A phase 1 dose-escalation and -expansion study of IMP7068, a WEE1 inhibitor, in patients with advanced solid tumors.

Abstract

e15052 Background: WEE1 kinase is a cell-cycle regulator that is important in DNA repair, and a validated antitumor target. IMP7068 is a potent and selective WEE1 inhibitor that has demonstrated antitumor activity in preclinical pharmacological models. A first-in-human, multicenter, open-label study was conducted to evaluate the safety, tolerability, pharmacokinetic (PK) characteristics, pharmacodynamic (PD) profiles and preliminary antitumor activity of IMP7068 in patients (pts) with advanced solid tumors. Methods: This phase 1 study included both a dose-escalation and dose-expansion stage. The dose-escalation stage was designed with 6 dose cohorts of IMP7068 at 30, 60, 120, 200, 300, and 400 mg (administered orally, once daily [QD] for 3 days, followed by 4 days off weekly for 21-day cycles). An accelerated titration design was used for the 30- and 60-mg dose levels, and an i3+3 design for all doses > 60 mg. Pts were adults (age ≥18 years) with confirmed advanced solid tumors that were refractory or intolerant to standard treatment, or for which no standard treatment exists. The objectives of the dose-escalation stage were to evaluate the safety and tolerability, PK and PD profiles, and antitumor activity (per RECIST v1.1) of IMP7068. Results: As of Jan 7, 2022, 9 pts were enrolled in the dose-escalation phase (average age, 56 years). An additional cohort of IMP7068 160 mg was recommended by the Safety Monitoring Committee based on PK data from the 120-mg cohort. Pts received escalating doses at 30 mg (n = 1), 60 mg (n = 1), 120 mg (n = 3), and 160 mg (n = 4). No dose-limiting toxicities (DLTs) were observed. Treatment-related adverse events (TRAEs) occurred in 4 pts, most frequently alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and diarrhea (all in 2 pts each). Most TRAEs were grade 1 or 2 in severity; and only 1 patient had grade 3 TRAEs (AST and ALT increased). Time to reach the maximum plasma concentration of IMP7068 was approximately 2–6 hours following administration of 30–160 mg doses, respectively. Following repeated QD administration for 3 days, the accumulation ratios for IMP7068 exposure parameters Cmax and AUC0-tau were 1.74–2.49 and 3.17–3.46, respectively, across the dose levels. The elimination half-life was approximately 10–28 hours after administration of 60–160 mg IMP7068. PD data showed that levels of phosphorylated cyclin-dependent kinase 1 decreased by ≥50% after treatment in the 160-mg cohort. Five of 8 evaluable pts had a best tumor response of stable disease (SD); 1 patient with colorectal cancer maintained a best response of SD for 22 weeks. Four pts remain on study. Conclusions: IMP7068 was well-tolerated with no DLTs, and conferred a meaningful PD effect and preliminary antitumor activity at doses of up to 160 mg in pts with advanced solid tumors. Dose escalation to establish the recommended phase 2 dose and/or maximum tolerated dose is continuing. Clinical trial information: NCT04768868.

Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders

“…The trial so far recommends doses up to 160 mg to observe sound preliminary antitumor activities and pharmacodynamics; additionally, well-tolerated treatmentrelated toxicity profile with negligible dose-limiting toxicities was observed. 138 Figure Pyrazolopyrimidine (80−83) 137 The 2-amino substitutions extend out of the pocket and are solvent-exposed. The aryl substitution on the 2-amino group is very essential as it is sandwiched between I305 and G382 and forms π−σ interactions.…”

“…This series offered IMP7068 ( 95 ) from Impact Therapeutics, a potential phase-I clinical candidate against advanced solid tumors in monotherapy ( NCT04768868 ). The trial so far recommends doses up to 160 mg to observe sound preliminary antitumor activities and pharmacodynamics; additionally, well-tolerated treatment-related toxicity profile with negligible dose-limiting toxicities was observed …”

“…Initially, the toxicity profile of AZD1775 was inseparable from its off-target activity against PLK1, but recent studies and trials using more selective analogue ZN-c3 also showed treatment-related adverse events, including all grades of GI toxicities, ≥ grade 3 neutropenia, and other hematological toxicities. , Additionally, a 2023 study to optimize selective AZD1775 analogues identified thrombocytopenia as an inevitable consequence of WEE1 inhibition and not PLK inhibition, asserting thrombocytopenia as an on-target toxicity . On the other hand, IMP7068 exhibited negligible DLTs and treatment-related adverse events (TRAEs), including grade 1/2 increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and grade 1/2 diarrhea, which are tolerable . Other candidate Debio-0123 is currently tested against advanced solid tumors ( NCT05109975, NCT03968653 ) in phase-I and glioblastoma ( NCT05765812 ) phase-I, II in monotherapy and combination therapy with manageable toxicity profile .…”

Mitotic Checkpoints and the Role of WEE1 Inhibition in Head and Neck Squamous Cell Carcinoma

“…Preliminary results from NCT04768868, a phase I trial investigating the WEE1 inhibitor IMP7068 as monotherapy in patients with advanced solid tumors, demonstrated stable disease in 5 of 8 evaluable patients, with 1 patient with colorectal cancer maintaining a best response of stable disease for 22 weeks. Adverse events occurred in 4 patients and included transaminitis and diarrhea 35 . Phase I trials of the WEE1 inhibitor Debio 0123 in combination with carboplatin (NCT03968653) or as monotherapy (NCT05109975) are also underway 36 .…”

“…Adverse events occurred in 4 patients and included transaminitis and diarrhea. 35 Phase I trials of the WEE1 inhibitor Debio 0123 in combination with carboplatin (NCT03968653) or as monotherapy (NCT05109975) are also underway. 36 Taken together, these promising results suggest clinical activity of newer generation WEE1 inhibitors in patients with advanced solid tumors with additional clinical data anticipated in the future.…”