CML-399 CARDINAL: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Dose-Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TERN-701 in Chronic Myeloid Leukemia

Abstract

ObjectiveDespite improvements in outcomes achieved with BCR::ABL1 active-site-targeting tyrosine kinase inhibitors (TKIs) for treatment of chronic-phase (CP) chronic myeloid leukemia (CML), many patients need to switch treatments due to disease progression, intolerance, or resistance. Because active-site TKIs utilize similar mechanisms of action, novel treatment options are needed for patients. TERN-701 is a highly selective, oral, investigational, allosteric BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket. Preclinical data suggest that TERN-701 is highly potent against native BCR::ABL1 and most common BCR::ABL1 mutations, including T315I, acquired with use of second-generation active-site TKIs. CARDINAL (NCT06163430) is an open-label, global, 2-part, phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of TERN-701 in patients with previously treated CP-CML. MethodsEligible patients are ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0–2, a confirmed diagnosis of BCR::ABL1-positive CP-CML, with or without the T315I mutation, and treatment failure/intolerance of ≥1 prior second-generation TKI (dasatinib, nilotinib, or bosutinib). Patients intolerant of asciminib without overt resistance are eligible. Patients with CML in accelerated or blast phase are ineligible. Patients will receive TERN-701 orally once daily in continuous 28-day cycles. Part 1 (dose escalation) has been initiated and will include ≈24–36 patients assigned to sequential dose-escalation cohorts, starting at 160 mg, and optional backfill cohorts; dose escalation will be guided by a Bayesian optimal interval algorithm. Primary endpoints of Part 1 include incidence of dose-limiting toxicities during the first treatment cycle and other measures of safety and tolerability; secondary endpoints include PK and efficacy measures, such as hematologic and molecular responses. Based upon the results of Part 1, ≥2 TERN-701 dose levels will be selected for further evaluation in Part 2. In Part 2 (dose expansion), ≈40 patients will be randomized to one of the selected dose levels. Part 2 primary endpoints will measure efficacy (hematologic response, molecular response, and best categorical shift in BCR::ABL1 transcript levels from baseline); secondary endpoints include safety, tolerability, and PK. The study is being conducted in the US, Europe, Australia, and South Korea.