Clinical trial NCT03662126: KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
Official title: A Phase 2/3 Randomized, Controlled, Open-Label Study of KRT 232 in Subjects With Primary Myelofibrosis (PMF), Post Polycythemia Vera MF (Post-PV-MF), Or Post Essential Thrombocythemia MF (Post-ET-MF) Who Are Relapsed or Refractory to Janus Kinase (JAK) Inhibitor Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Primary Myelofibrosis (PMF)
Post-Polycythemia Vera MF (Post-PV-MF)
Post-Essential Thrombocythemia MF (Post-ET-MF)
Keywords: navtemadlin
Lead sponsor: Kartos Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-09-07
Enrollment: 385
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.

This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.


Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of PMF, post-PV MF or post-ET MF (WHO)
* High, intermediate-2, or intermediate-1 risk Dynamic International Prognostic System (DIPSS)
* Failure of prior treatment with JAK inhibitor
* ECOG ≤ 2

Exclusion Criteria:

* Prior splenectomy
* Splenic irradiation within 3 months prior to randomization
* History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
* History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization
* Prior MDM2 inhibitor therapy or p53-directed therapy
* Prior allogeneic stem-cell transplant or plans for allogeneic stem cell transplant
* History of major organ transplant
* Grade 2 or higher QTc prolongation (\> 480 milliseconds per NCI-CTCAE criteria, version 5.0)

