Clinical Trials /

Testing Treatment With Ipilimumab and Nivolumab Compared to Treatment With Ipilimumab Alone in Advanced Melanoma

NCT03033576

Description:

This phase II trial studies how well ipilimumab with or without nivolumab work in treating patients with melanoma that is stage IV or stage III and cannot be removed by surgery. 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.

Related Conditions:
  • Melanoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ipilimumab With or Without Nivolumab in Treating Patients With Melanoma That is Stage IV or Stage III and Cannot Be Removed by Surgery
  • Official Title: A Phase II Randomized Study of Nivolumab (NSC-732442) With Ipilimumab (NSC-748726) or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1 or Anti-PD-L1 Agent

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00105
  • SECONDARY ID: NCI-2017-00105
  • SECONDARY ID: S1616
  • SECONDARY ID: S1616
  • SECONDARY ID: S1616
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03033576

Conditions

  • Stage III Skin Melanoma
  • Stage IIIA Skin Melanoma
  • Stage IIIB Skin Melanoma
  • Stage IIIC Skin Melanoma
  • Stage IV Skin Melanoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm I (ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm II (nivolumab, ipilimumab)

Purpose

This randomized phase II studies how well ipilimumab with or without nivolumab work in treating patients with melanoma that is stage IV or stage II and cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare progression free survival (PFS) of patients with advanced melanoma refractory
      to an anti-PD-1 or anti-PD-L1 agent, treated with combination therapy ipilimumab plus
      nivolumab versus ipilimumab alone.

      SECONDARY OBJECTIVES:

      I. To estimate difference in T-cell infiltrate between on-study biopsy samples of patients
      who respond to combination therapy (including confirmed and unconfirmed, complete and
      partial response per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) as compared
      to those who do not respond.

      II. To evaluate the objective response rate (ORR), defined as confirmed complete or partial
      response per RECIST 1.1, in each treatment arm.

      III. To evaluate the overall survival (OS) of patients in each treatment arm. IV. To
      evaluate the toxicity profile of patients in each treatment arm.

      TERTIARY OBJECTIVES:

      I. To assess the marginal prognostic value of baseline T-cell density, T-cell receptor (TCR)
      clonality, and mutational load in terms of response.

      II. To assess the joint prognostic value of T-cell density, TCR clonality, and mutational
      load in terms of response.

      III. To identify T-cell poor subtype(s) that are associated with response.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment
      repeats every 21 days for up to 4 courses in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on
      day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease
      progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on
      days 1 and 15. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 2 years and
      then annually for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ipilimumab)Active ComparatorPatients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
    Arm II (nivolumab, ipilimumab)ExperimentalPatients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Patients must have pathologically confirmed melanoma that is either stage IV or
                   unresectable stage III; patients may have primaries of cutaneous, mucosal or unknown
                   origin; patients with uveal (ocular) primary are not eligible
      
                -  Patients must have measurable disease per RECIST 1.1; computed tomography (CT) scans
                   or magnetic resonance imaging (MRI)s used to assess measurable disease must have been
                   completed within 28 days prior to registration; if the only measurable disease is
                   cutaneous or subcutaneous, lesions must be at least 10 mm in greatest dimension and
                   able to be serially recorded using calipers and photographs; tests used to assess
                   non-measurable disease must have been performed within 42 days prior to registration;
                   all disease must be assessed and documented on the Baseline Tumor Assessment Form
      
                -  Patients with central nervous system (CNS) metastases must have all lesions
                   adequately treated with stereotactic radiation therapy, craniotomy, or gamma knife
                   therapy with no subsequent evidence of CNS progression; patients must not have
                   required steroids for at least 14 days prior to registration; patients with central
                   nervous system (CNS) metastases must have all lesions adequately treated with
                   stereotactic radiation therapy, craniotomy, gamma knife therapy, or whole brain
                   radiotherapy, with no subsequent evidence of CNS progression; patients must not have
                   required steroids for at least 14 days prior to registration
      
                -  Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had
                   documented disease progression either while on these agents or after stopping therapy
                   with these agents without intervening therapy; patients must have discontinued
                   anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registration
      
                -  Patients must not have achieved a confirmed partial or complete response to the
                   anti-PD-1 or anti-PD-L1 agents prior to progression
      
                -  Patients must not have had systemic therapy, excluding anti-PD-1 or anti-PD-L1
                   agents, within 21 days prior to registration
      
                -  Patients must not have had prior radiation therapy within 14 days prior to
                   registration
      
                -  Patients must not have had:
      
                     -  Prior treatment with ipilimumab or other CTLA-4 antagonists
      
                     -  Systemic therapy between progression on the anti-PD-1 or anti-PD-L1 agents and
                        registration
      
                     -  Note: Systemic therapy (including BRAF-targeting agents) prior to anti-PD-1 or
                        anti-PD-L1 therapy is allowed
      
                -  Patients must not be planning to require any additional form of systemic anti-tumor
                   therapy while on protocol treatment
      
                -  Patients must have Zubrod performance status of =< 2
      
                -  Patients must have complete history and physical examination within 28 days prior to
                   registration
      
