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Clinical Trial 20749

Cancer Type: Malignant Hematology
Study Type: Treatment
NCT#: NCT04278768

Phase: Phase I
Principal Investigator: Sallman, David

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or 1-800-679-0775 Learn More

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 (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 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: IPSS-R High, hrMDS, ineligible for intensive chemotherapy Doublet Arm: CA-4948 + Venetoclax Patients with: R/R AML or hrMDS, after first line therapy Phase 2a Dose Expansion (Monotherapy), Patients with: -R/R AML, FLT3-ITD mutations, R/R including a FLT3 inhibitor -R/R AML spliceosome mutations of SF3B1 or U2AF1 -R/R hrMDS with spliceosome mutations of SF3B1 or U2AF1, bone marrow blast count greater than or equal to 8, ineligible for intensive chemotherapy. Number of pretreatments: 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 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 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 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

Known hypersensitivity to azacitidine or mannitol, as stated per label (Phase 1b only)

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, 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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