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Nivolumab With or Without Ipilimumab or Relatlimab Before Surgery in Treating Patients With Stage IIIB-IV Melanoma That Can Be Removed by Surgery

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ClinicalTrials.gov Identifier: NCT02519322
Recruitment Status : Recruiting
First Posted : August 10, 2015
Last Update Posted : November 8, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This randomized phase II trial studies how well nivolumab with or without ipilimumab or relatlimab before surgery works in treating patients with stage IIIB-IV melanoma that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, and relatlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab alone or in combination with ipilimumab or relatlimab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Condition or disease Intervention/treatment Phase
Cutaneous Melanoma Mucosal Melanoma Ocular Melanoma Stage III Acral Lentiginous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIB Uveal Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IIIC Uveal Melanoma AJCC v7 Stage IV Acral Lentiginous Melanoma AJCC v6 and v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Stage IV Uveal Melanoma AJCC v7 Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Biological: Relatlimab Procedure: Therapeutic Conventional Surgery Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma
Actual Study Start Date : February 2, 2016
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : February 1, 2020


Arm Intervention/treatment
Experimental: Arm A (nivolumab, surgery)
Patients receive Nivolumab 3 mg/kg by vein over 30 minutes on days 1, 15, 29, and 43. Patients then undergo surgery on day 57. After surgery, patients receive Nivolumab 3mg/kg by vein over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Procedure: Therapeutic Conventional Surgery
Undergo surgery

Experimental: Arm B (nivolumab, ipilimumab, surgery)
Patients receive Nivolumab 1 mg/kg by vein combined with Ipilimumab 3 mg/kg by vein Q3W (3 doses) prior to surgical excision. Patients then undergo surgery on day 57. After surgery, patients receive Nivolumab 3mg/kg by vein over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity.
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Procedure: Therapeutic Conventional Surgery
Undergo surgery

Experimental: Arm C (nivolumab, relatlimab, surgery)
Patients receive Nivolumab 480 mg by vein over 1 hour and Relatlimab 160 mg by vein over 1 hour on days 1 and 29. Patients then undergo surgery on day 57. After surgery, patients receive Nivolumab 480 mg by vein over 1 hour and Relatlimab 160 mg by vein over 1 hour every 4 weeks for 10 doses in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Biological: Relatlimab
Given IV
Other Names:
  • BMS-986016
  • BMS986016
  • Immunoglobulin G4, Anti-(human Lymphocyte Activation Gene-3 Protein) (Human Heavy Chain), Disulfide with Human Light Chain, Dimer

Procedure: Therapeutic Conventional Surgery
Undergo surgery




Primary Outcome Measures :
  1. Proportion of patients experiencing pathologic response to neoadjuvant nivolumab monotherapy [ Time Frame: Up to 2 years ]
    The proportion of patients experiencing pathologic response will be computed with associated 95% confidence interval for each treatment arm.

  2. Proportion of patients experiencing pathologic response to neoadjuvant nivolumab and ipilimumab combination therapy [ Time Frame: Up to 2 years ]
    The proportion of patients experiencing pathologic response will be computed with associated 95% confidence interval for each treatment arm.


Secondary Outcome Measures :
  1. Immunological response, assessed by change in T cell infiltrate [ Time Frame: Baseline up to 2 years ]
    Immunologic response will be assessed by change in T cell infiltrate from baseline to each study procedure visit (approximately 9 weeks). The change in T cell infiltrate will be assessed over time for each treatment arm using a generalized linear mixed model with terms for visit, stage of disease, and PD-L1 tumor status.

  2. Proportion of patients experiencing objective response (complete response, partial response, stable disease, and progressive disease) [ Time Frame: Up to 2 years ]
    The proportion of patients experiencing objective response will be computed with associated 95% confidence interval for each treatment arm.

  3. Recurrence-free survival [ Time Frame: Time of surgical resection to the date of documented disease recurrence, assessed up to 2 years ]
    Recurrence-free survival will be estimated using the Kaplan-Meier method for each treatment arm.

