CARDINAL: A Phase 1 study of TERN-701, a novel investigational allosteric BCR::ABL1 inhibitor for patients with previously treated CML

Abstract

Abstract Introduction: While outcomes for patients (pts) with chronic phase chronic myeloid leukemia (CML-CP) have substantially improved with tyrosine kinase inhibitors (TKIs) targeting the BCR::ABL1 active-site domain, ≥50% of pts experience progression and/or intolerance to currently approved active-site TKIs. TERN-701, an investigational, highly selective, oral allosteric BCR::ABL1 inhibitor targeting the ABL1 myristoyl binding pocket, is being developed to improve further on safety and efficacy within the allosteric inhibitor class. In preclinical studies, TERN-701 demonstrated greater potency than the currently approved allosteric inhibitor, asciminib, against several BCR::ABL1 resistance mutations. Here we report initial results from the ongoing Phase 1 study of TERN-701 in pts with previously treated CML-CP. Methods: CARDINAL (NCT06163430) is an ongoing, open-label, two-part, global, multicenter Phase 1 study in pts ≥18 years old with BCR::ABL1-positiveCML-CP (with or without T315I mutation and without myristoyl binding pocket mutations) previously treated with ≥1 prior second-generation (2G) TKI (bosutinib, dasatinib, or nilotinib). Prior asciminib/ponatinib treatment was also permitted. TERN-701 was dosed once-daily (QD) in continuous 28-day cycles. Study comprised dose escalation (Part 1) of TERN-701 through 4 cohorts (160 mg, 320 mg, 400 mg, 500 mg QD) with optional backfill at each dose followed by randomized dose expansion (Part 2). Two recommended doses for expansion (RDE) were selected based on totality of Part-1 data. The study objectives were to assess safety/tolerability, PK, and efficacy. Efficacy, defined as cumulative major molecular response (MMR) by 24 weeks (wks), was measured as change in BCR::ABL1 transcripts (IS) from baseline using centrally assessed RT-qPCR. Pts were evaluable for efficacy if they had >1 post-baseline molecular response assessment and met at least one of the following: had response assessment at 24 wks, achieved MMR prior to 24 wks (if no MMR at baseline), maintained MMR for >24 wks (if in MMR at baseline), or discontinued treatment for any reason prior to 24 wks. Pts with T315I mutation were not included in the efficacy analyses reported here. Results: As of 30 June 2025, 55 pts were enrolled, 52 to Part 1 and 3 to Part 2 (56% male; median age 58 years [29‒86]). Forty-eight pts remained on treatment (median duration of exposure 4.5 months (range: 0.25‒16.2 months); and 7 discontinued (disease progression [n=4], adverse events [n=1], consent withdrawal/lost to follow up [n=2]). Baseline characteristics included: median 3 prior TKIs (range: 1‒6); 35% had ≥4 prior TKIs; 36% had prior asciminib; 25% had prior ponatinib and/or investigational TKI (olverembatinib/ELVN-001); 56% had baseline BCR::ABL1>1%, with 44% having baseline BCR::ABL1>10%; and 13% with BCR::ABL1 mutations (9% T315I, 4% F317L). Moreover, 64% and 31% had lack of efficacy (per ELN 2020 criteria) and intolerance to last TKI, respectively. No dose-limiting toxicities (DLTs) were observed in dose escalation, and a maximal tolerated dose (MTD) was not reached. The majority (74%) of treatment-emergent adverse events (TEAEs) were low grade with no apparent dose relationship. The most common TEAEs were diarrhea (22%), headache (18%), and nausea (16%), all Grade 1 or 2. Grade 3 or higher TEAEs were all ≤10%, most commonly neutropenia (7%) and thrombocytopenia (4%). TERN-701 exposures were approximately dose proportional across the dose range. Of 32 efficacy-evaluable pts, 75% (24/32) were in >MMR by 24 wks, of whom 64% (14/22) achieved and 100% (10/10) maintained that response. Notably, in the subgroups of evaluable pts who 1) discontinued last TKI for lack of efficacy, 2) had prior treatment with asciminib, or 3) had prior asciminib/ponatinib/investigational TKI, 69% (11/16), 60% (6/10), and 67% (8/12) were in >MMR by 24 wks, respectively. No patients had lost MMR at the time of data cutoff. Conclusions: TERN-701 demonstrated encouraging safety/tolerability and efficacy in a heavily pre-treated patient population with CML-CP previously treated with approved 1G/2G TKIs, ponatinib, asciminib, and other investigational, active-site TKIs. Based on data from dose escalation, 320 mg and 500 mg QD were selected as RDEs for further evaluation in the randomized dose expansion (currently enrolling).