                -  Absolute neutrophil count (ANC) >= 1,500/mcL
      
                -  Hemoglobin >= 8 g/dL
      
                -  Platelets >= 100,000/mcL
      
                -  Total bilirubin =< 2.5 x institutional upper limit of normal (IULN) (except patients
                   with Gilbert's syndrome)
      
                -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x IULN
      
                -  Serum creatinine =< 2.0 x IULN
      
                -  Patients with a known history of human immunodeficiency virus (HIV) must have CD4
                   count >= institutional lower limit of normal within 28 days prior to registration
      
                -  Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus
                   (HCV) infection prior to registration
      
                -  Patients must not have an active infection requiring systemic therapy at time of
                   registration
      
                -  Patients must not have organ allografts
      
                -  Patients must not have received systemic treatment with corticosteroids (> 10 mg
                   daily prednisone or equivalent) or other immunosuppressive medications within 14 days
                   prior to registration; inhaled or topical steroids, and adrenal replacement doses =<
                   10 mg daily prednisone or equivalent are permitted in the absence of active
                   autoimmune disease
      
                -  Patients must not have a history of immune-mediated pneumonitis or colitis that
                   required interruption of therapy or treatment of steroids
      
                -  No other prior malignancy is allowed except for the following: adequately treated
                   basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
                   stage 0, I or II cancer from which the patient is currently in complete remission, or
                   any other cancer from which the patient has been disease free for two years
      
                -  Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm;
                   females of reproductive potential must have negative serum pregnancy test within 2
                   days prior to registration and agree to use an effective contraceptive method
                   throughout the study and for 23 weeks after completion of protocol treatment; a woman
                   is considered to be of "reproductive potential" if she has had menses at any time in
                   the preceding 12 consecutive months; in addition to routine contraceptive methods,
                   "effective contraception" also includes heterosexual celibacy and surgery intended to
                   prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a
                   hysterectomy, bilateral oophorectomy or bilateral tubal ligation; if at any point a
                   previously celibate patient chooses to become heterosexually active during or within
                   23 weeks after protocol treatment, she is responsible for beginning effective
                   contraceptive measures
      
                -  Males who are sexually active with women of reproductive potential must have agreed
                   to use birth control throughout the study and for 31 weeks after completion of
                   protocol treatment; in addition to routine contraceptive methods, "effective
                   contraception" also includes heterosexual celibacy and surgery intended to prevent
                   pregnancy (vasectomy); if at any point a previously celibate patient chooses to
                   become heterosexually active during or within 31 weeks after completion of protocol
                   treatment, he is responsible for beginning effective contraceptive measures
      
                -  Patients must be offered the opportunity to submit archival tissue for translational
                   medicine; patients must also be willing to undergo biopsies and submit fresh tissue
                   and blood for translational medicine
      
                -  Patients must be informed of the investigational nature of this study and must sign
                   and give written informed consent in accordance with institutional and federal
                   guidelines
      
                -  As a part of the OPEN registration process the treating institution's identity is
                   provided in order to ensure that the current (within 365 days) date of institutional
                   review board approval for this study has been entered in the system
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:PFS
      Time Frame:From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years
      Safety Issue:
      Description:Will be compared between arms using a log-rank test. Kaplan-Meier plots will be constructed and median PFS for each arm with corresponding 95% Brookmeyer-Crowley confidence intervals will be estimated.

      Secondary Outcome Measures

      Measure:CD8+ expression levels
      Time Frame:Up to 3 years
      Safety Issue:
      Description:will evaluate by comparing the quantitative CD8+ expression levels between patients who eventually respond and patients who do not respond using a two-sample t-test and control the type I error at the two-sided 0.05 level. Assuming that the trial accrues to completion, 90% compliance in tissue and biopsy submission, and that 25% of patients respond, then we anticipate 80% power to detect a mean difference in CD8+ expression of 0.875 standard deviations.
      Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
      Time Frame:Up to 3 years
      Safety Issue:
      Description:Toxicity will be assessed in each arm separately. Any toxicity with at least 5% chance of occurring has 93.7% and 60.3% chance of being observed at least once in the combination therapy and ipilimumab alone arms, respectively. We will be able to estimate the rate of occurrence of any particular toxicity to within 12.3% (95% CI) and 21.4% in the combination therapy and ipilimumab alone arms, respectively
      Measure:OS
      Time Frame:Up to 3 years
      Safety Issue:
      Description:Will construct Kaplan-Meier plots and estimate the median OS and construct 95% Brookmeyer-Crowley confidence intervals. We will be able to estimate the ORR or the OS rates at a particular time point (e.g. 13 weeks) to within 12.3% (95% confidence interval [CI]) and 21.4% in the combination therapy and ipilimumab alone arms, respectively. Waterfall plots will be constructed to represent each patient's best change in tumor burden.
      Measure:Response rate (confirmed and unconfirmed, complete and partial responses)
      Time Frame:Up to 3 years
      Safety Issue:
      Description:Will estimate the response rate in each arm and construct 95% binomial confidence intervals. All randomized patients will be included in the analysis of response. Patients who cannot have their exact response determined due to inadequate disease assessments will be counted in the denominator as non-responders.

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:National Cancer Institute (NCI)

      Last Updated

      April 18, 2017