TERN-701 Shows Promising Early Results in Heavily Pre-Treated CML

Microscopic, photorealistic image of chronic myeloid leukemia (CML) cells - Generated with Adobe Firefly

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.

“These exciting early data from our phase 1 dose escalation cohorts clearly show TERN-701 has compelling clinical activity with a highly encouraging cumulative MMR rate of 50% at 3 months. At the first 2 dose levels, we see clinically meaningful molecular and hematologic responses in patients with high baseline BCR-ABL transcript levels who had poor responses on prior 2G tyrosine kinase inhibitors [TKIs], 3G TKIs including ponatinib, as well as asciminib,” said Emil Kuriakose MD, chief medical officer of Terns, in a press release.

Across dose levels of 160 mg to 400 mg, TERN-701 showed no dose-limiting toxicities (DLTs), treatment-related serious AEs, or grade 3 or higher AEs. In addition, there were no clinically meaningful changes in liver enzymes, blood pressure, or other vital parameters observed.

Further, data regarding linear pharmacokinetics showed that at 160 mg and 320 mg, dose-proportional increases in exposure were observed, achieving drug concentrations well above the thresholds necessary for potent BCR-ABL inhibition.

“The emerging safety data show a profile supporting best-in-class potential with no dose-limiting toxicities across 3 completed dose levels, no clinically meaningful changes in liver or pancreatic enzymes, and no AE-related dose reductions or discontinuations at doses that achieve plasma exposures well above target efficacious concentrations. Taken together, the clinical activity and safety data across the dose range in these heavily pre-treated patients with refractory disease support a potential wide therapeutic index that allows for high levels of target coverage with favorable safety/tolerability,” added Kuriakose.

Background and Study Design

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.

Next Steps

The CARDINAL study is on track to begin dose expansion cohorts in early 2025, with further safety and efficacy data, including long-term MMR rates, expected in late 2025. These results could further validate TERN-701’s role in addressing the unmet needs of patients with relapsed/refractory CML.

“We are thrilled to share these impactful early data from the phase 1 CARDINAL study of TERN-701, which support its potential to be a best-in-class allosteric inhibitor for the treatment of CML,” said Amy Burroughs, chief executive officer of Terns, in the press release.1 “In addition to the meaningful clinical data, the CARDINAL study highlights yet another example of excellent clinical and operational execution at Terns, with patients enrolled in all 4 dose escalation cohorts in less than a year. We are well-positioned to initiate dose expansion cohorts in the first half of 2025 and look forward to sharing additional safety and efficacy data, including longer term MMR data in late 2025.”

REFERENCES:

1. Terns Pharmaceuticals announces positive early data from phase 1 CARDINAL trial of TERN-701 for chronic myeloid leukemia. News release. December 3, 2024. Accessed December 3, 2024. https://tinyurl.com/muj2fryv

2. CARDINAL- A clinical study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TERN-701 in participants with chronic myeloid leukemia. ClinicalTrials.gov. Updated December 8, 2023. Accessed December 3, 2024. https://clinicaltrials.gov/study/NCT06163430