A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1–3 inhibitor, cediranib, in recurrent women’s cancers with biomarker analyses

• Main Authors: Alexandra S. Zimmer, Erin Nichols, Ashley Cimino-Mathews, Cody Peer, Liang Cao, Min-Jung Lee, Elise C. Kohn, Christina M. Annunziata, Stanley Lipkowitz, Jane B. Trepel, Rajni Sharma, Lekha Mikkilineni, Margaret Gatti-Mays, William D. Figg, Nicole D. Houston, Jung-Min Lee
• Format: Article
• Language: English
• Published: BMJ Publishing Group 2019-07-01
• Series: Journal for ImmunoTherapy of Cancer
• Subjects: Ovarian cancer; Immune checkpoint inhibitor; PARP inhibitor; VEGF inhibition
• Online Access: http://link.springer.com/article/10.1186/s40425-019-0680-3

Abstract Background Strategies to improve activity of immune checkpoint inhibitors are needed. We hypothesized enhanced DNA damage by olaparib, a PARP inhibitor, and reduced VEGF signaling by cediranib, a VEGFR1–3 inhibitor, would complement anti-tumor activity of durvalumab, a PD-L1 inhibitor, and the 3-drug combination would be tolerable. Methods This phase 1 study tested the 3-drug combination in a 3 + 3 dose escalation. Cediranib was taken intermittently (5 days on/2 days off) at 15 or 20 mg (dose levels 1 and 2, respectively) with durvalumab 1500 mg IV every 4 weeks, and olaparib tablets 300 mg twice daily. The primary end point was the recommended phase 2 dose (RP2D). Response rate, pharmacokinetic (PK), and correlative analyses were secondary endpoints. Results Nine patients (7 ovarian/1 endometrial/1 triple negative breast cancers, median 3 prior therapies [2–6]) were treated. Grade 3/4 adverse events include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No patients experienced dose limiting toxicities. The RP2D is cediranib, 20 mg (5 days on/2 days off) with full doses of durvalumab and olaparib. Four patients had partial responses (44%) and 3 had stable disease lasting ≥6 months, yielding a 67% clinical benefit rate. No significant effects on olaparib or cediranib PK parameters from the presence of durvalumab, or the co-administration of cediranib or olaparib were identified. Tumoral PD-L1 expression correlated with clinical benefit but cytokines and peripheral immune subsets did not. Conclusions The RP2D is tolerable and has preliminary activity in recurrent women’s cancers. A phase 2 expansion study is now enrolling for recurrent ovarian cancer patients. Trial registration ClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.