Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia

Status: Recruiting

Location: See location...

Intervention Type: Drug

Study Type: Interventional

Study Phase: Phase 1

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.

Eligibility

Participation Requirements

Sex: All

Minimum Age: 18

Maximum Age: 80

Healthy Volunteers: f

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• 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 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 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

∙ 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.

Locations

United States

Colorado

University of Colorado Hospital

RECRUITING

Aurora

Contact Information

Primary

Derek Schatz

derek.schatz@cuanschutz.edu

720-848-0628

Time Frame

Start Date: 2024-07-21

Estimated Completion Date: 2027-11

Participants

Target number of participants: 30

Treatments

Experimental: Cohort 1

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.

Experimental: Cohort 2

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.

Experimental: Cohort 3

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.

Experimental: Cohort 4

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.

Related Therapeutic Areas

Acute Myeloid Leukemia (AML)

Leukemia

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Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia

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