Vodobatinib for patients with Philadelphia chromosome-positive chronic myeloid leukaemia resistant or intolerant to multiple lines of previous therapy: an open-label, multicentre, phase 1/2 trial.

Abstract

Background: Resistance or intolerance to the available tyrosine kinase inhibitors (TKIs) remains a treatment challenge for patients with chronic myeloid leukaemia. We aimed to report the safety, antileukaemic activity, and pharmacokinetics of oral vodobatinib, a novel selective BCR::ABL1 TKI, in patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukaemia who previously received at least three TKIs, including ponatinib and asciminib.

Methods: This open-label, multicentre, phase 1/2 trial was conducted at 28 clinical sites across ten countries (Belgium, France, Hungary, India, Italy, Romania, South Korea, Spain, UK, and the USA). Patients aged 18 years or older with Ph-positive chronic myeloid leukaemia or acute lymphoblastic leukaemia (eligible only for the phase 1 study), and an Eastern Cooperative Oncology Group performance status of 2 or lower were eligible. Phase 1 included patients who previously received at least three TKIs or had no other available treatment options. Phase 2 required patients to have treatment resistance or intolerance (or both) with loss of response to at least three TKIs and previous ponatinib use. A key exclusion criterion for both phases was presence of the Thr315Ile mutation. Patients self-administered oral vodobatinib (12-240 mg) once per day for each 28-day treatment cycle and for up to 60 months (ie, 65 cycles) unless patient discontinuation due to adverse events, progressive disease, lost to follow-up, or death. The primary endpoints were to determine the maximum tolerated dose (based on dose-limiting toxicities in phase 1) and antileukaemic activity of vodobatinib (ie, major cytogenetic response for chronic-phase and major haematological response for accelerated-phase or blast-phase in phase 2). Assessment of vodobatinib safety, activity, and pharmacokinetics were determined based on the pooled analysis of data from the phase 1 and 2 studies. This trial is registered with ClinicalTrials.gov, NCT02629692 (active). At data cutoff (July 15, 2023), phase 2 enrolment was closed early on June 22, 2023, due to recruitment-related challenges.

Findings: 78 patients were enrolled and received at least one vodobatinib dose (safety and efficacy analysis set). Between April 6, 2017, and June 20, 2023, phase 1 enrolled 58 patients and phase 2 enrolled 20 patients between March 3, 2020, and March 29, 2023. We included 66 (85%) patients with chronic-phase, eight (10%) with accelerated-phase, and four (5%) with blast-phase chronic myeloid leukaemia. 43 (55%) of 78 patients were male and 35 (45%) were female. The median age was 59·0 years (IQR 47·0-66·0). The median follow-up was 22·3 months (IQR 11·1-43·9). Two patients receiving vodobatinib 240 mg had dose-limiting toxicities (one had grade 3 dyspnoea and the other had grade 2 fluid overload), thus the 204 mg dose was considered to be the maximum tolerated dose. 73 (94%) patients had one or more treatment-emergent adverse events, with most events being haematological or gastrointestinal that were grade 2 or lower in severity. Grade 3 or higher treatment-emergent adverse events occurred in 47 (60%) patients and included thrombocytopenia (14 [18%]), neutropenia (10 [13%]), anaemia (nine [12%]), and increased lipase (eight [10%]). Seven (9%) patients died during the study; one death was considered related to treatment by the clinical investigator. At data cutoff, major cytogenetic response was observed in 44 (70%) of 63 patients with chronic-phase chronic myeloid leukaemia, of which 12 (75%) of 16 patients in the phase 2 study had major cytogenetic response. For patients with accelerated-phase chronic myeloid leukaemia, six (86%) of seven patients had a major haematological response (median duration 17·8 [IQR 10·2-24·3]) at data cutoff; major haematological response was observed in three (100%) evaluable patients in the phase 2 study. Major haematological response was reached by two (50%) of four patients with blast-phase chronic myeloid leukaemia and the median duration of response was 6·2 months (IQR 3·2-9·3); no blast-phase patients were enrolled in the phase 2 study.

Interpretation: Pooled analysis of the phase 1 and 2 studies showed clinically meaningful antileukaemic activity of vodobatinib and a tolerable safety profile in patients with advanced chronic myeloid leukaemia who previously received multiple TKIs, including ponatinib and asciminib, addressing an otherwise unmet clinical need. The phase 2 study was statistically underpowered and warrants further investigation in a phase 3, randomised controlled trial and in an earlier treatment setting of the disease.

Funding: Sun Pharma Advanced Research Company.