Recruitment Status: Recruiting
• First Posted: January 15, 2015
• Last Update Posted: February 23, 2021
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: January 12, 2015
• First Posted Date: January 15, 2015
• Last Update Posted Date: February 23, 2021
• Actual Study Start Date: September 10, 2015
• Estimated Primary Completion Date: November 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 19, 2017)

Overall survival [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years ]

Overall survival between the two arms will be compared using the stratified log-rank test. One-sided type I error rate of 0.2 will be used. Kaplan-Meier plot will be generated and two-sided p-values will be reported. This analysis will be summarized using the forest plots with hazard ratios and 95% confidence intervals. Cox multivariate models will be developed for overall survival.

Original Primary Outcome Measures (submitted: January 12, 2015)

OS [ Time Frame: Time from randomization to death from any cause, assessed up to 5 years ]

OS will be compared using the stratified log-rank test. One-sided type I error rate of 0.2 will be used. Kaplan-Meier plot will be generated and two-sided p-values will be reported. This analysis will be summarized using the forest plots with hazard ratios (HRs) and 95% confidence intervals (CIs). Cox multivariate models will be developed for OS.

Current Secondary Outcome Measures (submitted: April 11, 2019)

• Progression free survival [ Time Frame: Time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years ]
  Evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1). This analysis will be summarized using the forest plots with hazard ratios and 95% confidence intervals. Cox multivariate models will be developed for progression free survival.
• Incidence of toxicities [ Time Frame: Up to 90 days after the last study drug administration ]
  Defined using the Common Terminology Criteria for Adverse Events version 4.0 criteria. Individual toxicity type adverse event and categorized adverse event data (by autoimmune disorders, endocrine, gastrointestinal, liver, nervous system, pancreas, psychiatric disorders, skin, thromboembolic disorders) will be summarized by grade and treatment arm. The percentages of patients experiencing the worst degree toxicities (highest grade event per adverse event type per patient) will be evaluated and the distribution of the worst degree toxicities will be compared among the treatment arms. The proportion of patients with worst degree toxicities with 3 or higher will be summarized and compared among the treatment arms.
• Immune response [ Time Frame: Up to 5 years ]
  Assessed using the utility of immune related response criteria. The immune related response criteria and the Response Evaluation Criteria in Solid Tumors-based clinical response data will be compared between the two treatment arms, using the Fisher's exact test. Two-sided p-values will be reported. Furthermore immune related response criteria data will be associated with the Response Evaluation Criteria in Solid Tumors-based clinical response. The Kappa statistics which measures the degree of agreement between the Response Evaluation Criteria in Solid Tumors-based response and immune related response criteria will be estimated. McNemar's test will be used to evaluate the agreement between immune related response criteria and Response Evaluation Criteria in Solid Tumors-based clinical response.
• Clinical response [ Time Frame: Up to 5 years ]
  Assessed using the utility of immune related response criteria. Standard response criteria (based on the Response Evaluation Criteria in Solid Tumors) will be applied to assess clinical response. The immune related response criteria and the Response Evaluation Criteria in Solid Tumors-based clinical response data will be compared between the two treatment arms, using the Fisher's exact test. Two-sided p-values will be reported. Furthermore immune related response criteria data will be associated with the Response Evaluation Criteria in Solid Tumors-based clinical response. The Kappa statistics which measures the degree of agreement between the Response Evaluation Criteria in Solid Tumors-based response and immune related response criteria will be estimated. McNemar's test will be used to evaluate the agreement between immune related response criteria and Response Evaluation Criteria in Solid Tumors-based clinical response.

Original Secondary Outcome Measures (submitted: January 12, 2015)

• PFS, evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [ Time Frame: Time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years ]
  Stratified log-rank test will be used to compare the PFS between the two arms. This analysis will be summarized using the forest plots with HRs and 95% CIs. Cox multivariate models will be developed for PFS.
• Incidence of toxicities, defined using the Common Terminology Criteria for Adverse Events version 4.0 criteria [ Time Frame: Up to 90 days after the last study drug administration ]
  Individual toxicity type AE and categorized AE data (by autoimmune disorders, endocrine, gastrointestinal, liver, nervous system, pancreas, psychiatric disorders, skin, thromboemblic disorders) will be summarized by grade and treatment arm. The percentages of patients experiencing the worst degree toxicities (highest grade event per AE type per patient) will be evaluated and the distribution of the worst degree toxicities will be compared among the treatment arms. The proportion of patients with worst degree toxicities with 3 or higher will be summarized and compared among the treatment arms.
• Immune response, assessed using the utility of Immune related response criteria (irRC) [ Time Frame: Up to 5 years ]
  The irRC and the RECIST-based clinical response data will be compared between the two treatment arms, using the Fisher's exact test. Two-sided p-values will be reported. Furthermore irRC data will be associated with the RECIST-based clinical response. The Kappa statistics which measures the degree of agreement between the RECIST-based response and irRC will be estimated. McNemar's test will be used to evaluate the agreement between irRC and RECIST-based clinical response.
• Clinical response, assessed using the utility of irRC [ Time Frame: Up to 5 years ]
  Standard response criteria (based on the RECIST) will be applied to assess clinical response. The irRC and the RECIST-based clinical response data will be compared between the two treatment arms, using the Fisher's exact test. Two-sided p-values will be reported. Furthermore irRC data will be associated with the RECIST-based clinical response. The Kappa statistics which measures the degree of agreement between the RECIST-based response and irRC will be estimated. McNemar's test will be used to evaluate the agreement between irRC and RECIST-based clinical response.

