Venetoclax-Navitoclax With Cladribine-based Salvage Therapy in Patients With Relapsed/Refractory Acute Myeloid Leukemia

NCT06007911 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: PRO00050186
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label phase I study designed to evaluate the safety of venetoclax-navitoclax with cladribine-based salvage therapy.

Conditions

Relapsed Adult AML; Refractory AML

Keywords

Acute Myeloid Leukemia; AML; Venetoclax; Navitoclax; cladribine-based salvage therapy; CLAG-M

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose of Navitoclax for the Cladribine-Low Dose Cytarabine Backbone

  The dose identified in this trial that will be used in future clinical trials.

  Up to three years

• Recommended Phase 2 Dose for Navitoclax for the CLAG-M Backbone

  The dose identified in this trial that will be used in future clinical trials.

  Up to three years

Study Arms (10)

Cladribine-Low Dose Cytarabine Backbone Dose Level -1

EXPERIMENTAL

Dose level -1 will be considered only if there are dose-limiting toxicities at dose level 0. This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.

Drug: Navitoclax Dose Level -1; Drug: Venetoclax Dose Level -1; Drug: Cladribine; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

Cladribine-Low Dose Cytarabine Backbone Dose Level 0

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.

Drug: Navitoclax Dose Level 0; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

Cladribine-Low Dose Cytarabine Backbone Dose Level 1

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.

Drug: Navitoclax Dose Level 1; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

Cladribine-Low Dose Cytarabine Backbone Dose Level 2

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.

Drug: Navitoclax Dose Level 2; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

EXPERIMENTAL

The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.

Drug: Navitoclax Dose Level -1; Drug: Navitoclax Dose Level 0; Drug: Navitoclax Dose Level 1; Drug: Navitoclax Dose Level 2; Drug: Venetoclax Dose Level -1; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

CLAG-M Backbone Level -1

EXPERIMENTAL

Dose level -1 will be considered only if there are dose-limiting toxicities at dose level 0. This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.

Drug: Navitoclax Dose Level -1; Drug: Venetoclax Dose Level -1; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Granulocyte Colony-Stimulating Factor

CLAG-M Backbone Level 0

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).

Drug: Navitoclax Dose Level 0; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Granulocyte Colony-Stimulating Factor

CLAG-M Backbone Level 1

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.

Drug: Navitoclax Dose Level 1; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Granulocyte Colony-Stimulating Factor

CLAG-M Backbone Level 2

EXPERIMENTAL

This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.

Drug: Navitoclax Dose Level 2; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Granulocyte Colony-Stimulating Factor

CLAG-M Backbone Maximum Tolerated Dose

EXPERIMENTAL

The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.

Drug: Navitoclax Dose Level -1; Drug: Navitoclax Dose Level 0; Drug: Navitoclax Dose Level 1; Drug: Navitoclax Dose Level 2; Drug: Venetoclax Dose Level -1; Drug: Venetoclax Dose Levels 0 to 2; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Granulocyte Colony-Stimulating Factor

Interventions

Navitoclax Dose Level 1 DRUG

75 mg by mouth on days 1-10.

Also known as: ABT-263

CLAG-M Backbone Level 1; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level 1; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Navitoclax Dose Level 0 DRUG

50 mg by mouth on days 1-10.

Also known as: ABT-263

CLAG-M Backbone Level 0; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level 0; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Navitoclax Dose Level 2 DRUG

100 mg by mouth on days 1-10.

Also known as: ABT-263

CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level 2; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Venetoclax Dose Level -1 DRUG

400 mg by mouth on days 1-7.

Also known as: Venclexta

CLAG-M Backbone Level -1; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level -1; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Venetoclax Dose Levels 0 to 2 DRUG

400 mg by mouth on days 1-14.

Also known as: Venclexta

CLAG-M Backbone Level 0; CLAG-M Backbone Level 1; CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level 0; Cladribine-Low Dose Cytarabine Backbone Dose Level 1; Cladribine-Low Dose Cytarabine Backbone Dose Level 2; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Cladribine DRUG

5 mg/m\^2 intravenously days 1-5.

Also known as: Mavenclad, Leustatin DSC

CLAG-M Backbone Level -1; CLAG-M Backbone Level 0; CLAG-M Backbone Level 1; CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose; Cladribine-Low Dose Cytarabine Backbone Dose Level -1; Cladribine-Low Dose Cytarabine Backbone Dose Level 0; Cladribine-Low Dose Cytarabine Backbone Dose Level 1; Cladribine-Low Dose Cytarabine Backbone Dose Level 2; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Cytarabine (Cladribine Low Dose Cytarabine Backbone) DRUG

20 mg/m\^2 subcutaneous days 1-10.

