Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03033576
Recruitment Status : Recruiting
First Posted : January 27, 2017
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 26, 2017
First Posted Date  ICMJE January 27, 2017
Last Update Posted Date July 9, 2020
Actual Study Start Date  ICMJE July 17, 2017
Estimated Primary Completion Date March 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2018)
Progression free survival (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 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 26, 2017)
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 ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2019)
  • CD8+ expression levels [ Time Frame: Up to 3 years ]
    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.
  • Response rate (confirmed and unconfirmed, complete and partial responses) [ Time Frame: Up to 3 years ]
    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.
  • Overall survival (OS) [ Time Frame: Up to 3 years ]
    Will construct Kaplan-Meier plots and estimate the median OS and construct 95% Brookmeyer-Crowley confidence intervals. We will be able to estimate the objective response rate (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.
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 will be utilized for serious adverse events reporting only). 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2017)
  • CD8+ expression levels [ Time Frame: Up to 3 years ]
    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.
  • Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]
    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
  • OS [ Time Frame: Up to 3 years ]
    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.
  • Response rate (confirmed and unconfirmed, complete and partial responses) [ Time Frame: Up to 3 years ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Testing Treatment With Ipilimumab and Nivolumab Compared to Treatment With Ipilimumab Alone in Advanced Melanoma
Official Title  ICMJE A Phase II Randomized Study of Nivolumab (NSC-748726) With Ipilimumab (NSC-732442) or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1 or Anti-PD-L1 Agent
Brief Summary 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.
Detailed Description

PRIMARY OBJECTIVE:

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, in each treatment arm).

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.

TRANSLATIONAL OBJECTIVES:

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

II. To assess the joint prognostic value of T-cell density, TCR clonality, and mutational load, and mRNA expression levels 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 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Melanoma
  • Melanoma of Unknown Primary
  • Mucosal Melanoma
  • Refractory 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
  • Unresectable Melanoma
Intervention  ICMJE
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
Study Arms  ICMJE
  • Active Comparator: Arm I (ipilimumab)
    Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: Ipilimumab
  • Experimental: Arm II (nivolumab, ipilimumab)
    Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Biological: Ipilimumab
    • Biological: Nivolumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 26, 2017)
94
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 15, 2022
Estimated Primary Completion Date March 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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; all measurable lesions must be assessed by physical examination, computed tomography (CT) scans or magnetic resonance imaging (MRI)s 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, 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 with a history of central nervous system metastases must have MRI of the brain within 42 days prior to registration
  • Patients must have had prior treatment with anti-PD1 or anti-PD-L1 agents and had documented disease progression per the treating physician either while on these agents or after stopping therapy with these agents without intervening therapy; patients who received adjuvant therapy for previously resected disease with PD-1 or PD-L1 agents may also be eligible if disease recurrence occurred while still receiving the PD-1 or PD-L1 therapy and no intervening therapy was received; patients must have discontinued anti-PD-1 or anti-PD-L1 therapy at least 21 days prior to registration
  • 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 (within 28 days prior to registration)
  • Hemoglobin >= 8 g/dL (within 28 days prior to registration)
  • Platelets >= 100,000/mcL (within 28 days prior to registration)
  • Total bilirubin =< 2.5 x institutional upper limit of normal (IULN) (except patients with Gilbert's syndrome) (within 28 days prior to registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x IULN (within 28 days prior to registration)
  • Serum creatinine =< 2.0 x IULN within 28 days prior to registration
  • 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 with a known history of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications, or with a clinical history suggestive of the above must have an electrocardiography (EKG) and echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment
  • Patients with new symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, myocardial infarction (MI), or exposure to cardiotoxic medications must have a cardiology consultation, creatinine phosphokinase (CPK), and troponin testing at prestudy and as clinically indicated
  • Males who are sexually active with women of reproductive potential must have agreed to use birth control throughout the study and for 7 months 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 7 months after completion of protocol treatment, he is responsible for beginning effective contraceptive measures
  • Patients must submit archival tissue (if available) for translational medicine; patients must also be willing to undergo biopsies and submit fresh tissue and blood for translational medicine
  • Patients must be offered the opportunity to participate in specimen banking of leftover tissue for future research
  • 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 Oncology Patient Enrollment Network (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

Exclusion Criteria:

  • Patients must not have achieved a partial or complete response to the anti-PD-1 or anti-PD-L1 agents prior to progression per the treating physician
  • Patients must not have had any systemic therapy, including 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 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 5 months 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 5 months after protocol treatment, she is responsible for beginning effective contraceptive measures
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03033576
Other Study ID Numbers  ICMJE NCI-2017-00105
NCI-2017-00105 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1616
S1616 ( Other Identifier: SWOG )
S1616 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ari M Vanderwalde Southwest Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP