Olaparib and Durvalumab With Carboplatin, Etoposide, and/or Radiation Therapy for the Treatment of Extensive-Stage Small Cell Lung Cancer, PRIO Trial

Stage IV Lung Cancer AJCC v8 Clinical Trial

Official title: A Phase I/II Trial of PARP Inhibition, Radiation, and Immunotherapy in Patients With Extensive-Stage Small Cell Lung Cancer (ES-SCLC) - PRIO Trial

Status Recruiting

Clinical Trial Summary

This phase I/II trials investigates the side effects of olaparib and durvalumab and how well it works in combination with carboplatin, etoposide, and/or radiation therapy in treating patients with extensive stage-small cell lung cancer (ES-SCLC) who have not received treatment for their disease. PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as carboplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy sources to kill tumor cells and shrink tumors. Giving olaparib and durvalumab together with carboplatin, etoposide, and/or radiation therapy may help treat patients with ES-SCLC.

Clinical Trial Description

PRIMARY OBJECTIVE:

I. To assess the toxicity and feasibility of sequential treatment with olaparib, thoracic radiotherapy (TRT)/durvalumab, and olaparib/durvalumab for consolidation and maintenance therapy in patients status post (s/p) chemoimmunotherapy for ES-SCLC.

SECONDARY OBJECTIVE:

I. To assess the efficacy of sequential treatment with olaparib, TRT/durvalumab, and olaparib/durvalumab for consolidation and maintenance therapy in patients s/p chemoimmunotherapy for ES-SCLC.

EXPLORATORY OBJECTIVES:

I. Perform a comparative analysis of patient clinical outcome according to tumor biomarkers in circulating tumor cell (CTC), blood samples and tumor tissue, such as SLFN11 expression H- scores and stratifying tumors as SLFN11 positive or negative on the basis of H-score >= 1.

II. Perform a comparative analysis of patient clinical outcome according to immune biomarkers in blood and tumor tissue, such as PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay and stratifying tumors as PD-L1 positive or negative on the basis of PD-L1 combined positive score >= 1% in patients treated with anti- PD-L1 therapy.

III. Perform whole exome sequencing (WES) and methylation profiling on tumor samples and from circulating-free deoxyribonucleic acid (cfDNA) to evaluate whether tumor mutational burden (TMB) or specific genomic alterations are associated with improved progression free survival (PFS) with the trial regimen.

IV. Gene and protein expression of tumor tissue through ribonucleic acid (RNA) sequencing and Reverse Phase Protein Array (RPPA).

V. Quantify pre-treatment, pre- and post-olaparib, post-TRT, and at progression levels for blood-based biomarkers, such as cytokines associated with immune activation (e.g., STING pathway cytokines, CXCL10 and CCL5) to establish correlations with PFS and overall survival (OS).

VI. Using longitudinal blood samples (e.g. pre-treatment, pre- and post-olaparib, post-TRT, and at progression), assess CTC number, CTC (single-cell) biomarker expression (such as SLFN11 and PD-L1 expression), and immune profile of PBMCs.

VIa. Correlate baseline expression or changes with PFS and OS. VII. Assess pre- and post-olaparib, and at progression tumor tissue for immune markers, such as CD8+ T cells, through multiplex IHC.

VIII. Assessment of single-cell biomarker expression on CTCs and tumor tissue (such as SLFN11 and PD-L1 expression) and immune profile of peripheral blood mononuclear cells (PBMCs).

VIIIa. Correlate pre-treatment expression or changes with PFS and/or OS. IX. Generation of CTC-derived and/or biopsy-derived xenograft models from individual patients

OUTLINE:

CHEMO-IMMUNOTHERAPY: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1, carboplatin IV over 60 minutes on day 1, etoposide IV over 60 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with response or stable disease (SD) after cycle 4 and are candidates for TRT proceed to Induction. Patients that are not candidates for TRT proceed to Single-Agent Maintenance.

INDUCTION (WEEKS 13-14): Patients receive olaparib orally (PO) twice daily (BID) on days 1-11 in the absence of disease progression or unacceptable toxicity.

IMMUNORADIATION (WEEKS 15-18): Patients receive durvalumab IV over 60 minutes on day 1. Patients also undergo consolidative TRT daily on days 1-5 and 8-12 in the absence of disease progression or unacceptable toxicity.

MAINTENANCE (WEEKS 19 AND BEYOND): Patients without progressive disease receive durvalumab IV over 60 minutes on day 1, and olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

SINGLE-AGENT MAINTENANCE: Patients receive durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 30 days, then every 3 months. ;

Related Conditions & MeSH terms

• Carcinoma, Small Cell
• Extensive Stage Lung Small Cell Carcinoma
• Lung Neoplasms
• Small Cell Lung Carcinoma
• Stage IV Lung Cancer AJCC v8
• Stage IVA Lung Cancer AJCC v8
• Stage IVB Lung Cancer AJCC v8

• NCT number: NCT04728230
• Study type: Interventional
• Source: M.D. Anderson Cancer Center
• Contact: Marcelo V Negrao
• Phone: 713-792-6363
• Email: mvnegrao@mdanderson.org
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 5, 2021
• Completion date: December 31, 2025