Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia

NCT06429449 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 24-0178.ccNCI-2024-04761
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label, phase 1 study for AML subjects with relapsed or refractory disease or subjects in morphologic remission with MRD+ after first line therapy with venetoclax+HMA. A preliminary dose-finding cohort will be followed by 3 expansion cohorts.

Conditions

Leukemia; Myeloid Leukemia; Monocytic Leukemia

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD)

  Cohort 1: Determine the maximum tolerated (MTD) and/or recommended phase 2 dose (RP2D) of mitoxantrone in combination with venetoclax+azacitidine.

  Reassessment at end of each cycle (28 days) until MTD reached, up to 5 cycles total if needed

• Overall response rate

  Cohort 2: Overall response rate (CR+CRi+PR+MLFS) after treatment with mitoxantrone and venetoclax+azacitidine

  Baseline to End of Treatment (up to 1 year)

• Number of grade 4 or 5 adverse events

  Cohorts 3 and 4: determine the safety of mitoxantrone in combination or in sequence with standard of care venetoclax+azacitidine

  Baseline to End of Treatment (up to 1 year)

Secondary Outcomes (2)

• Survival data

  Through study completion, up to 5 years

• Number of conversions from MRD+ to MRD-

  After each cycle of treatment (28 days), up to 3 cycles total

Study Arms (4)

Cohort 1

EXPERIMENTAL

Cohort 1 will be a conventional 3+3 dose-escalation study to determine maximum tolerated (MTD) or recommended dose of mitoxantrone when used with venetoclax+azacitidine.

Drug: Venetoclax; Drug: Azacitidine; Drug: Mitoxantrone

Cohort 2

EXPERIMENTAL

After establishing the MTD of mitoxantrone, an expansion cohort will open. 10 subjects refractory to first-line therapy w/venetoclax+HMA, or respond then relapse after first-line therapy w/venetoclax+HMA, will enroll in the study \& receive a subsequent cycle of venetoclax+azacitidine at the dose \& schedule being administered per the standard of care, w/the determined MTD/recommended dose of IV mitoxantrone given days 1-4. Day 28 +/- 7 days of this cycle, a bone marrow biopsy will be repeated. In the absence of a ≥50% blast reduction from baseline, the subject will discontinue the study. If a CR, CRi, MLFS or blast reduction from baseline of ≥50% occurs, the subject can continue sequential cycles of venetoclax+azacitidine at the dose \& schedule being administered per the standard of care, with the MTD/recommended dose of mitoxantrone on days 1-4, up to 3 cycles. No subject will receive \>3 cycles of mitoxantrone.

Drug: Venetoclax; Drug: Azacitidine; Drug: Mitoxantrone

Cohort 3

EXPERIMENTAL

Subjects in a morph remission w/ MRD+ after ≤3 cycles of soc ven+HMA will enroll \& receive mitox on days 1-4 at dose tbd that is below the MTD from cohort 1, concurrently w/ven+aza, at the dose \& schedule being soc admin, over a 28-day cycle. A BMBX w/ MRD assessment will be done day 28. If MRD- occurs, subseq treatment cycles will continue to admin ven+aza, at the dose \& schedule being soc admin, w/ the tbd dose of mitox on days 1-4, for max of 3 cycles. If MRD- does not occur, the next cycle may escalate the mitox dose to a level tbd \& not exceeding the MTD, w/ ven+aza at the dose \& schedule being soc admin. If MRD- occurs, subseq treatment cycles will continue to admin ven+aza, at the dose \& schedule being soc admin, with the tbd dose of IV mitox on days 1-4, for a max of 3 cycles. If MRD- does not occur, the next cycle may escalate the mitox to a level tbd \& not exceeding the MTD, w/ ven+aza at the dose \& schedule being admin per the soc. Subjects will not receive \>3 cycles.

Drug: Venetoclax; Drug: Azacitidine; Drug: Mitoxantrone

Cohort 4

EXPERIMENTAL

Subjects in a morphologic remission w/ MRD+ after \>3 cyc of soc ven/HMA will enroll 28-50 days after the previous ven/HMA cyc. Subjects will receive mitox IV days 1-4 at a dose tbd below the MTD from cohort 1; on day 14, the subject will start ven+aza at the dose \& schedule per the soc. On day 42, a BMBX, w/ MRD assessment, will be repeated. If MRD- occurs, subseq cyc will cont to admin ven+aza, at the dose \& schedule per the soc, with the tbd dose of IV mitox on days 1-4, for a max of 3 cyc of mitox. If MRD- does not occur, the next cyc will retain the same schedule \& may escalate the mitox to a dose level tbd \& not exceeding the MTD. If MRD- occurs, 1 add'l cyc of mitox at this dose, w/ ven+aza at the dose \& schedule per the soc, will be given. If MRD- does not occur, the next cyc will retain the same schedule \& may escalate the mitox to a level tbd \& not exceeding the MTD.

Drug: Venetoclax; Drug: Azacitidine; Drug: Mitoxantrone

Interventions

Mitoxantrone DRUG

Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione for intravenous use.

Also known as: Novantrone

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Venetoclax DRUG

Venetoclax attaches to a protein called Bcl-2. This protein is present in high amounts in CLL cancer cells, where it helps the cells survive for longer in the body and makes them resistant to cancer medicines. By attaching to Bcl-2 and blocking its actions, venetoclax causes the death of cancer cells and thereby slows down progression of the disease.

Also known as: Venclexta, Venclyxto

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Azacitidine DRUG

An analog of the pyrimidine nucleoside cytidine, has effects on cell differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism, and causes cytotoxicity.

Also known as: Onureg, Vidaza

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must have confirmation of non-APL AML by WHO criteria and have been treated with first-line venetoclax/HMA (azacitidine or decitabine).
• Subject must have relapsed disease per IWG criteria or disease refractory to first line venetoclax/HMA defined by less than a PR response after ≥ 1 complete cycle of venetoclax/HMA.
• Subject must have either measurable residual disease (MRD+), as measured by FDA-approved flow cytometric test performed by Hematologics (cohort 3 and 4) or relapsed/refractory disease (cohort 1 and 2).
• Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤ 2.
• Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation
• Subject must have adequate heart function as measured by left ventricular ejection fraction (LVEF) \>50%, assessed by multigated acquisition (MUGA) or echocardiogram (ECHO) within 1 month prior to study day 1
• Subject must have adequate liver function as demonstrated by:
• aspartate aminotransferase (AST) ≤ 3.0 × ULN\*
• alanine aminotransferase (ALT) ≤ 3.0 × ULN\*
• bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome\*
• Unless considered due to leukemic organ involvement
• 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. 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).
• 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

You may not qualify if:

• Subject has known active CNS involvement from AML.
• Subject has any history of 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:
• Significant active cardiac disease within the previous 6 months including: New York Heart Association heart failure \> class 2, unstable angina, or myocardial infarction.
• Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. This includes history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease (e.g.
• sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
• Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Uncontrolled is defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment.
• Subject has a history of other malignancies prior to study entry, with the exception of:
• Adequately treated in situ carcinoma of the breast or cervix uteri
• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
• Prostate cancer not requiring therapy beyond hormonal therapy
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
• Subject has a white blood cell count \> 25 × 109/L. Note: hydroxyurea or apheresis are permitted to meet this criterion (cohort 3 only).
• Pregnant or breast-feeding females.
• Known or suspected hypersensitivity to azacitidine or mannitol.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• The Leukemia and Lymphoma Society: collaborator

Study Sites (1)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

RECRUITING

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid; Leukemia, Monocytic, Acute

Interventions

venetoclax; Azacitidine; Mitoxantrone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Quinones; Polycyclic Compounds

Study Officials

• Andrew Kent, MD, PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Derek Schatz

CONTACT

720-848-0628; derek.schatz@cuanschutz.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2024
• First Posted: May 28, 2024
• Study Start: July 21, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): November 1, 2027
• Last Updated: January 15, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)