Phase II De-Escalation Study of Metronomic Decitabine/Cedazuridine Plus Venetoclax in AML

This is an open-label, phase II, safety-primary study evaluating metronomic maintenance with once-weekly Decitabine/cedazuridine plus once-weekly Ven in patients with AML who are in CR, CRh, CRi,following standard HMAs + Ven induction and are candidates for maintenance.The study uses a single starting regimen (Venetoclax 400 mg weekly) with a pre-specified Venetoclax dose-reduction step in the event of treatment-limiting toxicity (TLT), while maintaining weekly Decitabine/cedazuridine dosing.

• Venetoclax, Decitabine/Cedaruridine (Drug): Patients who consent to the study will receive weekly Decitabine/Cedaruridine plus Venetoclax until intolerance or disease progression. Both Decitabine/Cedaruridine and Venetoclax are administered orally once on D1, 8, 15, 22 each
• decitabine/cedazuridine (Drug): Patients who consent to the study will receive weekly decitabine/cedazuridine plus Venetoclax until intolerance or disease progression. Venetoclax is administered orally once on D1, 8, 15, 22 each 28-day cycle with food and water. Decitabine/Cedazuridine is administered orally once on D1, D8, D15 D22 with empty stomach.

Primary outcomes

• Primary Outcome [12 months]: To evaluate the relapse free survival in patients with AML receiving metronomic maintenance therapy with weekly Decitabine/cedazuridine plus Venetoclax. RFS is measured from the date of first documented CR/CRi until the date of confirmed relapse or death from any cause, whichever occurs first.

Secondary outcomes

• Secondary Outcome 1 [8 days]: To assess treatment delay defined as postponing treatment for more than 7 days or cancellation of treatment due to adverse effects caused by maintenance chemotherapy.
• Secondary Outcome 2 [24 months]: To determine the overall survival, defined as the number of days from the start of induction therapy to the date of death. Subjects that have not died will be censored at the last known date to be alive.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Newly diagnosed AML (WHO 2022 classification or ICC 2022 classification)
* Participants must be considered Ineligible for intensive induction defined by the following:

  1. Age 75 years or older, or
  2. Age 18 to 74 years with at least one of the following comorbidities:

  i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina). ii) Severe pulmonary disorder (eg, DLCO ≤65% or FEV1 ≤65%). iii) Creatinine clearance ≥30 mL/min to <45 mL/min iv) Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN).
* Must have achieved CR,CRh, CRi, following induction with maximum 3 cycles of standard IV HMAs and venetoclax.
* Able to provide informed consent
* Prior and concomitant hydroxyurea is permitted
* ECOG performance status 0 to 3

Exclusion Criteria:

* Progression or relapse after induction standard HMAs + Venetoclax therapy
* Pregnancy or breastfeeding
* Uncontrolled infection, active CNS disease, or concurrent malignancy requiring systemic therapy
* Inability to take oral medication or presence of malabsorption syndrome or any other uncontrolled gastrointestinal condition
* Candidate for intensive chemotherapy
* Uncontrolled infection, active CNS disease, or concurrent malignancy requiring systemic therapy
* Candidate for stem cell transplant

• Xiaoyi Chen, MD, PhD, Principal investigator, Rutgers Cancer Institute of New Jersey