A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia (AML) ≥ Age 60 years.

Abstract

Purpose: Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53 mutant AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.

Methods: This was a multicenter, open-label, Phase 1b/2 substudy of the Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The Phase 1b portion used a 3+3 design, and the Phase 2 portion used a Simon two-stage design. Eligible patients aged ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (Group 1) or 25 mg (Group 2) TP-0903 orally on Days 1-21 with decitabine 20 mg/m2 on days 1-10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which the decitabine was reduced to days 1-5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.

Results: The overall composite remission rate (CR/CRi/CRh) was 33.3% in Group 1 and 50.0% in Group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for Groups 1 and 2 was 7.6 months and 7.5 months, respectively.

Conclusions: The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.