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

Primary Purpose

Myelofibrosis, Post-PV MF, Post-ET Myelofibrosis

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
KRT-232
TL-895
Sponsored by
Kartos Therapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelofibrosis focused on measuring Relapsed/Refractory Myelofibrosis, Janus associated Kinase Inhibitor-Intolerant Myelofibrosis, MDM2, navtemadlin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • University of Alabama at Birmingham School of Medicine, Division of Hematology and OncologyRecruiting
  • The Oncology Institute of HopeRecruiting
  • Lake City Cancer CenterRecruiting
  • Carle Cancer CenterRecruiting
  • Columbia University Medical CenterRecruiting
  • Memorial Sloan Kettering Cancer Center (MSKCC)Recruiting
  • LKH HochsteiermarkRecruiting
  • Meduni Wien, Univ. Klinik für Innere Medizin IRecruiting
  • University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, PlevenRecruiting
  • University Multiprofile Hospital for Active Treatment Dr. Georgi PlovdivRecruiting
  • Hematology Clinic Specialized Hospital for Active Treatment of Hematological Diseases, SofiaRecruiting
  • Chu Amiens Picardie Site SudRecruiting
  • CHU de Limoges Service Hématologie Clinique et Thérapie CellulaireRecruiting
  • CHU Nantes - Hôtel DieuRecruiting
  • CHU de Nice HospitalRecruiting
  • Hôpital Saint LouisRecruiting
  • Centre Hospitalier Lyon SudRecruiting
  • University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and OncologyRecruiting
  • University Hospital Marburg, Department of Hematology, Oncology and ImmunologyRecruiting
  • Moritz Kaposi General Hospital, Department of HematologyRecruiting
  • Szabolcs-Szatmar-Bereg County Hospitals and University Teaching Hospital, Department of HematologyRecruiting
  • Medical Center of the University of Pecs, 1st Department of Internal Medicine, Division of HematologyRecruiting
  • Fejer County St. Gyorgy University Teaching Hospital, Department of Internal Medicine III, HematologyRecruiting
  • Polyclinic S. Orsola-MalpighiRecruiting
  • ASST Spedali Civili di BresciaRecruiting
  • Careggi University HospitalRecruiting
  • Hospital Casa Sollievo della Sofferenza, Department of Oncology and Hematology, Division of HematologyRecruiting
  • Hospital of Ravenna, Operative Unit of HematologyRecruiting
  • Jan Biziel University Hospital #2 in Bydgoszcz, Department of HematologyRecruiting
  • Pratia Onkologia KatowiceRecruiting
  • Frederic Chopin Provincial Teaching Hospital No. 1 in Rzeszow, Department of HematologyRecruiting
  • Slupsk Provincial Specialist Hospital n.a. Janusz Korczak, Department of HematologyRecruiting
  • Nasz Lekarz Medical Outpatient Clinics Slawomir JekaRecruiting
  • Clinical Center of SerbiaRecruiting
  • Clinical Center of VojvodinaRecruiting
  • Hematologia ClínicaRecruiting
  • University Clinical Hospital of Salamanca, Department of HematologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1 (R/R MF), Dose Level 1

Cohort 1 (R/R MF), Dose Level 2

Cohort 2 (R/R MF), Dose Level 1

Cohort 2 (R/R MF), Dose Level 2

Cohort 3 (JAKi Intolerant MF)

Arm Description

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.

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.

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.

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.

KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.

Outcomes

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)
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
A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24

Secondary Outcome Measures

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

Full Information

First Posted
November 17, 2020
Last Updated
May 5, 2022
Sponsor
Kartos Therapeutics, Inc.
Collaborators
Telios Pharma, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04640532
Brief Title
KRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF
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.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 17, 2020 (Actual)
Primary Completion Date
May 11, 2022 (Anticipated)
Study Completion Date
July 24, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kartos Therapeutics, Inc.
Collaborators
Telios Pharma, Inc.

