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Safety and Tolerability of Ziftomenib Combinations in Patients With Relapsed/Refractory Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT06001788
Recruitment Status : Recruiting
First Posted : August 21, 2023
Last Update Posted : May 16, 2024
Sponsor:
Information provided by (Responsible Party):
Kura Oncology, Inc.

Study Description
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Brief Summary:
The safety, tolerability, and antileukemic response of ziftomenib in combination with standard of care treatments for patients with relapsed/refractory acute myeloid leukemia will be examined with the following agents: FLAG-IDA, low-dose cytarabine, and gilteritinib.

Condition or disease Intervention/treatment Phase
AML AML With Mutated NPM1 Hematologic Malignancy KMT2Ar NPM1 Mutation MLL Rearrangement Leukemia Acute Myeloid Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Acute Leukemia Neoplasms by Histologic Type Drug: Ziftomenib Drug: Fludarabine Drug: Idarubicin Drug: Cytarabine Drug: Gilteritinib Biological: Granulocyte colony-stimulating factor Phase 1

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 171 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-rearranged or NPM1-mutant Relapsed/Refractory Acute Myeloid Leukemia
Actual Study Start Date : February 22, 2024
Estimated Primary Completion Date : August 2026
Estimated Study Completion Date : August 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase 1a

Oral ziftomenib; sequential cohorts of escalating dose levels of ziftomenib to identify the safety and tolerability of the combination regimens. Participants will be enrolled in 1 of 5 dose escalation cohorts:

A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA

A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)

A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib

B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA

B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)

 Drug: Ziftomenib
Oral administration
Other Name: KO-539

Drug: Fludarabine
Intravenous infusion

Drug: Idarubicin
Intravenous infusion

Drug: Cytarabine
Intravenous Infusion

Drug: Gilteritinib
Oral administration
Other Name: Xospata

Biological: Granulocyte colony-stimulating factor
Subcutaneous injection
Experimental: Phase 1b

Oral ziftomenib; Following the determination of the maximum tolerated dose in Phase 1a, participants will be enrolled in 1 of 5 dose validation/expansion cohorts:

A-1: Participants with a NPM1 mutation: ziftomenib plus FLAG-IDA

A-2: Participants with a NPM1 mutation: ziftomenib plus low-dose cytarabine (LDAC)

A-3: Participants with a NPM1 mutation: ziftomenib plus gilteritinib

B-1: Participants with a KMT2A rearrangement: ziftomenib plus FLAG-IDA

B-2: Participants with a KMT2A rearrangement: ziftomenib plus low-dose cytarabine (LDAC)

 Drug: Ziftomenib
Oral administration
Other Name: KO-539

Drug: Fludarabine
Intravenous infusion

Drug: Idarubicin
Intravenous infusion

Drug: Cytarabine
Intravenous Infusion

Drug: Gilteritinib
Oral administration
Other Name: Xospata

Biological: Granulocyte colony-stimulating factor
Subcutaneous injection


Outcome Measures
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Primary Outcome Measures :
  1. Rate of dose limiting toxicities (DLTs) per dose level [ Time Frame: During the first 28 days of ziftomenib in combination with SOC treatment (1 cycle) ]
    Assessed by the NCI-CTCAE v5.0

  2. Descriptive statistics of adverse events [ Time Frame: First dose of ziftomenib up to and including 28 days after last dose of ziftomenib, or if the patient is lost to follow-up, whichever comes first ]
    Assessed by the NCI-CTCAE v5.0


Secondary Outcome Measures :
  1. Complete remission (CR) rate for cohorts A-1, A-2, B-1, and B-2 [ Time Frame: Up to 12 months following discontinuation of treatment ]
    Assessed by ELN 2022 criteria

  2. Complete remission (CR) / Complete remission with partial hematologic recovery (CRh) rate for cohort A-3 [ Time Frame: Up to 12 months following discontinuation of treatment ]
    Assessed by ELN 2022 criteria

  3. Composite complete remission (CRc) rate [ Time Frame: Up to 12 months following discontinuation of treatment ]
    Assessed by ELN 2022 criteria

  4. Morphologic leukemia-free state (MLFS) rate [ Time Frame: Up to 12 months following discontinuation of treatment ]
    Assessed by ELN 2022 criteria

  5. OS [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess overall survival

  6. 6-month OS [ Time Frame: Up to 6 months following discontinuation of treatment ]
    To assess proportion of patients alive at 6 months

  7. Median EFS [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess median event free survival

  8. 6-month EFS [ Time Frame: Up to 6 months following discontinuation of treatment ]
    To assess 6-month event free survival