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 12, 2015)

• Change in QOL, using Functional Assessment of Cancer Therapy-General [ Time Frame: Baseline to up to 1 year ]
  Descriptive statistics on QOL measurements will be provided. Two-sample t-test will be used for each comparison and two-sided p-values will be reported. The changes between before and after treatment will be compared between the two treatment arms. The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.
• Change in treatment related side effects that may have an impact on the health-related domains of QOL, as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Diarrhea [ Time Frame: Baseline to up to 1 year ]
  Descriptive statistics on QOL measurements will be provided. Two-sample t-test will be used for each comparison and two-sided p-values will be reported. The changes between before and after treatment will be compared between the two treatment arms. The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.
• Change in treatment related side effects that may have an impact on the health-related domains of QOL, as measured by the FACIT-Biologic Response Modifiers [ Time Frame: Baseline to up to 1 year ]
  Descriptive statistics on QOL measurements will be provided. Two-sample t-test will be used for each comparison and two-sided p-values will be reported. The changes between before and after treatment will be compared between the two treatment arms. The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.

Descriptive Information

• Brief Title: A Phase II/III Trial of Nivolumab, Ipilimumab, and GM-CSF in Patients With Advanced Melanoma
• Official Title: Randomized Phase II/III Study of Nivolumab Plus Ipilimumab Plus Sargramostim Versus Nivolumab Plus Ipilimumab in Patients With Unresectable Stage III or Stage IV Melanoma
• Brief Summary: This phase II/III trial studies the side effects of nivolumab and ipilimumab when given together with or without sargramostim and to see how well they work in treating patients with stage III-IV melanoma that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Detailed Description

PRIMARY OBJECTIVE:

I. To compare the overall survival (OS) of nivolumab/ipilimumab/sargramostim (GM-CSF) versus nivolumab/ipilimumab.

SECONDARY OBJECTIVES:

I. To evaluate progression free survival (PFS) of patients treated with nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.

II. To assess for differences in tolerability, specifically the rate of grade III or higher adverse events, between nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.

III. To evaluate immune-related response rate (based on immune-related response criteria) and response rate (based on Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and to compare them.

EXPLORATORY TOBACCO USE OBJECTIVES:

I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose modifications).

II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.

III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.

IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, ipilimumab IV over 30 minutes on day 1, and sargramostim subcutaneously (SC) on days 1-14. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in induction therapy. Patients with partial response (PR), stable disease (SD), or complete response (CR) at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM B: INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive nivolumab as in induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Cutaneous Melanoma
• Stage III Cutaneous Melanoma AJCC v7
• Stage IIIA Cutaneous Melanoma AJCC v7
• Stage IIIB Cutaneous Melanoma AJCC v7
• Stage IIIC Cutaneous Melanoma AJCC v7
• Stage IV Cutaneous Melanoma AJCC v6 and v7
• Unresectable Cutaneous Melanoma

Intervention

• Biological: Ipilimumab
  Given IV
  Other Names:

  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy
• Biological: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
• Biological: Sargramostim
  Given SC
  Other Names:

  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

Study Arms

• Experimental: Arm A (nivolumab, ipilimumab, sargramostim)

  INDUCTION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1, ipilimumab IV over 30 minutes on day 1, and sargramostim SC on days 1-14. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

  MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in Induction therapy. Patients with PR, SC, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity.

  Interventions:

  • Biological: Ipilimumab
  • Biological: Nivolumab
  • Biological: Sargramostim
• Experimental: Arm B (nivolumab, ipilimumab)

  INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

  MAINTENANCE THERAPY: Patients receive nivolumab as in Induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of disease progression or unacceptable toxicity.

