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

NCT05766514 | Withdrawn Phase 2 DMC FDA Drug

• 3 other identifiers: UF-HEM-011OCR43074IRB202300983
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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 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).

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

acute myeloid leukemia; myelodysplastic syndrome; AML; MDS; induction therapy; low-dose cytarabine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Time to complete remission

  18 months

• Time to minimal residual disease (MRD) negativity

  18 months

• Overall survival

  30 months

• Overall response rate

  18 months

• Time to overall response

  18 months

Study Arms (2)

Arm A (investigational arm): cladribine, cytarabine, and decitabine

EXPERIMENTAL

Drug: Cladribine; Drug: Cytarabine; Drug: Decitabine

Arm B (control arm): azacitidine with venetoclax or decitabine with venetoclax

ACTIVE COMPARATOR

Drug: azacitidine or decitabine; Drug: Venetoclax

Interventions

Cladribine DRUG

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.

Arm A (investigational arm): cladribine, cytarabine, and decitabine

Cytarabine DRUG

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.

Arm A (investigational arm): cladribine, cytarabine, and decitabine

Decitabine DRUG

Subjects will be given 20 mg/m2 decitabine intravenously on days 1-5 of cycles 3, 4, 7, 8, 11, 12, 15 and 16

Arm A (investigational arm): cladribine, cytarabine, and decitabine

azacitidine or decitabine DRUG

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.

Arm B (control arm): azacitidine with venetoclax or decitabine with venetoclax

Venetoclax DRUG

Subject will take 400 mg venetoclax orally once daily on days 1-21 of each cycle.

Arm B (control arm): azacitidine with venetoclax or decitabine with venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead

Study Sites (1)

University of Florida

Gainesville, Florida, 32608, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Cladribine; Cytarabine; Decitabine; Azacitidine; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Aza Compounds; Organic Chemicals

Study Officials

• Paul Crispen, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2023
• First Posted: March 13, 2023
• Study Start: April 1, 2025
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2030
• Last Updated: April 22, 2025

Record last verified: 2025-04

Locations

US (1)