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

Study Overview
=================
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 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).

Official Title
-----------------
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

Conditions
-----------------
Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Cladribine
* Drug: Cytarabine
* Drug: Decitabine
* Drug: azacitadine or decitabine
* Drug: Venetoclax


Participation Criteria
=================
Eligibility 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.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission/ complete remission with incomplete count recovery (CR/CRi) | Evaluate the efficacy (as measured by rate of CR/CRi per 2017 European LeukemiaNet criteria for AML response assessment) of treatment with cladribine/cytarabine alternating with decitabine compared with treatment with decitabine or azacitadine and venetoclax | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CR/CRi | Compare time to CR/CRi (per 2017 European LeukemiaNet criteria for AML response assessment) in patients treated with cladribine/cytarabine alternating with decitabine compared with patients treated with decitabine or azacitadine and venetoclax | 18 months | 
| Time to minimal residual disease (MRD) negativity | Compare time to MRD negativity (as measured by multicolor flow cytometry) in patients treated with cladribine/cytarabine alternating with decitabine compared with patients treated with decitabine or azacitadine and venetoclax | 18 months | 
| Overall survival (Arm A vs Arm B) | Compare overall survival (defined as the time from date of randomization until date of death) in patients treated with cladribine/cytarabine alternating with decitabine compared with patients treated with decitabine or azacitadine and venetoclax | 30 months | 
| Progression-free survival | Compare progression-free survival (defined as the time from date of randomization to the date of disease progression or death due to any cause) in patients with DNMT3A mutations to that of patients with wild-type DNMT3A | 30 months | 
| Overall survival (patients with DNMT3A mutations vs patients with wild-type DNMT3A) | Compare overall survival (defined as the time from date of randomization to the date of death) in patients with DNMT3A mutations to that of patients with wild-type DNMT3A | 30 months | 
| Rate of adverse events | Compare rate of adverse events in in patients treated with cladribine/cytarabine alternating with decitabine compared with patients treated with decitabine or azacitadine and venetoclax | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AML, acute myeloid leukemia, myelodysplastic syndrome, MDS, induction therapy, low-dose cytarabine