719TiP - A phase I/Ib study of the Werner (WRN) helicase inhibitor HRO761 as single agent and in combination with irinotecan or tislelizumab in patients with microsatellite instability-high (MSIhi) or mismatch repair deficient (dMMR) advanced solid tumors

Background

HRO761 is a first-in-class selective WRN inhibitor that binds allosterically to the helicase domain of the WRN protein locking it in an inactive conformation. HRO761 has shown anti-tumor activity in MSIhi preclinical models.

Trial design

This is a phase I/Ib (NCT05838768), global, multicenter (approximately 27 sites to open across 14 countries) dose finding study that consists of a dose escalation part to allow the determination of a dose range for optimization (DRO) or a recommended dose (RD) for HRO761 single agent (s.a.), and an optional randomized dose optimization part (Arm A). HRO761 will be administered orally daily in a 28-day cycle. The dose escalation part will enroll MSIhi/dMMR advanced/metastatic (a/m) CRC and solid tumors (approximately 40 patients), and the randomized dose optimization part will enroll patients with a/m MSIhi /dMMR CRC (20 patients per dose) and solid tumors (up to 10 pts per dose). Based on an integrated analysis of the safety, tolerability, pharmacokinetic, pharmacodynamic, and preliminary anti-tumor activity data of HRO761, RD will be determined and subsequently tested in optional expansion arms of a/m MSIhi/dMMR CRC (20-40 patients), and solid tumor (20-40 patients). HRO761 at the RD will be investigated in a dose escalation in combination with either tislelizumab (Arm B) or irinotecan (Arm C) to determine the RD of the combinations. After the determination of the RDs, the combination treatments will be tested in expansion cohorts of a/m MSIhi or dMMR CRC and other solid tumors. AEs will be assessed according to CTCAE v5. Tumor response will be determined according to RECIST 1.1 criteria. Key eligibility criteria include: 1) Patients with advanced unresectable or metastatic MSIhi or dMMR solid tumors who have progressed after or are intolerant to prior standard therapy; 2) patients should have received at least one prior line of chemotherapy or targeted therapy, and prior immune checkpoint inhibitor therapy (Arm A and C). Checkpoint inhibitor therapy is permitted but not required and prior adjuvant therapy is allowed in Arm B.

Clinical trial identification

NCT05838768, First posted 3 May 2023.

Editorial acknowledgement

None to declare

Legal entity responsible for the study

Novartis Pharmaceuticals.

Funding

Novartis Pharmaceuticals.

Disclosure

M. Moschetta, H. Möbitz, I. Jaco, M. Cortes Cros, S. Ferretti, D. Jankovic, M. Thérier, G. Clementi, Y. Li, R. De Kanter, C. Quadt: Financial Interests, Personal, Stocks/Shares: Novartis; Financial Interests, Personal, Full or part-time Employment: Novartis. T. Doi: Financial Interests, Institutional, Research Grant: Taiho, MSD, AbbVie, Eisai, Pfizer, BMS, Janssen Pharma, Daiichi Sankyo, Chugai Pharma, Boehringer Ingelheim, PRA Health Sciences, Amgen, GSK, SHIONOGI, RIN Institute, ONO Pharma; Financial Interests, Personal, Advisory Role: Noile-Immune Biotech, Oncolys BioPharma, Boehringer Ingelheim, A2 Healthcare, Nano Carrier, PRA Health Sciences, KAKEN Pharma, Chugai Pharma, Sumitomo Pharma, Shionogi, Otsuka Pharma, Takeda, Kyowa Kirin, Rakuten Medical, Gilead; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo. Y. Kuboki: Financial Interests, Institutional, Research Grant: Taiho, Astellas, Eli Lilly, Takeda, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Chugai, Genmab, Incyte, AbbVie, Amgen, Merk ; Financial Interests, Personal, Advisory Role: Incyte, Takeda, Boehringer Ingelheim, Amgen; Financial Interests, Personal, Speaker, Consultant, Advisor: Taiho, Eli Lilly, Takeda. R. Sundar: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, BMS, Roche, Taiho, AstraZeneca, DKSH, Ipsen; Financial Interests, Personal, Stocks/Shares: Teladoc; Financial Interests, Institutional, Advisory Board: Paxman Coolers; Financial Interests, Personal and Institutional, Local PI: Taiho, MSD, BMS, Novartis; Non-Financial Interests, Advisory Role: Paxman Coolers; Non-Financial Interests, Principal Investigator: MSD, Natera.