Clinical trial NCT02302339: A Study of Glembatumumab Vedotin as Monotherapy or in Combination With Immunotherapies in Patients With Advanced Melanoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Melanoma
Keywords: Advanced melanoma
Unresectable melanoma
Metastatic melanoma
Targeted Treatment for melanoma
GPNMB
CDX-011
Glembatumumab vedotin
Antibody-drug-conjugate
Skin neoplasm
Varlilumab
CDX-1127
Lead sponsor: Celldex Therapeutics
Sponsor class: INDUSTRY
First posted: 2014-11-27
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. BRAF or MEK inhibitors within 2 weeks
  2. Monoclonal based therapies within 4 weeks except for the PD-1 targeted checkpoint inhibitor in cohort 3
  3. Immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks
  4. Chemotherapy within 21 days or at least 5 half-lives (whichever is longer)
  5. 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:

  1. Patients with adequately treated and cured non-melanoma skin cancer or in situ cancer
  2. 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)

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Every 6 to 9 weeks following treatment initiation until disease progression.
measure: Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4).
timeFrame: Up to 18 months following the screening visit
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: 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.
measure: Progression-free Survival (PFS)
timeFrame: Evaluated every 6 to 9 weeks following treatment initiation until progression.
measure: Overall Survival (OS)
timeFrame: During treatment and every 3 months from end of treatment through death or end of study
measure: Correlation of Activity to gpNMB Expression
timeFrame: Up to 18 months following the screening visit
measure: Adverse Events
timeFrame: 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)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: San Francisco
country: United States
facility: Northern California Melanoma Center/St. Mary's Medical Center
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Institute-Sammons Cancer Center
state: Texas
Study officials:
References: