Abstract 480P
Background
X is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP inhibition may synergize with immune checkpoint blockers (ICB) by modulating the NF-KB pathway in immune cells.
Methods
Adult pts with non-MSI-H advanced/ metastatic PDAC or CRC received a flat dose of P (200mg q3w, IV) and ascending doses of X (100, 150 and 200mg daily for 14/21 days orally). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT)-evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 pts with PDAC and 14 pts with CRC were enrolled in expansion cohorts to assess preliminary efficacy (response rate after 12 weeks of treatment) according to the first stage of a Gehan design.
Results
13 pts (7M/6F, median age, 65 y [range, 50-80y]) were enrolled in 3 dose levels (DL) (X 100 and 150mg/d: 3 pts each and X 200mg/d: 7 pts). One pt who received less than 10 doses of X during cycle 1 was considered non-evaluable for DLT at DL3 and efficacy, and was replaced. No DLT was identified during dose-escalation. Related grade 2 AEs included fatigue (n=6 pts), dysgeusia, abdominal pain, dry skin, lipase and amylase increased (n=1 pt for each). Two related grade 3 AE were reported at DL3: myocarditis (n=1 pt) and rash maculo-papular (n=1 pt). The best overall response in dose escalation was SD in 3 pts, and PD in 9 other pts. The RP2D for the combination was X 200mg/d + P 200mg q3w. Enrolment in the expansion cohorts was completed in Dec-2021. One PR was reported in the PDAC expansion cohort; no PR or CR were observed in the CRC cohort.
Conclusions
The combination of X+P was overall well tolerated with no unexpected adverse event. However, the overall anti-tumor activity was low. Updated data regarding efficacy, pharmacokinetic and pharmacodynamics analysis will be presented at the meeting.
Clinical trial identification
NCT03871959.
Editorial acknowledgement
Legal entity responsible for the study
This trial was sponsored by Centre Léon Bérard.
Funding
Funding from Merck & Co (MSD). Study treatments were provided by MSD and Debiopharm.
Disclosure
P.A. Cassier: Financial Interests, Personal, Advisory Board: Merck Serono/EMD, Roche, Amgen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Advisor: OSE immunotherapeutics; Financial Interests, Institutional, Invited Speaker: AbbVie, Amgen, Blueprint, Exelixis, GSK, Janssen, Novartis, Roche, Taiho, LOXO/Eli Lilly; Non-Financial Interests, Institutional, Product Samples: plexxikon, Novartis, MSD, AstraZeneca, GSK. C. Terret: Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Research Grant: GSK; Other, Personal, Other: Mundipharma. D. Perol: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Boehringher-Ingelheim, BMS, Lilly, Ipsen, Roche, Novartis, MSD, Takeda. A. Vinceneux: Non-Financial Interests, Personal, Other: Roche, Sandoz, Novartis. All other authors have declared no conflicts of interest.