681P - First-in-human study of ATR inhibitor IMP9064 monotherapy and in combination with PARP inhibitor senaparib in patients with advanced solid tumors

Background

IMP9064 is a potent oral ataxia telangiectasia and rad3-related (ATR) inhibitor with anti-tumor activity demonstrated in vitro and in vivo. This ongoing first-in-human study (NCT05269316) explores IMP9064 monotherapy and in combination with senaparib (IMP4297) in patients with advanced solid tumors.

Methods

This phase I/II, open-label study aims to evaluate the safety, pharmacokinetics, anti-tumor activity, maximum tolerated dose, recommended phase 2 dose for IMP9064 monotherapy and combination with senaparib. Here, we report the preliminary results in dose escalation of monotherapy stage. Patients received IMP9064 once daily, 3 days on and 4 days off per 21-day cycle using an i3+3 dose escalation design.

Results

As of Feb 14th,2023, 16 patients were enrolled: Cohort 1 (n=1, 7.5 mg); Cohort 2 (n=1,15 mg); Cohort 3 (n=4, 30 mg); Cohort 4 (n=3, 45 mg); Cohort 5 (n=4, 80 mg); Cohort 6 (n=3, 120 mg). No dose-limiting toxicities were observed in the dose range of 7.5 to 80 mg. 10 (62.5%) patients experienced at least one treatment emergent adverse event (TEAE). TEAEs reported in 3 or more patients included nausea (25.0%), diarrhea (18.8%), fatigue (18.8%). Grade ≥3 TEAEs occurred in 4 (25.0%) patients. The only grade ≥ 3 AE related to IMP9064 was grade 3 diarrhea, which led to dose interruption and resolved within 48 hours. No drug-related death was reported. 9 of 13 evaluable patients had stable disease as their best response. A patient with advanced renal tumor from cohort 4 experienced stable disease and remains on trial with more than 7 cycles to date. In Cohort 3, a non-small cell lung cancer patient displayed a 158% ctDNA increase on C2D1, followed by a 58.2% decrease on C4D1 and an 84% decrease on C6D1 relative to C2D1. In the dose range of 7.5 to 80 mg investigated, the IMP9064 exposure increased as the dose increased; the median Tmax ranged from 1 to 3 hours, the mean elimination half-life ranged from 4 to 6 hours, and with minimal accumulation.

Conclusions

These results indicate that IMP9064 monotherapy appears to be well-tolerated and support further dose escalation. More MRD and biomarker analyses are underway.

Clinical trial identification

NCT05269316.

Editorial acknowledgement

Legal entity responsible for the study

IMPACT Therapeutics Inc.

Funding

IMPACT Therapeutics Inc.

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; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics. R.E. Schneider: Financial Interests, Institutional, Principal Investigator: IMPACT Therapeutics Inc. M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Invited Speaker: 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 Sereno, Fate Therapeutics, GSK, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta. L. Shen, B. Gao, K. Chung, D.B. Doroshow, M. Millward: Financial Interests, Institutional, Principal Investigator: IMPACT Therapeutics Inc. C. Hsieh, S.X. Cai, Y.E. Tian: Financial Interests, Institutional, Leadership Role: IMPACT Therapeutics Inc. C. Xu: Financial Interests, Institutional, Member of Board of Directors: IMPACT Therapeutics Inc. L. Liu, C. Shen, B. Li, Y. Tan, C. Zhang, M. Ma, X. Chen: Financial Interests, Institutional, Member: IMPACT Therapeutics Inc. L. Li: Financial Interests, Institutional, Other: IMPACT Therapeutics Inc.