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

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-mutated AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.

PATIENTS AND

METHODS

This was a multicenter, open-label, phase 1b/2 substudy of 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 ages ≥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 to 21 with decitabine 20 mg/m2 on days 1 to 10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which decitabine dosing was reduced to days 1 to 5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.

RESULTS

The overall composite remission rate (CR/CR with incomplete count recovery/CR with hematologic improvement) 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 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.

SIGNIFICANCE: Treatment options for AML with mutant TP53 and/or complex karyotype are limited. In a phase 1b/2 clinical trial, TP-0903, a multikinase inhibitor, was well-tolerated and had activity comparable with other emerging therapies. Our results suggest that TP-0903 may offer insight and serve as a benchmark for the development of future agents leveraging similar strategies or scaffolds to improve outcomes in these intractable subtypes of AML.