TY - JOUR T1 - 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 JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-019-0680-3 VL - 7 IS - 1 SP - 197 AU - Alexandra S. Zimmer AU - Erin Nichols AU - Ashley Cimino-Mathews AU - Cody Peer AU - Liang Cao AU - Min-Jung Lee AU - Elise C. Kohn AU - Christina M. Annunziata AU - Stanley Lipkowitz AU - Jane B. Trepel AU - Rajni Sharma AU - Lekha Mikkilineni AU - Margaret Gatti-Mays AU - William D. Figg AU - Nicole D. Houston AU - Jung-Min Lee Y1 - 2019/12/01 UR - http://jitc.bmj.com/content/7/1/197.abstract N2 - 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.Abbreviations:AEAdverse eventCBRClinical benefit rateCRComplete responseDLTDose-limiting toxicityIHCImmunohistochemistryMDSCsMyeloid-derived suppressor cellsMFIMedian fluorescence intensityMMRMismatch repairMSIMicrosatellite instabilityMTDMaximum tolerated dosePARP-inhibitorPoly ADP ribose polymerase inhibitorPBMCsPeripheral blood mononuclear cellsPKPharmacokineticPRPartial responseRP2DRecommended phase 2 doseRRResponse rateSDStable diseaseTILTumor infiltrating lymphocytesTMBTumor mutational burdenTNBCTriple-negative breast cancerTregRegulatory T cellsVEGFR 1–3 inhibitorVascular endothelial growth factor receptors 1–3 inhibitor ER -