Advanced Malignant Solid Neoplasm Clinical Trial
Official title:
A Phase 1b Biomarker-Driven Combination Trial of Copanlisib, Olaparib, and Durvalumab (MEDI4736) in Patients With Advanced Solid Tumors
This phase Ib trial studies side effects and best dose of copanlisib and olaparib when given together with durvalumab, and how well they work in treating patients with solid tumors that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving combinations of copanlisib and olaparib or copanlisib, olaparib, and durvalumab may work better in treating patients with solid tumors compared to usual treatments such as surgery, radiation, or other chemotherapy drugs.
PRIMARY OBJECTIVE: I. To evaluate the safety and establish the recommended phase 2 dose (RP2D) of the doublet combination of copanlisib and olaparib and of the triplet combination of copanlisib, olaparib and MEDI4736 (durvalumab) in patients with molecularly-selected solid tumors. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity of the doublet combination of copanlisib and olaparib, and of the triplet combination of copanlisib, olaparib and MEDI4736 (durvalumab) in patients with molecularly-selected advanced solid tumors, as measured by objective response rate (ORR) (complete response [CR] + partial response [PR]). Although the clinical benefit of the doublet and triplet combination of these drugs has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. II. To assess overall duration of response (DoR), progression free survival (PFS) and overall survival (OS). III. To assess the pharmacokinetic (PK) profiles of these combinations, and explore exposure-response relationships. IV. To correlate molecular alterations with OR (CR+PR). OUTLINE: This is a dose-escalation study of copanlisib and olaparib. Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1 and 15 or days 1, 8, and 15 depending on dose level and olaparib orally (PO) twice daily (BID) on days 1-28 of each cycle. Beginning cycle 2, patients receive durvalumab IV over 1 hour on day 1 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples at baseline within 7 days of cycle 1 day 1 (C1D1), days 8 and 15 of cycle 1 and day 15 of subsequent cycles, at time of restaging, and end of treatment/progression. Patients undergo x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) at the end of cycle 2 and then every 8 weeks. Patients also undergo an echocardiography (ECHO) during pre-study within 28 days of C1D1 and tumor biopsy at baseline within 7 days of C1D1 and day 15 of cycle 1 or 2, and may undergo an optional biopsy at end of treatment/progression. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years. ;
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