Advanced Malignant Neoplasm, Acute Myeloid Leukemia, Mixed Lineage Leukemia, Mixed Lineage Acute Leukemia, Acute Leukemia of Ambiguous Lineage, Mixed Phenotype Acute Leukemia, Acute Lymphoblastic Leukemia
Conditions
Keywords
AML, Hematological malignancy, KMT2A, NPM1, Menin, Leukemia, Acute Leukemia, ALL, MLL, Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, MEIS1
Brief summary
In this trial, ziftomenib, a menin-MLL(KMT2A) inhibitor, will be tested in patients for the first time. The trial includes a Main Study and four sub-studies. In the Main Study (including Phase 1a, Phase 1b, and Phase 2 portions), ziftomenib will be evaluated in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The main study has completed enrollment. In Sub-studies 1 and 2, the effects of taking ziftomenib and other common drugs at the same time will be investigated in AML patients. In Sub-study 3, ziftomenib will be evaluated in patients with R/R acute lymphoblastic leukemia (ALL). In Sub-study 4, ziftomenib will be evaluated in patients with R/R AML with certain genetic mutations.
Detailed description
This first-in-human (FIH), open-label study will assess ziftomenib, a menin-MLL(KMT2A) inhibitor, in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The trial includes a Main Study and four sub-studies. The Main Study is a Phase 1/2 dose-escalation and dose-validation/expansion study to assess ziftomenib in patients with R/R AML. The dose-escalation part of the study (Phase 1a) will determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D). The dose-validation/expansion part of the study (Phase 1b) will determine the safety, tolerability, and minimal biologically effective dose (MBED) of ziftomenib in biomarker-specific dosing cohorts from among doses that demonstrated early biological activity and are determined to be safe in the dose-escalation phase. The Phase 2 portion of the study will determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with nucleophosmin 1-mutant (NPM1-m) AML. In Sub-study 1, the effects of co-administration of ziftomenib on the pharmacokinetics (PK) of midazolam will be studied in patients with R/R AML with certain genetic mutations. In Sub-study 2, the effects of co-administration of itraconazole on the PK of ziftomenib will be studied in patients with R/R AML with certain genetic mutations. In Sub-study 3, the safety, tolerability, and MBED/RP2D of ziftomenib will be studied in patients with R/R KMT2A-rearranged (KMT2A-r) ALL (Phase 1a dose escalation). These parameters will be investigated further for the RP2D in a Phase 1b dose-validation/cohort expansion part of the sub-study. In Sub-study 4, the clinical activity of ziftomenib will be studied in patients with R/R AML with certain genetic mutations.
Interventions
DRUGZiftomenib
Oral administration
DRUGMidazolam
Oral administration
DRUGItraconazole
Oral administration
Sponsors
Kura Oncology, Inc.
Study design
Allocation
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 with refractory or relapsed AML defined as the reappearance of ≥ 5% blasts in the bone marrow and who have also failed or are ineligible for any approved standard of care therapies, including HSCT. 1. Phase 1b: * Patients with a documented lysine\[K\]-specific methyltransferase 2-rearrangement (KMT2A-r), or * Patients with a documented nucleophosmin 1 mutation (NPM1-m) 2. Phase 2: * Patients with a documented nucleophosmin 1 mutation (NPM1-m) 3. Sub-studies: * Sub-studies 1 and 2: Patients with R/R AML with NPM1-m or other mutations associated with MEIS1 overexpression. * Sub-study 3: Patients with R/R Acute Lymphoblastic Leukemia (ALL) with KMT2A-r. * Sub-study 4: Patients with R/R AML with mutations associated with MEIS1 overexpression. 4. ≥ 18 years of age. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months. 6. Adequate liver and kidney function according to protocol requirements. 7. Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment. 8. Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 187 days after the last dose of study treatment. 9. Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 97 days after the last dose of study treatment. Key
Exclusion criteria
