Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

Summary

Participation Requirements

Description

Background: Disruption of the immune checkpoint PD-1/PD-L1 pathway yielded clinical activity in subsets of advanced solid tumors, such as melanoma and lung cancer. Olaparib (O), a PARP inhibitor (PARPi), has demonstrated single agent activity in recurrent ovarian cancer (OvCa), and subsets of prosta...

Background: Disruption of the immune checkpoint PD-1/PD-L1 pathway yielded clinical activity in subsets of advanced solid tumors, such as melanoma and lung cancer. Olaparib (O), a PARP inhibitor (PARPi), has demonstrated single agent activity in recurrent ovarian cancer (OvCa), and subsets of prostate, triple negative breast or lung cancers. Our recent randomized phase 2 study showed that O and cediranib (C), a VEGFR1-3 inhibitor was clinically superior to O alone in platinum-sensitive recurrent OvCa. We hypothesize that increased DNA damage by PARP inhibition and/or reduced angiogenesis by VEGFR inhibition will complement the anti-tumor activity of an immune checkpoint nhibitor, MEDI4736, in recurrent OvCa and other solid tumors. Objectives: Phase I: To determine the recommended phase II dose (RP2D) and the safety of doublet herapies (MEDI4736/olaparib [MEDI+O] and MEDI4736/cediranib [MEDI+C]) and triplet therapy (MEDI+O+C) in patients with advanced solid tumors. Phase II Cohort 1 OvCa; MEDI+O, MEDI+C and MEDI+O+C arms: To determine clinical efficacy as measured by overall response rate (ORR) Phase II Cohort 2 non-small cell lung cancer (NSCLC); MEDI+O and MEDI+C arms: To determine clinical efficacy as measured by progression-free survival (PFS) Phase II Cohort 3 small cell lung cancer (SCLC); MEDI+O arm: To determine clinical efficacy as measured by ORR Phase II Cohort 4 metastatic castrate-resistant prostate cancer (mCRPC); MEDI+O arm: To determine clinical efficacy as measured by PFS Phase II Cohort 5 triple negative breast cancer (TNBC); MEDI+O arm: To determine clinical efficacy as measured by ORR Phase II Cohort 6 colorectal cancer (CRC): C+MEDI arm: To determine clinical efficacy as measured by PFS Eligibility: Phase I: Advanced or recurrent solid tumors with evaluable disease. Phase II Cohort 1 MEDI+O, MEDI+C and MEDI+O+C arms: Advanced or recurrent OvCa Phase II Cohort 2 MEDI+O and MEDI+C arms: Advanced or recurrent NSCLC Phase II Cohort 3 MEDI+O arm: Advanced or recurrent SCLC Phase II Cohort 4 MEDI+O arm: mCRPC Phase II Cohort 5 MEDI+O arm: Advanced or recurrent TNBC Phase II Cohort 6 C+MEDI arm: Advanced or recurrent CRC Patients must be off prior chemotherapy, radiation therapy or biologic therapy for at least 3 weeks. mCPRC patients (Cohort 4) may be on hormonal therapy with GnRH agonists/antagonists. Adults with ECOG performance status 0-2, and adequate organ and marrow function. Design: Phase I: MEDI+O, MEDI+C and MEDI+O+C will dose escalate simultaneously. MEDI4736 will be administered once every 2 weeks or once every 4 weeks until disease progression. O tablets and C will be given orally on a continuous or intermittent dosing schedule. The DLT period will be one cycle, 28 days. Patients on the 2-week schedule greater than one year will be changed to the 4-week schedule until progression. MEDI+O: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg every 4 weeks) and O tablets (150 mg or 200 mg or 300 mg BID) MEDI+C: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg every 4 weeks) and C (15 mg or 20 mg or 30 mg daily or 5 days/week) MEDI+O+C: MEDI4736 (a fixed dose of 1500mg every 4 weeks) with O tablets (200 mg or 300 mg BID) and C (15 mg or 20 mg 5 days/week) Phase II Cohort 1 OvCa MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks). Phase II Cohort 1 OvCa MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks). Phase II Cohort 1 OvCa MEDI+O+C arm: Patients with OvCa (Cohort 1) will be treated with RP2D (O tablets 300mg BID, C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks). Phase II Cohort 2 NSCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks). Phase II Cohort 2 NSCLC; MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks). Phase II Cohort 3 SCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks). Phase II Cohort 4 mCRPC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks). Phase II Cohort 5 TNBC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks). Phase II Cohort 6 CRC; C+MEDI arm: Patients in the Cohort 6 will be treated with C 20mg daily alone for 14 days followed by the combination at RP2D (C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks). Phase II Correlative studies: Research samples including whole blood, CTCs, cell free DNA and plasma will be obtained at pretreatment, prior to cycle 1 day 15, prior to cycle 3 day 1 and at progression. Mandatory baseline core biopsy and two optional biopsies will be obtained. Patients will be evaluated for toxicity every 4 weeks by CTCAEv4.0, and for response every two cycles (8 weeks) by RECIST 1.1. Patients with mCRPC (MEDI+O Cohort 4) will be evaluated for response initially at 8 weeks then every 12 weeks using RECIST v1.1 criteria as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2).

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