A Phase 1, Open Label Dose Escalation Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome
his is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered CA-4948 monotherapy and in combination with azacitidine or venetoclax in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS).
To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 in patients with AML and high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and PK/PD findings
To characterize the pharmacokinetic
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2
Cytomorphology based confirmed diagnosis of MDS or AML 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).
High-risk R/R MDS that are considered resistant/refractory following at least 2 to 3 cycles of hypermethylating agent (HMA) or evidence of early progression
Phase 1b (Combination Therapy) Doublet Arm: CA-4948 + AZA, Patients with:
International Prognostic Scoring System- revised (IPSS- R) High, high risk myelodysplastic syndrome (hrMDS)
HMA and ventoclax naïve, and ineligible for intensive chemotherapy
Doublet Arm: CA-4948 + Venetoclax
R/R AML or hrMDS, after first line therapy
Phase 2a Dose Expansion (Monotherapy), Patients with:
-R/R AML, FLT3-ITD mutant AML patients after failing at least 1 and maximal 3 pretreatments, including a FLT3 inhibitor FLT3 inhibitor
-R/R AML with FLT3 WT, after failing 1 to 3 pretreatments. Desired enrichment for expression of spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR1)
-R/R hrMDS with spliceosome mutations of SF3B1 and U2AF1 only resistant/refractory to HMA; ineligible for intensive chemotherapy. maximal 3 pretreatments
-R/R hrMDS without SF3B1 or U2AF1spliceosome mutations (can have SRSF2 or ZRSR2 mutations); resistant/refractory to r/r to HMA; ineligible for intensive chemotherapy, maximal 3 pretreatments
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 90 days after the last dose of CA-4948
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
Other criteria may apply
Diagnosed with acute promyelocytic leukemia (APL, M3)
Has known active central nervous system (CNS) leukemia
Allogeneic hematopoietic stem cell transplant (Allo-HSCT) within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948
Chronic myeloid leukemia (CML)
Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to start of CA-4948. Localized radiation or surgical resection of skin cancers allowed.
Use of any investigational agent within 28 days or 5 half-lives, whichever is shorter, prior to start of CA-4948
Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤1 within 7 days prior to start of CA-4948
Known allergy or hypersensitivity to any component of the formulation of CA-4948
Major surgery, other than diagnostic surgery, less than 28 days from the start of CA-4948; minor surgery less than 14 days from the start of CA-4948
Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)
Patients with active advanced malignant solid tumors
Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
Hepatitis B virus (HBV) DNA positive or Hepatitis C virus (HCV) infection > Uncontrolled or severe cardiovascular disease
Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948
History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician
Pregnant or lactating female
Systemic fungal, bacterial, viral, or other infection that is not controlled
Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of trial participation or CA-4948 administration
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