4. Oversight

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

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelofibrosis, Post-PV MF, Post-ET Myelofibrosis, Primary Myelofibrosis
Keywords
Relapsed/Refractory Myelofibrosis, Janus associated Kinase Inhibitor-Intolerant Myelofibrosis, MDM2, navtemadlin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
116 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1 (R/R MF), Dose Level 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 1 (R/R MF), Dose Level 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2 (R/R MF), Dose Level 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2 (R/R MF), Dose Level 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 3 (JAKi Intolerant MF)
Arm Type
Experimental
Arm Description
KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle.
Intervention Type
Drug
Intervention Name(s)
KRT-232
Intervention Description
KRT-232, administered by mouth
Intervention Type
Drug
Intervention Name(s)
TL-895
Intervention Description
TL-895, administered by mouth
Primary Outcome Measure Information:
Title
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)
Description
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.
Time Frame
56 Days
Title
Phase 2 - Spleen response rate for each cohort
Description
A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24
Time Frame
24 Weeks
Secondary Outcome Measure Information:
Title
Total Symptom Score (TSS)
Description
The change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)
Time Frame
24 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
John Mei
Phone
650-542-0136
Email
jmei@kartosthera.com
First Name & Middle Initial & Last Name or Official Title & Degree
Irene Dea
Phone
(650) 839-7341
Email
idea@kartosthera.com
Facility Information:
Facility Name
University of Alabama at Birmingham School of Medicine, Division of Hematology and Oncology
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Individual Site Status
Recruiting
Facility Name
The Oncology Institute of Hope
City
Whittier
State/Province
California
ZIP/Postal Code
90603
Country
United States
Individual Site Status
Recruiting
Facility Name
Lake City Cancer Center
City
Lake City
State/Province
Florida
ZIP/Postal Code
32024
Country
United States
Individual Site Status
Recruiting
Facility Name
Carle Cancer Center
City
Urbana
State/Province
Illinois
ZIP/Postal Code
61801
Country
United States
Individual Site Status
Recruiting
Facility Name
Columbia University Medical Center
City
Fort Lee
State/Province
New Jersey
ZIP/Postal Code
07024
Country
United States
Individual Site Status
Recruiting
Facility Name
Memorial Sloan Kettering Cancer Center (MSKCC)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Name
LKH Hochsteiermark
City
Leoben
ZIP/Postal Code
8700
Country
Austria
Individual Site Status
Recruiting
Facility Name
Meduni Wien, Univ. Klinik für Innere Medizin I
City
Wien
ZIP/Postal Code
1090
Country
Austria
Individual Site Status
Recruiting
Facility Name
University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven
City
Pleven
ZIP/Postal Code
5800
Country
Bulgaria
Individual Site Status
Recruiting
Facility Name
University Multiprofile Hospital for Active Treatment Dr. Georgi Plovdiv
City
Plovdiv
ZIP/Postal Code
4002
Country
Bulgaria
Individual Site Status
Recruiting
Facility Name
Hematology Clinic Specialized Hospital for Active Treatment of Hematological Diseases, Sofia
City
Sofia
ZIP/Postal Code
1756
Country
Bulgaria
Individual Site Status
Recruiting
Facility Name
Chu Amiens Picardie Site Sud
City
Amiens
ZIP/Postal Code
80054
Country
France
Individual Site Status
Recruiting
Facility Name
CHU de Limoges Service Hématologie Clinique et Thérapie Cellulaire
City
Limoges
ZIP/Postal Code
87042
Country
France
Individual Site Status
Recruiting
Facility Name
CHU Nantes - Hôtel Dieu
City
Nantes
ZIP/Postal Code
44093
Country
France
Individual Site Status
Recruiting
Facility Name
CHU de Nice Hospital
City
Nice
ZIP/Postal Code
06200
Country
France
Individual Site Status
Recruiting
Facility Name
Hôpital Saint Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Individual Site Status
Recruiting
Facility Name
Centre Hospitalier Lyon Sud
City
Pierre-Bénite
ZIP/Postal Code
63310
Country
France
Individual Site Status
Recruiting
Facility Name
University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology
City
Halle
ZIP/Postal Code
06120
Country
Germany
Individual Site Status
Recruiting
Facility Name
University Hospital Marburg, Department of Hematology, Oncology and Immunology
City
Marburg
ZIP/Postal Code
35043
Country
Germany
Individual Site Status
Recruiting
Facility Name
Moritz Kaposi General Hospital, Department of Hematology
City
Kaposvár
ZIP/Postal Code
H-7400
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Szabolcs-Szatmar-Bereg County Hospitals and University Teaching Hospital, Department of Hematology
City
Nyíregyháza
ZIP/Postal Code
H-4400
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Medical Center of the University of Pecs, 1st Department of Internal Medicine, Division of Hematology
City
Pécs
ZIP/Postal Code
H-7624
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Fejer County St. Gyorgy University Teaching Hospital, Department of Internal Medicine III, Hematology
City
Székesfehérvár
ZIP/Postal Code
H-8000
Country
Hungary
Individual Site Status
Recruiting
Facility Name
Polyclinic S. Orsola-Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Individual Site Status
Recruiting
Facility Name
ASST Spedali Civili di Brescia
City
Brescia
ZIP/Postal Code
25123
Country
Italy
Individual Site Status
Recruiting
Facility Name
Careggi University Hospital
City
Florence
ZIP/Postal Code
50134
Country
Italy
Individual Site Status
Recruiting
Facility Name
Hospital Casa Sollievo della Sofferenza, Department of Oncology and Hematology, Division of Hematology
City
Foggia
ZIP/Postal Code
71013
Country
Italy
Individual Site Status
Recruiting
Facility Name
Hospital of Ravenna, Operative Unit of Hematology
City
Ravenna
ZIP/Postal Code
48121
Country
Italy
Individual Site Status
Recruiting
Facility Name
Jan Biziel University Hospital #2 in Bydgoszcz, Department of Hematology
City
Bydgoszcz
ZIP/Postal Code
85-168
Country
Poland
Individual Site Status
Recruiting
Facility Name
Pratia Onkologia Katowice
City
Katowice
ZIP/Postal Code
40-519
Country
Poland
Individual Site Status
Recruiting
Facility Name
Frederic Chopin Provincial Teaching Hospital No. 1 in Rzeszow, Department of Hematology
City
Rzeszów
ZIP/Postal Code
35-055
Country
Poland
Individual Site Status
Recruiting
Facility Name
Slupsk Provincial Specialist Hospital n.a. Janusz Korczak, Department of Hematology
City
Słupsk
ZIP/Postal Code
76-200
Country
Poland
Individual Site Status
Recruiting
Facility Name
Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka
City
Toruń
ZIP/Postal Code
87-100
Country
Poland
Individual Site Status
Recruiting
Facility Name
Clinical Center of Serbia
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Individual Site Status
Recruiting
Facility Name
Clinical Center of Vojvodina
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia
Individual Site Status
Recruiting
Facility Name
Hematologia Clínica
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Individual Site Status
Recruiting
Facility Name
University Clinical Hospital of Salamanca, Department of Hematology
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Individual Site Status
Recruiting

12. IPD Sharing Statement

Learn more about this trial

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

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