  9. DOR [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess duration of remission

  10. MRD assessment [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess minimum residual disease in bone marrow as assessed by multiparameter flow cytometry (MFC) and molecular analysis

  11. HSCT [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess proportion of patients that undergo a hematopoietic stem-cell transplant

  12. Transfusion independence [ Time Frame: Up to 12 months following discontinuation of treatment ]
    To assess rate of transfusion independence

  13. Ziftomenib Cmax [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the maximum plasma combination of ziftomenib and its metabolites

  14. Ziftomenib Tmax [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the time to observed maximum plasma concentration of ziftomenib and its metabolites

  15. Ziftomenib AUC(0-last) [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of ziftomenib and its metabolites

  16. Ziftomenib AUC(tau) [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the area under the plasma concentration-time-curve over a dosing interval for ziftomenib and its metabolites

  17. Gilteritinib Cmax [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the maximum plasma combination of gilteritinib

  18. Gilteritinib Tmax [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the time to observed maximum plasma concentration of gilteritinib

  19. Gilteritinib AUC(0-last) [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the area under the plasma concentration-time-curve from time 0 to time of last measurable concentration of gilteritinib

  20. Gilteritinib AUC(tau) [ Time Frame: Cycle 1 (Each cycle is 28 days) ]
    To assess the area under the plasma concentration-time-curve over a dosing interval for gilteritinib


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Has been diagnosed with relapsed/refractory AML.
  • Has a documented NPM1 mutation or KMT2A rearrangement.
  • Has a documented FLT3 mutation (cohort A-3 only).
  • Has an Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2.
  • Has adequate hepatic and renal function as defined per protocol.
  • Has an ejection fraction above a protocol defined limit.
  • Participant, or legally authorized representative, must be able to understand and provide written informed consent prior to the first screening procedure.
  • Has agreed to use contraception as defined per protocol.

Key Exclusion Criteria:

  • Has a diagnosis of acute promyelocytic leukemia or blast chronic myeloid leukemia.
  • Has clinically active central nervous system leukemia.
  • Has an active and uncontrolled infection.
  • Has a mean corrected QT interval (QTcF) > 480ms.
  • Has uncontrolled intercurrent illness, including, but not limited to protocol defined cardiac disease.
  • Has received radiation, chemotherapy, immunotherapy, or any other anticancer therapy including investigational therapy <14 days or within 5 drug half-lives prior to the first dose of study intervention.
  • Has had major surgery within 4 weeks prior to the first dose of study intervention.
  • Has received a hematopoietic stem cell transplant (HSCT) and has not previously had adequate recovery per protocol defined criteria.
  • Has active graft-versus-host disease (GvHD) and or on immunosuppressive drugs for the treatment of GvHD.
  • Participant is pregnant or lactating.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06001788


Contacts
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Contact: Clinical Operations 858 500 8800 KO-MEN-008@kuraoncology.com

Locations
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United States, Connecticut
Smilow Cancer Hospital at Yale New Haven Recruiting
New Haven, Connecticut, United States, 06511
Contact: Farah Fasihuddin       farah.fasihuddin@yale.edu   
United States, Kansas
The University of Kansas Recruiting
Kansas City, Kansas, United States, 66160
Contact: KUCC Navigation Team    913-588-3671    kucc_navigation@kumc.edu   
United States, Michigan
Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Cathy Galasso       galassoc@karmanos.org   
Henry Ford Cancer Institute Recruiting
Detroit, Michigan, United States, 48202
Contact: Kristyn Dailey       KDailey6@hfhs.org   
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10021
Contact: Aaron Goldberg, MD, PhD    646-608-3752    goldbera@mskcc.org   
United States, South Carolina
Prisma Health Recruiting
Greenville, South Carolina, United States, 29615
Contact: Lisa Johnson    864-455-3735    lisa.johnson@prismahealth.org   
Contact: Fiona Davidson    864-455-3737    fiona.davidson@prismahealth.org   
Sponsors and Collaborators
Kura Oncology, Inc.
Investigators
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Study Director: Clinical Development Kura Oncology
More Information
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Responsible Party: Kura Oncology, Inc.
ClinicalTrials.gov Identifier: NCT06001788    
Other Study ID Numbers: KO-MEN-008
First Posted: August 21, 2023    Key Record Dates
Last Update Posted: May 16, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Neoplasms by Site
Cytarabine
Fludarabine
Idarubicin
Lenograstim
Gilteritinib
Antineoplastic Agents
Antimetabolites, Antineoplastic
 Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Adjuvants, Immunologic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Tyrosine Kinase Inhibitors
Protein Kinase Inhibitors