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: Phase 1b interim results.
Authors: Mims Alice S. , Huang Ying , Eisenmann Eric , Buelow Daelynn , Swords Ronan T. , Foster Matthew Charles , Lin Tara L. , Baer Maria R. , Kovacsovics Tibor , Al-Mansour Zeina , Stefanos Mona , Druggan Franchesca , Chen Timothy , Yocum Ashley , Borate Uma , Druker Brian J. , Burd Amy , Levine Ross L. , Baker Sharyn D. , Byrd John C. 
Published: June 2022

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Background: TP-0903 is a multi-kinase inhibitor designed to target AXL, a receptor tyrosine kinase, and also inhibits cell cycle regulators such as Chk1/2 and other AML associated kinases. TP-0903 has shown prior anti-tumor activity at a safe dose in solid tumors. In pre-clinical AML studies, TP-0903 shows potent cytotoxicity in TP53 mutant ( TP53m) AML cell lines, an adverse prognostic genomic sub-group of AML. TP-0903 also had synergistic activity with decitabine (dec) in TP53m AML and prolonged survival in xenograft and genetically engineered mouse models. We report here on the initial safety and clinical results from the Leukemia and Lymphoma Society’s ongoing Beat AML phase 1b/2 (Ph1b/2) trial of TP-0903 in combination with dec (ClinicalTrials.gov NCT03013998). Methods: Newly diagnosed AML pts ≥60 years with TP53m and/or complex karyotype (≥3 abnormalities) were selected for a Ph1b/2 dose escalation study of TP-0903 combined with dec. Seven Ph1b pts were given TP-0903 every 28-day cycle from days 1-21 (Dose level (DL) 1 = 37 mg/day) and dec IV days 1-10 (20 mg/m2). A standard 3+3 design was used to evaluate the safety and tolerability. Nine additional patients enrolled onto Ph2 at DL1, but further assessments of safety, pharmacokinetics (PK) and correlative data was used to update the final recommended Ph2 dose (RP2D) of TP-0903 to DL-1 (25 mg/day) with dec. Results: At data cutoff (10Jan2022), 16 total pts were accrued. Ph1b treated 7 pts at DL1, 6 were DLT evaluable, and no DLTs were observed. Ph2 enrolled and treated 9 pts at DL1 before concerns of delayed count recovery led to the reduction of the Ph2 dose of TP-0903 to DL-1 (25 mg/day). For all 16 pts treated at DL1, 1 pt achieved CR, 4 pts CRh, and 1 pt CRi, for a composite CR (CR/CRh/CRi) rate of 37.5% (95% CI, 15.2-64.6), with 4 pts achieving MRD negativity by central flow cytometry. For the remaining 10 pts, 1 pt achieved MLFS (6%), 6 pts had stable disease (37.5%), 1 pt had treatment failure (6%), and 2 pts were not evaluable (12.5%) due to withdrawal of consent and death from early disease progression. Two pts (1 CR and 1 CRh) proceeded to stem cell transplantation. The most common grade 3 and above treatment-related AEs include decreased neutrophil counts (37.5%), platelet counts (31.3%), and anemia (18.8%). Finally, PK and correlative data analysis looking at soluble Axl and Gas6 also supported reduction to DL-1. Conclusions: Initial results with DL1 suggest that TP-0903/dec shows preliminary clinical activity in the prognostically poor TP53m/complex karyotype AML sub-group, with 4 pts achieving MRD negative status out of 6 patients who achieved a CR/CRh/CRi (66%). After further patients were treated on DL1, the toxicity profile and correlative data supported the de-escalation to DL-1 as the RP2D. The Ph2 study is ongoing to determine the clinical activity of this new RP2D (DL-1). Clinical trial information: NCT03013998.