Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Cutaneous Melanoma
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 53
- Locations
- 2
- Primary Endpoint
- Arm C: Number of Participants With the Pathologic Response Rate
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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.
Detailed Description
PRIMARY OBJECTIVES: I. To assess the pathologic response of nivolumab monotherapy and nivolumab and ipilimumab dual therapy administered in the neoadjuvant setting in patients with high-risk resectable melanoma. Pathologic response will be assessed by percent viable tumor cells, percent tumor necrosis, presence of fibrosis and melanoma proliferation as assessed by phosphohistone H3 from baseline, to on-treatment and surgical specimens. (Arm A and Arm B) II. To assess the pathologic response rate of combination relatlimab with nivolumab in the neoadjuvant setting in patients with high-risk resectable Stage IIIB/C or oligometastatic Stage IV melanoma. Pathologic response will be assessed by percent viable tumor cells, percent tumor necrosis, presence of fibrosis and melanoma proliferation as assessed by phosphohistone H3 from baseline, to on- treatment and surgical specimens. (Arm C) SECONDARY OBJECTIVES: I. To assess the immunologic response of neoadjuvant nivolumab monotherapy and neoadjuvant nivolumab and ipilimumab dual therapy in patients with high-risk resectable melanoma. Immunologic response will be determined by change in T cell infiltrate from baseline to on-treatment and surgical specimens in response to therapy. (Arm A and Arm B) II. To assess the objective response rate (ORR) of nivolumab monotherapy and nivolumab and ipilimumab dual therapy administered in the neoadjuvant setting as assessed by imaging (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria) in patients with high-risk resectable melanoma. (Arm A and Arm B) III. To assess the 12-month recurrence-free survival (RFS) and overall survival (OS) of patients with high-risk resectable melanoma treated with neoadjuvant nivolumab monotherapy or nivolumab and ipilimumab dual therapy followed by adjuvant nivolumab. (Arm A and Arm B) IV. To evaluate the safety of nivolumab monotherapy and dual ipilimumab and nivolumab in the neoadjuvant setting and peri-operatively as well as assess the safety of adjuvant nivolumab. (Arm A and Arm B) V. To evaluate safety and feasibility of relatlimab with nivolumab delivered in the neoadjuvant setting. (Arm C) VI. To assess the objective response rate (ORR) of relatlimab with nivolumab administered in the neoadjuvant setting as assessed by imaging (RECIST 1.1 criteria) in patients with high-risk resectable melanoma. (Arm C) VII. To assess the 12-month recurrence-free survival (RFS) and overall survival (OS) of patients with high-risk resectable melanoma treated with neoadjuvant and adjuvant relatlimab with nivolumab. (Arm C) VIII. To evaluate immunologic and molecular mechanisms of response and resistance to relatlimab with nivolumab. (Arm C) EXPLORATORY OBJECTIVES: I. Identification of immunologic and genomic markers correlating with clinical response or resistance to nivolumab monotherapy and ipilimumab with nivolumab combination therapy. OUTLINE: Patients are randomized to 1 of 3 arms. ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, 29, and 43. Patients then undergo surgery on day 57. After surgery, patients receive nivolumab IV over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity. (CLOSED TO ENROLLMENT AS OF 10/3/2018) ARM B: Patients receive nivolumab IV over 1 hour and ipilimumab IV over 90 minutes on days 1, 22, and 43. Patients then undergo surgery on day 57. After surgery, patients receive nivolumab IV over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity. (CLOSED TO ENROLLMENT AS OF 10/3/2018) ARM C: Patients receive nivolumab IV over 1 hour and relatlimab IV over 1 hour on days 1 and 29. Patients then undergo surgery on day 57. After surgery, patients receive nivolumab IV over 1 hour and relatlimab IV over 1 hour every 4 weeks for 10 doses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for 2 years.
Investigators
Eligibility 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
- •Age \>/= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Absolute neutrophil count (ANC) \>= 1.5 X 10\^9/L (within 28 days of first study treatment)
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
Outcomes
Primary Outcomes
Arm C: Number of Participants With the Pathologic Response Rate
Time Frame: up to 2 years
Number of participants with the Pathologic response rate will be assessed by percent viable tumor cells, percent tumor necrosis, presence of fibrosis and melanoma proliferation as assessed by phosphohistone H3 from baseline, to on-treatment and surgical specimens.
Secondary Outcomes
- Arm C: Number of Participants With Objective Response Rate (ORR) of Relatlimab With Nivolumab Administered in the Neoadjuvant Setting.(Up to 2 years)
- Arm C: Number of Participants With Immunologic and Molecular Mechanisms of Response and Resistance.(up to 2 years)
- Arm C: Number of Participants Assessed by Safety and Feasibility of Relatlimab With Nivolumab Delivered in the Neoadjuvant Setting(up to 2 years)
- Arm C: Number of Participants With Recurrence-Free Survival (RFS) and Overall Survival (OS)(up to 12 months)