1. Diagnosis of acute promyelocytic leukemia. 2. Diagnosis of chronic myelogenous leukemia in blast crisis. 3. Donor lymphocyte infusion \< 30 days prior to study entry. 4. Clinically active central nervous system (CNS) leukemia. 5. Undergone HSCT and have not had adequate hematologic recovery. 6. Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1. 7. Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity. 8. Received chemotherapy immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) \< 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug. 9. Not recovered to \< Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) from all acute toxicities or deemed back to a stable baseline. 10. Treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4), as follows: * Phase 1a, 1b, 2, and sub-studies 3 and 4: with the exception of antibiotics, antifungals, and antivirals that are used as standard of care or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient. * Sub-studies 1 and 2: No exceptions will be allowed except for the use of moderate CYP3A4 antifungal prophylaxis such as fluconazole or isavuconazole which is at steady state on Cycle 1 Day 1 and will continue through the completion of PKs on Cycle 1 Day 15 (for sub-study 1) or Cycle 1 Day 18 (for sub-study 2). 11. Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection. Patients with controlled disease will not be excluded from study enrollment. 12. Pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML). 13. Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection. 14. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within the past 6 months, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment. 15. Mean QTcF \>480 ms on triplicate ECG. 16. Major surgery within 4 weeks prior to the first dose of study treatment. 17. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative serum pregnancy test within 72 hours prior to starting treatment. 18. For sub-studies 1 and 2: Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of ziftomenib until the end of Cycle 1. 19. For sub-studies 1 and 2: Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) | Dose Limiting Toxicities (DLTs) will be evaluated during the first 28 days (1 cycle) | MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients. |
| Phase 1b: Number of patients who experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. | Assessed by NCI-CTCAE v5.0 |
| Phase 1b: Minimum biologically effective dose | For at least 12 months following end of treatment | Minimum biologically effective dose in dosing cohorts which have demonstrated biological activity and have been determined to be safe as a part of Part 1a |
| Phase 1a, 1b, and 2: Evidence of anti-leukemia activity | For at least 12 months following end of treatment | Assessed by the CR + CRh rate |
| Sub-study 1: Time to observed maximum plasma concentration (Tmax) of ziftomenib and midazolam | Cycle 1 on Days 1 and 15 at predose and postdose | Tmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam |
| Sub-study 1: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and midazolam | Cycle 1 on Days 1 and 15 at predose and postdose | AUC0-t of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam |
| Sub-study 1: Maximum observed plasma concentration (Cmax) of ziftomenib and midazolam | Cycle 1 on Days 1 and 15 at predose and postdose | Cmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam |
| Sub-study 2: Time to observed maximum plasma concentration (Tmax) of ziftomenib and itraconazole | Cycle 1 on Days 1, 15, and 22 at predose and postdose | Tmax of ziftomenib, its metabolites, and itraconazole |
| Sub-study 2: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib and itraconazole | Cycle 1 on Days 1, 15, and 22 at predose and postdose | AUC0-t of ziftomenib, its metabolites, and itraconazole |
| Sub-study 2: Maximum observed plasma concentration (Cmax) of ziftomenib and itraconazole | Cycle 1 on Days 1, 15, and 22 at predose and postdose | Cmax of ziftomenib, its metabolites, and itraconazole |
| Sub-study 3: Minimum biologically effective dose (MBED) and/or the recommended Phase 2 dose (RP2D) | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first | Assessed by the number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) per NCI-CTCAE v5.0 |
| Sub-study 3: Change in Eastern Cooperative Oncology Group (ECOG) status | Timeframe: from Baseline to End of Treatment | To assess the change in ECOG status |
| Sub-study 3: Time to observed maximum plasma concentration (Tmax) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards | Tmax of ziftomenib |
| Sub-study 3: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards | AUC0-t of ziftomenib |
