Abstract B046: A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study

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Abstract Background: PEP-010 is a first-in-class bifunctional peptide that penetrates cells and specifically disrupts the interaction between Caspase9 and PP2A, two proteins involved in the apoptotic cascade, leading to Caspase9-dependent apoptosis in cancer cells. Safety, PK, and preliminary anti-tumor activity from the dose escalation part of a Phase 1a/b study of PEP-010 as a monotherapy and in combination with paclitaxel (P) in recurrent and/or metastatic solid cancer are presented. Methods: PEP-010 was administered as a 3-hour intravenous weekly infusion on 3 consecutive days in patients (pts) with advanced cancer ineligible for standard therapy, in monotherapy (Arm A) or in combination with weekly P (Arm B) for pts eligible for P. In Arm A, pts were enrolled into 8 dose cohorts starting at 0.15 mg/kg up to 15 mg/kg, using an accelerated titration design (first 4 dose levels (DLs)), followed by a 3+3 design. In Arm B, 5 DLs of PEP-010 combined with weekly P (80mg/m²) were explored. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 in both arms, based on occurrence of dose-limiting toxicities (DLTs). Secondary objectives were the safety and tolerability profile, PK and preliminary antitumor activity assessed by RECIST1.1. Results: At data cutoff (March 7, 2023), 19 (Arm A) and 15 (Arm B) pts received PEP-010 across 8 and 3 DLs, respectively. Median age was 57 [32-78] years and 56% were female. Median number of prior therapies was 6 [2-13]. A DLT (Grade 2 infusion-related reaction (IRR)) was observed in 1 pt in Arm A at DL 8 (15 mg/kg). In Arm B, 3 pts experienced a DLT at DL 5 mg/kg: 1 Grade 4 neutropenia and 2 IRR (inacceptable Grade 2 and 4). All DLTs led to permanent treatment discontinuation. MTD was defined as 15 mg/kg in Arm A and 2.5 mg/kg in Arm B. Most common adverse events (AE) related to PEP-010 included asthenia (26.5%) and IRR (14.7%) whereas most common AEs related to P included anemia (66.7%), peripheral neuropathy (33.3%), neutropenia (20%), onychopathy (20%), and diarrhea (20%). Median time on treatment was 5.1 weeks [2.1-25.3] in Arm A and 5.3 [3-18] in Arm B. In Arm A, for 7 pts (36.8%) a stable disease (SD) was observed for a median of 2.8 months [0.6-4.5]. In Arm B, 4 (26.7%) confirmed partial responses were observed in pts with ovarian, pancreatic and thyroid adenocarcinomas, and squamous cell lung carcinoma, and 2 pts (13.3%) had SD for a median of 4 months [2.7-9.6]. PK data indicated a proportionally dose-related increase of systemic exposure to PEP-010. No significant accumulation of PEP-010 over time or impact of P combination was observed. Conclusions: Data from the Escalation Part of the Phase 1a/b clinical trial showed an acceptable safety profile of PEP-010 in monotherapy. In combination, the dose of PEP-010 could not be escalated to the same level because of IRR. Preliminary antitumoral activity was observed with PEP-010 in combination with P including in pts who had previously received taxanes. Further clinical development is warranted. Citation Format: Pauline Du Rusquec, Elodie Coquan, Frederique Berger, Keyvan Rezai, Pierre-Emmanuel Brachet, Sophie Postel-Vinay, Zahra Castel-Ajgal, Gregoire Marret, Marie-Paule Sablin, Segolene Hescot, Raphael Sanchez, Anne-Claire Coyne, Claire Bertrand, Clementine Bouchez, Elsa Lafitte, Lucas Frezouls, Carole Mardesson, Abdelkrim Taamma, Chantal Krezel, Laura Dadon, Christophe Le Tourneau. A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B046.

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