Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms

A Phase 1 Single-Center Trial Combining Venetoclax With G-CSF, Cladribine, Cytarabine, and Mitoxantrone (CLAG-M) for Patients With AML and High-Grade Myeloid Neoplasms

This phase I trial finds the best dose and side effects of venetoclax in combination with cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in treating patients with acute myeloid leukemia and high-grade myeloid neoplasms. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cladribine, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with CLAG-M may kill more cancer cells.

Study Overview

• Status: Suspended
• Conditions: Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Mixed Phenotype Acute Leukemia; Myeloid Neoplasm; Acute Biphenotypic Leukemia; Refractory Acute Biphenotypic Leukemia; Relapsed Acute Myeloid Leukemia; Mixed Phenotype Acute Leukemia; Relapsed Acute Biphenotypic Leukemia; Relapsed Mixed Phenotype Acute Leukemia; Relapsed Myeloid Neoplasm; Refractory Myeloid Neoplasm; Recurrent Myeloid Sarcoma
• Intervention / Treatment: Drug: Cytarabine; Drug: Venetoclax; Drug: Mitoxantrone; Drug: Cladribine; Biological: Recombinant Granulocyte Colony-Stimulating Factor

Detailed Description

OUTLINE:

This is a dose-escalation study of venetoclax.

Patients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days 1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone, and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kim Quach; Phone Number: 206.606.8311; Email: kquach@fredhutch.org
• Study Contact Backup: Name: Mary-Beth M. Percival; Phone Number: 206.606.1320; Email: mperciva@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of acute myeloid leukemia (per the World Health Organization [WHO] 2016 classification) or high-grade myeloid neoplasm (>= 10% myeloid blasts in peripheral blood or marrow as assessed by morphology or multiparameter flow cytometry at initial presentation). Patients with biphenotypic or mixed phenotype acute leukemia are eligible.

  • Newly diagnosed patients presenting for trial entry must have adverse risk disease as per the European LeukemiaNet 2017 guidelines
  • Relapsed/refractory patients presenting for trial entry must require first or subsequent salvage therapy and have detectable blasts in peripheral blood or >= 5% blasts in bone marrow, as assessed by morphology or multiparameter flow cytometry; or extramedullary myeloid sarcoma, per European LeukemiaNet 2017 guidelines.
• Age >= 18 years
• Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 X upper limit of normal (ULN)
• Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
• Subject must have adequate renal function as demonstrated by a creatinine clearance >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
• Left ventricular ejection fraction (LVEF) >= 45%, assessed by multigated acquisition (MUGA) or echocardiogram (ECHO) within 3 months prior to study day 0 or after most recent anthracycline administration if appropriate and no clinical evidence of congestive heart failure
• Eastern Cooperative Oncology Group (ECOG) =< 2
• Treatment-related mortality (TRM) score < 13.1
• Female subjects of childbearing potential must have negative results for pregnancy test. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must agree to use an effective method of birth control from the time of signing the consent form until at least 3 months after the last dose of study drug
• Ability to understand and the willingness to sign a written informed consent document
• White blood cell count in peripheral blood must be < 25,000/ul prior to initiation of study therapy (CLAG-M plus venetoclax). Cytoreduction with hydroxyurea and/or cytarabine (e.g., 500 mg/m^2 per dose) is allowed to decrease the risk of tumor lysis syndrome

Exclusion Criteria:

• Acute promyelocytic leukemia or chronic myeloid leukemia in myeloid blast crisis
• Known active central nervous system (CNS) involvement with acute myeloid leukemia (AML)
• Concomitant illness associated with a likely survival of < 1 year
• Active systemic infection, unless disease is under treatment with antimicrobials and considered controlled or stable; patients with fever thought to be likely secondary to leukemia are eligible. Patients with chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment would be excluded. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• Known hypersensitivity to any study drug
• Pregnancy or lactation because of the unknown risks of this combination
• Concurrent treatment with any other investigational agent
• Subject is known to be positive for human immunodeficiency virus (HIV)
• Subjects who cannot discontinue concomitant CYP3A inhibitors, except for voriconazole, prior to cycle 1 day 1 (C1D1)

• Treatment with any of the following within 7 days prior to the first dose of venetoclax

  • Steroid therapy for anti-neoplastic intent

• Administration or consumption of any of the following within 3 days prior to the first dose of venetoclax:

  • Grapefruit or grapefruit products
  • Seville oranges (including marmalade containing Seville oranges)
  • Star fruit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (CLAG-M, venetoclax); Patients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days 1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone, and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression or unacceptable toxicity.

Drug: Cytarabine; Given IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Drug: Venetoclax; Given PO; Other Names: Venclexta; ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclyxto; Drug: Mitoxantrone; Given IV; Other Names: Dihydroxyanthracenedione; Mitozantrone; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; 2CDA; Cladribina; Leustat; Leustatin; Leustatine; RWJ-26251; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Given subcutaneously; Other Names: rhG-CSF; Recombinant Colony-Stimulating Factor 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of adverse events	Up to 12 months
Maximum tolerated dose of venetoclax in combination with CLAG-M	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Complete remission rate	After 2 cycles (each cycle is approximately 35 days)
1-year survival rate	At 1 year
Rate of allogeneic hematopoietic cell transplant	At 1 year

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: AbbVie
• Investigators: Principal Investigator: Mary-Beth M. Percival, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 10, 2021
• First Submitted That Met QC Criteria: March 10, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, Lymphoid; Sarcoma; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Acute Disease; Sarcoma, Myeloid; Leukemia, Biphenotypic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Venetoclax; Lenograstim; Cytarabine; Mitoxantrone; Cladribine; 2-chloro-3'-deoxyadenosine
• Other Study ID Numbers: RG1121403; 10793 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2021-01379 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No