• 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, and Jung-Min Lee.
• Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. alexandra.zimmer@nih.gov.
• J Immunother Cancer. 2019 Jul 25; 7 (1): 197.

BackgroundStrategies 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.MethodsThis 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.ResultsNine 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.ConclusionsThe 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 RegistrationClinicalTrials.gov identifier: NCT02484404. Registered June 29, 2015.

39 keywords...

hide…