Cardinal: A Phase I, Multicenter, Open-Label, Dose-Escalation and Dose-Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Tern-701 in Chronic Myeloid Leukemia
Authors: Jabbour Elias , Rea Delphine , Cortes Jorge E. , Hochhaus Andreas , Hughes Timothy P , Kim Dong-Wook , Kantarjian Hagop M. , Holes Leanne , Kuriakose Emil T. , Mauro Michael J. 
Published: December 2024

Background: Despite improvements in patient outcomes achieved with BCR::ABL1 adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) for the treatment of chronic phase (CP) chronic myeloid leukemia (CML), many patients eventually need to switch treatments due to suboptimal response, treatment failure, or intolerance. Because all ATP-competitive TKIs operate via the same mechanism of action, novel treatment options are needed. Allosteric inhibition of BCR::ABL1 through specific targeting of the ABL myristoyl pocket has shown superior efficacy and safety/tolerability compared to first- and second-generation ATP-competitive TKIs in patients with previously treated CML. TERN-701 is an investigational allosteric BCR::ABL1 inhibitor, specifically targeting the ABL1 myristoyl pocket. Nonclinical data have shown that TERN-701 is highly selective and has high antiproliferative potency against native and mutant CML cell lines, including cells harboring the T315I mutation. Preliminary pharmacokinetic (PK) results support once daily dosing of TERN-701 without regard to food. CARDINAL (NCT06163430) is an open-label, global, two-part, Phase I study evaluating the safety, tolerability, PK, and efficacy of TERN-701 in patients with previously treated CP-CML.

Methods: Eligible 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 on or intolerance of ≥1 prior second-generation TKI (dasatinib, nilotinib, or bosutinib). Patients intolerant of asciminib without overt resistance are eligible. Patients with CML in the accelerated or blast phase are not eligible. All patients will receive TERN-701 administered 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 the 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 (randomized dose expansion), ≈40 patients will be randomized to one of the selected dose levels. Primary endpoints of Part 2 will measure efficacy, including hematologic response, molecular response, and best categorical shift in BCR::ABL1 transcript levels from baseline; secondary endpoints will include safety, tolerability, and PK. The study is being conducted in the US, Europe, Australia and South Korea and currently open to enrollment.