Abstract 482P
Background
The potent, selective, orally available WEE1 kinase inhibitor IMP7068 has demonstrated antitumor activity in preclinical models.
Methods
In a phase I study, pts with advanced/metastatic solid tumors received oral doses of IMP7068 at 30, 60, 120, 160, 200, 300, or 400 mg once daily (QD) for 3 days, followed by 4 days off per week (21-day cycles). The 160-mg was added based on Study Monitoring Committee review of PK data from the 120-mg dose cohort, to better characterize the safety and antitumor activity of IMP7068. An accelerated titration design was used for the 30- and 60-mg dose levels, and an i3+3 design for all others. The primary objective was to determine the safety, tolerability, and recommended phase II dose (RP2D) of IMP7068 monotherapy.
Results
As of Apr 12 2022,of 24 pts enrolled in 6 cohorts across doses of 30–300 mg, ≥50% had received ≥4 prior lines of anticancer therapy. Dose-limiting toxicities (DLTs) occurred in 2 of 22 (9%) DLT evaluable pts: pulmonary embolism (1 pt, 160-mg cohort) and QTc prolongation (1 pt, 300-mg cohort). Treatment-related adverse events (TRAEs) occurred in 6 (25%) pts, and were mostly grade 1–2; 7 grade ≥3 TRAEs occurred in 3 (13%) pts. Nine of 14 (64%) evaluable pts had a best tumor response of stable disease (SD); 1 (7.1%) pt with colorectal cancer (CRC) achieved SD and a 6.7% reduction in tumor size, and another with CRC maintained SD for >30 weeks; 12 pts remain on study. PK modeling predicted that a twice-daily (BID) regimen would increase IMP7068 exposure versus the same QD dose and be more favorable for concentration-dependent adverse events. Levels of phosphorylated cyclin-dependent kinase 1 decreased by ≥50% after treatment at doses of 160–200 mg.
Conclusions
IMP7068 was well-tolerated, with a PK and PD profile consistent with WEE1 inhibition at doses of up to 300 mg. Dose escalation including a BID regimen is under evaluation. The RP2D is expected to be determined soon, and multiple expansion cohorts (including uterine serous carcinoma and biomarker-selected populations) are planned for initiation later this year.
Clinical trial identification
NCT04768868.
Editorial acknowledgement
Jacqueline Kolston of Parexel.
Legal entity responsible for the study
IMPACT Therapeutics, Inc.
Funding
IMPACT Therapeutics, Inc.
Disclosure
C. Lin: Financial Interests, Personal, Advisory Role: AbbVie, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Bristol Myers Squibb, Merck KGaA, PharmaEngine; Financial Interests, Personal, Other, Travel Support: BeiGene; Financial Interests, Personal, Advisory Role, Travel Support: Daiichi Sanlyo; Financial Interests, Personal, Other, Honorarium, Travel Support: Eli Lilly; Financial Interests, Personal, Advisory Role, Honorarium: Novartis; Financial Interests, Personal, Other, Honorarium: Roche. L. Shen: Financial Interests, Personal, Research Grant: Yaojie Ankang (Nanjing) Technology Co., Ltd., Baiji Shenzhou (Beijing) Biotechnology Co., Ltd., Beijing Xiantong Biomedical Technology Co., Ltd., QiLu Pharmaceutical, Zaiding Pharmaceutical; Other, Personal, Speaker’s Bureau: Hutchison Whampoa; Other, Personal, Speaker’s Bureau, Consulting or Advisory Role: MSD; Other, Personal, Advisory Role: Bristol-Myers Squib, AstraZeneca, Daiichi Sankyo, Roche, Mingji biopharmaceutical, Harbour BioMed, Merck. J.C. Baranda: Other, Personal and Institutional, Other, Study funding and support for Medical Writing/editing: Astellas; Other, Personal and Institutional, Other, Medical Writing/editing support: OPEN Health; Financial Interests, Institutional, Research Grant: Astellas, Exelixis, Pfizer, Tolero, Xencor, Changchun Intellicrown, Synermore, Impact Therapeutics, Nektar; Financial Interests, Institutional, Research Grant, Institution and Consulting Fees: Sanofi; Financial Interests, Personal, Stocks/Shares: Forty-seven, Zymeworks, Moderna, Aprea, Merux. C. Hsieh, S.X. Cai, Y.E. Tian, N. Ma, H. Xia, C. Zhang, M. Zhang, Z. Yu: Financial Interests, Institutional, Full or part-time Employment: Impact Therapeutics. All other authors have declared no conflicts of interest.