A Phase 1/2A, Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy in adult patients with AML or higher- risk Myelodysplastic Syndrome (hrMDS). Patients enrolling in the Phase 1 dose escalation of the study must meet one of the following criteria prior to consenting to the study: * Relapse/refractory (R/R) AML with FMS-like tyrosine kinase-3 (FLT3) mutations who have been previously treated with a FLT3 inhibitor * R/R AML with spliceosome mutations of splicing factor 3B subunit 1 (SF3B1) or U2AF1 * R/R hrMDS with spliceosome mutations of SF3B1 or U2 small nuclear RNA auxiliary factor 1 (U2AF1) * Number of pretreatments: 1 or 2 The Phase 2a Dose Expansion will be in 3 Cohorts of patients: 1. R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor; 2. R/R AML with spliceosome mutations of SF3B1 or U2AF1; and 3. R/R hrMDS (Revised International Prognostic Scoring System \[IPSS-R\] score \> 3.5) with spliceosome mutations of SF3B1 or U2AF1. All patients above have had ≤ 2 lines of prior systemic anticancer treatment. In previous versions of this protocol there was a Phase 1b portion of the study, in which patients with AML or hrMDS received CA-4948 in combination with venetoclax. This part of the study is no longer open for enrollment.
• Males and females ≥18 years of age
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
• Cytomorphology based confirmed diagnosis of MDS or AML (as per World Health Organisation \[WHO\] 2016 classification) with the following characteristics.
• Phase 1 Dose Escalation (Monotherapy)
• • AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation).
• OR
• • Higher-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypomethylating agent (HMA) or evidence of early progression
• Phase 2a Dose Expansion (Monotherapy)
• Patients with:
⁃ R/R AMLwith FLT3 mutations who have been previously treated with a FLT3 inhibitor
⁃ R/R AML with spliceosome mutations of SF3B1 or U2AF1
⁃ R/R hrMDS (IPSS-R score \> 3.5) with spliceosome mutations of SF3B1 or U2AF1
⁃ Number of prior treatments: 1 or 2
• Acceptable organ function at screening
• Ability to swallow and retain oral medications
• Negative serum pregnancy test in women of childbearing potential
• Women of childbearing potential and men who partner with a woman of childbearing potential must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of emavusertib
• Willing and able to provide written informed consent and comply with the requirements of the trial
⁃ Able to undergo serial bone marrow sampling and peripheral blood sampling