FDA and EMA Clear Phase 3 POLARIS-1 Trial in Newly Diagnosed Ph+ ALL

Olverembatinib plus low-intensity chemotherapy achieved an MRD-negativity rate in about 65% of patients with newly diagnosed Ph+ ALL.

The FDA and European Medicines Agency (EMA) have cleared the global, registrational phase 3 POLARIS trial (NCT06051409), which will be evaluating olverembatinib, an oral third-generation tyrosine kinase inhibitor, in combination with chemotherapy for the treatment of patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), according to a press release from the developer, Ascentage Pharma Group International.1

The trial is simultaneously enrolling patients in trial centers in multiple countries in hopes of accelerating the drug’s path to worldwide registration, with an added focus on the US and European markets. POLARIS-1 was initiated in China in 2023 following clearance by the China Center for Drug Evaluation.

The first dataset from the trial will be shared at the 2025 American Society of Hematology (ASH) Annual Meeting. Reportedly, in the trial, olverembatinib plus low-intensity chemotherapy led to a minimal residual disease (MRD)-negativity rate and a molecular MRD-negative complete response (CR) rate of approximately 65% at the end of 3 treatment cycles in patients who are treatment-naïve with Ph+ ALL. Additionally, patients with certain high-risk subtypes, including those harboring the IKZF1plus mutation, experienced favorable clinical benefit with the combination regimen.

The safety profile of olverembatinib plus low-intensity chemotherapy was favorable, as a low incidence of adverse events was reported, most of which were manageable.

“Clearances from the FDA and the EMA for this global registrational phase 3 study mark a significant step forward in the global development of olverembatinib in Ph+ ALL,” said Dr Yifan Zhai, chief medical officer of Ascentage Pharma, in the press release.1 “Fulfilling our mission of addressing unmet clinical needs in China and around the world, we will press ahead with the clinical development of olverembatinib in Ph+ ALL and strive to bring a new treatment option to patients around the world as soon as possible.”

As of November 7, 2024, POLARIS-1 had an estimated enrollment of 350 patients with newly diagnosed Ph+ ALL.2 These patients were assigned to receive either oral olverembatinib once every other day with chemotherapy or oral imatinib (Gleevec) once daily with chemotherapy.

Eligible patients were 18 years or older and met the World Health Organization 2016 Ph chromosome or BCR/ABL1-positive Ph+ ALL diagnostic and typing criteria for ALL; they also had an ECOG performance status of 2 or lower, an expected survival of at least 3 months, and adequate organ function.2

Exclusion criteria include a history of chronic myeloid leukemia, clinical manifestations of central nervous system (CNS) leukemia or ALL extramedullary infiltration, previous or current clinical CNS diseases, use of therapeutic doses of anticoagulants and/or antiplatelet agents, uncontrolled heart disease, and active infections requiring systemic treatment.

The primary end point of the trial was the MRD negativity rate from cycle 1 to cycle 3, with each cycle being 28 days. The secondary end point of the trial was the number of patients with treatment-related adverse events as assessed by CTCAE v5.0, plasma concentrations of olverembatinib, and patient-reported outcomes.

Olverembatinib has received consecutive recommendations by the Chinese Society of Clinical Oncology Guidelines for the Diagnosis and Treatment of Hematologic Malignancies, as well as the breakthrough therapy designation by China. Currently, the agent is approved in China for multiple drug-resistant chronic myeloid leukemia indications, with all indications covered by the China National Reimbursement Drug List.

The developer noted that olverembatinib is not currently approved by the FDA in the US, though it is under investigation.

References

1. Ascentage Pharma announces global registrational phase III study of olverembatinib in first-line treatment of Ph+ ALL cleared by US FDA and EMA. News release. December 5, 2025. Accessed December 5, 2025. https://tinyurl.com/4vju9x5k
2. A study of olverembatinib in patients with newly diagnosed Ph+ALL. Clinical Trials.gov. Updated November 7, 2024. Accessed December 5, 2025. https://tinyurl.com/2wz73mdk