  4. Overall survival [ Time Frame: From treatment start date to date of death, assessed up to 2 years ]
    Overall survival will be estimated using the Kaplan-Meier method for each treatment arm.

  5. Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 2 years ]
    Safety and tolerability will be assessed by vital signs, laboratory assessments, adverse events, and serious adverse events for the safety population. Categorical measures will be summarized using frequencies and percentages while continuous variables will be summarized using mean, standard deviation, median, minimum, and maximum.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Patients must have histologically or cytologically confirmed stage IIIB/C or stage IV oligometastatic melanoma; oligometastatic melanoma is defined as three or fewer areas of resectable disease excluding central nervous system and bone involvement; patients with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for enrollment; for patients with stage IV disease with distant lymph nodes (stage M1a), a maximum of three separate lymph node sites fit the definition of oligometastatic disease; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable
  • Patients will have at least one melanoma deposit that can undergo serial biopsy (at least 2 time points) during the neoadjuvant phase of the protocol; patients must be willing to provide tumor samples at the time points specified in the Study Procedure Tables
  • All patients must undergo a baseline tumor biopsy; in Arms A and B, tumor biopsy for PD-L1 testing (PD-L1 positivity is determined by greater than or equal to 1% of cells staining in the membrane by immunohistochemistry) is required for stratification; PD-L1 status is not required for enrollment on Arm C; the 28-8 clone for PD-L1 testing is required for assessment of PD-L1 status; for patients with stage IV disease, site of tumor biopsy will preferably be from non-lymph node disease site; for PD-L1 testing, the biopsy should contain sufficient tumor content (> 100 tumor cells/4-micron tissue section); if a sample contains insufficient tumor content, a re-biopsy will be required to obtain a sample with sufficient tumor content prior to treatment
  • Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team
  • Patients who have been previously treated in the adjuvant setting for melanoma will be eligible for treatment after a 28 day wash-out period
  • Patients must have measurable disease, defined by RECIST 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Hematologic absolute neutrophil count (ANC) >= 1.5 X 10^9/L (within 28 days of first study treatment)
  • Hemoglobin >= 9.5 g/dL (within 28 days of first study treatment)
  • Platelets >= 100 X 10^9/L (within 28 days of first study treatment)
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 X upper limit of normal (ULN) (within 28 days of first study treatment)
  • White blood cells (WBC) >= 2.0 X 10^9/L (within 28 days of first study treatment)
  • Hepatic total bilirubin =< 1.5 X ULN (except subjects with Gilbert's syndrome who must have normal direct bilirubin) [3 mg/dL for HCC] (within 28 days of first study treatment)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN (=< 5 X ULN for HCC) (within 28 days of first study treatment)
  • Albumin >= 2.5 g/dL (within 28 days of first study treatment)
  • Renal creatinine =< 1.5 X ULN OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance =< 1.5 X ULN (within 28 days of first study treatment)
  • Lipase < 1.5 X ULN (within 28 days of first study treatment)
  • Amylase < 1.5 X ULN (within 28 days of first study treatment)
  • Normal thyroid function (or stable on hormone supplementation) 0.27 - 10 X 10^9/L (within 28 days of first study treatment)
  • Left ventricular ejection fraction (LVEF) >= 50% by transthoracic echocardiography (TTE) (preferred) or multigated acquisition (MUGA) within 6 months from first study drug administration
  • Women are eligible to participate if: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] > 40 MlU/mL and estradiol < 40 pg/mL [< 140 pmol/L] is confirmatory); females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment; for most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT; following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
  • A woman of childbearing potential (WOCBP) agrees to use method(s) of contraception; for a teratogenic study drug and/or when there is insufficient information to assess teratogenicity, a highly effective method(s) of contraception (failure rate of < 1% per year) is required; the individual methods of contraception and duration should be determined in consultation with the investigator; WOCBP must follow instructions for birth control when the half-life of the study drug is > 24 hours; contraception should be continued for a period of 30 days plus the time required for the study drug to undergo 5 half-lives; WOCBP should use an adequate method to avoid pregnancy for 24 weeks (30 days plus the time required for study drug to undergo 5 half-lives) after the last dose of study drug; WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of investigational product
  • Women must not be breastfeeding
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of < 1% per year; the investigator shall review contraception methods and the time period that contraception must be followed; men who are sexually active with WOCBP must follow instructions for birth control when the half-life of the study drug is > 24 hours, contraception should be continued for 90 days plus the time required for the study drug to undergo 5 half-lives; therefore, men who are sexually active with WOCBP must continue contraception for 33 weeks (90 days plus the time required for nivolumab and/or relatlimab to undergo 5 half-lives) after the last dose of study drug; in addition, male participants must be willing to refrain from sperm donation during this time; men who are sexually active with women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile and azoospermic men) do not require contraception
  • For Arm C: Cardiac assessment at baseline by trans- thoracic echocardiogram (TTE) with LVEF 50%

