Melanoma
Conditions
Keywords
Advanced melanoma, Unresectable melanoma, Metastatic melanoma, Targeted Treatment for melanoma, GPNMB, CDX-011, Glembatumumab vedotin, Antibody-drug-conjugate, Skin neoplasm, Varlilumab, CDX-1127
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.
Interventions
DRUGglembatumumab vedotin and varlilumab
DRUGglembatumumab vedotin and PD-1 targeted checkpoint inhibitor (nivolumab OR pembrolizumab)
DRUGglembatumumab vedotin and CDX-301
Sponsors
Celldex Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Every 6 to 9 weeks following treatment initiation until disease progression. | 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. |
| Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Up to 18 months following the screening visit | The percentage of patients experiencing one or more adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | During treatment and every 3 months from end of treatment through death or end of study | Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause. |
| Duration of Response (DOR) | 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. | 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. |
| Adverse Events | 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) | The percentage of patients experiencing one or more AEs will be summarized by relationship to study drug and severity. |
| Correlation of Activity to gpNMB Expression | Up to 18 months following the screening visit | 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. |
| Progression-free Survival (PFS) | Evaluated every 6 to 9 weeks following treatment initiation until progression. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Glembatumumab Vedotin glembatumumab vedotin administered as an intravenous infusion on Day 1 of each 21 day cycle.
glembatumumab vedotin | 62 |
| Glembatumumab Vedotin and Varlilumab 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.
glembatumumab vedotin and varlilumab | 34 |
| Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor 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.
glembatumumab vedotin and PD-1 targeted checkpoint inhibitor (nivolumab OR pembrolizumab) | 29 |
| Glembatumumab Vedotin and CDX-301 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.
glembatumumab vedotin and CDX-301 | 7 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Glembatumumab Vedotin | Glembatumumab Vedotin and Varlilumab | Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor | Glembatumumab Vedotin and CDX-301 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 36 Participants | 13 Participants | 18 Participants | 1 Participants | 68 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 21 Participants | 11 Participants | 6 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 2 Participants | 0 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 32 Participants | 27 Participants | 7 Participants | 123 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 61 Participants | 32 Participants | 27 Participants | 6 Participants | 126 Participants |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 11 Participants | 4 Participants | 57 Participants |
| Sex: Female, Male Male | 34 Participants | 20 Participants | 18 Participants | 3 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 53 / 62 | 26 / 34 | 8 / 29 | 1 / 7 |
| other Total, other adverse events | 61 / 62 | 34 / 34 | 29 / 29 | 7 / 7 |
| serious Total, serious adverse events | 19 / 62 | 14 / 34 | 14 / 29 | 2 / 7 |
Outcome results
Primary
Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4).
The percentage of patients experiencing one or more adverse events.
Time frame: Up to 18 months following the screening visit
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Leukopenia | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Abdominal pain | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Constipation | 2 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Dyspepsia | 2 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Nausea | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Stomatitis | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Vomiting | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Fatigue | 3 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Hepatic pain | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Mucosal infection | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Urinary tract infection | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Alanine aminotransferase increased | 2 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Aspartate aminotransferase increased | 3 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Blood alkaline phosphatase increased | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Neutrophil count decreased | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Platelet count decreased | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Weight decreased | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Decreased appetite | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Hyperglycemia | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Hyperuricemia | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Hypokalemia | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Myalgia | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Pain in extremity | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Peripheral sensory neuropathy | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Anxiety | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Depression | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Vaginal hemorrhage | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Vulvovaginal pain | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Epistaxis | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Alopecia | 3 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Rash erythematous | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Rash maculopapular | 3 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Skin discoloration | 1 Participants |
| Glembatumumab Vedotin | Adverse Events of the Combination of Glembatumumab Vedotin and CDX-301 (in Cohort 4). | Hypertension | 1 Participants |
Primary
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.
Time frame: Every 6 to 9 weeks following treatment initiation until disease progression.
Population: Response evaluable (at least one dose and a post treatment disease assessment)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glembatumumab Vedotin | Objective Response Rate (ORR) | 7 Participants |
| Glembatumumab Vedotin and Varlilumab | Objective Response Rate (ORR) | 1 Participants |
| Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor | Objective Response Rate (ORR) | 4 Participants |
| Glembatumumab Vedotin and CDX-301 | Objective Response Rate (ORR) | 0 Participants |
Secondary
Adverse Events
The percentage of patients experiencing one or more AEs will be summarized by relationship to study drug and severity.
Time frame: 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)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glembatumumab Vedotin | Adverse Events | 61 Participants |
| Glembatumumab Vedotin and Varlilumab | Adverse Events | 34 Participants |
| Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor | Adverse Events | 29 Participants |
| Glembatumumab Vedotin and CDX-301 | Adverse Events | 7 Participants |
Secondary
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.
Time frame: Up to 18 months following the screening visit
Population: Analysis not completed. gpNMB expression in tumor tissue was not done.
Secondary
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.
Time frame: 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.
Population: Number of patients analyzed are the number of patients who achieved an objective response per Cohort. The response was observed at the last measurement without further follow up due to study closure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glembatumumab Vedotin | Duration of Response (DOR) | 6.0 months |
| Glembatumumab Vedotin and Varlilumab | Duration of Response (DOR) | 2.2 months |
| Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor | Duration of Response (DOR) | 6.2 months |
Secondary
Overall Survival (OS)
Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause.
Time frame: During treatment and every 3 months from end of treatment through death or end of study
Population: Response evaluable (at least one dose and a post treatment disease assessment). The analysis was not completed for the glembatumumab + CDX-301 cohort or the glembatumumab vedotin and PD-1 targeted checkpoint inhibitor cohort because sufficient data were not collected to perform the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glembatumumab Vedotin | Overall Survival (OS) | 8.8 months |
| Glembatumumab Vedotin and Varlilumab | Overall Survival (OS) | 6.6 months |
Secondary
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.
Time frame: Evaluated every 6 to 9 weeks following treatment initiation until progression.
Population: Response evaluable (at least one dose and a post treatment disease assessment). The analysis was not completed for the glembatumumab + CDX-301 cohort because sufficient data were not collected to perform the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glembatumumab Vedotin | Progression-free Survival (PFS) | 4.4 months |
| Glembatumumab Vedotin and Varlilumab | Progression-free Survival (PFS) | 2.6 months |
| Glembatumumab Vedotin and PD-1 Targeted Checkpoint Inhibitor | Progression-free Survival (PFS) | 4.1 months |