A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination With Venetoclax/Azacitidine, Venetoclax, 7+3, or 7+3+Quizartinib in Patients With AML

NCT05735184
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Phase
Phase 1
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Recruitment status
Recruiting
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Participants
420
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Lead sponsor
Kura Oncology, Inc.
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Start date
2023-07-18
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Number of sites
44
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Summary
Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with certain genetic alterations. This protocol has 3 separate arms that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) drug treatments in patients who have AML with certain genetic mutations. Both newly diagnosed and relapsed refractory patients with AML will be assigned to different cohorts based on specific study criteria and physician discretion. The purpose of this study is to assess the safety, tolerability, and early signs of efficacy of ziftomenib in combination with SOC drugs to treat AML.
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Short title
A Study to Investigate the Safety and Tolerability of Ziftomenib in Combination With Venetoclax/Azacitidine, Venetoclax, 7+3, or 7+3+Quizartinib in Patients With AML
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Official title
Phase 1 Study of Venetoclax/Azacitidine or Venetoclax in Combination With Ziftomenib or Standard Induction Cytarabine/Daunorubicin (7+3) Chemotherapy in Combination With Ziftomenib for the Treatment of Patients With Acute Myeloid Leukemia
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Control arm
Open label
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Registry reports results
No
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Listing at source
Listed
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Recruitment status
Recruiting
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Phase
Phase 1
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Study type
Interventional
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Completion date
2030-04-01
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First posted
2023-02-21
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Registry last updated
2026-03-13
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Primary completion date
2030-04-01
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Start date
2023-07-18
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Participants
420
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Participant count basis
Estimated
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Planned participants
420
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Protocol amendments
4
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Number of sites
44
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
Kura Oncology, Inc.
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Source registry
ClinicalTrials.gov
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Registry ID
NCT05735184
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ClinicalTrials.gov ID
NCT05735184
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Registry record
Open registry record
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Allocation
Not randomised
Model
Parallel groups
Purpose
Treatment
Masking
No masking
Sources for study design
clinicaltrials.gov

  1. Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only)

    Timeframe: During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle)

    Assessed by the NCI-CTCAE v5.0

  2. Descriptive statistics of adverse events

    Timeframe: From Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment

    Assessed by the NCI-CTCAE v5.0

  3. Complete remission (CR) rate

    Timeframe: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first

    Assessed by the ELN 2022 criteria

  1. Composite Complete Remission (CRc)

    Timeframe: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first

    Assessed by the ELN 2022 criteria

  2. Morphologic leukemia-free state (MLFS) rate

    Timeframe: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first

    Assessed by the ELN 2022 criteria

  3. Measurable residual disease (MRD)

    Timeframe: Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first

    Assessed by multiparameter flow cytometry (MFC) and/or molecular analysis (NGS, PCR)

  4. Median OS

    Timeframe: From Cycle 1 Day 1 to date of death from any cause, assessed up to 36 months of treatment

    To assess overall survival of ziftomenib

  5. Proportion of patients alive

    Timeframe: From Cycle 1 Day 1 until death from any cause, assessed up to 1 year following start of treatment

    To assess proportion of patients alive at 1 year following start of treatment with ziftomenib

  6. Median EFS

    Timeframe: From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 36 months of treatment

    To assess median event free survival

  7. EFS

    Timeframe: From Cycle 1 Day 1 to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 1 year following start of treatment

    To assess event free survival at 1 year

  8. Median DOR

    Timeframe: From time of first remission to relapse or death, whichever occurs first, assessed up to 36 months from start of treatment

    To assess median duration of remission

  9. Proportion of patients who undergo HSCT

    Timeframe: From Cycle 1 Day 1 until date of HSCT, assessed up to 36 months of treatment

    To assess proportion of patients who undergo hematopoietic stem cell transplant

  10. TI

    Timeframe: From 28 days prior to Cycle 1 Day 1 up to and including 28 days following the end of 36 months of treatment

    To assess rate of transfusion independence

  11. Cmax

    Timeframe: Cycle 1; each cycle is 28 days

    Maximum plasma concentration (Cmax) of ziftomenib and metabolites

  12. Tmax

    Timeframe: Cycle 1; each cycle is 28 days

    Time to maximum plasma concentration (Tmax) of ziftomenib and metabolites

  13. AUC0-last

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of ziftomenib and metabolites

  14. AUCtau

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve over a dosing interval (AUCtau) of ziftomenib

  15. Accumulation ratio of ziftomenib and metabolites

    Timeframe: Cycle 1; each cycle is 28 days

    To assess accumulation ratio of ziftomenib and metabolites

  16. Cmax of venetoclax

    Timeframe: Cycle 1; each cycle is 28 days

    Maximum plasma concentration (Cmax) of venetoclax

  17. Tmax of venetoclax

    Timeframe: Cycle 1; each cycle is 28 days

    Time to maximum plasma concentration (Tmax) of venetoclax

  18. AUC0-last of venetoclax

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of venetoclax

  19. AUCtau of venetoclax

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve over a dosing interval (AUCtau) of venetoclax

