KRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF

Sponsor

Kartos Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04640532

Collaborator

Telios Pharma, Inc. (Industry)

116

Enrollment

Locations

Arms

56.2

Anticipated Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluates KRT-232 in Combination With TL-895 for the Treatment of Relapsed or Refractory Myelofibrosis and KRT-232 for the Treatment of JAK Inhibitor Intolerant Myelofibrosis.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis Post-PV MF Post-ET Myelofibrosis Primary Myelofibrosis	Drug: KRT-232 Drug: TL-895	Phase 1/Phase 2

Detailed Description

Cohorts 1 and 2 will undergo dose finding and dose expansion. Eligible patients will be randomly assigned to an open cohort, either Cohort 1 or Cohort 2. Cohort 3 will be conducted as a dose expansion, independent of Cohorts 1 and 2.

Cohort 1 will follow a 3+3 dose escalation design to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of TL-895 administered QD in combination with KRT-232. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.

Cohort 2 will follow a 3+3 dose escalation design to determine the MTD/MAD and recommended RP2D of TL-895 administered BID in combination with KRT-232. An SRC will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.

Cohort 3 will be conducted a 2-stage design. In stage 1, enrollment will continue until 15 evaluable patients have been enrolled. An SRC will review the data during the study and if there are ≥4 responders based on the futility criteria and safety data from Stage 1, Cohort 3 expansion will commence. If there are ≤3 patients responding to therapy, Cohort 3 will be terminated. Once expansion criteria have been met, Cohort 3 will be expanded to a total of 46 evaluable patients for Stage 2 analyses.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

116 participants

Allocation:

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 KRT-232 in Combination With TL-895 for the Treatment of Relapsed or Refractory Myelofibrosis and KRT-232 for the Treatment of JAK Inhibitor Intolerant Myelofibrosis.

Actual Study Start Date :

Nov 17, 2020

Anticipated Primary Completion Date :

May 11, 2022

Anticipated Study Completion Date :

Jul 24, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 (R/R MF), Dose Level 1 TL-895 at 200 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.	Drug: KRT-232 KRT-232, administered by mouth Drug: TL-895 TL-895, administered by mouth
Experimental: Cohort 1 (R/R MF), Dose Level 2 TL-895 at 300 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.	Drug: KRT-232 KRT-232, administered by mouth Drug: TL-895 TL-895, administered by mouth
Experimental: Cohort 2 (R/R MF), Dose Level 1 TL-895 at 100 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.	Drug: KRT-232 KRT-232, administered by mouth Drug: TL-895 TL-895, administered by mouth
Experimental: Cohort 2 (R/R MF), Dose Level 2 TL-895 at 150 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.	Drug: KRT-232 KRT-232, administered by mouth Drug: TL-895 TL-895, administered by mouth
Experimental: Cohort 3 (JAKi Intolerant MF) KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.	Drug: KRT-232 KRT-232, administered by mouth

Outcome Measures

Primary Outcome Measures

Phase 1b - The MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2) [56 Days]
DLTs will be used to establish the MTD. RP2D will be determined by the SRC based on safety data from the combination of TL-895 and KRT-232.
Phase 2 - Spleen response rate for each cohort [24 Weeks]
A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24

Secondary Outcome Measures

Total Symptom Score (TSS) [24 Weeks]
The change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, (WHO 2016)
ECOG ≤ 2
Cohort 1 and Cohort 2: R/R following JAK inhibitor treatment
Cohort 3: patients who are intolerant to JAK inhibitor treatment

Exclusion Criteria:

