This phase Ib/II trial studies the best dose of glembatumumab vedotin when giving together with nivolumab and ipilimumab in treating patients with solid tumor that has spread to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as glembatumumab vedotin, nivolumab, and ipilimumab, may interfere with the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) for the combination of glembatumumab vedotin and nivolumab in patients with solid tumors. (Phase Ib) II. To evaluate the antitumor activity of the combination in 4 expansion cohorts (melanoma, uveal melanoma, GPNMB overexpressing triple negative breast cancer \[TNBC\], other GPNMB overexpressing solid tumors) as measured by overall response by Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST)/Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase II) SECONDARY OBJECTIVES: I. To characterize the safety and toxicity profile of the combination. II. To evaluate the clinical benefit rate (no disease progression within 6 months), progression free survival (PFS), and overall survival (OS) in patients receiving the combination treatment. III. To evaluate the pharmacokinetics (PK) of glembatumumab vedotin and nivolumab in combination in serum and in mononuclear phagocyte system (MPS) cells in peripheral blood mononuclear cells. IV. Profile differences in the type, number and density of Fc-receptors (FcgammaR) on MPS cells in blood of patients prior to and after administration of glembatumumab vedotin and nivolumab as a method to evaluate the factors affecting PK and pharmacodynamics (PD) variability and mechanisms of drug-drug interactions. V. Characterize differences in chemokines (CCL2 and CCL5) and other cytokines in blood of patients prior to and after administration of glembatumumab vedotin and nivolumab as a method to evaluate the factors affecting PK and PD variability and mechanisms of drug-drug interactions. VI. To evaluate the pharmacodynamic (PD) effects of the combination in plasma and tissue biomarkers. OUTLINE: Patients receive glembatumumab vedotin intravenously (IV) over 90 minutes and nivolumab IV over 60 minutes on day 8 of course 1 and on day 1 of subsequent courses. Patients in melanoma expanded cohort also receive ipilimumab IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 21 days for 4 courses in the absence of disease progression or unaccepted toxicity and courses with glembatumumab vedotin and nivolumab repeat every 21 days in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up for 4 weeks and then at 30 and 70 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Given IV
Given IV
Correlative studies
Given IV
Correlative studies
Recommended phase 2 dose for the combination of glembatumumab vedotin and nivolumab (Phase Ib)
All adverse events and toxicities will be tabulated and reported by type and grade for all dose levels of all treatment combinations and the proportions will be reported with exact 90% binomial confidence intervals.
Time frame: Up to 21 days
Antitumor activity measured by Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST)/Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase II)
Descriptive statistics and graphical analysis will be used to summarize patients' demographic and clinicopathological characteristics, patient safety and efficacy outcomes and correlative markers. Overall response rates will be calculated and 2-sided 90% confidence intervals will also be provided for each cohort.
Time frame: Up to 70 days
Incidence of adverse events
Will be assessed by Common Terminology Criteria for Adverse Events version 4.03. Will be tabulated and reported by type and grade for each cohort and the proportions will be reported with exact 90% binomial confidence intervals.
Time frame: Up to 70 days
Overall response rate
Will be analyzed by the Kaplan-Meier method. The association between subgroups of interest and response to treatment will be assessed using Fisher's exact test.
Time frame: Up to 70 days
Clinical benefit rate
Will be analyzed by the Kaplan-Meier method. The association between subgroups of interest and response to treatment will be assessed using Fisher's exact test.
Time frame: Up to 70 days
Progression free survival
Will be analyzed by the Kaplan-Meier method. The association between subgroups of interest and response to treatment will be assessed using Fisher's exact test.
Time frame: Up to 70 days
Overall survival
Will be analyzed by the Kaplan-Meier method. The association between subgroups of interest and response to treatment will be assessed using Fisher's exact test.
Time frame: Up to 70 days
Pharmacokinetic parameters
The pharmacokinetics (PK) of glembatumumab vedotin and nivolumab in combination in serum and in mononuclear phagocyte system (MPS) cells in peripheral blood mononuclear cells will also be assessed descriptively. The descriptive statistics of plasma concentration-time data will first be tabulated. PK parameters will be estimated using both standard non-compartmental and compartmental methods. A repeated measurement statistical model will also be used to perform intra patient evaluation of changes in PK.
Time frame: Up to 70 days
Levels of plasma and tissue biomarkers
PD-L1 and other immune biomarkers including tumor infiltrating lymphocytes before and after treatment (after glembatumumab vedotin, and then after the combination) will be described using summary statistics. The change of immune markers will be assessed using linear mixed model for repeated measurement data. Data transformation will be performed if necessary to better satisfy the assumption of normality distribution. Univariate and multivariate logistic regression models will be used to evaluate predictive ability of these baseline biomarkers on the response to the combination of glembatumumab vedotin and nivolumab. Receiver operating characteristic (ROC) curves will be used to explore the optimal cut-off points for each biomarker to differentiate responders versus non-responders. The predictive ability will also be summarized using the area under ROC curves (AUC), and the 95% confidence intervals of AUC will be obtained using bootstrap resampling methods.
Time frame: Up to 70 days
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