Also known as: ara-C

Cladribine-Low Dose Cytarabine Backbone Dose Level -1; Cladribine-Low Dose Cytarabine Backbone Dose Level 0; Cladribine-Low Dose Cytarabine Backbone Dose Level 1; Cladribine-Low Dose Cytarabine Backbone Dose Level 2; Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)

Cytarabine (CLAG-M Backbone) DRUG

1.5 g/m\^2 intravenously days 1-5.

Also known as: ara-C

CLAG-M Backbone Level -1; CLAG-M Backbone Level 0; CLAG-M Backbone Level 1; CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose

Mitoxantrone DRUG

10 mg/m\^2 intravenously days 1-3.

Also known as: Novantrone

CLAG-M Backbone Level -1; CLAG-M Backbone Level 0; CLAG-M Backbone Level 1; CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose

Granulocyte Colony-Stimulating Factor DRUG

300 mcg subcutaneously days 1-5.

Also known as: G-CSF, filgrastim, Neupogen

CLAG-M Backbone Level -1; CLAG-M Backbone Level 0; CLAG-M Backbone Level 1; CLAG-M Backbone Level 2; CLAG-M Backbone Maximum Tolerated Dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subjects 18 years or older.
• Patients must have a diagnosis of morphologically documented AML or secondary AML from prior conditions, such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), MDS/MPN, chronic myelomonocytic leukemia (CMML) or therapy-related AML (t-AML), as defined by the World Health Organization (WHO) 2022 criteria.
• Relapsed or refractory to at least one prior line of therapy.
• Previous therapy with venetoclax.
• Eastern Cooperative Oncology Group (ECOG) performance status of:
• for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
• for Arm B (i.e., CLAG-M backbone arm).
• Left ventricular ejection fraction (LVEF) of:
• LVEF ≥35% for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
• LVEF ≥45% for Arm B (i.e., CLAG-M backbone arm).
• Creatinine clearance (CrCl) as calculated by the Cockroft-Gault formula, of:
• CrCl ≥ 30 mL/min for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
• CrCl ≥ 40 mL/min for Arm B (i.e., CLAG-M backbone arm).
• Clinical laboratory values within the following parameters:
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) unless attributable to underlying leukemia. Patient with total bilirubin \> 1.5 × institutional ULN may enroll if direct bilirubin ≤ 1.5 × institutional ULN of the direct bilirubin.

You may not qualify if:

• Acute promyelocytic leukemia.
• Prior therapy with B-cell lymphoma-extra large (BCL-XL) inhibitor.
• Treatment with systemic antineoplastic therapy within 14 days or five half-lives from the last dose - whichever is longer - before Cycle 1, Day 1 of therapy. Radiation within 14 days before Cycle 1, Day 1 of therapy. The use of hydroxyurea/cytarabine for leukoreduction is permitted.
• Hematopoietic stem cell transplantation (HCT) or chimeric antigen receptor T-cell therapy (CAR-T cell) within 60 days of enrollment. (If patients had prior allogeneic HCT, they should have no active graft-versus-host disease and should be off calcineurin inhibitors at least four weeks prior to cycle 1 day 1 of therapy.)
• Current systemic treatment with strong or moderate Cytochrome P4503A (CYP3A) inducers within 7 days prior to Cycle 1, Day 1 of therapy.
• Presence of another active malignancy requiring systemic treatment within the last 12 months, except for localized cancers that have been adequately treated.
• Known HIV positive patients who DO NOT meet the following criteria:
• Cluster of differentiation (CD) 4 count \> 350 cells/mm\^3.
• Undetectable viral load.
• Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents.
• No history of AIDS-defining opportunistic infections.
• Known hepatitis B surface antigen seropositive or active hepatitis C infection. Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
• Female subjects who are both lactating and breastfeeding or of childbearing potential who have a positive serum test during screening.
• Female subjects who intend to donate eggs (ova) during the course of the study or four months after receiving their last dose of the study drug(s).
• Male subjects who intend to donate sperm during the course of this study or four months after receiving their last dose of the study drug(s).

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (1)

Froedtert Hospital & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

navitoclax; venetoclax; Cladribine; Cytarabine; Mitoxantrone; Granulocyte Colony-Stimulating Factor; Filgrastim

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Guru Subramanian Guru Murthy, MD, MS

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: August 17, 2023
• First Posted: August 23, 2023
• Study Start: August 31, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): April 1, 2027
• Last Updated: August 13, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)