Trial Title:
Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia
NCT ID:
NCT06429449
Condition:
Leukemia
Myeloid Leukemia
Monocytic Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Azacitidine
Venetoclax
Mitoxantrone
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
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.
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Other name:
Venclexta
Other name:
Venclyxto
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
An analog of the pyrimidine nucleoside cytidine, has effects on cell differentiation,
gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism, and causes
cytotoxicity.
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Other name:
Onureg
Other name:
Vidaza
Intervention type:
Drug
Intervention name:
Mitoxantrone
Description:
Mitoxantrone Injection, USP (concentrate) is a synthetic antineoplastic anthracenedione
for intravenous use.
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Other name:
Novantrone
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.
Detailed description:
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.
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. Subjects
who are refractory to first-line therapy with venetoclax+HMA, or who respond and then
relapse after first line therapy with venetoclax+HMA, will enroll in the study and
receive a subsequent cycle of venetoclax+azacitidine at the dose and schedule being
administered per the standard of care, along with a starting dose of 4mg/m2 of
mitoxantrone administered IV on days 1-4. Depending on the absence or frequency of
dose-limiting toxicities, additional patients will be enrolled at the appropriate dose
levels, increasing by 2mg/m2 per cycle, per the 3+3 design until the MTD or a dose of
10mg/m2 of mitoxantrone is reached. The dose escalation phase will conclude when the MTD
is determined; if the MTD is not reached, a recommendation for a dose of mitoxantrone in
combination with venetoclax+azacitidine will be made based on toxicity and efficacy data.
After the establishment of the MTD or recommended dose of mitoxantrone, an expansion
cohort (cohort 2) will open. 10 subjects who are refractory to first-line therapy with
venetoclax+HMA, or who respond and then relapse after first line therapy with
venetoclax+HMA, will enroll in the study and receive a subsequent cycle of
venetoclax+azacitidine at the dose and schedule being administered per the standard of
care, with the determined MTD/recommended dose of IV mitoxantrone given on days 1-4. On
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 and schedule being administered
per the standard of care, with the MTD/recommended dose of mitoxantrone on days 1-4, for
up to 3 total cycles. No subject will receive >3 cycles of mitoxantrone. After
mitoxantrone cycles have been completed, subjects will receive a bone marrow biopsy after
the third cycle, and then continue bone marrow biopsies with MRD assessments every 6
months, until disease progression or the administration of any therapy other than
venetoclax+azacitidine, at which time the subject will be discontinued from the study.
In cohort 3, subjects who are in a morphologic remission with MRD+ after ≤3 cycles of
standard of care venetoclax+HMA will enroll and receive mitoxantrone on days 1-4 at a
dose to-be-determined that is below the MTD from cohort 1, concurrently with
venetoclax+azacitidine, at the dose and schedule being administered per the standard of
care, over a 28-day treatment cycle. A bone marrow biopsy with MRD assessment will be
performed on day 28 +/- 7 days. If MRD conversion to negative occurs, subsequent
treatment cycles will continue to administer venetoclax+azacitidine, at the dose and
schedule being administered per the standard of care, with the to-be-determined dose of
mitoxantrone on days 1-4, for a maximum of three total cycles of mitoxantrone. If MRD
conversion to negative does not occur, the next cycle may escalate the mitoxantrone dose
to a level to-be-determined and not exceeding the MTD, with venetoclax+azacitidine at the
dose and schedule being administered per the standard of care. If MRD conversion to
negative occurs, subsequent treatment cycles will continue to administer
venetoclax+azacitidine, at the dose and schedule being administered per the standard of
care, with the to-be-determined dose of IV mitoxantrone on days 1-4, for a maximum of
three total cycles of mitoxantrone. If MRD conversion to negative does not occur, the
next cycle may escalate the mitoxantrone to a level to-be-determined and not exceeding
the MTD, with venetoclax+azacitidine at the dose and schedule being administered per the
standard of care. Subjects will not receive >3 cycles of mitoxantrone. After mitoxantrone
cycles have been completed, subjects will continue bone marrow biopsies with MRD
assessments every 6 months, until disease progression or the administration of any
therapy other than venetoclax+azacitidine, at which time the subject will be discontinued
from the study.
