This phase Ib/II trial studies the side effects and best dose of plinabulin in combination with radiation therapy and immunotherapy in patients with select cancers that have spread to other places in the body (advanced) after progression on PD-1 or PD-L1 targeted antibodies. Plinabulin blocks tumor growth by targeting both new and existing blood vessels going to the tumor as well as killing tumor cells. Immunotherapy may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving plinabulin in combination with radiation therapy and immunotherapy may work better in treating advanced cancers.
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of plinabulin when administered in combination with radiation/immunotherapy regimen in subjects with select advanced solid malignancies after progression on anti-PD-1/PD-L1 monoclonal antibody (mAb). II. To assess the objective tumor response rate (complete response + partial response). SECONDARY OBJECTIVES: I. To assess disease control rate (complete response, partial response + stable disease). II. To determine progression-free survival (PFS). III. To assess overall survival. EXPLORATORY OBJECTIVES: I. To analyze the gene mutation density within each sample. II. To assess T-cell receptor (TCR) sequencing in tumor tissue and peripheral blood, pre- and post- treatment. III. To perform imaging mass flow cytometry (CyTOF) and/or single cell ribonucleic acid sequencing (RNAseq) analysis on tumor tissue: Immune phenotyping, including dendritic cell (DC), T cells, tumor-associated macrophage (TAM)s, pre and post treatment. IV. To conduct phenotyping analysis of immune cells from peripheral blood using multicolor flow cytometry. V. To evaluate dendritic cell activation from whole blood upon the treatment. VI. To explore general predictive and response biomarker measurements from the collected biomarkers. OUTLINE: This is a phase Ib, dose-escalation study of plinabulin followed by a phase II study. Patients are randomized to 1 of 2 arms. ARM A: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients receive plinabulin intravenously (IV) over 30-60 minutes on days 1 and 4 of cycle 1, days 1 and 4 of cycle 2 (if receiving radiation therapy in cycle 2), and day 1 and or 15 (any day receiving immunotherapy) of subsequent cycles. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
19
Given IV
Given IV
Given IV
Given IV
Given IV
Given IV
Undergo radiation therapy
M D Anderson Cancer Center
Houston, Texas, United States
Incidence of adverse events (AEs)
AEs will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Up to 30 days after last dose of plinabulin
Objective tumor response rate (ORR) (complete response + partial response)
Radiologic evaluations will be performed at screening and every 9 weeks (± 1 week) for 27 weeks (during Q3W dosing) or every 8 weeks (± 1 week) for 24 weeks (during Q4W dosing), then every 12 weeks during treatment cycles in the Treatment Phase regardless of treatment cycles and follow up period. Categorization of response will be based on both immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) and modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
Time frame: Up to 4 years
Disease control rate (complete response, partial response + stable disease)
Assessed according to irRECIST criteria.
Time frame: Up to 4 years
Progression-free survival
Will be analyzed using Kaplan-Meier method or Cox regression.
Time frame: From the first study dose date to the date of first documentation of confirmed disease progression or death (whichever occurs first), assessed up to 4 years
Overall survival
Will be analyzed using Kaplan-Meier method or Cox regression.
Time frame: From the start date of the treatment period until date of death from any cause, assessed up to 4 years
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