Testing the Combination of the Anti-cancer Drugs Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients With Advanced Solid Tumors With Selected Mutations

Description

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 and expansion study of the doublet combination of copanlisib and olaparib or the triplet combination of copanlisib, olaparib, durvalumab.

In the dose escalation phase of the study, patients treated with the doublet combination will 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. Patients treated with the triplet combination will also receive copanlisib hydrochloride and olaparib, in addition to also receiving durvalumab beginning in cycle 2. Beginning in cycle 2, patients treated with the triplet combination will receive durvalumab IV over 1 hour on day 1 of each cycle. In the dose expansion phase of the study, patients will be treated with the best study drug dose identified in the dose escalation phase of the study.

For all patients treated with the doublet and triplet combinations, the cycles will 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, all patients are followed up at 30 days and then every 3 months for up to 2 years.