Exclusion Criteria:

  • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
  • Any major surgery within the last 3 weeks
  • Brain metastases, leptomeningeal disease or bone metastases
  • Pregnant or lactating female
  • Unwillingness or inability to follow the procedures required in the protocol
  • Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels
  • Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
  • Prior malignancy active within the previous 3 years except for patient's prior diagnosis of melanoma and locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast with local control measures (surgery, radiation)
  • Subjects with active, known or suspected autoimmune disease; subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
  • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Prior treatment with an anti-programmed cell death (PD)-1, anti-PD-L1 or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody
  • Any positive test result for hepatitis B or C virus indicating acute or chronic infection
  • Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Prisoners or subjects who are involuntarily incarcerated
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (infection disease) illness
  • A known or underlying medical condition that, in the opinion of the Investigator, could make the administration of the study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate the study
  • A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
  • Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy 7 days prior to initiation of study drug therapy
  • Any other acute or chronic medical illness
  • Subjects who are unable to undergo venipuncture and/or tolerate venous access
  • Any other sound medical, psychiatric, and/or social reason as determined by the Investigator
  • Any of the following procedures or medications:

    • Within 2 weeks prior to time of study treatment:

      • Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent); inhaled or topical steroids, and adrenal replacement steroid doses of > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
      • Palliative radiation or gamma
    • Within 4 weeks prior to study drug administration:

      • Any investigational cytotoxic drug; exposure to any non-cytotoxic drug within 4 weeks or 5 half-lives (whichever is shorter) is prohibited; if 5 half-lives is shorter than 4 weeks, agreement with sponsor/medical monitor is mandatory
  • Subjects with history of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy)
  • Troponin T (TnT) or I (TnI) > 2 x institutional upper limit of normal (ULN); subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are </= 1 x ULN; if TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the investigator or designee; when repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible; if TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the investigator or designee
  • For Arm C: Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

    • Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
    • Uncontrolled angina within the 3 months prior to consent
    • Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
    • Corrected QT interval (QTc) prolongation > 480 msec
    • History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc )
    • Cardiovascular disease-related requirement for daily supplemental oxygen
    • History of two or more MIs OR two or more coronary revascularization procedures
    • Subjects with history of myocarditis, regardless of etiology

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02519322


Contacts
Contact: Rodabe Amaria 713-792-2921 rnamaria@mdanderson.org

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Rodabe N. Amaria    713-792-2921      
Principal Investigator: Rodabe N. Amaria         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Rodabe Amaria M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02519322     History of Changes
Other Study ID Numbers: 2015-0041
NCI-2015-01520 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2015-0041 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: August 10, 2015    Key Record Dates
Last Update Posted: November 8, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Melanoma
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases
Nivolumab
Antibodies, Monoclonal
Immunoglobulins
Immunoglobulin G
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs