Clinical Trials /

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

NCT02339571

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-02674
  • SECONDARY ID: NCI-2014-02674
  • SECONDARY ID: EA6141
  • SECONDARY ID: EA6141
  • SECONDARY ID: EA6141
  • SECONDARY ID: U10CA180820
  • SECONDARY ID: U24CA196172
  • NCT ID: NCT02339571

Conditions

  • 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

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm A (nivolumab, ipilimumab, sargramostim)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab, ipilimumab, sargramostim)
Sargramostim23-L-Leucinecolony-Stimulating Factor 2, DRG-0012, Leukine, Prokine, rhu GM-CFS, Sagramostim, SargramostatinArm A (nivolumab, ipilimumab, sargramostim)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab, ipilimumab, sargramostim)ExperimentalINDUCTION 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.
  • Ipilimumab
  • Nivolumab
  • Sargramostim
Arm B (nivolumab, ipilimumab)ExperimentalINDUCTION 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.
  • Ipilimumab
  • Nivolumab

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:Time from randomization to death from any cause, assessed up to 5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:Time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years
Safety Issue:
Description: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.
Measure:Incidence of toxicities
Time Frame:Up to 90 days after the last study drug administration
Safety Issue:
Description: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.
Measure:Immune response
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Clinical response
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

August 11, 2020