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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

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ClinicalTrials.gov Identifier: NCT04640532
Recruitment Status : Recruiting
First Posted : November 23, 2020
Last Update Posted : November 23, 2020
Sponsor:
Collaborator:
Telios Pharma, Inc.
Information provided by (Responsible Party):
Kartos Therapeutics, Inc.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : November 17, 2020
Estimated Primary Completion Date : May 11, 2022
Estimated Study Completion Date : July 24, 2025


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




Primary Outcome Measures :
  1. Phase 1b - To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2) [ Time Frame: 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.

  2. Phase 2 - To determine the spleen response rate for each cohort [ Time Frame: 24 Weeks ]
    A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24


Secondary Outcome Measures :
  1. Total Symptom Score (TSS) [ Time Frame: 24 Weeks ]
    To determine the change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)



Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04640532


Contacts
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Contact: John Mei 650-542-0136 jmei@kartosthera.com
Contact: Irene Dea (650) 839-7341 idea@kartosthera.com

Locations
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United States, California
The Oncology Institute of Hope Recruiting
Whittier, California, United States, 90603
Contact: S. Tieng       stieng@icrinstitute.com   
Contact: R. Ibrahim       ribrahim@icrinstitute.com   
United States, Florida
Lake City Cancer Center Recruiting
Lake City, Florida, United States, 32024
Contact: J. Endsley       jendsley@ccofnf.com   
Sponsors and Collaborators
Kartos Therapeutics, Inc.
Telios Pharma, Inc.
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Responsible Party: Kartos Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04640532    
Other Study ID Numbers: KRT-232-113
First Posted: November 23, 2020    Key Record Dates
Last Update Posted: November 23, 2020
Last Verified: November 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kartos Therapeutics, Inc.:
Relapsed/Refractory Myelofibrosis
Janus associated Kinase Inhibitor-Intolerant Myelofibrosis
MDM2
Additional relevant MeSH terms:
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Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases