TL-895 and KRT-232 Study in Acute Myeloid Leukemia

Phase 1

Active, not recruiting

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: TL-895; Drug: KRT-232

• Registration Number: NCT04669067
• Lead Sponsor: Telios Pharma, Inc.

Brief Summary

This study evaluates TL-895, a potent, orally available and highly selective irreversible tyrosine kinase inhibitor combined with navtemadlin (KRT-232), a novel oral small molecule inhibitor of MDM2 for the treatment of adults with FLT3 mutated Acute Myeloid Leukemia. Participants must be relapsed/refractory (e.g., having failed prior therapy) to be eligible for this study.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-12-02
• Study First Submitted QC: 2020-12-10
• Study First Posted: 2020-12-16
• Study Start: 2021-03-31
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-15
• Last Update Posted: 2023-02-17
• Primary Completion: 2024-11
• Study Completion: 2025-11

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

• TP53 wildtype AML
• Relapsed/Refractory to at least one prior therapy, one of which must have included a FLT-3 inhibitor
• FLT3 mutation (FLT3-TKD or FLT3-ITD)
• ECOG 0-2
• Adequate hematologic, hepatic, and renal functions

Exclusion Criteria

• AML subtype 3
• Prior treatment with MDM2 antagonist therapies
• Eligible for HSCT

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 2 - Dose Expansion	KRT-232	Dose expansion of the recommended phase 2 dose of TL-895 in combination with KRT-232 as determined in Phase 1b.
Phase 1b - Dose Level 1	KRT-232	KRT-232 240mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 2	KRT-232	KRT-232 300mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 3	KRT-232	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 150 mg BID continuously for the first 28-day cycle Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 150 mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 4	KRT-232	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 300 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 300 mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 5	KRT-232	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 450 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 450 mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 1	TL-895	KRT-232 240mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 2	TL-895	KRT-232 300mg QD, orally administered on days 1 through 7 of each 28-day cycle in combination with TL-895 150mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 3	TL-895	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 150 mg BID continuously for the first 28-day cycle Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 150 mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 4	TL-895	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 300 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 300 mg BID continuously for each 28-day cycle.
Phase 1b - Dose Level 5	TL-895	Cycle 1 only: KRT-232 360 mg QD orally administered on Days 1 through 7 of the first 28-day cycle in combination with TL-895 450 mg BID continuously for the first 28-day cycle. Cycle 2 and beyond: KRT-232 300 mg QD orally administered on Days 1 through 7 of each 28-day cycle in combination with TL-895 450 mg BID continuously for each 28-day cycle.
Phase 2 - Dose Expansion	TL-895	Dose expansion of the recommended phase 2 dose of TL-895 in combination with KRT-232 as determined in Phase 1b.

Primary Outcome Measures

Name	Time	Method
Primary Objective, Phase 2: To determine the rates of complete remission (CR) and complete remission with partial hematologic recovery (CRh)	41 months	The proportion of subjects who achieved CR or CRh as their best response based on the Modified 2017 European LeukemiaNet (ELN) Response Criteria (Appendix 4).
Primary Objective, Phase 1b: To determine the MTD/MAD and recommended Phase 2 dose (RP2D) of TL-895 in combination with KRT-232	13 months	Dose limiting toxicities will be used to established the MTD/MAD of TL-895 combined with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL-895 and KRT-232.

Secondary Outcome Measures

Name	Time	Method
Key Secondary Objective: To determine the overall response rate (ORR)	41 months	The proportion of subjects who achieve PR or better.
Key Secondary Objective: To determine the duration of CR/CRh response (DOR)	41 months	Median DOR (Kaplan-Meier estimate) defined as the time from first observation of CR/CRh to relapse or death from any cause, whichever occurs first. Subjects with MLFS by bone marrow biopsy performed earlier in the course of therapy who convert to CR or CRh do not require a separate bone marrow aspirate at the time of CR or CRh to document this.

Trial Locations

Locations (35)

Keck School of Medicine; 🇺🇸 Los Angeles, California, United States

University of California, Irvine Medical Center; 🇺🇸 Orange, California, United States

Georgia Cancer Center; 🇺🇸 Augusta, Georgia, United States

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

Rush University Medical Center, Division of Hematology Oncology and Cell Therapy; 🇺🇸 Chicago, Illinois, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Weill Cornell Medical College; 🇺🇸 New York, New York, United States

University of Cincinnati; 🇺🇸 Cincinnati, Ohio, United States

Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization; 🇺🇸 Philadelphia, Pennsylvania, United States

UT Southwestern Medical Center, Harold C. Simmons Cancer Center; 🇺🇸 Dallas, Texas, United States

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