Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Cancers After Progression on PD-1 or PD-L1 Targeted Antibodies

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.