Primary outcomes:
measure: (Part A Only) Spleen Volume Reduction (SVR)
timeFrame: 24 weeks
measure: (Part B Only) Spleen Volume Reduction (SVR)
timeFrame: 24 Weeks
Secondary outcomes:
measure: (Part A only) Improvement in Total Symptom Score (TSS)
timeFrame: 48 weeks
measure: (Part B only) Improvement of Total Symptom Score (TSS)
timeFrame: 24 Weeks
measure: (Part B only) Overall Survival (OS)
timeFrame: 48 months
measure: (Part B only) Progression free survival (PFS)
timeFrame: 48 months
measure: (Part B Only) Overall Spleen Volume Reduction (SVR)
timeFrame: 48 months
measure: (Part B Only) Spleen Response Duration
timeFrame: 48 months
measure: (Part B Only) Rate of conversion from RBC transfusion dependent to independent
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Kirklin Clinic of UAB Hospital
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California Norris Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center - Palo Alto
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Boynton Beach
country: United States
facility: University Cancer Institute
state: Florida
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Brooklyn
country: United States
facility: Brookdale University Hospital and Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian/Weill Cornell Medical Center
state: New York
city: New York
country: United States
facility: Mt. Sinai
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin - Froedtert Hospital
state: Wisconsin
city: Rosario
country: Argentina
facility: Sanatorio de la Mujer
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Instituto Medico Alexander Fleming
city: Caba
country: Argentina
facility: Centro Medico San Luis
city: Córdoba
country: Argentina
facility: Hospital Privado - Centro Medico de Cordoba - Oncology
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hosital
state: Western Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Noble Park
country: Australia
facility: South Eastern Private Hospital
city: South Brisbane
country: Australia
facility: Icon Cancer Center
city: Fortaleza
country: Brazil
facility: Centro de oncologia Leonardo da Vinci
state: Ceara
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: Parana
city: Campinas
country: Brazil
facility: UNICAMP - Universidade Estadual de Campinas Hemocentro
state: São Paulo
city: Goiânia
country: Brazil
facility: Hospital das Clínicas UFG
city: Jau
country: Brazil
facility: Fundacao Doutor Amaral Carvalho
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre - Centro de Pesquisa Clinica
city: Porto Alegre
country: Brazil
facility: Associação Educadora São Carlos AESC - Hospital Mãe de Deus - Centro de Pesquisa
city: Sao Paulo
country: Brazil
facility: Instituto de Ensino e Pesquisa São Lucas
city: Sao Paulo
country: Brazil
facility: Hospital A C Camargo - Fundacao Antonio Prudente
city: Sao Paulo
country: Brazil
facility: Hospital das Clínicas da Universidade de São Paulo
city: São Paulo
country: Brazil
facility: Instituto D'or de Pesquisa e Ensino
city: São Paulo
country: Brazil
facility: Instituto COI São Paulo
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 Sveti Georgi, Plovdiv
city: Sofia
country: Bulgaria
facility: Military Medical Academy, Multiprofile for active treatment, Sofia
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic Tokuda Hospital, Sofia
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Therapy of Hematological Disorders
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Alexandrovska, Sofia
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment Saint Ivan Rilski, Sofia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Sibenik
country: Croatia
facility: General Hospital Sibenik
city: Zagreb
country: Croatia
facility: Clinical Hospital Centre Osijek
city: Zagreb
country: Croatia
facility: KB Sestre Milosrdnice
city: Králová
country: Czechia
facility: FN Hradec Kralove
city: Nové Město
country: Czechia
facility: Vseonecma fakultni nemocrince V Praze
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Amiens
country: France
facility: Centre Hospitalier Universitaire D'Amiens (Hopital Sud) - Hématologie Clinique
city: Angers
country: France
facility: Center Hospitalier Universitaire d'Angers
city: Bayonne
country: France
facility: C.H de la Côte Basque - Serviv
city: Brest Cedex
country: France
facility: Centre Hospitalier Regional Universitaire Brest Hopital Morvan
city: Caen
country: France
facility: Centre Hospitalier Universitaire of Caen Normandie - Côte de Nacre
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
city: Nîmes
country: France
facility: Centre Hospitalier Universitaire de Nîmes
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
city: Villejuif
country: France
facility: Hopital Paul Brousse - Aphp Hôpitaux Universitaires Paris Su
city: München
country: Germany
facility: Klinikum Rechts der Isar der Technischen Universität München Apotheke
state: Bayern
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein-Westfalen
city: Halle
country: Germany
facility: Universitätsklinikum Halle
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Haematologie - Onkologie - Hauptstelle
state: Sachsen
city: Dresden
country: Germany
facility: Technische Universität Dresden
state: Sachsen
city: Jena
country: Germany
facility: Universitätsklinikum Jena
state: Thuringen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: UKE - Universitätsklinikum Hamburg-Eppendorf
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg Universität Mainz
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Saarbrücken
country: Germany
facility: Praxis für Hämatologie und Onkologie
city: Ioánnina
country: Greece
facility: University General Hospital of Ioannina
state: Ioannina
city: Patras
country: Greece
facility: University Campus of Patras - Hematology
city: Thessaloníki
country: Greece
facility: AHEPA General Hospital of Thessaloniki
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital - Medicine
city: Kaposvár
country: Hungary
facility: Somogy Megyei Kaposi Mór Oktató Kórház
state: Somogy
city: Nyíregyháza
country: Hungary
facility: Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház
state: Szabolcs-Szatmar-Bereg
city: Szombathely
country: Hungary
facility: Markusovszky Egyetemi Oktatókórház
state: Vas
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem
city: Afula
country: Israel
facility: Ha'Emek Medical Center
city: Ashdod
country: Israel
facility: Assuta Ashdod University Hospital
city: Haifa
country: Israel
facility: Rambam Medical Centre
city: Haifa
country: Israel
facility: Carmel MC
