A Phase 1/2 First in Human Study of the Menin-MLL (KMT2A) Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Kura Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jun 2020 → ongoing

Decision date (initial)

2024-07-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Kura Oncology Inc.

External identifiers

EU CT number

2023-510509-17-00

EudraCT number

2019-001545-41

ClinicalTrials.gov

NCT04067336

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response, Pharmacogenomic, Efficacy, Pharmacodynamic, Safety, Therapy

Phase 1 Part 1a: Dose-Escalation
- To determine the MTD and/or the RP2D of ziftomenib in patients with R/R AML
Phase 1 Part 1b: Dose-Validation/ Cohort Expansion
- Determine the safety, tolerability and MBED of ziftomenib in biomarker specific dosing cohorts, which have demonstrated early biological activity and have been determined to be safe as part of the dose-escalation phase

Phase 2:
- Assess evidence of ALA of ziftomenib in patients with NPM1-m R/R AML

Sub study 2:
- will evaluate the effect of CYP3A4 inhibition on ziftomenib exposure in patients with R/R AML with mutations associated with MEIS1 overexpression
- To confirm adequate itraconazole exposure

Sub-Study 3:
- Determine the safety, tolerability, and MBED/RP2D of ziftomenib in patients with R/R KMT2A-r ALL

Sub study 4:
- Assess evidence of clinical activity of ziftomenib according to the 2022 ELN Recommendations for AML and the US FDA Guidance for Industry for AML in patients with R/R AML with mutations associated with MEIS1 overexpression.

Secondary objectives 11

1. Phase 1 Part 1a: Dose-Escalation: 1.To investigate the safety and tolerability of ziftomenib in patients with R/R AML
2. Phase 1 Part 1a: Dose-Escalation: 2.To characterize the PK of ziftomenib and metabolites after single oral (PO) dose administration and after multiple PO dose administrations in patients with R/R AML
3. Phase 1 Part 1a: Dose-Escalation: 3.Explore early evidence of ALA
4. Phase 1 Part 1b: Dose-Validation/ Cohort Expansion: 1.Explore early evidence of anti-leukemia activity (ALA) in patients with R/R AML
5. Phase 2: 1.Assess evidence of clinical activity of ziftomenib in patients with NPM1-m R/R AML
6. Phase 2: 2.Assess safety and tolerability of ziftomenib in patients with NPM1-m R/R AML
7. Sub-Study 3: Explore early evidence of anti-leukemia activity (ALA) of ziftomenib in patients with R/R KMT2A-r ALL
8. Sub-Study 4: Assess additional evidence of clinical activity of ziftomenib in patients with R/R AML with mutations associated with MEIS1 overexpression.
9. Sub-study 4: Assess safety and tolerability of ziftomenib in patients with R/R AML with mutations associated with MEIS1 overexpression.
10. Sub-study 4: Determine concentrations of ziftomenib and metabolite(s) following ziftomenib PO administration in patients with R/R AML with mutations associated with MEIS1 overexpression.
11. Sub study 2: To evaluate the relationship between ziftomenib plasma concentrations and corrected QT (QTc) intervals

Conditions and MedDRA coding

Relapsed and/or refractory Acute Myeloid Leukemia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. Relapsed/refractory (R/R) acute myeloid leukemia (AML) defined as those who have also failed or are not appropriate for any approved standard-of-care (SOC) therapies or hematopoietic stem cell transplant (HSCT)with reappearance of ≥ 5% blasts in the bone marrow (BM)
2. 2. ≥ 18 years of age
3. 3. Eastern Cooperative Oncology Group performance status of ≤ 2, and a life expectancy of at least 2 months
4. 4. Peripheral white blood cell counts ≤ 30,000/μL

