Treatment for relapsed or refractory acute myeloid leukemia with cladribine and venetoclax

Study of Cladribine+Venetoclax After Failure of Venetoclax+Hypomethylating Agent in Monocytic AML

This study is testing a new combination of cladribine and venetoclax to see if it can help people with a tough form of acute myeloid leukemia that hasn’t responded to previous treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 100 Years
• Sex: All
• Sponsor: University of Colorado, Denver (Academic / other)
• Locations: 1 site (Aurora, Colorado)
• Trial ID: NCT06232655 on ClinicalTrials.gov

What this trial studies

This study investigates the efficacy of cladribine and venetoclax in patients with relapsed or refractory acute myeloid leukemia (AML) that has a monocytic phenotype, following failure of previous treatment with hypomethylating agents and venetoclax. Participants will receive cladribine intravenously for five days and venetoclax daily for 28 days, with response assessed through a bone marrow biopsy at the end of the first cycle. Those who respond may continue on alternating cycles of azacitidine and venetoclax or cladribine and venetoclax. The study aims to provide a new treatment option for this challenging patient population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with relapsed or refractory AML that has a monocytic phenotype after prior treatment with hypomethylating agents and venetoclax.

Not a fit: Patients with acute promyelocytic leukemia or those who have not previously been treated with hypomethylating agents and venetoclax may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve outcomes for patients with difficult-to-treat forms of acute myeloid leukemia.

How similar studies have performed: While this approach is novel for this specific patient population, similar combinations have shown promise in other studies involving AML treatments.

Eligibility criteria

Inclusion Criteria:

A subject will be eligible for study participation if they meet the following criteria within 28 days prior to the first day of treatment. Historical records are permitted per investigator discretion.

1. Subject must have confirmation of non-acute promyelocytic leukemia (APL) Acute Myeloid Leukemia (AML) with a monocytic or monoblastic phenotype or a Ras pathway mutation. The subject's AML must be relapsed after or refractory to prior treatment with hypomethylating agent (HMA) and venetoclax combination.

   Note: other prior line(s) of therapy including stem cell transplant (SCT) are allowed, but HMA/Ven must be one of the preceding treatments. Subjects who have progressed to AML after prior treatment with HMA/Ven for high grade Chronic Myelomonocytic Leukemia (CMML) or Myelodysplastic Syndrome (MDS) are also eligible.
2. Age ≥ 18 years
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
4. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation (2021).
5. Adequate liver function, as demonstrated by:

   * Aspartate aminotransferase (AST) ≤ 3.0 x ULN\*
   * Alanine aminotransferase (ALT) ≤ 3.0 x ULN\*
   * Total bilirubin ≤ 1.5 x ULN, unless considered to be due to leukemic organ involvement or Gilbert's syndrome\* \*In subjects with Gilbert's syndrome, bilirubin needs to be ≤ 4 x ULN
6. Non-sterile male subjects must use contraceptive methods with partner(s) at least prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug. No contraception is required if male subjects are surgically sterile (vasectomy with medical assessment confirming surgical success) or if the male subject has a female partner who is postmenopausal or permanently sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
7. Female subjects must be either:

   * Postmenopausal: defined as age \> 60 years with no menses for 12 or more months without an alternative medical cause; OR
   * Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy); OR
   * If subject is of childbearing potential, use of contraception is required while on study treatment and for 6 months after the last dose.
8. Subject must voluntarily sign an informed consent, approved by the Institutional Research Board (IRB), prior to the initiation of any research-related screening or study procedures.

Exclusion Criteria:

1. Subject has received prior treatment with cladribine for AML.
2. Subject has a white blood cell count \> 25 x 109/L. Note: hydroxyurea and/or leukapheresis are permitted to meet this criterion.
3. Subject has known active central nervous system (CNS) involvement of AML.
4. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal). Uncontrolled is defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. Patients on antibiotics, antivirals, or antifungals with controlled systemic symptoms will not be excluded.
5. Subject has any clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study, including but not limited to:

   * New York Heart Association heart failure \> class 2
   * Renal, neurologic, psychiatric, endocrine, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
6. Subject has a QTc interval \> 470 msec.
7. Subject has a history of other malignancies within 2 years prior to study entry, with the following exceptions:

   * Adequately treated in situ carcinoma of the breast or cervix
   * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
   * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
   * Prostate cancer not requiring therapy beyond hormonal therapy
8. Subject is pregnant or breastfeeding.
9. Subject is known to be positive for HIV. HIV testing is not required.
10. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required, and subjects with serologic evidence of prior vaccination to HBV may participate.

Where this trial is running

Aurora, Colorado

• Universtiy of Colorado Hospital — Aurora, Colorado, United States (Recruiting)

Study contacts

• Principal investigator: Christine McMahon, MD — University of Colorado, Denver
• Study coordinator: Derek Schatz

Conditions Acute Myeloid Leukemia; Relapsed; Refractory