Cladribine Venetoclax in Monocytic AML

• ClinicalTrials.gov Identifier: NCT06232655
• Recruitment Status: Not yet recruiting
• First Posted: January 31, 2024
• Last Update Posted: May 15, 2024
• Sponsor: University of Colorado, Denver
• Collaborator: The Leukemia and Lymphoma Society
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

Investigation of Relapsed or refractory AML with a monocytic phenotype after failure of hypomethylating agent+venetoclax

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Cladribine; Drug: Venetoclax; Drug: Azacitidine	Phase 2

Detailed Description:

This is an investigator-initiated, open label, single institution, Study to assess the efficacy of Clad/Ven following failure of HMA/Ven in AML with a monocytic phenotype. In cycle 1, subjects will receive cladribine at a dose of 5mg/m2 daily via intravenous infusion on days 1 through 5 and venetoclax 400mg daily (following standard dose escalation over the first 3 days) on days 1 through 28 of a 28 day cycle. A bone marrow biopsy will be performed to assess response on day 28 of cycle 1. Subjects who respond to cycle 1, defined as achieving a CR, CRi, MLFS, or PR per ELN criteria, or a blast reduction of at least 50% from baseline, may continue on alternating 28-day consolidation cycles of Aza/Ven (even cycles) and Clad/Ven (odd cycles). Cycles will continue unless the subject needs to be removed from the study due to disease progression, treatment failure (defined as failure to achieve CR, CRi, or MLFS after 4 cycles of treatment), intolerance or toxicity, patient preference, or other reasons.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study of Cladribine+Venetoclax After Failure of Venetoclax+Hypomethylating Agent in Monocytic AML
• Estimated Study Start Date: December 2024
• Estimated Primary Completion Date: October 2026
• Estimated Study Completion Date: October 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cladribine plus Venetoclax; Subjects will receive cladribine at a dose of 5mg/m2 daily via intravenous infusion on days 1 through 5 of a 28 day cycle. Concomitantly, venetoclax will be administered orally at a dose of 100mg on day 1, 200mg on day 2, and 400mg daily on days 3 through 28.	Drug: Cladribine; A medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.; Other Names: Mavenclad; Leustatin; Drug: Venetoclax; A medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).; Other Name: Venclyxto
Experimental: Alternating Aza/Ven and Clad/Ven; Alternating 28-day consolidation cycles of Aza/Ven (even cycles) and Clad/Ven (odd cycles), while those who do not respond will come off the study.	Drug: Cladribine; A medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.; Other Names: Mavenclad; Leustatin; Drug: Venetoclax; A medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).; Other Name: Venclyxto; Drug: Azacitidine; Medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA.. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.; Other Names: Vidaza; Onureg

Outcome Measures

Primary Outcome Measures :

1. Overall response rate (ORR) [ Time Frame: End of Treatment, an average of 6 months ]
   Defined as the proportion of subjects who achieve a CR, CRi, or MLFS that is relapsed after or refractory to HMS/Ven

Secondary Outcome Measures :

1. Adverse Events [ Time Frame: Duration of Treatment, an average of 6 months ]
   Frequency of adverse events (AEs) and serious adverse events (SAEs)
2. Event-free survival [ Time Frame: Minimum of 3 years off study ]
   Event-free survival (EFS)
3. Overall survival [ Time Frame: minimum of 3 years or off study ]
   Overall survival (OS)
4. Duration of response [ Time Frame: minimum of 3 years or off study ]
   Duration of response (DOR)
5. Measurable residual disease [ Time Frame: Baseline through End of Treatment, an average of 6 months ]
   Rate of measurable residual disease (MRD)-negativity

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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) by the World Health Organization (WHO) criteria with a monocytic or monoblastic phenotype or a Ras pathway mutation.

2. 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.

3. Age ≥ 18 years
4. Projected life expectancy of at least 12 weeks
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
6. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation (2021).

7. 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
8. 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).

9. 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.
10. 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.

Contacts and Locations

Contacts

Contact: Derek Schatz; 720-848-0628; derek.schatz@cuanschutz.edu

Locations

United States, Colorado

Colorado Research Center

Aurora, Colorado, United States, 80045

Contact: Derek Schatz 720-848-0628 derek.schatz@cuanschutz.edu

Principal Investigator: Christine McMahon, MD

Sponsors and Collaborators

University of Colorado, Denver

The Leukemia and Lymphoma Society

Investigators

• Principal Investigator: Christine McMahon, MD; University of Colorado, Denver

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT06232655
• Other Study ID Numbers: 23-0273.cc
• First Posted: January 31, 2024
• Last Update Posted: May 15, 2024
• Last Verified: May 2024

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Colorado, Denver:

Relapsed; Refractory

Additional relevant MeSH terms:

Azacitidine; Venetoclax; Cladribine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs