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Publications

Journal Article Randomized Controlled Trial Clinical Trial, Phase I Multicenter Study Ppublish 21 citations

PubMed: 39570620 DOI: 10.1001/jamaoncol.2024.5157

Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.

JAMA Oncol 11(1):28-35

Authors: Elias Jabbour, Vivian G Oehler, Paul B Koller, Omer Jamy, Elza Lomaia, Anthony M Hunter, Olga Uspenskaya, Svetlana Samarina, Sudipto Mukherjee, Jorge E Cortes, Maria R Baer, Vera Zherebtsova, Vasily Shuvaev, Anna Turkina, Igor Davydkin, Huanshan Guo, Zi Chen, Tommy Fu, Lixin Jiang, Cunlin Wang, Hengbang Wang, Dajun Yang, Yifan Zhai, Hagop Kantarjian

Affiliations

  • Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.
  • Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington.
  • Department of Hematology and Hematopoietic Cell Transplantation in the Division of Leukemia, City of Hope National Medical Center, Duarte, California.
  • Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham.
  • Research Department of Immuno-Oncology, Almazov Medical Research Centre, St Petersburg, Russian Federation.
  • Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • Leningrad Regional Clinical Hospital, St Petersburg, Russian Federation.
  • Kirov Scientific Research Institute of Hematology and Blood Transfusion of the FMBA, Kirov, Russian Federation.
  • Department of Hematology and Medical Oncology, Leukemia Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
  • Georgia Cancer Center, Augusta University, Augusta, Georgia.
  • University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore.
  • S.P. Botkin City Clinical Hospital, Moscow, Russian Federation.
  • A. Tsyb Medical Radiological Research Center, Obninsk, Russian Federation.
  • National Medical Research Center for Hematology, Moscow, Russian Federation.
  • Samara State Medical University, Samara, Russian Federation.
  • Guangzhou Healthquest Pharma Co Ltd, Guangzhou, China.
  • Ascentage Pharma (Suzhou) Co Ltd, Suzhou, China.
  • Ascentage Pharma Group Inc. Rockville, Maryland.
  • Department of Experimental Research, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Abstract

Importance

Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.

Objective

To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.

Design, Setting, and Participants

This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.

Interventions

Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.

Main Outcomes and Measures

Pharmacokinetic profile of olverembatinib.

Results

Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.

Conclusions and Relevance

In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.

Trial Registration

ClinicalTrials.gov Identifier: NCT04260022.

MeSH

Precursor Cell Lymphoblastic Leukemia-Lymphoma, Neoplasms, Leukemia, Drug-Related Side Effects And Adverse Reactions, Protein-Tyrosine Kinases, Tyrosine, Therapeutics, Chromosomes

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