Metastatic Malignant Solid Neoplasm Clinical Trial
Official title:
DNA Damage Repair (DDR) Inhibitor-Based Basket of Baskets Phase I/II Trial in Patients With Advanced Solid Tumors Harboring Aberrations in DDR Genes (D-BoB)
This phase I/II trial studies the side effects and best dose of avelumab with M6620 in treating patients with deoxyribonucleic acid (DNA) damage repair (DDR) deficient solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). DDR deficiency refers to a decrease in the ability of cells to respond to damaged DNA and to repair the damage, which can be caused by genetic mutations. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving avelumab together with M6620 may help to control DDR deficient metastatic or unresectable solid tumors.
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of the combination of berzosertib (M6620) and avelumab in patients with DNA damage response (DDR) deficient advanced solid tumors. (Arm A: M6620 + avelumab) II. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of M6620 and avelumab in patients with DDR deficient advanced solid tumors. (Arm A: M6620 + avelumab) SECONDARY OBJECTIVES: I. To determine the clinical benefit of the combination as defined by clinical benefit rate (CBR) - complete response [CR] + partial response [PR] + stable disease [SD] > 6 months (CR + PR + SD > 6 months). (Arm A: M6620 + avelumab) II. To assess clinical benefit of the combination as defined by objective response rate (ORR), overall survival (OS), duration of response (DoR) and progression free survival (PFS). (Arm A: M6620 + avelumab) EXPLORATORY OBJECTIVES: I. To evaluate clinical benefit of the combination of M6620 and avelumab based on specific DDR aberrations. (Arm A: M6620 + avelumab) II. To evaluate clinical benefit of the combination of M6620 and avelumab based on DDR gene expression signatures. (Arm A: M6620 + avelumab) III. To evaluate the impact of treatment on programmed death ligand 1 (PD-L1) expression and immune cell populations. (Arm A: M6620 + avelumab) IV. To assess potential mechanisms of resistance by comparing pre- and on-treatment biopsies in responders and non-responders. (Arm A: M6620 + avelumab) V. To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of M6620 in combination with avelumab in patients with DDR deficient advanced solid tumors. (Arm A: M6620 + avelumab) OUTLINE: This is a phase I, dose-escalation study of M6620, followed by a phase II study. Patients receive avelumab intravenously (IV) over 60 minutes on days 1 and 15, and M6620 IV over 60 minutes on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30, 60, and 90 days, then every 12 weeks afterwards. ;
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