632P - Results from the first-in-human study of ATR inhibitor, IMP9064 monotherapy dose escalation in patients with advanced solid tumors

Background

ATR inhibitor exhibits synthetic lethal interactions, either as monotherapy or synergize with genotoxic therapies. IMP9064 has demonstrated anti-tumor activity in vitro and in vivo. Here reports the results of Part 1 from the phase 1/2 study.

Methods

The study consists of 4 parts: dose-escalation and dose-expansion of IMP9064 monotherapy and combination with senaparib (PARPi). IMP9064 was given orally once daily, 3 days on/4 days off using accelerated titration and i3+3 dose escalation design from 7.5 to 320 mg in advanced solid tumors (AST) patients with no biomarker selection in Part 1. Endpoints include safety, tolerability, MTD/RP2D, etc.

Results

As of Apr 10, 2024, 34 patients were enrolled: colorectal [n=6], endometrial [n=5], uterine leiomyosarcoma [n=4], lung [n=3], ovarian [n=2], cholangiocarcinoma [n=2] and others [n=12]. Median lines of prior anti-tumor therapy were 3 [range (1,7)]. 1 DLT was reported in 1 of 5 patients at the 320 mg dose level. 24 (70.6%) patients experienced at least one TRAE. The most frequent TRAEs were nausea (35.3%), diarrhea (32.4%), vomiting (29.4%), and anaemia (26.5%). Grade ≥ 3 TRAEs occurred in 6 (17.6%) patients, with only anaemia (11.8%) was reported in ≥10 % patients. 28 patients had ≥1 post treatment scan. 1 endometrial cancer patient at the 280 mg dose level had PR with rapid target lesion decreased by 31.8% at the 6th week scan which is ongoing. 18 patients had SD as best response for a DCR 67.9% and CBR (SD ≥ 4 months) 39.3%; median PFS was 4.0 months. 2 patients have had SD >1 year and continue treatment in lower dose levels [80 mg, 160 mg]. IMP9064 demonstrated rapid absorption, with median Tmax within 4.5 h following both single and multiple doses administration from 7.5 ∼ 320 mg. Plasma exposure increased as the dose increased. Additional PK, PD, DDR status and ctDNA monitoring analyses are ongoing, including correlative studies of phospho-Chk1 expression.

Conclusions

IMP9064 has demonstrated a favorable safety profile and preliminary clinical efficacy signal and sustained clinical benefit in late-stage AST, which warrants further development of IMP9064. After RP2D is determined in May, enrollment in an expansion cohort will proceed.

Clinical trial identification

NCT05269316.

Editorial acknowledgement

Legal entity responsible for the study

IMPACT Therapeutics, Inc. (Shanghai).

Funding

IMPACT Therapeutics, Inc. (Shanghai).

Disclosure

C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim, Anbogen, IMPACT Therapeutics; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics; Financial Interests, Institutional, Other, Local principal investigator: Nuvalent. R. Schneider, L. Shen, K. Chung, D.B. Doroshow, B. Gao: Financial Interests, Institutional, Local PI: IMPACT Therapeutics. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Other, Consultant: Merck; Financial Interests, Personal, Advisory Board: Sanofi, Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Local PI: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Serono, Fate Therapeutics, GSK, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta, IMPACT. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Professor of Clinical Cancer Research: University of Western Australia; Financial Interests, Personal, Full or part-time Employment, Medical Oncology Director: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. C. Hsieh: Financial Interests, Personal, Other, external medical consultant: Anbogen Therapeutics, HanchorBio Inc.; Financial Interests, Personal, Full or part-time Employment, Chief Medical Officer: IMPACT Therapeutics; Financial Interests, Personal, Stocks/Shares: IMPACT Therapeutics, Anbogen Therapeutics, HanchorBio Inc. C. Xu, S.X. Cai, Y.E. Tian: Financial Interests, Personal, Leadership Role: IMPACT Therapeutics. L. Liu, C. Shen, Y. Tan, Y. He, C. Zhang, M. Ma, L. Xu: Financial Interests, Personal, Full or part-time Employment: IMPACT Therapeutics. L. Li: Financial Interests, Institutional, Advisory Role: IMPACT Therapeutics.