Exclusion criteria 12

1. 1. Diagnosis of acute promyelocytic leukemia or chronic myelogenous leukemia in blast crisis
2. 2. Donor lymphocyte infusion < 30 days prior to study entry
3. 3. Clinically active central nervous system (CNS) leukemia
4. 4. Has undergone HSCT and has not had adequate hematologic recovery (Recovery is defined as peripheral absolute neutrophil count (ANC) ≥ 1 × 10^9/L and platelets at least ≥ 50 × 10^9/L [but preferably ≥ 100 × 10^9/L] and signs of a cellular BM at any time after HSCT).
5. 5. Patients on immunosuppressive therapy post HSCT must be off all immunosuppression therapy within 2 weeks of Cycle 1 Day 1
6. 6. ≥ Grade 2 active acute GvHD, moderate or severe limited chronic GvHD, or extensive chronic GvHD of any severity
7. 7. Has received prior menin inhibitor
8. 8. Has received chemotherapy, immunotherapy, radiotherapy (unless if given for management of CNS leukemia), or any ancillary therapy that is considered to be investigational (ie, 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, whichever is shorter, to ensure that patient time without necessary AML therapy is appropriately limited
9. 9. Requires treatment with concomitant drugs that are strong inducers of CYP3A4 with the exception of antibiotics, antifungals, and antivirals that are used as SOC or to prevent or treat infections. Other such drugs that are considered absolutely essential by the Investigator for the care of the patient should be discussed on a case-by-case basis with the Medical Monitor
10. 10. Has an active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection
11. 11. 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 (New York Heart Association 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
12. 12. Mean corrected QT interval by Fredericia's formula > 480 ms on triplicate electrocardiograms

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. Phase 1 Part 1a: 1. Maximum Tolerated Dose (MTD)
2. Phase 1 Part 1a: 2. Recommended Phase 2 dose (RP2D)
3. Phase 1 Part 1b: 1. Safety, tolerability, and efficacy at multiple timepoints during the study
4. Phase 2: 1. Based on evaluation of CR/CRh
5. Sub-study 3: Safety, tolerability, and efficacy at multiple timepoints during the study
6. Sub study 4: Based on evaluation of CR/CRh
7. Sub study 2: PK parameters of ziftomenib and ziftomenib metabolites: AUC0-∞, AUC0-t, Cmax, Tmax, t1/2, CL/F, and Vz/F

Secondary endpoints 13

1. Phase 1 Part 1a: 1. Safety/tolerability assessed at multiple timepoints during the study
2. Phase 1 Part 1a: 2. From blood samples collected at specified timepoints during treatment
3. Phase 1 Part 1a: 3. Plasma concentrations of ziftomenib and metabolite(s)
4. Phase 1 Part 1a: 4. Plasma PK parameters (Cmax, Cmin, Tmax, AUC0-t, AUC0-8, CL/F, Vz/F, and t½)
5. Phase 1 Part 1a: 5. Based on evaluation of (including but not limited to): a. Duration of CR/CRh, b. TI, c. CR/CRh MRD negativity, d. CRc (CR+ CRh + CRi), e. ORR (CR + CRh + CRi + MLFS), f. EFS, g. OS
6. Phase 1 Part 1b: 1. Based on evaluation of (including but not limited to): a. Duration of CR/CRh, b. TI, c. CR/CRh MRD negativity, d. CRc, e. EFS, f. OS
7. Phase 2: 1. Based on evaluation of (including but not limited to): a. Duration of CR/CRh, b. TI, c. CR/CRh MRD negativity, d. CRc e. EFS, f. OS
8. Phase 2: 2. Safety and tolerability assessed at multiple timepoints during the study
9. Sub-study 3: Based on evaluation of (including but not limited to): a. Rate of CR, b. Duration of CR, c. CR MRD negativity, d. Rate of CR/CRh/CRi, e. Duration of CR/CRh/CR, f. CR/CRh/CRi MRD negativity, g. EFS, h. OS
10. Sub-study 4: Based on evaluation of (including but not limited to): a. Duration of CR/CRh b. TI c. CR/CRh, CRc, and ORR MRD negativity d. CRc e. ORR f. EFS g.OS
11. Sub study 4: Safety, tolerability, and efficacy assessed at multiple timepoints during the study: a. Incidence and severity of AEs according to NCI CTCAE v5.0 b. Incidence of SAEs c. Deaths on treatment d. Discontinuations of study treatment due to AEs e. Clinically significant changes in clinical laboratory parameters, vital signs parameters, ECG parameters f. Change in ECOG status
12. Sub study 4: Plasma PK parameters (Cmax, Cmin, Tmax, AUC0-t, AUC0∞, CL/F, Vz/F, and t1/2)
13. Sub study 2: QT interval corrected for heart rate using Fridericia’s formula and time-matched ziftomenib plasma concentration measurements

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Kura Oncology Inc.

Sponsor organisation

Kura Oncology Inc.

Address

4930 Directors Place Suite 500

City

San Diego

Postcode

92121-3848

Country

United States

Scientific contact point

Organisation

Kura Oncology Inc.

Contact name

Clinical Operations

Public contact point

Organisation

Kura Oncology Inc.

Contact name

Clinical Operations

Third parties 10

Locations

6 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 78 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications