Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Eye Diseases

Rare Diseases

Recurrence

Melanoma

Uveal Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Eye Neoplasms

Uveal Diseases

Ocular Melanoma

Intraocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Imidazole

Temozolomide

Dacarbazine

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate

Laboratory Biomarker Analysis

Jason J Luke

This randomized phase II trial studies how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye (ocular melanoma) that has spread to other parts of the body and cannot be removed by surgery. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cabozantinib-s-malate works better than temozolomide or dacarbazine in treating patients with melanoma of the eye.

PRIMARY OBJECTIVES:

I. Compare the progression-free survival rate at 4 months (PFS4) of patients with ocular melanoma treated with cabozantinib-s-malate (cabozantinib) or temozolomide (or dacarbazine).

SECONDARY OBJECTIVES:

I. Estimate the distribution of progression-free survival (PFS) times. II. Estimate the distribution of overall survival (OS) times. III. Estimate the confirmed response rate as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

IV. Assess the safety of these agents by examining the toxicity profile. V. Correlate the response of MET molecular status.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine intravenously (IV) over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Metastatic Melanoma of the Eye That Cannot Be Removed by Surgery

Randomized Phase II Study Comparing the MET Inhibitor Cabozantinib to Temozolomide/Dacarbazine in Ocular Melanoma

The proportions of patients within these groups pre-treatment will be presented with 90% exact binomial confidence intervals. These findings will be correlated with overall survival using a Student's T-test.

A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The success for each arm will be calculated independently as the number of successes divided by the total number of evaluable patients. A one-sided chi-squared test for a difference in PFS4 proportions will be used to test for a difference between arms.

The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated.

percentage of patients who experienced grade 3+ adverse events regardless of attribution, graded according to the National Cancer Institute CTCAE version 4.0

The distribution of OS time will be estimated using the method of Kaplan Meier.

The distribution of PFS time will be estimated using the method of Kaplan Meier and is defined as the number of days from registration until disease progression (or death). Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Exelisis

National Cancer Institute (NCI)

Patients receive 60 mg cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm I (Cabozantinib-s-malate)

Patients receive 150 mg/m\^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arm II (Temozolomide)

Patients receive 1000 mg/m\^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Arm II (Dacarbazine)

Patients receive 150 mg/m\^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. \>\>

\>\> If temozolomide is not available, patients receive 1000 mg/m\^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Arm II (Temozolomide or Dacarbazine)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Canada

United States

Region of Enrollment

All participants that began study treatment are included in the baseline analysis.

Jason J. Luke, M.D.

A one-sided chi-squared test for a difference in PFS4 rates will be used to test for a difference between arms.

Patients receive 150 mg/m\^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

\>

\> If temozolomide is not available, patients receive 1000 mg/m\^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

All patients that began protocol treatment were included in this analysis.

Proportion of Patients Without a Progression Free Survival Event at 4 Months (PFS4)

Patients receive 150 mg/m\^2 temozolomide PO daily on days 1-5 of a 28 day cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

If temozolomide is not available, patients receive 1000 mg/m\^2/day dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Confirmed Response Rate as Determined by the RECIST Criteria (Version 1.1)

Percentage of Patients Who Experienced Grade 3+ Adverse Events Regardless of Attribution

Overall Survival (OS)

Pre-treatment GNAQ/GNA11 and Potentially Other Mutations in Tissue

Pre-treatment Immune Gene Expression in Tissue Defined as T Cell-inflamed, Intermediate and Non-T Cell-inflamed

Overall Study

Melanoma, Cutaneous Malignant

Acral Lentiginous Melanoma

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.

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.

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

Age, Categorical

Ethnicity (NIH/OMB)

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
Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Metastatic Melanoma of the Eye That Cannot Be Removed by Surgery	NCT01835145	Recurrent Uveal... Stage III Uveal... Stage IIIA Uvea... Stage IIIB Uvea... Stage IIIC Uvea... Stage IV Uveal ...	Cabozantinib S-... Dacarbazine Laboratory Biom... Temozolomide	18 Years -	National Cancer Institute (NCI)
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 iiib uveal melanoma ajcc v7