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

Sponsor

Telios Pharma, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04669067

Collaborator

Kartos Therapeutics, Inc. (Industry)

Enrollment

Locations

Arms

55.1

Anticipated Duration (Months)

2.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: TL-895 Drug: KRT-232	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined With KRT-232 in Patients With Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia (AML)

Actual Study Start Date :

Mar 31, 2021

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Nov 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b - Dose Level 1 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.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.
Experimental: Phase 1b - Dose Level 2 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.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.
Experimental: Phase 1b - Dose Level 3 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.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.
Experimental: Phase 1b - Dose Level 4 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.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.
Experimental: Phase 1b - Dose Level 5 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.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.
Experimental: Phase 2 - Dose Expansion Dose expansion of the recommended phase 2 dose of TL-895 in combination with KRT-232 as determined in Phase 1b.	Drug: TL-895 TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth. Drug: KRT-232 KRT-232 is an experimental MDM2 inhibitor anticancer drug taken by mouth.

Outcome Measures

Primary Outcome Measures

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.
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).

Secondary Outcome Measures

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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck School of Medicine	Los Angeles	California	United States	90033
2	University of California, Irvine Medical Center	Orange	California	United States	92868
3	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
4	Rush University Medical Center, Division of Hematology Oncology and Cell Therapy	Chicago	Illinois	United States	60612
5	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
6	Weill Cornell Medical College	New York	New York	United States	10065
7	University of Cincinnati	Cincinnati	Ohio	United States	45219
8	Thomas Jefferson University, Sidney Kimmel Cancer Center, Clinical Research Organization	Philadelphia	Pennsylvania	United States	19107
9	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
10	Box Hill Hospital	Melbourne		Australia	3128
11	University of Sunshine Coast-Sippy Downs	Sippy Downs		Australia	4556
12	Westmead Hospital	Sydney		Australia	2145
13	Ordensklinikum Linz GmbH Elisabethinen	Linz		Austria	4020
14	Medical University Vienna, Department of Internal Medicine I, Clinical Department of Hematology and Hemostaseology	Vienna		Austria	1090
15	Claude Huriez Hospital	Lille		France	59037
16	South Lyon Hospital Center	Lyon		France	48178
17	Paoli-Calmettes Institute	Marseille		France	13009
18	University Hospital of Nantes	Nantes		France	44000
19	Hospital Center Universitaire De Nice	Nice		France	06000
20	Saint-Louis Hospital	Paris		France	75010
21	University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology	Halle	Sachsen-Anhalt	Germany	06120
22	University Duisburg-Essen, University Hospital Essen, Department of Internal Medicine	Essen		Germany	45147
23	University Hospital Hamburg-Eppendorf, Department of Internal Medicine II	Hamburg		Germany	20246
24	Hannover Medical School, Center for Internal Medicine, Clinic of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation	Hannover		Germany	30625
25	University Hospital Jena, Clinic of Internal Medicine II, Department of Hematology and Medical Oncology	Jena		Germany	07747
26	University Hospital - Ospedali Riuniti Umberto I - GM Lancisi - G Salesi of Ancona, Haematology Clinic	Ancona		Italy	60126
27	Polyclinic S. Orsola-Malpighi, Operative Unit of Hematology	Bologna		Italy	40138
28	Romagnolo Scientific Institute of Meldola (IRST) S.r.l., Department of Oncology and Clinical and Experimental Haematology	Meldola		Italy	47014
29	Gachon University Gil Medical Center	Incheon		Korea, Republic of	21565
30	Seoul National University Hospital, Department of Hemato-Oncology	Seoul		Korea, Republic of	03080
31	University Hospital Germans Trias i Pujol, Department of Clinical Hematology	Badalona		Spain	08916
32	University Hospital Vall d'Hebron	Barcelona		Spain	08035
33	University Clinical Hospital of Valencia, Department of Hematology and Medical Oncology	Valencia		Spain	46010
34	Hospital Universitario y Politécnico de La Fe	València		Spain	46026