A Study of Glembatumumab Vedotin as Monotherapy or in Combination With Immunotherapies in Patients With Advanced Melanoma

Study Overview
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Brief Summary
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This study will examine the effectiveness and safety of glembatumumab vedotin as monotherapy or in combination with immunotherapies in patients with advanced melanoma.

Detailed Description
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Glembatumumab vedotin consists of an antibody attached to a drug, monomethyl auristatin E (MMAE), that can kill cancer cells. The fully human antibody is designed to deliver the drug to cancer cells by attaching to a protein called glycoprotein NMB (gpNMB) that is expressed on the cancer cell. The MMAE is then released inside of the cell, where it interferes with cell growth and can lead to cell death of the targeted cell, as well as neighboring cells. Varlilumab is a fully human antibody that binds to CD27. This antibody allows the body's immune system to work against cancer cells. Nivolumab is a fully human antibody and pembrolizumab is a humanized antibody. Both bind to PD-1. CDX-301 is a fully human protein that helps boost production of certain white blood cells. This protein allows the body's immune system to work against tumor cells. Eligible patients who enroll in the study will receive treatment with one of the following: glembatumumab vedotin, glembatumumab vedotin and varlilumab, glembatumumab vedotin and CDX-301 or glembatumumab vedotin and either nivolumab OR pembrolizumab. All patients enrolled in the study will be closely monitored to determine if their cancer is responding to treatment and for any side effects that may occur.

Official Title
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A Phase 2 Study of Glembatumumab Vedotin, an Anti-gpNMB Antibody-drug Conjugate, as Monotherapy or in Combination With Immunotherapies in Patients With Advanced Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: glembatumumab vedotin
* Drug: glembatumumab vedotin and varlilumab
* Drug: glembatumumab vedotin and PD-1 targeted checkpoint inhibitor (nivolumab OR pembrolizumab)
* Drug: glembatumumab vedotin and CDX-301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Among other criteria, patients must meet all of the following conditions to be eligible for the study: Unresectable, histologically-confirmed advanced (Stage III or Stage IV) melanoma Disease progression during or after the last anticancer therapy received. For Cohort 3, progression must have occurred during the PD-1 targeted CPI (checkpoint inhibitor) treatment and the investigator has deemed it appropriate to continue treatment with the PD-1 targeted CPI beyond confirmed disease progression No more than one prior chemotherapy-containing regimen for advanced disease. Prior treatments received must include at least one CPI inhibitor (e.g., anti-CTLA-4, PD-1-, PD-L1-targeted immunotherapy) and for patients with a BRAF mutation at least one BRAF- or MEK-targeted therapy, unless patients are not candidates for, or refused, these therapies. For cohort 3, prior treatment received must include a PD-1 targeted CPI administered during the most recent disease progression and for patients with BRAF mutation at least one BRAF- or MEK-targeted therapy when appropriate The study site will submit paraffin-embedded tumor tissue obtained from the patient for gpNMB analysis. Patients may require a biopsy if recent tumor tissue is not available. Patients in cohort 2 and 3 must submit a recently obtained biopsy of the skin fold for gpNMB analysis. Patients in Cohort 4 will submit a tumor tissue sample while on study. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 Adequate bone marrow, liver and renal function. Exclusion Criteria: Among other criteria, patients who meet any of the following conditions are NOT eligible for the study: Previously received glembatumumab vedotin (CR011-vcMMAE, CDX-011) or other MMAE-containing agents Treatment with the following therapies before the planned start of study treatment: BRAF or MEK inhibitors within 2 weeks Monoclonal based therapies within 4 weeks except for the PD-1 targeted checkpoint inhibitor in cohort 3 Immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks Chemotherapy within 21 days or at least 5 half-lives (whichever is longer) Investigational therapy within 2 weeks (or at least 5 half-lives, whichever is longer) Patients with ocular melanoma Neuropathy that is moderate (Grade 2) or worse. Cancer that has spread to the brain or spine will be discussed with the study sponsor and may exclude patients from the trial. History of another cancer except: Patients with adequately treated and cured non-melanoma skin cancer or in situ cancer Patients with any other cancer from which the patient has been disease-free for ≥ 3 years Significant cardiovascular disease Previously received varlilumab or any other anti-CD27 mAb (Cohort 2 only) Active systemic infection requiring treatment Treatment with immunosuppressive medications within 4 weeks or corticosteroids within two weeks Patients with interstitial lung disease (Cohort 3 only) Patients with active diverticulitis (Cohort 3 only) Any non-study vaccination within 4 weeks, or influenza vaccine within 2 weeks, prior to CDX-301 dosing (Cohort 4 only)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glembatumumab vedotin<br>glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. | Drug: glembatumumab vedotin<br> <br> * Other names: Cohort 1;|
| Experimental: Glembatumumab vedotin and varlilumab<br>glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. Varlilumab administered as an intravenous infusion on Day 1 of cycles 1, 2, 4, 6, 8 and 10. | Drug: glembatumumab vedotin and varlilumab<br> <br> * Other names: Cohort 2;|
| Experimental: Glembatumumab vedotin and PD-1 targeted checkpoint inhibitor<br>glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. Nivolumab OR pembrolizumab administered according to institutional standard of care. | Drug: glembatumumab vedotin and PD-1 targeted checkpoint inhibitor (nivolumab OR pembrolizumab)<br> <br> * Other names: Cohort 3;|
| Experimental: Glembatumumab vedotin and CDX-301<br>glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle. CDX-301 is injected once a day for five days before cycles 1 and 2. | Drug: glembatumumab vedotin and CDX-301<br> <br> * Other names: Cohort 4;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients who achieved best overall response of complete or partial response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST version 1.1), Complete Response (CR) = disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions. ORR was the primary outcome for Cohorts 1-3 and a secondary outcome for Cohort 4. | Every 6 to 9 weeks following treatment initiation until disease progression. | 
| Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | The percentage of patients experiencing one or more adverse events. | Up to 18 months following the screening visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR is the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented per RECIST 1.1. | From start date of partial or complete response (whichever is achieved first) to first date that recurrent of progressive disease is objectively documented, assessed up to 18 months. | 
| Progression-free Survival (PFS) | PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or progression in a non-target lesion, or the appearance of new lesions. | Evaluated every 6 to 9 weeks following treatment initiation until progression. | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause. | During treatment and every 3 months from end of treatment through death or end of study | 
| Correlation of Activity to gpNMB Expression | To investigate if the anti-cancer activity of glembatumumab vedotin as monotherapy or in combination with immunotherapies in advanced melanoma is dependent upon the degree of gpNMB expression in tumor tissue. | Up to 18 months following the screening visit | 
| Adverse Events | The percentage of patients experiencing one or more AEs will be summarized by relationship to study drug and severity. | Following at least one dose of study treatment through 28 days after last dose of glembatumumab vedotin, or 70 calendar days after last administration of varlilumab, CDX-301 or PD-1 targeted checkpoint inhibitor (whichever occurs latest) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced melanoma, Unresectable melanoma, Metastatic melanoma, Targeted Treatment for melanoma, GPNMB, CDX-011, Glembatumumab vedotin, Antibody-drug-conjugate, Skin neoplasm, Varlilumab, CDX-1127