Combining ziftomenib, venetoclax, and azacitidine for treating pediatric acute leukemia

A Phase I Study Investigating the Combination of the Ziftomenib, Venetoclax and Azacitidine in Pediatric Relapsed and Refractory Acute Leukemias

This study is testing a new combination of three medications to see if it can safely help children with tough-to-treat acute leukemia feel better and live longer.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 22 (estimated)
• Ages: 2 Years to 21 Years
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (other)
• Drugs / interventions: chemotherapy, immunotherapy, prednisone
• Locations: 1 site (Houston, Texas)
• Trial ID: NCT06397027 on ClinicalTrials.gov

What this trial studies

This study aims to determine the highest safe dose of ziftomenib when combined with venetoclax and azacitidine in pediatric patients suffering from relapsed or refractory acute leukemias with specific genetic mutations. The primary focus is on assessing the safety and tolerability of this combination therapy, while also evaluating its efficacy through various response metrics such as complete remission and overall survival. Participants will be closely monitored for clinical outcomes and potential predictive markers of treatment response.

Who should consider this trial

Good fit: Ideal candidates include pediatric patients aged 2 to 21 years with relapsed or refractory acute leukemia and specific genetic mutations.

Not a fit: Patients without the specified genetic mutations or those with rapidly proliferative disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this combination therapy could provide a new treatment option for children with difficult-to-treat acute leukemias.

How similar studies have performed: While this approach is novel, similar studies combining targeted therapies have shown promise in adult populations, indicating potential for success in pediatric cases.

Eligibility criteria

Inclusion Criteria:

1. Age ≥ 2 year to 21 years
2. ECOG performance status of ≤ 2.
3. Relapsed/refractory: AML60, Mixed phenotype acute leukemia61 (MPAL), ALL61, Acute leukemia of ambiguous lineage (ALAL)62 patients with KMT2A-r, NPM1-m, NUP98-r, or HOX pathway mutation as detailed in background section

   a. ≥5% leukemic blasts in the bone marrow:
4. WBC must be below 25 K/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment.
5. Baseline ejection fraction must be \> 40%.
6. Adequate hepatic function (direct bilirubin \< 1.5x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, and AST and/or ALT \< 5x ULN unless considered due to leukemic involvement, in which case direct bilirubin \< 3x ULN or AST and/or ALT \< 5x ULN will be considered eligible).
7. Adequate renal function (creatinine clearance ≥ 30 mL/min) unless related to disease. (Justification on page 11)
8. In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy (whichever is shorter). Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI. Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
9. Unless surgically or biologically sterile: Women of childbearing potential must agree to adequate methods of contraception during the study and at least 3 months for males, and 6 months for females, after the last treatment.

Exclusion Criteria:

1. Participants who weigh less than 10kg.
2. Participants with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
3. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions (1) intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia. (2) use of hydroxyurea for patients with rapidly proliferative disease or for control of counts during differentiation syndrome. (3) use of steroids for treatment of differentiation syndrome.
4. Participants with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
5. Participants with a concurrent active malignancy under treatment.
6. Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or active/uncontrolled HIV infection, AIDS, or currently taking contraindicated medications for HIV control.
7. Female participants who are pregnant or breast-feeding.
8. Participant has an active uncontrolled infection.
9. Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class .II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
10. Corrected QT interval by Fredericia's formula \>480 ms on 12-lead electrocardiograms.
11. History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate.
12. Clinically active central nervous system (CNS) leukemia.
13. The use of topical steroids for cutaneous graft-versus-host disease (GVHD) or stable systemic steroid doses less than or equal to 20 mg of prednisone daily are permitted.
14. Participants with Grade \> 2 active acute GVHD, moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
15. Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the first dose of venetoclax.

Where this trial is running

Houston, Texas

• MD Anderson Cancer Center — Houston, Texas, United States (RECRUITING)

Study contacts

• Principal investigator: David McCall, MD — M.D. Anderson Cancer Center
• Study coordinator: David McCall, MD

Conditions: Refractory Acute Leukemia, Pediatric Relapsed