Neoplasms

Skin and Connective Tissue Diseases

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Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

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Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Eye Neoplasms

Uveal Diseases

Ocular Melanoma

Intraocular Melanoma

Acral Lentiginous Melanoma

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Nivolumab

Ipilimumab

Relatlimab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunologic Factors

Patients receive nivolumab 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.

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.

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.

Laboratory Biomarker Analysis

Therapeutic Conventional Surgery

Rodabe N Amaria

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.

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.

Neoadjuvant and Adjuvant Checkpoint Blockade

Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma

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.

Number of Participants assessed by the safety and feasibility of relatlimab with nivolumab Delivered in the Neoadjuvant Setting

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 participants with high-risk resectable melanoma

To assess the 12-month recurrence and overall survival (OS) of participants with high-risk resectable melanoma treated with neoadjuvant and adjuvant relatlimab with nivolumab

To assess by immunologic and molecular mechanisms of response and resistance to relatlimab with nivolumab.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

No participants were analyzed in Arm A and Arm B, only in Arm C.

Nivolumab IV over 30 minutes D1, 15, 29 \& 43; surgery D57; post-surgery nivolumab IV over 30 minutes for Q2wks for 13 doses

Arm A (Nivolumab, Surgery)

Nivolumab IV ocer 1 hr and ipilimumab IV over 90 minutes D1, 22, \& 43; Surgery D57; Nivolumab IV over 30 minutes Q2wks for 13 doses

Nivolumab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Arm B (Nivolumab, Ipilimumab, Surgery)

Nivolumab IV ocer 1 hr and ipilimumab IV over 90 minutes D1, 22, \& 43; Surgery D57; Nivolumab IV over 30 minutes Q2wks for 13 doses

Relatlimab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Arm C (Nivolumab, Relatlimab, Surgery)

Nivolumab IV over 30 minutes D1, 15, 29, \& 43; Surgery D57; Post-surgery Nivolumab IV over 30 minutes Q2wks for 13 doses

Nivolumab IV ocer 1 hr and ipilimumab IV over 90 minutes D1, 22, \& 43; Surgery D57; Nivolumab IV over 30 minutes Q2wks for 13 doses

Nivolumab IV and relatilmab IV over 1 hr D1 and D29; Surgery D57; Post-surgery Nivolumab IV and relatimab IV over 1 hr Q4wks for 10 doses

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

No participants were in the Arm A or Arm B only Arm C

Dr. Rodabe Amaria

Participants receive nivolumab IV over 30 minutes on days 1, 15, 29, and 43. Participants then undergo surgery on day 57. After surgery, participants receive nivolumab IV over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Participants receive nivolumab IV over 1 hour and ipilimumab IV over 90 minutes on days 1, 22, and 43. Participants then undergo surgery on day 57. After surgery, participants receive nivolumab IV over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity.

Ipilimumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Participants receive nivolumab IV over 1 hour and relatlimab IV over 1 hour on days 1 and 29. Participants then undergo surgery on day 57. After surgery, participants 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Relatlimab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

No data to report due to study Closed to entry as of 07/2017 regarding Arm A and Arm B.

Arm C: Number of Participants With the Pathologic Response Rate

Arm C: Number of Participants Assessed by Safety and Feasibility of Relatlimab With Nivolumab Delivered in the Neoadjuvant Setting

Arm C: Number of Participants With Objective Response Rate (ORR) of Relatlimab With Nivolumab Administered in the Neoadjuvant Setting.

Arm C: Number of Participants With Recurrence-Free Survival (RFS) and Overall Survival (OS)

Arm C: Number of Participants With Immunologic and Molecular Mechanisms of Response and Resistance.

Participants receive nivolumab IV over 30 minutes on days 1, 15, 29, and 43. Participants 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Participants 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, Participants receive nivolumab IV over 30 minutes every 2 weeks for 13 doses in the absence of disease progression or unacceptable toxicity.

Ipilimumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Participants receive nivolumab IV over 1 hour and relatlimab IV over 1 hour on days 1 and 29. Participants then undergo surgery on day 57. After surgery, Participants 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.

Laboratory Biomarker Analysis: Correlative studies

Nivolumab: Given IV

Relatlimab: Given IV

Therapeutic Conventional Surgery: Undergo surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant and Adjuvant Checkpoint Blockade	NCT02519322	Cutaneous Melan... Mucosal Melanom... Ocular Melanoma Stage III Acral... Stage IIIB Cuta... Stage IIIB Uvea... Stage IIIC Cuta... Stage IIIC Uvea... Stage IV Acral ... Stage IV Cutane... Stage IV Uveal ...	Ipilimumab Laboratory Biom... Nivolumab Relatlimab Therapeutic Con...	18 Years -	M.D. Anderson Cancer Center
Neoadjuvant and Adjuvant Checkpoint Blockade	NCT02519322	Cutaneous Melan... Mucosal Melanom... Ocular Melanoma Stage III Acral... Stage IIIB Cuta... Stage IIIB Uvea... Stage IIIC Cuta... Stage IIIC Uvea... Stage IV Acral ... Stage IV Cutane... Stage IV Uveal ...	Ipilimumab Laboratory Biom... Nivolumab Relatlimab Therapeutic Con...	18 Years -	M.D. Anderson Cancer Center
Neoadjuvant and Adjuvant Checkpoint Blockade	NCT02519322	Cutaneous Melan... Mucosal Melanom... Ocular Melanoma Stage III Acral... Stage IIIB Cuta... Stage IIIB Uvea... Stage IIIC Cuta... Stage IIIC Uvea... Stage IV Acral ... Stage IV Cutane... Stage IV Uveal ...	Ipilimumab Laboratory Biom... Nivolumab Relatlimab Therapeutic Con...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for stage iii acral lentiginous melanoma ajcc v7