| Sub-study 3: Maximum observed plasma concentration (Cmax) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose at Cycle 2 onwards. | Cmax of ziftomenib |
| Sub-study 4: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) | For at least 12 months following end of treatment | To assess the CR+CRh rate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sub-study 3: Complete remission (CR) measurable residual disease (MRD) negativity | For at least 12 months following discontinuation of treatment | To assess the CR MRD negativity |
| Sub-studies 3 and 4: Composite complete remission (CRc) | For at least 12 months following discontinuation of treatment | To assess CRc |
| Sub-study 3: Duration of response (DOR) | For at least 12 months following discontinuation of treatment | To assess the DOR, defined as the duration of CR |
| Sub-studies 3 and 4: Overall survival (OS) | For at least 12 months following discontinuation of treatment | To assess overall survival |
| Sub-studies 3 and 4: Event-free survival (EFS) | For at least 12 months following discontinuation of treatment | To assess event-free survival |
| Sub-study 4: Duration of response (DOR) | For at least 12 months following discontinuation of treatment | To assess the DOR, defined as the duration of CR/CRh |
| Sub-studies 3 and 4: Overall response rate (ORR) measurable residual disease (MRD) negativity | For at least 12 months following discontinuation of treatment | To assess the ORR MRD negativity |
| Sub-study 4: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. | Assessed by NCI-CTCAE v5.0 |
| Sub-study 4: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards | AUC0-t of ziftomenib and its metabolites |
| Sub-study 4: Maximum plasma concentration (Cmax) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards | Cmax of ziftomenib and its metabolites |
| Sub-study 4: Transfusion independence (TI) | For at least 12 months following discontinuation of treatment | To assess transfusion independence |
| Sub-study 4: Time to observed maximum plasma concentration (Tmax) of ziftomenib | Postdose on Cycle 1 Day 1 and Cycle 2 Day 1. Predose on Cycle 2 onwards | Tmax of ziftomenib and its metabolites |
| Phase 1a and 2: Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. | Assessed by NCI-CTCAE v5.0 |
| Phase 1a: Tmax | Cycle 1 and Cycle 2. Each cycle is 28 days. | Time to observed maximum plasma concentration of ziftomenib and/or its metabolites |
| Phase 1a: AUC(0-t) | Cycle 1 and Cycle 2. Each cycle is 28 days. | Area under the plasma concentration-time curve from time 0 to time t of ziftomenib and/or its metabolites |
| Phase 1a: Cmax | Cycle 1 and Cycle 2. Each cycle is 28 days. | Maximum plasma concentration of ziftomenib and/or its metabolites |
| Phases 1a, 1b, and 2: Complete remission (CR) and complete remission with partial hematologic recovery (CRh) measurable residual disease (MRD) negativity | For at least 12 months following discontinuation of treatment | To assess the CR/CRh MRD negativity |
| Phases 1a, 1b, and 2: Duration of response (DOR) | For at least 12 months following discontinuation of treatment | To assess the DOR, defined as the duration of CR/CRh |
| Phases 1a, 1b, and 2: Transfusion independence (TI) | For at least 12 months following discontinuation of treatment | To assess transfusion independence |
| Phases 1a, 1b, and 2: Overall response rate (ORR) | For at least 12 months following discontinuation of treatment | To assess the ORR |
| Phases 1a, 1b, and 2: Event-free survival (EFS) | For at least 12 months following end of treatment | To assess event-free survival |
| Phases 1a, 1b, and 2: Overall survival (OS) | For at least 12 months following end of treatment | To assess overall survival |
| Phases 1a, 1b, and 2: Composite complete remission (CRc) | For at least 12 months following discontinuation of treatment | To assess CRc |
| Phases 1b and 2: Composite complete remission (CRc) measurable residual disease (MRD) negativity | For at least 12 months following discontinuation of treatment | To assess the CRc MRD negativity |
| Phases 1b and 2: Overall response rate (ORR) measurable residual disease (MRD) negativity | For at least 12 months following discontinuation of treatment | To assess the ORR MRD negativity |
| Sub-study 2: Corrected QT (QTc) intervals | During Cycle 1 | Assessed by QTc intervals |
Countries
Belgium, Canada, France, Germany, Italy, Poland, Spain, United Kingdom, United States
Contacts
Primary ContactKura Medical Information
Outcome results
None listed