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 Induction

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 Induction

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 azacitidine) plus venetoclax in patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome (MDS) who are either elderly or unfit for intensive induction. 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).

Study Overview

• Status: Withdrawn
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Cladribine; Drug: Cytarabine; Drug: Decitabine; Drug: Venetoclax; Drug: azacitidine or decitabine

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 60 years.

  • Adults < 60 years are eligible if deemed unfit for intensive induction by their treating physician (or choose to receive a non-intensive regimen due to patient's preference)

• Diagnosis of treatment-naive AML (excluding acute promyelocytic leukemia treated with hydroxyurea) or high grade MDS defined as >10% marrow blasts or R-IPSS of intermediate 2 risk or higher with > 10% bone marrow blasts, and 1 or more of the following:

  • Circulating blasts in peripheral blood
  • Rapidly declining blood counts over the past 8 weeks, as determined by treating investigator
  • Transfusion dependence
  • Adverse cytogenetic changes or molecular mutations with high risk of rapid progression to AML, as determined by treating investigator
  • Significant B-symptoms attributed to MDS (weight loss, fatigue, unexplained fever, night sweats)
  • Evidence of clonal evolution with emergence of new cytogenetic changes or new mutations compared to previous bone marrow biopsy.
• White blood cell count < 25 K/uL. Cytoreduction with hydroxyurea is allowed prior to enrollment to obtain white blood cell count < 25 K/uL.
• Subjects of childbearing potential (SOCBP) must have a negative pregnancy test and agree to use of an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 months after the last dose of study drug. Prior to study enrollment, subjects of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional 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)
• Patient with active central nervous system leukemia

• Karnofsky performance status < 50 at screening

  • Karnofsky performance status of 40-50 is allowed to proceed on study if the patient had a performance status of 50-100 at screening and the decline to 40 is deemed definitely related to disease (AML/MDS).

• Patients with AML with molecular mutations with FDA approved targeted therapies in the first line setting.

  • This 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 and will be excluded once approval is obtained).
• Subjects with familial AML/MDS syndromes and those with inherited DNA repair syndromes like Fanconi Anemia
• 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 mL/min (per Cockcroft Gault equation) or dialysis-depended renal failure
• Class III-IV NYHA heart failure
• Child-Pugh class C liver cirrhosis
• 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.

• Subjects with uncontrolled life-threatening infections

  • Subjects with fever (temperature > 38.3 C) thought to be related to AML/MDS are eligible
• History of allergic reaction to hypomethylating agents (decitabine, azacitidine), venetoclax, cladribine, or cytarabine.

• Active solid tumor malignancy requiring treatment within previous 2 years.

  • Patients with prior history of malignancy who completed treatment > 2 years prior to baseline are eligible to enroll if there is currently no evidence of disease and all toxicities of prior treatments are resolved.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
• Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (investigational arm): cladribine, cytarabine, and decitabine	Drug: Cladribine; Subjects will be given 5 mg/m2 cladribine intravenously on days 1-5 of cycle 1 and on days 1-3 of cycles 2, 5, 6, 9, 10, 13, 14, 17 and 18.; Drug: Cytarabine; Subjects will be given 20 mg cytarabine subcutaneously twice daily on days 1-10 of cycles 1, 2, 5, 6, 9, 10, 13, 14, 17 and 18.; Drug: Decitabine; Subjects will be given 20 mg/m2 decitabine intravenously on days 1-5 of cycles 3, 4, 7, 8, 11, 12, 15 and 16
Active Comparator: Arm B (control arm): azacitidine with venetoclax or decitabine with venetoclax	Drug: Venetoclax; Subject will take 400 mg venetoclax orally once daily on days 1-21 of each cycle.; Drug: azacitidine or decitabine; Subjects will be given either 20 mg/m2 decitabine intravenously on days 1-5 of each cycle or 75 mg/m2 azacitidine intravenously or subcutaneously on days 1-7 of each cycle. The treating physician will determine which drug each subject will receive.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete remission	Compare the rate of complete remission (per 2017 European LeukemiaNet criteria for AML response assessment) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to complete remission	Compare time to complete remission (per 2017 European LeukemiaNet criteria for AML response assessment) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	18 months
Time to minimal residual disease (MRD) negativity	Compare time to MRD negativity (as measured by multicolor flow cytometry per current NCCN guidelines) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	18 months
Overall survival	Compare overall survival (defined as the time from date of randomization until date of death) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	30 months
Overall response rate	Compare overall response rate (defined as the number of patients who achieve either complete or partial remission per 2017 European LeukemiaNet criteria for AML response assessment) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	18 months
Time to overall response	Compare time to overall response in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax. Time to overall response is defined as the time interval from the date of treatment initiation to achievement of overall response.	18 months
Rate of MRD negativity	Compare rate of MRD negativity (as measured by multicolor flow cytometry per current NCCN guidelines) in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax	18 months
Event-free survival	Compare event-free survival in patients treated with cladribine/cytarabine alternating with decitabine to that for patients treated with decitabine or azacitidine and venetoclax. Event-free survival is defined as the time from the date of randomization to induction treatment failure, relapse in those with a complete remission after induction, or death from any cause.	30 months

Collaborators and Investigators

• Sponsor: University of Florida
• Investigators: Principal Investigator: Paul Crispen, MD, University of Florida

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: March 1, 2023
• First Submitted That Met QC Criteria: March 1, 2023
• First Posted (Actual): March 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 22, 2025
• Last Update Submitted That Met QC Criteria: April 16, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: AML; MDS; acute myeloid leukemia; myelodysplastic syndrome; induction therapy; low-dose cytarabine
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Decitabine; Venetoclax; Cytarabine; Azacitidine; Cladribine
• Other Study ID Numbers: UF-HEM-011; OCR43074 (Other Identifier: University of Florida); IRB202300983 (Other Identifier: University of Florida)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No