A phase I study of durvalumab (D) in combination with olaparib (O) and cediranib (C) in recurrent women’s cancers

Abstract

Background: Recent data showed a PARP inhibitor, O and a VEGFR1-3 inhibitor, C together are clinically superior to O alone in recurrent platinum-sensitive ovarian cancer (OvCa). We hypothesized reduced VEGF signaling by C and DNA damage by O may complement anti-tumor activity of immune checkpoint blockade, D. We previously reported the safety data and RP2D of D in combination with O or C. We now report RP2D and PK/PD data of the D+O+C therapy (NCT02484404). Methods: Eligible patients (pts) with PS 0-1 and good end organ function received D+O+C in a 3+3 design. An intermittent C schedule (C; 5 days on/2 days off) at 15 or 20 mg (dose level: 1, 2) was combined with D 1500 mg IV q28 days, and O tablets 300 mg BID. The DLT period was one 28d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1. Plasma samples were collected for O and C PK analysis and for pro-inflammatory cytokines (IFN-γ, IL-10, IL-12, IL-2, IL-6, IL-8 and TNF-a) pretreatment and on therapy (cycle 1 day 15 and cycle 3 day 1). Results: Nine women (median age 59yr [44-73], and median 3 prior therapies [2-6]) were treated. Of the 9 pts, 7 had OvCa, 1 endometrial (EnCa) and 1 triple negative breast Ca. Grade 3/4 AEs include hypertension (1/9), anemia (1/9) and lymphopenia (3/9). No pts experienced DLTs. One patient required dose reduction during cycle 5, for grade 3 anemia. Three PRs were observed in 2 OvCa and 1 EnCa (response rate of 33%, median 5months [4+-6+]), and 4 had SD (median 5 months [3+-10+]), yielding 78% disease control rate. There were no significant changes in O and C PK parameters caused by D and the co-administration of C or O. All cytokines plasma levels were not changed significantly by the treatment. PD-L1 expression by IHC and immune subsets by flow cytometry are under analysis. Conclusions: The RP2D for D+O+C (D 1500 mg q28d+O 300 mg tablets BID+C 20 mg 5 days on/2 days off) is tolerable and active in recurrent women's cancers. A phase II expansion study of D+O+C is to open in OvCa.