Aptose Biosciences' TUSCANY Phase 1/2 trial evaluating tuspetinib (TUS) in combination with venetoclax (VEN) and azacitidine (AZA) shows promising early results in newly diagnosed acute myeloid leukemia (AML) patients. The TUS+VEN+AZA triplet is being developed as a frontline therapy for AML patients ineligible for induction chemotherapy.
Early Efficacy and Safety Data
Initial data from the first cohort of four patients treated with a 40 mg dose of tuspetinib have been reported. Notably, two patients with FLT3-wildtype AML achieved complete remissions (CR and CRh) after one cycle of treatment. A patient with biallelic TP53 mutations and a complex karyotype also achieved CR. The third FLT3-WT patient experienced significant reductions in bone marrow leukemic blasts during Cycle 1 and remains on therapy in Cycle 2. The fourth patient, harboring FLT3-ITD and NPM1 mutations, is currently dosing in Cycle 1 and is not yet eligible for response evaluation.
According to Rafael Bejar, M.D., Ph.D., Chief Medical Officer of Aptose, achieving a complete remission in Cycle 1 in a subject harboring a TP53 mutation is particularly encouraging. The therapy also demonstrated a favorable safety profile, with no dose-limiting toxicities (DLTs) or prolonged myelosuppression observed. Furthermore, no dose reductions to the standard-of-care components of the regimen (AZA/VEN) were required in the first cohort.
Dose Escalation Approved
Based on the favorable safety review of data from the first four patients, the Cohort Safety Review Committee (CSRC) has unanimously approved escalating the tuspetinib dose from 40 mg to 80 mg. Enrollment is now open for the 80 mg cohort.
Pharmacokinetic Analysis
Pharmacokinetic (PK) analyses for tuspetinib show plasma levels unaffected by the addition of azacitidine, providing predictability and avoiding the need for dose alterations due to PK interactions. Venetoclax plasma levels in Cycle 1 are consistent with published results and the prior TUS/VEN APTIVATE study in R/R AML, indicating no clinically significant interactions with tuspetinib.
TUSCANY Trial Design
The TUSCANY trial is a Phase 1/2 study designed to test various doses and schedules of tuspetinib in combination with standard dosing of azacitidine and venetoclax for patients with AML who are ineligible to receive induction chemotherapy. Tuspetinib, a convenient, once-daily oral agent, is administered in 28-day cycles. The trial is enrolling patients at multiple U.S. sites, with anticipated enrollment of 18-24 patients by mid-late 2025. Data will be released as it becomes available.
Potential Impact
If the TUS+VEN+AZA triplet shows efficacy and tolerability in difficult-to-treat AML populations with little myelosuppression, tuspetinib could be a game changer for frontline AML treatment.