  Interventions:

  • Biological: Ipilimumab
  • Biological: Nivolumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 20, 2020): 600
• Original Estimated Enrollment (submitted: January 12, 2015): 400
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: November 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1
• Patients must have known BRAF mutational status of tumor; wild-type (WT) or mutated, prior to randomization
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for at least one week prior to the start of the research study, and continuing for 5 months for women of childbearing potential and 7 months for sexually active males after the last dose of the study drugs
• Patients must have unresectable stage III or stage IV melanoma; patients must have histological or cytological confirmation of melanoma that is metastatic or unresectable and clearly progressive
• Patients must have measurable disease per RECIST 1.1 criteria; all sites of disease must be evaluated within 4 weeks prior to randomization
• Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon, BRAF, or mitogen-activated protein kinase [MEK] agents); patients may have had prior anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) in the adjuvant setting, if at least one year from last dose of treatment has passed prior to beginning treatment; patients may not have had any prior programmed cell death (PD)-1/PD-ligand (PD-L)1 agent in the adjuvant setting
• Patients must have discontinued chemotherapy, immunotherapy or other investigational agents used in the adjuvant setting >= 4 weeks prior to randomization and recovered from adverse events due to those agents; mitomycin and nitrosoureas must have been discontinued at least 6 weeks prior to entering the study; patients must have discontinued radiation therapy >= 2 weeks prior to entering the study and recovered from any adverse events associated with treatment; prior surgery must be >= 4 weeks from randomization and patients must be fully recovered from post-surgical complications
• White blood count >= 3,000/uL (obtained within 4 weeks prior to randomization)
• Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to randomization)
• Platelet count >= 100,000/uL (obtained within 4 weeks prior to randomization)
• Hemoglobin >= 9 g/dL (obtained within 4 weeks prior to randomization)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40 ml/min (obtained within 4 weeks prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x ULN for patients with documented liver metastases) (obtained within 4 weeks prior to randomization)
• Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement and =< 7 x ULN for patients with known bone involvement) (obtained within 4 weeks prior to randomization)
• Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those with known Gilbert's syndrome (obtained within 4 weeks prior to randomization)
• Serum lactate dehydrogenase (LDH) =< 10 X ULN (obtained within 4 weeks prior to randomization)
• Patients with autoimmune hypothyroid disease or type I diabetes on replacement treatment are eligible

Exclusion Criteria:

• Women must not be pregnant or breast-feeding due to use of cytotoxic immunotherapy and risk of teratogenic side effects; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patients may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the metastatic setting
• Patients must not receive any other investigational agents while on study or within four weeks prior to randomization
• Patients are excluded for receiving any non-oncology vaccine therapy used for prevention of infectious diseases for up to four weeks (28 days) prior to or after any dose of ipilimumab; NOTE: Patients are permitted to receive the seasonal influenza vaccine; if seasonal influenza vaccine is considered, killed vaccines should be recommended
• Patients are ineligible if they have any currently active central nervous system (CNS) metastases; patients who have treated brain metastases (with either surgical resection or stereotactic radiosurgery) that have been stable on head magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4 weeks following treatment and within 4 weeks prior to randomization are eligible; patients must not have taken any steroids =< 14 days prior to randomization for the purpose of managing their brain metastases; patients with only whole brain irradiation for treatment of CNS metastases will be ineligible
• Patients must not have other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for > 3 years prior to the time of randomization
• Patients must not have any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), including but not limited to, ongoing or active infection requiring parenteral antibiotics on day 1, history of bleeding diathesis or need for concurrent anticoagulation (international normalized ratio [INR] =< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), or psychiatric illness/social situations that would limit compliance with study requirements, interfere with subject's safety, or obtaining informed consent
• Patients with human immunodeficiency virus (HIV) infection are ineligible; due to the mechanism of action of ipilimumab and GM-CSF, activity and side effects in an immune compromised patient are unknown
• Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are not eligible; patients with cleared HBV and HCV (0 viral load) infection will be allowed
• Patients must not have autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or ophthalmologic steroids; a history of occasional (but not continuous) use of steroid inhalers is allowed; replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study
• Exclusion from this study also includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis); other CNS autoimmune disease (e.g., multiple sclerosis)
• Patients must not have a history of inflammatory bowel disease or diverticulitis (history of diverticulosis is allowed)
• Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that in the opinion of the investigator may interfere with compliance, make the administration of the study drugs hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea; patients must not have an active infection requiring current treatment with parenteral antibiotics

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02339571
• Other Study ID Numbers: NCI-2014-02674; NCI-2014-02674 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA6141; EA6141 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA6141 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U24CA196172 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Frank S Hodi; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: February 2021