Phase II Prospective Randomized Control Trial of Cladribine and Low-Dose Cytarabine (LoDAC) Alternating With Decitabine vs. Hypomethylating Agents (HMA) Plus Venetoclax as Frontline Therapy for AML or High-Grade MDS in Patients Unfit for Intensive I

• Status: Not yet recruiting
• Trial end date: 2030-12-01
• Target enrollment: 0
• Participant gender: All

Summary

This phase II, open-label, randomized trial will compare the efficacy of the novel regimen of cladribine/low-dose cytarabine alternating with decitabine to the current standard of care regimen of hypomethylating agents (decitabine or azacytidine) plus venetoclax in elderly and unfit patients presenting with AML or high grade MDS for whom targeted therapy based on the molecular/genetic subtype is not available. Subjects will be randomized to be treated with either cladribine/low-dose cytarabine alternating with decitabine (Arm A) or decitabine or azacitadine plus venetoclax (Arm B).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Florida
• Treatments: Cladribine; Cytarabine; Decitabine; Venetoclax

Criteria

Inclusion Criteria:

• Age ≥ 60 years.

• ECOG Performance status (PS) of 0 to 2 is required at baseline. (Note: ECOG PS of 3 is allowed to enroll only if the patient had a PS of 0-2 at baseline and the current decline to an ECOG PS of 3 is deemed to be due to disease (AML/MDS)).

• Patient < 60 years are eligible to enroll if deemed unfit for intensive induction by their treating physician, or choose to receive a non-intensive regimen due to patient/physician preference.

• Participants must have a diagnosis of treatment-naive AML (excluding acute promyelocytic leukemia [APL]) or high grade MDS defined as >10% marrow blasts or R-IPSS of intermediate 2 risk or higher.

• Adequate kidney function: creatinine clearance (CrCL) ≥ 10

• Prior therapy with hypomethylating agents (HMA) is allowed, unless the patient experienced progression to AML while on treatment with HMA/Venetoclax for high-grade MDS.

• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.

• Subjects of childbearing potential must have a negative pregnancy test and must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of study drug to minimize the risk of pregnancy.

• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 4 months following the last dose of study drug.

Exclusion Criteria:

• Participants with acute promyelocytic leukemia (APML, APL, AML-M3) or any morphologic and molecular variants, inclusive.

• Patient with central nervous system (CNS) leukemia

• ECOG Performance Status of ≥ 3 at baseline

• Patients with AML with molecular mutations with FDA approved targeted therapies in the first line setting. This currently includes FLT3 ITD/TKD + AML, IDH1+ AML. (Note: IDH2+ AML has targeted therapy approved in relapsed setting only, FDA approval for first line setting is pending).

• Patients who were previously treated with HMA/Venetoclax for high-grade MDS and failed to respond, or progressed to AML while on treatment, are not eligible

• Participants with a serious concurrent illness that in the opinion of the Investigator would pose an undue risk to the subject participating in this clinical study.

• Severe kidney impairment CrCL < 10, or dialysis-depended renal failure

• Class III-IV NYHA heart failure

• Child-Pugh class C liver cirrhosis

• A known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

• Known seropositivity or active viral infection with human immunodeficiency virus (HIV), hepatis B virus (HBV), or hepatitis C virus (HCV) unless fully treated and negative by PCR. Patients who are seropositive because of HBV vaccine are eligible.

• History of allergic reaction to hypomethylating agents (decitabine, azacytidine), Venetoclax, Cladribine, or Cytarabine.

• Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 months after the last dose of study drug.

• Subjects who are pregnant or breastfeeding, or expecting to conceive, children within the projected duration of the study, starting with the screening visit through 30 days after the last dose of study treatment.

• Subjects with uncontrolled life-threatening infections.

• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.