  20. Cmax of quizartinib

    Timeframe: Cycle 1; each cycle is 28 days

    Maximum plasma concentration (Cmax) of quizartinib

  21. Tmax of quizartinib

    Timeframe: Cycle 1; each cycle is 28 days

    Time to maximum plasma concentration (Tmax) of quizartinib

  22. AUC0-last of quizartinib

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last) of quizartinib

  23. AUCtau of quizartinib

    Timeframe: Cycle 1; each cycle is 28 days

    Area under the concentration-time curve over a dosing interval (AUCtau) of quizartinib

Sources for outcomes
clinicaltrials.gov

Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
Healthy volunteers
No

Key Inclusion Criteria:

  • Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML

    • Those intending treatment with intensive chemotherapy in Arm C should be NPM1-m and FLT3-ITD+ with an allelic ratio ≥0.05 and eligible for FLT3-targeted treatment

  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

  • Adequate liver, renal, and cardiac function according to protocol defined criteria

  • A female of childbearing potential must agree to use adequate contraception as well as a double barrier method from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or use a double barrier method of contraception from the time of screening through 180 days following the last dose of study intervention

    • Female patients of childbearing potential who receive quizartinib in Arm C should use a highly effective method of contraception during quizartinib treatment and for 7 months after the last dose

Key Exclusion Criteria:

  • Diagnosis of either acute promyelocytic leukemia or blast phase chronic myeloid leukemia

  • Known history of BCR-ABL alteration

  • Advanced malignant hepatic tumor

  • Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery

  • Active central nervous system (CNS) involvement by AML.

  • Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine if used per institutional SOC for control of leukocytosis are permitted to meet this criterion

  • Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia

  • Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection

  • For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis and/or up to 2 doses of cytarabine per institutional standards to control leukocytosis, or prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia

  • For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug

  • Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol

  • Mean QT interval corrected for heart rate by Fredericia's formula (QTcF)

    • Arm A and Arm B: >480 ms on triplicate ECGs
    • Arm C: >450 ms on triplicate ECGs

  • Uncontrolled infection

  • Women who are pregnant or lactating

  • An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing

  • Patients who have active GVHD requiring >0.5 mg/kg prednisone or any new or increase in immunosuppressants in the prior 2 weeks for GVHD treatment

Sources for eligibility
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  • Mayo Clinic - PhoenixPhoenix, United StatesRecruiting
  • Moores UC San Diego Cancer CenterLa Jolla, United StatesRecruiting
  • USC / Norris Comprehensive Cancer CenterLos Angeles, United StatesRecruiting
  • UCLA - Bowyer Oncology CenterLos Angeles, United StatesRecruiting
  • UC Irvine Health Chao Family Comprehensive Cancer CenterOrange, United StatesRecruiting
  • University of ColoradoAurora, United StatesRecruiting
  • Colorado Blood Cancer InstituteDenver, United StatesRecruiting
  • Yale Cancer Center and Smilow Cancer HospitalNew Haven, United StatesRecruiting
  • Mayo Clinic JacksonvilleJacksonville, United StatesRecruiting
  • Emory Healthcare - The Emory ClinicAtlanta, United StatesRecruiting
  • Georgia Cancer Center at Augusta UniversityAugusta, United StatesRecruiting
  • Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, United StatesRecruiting
  • Loyola University Medical CenterMaywood, United StatesRecruiting
  • University of Iowa Hospitals & ClinicsIowa City, United StatesRecruiting
  • The University of Kansas Medical Center Research InstituteFairway, United StatesRecruiting
  • University of Kentucky Markey Cancer CenterLouisville, United StatesRecruiting
  • Norton Cancer Institute - St. MatthewsLouisville, United StatesRecruiting
  • Ochsner MD Anderson Cancer CenterJefferson, United StatesRecruiting
  • Johns Hopkins School of MedicineBaltimore, United StatesRecruiting
  • Massachusetts General HospitalBoston, United StatesRecruiting
  • UMass Chan Medical SchoolWorcester, United StatesRecruiting
  • University of Michigan Comprehensive Cancer CenterAnn Arbor, United StatesRecruiting
  • Karmanos Cancer InstituteDetroit, United StatesRecruiting
  • University of MinnesotaMinneapolis, United StatesRecruiting
  • Mayo Clinic - RochesterRochester, United StatesRecruiting

And 19 more, listed on the interactive page.

Sources for sites
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Sources for references
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Related records

Drugs (6)

Lead sponsors (1)

Conditions (5)

Targets (10)