TERN-701 is being evaluated as part of the ongoing CARDINAL trial, a global, multicenter, phase 1 study in patients with relapsed/refractory CML, including those resistant to prior therapies like second- and third-generation TKIs and asciminib (Scemblix).

The study has 2 parts: part 1 of the trial is the dose-escalation phase, which will evaluate sequential dose-escalation cohorts of TERN-701 administered once daily, and part 2, the dose-expansion portion, consists of randomized, parallel dose-expansion cohorts of TERN-701 that will continue to assess the efficacy and safety of at least 2 recommended dose levels for expansion selected from part 1.2

Male or female patients aged 18 years or older with an established cytopathologically confirmed diagnosis of BCR-ABL1–positive CML in chronic phase with or without a T315l mutation are eligible for enrollment in the study. Patients must have an ECOG performance status of 0 to 2, have received treatment with active-site targeting TKIs and have experienced treatment failure, suboptimal response, or treatment intolerance, and have adequate organ function. Further, patients must be intolerant of asciminib and are required to not have resistant or relapsing disease.

In part 1, the primary safety end points include the incidence of DLTs during the first cycle of treatment (28 days), determination of the maximum tolerated dose, and recommended doses for expansion cohorts of TERN-701. Additionally, safety is assessed by tracking serious AEs and general AEs.

In part 2, key end points include achieving a complete hematologic response, evaluating MMR, and tracking the best categorical molecular response shift from baseline in BCR-ABL1 transcript levels during treatment.

As of the October 2024 data cutoff, the study enrolled 15 patients across 3 dose levels (160 mg, 320 mg, 400 mg).1 These patients had a median of 4 prior TKIs (range, 1-6). A total of 80% of patients had been treated with 3 or more TKIs, 47% had received ponatinib (Iclusig), and 40% had been treated with asciminib.

Seventy-three percent of patients were not in MMR at baseline, and 60% had baseline BCR-ABL transcript levels exceeding 1% on the international scale. Patients had a median treatment duration of 3 months (range, 0.79 to 7.5 months), with 14 of 15 patients remaining on treatment as of the data cutoff. Moreover, 12 patients were efficacy evaluable.

Encouraging early data from the phase 1 CARDINAL study (NCT06163430) revealed that TERN-701, an investigational oral allosteric BCR-ABL inhibitor, demonstrated significant molecular responses and a strong safety profile in heavily pre-treated patients with chronic myeloid leukemia (CML).1

Upon completion of its dose-escalation phase, the study showed a cumulative major molecular response (MMR) rate of 50% at 3 months, with promising results even at the lowest dose levels. All patients with an MMR or better (n = 4) maintained their response, and no patients discontinued treatment due to adverse events (AEs).

At the 160 mg and 320 mg dose levels, 88% of patients with high baseline BCR-ABL transcript levels (>1%) experienced reductions in BCR-ABL transcripts. Two notable outcomes included MR2 within 5 months in a fourth-line patient and deep molecular response within 3 months in a fifth-line patient.