This is a two-agent, open-label, non-randomized, Phase 1/2 dose escalation and dose expansion study of combinatorial oral vorolanib plus infusional nivolumab in patients with Non-Small Cell Lung Cancer naïve to checkpoint inhibitor therapy, Non-Small Cell Lung Cancer who have progressed on checkpoint inhibitor therapy, Small Cell Lung Cancer ( who have progressed on platinum-based chemotherapy, and thymic carcinoma.
Primary Objectives: * Phase I: To assess the safety and tolerability of nivolumab and vorolanib in combination in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma. * Phase II: To evaluate the efficacy as measured by response to the combination nivolumab and vorolanib in patients with refractory non small cell lung cancer naïve to checkpoint inhibitor therapy, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered primary refractory, non small cell lung cancer progressed on prior checkpoint inhibitor therapy considered acquired resistance, small cell lung cancer progressed on platinum-based chemotherapy, and thymic carcinoma as compared to historical controls. Secondary Objectives: * Phase I: To assess antitumor activity as measured by response rate for this novel combination. * Phase II: To assess, safety, progression free survival and overall survival Exploratory Objectives: • To assess the effects of combinatorial treatment on specific pharmacodynamic and pharmacogenetic biomarkers including PD-L1 expression and tumor mutation burden.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
88
Stanford Cancer Institute
Palo Alto, California, United States
Winship Cancer Institute, Emory University
Atlanta, Georgia, United States
University of Chicago Medical Center
Chicago, Illinois, United States
Providence Cancer Institute Franz Clinic
Portland, Oregon, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Baptist Clinical Research Institute
Memphis, Tennessee, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Recommended Phase II Combination Dose in Phase I (Per Common Terminology Criteria for Adverse Events (CTCAE) Criteria Version 5)
Maximum tolerated dose for vorolanib daily combined with 240mg nivolumab every 2 weeks based on 3+3 dose escalation design. When 2 out of 6 patients at one dose experienced dose limiting toxicity, lower dose will be used. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: At 28 days
Objective Response Rate in Phase II.
Antitumor activity will be assessed by objective response rate. Best response is determined as complete response(CR), partial response(PR), stable disease and progressive disease based on per Response Evaluation Criteria in Solid Tumors (RECIST). Objective response rate is the percentage of patients who had a CR or PR. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: Up to 1 year.
Progression Free Survival in Phase II
Antitumor activity will be assessed by progression free survival. Progression is termined per Response Evaluation Criteria in Solid Tumors (RECIST). Progression free survival (PFS) is defined as time from on treatment to disease progression or death (whicever comes first). Those without progression and alive were censored at last follow up. Kaplan-meier method is used to estimate the median survival time. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: Up to 1 year.
Duration of Response in Phase II.
Duration of best response among patients who responsed to the treatment. Best response per Response Evaluation Criteria in Solid Tumors (RECIST). The duration of response was estimated from the first date of best overall response of a complete (CR) or partial response (PR) to the date of disease progression or death, using the Kaplan-Meier method. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: Up to 1 year
Disease Control Rate in Phase II. Best Response Per Response Evaluation Criteria in Solid Tumors (RECIST)
Antitumor activity will be assessed by disease control rate. Best response (complete response,CR; partial response, PR;stable disease , SD; or progression,PD) per Response Evaluation Criteria in Solid Tumors (RECIST). Disease control rate is the percentage of patients who had a CR,PR or SD. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: Up to 1 year
Overall Survival in Phase II.
Antitumor activity will be assessed by overall survival. Overall survial is defined as the time from on treatment to death. Those alive were censored at last follow up. Kaplan-meier method is used to estimate the median overall survival time. We have specified the phase I and phase II populations as study arms; note outcome measures are then distinct for each arm, with the phase I arm intended to assess safety (MTD), and the phase 2 arm intended to assess efficacy, as typical for phase I-II studies. Thus, for each outcome, only the phase I cohort is included in the analysis population, or only the phase II cohort is including in the analysis population, as relevant to the outcome measure.
Time frame: Up to 2 years.
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