Pembrolizumab, maveropepimut-S, and low-dose cyclophosphamide in advanced epithelial ovarian cancer: Results from phase 1 and expansion cohort of PESCO trial.
Authors: Veneziani Ana , Lheureux Stephanie , Alqaisi Husam , Bhat Gita , Colombo Ilaria , Gonzalez Eduardo , Newton Sara , Msan Anthony , Quintos Judy , Ramsahai Janelle , Grant Robert C. , Dhani Neesha C. , Wang Lisa , Bowering Valerie , Oza Amit M. 
Published: June 2022

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Background: Platinum-resistant ovarian cancer (PROC) continues to have a poor prognosis. Maveropepimut-S (MVP-S, namely DPX-Survivac) leverages the lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from survivin, a cancer-related protein commonly upregulated in several cancers. MVP-S in combination with Pembrolizumab (Pemb) and low-dose Cyclophosphamide (CPA) is expected to enhance immune response. This trial aims to assess the safety and efficacy of this regimen in patients (pts) with PROC. Methods: Phase 1 escalation cohort allowed all PROC subtypes and comprised 2 dose levels (DL) of MVP-S with 1 initial dose 0.25 mL followed by boosters of 0.25 mL (DL1) or 0.5mL (DL2) SC q6w, combined with CPA (50 mg BID every other week) and Pemb (200 mg q3w). Dose escalation was performed using 3+3 design. Dose-limiting toxicities (DLT) were defined as G4 non-hematologic, ≥G3 persistent non-hematologic toxicity, laboratory value or febrile neutropenia; ≥G2 persistent injection site skin ulceration ( > 1wk) or allergic/immune reactions by CTCAE v4.03. DL was considered safe if ≤1 DLT occurred in 6 pts until 21 days after initial and first boosting dose. Pts with high-grade serous (HGSOC) or endometrioid ovarian cancer were allowed in the Phase 2 expansion cohort (P2EC) and treated with the Recommended Phase 2 Dose (RP2D). Response was assessed every 6 wks. Activity in P2EC was defined as at least 2/10 partial response (PR) or stable disease (SD) for 12 wks according to RECIST 1.1. Primary endpoint is overall response rate (ORR), and secondary includes safety, PFS, and OS. Biopsies and blood draws were performed prior to and on treatment for genomic analysis, immune profiling and ctDNA. Results: Twenty-six pts were enrolled, 24 were evaluable for safety (8 DL1, 6 DL2, and 10 in P2EC). HGSOC represented 62% of phase I and 100% of P2EC. Median age was 61y (49-78). Pts received a median of 4 (1-7) prior lines of therapy. Median cycles of MVP-S were 2 (1-8). Toxicity G4/G3/G2 occurred in 1/3/7 pts of DL1 and 0/3/6 of DL2. G3/G2 immune-related AE (irAE) and injection site reactions (ISR) were observed in 1/1 and 1/3 pts treated at DL1, and in 1/0 and 2/2 pts at DL2, respectively. DL1 was selected as RP2D due to the occurrence of nephritis and ISR G3 at DL2. No AEs were qualified as DLT. On the P2EC, 5 G3 (1 irAE, 0 ISR) and 28 G2 (0 irAE, 3 ISR) toxicities were observed. At Phase 1, one pt with MSI-High clear cell subtype has ongoing CR after 26 mos of follow-up, 2 pts had PR and 6 SD.There were 1 PR and 3 SD on P2EC, of which 1 and 2, respectively, achieved response > 12wks. Conclusions: The combination of MVP-S, low-dose CPA, and Pemb was tolerable and met the efficacy endpoint in the expansion cohort in heavily treated PROC. Immuno-genomic correlative analyses are ongoing. Clinical trial information: NCT03029403. [Table: see text]