city: Jerusalem
country: Israel
facility: Hadassah Medical Organisation
city: Kfar Saba
country: Israel
facility: Hematology Institute
city: Nahariya
country: Israel
facility: Western Galilee Hospital - Nahariya
city: Petah Tikva
country: Israel
facility: Rabin Medical Center - Beilinson Hospital
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center - Oncology
city: Tel Aviv
country: Israel
facility: Assuta MC
city: Zerifin
country: Israel
facility: Assaf Harofeh Medical Center - Hematology
city: Monza
country: Italy
facility: A.O. San Gerardo di Monza - L'Ospedale San Gerardo di Monza e l'Università di Milano
state: Lombardia
city: Alessandria
country: Italy
facility: PO Civile SS.Antonio e Biagio
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi
city: Bologna
country: Italy
facility: A.O.di Bologna Policl.S.Orsola
city: Brescia
country: Italy
facility: AO Spedali Civili di Brescia
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico - Vittorio Emanuele
city: Firenze
country: Italy
facility: AOU Careggi
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST IRCCS
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Novara
country: Italy
facility: AOU Maggiore della Carità
city: Pesaro
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Marche Nord - Pesaro
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova, AO di Reggio Emilia
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Torino
country: Italy
facility: A.O. Citta della Salute e della Scienza di Torino
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas
city: Monterrey
country: Mexico
facility: Universidad Autonoma de Nuevo Leon (UANL) - Hospital Universitario "Dr. Jose Eleuterio Gonzalez
state: Nuevo Leon
city: Monterrey
country: Mexico
facility: Instituto Mexicano del Seguro Social
city: Oaxaca
country: Mexico
facility: Oaxaca Site Management Organization OSMO
city: Veracruz
country: Mexico
facility: Sociedad de Metabolismo y Corazón S.C. - Oncology
city: Cebu City
country: Philippines
facility: Perpetual Succour Hospital - Hemat/Transfusion Med
city: Manila
country: Philippines
facility: University of the Philippines - Philippine General Hospital
city: Wrocław
country: Poland
facility: Dolnośląskie Centrum Transplantacji Komórkowych z Krajowym Bankiem Dawców Szpiku
state: Dolnoslaskie
city: Brzozow
country: Poland
facility: Szpital Specjalistyczny w Brzozowie Podkarpacki Ośrodek Onkologiczny im. Ks. B. Markiewicza
state: Podkarpackie
city: Chorzów
country: Poland
facility: Samodzielny Publiczny Zakład Opieki Zdrowotnej Zespół Szpitali Miejskich
state: Slaskie
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im dr. Jana Biziela
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
city: Olsztyn
country: Poland
facility: SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii
city: Opole
country: Poland
facility: Szpital Wojewódzki w Opolu
city: Poznań
country: Poland
facility: Clinical Research Center Spółka z Ograniczoną Odpowiedzialnością Medic-R sp. k.
city: Słupsk
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.
city: Aveiro
country: Portugal
facility: H. Infante Dom Pedro. Centro Hospitalar do Baixo Vouga
city: Braga
country: Portugal
facility: Hospital de Braga
city: Coimbra
country: Portugal
facility: Instituto Português de Oncologia de Coimbra
city: Lisboa
country: Portugal
facility: H. São Francisco Xavier-Centro Hospitalar Lisboa Ocidental
city: Lisbon
country: Portugal
facility: Champalimaud Cancer Center
city: Brasov
country: Romania
facility: Cen Med de Diagn si Trat Amb NEOMED
city: Bucharest
country: Romania
facility: Spitalul Clinic Colentina
city: Bucuresti
country: Romania
facility: Spitalul Clinic Coltea
city: Bucuresti
country: Romania
facility: Medicover
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic "Prof. Dr. Ion Chiricuta"
city: Craiova
country: Romania
facility: Spitalul Clinic Municipal Filantropia Craiova
city: Iaşi
country: Romania
facility: Institutul Regional de Oncologie Iasi
city: Timişoara
country: Romania
facility: Spitalul Clinic Municipal de Urgenta Timisoara
city: Timişoara
country: Romania
facility: Oncomed
city: Târgu-Mureş
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Tg Mures
city: Omsk
country: Russian Federation
facility: Clinical oncological dispensary
city: St Petersburg
country: Russian Federation
facility: Saint-Petersburg SMU I.P.Pavlov
city: Syktyvkar
country: Russian Federation
facility: Oncologic dispensary of Komi Republic
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Doctor Negrin
state: Las Palmas
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital de La Santa Creu i Sant Pau
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra - H. de Navarra, Hematología C/ de Irunlarrea, 3, Pamplona
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario Doctor Peset
city: Zaragoza
country: Spain
facility: H. Quirón Zaragoza
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
state: Taipei
city: Chiayi City
country: Taiwan
facility: Chang Gung Medical Foundation - ChiaYi Chang Gung Memorial Hospital - Chiayi Branch
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University - Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital - Mahidol University - Hematology
city: Bangkok
country: Thailand
facility: Siriraj Hospital
city: Khlong Luang
country: Thailand
facility: Thammasat University Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital (KhonKaen University)
city: Songkhla
country: Thailand
facility: Songklanagarind Hospital
city: Adapazarı
country: Turkey
facility: Sakarya Research and Training Hospital
city: Ankara
country: Turkey
facility: Ankara University Faculty of Medicine
city: Ankara
country: Turkey
facility: Gazi University Medical Faculty
city: Denizli
country: Turkey
facility: Pamukkale University
city: Gaziantep
country: Turkey
facility: Gaziantep University Faculty of Medicine
city: Malatya
country: Turkey
facility: Inonu University Turgut Ozal Medical Center
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis University Medical Faculty - Hematology
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
city: London
country: United Kingdom
facility: Guy's and Saint Thomas' NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
Study officials:
References:
citation: Al-Ali, H.K.; Delgado, R.G.; Lange, A.; Pluta, A.; McLornan, D.; Vachhani, P.; Damaj, G.L.; Jost, P.J.; Rejto, L.; Hus, M.; et al. KRT-232, A First-In-Class, Murine Double Minute 2 Inhibitor, for Myelofibrosis Relapsed or Refractory to Janus-Associated Kinase Inhibitor Treatment. Eha. Libr. 2020, 295035, S215