Prior treatment with MDM2 inhibitors or p53-directed therapies
Prior treatment with a BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor
Prior splenectomy
Splenic irradiation within 3 months prior to the first dose of study treatment
Clinically significant thrombosis within 3 months of screening
Grade 2 or higher QTc prolongation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham School of Medicine, Division of Hematology and Oncology	Birmingham	Alabama	United States	35233
2	The Oncology Institute of Hope	Whittier	California	United States	90603
3	Lake City Cancer Center	Lake City	Florida	United States	32024
4	Carle Cancer Center	Urbana	Illinois	United States	61801
5	Columbia University Medical Center	Fort Lee	New Jersey	United States	07024
6	Memorial Sloan Kettering Cancer Center (MSKCC)	New York	New York	United States	10065
7	LKH Hochsteiermark	Leoben		Austria	8700
8	Meduni Wien, Univ. Klinik für Innere Medizin I	Wien		Austria	1090
9	University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven	Pleven		Bulgaria	5800
10	University Multiprofile Hospital for Active Treatment Dr. Georgi Plovdiv	Plovdiv		Bulgaria	4002
11	Hematology Clinic Specialized Hospital for Active Treatment of Hematological Diseases, Sofia	Sofia		Bulgaria	1756
12	Chu Amiens Picardie Site Sud	Amiens		France	80054
13	CHU de Limoges Service Hématologie Clinique et Thérapie Cellulaire	Limoges		France	87042
14	CHU Nantes - Hôtel Dieu	Nantes		France	44093
15	CHU de Nice Hospital	Nice		France	06200
16	Hôpital Saint Louis	Paris		France	75475
17	Centre Hospitalier Lyon Sud	Pierre-Bénite		France	63310
18	University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology	Halle		Germany	06120
19	University Hospital Marburg, Department of Hematology, Oncology and Immunology	Marburg		Germany	35043
20	Moritz Kaposi General Hospital, Department of Hematology	Kaposvár		Hungary	H-7400
21	Szabolcs-Szatmar-Bereg County Hospitals and University Teaching Hospital, Department of Hematology	Nyíregyháza		Hungary	H-4400
22	Medical Center of the University of Pecs, 1st Department of Internal Medicine, Division of Hematology	Pécs		Hungary	H-7624
23	Fejer County St. Gyorgy University Teaching Hospital, Department of Internal Medicine III, Hematology	Székesfehérvár		Hungary	H-8000
24	Polyclinic S. Orsola-Malpighi	Bologna		Italy	40138
25	ASST Spedali Civili di Brescia	Brescia		Italy	25123
26	Careggi University Hospital	Florence		Italy	50134
27	Hospital Casa Sollievo della Sofferenza, Department of Oncology and Hematology, Division of Hematology	Foggia		Italy	71013
28	Hospital of Ravenna, Operative Unit of Hematology	Ravenna		Italy	48121
29	Jan Biziel University Hospital #2 in Bydgoszcz, Department of Hematology	Bydgoszcz		Poland	85-168
30	Pratia Onkologia Katowice	Katowice		Poland	40-519
31	Frederic Chopin Provincial Teaching Hospital No. 1 in Rzeszow, Department of Hematology	Rzeszów		Poland	35-055
32	Slupsk Provincial Specialist Hospital n.a. Janusz Korczak, Department of Hematology	Słupsk		Poland	76-200
33	Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka	Toruń		Poland	87-100
34	Clinical Center of Serbia	Belgrade		Serbia	11000
35	Clinical Center of Vojvodina	Novi Sad		Serbia	21000
36	Hematologia Clínica	Barcelona		Spain	08003
37	University Clinical Hospital of Salamanca, Department of Hematology	Salamanca		Spain	37007

Sponsors and Collaborators

Kartos Therapeutics, Inc.
Telios Pharma, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Kartos Therapeutics, Inc.

ClinicalTrials.gov Identifier:

NCT04640532

Other Study ID Numbers:

KRT-232-113

First Posted:

Nov 23, 2020

Last Update Posted:

May 9, 2022

Last Verified:

May 1, 2022

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Kartos Therapeutics, Inc.

Relapsed/Refractory Myelofibrosis

Janus associated Kinase Inhibitor-Intolerant Myelofibrosis

MDM2

navtemadlin

Additional relevant MeSH terms:

Primary Myelofibrosis

Study Results

No Results Posted as of May 9, 2022