First in Human Study of KO-539 in Relapsed or Refractory Acute Myeloid Leukemia

• ClinicalTrials.gov Identifier: NCT04067336
• Recruitment Status: Recruiting
• First Posted: August 26, 2019
• Last Update Posted: January 19, 2021
• Sponsor: Kura Oncology, Inc.
• Information provided by (Responsible Party): Kura Oncology, Inc.

Study Description

Brief Summary:

This first-in-human (FIH) dose escalation and dose expansion study will determine the maximum tolerated dose (MTD) of KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed AML who have failed or are ineligible for any approved standard of care therapies, including HSCT.

Condition or disease	Intervention/treatment	Phase
Advanced Malignant Neoplasm; Acute Myeloid Leukemia; Mixed Lineage Leukemia; Mixed Lineage Acute Leukemia; Acute Leukemia of Ambiguous Lineage; Mixed Phenotype Acute Leukemia	Drug: KO-539	Phase 1; Phase 2

Detailed Description:

This Phase 1/2a, first-in-human (FIH), open-label, dose-escalation study of KO-539, a menin-MLL(KMT2A) inhibitor, will determine the safety and tolerability of escalating doses using a modified toxicity probability interval (mTPI) adaptive design when administered to patients with relapsed and/or refractory AML. If an maximum tolerated dose (MTD) cannot be identified, a recommended phase 2 dose (RP2D) will be determined. A expansion phase in patients with NPM1m and KMT2A-r R/R AML patients is planned following determination of the MTD/RP2D. KO-539 will be administered as a once daily oral dose in 28 continuous day cycles.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2A First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO 539 in Patients With Relapsed or Refractory Acute Myeloid Leukemia
• Actual Study Start Date: September 12, 2019
• Estimated Primary Completion Date: February 1, 2022
• Estimated Study Completion Date: August 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: KO-539; Phase 1 Dose escalation - R/R AML Phase 2A Dose Expansion Cohort 1- KMT2Ar R/R AML Cohort 2- NPM1m R/R AML	Drug: KO-539; Oral administration

Outcome Measures

Primary Outcome Measures :

1. To determine the maximal tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML) [ Time Frame: DLTs will be evaluated during the first 28 days (1 cycle) of KO-539 mono-therapy ]
   MTD is defined as the highest dose that is not expected to cause dose limiting toxicity (DLT) in more than 20% of patients.

Secondary Outcome Measures :

1. Number of patients that experience Adverse Events (AEs) and Serious Adverse Events (SAEs). [ Time Frame: During treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. ]
   Adverse Events (AEs) and Serious Adverse Events (SAEs) will be graded according to the NCI-CTCAE v5.01.
2. Early evidence of antileukemic activity according to 2017 European Leukemia Network (ELN) [ Time Frame: Up to 6 months following end of treatment. ]

   Key Secondary:

   • Complete remission (CR) with and without minimal residual disease (MRD)
   • Complete remission with incomplete hematology recovery (CRi)
   • Duration of remission (DOR) at 6 months
3. Time to reach maximum observed concentration (Tmax). [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
   Determine Tmax of KO-539.
4. Area under plasma-concentration time curve from time 0 to time of last quantifiable concentration (AUC(0-last)). [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
   Determine AUC(0-last) of KO-539.
5. Maximum observed plasma concentration (Cmax) of KO-539. [ Time Frame: Blood samples for determination of KO-539 concentration will be collected in Cycle 1 and Cycle 2. Each cycle is 28 days. ]
   Determine Cmax of KO-539.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Refractory or relapsed AML defined as the reappearance of > 5% blasts in the bone marrow and who have failed or are ineligible for any approved standard of care therapies, including HSCT.
2. ≥ 18 years of age.
3. Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures including serial bone marrow and peripheral blood sampling.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
5. Adequate liver and kidney function
6. Hydroxyurea will be allowed prior to enrollment and after the start of KO-539 to control and maintain peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients can continue on hydroxyurea through Cycle 1 Day 28 or until first disease assessment. After which, patients should be titrated off therapy.
7. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial and for at least 28 days or hematologic recovery whichever is longest after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.

Exclusion Criteria:

1. Patient has a diagnosis of acute promyelocytic leukemia.
2. Patient has a diagnosis of chronic myelogenous leukemia in blast crisis.
3. Donor lymphocyte infusion < 30 days prior to study entry.
4. WBC count > 30,000/mm3.
5. Clinically active central nervous system (CNS) leukemia.
6. Patients who have undergone HSCT and have not had adequate hematologic recovery (i.e. ANC >1000 and platelet count > 100K) or patients on immunosuppressive therapy post HSCT at the time of screening (must be off all immunosuppression therapy for at least 2 weeks), or with Grade > 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity. The use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted with Medical Monitor approval.
7. Patient has received chemotherapy immunotherapy, or 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 KO-539 or within 5 drug half-lives (whichever is longer) prior to the first dose of study drug. Patients must have recovered to NCI CTCAE v. 5.01 ≤ Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator.
8. Patient requires treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4) 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.
9. Patient has a known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection.
10. Patient has a 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).
11. Patient has an active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
12. 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.
13. Mean QTcF >480 ms on triplicate electrocardiograms (ECGs) performed within 5 minutes of each other as a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause torsades de pointes, https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.
14. Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
15. Underlying medical condition that, in the Principal Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).
16. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
17. Known alcohol or drug abuse or dependence.

Contacts and Locations

Contacts

Contact: Diana Hummel; 617-588-2609; dhummel@kuraoncology.com

Contact: Bridget Martell, MD; 858-500-8852; bridget@kuraoncology.com

Locations

United States, Illinois

Northwestern University; Recruiting

Chicago, Illinois, United States, 40411

Contact jillian.weeks@northwestern.edu

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Christine Connolly CCONNOLLY1@mgh.harvard.edu

United States, Michigan

University of Michigan Hospitals; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact 800-865-1125 canceranswerline@med.umich.edu

United States, New York

Roswell Park Comprehensive Cancer Center; Recruiting

Buffalo, New York, United States, 14263

Contact askroswell@roswellpark.org

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Rachel Abramowicz rrabramo@mdanderson.org

United States, Washington

Fred Hutchinson Cancer Research Center; Recruiting

Seattle, Washington, United States, 98109

Contact: Kaysey Orlowski korlowsk@fredhutch.org

France

Hopital Saint Louis; Recruiting

Paris, France, 75475

Institut Gustave Roussy; Recruiting

Villejuif, France, 94800

Sponsors and Collaborators

Kura Oncology, Inc.

More Information

• Responsible Party: Kura Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT04067336
• Other Study ID Numbers: KO-MEN-001
• First Posted: August 26, 2019
• Last Update Posted: January 19, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kura Oncology, Inc.:

AML; Hematological malignancy; KMT2A; NPM1; Menin; MLLr; Leukemia; Acute Leukemia

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute; Acute Disease; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Pathologic Processes; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases