Mitoxantrone with Venetoclax and Azacitidine for the Treatment of Venetoclax Resistant Acute Myeloid Leukemia
This phase I trial studies the side effects and best dose of mitoxantrone when given together with azacitidine and venetoclax and to see how well it works in treating patients with acute myeloid leukemia (AML) that remains despite treatment (resistant) with venetoclax. Chemotherapy drugs, such as mitoxantrone and azacitidine, 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving mitoxantrone with azacitidine and venetoclax may be safe, tolerable and/or effective in treating patients with venetoclax resistant AML.
Inclusion Criteria
- Subject must have confirmation of non-acute promyelocytic leukemia (APL) AML by World Health Organization (WHO) criteria and have been treated with first-line venetoclax/HMA (azacitidine or decitabine)
- Subject must have relapsed disease per International Working Group (IWG) criteria or disease refractory to first line venetoclax/HMA defined by less than a partial response (PR) response (per European LeukemiaNet [ELN] 2022 criteria) after ≥ 1 complete cycle of venetoclax/HMA
- Subject must have either measurable residual disease (MRD+), as measured by Food and Drug Administration (FDA)-approved flow cytometric test performed by hematologics (cohort 3 and 4) or relapsed/refractory disease (cohort 1 and 2)
- Subject must have a projected life expectancy of at least 12 weeks
- 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 Chronic Kidney Disease (CKD)-Epidemiology (EPI) Creatinine Equation (2021)
- 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
- Aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN) * Unless considered due to leukemic organ involvement
- Alanine aminotransferase (ALT) ≤ 3.0 × ULN * Unless considered due to leukemic organ involvement
- 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 * If subject is of childbearing potential, use of contraception is required while on study treatment and for 6 months after the last dose
- Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed procedures
Exclusion Criteria
- Subject has known active central nervous system (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 × 10^9/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
- Any prior exposure to an anthracycline or anthracenedione
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06429449.
Locations matching your search criteria
United States
Colorado
Aurora
Denver
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated (MTD) and/or recommended phase 2 dose (RP2D) of mitoxantrone in combination with venetoclax and hypomethylating agent (HMA). (Cohort 1)
II. Determine whether the addition of mitoxantrone can overcome resistance to venetoclax+HMA in subjects who have failed first line therapy with this regimen. (Cohort 2)
III. Assess the clinical efficacy and safety of mitoxantrone in subjects with minimal residual disease positive (MRD+) remissions after first-line venetoclax+HMA. (Cohorts 3 and 4)
SECONDARY OBJECTIVES:
I. Assess the clinical efficacy and safety of the addition of mitoxantrone with venetoclax+HMA therapy in subjects who have failed first-line venetoclax+HMA therapy. (Cohorts 1 and 2)
II. Determine whether the addition of mitoxantrone can result in the conversion of MRD+ to MRD negative (-) disease after remission with first-line venetoclax+HMA. (Cohorts 3 and 4)
OUTLINE: This is a dose-escalation study of mitoxantrone in combination with followed by a dose-expansion study. Patients are assigned to 1 of 4 cohorts.
COHORT 1 (DOSE-ESCALATION): Patients who are refractory to first-line therapy with venetoclax+HMA, or who respond and then relapse after first line therapy with venetoclax+HMA receive mitoxantrone intravenously (IV) on days 1-4, azacitidine IV on days 1-7, and venetoclax on days 1-28 of each cycle. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
COHORT 2 (DOSE-EXPANSION): Patients who are refractory to first-line therapy with venetoclax+HMA, or who respond and then relapse after first line therapy with venetoclax+HMA receive mitoxantrone IV on days 1-4, azacitidine IV on days 1-7, and venetoclax on days 1-28 of cycle 1. On day 28 of cycle 1 patients undergo bone marrow biopsy. If a complete remission (CR), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS) or blast reduction from baseline of ≥ 50% occurs, patients continue sequential cycles of treatment. In the absence of a ≥ 50% blast reduction from baseline, patients discontinue the study. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
COHORT 3 (DOSE-EXPANSION): Patients who are in a morphologic remission with MRD+ after ≤ 3 cycles of standard of care venetoclax+HMA receive mitoxantrone IV on days 1-4, azacitidine IV on days 1-7, and venetoclax on days 1-28 of cycle 1. On day 28 of cycle 1 patients undergo bone marrow biopsy. If MRD conversion to negative occurs, subsequent treatment cycles continue. If MRD conversion to negative does not occur, the next cycle retains the same schedule, and the mitoxantrone dose may be escalated to a level to-be-determined and not exceeding the MTD. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
COHORT 4 (DOSE-EXPANSION): Patients who are in a morphologic remission with MRD+ after > 3 cycles of standard of care venetoclax+HMA receive mitoxantrone IV on days 1-4, azacitidine IV on days 14-20, and venetoclax PO on days 14-42 of cycle 1. Treatment in cycle 1 continues for 42 days in the absence of disease progression or unacceptable toxicity. On day 42 of cycle 1, patients undergo bone marrow biopsy. If MRD conversion to negative occurs, subsequent treatment cycles continue. If MRD conversion to negative does not occur, the next cycle retains the same schedule, and the mitoxantrone dose may be escalated to a level to-be-determined and not exceeding the MTD. Treatment repeats every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
All patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and additional bone marrow aspiration and biopsies throughout the study.
After completion of study treatment, patients are followed up every 6 months until disease progression or the administration of any therapy other than venetoclax+azacitidine, and then annually for up to 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUCHealth University of Colorado Hospital
Principal InvestigatorAndrew Kent
- Primary ID24-0178
- Secondary IDsNCI-2024-04761
- ClinicalTrials.gov IDNCT06429449