Clinical Trial 20749

• Overview

  Study Title:

  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

  Summary:

  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).

  Objective:

  Primary 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 Secondary To characterize the pharmacokinetic

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  CA-4948 (); GDC-0199 (Venetoclax); Venetoclax (); azacitidine (5-azacitidine)

• Inclusion Criteria

  Inclusion Criteria:
  • Males and females 18 years of age or older
  • Life expectancy of at least 3 months
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to 1
  • Cytomorphology based confirmed diagnosis of MDS or AML with the following characteristics. Phase 1 Dose Escalation AML (primary or secondary, including treatment-related) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or stem cell transplantation) based on the assessment of the Investigator. Higher-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: IPSS-R High, hrMDS, ineligible for intensive chemotherapy Doublet Arm: CA-4948 + Venetoclax
  • Patients with R/R AML
  • FLT3-ITD mutations who have been previously treated with a FLT3 inhibitor
  • R/R AML spliceosome mutations of SF3B1 or U2AF1
  • R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1 and have had > Patients with
  • R/R AML with FLT-3 mutations who have been previously treated with a FLT3 inhibitor
  • R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1 AND
  • Have had > 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

• Exclusion Criteria

  Exclusion Criteria:
  • 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 3 weeks (or 5 half-lives) whichever is shorter, or radiotherapy received 2 weeks prior to the start of CA-4948.Note: Localized radiation or surgical resection of skin cancers is allowed.
  • Use of any investigational agent within 3 weeks (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 as determined by the NCI-CTAE v4.03 within 7 days prior to start of CA-4948 unless approved by the Medical Monitor.
  • 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
  • Patients with active advanced malignant solid tumors
  • Viral Infections:
  • 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 > Concomitant illnesses that would preclude safe participation in the study, identified within approximately 28 days of C1D1, including:
  • Uncontrolled or severe cardiovascular disease
  • Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948
  • 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
  • Systemic fungal, bacterial, viral or other infection that is not controlled
  • Pregnant or lactating
  • Other criteria may apply

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