Acute Myeloid Leukemia, Mixed Lineage Leukemia Gene Mutation, Refractory AML, AML With Mutated NPM1, Acute Myeloid Leukemia Recurrent, Acute Myeloid Leukemia, in Relapse, NPM1 Mutation, KMT2Ar, Myeloid Sarcoma, Nucleophosmin 1-mutated Acute Myeloid Leukemia
Conditions
Keywords
Leukemia, Myeloid, AML, Hematological malignancy, KMT2A, NPM1, Menin, Acute Leukemia, Newly diagnosed AML, Untreated AML, venetoclax, cytarabine, daunorubicin, KMT2A-r, NPM1 mutation, Refractory AML, Acute Myeloid Leukemia, in Relapse, quizartinib
Brief 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.
Interventions
DRUGZiftomenib
Oral Administration
DRUGVenetoclax
Oral Administration
DRUGAzacitidine
Subcutaneous or Intravenous Administration
DRUGDaunorubicin
Intravenous Administration
DRUGCytarabine
Intravenous Administration
DRUGQuizartinib
Oral Administration
Sponsors
Kura Oncology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Descriptive statistics of adverse events | 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 |
| Rate of dose limiting toxicities (DLTs) per dose level (Part 1a only) | During the first 28 days of ziftomenib in combination with SOC backbone treatment (1 cycle) | Assessed by the NCI-CTCAE v5.0 |
| Complete remission (CR) rate | Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first | Assessed by the ELN 2022 criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission (CRc) | Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever occurs first | Assessed by the ELN 2022 criteria |
| Proportion of patients alive | 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 |
| Median EFS | 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 |
| EFS | 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 |
| Median DOR | 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 |
| Proportion of patients who undergo HSCT | 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 |
| TI | 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 |
| Cmax | Cycle 1; each cycle is 28 days | Maximum plasma concentration (Cmax) of ziftomenib and metabolites |
| Tmax | Cycle 1; each cycle is 28 days | Time to maximum plasma concentration (Tmax) of ziftomenib and metabolites |
| AUC0-last | 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 |
| AUCtau | Cycle 1; each cycle is 28 days | Area under the concentration-time curve over a dosing interval (AUCtau) of ziftomenib |
| Accumulation ratio of ziftomenib and metabolites | Cycle 1; each cycle is 28 days | To assess accumulation ratio of ziftomenib and metabolites |
| Cmax of venetoclax | Cycle 1; each cycle is 28 days | Maximum plasma concentration (Cmax) of venetoclax |
| Tmax of venetoclax | Cycle 1; each cycle is 28 days | Time to maximum plasma concentration (Tmax) of venetoclax |
| AUC0-last of venetoclax | 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 |
| AUCtau of venetoclax | Cycle 1; each cycle is 28 days | Area under the concentration-time curve over a dosing interval (AUCtau) of venetoclax |
| Cmax of quizartinib | Cycle 1; each cycle is 28 days | Maximum plasma concentration (Cmax) of quizartinib |
| Tmax of quizartinib | Cycle 1; each cycle is 28 days | Time to maximum plasma concentration (Tmax) of quizartinib |
| AUC0-last of quizartinib | 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 |
| Morphologic leukemia-free state (MLFS) rate | Until relapse, new anti-cancer therapy, death, or up to 36 months of treatment, whichever comes first | Assessed by the ELN 2022 criteria |
| AUCtau of quizartinib | Cycle 1; each cycle is 28 days | Area under the concentration-time curve over a dosing interval (AUCtau) of quizartinib |
| Measurable residual disease (MRD) | 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) |
| Median OS | 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 |
Countries
United States
Contacts
CONTACTKura Medical Information
Outcome results
None listed