Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.1 ), and Clinical Studies ( 14 )] . FDA label
Also known as KO 539, Menin-KMT2A Inhibitor KO 539, Menin-MLL Inhibitor KO-539, Menin-MLL Interaction Inhibitor KO 539
Ziftomenib · 7 trials · 33 indications
OS
CR rate per European Leukemia Network (ELN) 2022 criteria per Investigator assessment
EFS
CR rate per ELN 2022 criteria per Investigator assessment with central BM MRD negativity
Will be assessed after 6 cycles of treatment using the best response achieved in that time. Will be calculated in each arm for the efficacy analysis population and reported along with two-sided 95% exact binomial confidence limits, in a modified intent-to-treat analysis.
Rate of DLTs per dose level
Per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0
CBR is the rate of participants achieving complete response (CR), partial response (PR), or stable disease (SD), assessed per Response Criteria in Solid Tumors (RECIST) v1.1 modified for GIST
Assessed by the NCI-CTCAE v5.0
Assessed by the NCI-CTCAE v5.0
Assessed by the NCI-CTCAE v5.0
Assessed by the ELN 2022 criteria
MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.
Assessed by NCI-CTCAE v5.0
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
Assessed by the CR + CRh rate
Tmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
AUC0-t of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
Cmax of ziftomenib, its metabolites, midazolam, and 1-hydroxymidazolam
Tmax of ziftomenib, its metabolites, and itraconazole
AUC0-t of ziftomenib, its metabolites, and itraconazole
Cmax of ziftomenib, its metabolites, and itraconazole
Assessed by the number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) per NCI-CTCAE v5.0
To assess the change in ECOG status
Tmax of ziftomenib
AUC0-t of ziftomenib
Cmax of ziftomenib
To assess the CR+CRh rate
| Arm | Type | Description |
|---|---|---|
| Nonintensive Therapy Study, Arm A | EXPERIMENTAL | Ziftomenib in combination with venetoclax+azacitidine |
| Nonintensive Therapy Study, Arm B | PLACEBO_COMPARATOR | Placebo in combination with venetoclax+azacitidine |
| Intensive Therapy Study, Arm A | EXPERIMENTAL | Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance) |
| Intensive Therapy Study, Arm B | EXPERIMENTAL | Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance) |
| Intensive Therapy Study, Arm C | PLACEBO_COMPARATOR | Placebo+cytarabine+daunorubicin (induction), placebo+cytarabine (consolidation), placebo (maintenance) |
| Treatment (ziftomenib) | EXPERIMENTAL | Patients receive ziftomenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo cytoreduction therapy with hydroxyurea up to end of cycle 1, cytarabine within 7 days of starting treatment, or leukapheresis within 7 days of treatment to reduce white blood cell count to =\< 10,000/uL. Additionally, patients undergo ECHO or MUGA at screening and bone marrow biopsy and/or aspiration and blood sample collection throughout the study. |
| Ziftomenib | EXPERIMENTAL | During Cycle 1 (49 days), participants will receive escalating doses of ziftomenib once daily (QD) on Days 8 to 49. Participants will also receive FLA chemotherapy consisting of fludarabine at a dose of 30 mg/m\^2 (1 mg/kg/dose in infants \<1 year of age or ≤10 kg) and cytarabine at a dose of 2000 mg/m\^2 (67 mg/kg/dose in infants \<1 year of age or ≤10 kg) QD on Day 1 to Day 5. Participants with \<5% blasts will continue ziftomenib monotherapy until Day 49. Participants with a response and \>5% blasts will continue to Cycle 2. During Cycle 2 (28 days), participants will receive escalating doses of ziftomenib QD on Day 1 to Day 28 in combination with FLA chemotherapy on Day 1 to Day 5. Participants who respond to treatment, but experience a delay prior to hematopoietic stem cell transplantation (HSCT), may receive up to 10 additional cycles (28 days) of ziftomenib monotherapy. Participants may also receive intrathecal therapy prophylaxis, if needed, during all cycles. |
| Dose Escalation | EXPERIMENTAL | Ziftomenib plus imatinib |
| Recommended Phase 2 Dose Determination | EXPERIMENTAL | Ziftomenib plus imatinib |
| Dose Expansion | EXPERIMENTAL | Ziftomenib plus imatinib |
| Phase 1a | EXPERIMENTAL | 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) |
| Phase 1b | EXPERIMENTAL | 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) |
| Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy |
| Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R NPM1-m (A-1) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy |
| Dose Escalation: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2) | EXPERIMENTAL | Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05 |
| Dose Validation/Expansion: Ziftomenib with 7+3 in 1L NPM1-m/FLT3 wildtype (A-2) | EXPERIMENTAL | Ziftomenib with 7+3 in newly diagnosed NPM1-m AML patients who are candidates for intensive chemotherapy and must be FLT3 wildtype or ITD ratio \<0.05 |
| Dose Validation/Expansion: Ziftomenib with Venetoclax in R/R NPM1-m (A-3) | EXPERIMENTAL | Ziftomenib with Venetoclax in relapsed/refractory NPM1-m AML patients who have failed at least one prior line of therapy |
| Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in 1L NPM1-m (A-4) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in newly diagnosed NPM1-m AML patients |
| Dose Escalation: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy |
| Dose Validation/Expansion: Ziftomenib with Venetoclax and Azacitidine in R/R KMT2A-r (B-1) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in relapsed/refractory KMT2A-r AML patients who have failed at least one prior line of therapy |
| Dose Escalation: Ziftomenib with 7+3 in 1L KMT2A-r (B-2) | EXPERIMENTAL | Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive chemotherapy |
| Dose Validation/Expansion: Ziftomenib with 7+3 in 1L KMT2A-r (B-2) | EXPERIMENTAL | Ziftomenib with 7+3 in newly diagnosed KMT2A-r AML patients who are candidates for intensive therapy |
| Dose Validation/Expansion: Ziftomenib with Venetoclax + Azacitidine in 1L KMT2A-r (B-3) | EXPERIMENTAL | Ziftomenib with Venetoclax and Azacitidine in newly diagnosed KMT2A-r AML patients |
| Dose Escalation: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1) | EXPERIMENTAL | Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy |
| Dose Validation/Expansion: Ziftomenib with 7+3+quizartinib in 1L NPM1-m/FLT3-ITD+ AML patients (C-1) | EXPERIMENTAL | Ziftomenib with 7+3 and quizartinib in newly diagnosed NPM1-m and FLT3-ITD+ (with allelic ratio ≥0.05) AML patients who are candidates for IC and eligible to receive FLT3-targeted therapy |
| Phase 1a - Dose Escalation | EXPERIMENTAL | AML patients will receive multiple doses of ziftomenib |
| Phase 1b - Dose-Validation Expansion | EXPERIMENTAL | Cohort 1: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib Cohort 2: KMT2A-r / NPM1-m R/R AML patients will receive ziftomenib |
| Phase 2 | EXPERIMENTAL | NPM1-m R/R AML patients will receive the recommended phase 2 ziftomenib dose |
| Sub-study 1 | EXPERIMENTAL | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + midazolam |
| Sub-study 2 | EXPERIMENTAL | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib + itraconazole |
| Sub-study 3 | EXPERIMENTAL | Part 1a: KMT2A-r R/R ALL patients will receive multiple ziftomenib doses Part 1b: KMT2A-r R/R ALL patients will receive ziftomenib |
| Sub-study 4 | EXPERIMENTAL | R/R AML patients with mutations associated with MEIS1 overexpression will receive ziftomenib |
| Name | Type | Description |
|---|---|---|
| Ziftomenib | DRUG | Oral administration |
| Placebo | DRUG | Oral administration |
| Venetoclax | DRUG | Oral administration |
| Azacitidine (AZA) | DRUG | Intravenous or subcutaneous administration |
| Daunorubicin | DRUG | Intravenous administration |
| Cytarabine (Ara-C) | DRUG | Intravenous administration |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow biopsy and/or aspiration |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy and/or aspiration |
| Cytarabine | DRUG | Given cytarabine |
| Echocardiography Test | PROCEDURE | Undergo ECHO |
| Hydroxyurea | DRUG | Given hydroxyurea |
| Leukapheresis | PROCEDURE | Undergo leukapheresis |
| Multigated Acquisition Scan | PROCEDURE | Undergo MUGA |
| Questionnaire Administration | OTHER | Ancillary studies |
| Fludarabine | DRUG | IV infusion |
| imatinib mesylate | DRUG | kinase inhibitor |
| Idarubicin | DRUG | Intravenous infusion |
| Gilteritinib | DRUG | Oral administration |
| Granulocyte colony-stimulating factor | BIOLOGICAL | Subcutaneous injection |
| Azacitidine | DRUG | Subcutaneous or Intravenous Administration |
| Quizartinib | DRUG | Oral Administration |
| Midazolam | DRUG | Oral administration |
| Itraconazole | DRUG | Oral administration |
Key Inclusion Criteria: The following criteria apply to both the Nonintensive Therapy Study and the Intensive Therapy Study unless otherwise noted: * Age ≥18 years at time of signing the informed consent form. * Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition...
Ziftomenib is an investigational small molecule being studied for acute myeloid leukemia (AML), including NPM1-mutated and KMT2A-rearranged subtypes, as well as relapsed or refractory acute leukemias and advanced gastrointestinal stromal tumors (GIST). It is being developed by Kura Oncology, Inc. (ticker: KURA) and has not been approved by the FDA.
Ziftomenib targets menin, a protein involved in regulating gene expression. By binding to menin, ziftomenib is designed to disrupt the interaction between menin and KMT2A, which is thought to drive certain leukemias. This mechanism is being evaluated in NPM1-mutated and KMT2A-rearranged acute myeloid leukemia.
Ziftomenib is being developed by Kura Oncology, Inc., a biopharmaceutical company traded on the Nasdaq under the ticker symbol KURA. Kura Oncology is focused on the development of small molecule therapeutics for the treatment of cancer, including ziftomenib for acute leukemias and gastrointestinal stromal tumors.
Ziftomenib is in clinical development, with trials ranging from Phase 1 to Phase 3. The Phase 3 trial (NCT07007312) is evaluating ziftomenib in combination with venetoclax and azacitidine or 7+3 chemotherapy in patients with untreated NPM1-mutated or KMT2A-rearranged AML. It is not FDA approved.
Ziftomenib is being studied in several clinical trials, including NCT07007312 (Phase 3, untreated NPM1-m or KMT2A-r AML), NCT06930352 (Phase 2, NPM1-mutated or KMT2A-rearranged AML not eligible for standard therapy), NCT06655246 (Phase 1, advanced GIST in combination with imatinib), and NCT06376162 (Phase 1, relapsed/refractory acute leukemia in children).
Ziftomenib has received Breakthrough Therapy, Fast Track, Orphan Drug, and Priority Review designations from the FDA. These designations are intended to expedite the development and review of drugs for serious conditions. The drug remains investigational and is not approved for any indication.