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

Phase 1

Withdrawn

• Conditions: Relapsed Adult AML; Refractory AML
• Interventions: Drug: Navitoclax Dose Level -1; Drug: Navitoclax Dose Level 0; Drug: Navitoclax Dose Level 2; Drug: Venetoclax Dose Level -1; Drug: Navitoclax Dose Level 1; Drug: Cladribine; Drug: Cytarabine (CLAG-M Backbone); Drug: Mitoxantrone; Drug: Venetoclax Dose Levels 0 to 2; Drug: Granulocyte Colony-Stimulating Factor; Drug: Cytarabine (Cladribine Low Dose Cytarabine Backbone)

• Registration Number: NCT06007911
• Lead Sponsor: Medical College of Wisconsin

Brief Summary

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

Detailed Description

The primary objective of the study is to determine a maximum-tolerated dose (MTD) combination of venetoclax-navitoclax with cladribine-based salvage therapy. Subjects will be entered sequentially to each dose level. For each dose level, if none of the first three subjects at that level experiences a dose-limiting toxicity (DLT), new subjects may be entered at the next higher dose level. If one of three subjects experience a DLT, up to three more subjects are to be treated at that same dose level. If none of the additional three subjects at that dose level experiences a DLT, new subjects may be entered at the next higher dose level. However, if one or more of the additional three subjects experience a DLT, then no further subjects are to be started at that dose level and either de-escalate one level or if the preceding dose is already completed then that dose is the MTD. The MTD will be defined as the highest dose level at which none of the first three treated subjects, or no more than one of the first six treated subjects, experiences a DLT.

Study Timeline

• Study First Submitted: 2023-08-17
• Study First Submitted QC: 2023-08-17
• Study First Posted: 2023-08-23
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-09
• Last Update Posted: 2024-08-13
• Study Start: 2024-08-31
• Primary Completion: 2025-12
• Study Completion: 2027-04

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

1. Male or female subjects 18 years or older.

2. 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.

3. Relapsed or refractory to at least one prior line of therapy.

4. Previous therapy with venetoclax.

5. Eastern Cooperative Oncology Group (ECOG) performance status of:

   1. 0-3 for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
   2. 0-2 for Arm B (i.e., CLAG-M backbone arm).

6. Left ventricular ejection fraction (LVEF) of:

   1. LVEF ≥35% for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
   2. LVEF ≥45% for Arm B (i.e., CLAG-M backbone arm).

7. Creatinine clearance (CrCl) as calculated by the Cockroft-Gault formula, of:

   1. CrCl ≥ 30 mL/min for Arm A (i.e., Cladribine-low dose cytarabine backbone arm).
   2. CrCl ≥ 40 mL/min for Arm B (i.e., CLAG-M backbone arm).

8. Clinical laboratory values within the following parameters:

   1. 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.
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × institutional ULN, unless attributable to underlying leukemia.
   3. White blood cell (WBC) count < 25,000/µL before Cycle 1, Day 1 of therapy (Note: Hydroxyurea, cytarabine or leukapheresis may be used to meet this criterion.)
   4. Platelet count of at least 20,000/µL before Cycle 1, Day 1 of therapy (Note: Platelet transfusion can be used to meet this criterion.)

9. Female subjects who:

   1. Are postmenopausal for at least one year before the screening visit, OR
   2. Are surgically sterile, OR
   3. If they are of childbearing potential:

   i. Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through four months after the last dose of study drug (female and male condoms should not be used together), OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).

10. Male subjects, even if surgically sterilized (i.e., status post vasectomy), who:

    1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through four months after the last dose of study drug (female and male condoms should not be used together), OR
    2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

11. Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria

1. Acute promyelocytic leukemia.

2. Prior therapy with B-cell lymphoma-extra large (BCL-XL) inhibitor.

3. 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.

4. 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.)

5. Current systemic treatment with strong or moderate Cytochrome P4503A (CYP3A) inducers within 7 days prior to Cycle 1, Day 1 of therapy.

6. Presence of another active malignancy requiring systemic treatment within the last 12 months, except for localized cancers that have been adequately treated.

7. Known HIV positive patients who DO NOT meet the following criteria:

   1. Cluster of differentiation (CD) 4 count > 350 cells/mm^3.
   2. Undetectable viral load.
   3. Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents.
   4. No history of AIDS-defining opportunistic infections.

8. 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.

9. Female subjects who are both lactating and breastfeeding or of childbearing potential who have a positive serum test during screening.

10. 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).

11. 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).

12. Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit from three days prior to Cycle 1, Day 1 to throughout the study treatment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Navitoclax Dose Level 1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level -1	Navitoclax Dose Level -1	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.
CLAG-M Backbone Level 0	Navitoclax Dose Level 0	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Cytarabine (Cladribine Low Dose Cytarabine Backbone)	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Venetoclax Dose Levels 0 to 2	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
Cladribine-Low Dose Cytarabine Backbone Dose Level 2	Cytarabine (Cladribine Low Dose Cytarabine Backbone)	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
CLAG-M Backbone Level -1	Cytarabine (CLAG-M Backbone)	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.
CLAG-M Backbone Level 1	Cytarabine (CLAG-M Backbone)	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 0	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
Cladribine-Low Dose Cytarabine Backbone Dose Level -1	Cytarabine (Cladribine Low Dose Cytarabine Backbone)	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.
Cladribine-Low Dose Cytarabine Backbone Dose Level 1	Navitoclax Dose Level 1	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Level 0	Cytarabine (Cladribine Low Dose Cytarabine Backbone)	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
CLAG-M Backbone Level 1	Mitoxantrone	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
Cladribine-Low Dose Cytarabine Backbone Dose Level -1	Navitoclax Dose Level -1	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.
Cladribine-Low Dose Cytarabine Backbone Dose Level -1	Venetoclax Dose Level -1	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.
Cladribine-Low Dose Cytarabine Backbone Dose Level 0	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Level 1	Cytarabine (Cladribine Low Dose Cytarabine Backbone)	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Level 2	Navitoclax Dose Level 2	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Navitoclax Dose Level 0	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level 1	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 1	Granulocyte Colony-Stimulating Factor	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
Cladribine-Low Dose Cytarabine Backbone Dose Level 0	Navitoclax Dose Level 0	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
CLAG-M Backbone Level -1	Venetoclax Dose Level -1	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.
CLAG-M Backbone Level 0	Cytarabine (CLAG-M Backbone)	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
CLAG-M Backbone Level 1	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Maximum Tolerated Dose	Navitoclax Dose Level 0	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
Cladribine-Low Dose Cytarabine Backbone Dose Level 1	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Navitoclax Dose Level 2	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level -1	Granulocyte Colony-Stimulating Factor	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.
CLAG-M Backbone Level 0	Mitoxantrone	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
CLAG-M Backbone Level 0	Granulocyte Colony-Stimulating Factor	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
Cladribine-Low Dose Cytarabine Backbone Dose Level 2	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Navitoclax Dose Level -1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Venetoclax Dose Level -1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level 1	Navitoclax Dose Level 1	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 2	Navitoclax Dose Level 2	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 2	Cytarabine (CLAG-M Backbone)	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Maximum Tolerated Dose	Navitoclax Dose Level 1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Granulocyte Colony-Stimulating Factor	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level 2	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 2	Venetoclax Dose Levels 0 to 2	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Level 2	Granulocyte Colony-Stimulating Factor	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Maximum Tolerated Dose	Navitoclax Dose Level -1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Navitoclax Dose Level 2	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Venetoclax Dose Levels 0 to 2	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Cytarabine (CLAG-M Backbone)	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Venetoclax Dose Level -1	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
Cladribine-Low Dose Cytarabine Backbone Dose Level -1	Cladribine	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.
Cladribine-Low Dose Cytarabine Backbone Dose Level 0	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Level 1	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Level 2	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine and cytarabine.
Cladribine-Low Dose Cytarabine Backbone Dose Maximum Tolerated Dose (MTD)	Cladribine	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Level -1	Cladribine	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.
CLAG-M Backbone Level -1	Mitoxantrone	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.
CLAG-M Backbone Level 0	Cladribine	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and granulocyte colony-stimulating factor (G-CSF).
CLAG-M Backbone Level 2	Mitoxantrone	This is a regimen of navitoclax, venetoclax, cladribine, cytarabine, mitoxantrone and G-CSF.
CLAG-M Backbone Maximum Tolerated Dose	Cladribine	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.
CLAG-M Backbone Maximum Tolerated Dose	Mitoxantrone	The MTD is the highest dose level at which no more than 1 of 6 treated participants, experiences a dose-limiting toxicity.

Primary Outcome Measures

Name	Time	Method
Recommended Phase 2 Dose for Navitoclax for the CLAG-M Backbone	Up to three years	The dose identified in this trial that will be used in future clinical trials.
Recommended Phase 2 Dose of Navitoclax for the Cladribine-Low Dose Cytarabine Backbone	Up to three years	The dose identified in this trial that will be used in future clinical trials.

Trial Locations

Locations (1)

Froedtert Hospital & the Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States