In cohort 4, subjects who are in a morphologic remission with MRD+ after >3 cycles of
standard of care venetoclax/HMA will enroll 28-50 days after the start of the previous
venetoclax/HMA cycle. They will receive mitoxantrone IV on days 1-4 at a dose
to-be-determined that is below the MTD from cohort 1; on day 14, the subject will start
venetoclax+azacitidine at the dose and schedule being administered per the standard of
care. On day 42 +/- 7 days, a bone marrow biopsy, with MRD assessment, will be repeated.
If MRD conversion to negative occurs, subsequent treatment cycles will continue to
administer venetoclax+azacitidine, at the dose and schedule being administered per the
standard of care, with the to-be-determined dose of IV mitoxantrone on days 1-4, for a
maximum of three total cycles of mitoxantrone. If MRD conversion to negative does not
occur, the next cycle will retain the same schedule, and may escalate the mitoxantrone to
a dose level to-be-determined and not exceeding the MTD. If MRD conversion to negative
occurs, one additional cycle of mitoxantrone at this dose, with venetoclax+azacitidine at
the dose and schedule being administered per the standard of care, will be given. If MRD
conversion to negative does not occur, the next cycle will retain the same schedule, and
may escalate the mitoxantrone to a level to-be-determined and not exceeding the MTD. No
subject will receive >3 cycles of mitoxantrone. After mitoxantrone cycles have been
completed, subjects will continue bone marrow biopsies with MRD assessments every 6
months, until disease progression or the administration of any therapy other than
venetoclax+azacitidine, at which time the subject will be discontinued from the study.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Subject must have confirmation of non-APL AML by WHO criteria and have been treated
with first-line venetoclax/HMA (azacitidine or decitabine).
2. 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.
3. 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).
4. Subject must have a projected life expectancy of at least 12 weeks.
5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of
≤ 2.
6. Subject must have adequate renal function as demonstrated by a calculated creatinine
clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation
7. 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
8. Subject must have adequate liver function as demonstrated by:
1. aspartate aminotransferase (AST) ≤ 3.0 × ULN*
2. alanine aminotransferase (ALT) ≤ 3.0 × ULN*
3. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome*
- Unless considered due to leukemic organ involvement
9. 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).
10. Female subjects must be either:
1. Postmenopausal; defined as Age > 60 years with no menses for 12 or more months
without an alternative medical cause; OR
2. Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy
or hysterectomy); OR
3. If subject is of childbearing potential, use of contraception is required while
on study treatment and for 6 months after the last dose.
11. 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:
1. Subject has known active CNS involvement from AML.
2. 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:
1. Significant active cardiac disease within the previous 6 months including: New
York Heart Association heart failure > class 2, unstable angina, or myocardial
infarction.
2. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic,
hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
3. 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.
4. 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.
5. Subject has a history of other malignancies prior to study entry, with the exception
of:
1. Adequately treated in situ carcinoma of the breast or cervix uteri
2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the
skin
3. Prostate cancer not requiring therapy beyond hormonal therapy
4. Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent
6. Subject has a white blood cell count > 25 × 109/L. Note: hydroxyurea or apheresis
are permitted to meet this criterion (cohort 3 only).
7. Pregnant or breast-feeding females.
8. Known or suspected hypersensitivity to azacitidine or mannitol.
9. Any prior exposure to an anthracycline or anthracenedione
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Colorado Hospital
Address:
City:
Aurora
Zip:
80045
Country:
United States
Status:
Recruiting
Contact:
Last name:
Derek Schatz
Phone:
720-848-0628
Email:
DEREK.SCHATZ@CUANSCHUTZ.EDU
Investigator:
Last name:
Andrew Kent, MD, PhD
Email:
Principal Investigator
Start date:
December 2024
Completion date:
November 2027
Lead sponsor:
Agency:
University of Colorado, Denver
Agency class:
Other
Collaborator:
Agency:
The Leukemia and Lymphoma Society
Agency class:
Other
Source:
University of Colorado, Denver
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06429449
