Clinical trial NCT04640532: 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
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myelofibrosis
Post-PV MF
Post-ET Myelofibrosis
Primary Myelofibrosis
Keywords: Relapsed/Refractory Myelofibrosis
Janus associated Kinase Inhibitor-Intolerant Myelofibrosis
MDM2
navtemadlin
Lead sponsor: Kartos Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Telios Pharma, Inc.
First posted: 2020-11-23
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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)
timeFrame: 56 Days
measure: Phase 2 - Spleen response rate for each cohort
timeFrame: 24 Weeks
Secondary outcomes:
measure: Total Symptom Score (TSS)
timeFrame: 24 Weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine, Division of Hematology and Oncology
state: Alabama
city: Whittier
country: United States
facility: The Oncology Institute of Hope
state: California
city: Lake City
country: United States
facility: Lake City Cancer Center
state: Florida
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Fort Lee
country: United States
facility: Columbia University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (MSKCC)
state: New York
city: Leoben
country: Austria
facility: LKH Hochsteiermark
city: Wien
country: Austria
facility: Meduni Wien, Univ. Klinik für Innere Medizin I
city: Pleven
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven
city: Plovdiv
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Dr. Georgi Plovdiv
city: Sofia
country: Bulgaria
facility: Hematology Clinic Specialized Hospital for Active Treatment of Hematological Diseases, Sofia
city: Amiens
country: France
facility: Chu Amiens Picardie Site Sud
city: Limoges
country: France
facility: CHU de Limoges Service Hématologie Clinique et Thérapie Cellulaire
city: Nantes
country: France
facility: CHU Nantes - Hôtel Dieu
city: Nice
country: France
facility: CHU de Nice Hospital
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Halle
country: Germany
facility: University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology
city: Marburg
country: Germany
facility: University Hospital Marburg, Department of Hematology, Oncology and Immunology
city: Kaposvár
country: Hungary
facility: Moritz Kaposi General Hospital, Department of Hematology
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmar-Bereg County Hospitals and University Teaching Hospital, Department of Hematology
city: Pécs
country: Hungary
facility: Medical Center of the University of Pecs, 1st Department of Internal Medicine, Division of Hematology
city: Székesfehérvár
country: Hungary
facility: Fejer County St. Gyorgy University Teaching Hospital, Department of Internal Medicine III, Hematology
city: Bologna
country: Italy
facility: Polyclinic S. Orsola-Malpighi
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Florence
country: Italy
facility: Careggi University Hospital
city: Foggia
country: Italy
facility: Hospital Casa Sollievo della Sofferenza, Department of Oncology and Hematology, Division of Hematology
city: Ravenna
country: Italy
facility: Hospital of Ravenna, Operative Unit of Hematology
city: Bydgoszcz
country: Poland
facility: Jan Biziel University Hospital #2 in Bydgoszcz, Department of Hematology
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
city: Rzeszów
country: Poland
facility: Frederic Chopin Provincial Teaching Hospital No. 1 in Rzeszow, Department of Hematology
city: Słupsk
country: Poland
facility: Slupsk Provincial Specialist Hospital n.a. Janusz Korczak, Department of Hematology
city: Toruń
country: Poland
facility: Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Novi Sad
country: Serbia
facility: Clinical Center of Vojvodina
city: Barcelona
country: Spain
facility: Hematologia Clínica
city: Salamanca
country: Spain
facility: University Clinical Hospital of Salamanca, Department of Hematology
Study officials:
References: