Primary Myelofibrosis (PMF) Clinical Trial
— BOREASOfficial 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
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.
| Status | Recruiting |
| Enrollment | 385 |
| Est. completion date | December 31, 2025 |
| Est. primary completion date | December 31, 2023 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | 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) |
| Country | Name | City | State |
|---|---|---|---|
| Argentina | Instituto Medico Alexander Fleming | Buenos Aires | |
| Argentina | Centro Medico San Luis | Caba | |
| Argentina | Hospital Privado - Centro Medico de Cordoba - Oncology | Córdoba | |
| Argentina | Sanatorio de la Mujer | Rosario | Santa Fe |
| Australia | Royal Adelaide Hospital | Adelaide | |
| Australia | Monash Medical Centre | Clayton | Victoria |
| Australia | The Alfred Hospital | Melbourne | |
| Australia | Fiona Stanley Hosital | Murdoch | Western Australia |
| Australia | South Eastern Private Hospital | Noble Park | |
| Australia | Icon Cancer Center | South Brisbane | |
| Brazil | UNICAMP - Universidade Estadual de Campinas Hemocentro | Campinas | São Paulo |
| Brazil | Hospital Erasto Gaertner | Curitiba | Parana |
| Brazil | Centro de oncologia Leonardo da Vinci | Fortaleza | Ceara |
| Brazil | Hospital das Clínicas UFG | Goiânia | |
| Brazil | Fundacao Doutor Amaral Carvalho | Jau | |
| Brazil | Associação Educadora São Carlos AESC - Hospital Mãe de Deus - Centro de Pesquisa | Porto Alegre | |
| Brazil | Hospital de Clinicas de Porto Alegre - Centro de Pesquisa Clinica | Porto Alegre | |
| Brazil | Hospital A C Camargo - Fundacao Antonio Prudente | Sao Paulo | |
| Brazil | Hospital das Clínicas da Universidade de São Paulo | Sao Paulo | |
| Brazil | Instituto de Ensino e Pesquisa São Lucas | Sao Paulo | |
| Brazil | Instituto COI São Paulo | São Paulo | |
| Brazil | Instituto D'or de Pesquisa e Ensino | São Paulo | |
| Bulgaria | University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven | Pleven | |
| Bulgaria | University Multiprofile Hospital for Active Treatment Sveti Georgi, Plovdiv | Plovdiv | |
| Bulgaria | Acibadem City Clinic Tokuda Hospital, Sofia | Sofia | |
| Bulgaria | Military Medical Academy, Multiprofile for active treatment, Sofia | Sofia | |
| Bulgaria | Specialized Hospital for Active Therapy of Hematological Disorders | Sofia | |
| Bulgaria | University Multiprofile Hospital for Active Treatment Alexandrovska, Sofia | Sofia | |
| Bulgaria | University Multiprofile Hospital for Active Treatment Saint Ivan Rilski, Sofia | Sofia | |
| Canada | Princess Margaret Cancer Center | Toronto | Ontario |
| Croatia | General Hospital Sibenik | Sibenik | |
| Croatia | Clinical Hospital Centre Osijek | Zagreb | |
| Croatia | KB Sestre Milosrdnice | Zagreb | |
| Czechia | FN Hradec Kralove | Králová | |
| Czechia | Vseonecma fakultni nemocrince V Praze | Nové Mesto | |
| Czechia | Fakultní Nemocnice Olomouc | Olomouc | |
| France | Centre Hospitalier Universitaire D'Amiens (Hopital Sud) - Hématologie Clinique | Amiens | |
| France | Center Hospitalier Universitaire d'Angers | Angers | |
| France | C.H de la Côte Basque - Serviv | Bayonne | |
| France | Centre Hospitalier Regional Universitaire Brest Hopital Morvan | Brest Cedex | |
| France | Centre Hospitalier Universitaire of Caen Normandie - Côte de Nacre | Caen | |
| France | Centre Hospitalier Le Mans | Le Mans | |
| France | Centre Hospitalier Universitaire de Nîmes | Nîmes | |
| France | Hôpital Saint-Louis | Paris | |
| France | Centre Hospitalier Universitaire de Poitiers | Poitiers | |
| France | Institut Universitaire du Cancer de Toulouse Oncopole | Toulouse | |
| France | Hopital Paul Brousse - Aphp Hôpitaux Universitaires Paris Su | Villejuif | |
| Germany | Universitätsklinikum Aachen | Aachen | Nordrhein-Westfalen |
| Germany | Charité Universitätsmedizin Berlin | Berlin | |
| Germany | Gemeinschaftspraxis Haematologie - Onkologie - Hauptstelle | Dresden | Sachsen |
| Germany | Technische Universität Dresden | Dresden | Sachsen |
| Germany | Universitaetsklinikum Essen | Essen | Nordrhein-Westfalen |
| Germany | Universitätsklinikum Halle | Halle | Sachsen-Anhalt |
| Germany | UKE - Universitätsklinikum Hamburg-Eppendorf | Hamburg | |
| Germany | Universitätsklinikum Jena | Jena | Thuringen |
| Germany | Universitätsmedizin der Johannes Gutenberg Universität Mainz | Mainz | |
| Germany | Klinikum Rechts der Isar der Technischen Universität München Apotheke | München | Bayern |
| Germany | Stauferklinikum Schwäbisch Gmünd | Mutlangen | |
| Germany | Praxis für Hämatologie und Onkologie | Saarbrücken | |
| Greece | University General Hospital of Ioannina | Ioánnina | Ioannina |
| Greece | University Campus of Patras - Hematology | Patras | |
| Greece | AHEPA General Hospital of Thessaloniki | Thessaloníki | |
| Hong Kong | Queen Mary Hospital | Hong Kong | |
| Hong Kong | Prince of Wales Hospital - Medicine | Shatin | |
| Hungary | Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet | Budapest | |
| Hungary | Semmelweis Egyetem | Budapest | |
| Hungary | Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum | Debrecen | |
| Hungary | Somogy Megyei Kaposi Mór Oktató Kórház | Kaposvár | Somogy |
| Hungary | Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház | Nyíregyháza | Szabolcs-Szatmar-Bereg |
| Hungary | Szegedi Tudományegyetem | Szeged | |
| Hungary | Markusovszky Egyetemi Oktatókórház | Szombathely | Vas |
| Israel | Ha'Emek Medical Center | Afula | |
| Israel | Assuta Ashdod University Hospital | Ashdod | |
| Israel | Carmel MC | Haifa | |
| Israel | Rambam Medical Centre | Haifa | |
| Israel | Hadassah Medical Organisation | Jerusalem | |
| Israel | Hematology Institute | Kfar Saba | |
| Israel | Western Galilee Hospital - Nahariya | Nahariya | |
| Israel | Rabin Medical Center - Beilinson Hospital | Petah Tikva | |
| Israel | Assuta MC | Tel Aviv | |
| Israel | Tel Aviv Sourasky Medical Center - Oncology | Tel Aviv | |
| Israel | Assaf Harofeh Medical Center - Hematology | Zerifin | |
| Italy | PO Civile SS.Antonio e Biagio | Alessandria | |
| Italy | AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi | Ancona | |
| Italy | A.O.di Bologna Policl.S.Orsola | Bologna | |
| Italy | AO Spedali Civili di Brescia | Brescia | |
| Italy | Azienda Ospedaliero Universitaria Policlinico - Vittorio Emanuele | Catania | |
| Italy | AOU Careggi | Firenze | |
| Italy | Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST IRCCS | Meldola | |
| Italy | ASST Grande Ospedale Metropolitano Niguarda | Milano | |
| Italy | Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda | Milano | |
| Italy | A.O. San Gerardo di Monza - L'Ospedale San Gerardo di Monza e l'Università di Milano | Monza | Lombardia |
| Italy | AOU Maggiore della Carità | Novara | |
| Italy | Azienda Ospedaliera Ospedali Riuniti Marche Nord - Pesaro | Pesaro | |
| Italy | Arcispedale S. Maria Nuova, AO di Reggio Emilia | Reggio Emilia | |
| Italy | Policlinico Universitario Agostino Gemelli | Roma | |
| Italy | A.O. Citta della Salute e della Scienza di Torino | Torino | |
| Korea, Republic of | Inje University Busan Paik Hospital | Busan | |
| Korea, Republic of | Keimyung University Dongsan Medical Center | Daegu | |
| Korea, Republic of | Kyungpook National University Hospital | Daegu | |
| Korea, Republic of | Yeungnam University Medical Center | Daegu | |
| Korea, Republic of | CHA Bundang Medical Center, CHA University | Seongnam-si | |
| Korea, Republic of | Samsung Medical Center | Seoul | |
| Korea, Republic of | Seoul National University Hospital | Seoul | |
| Korea, Republic of | The Catholic University of Korea, Seoul St. Mary's Hospital | Seoul | |
| Lithuania | Hospital of Lithuanian University of Health Sciences Kaunas | Kaunas | |
| Mexico | Instituto Mexicano del Seguro Social | Monterrey | |
| Mexico | Universidad Autonoma de Nuevo Leon (UANL) - Hospital Universitario "Dr. Jose Eleuterio Gonzalez | Monterrey | Nuevo Leon |
| Mexico | Oaxaca Site Management Organization OSMO | Oaxaca | |
| Mexico | Sociedad de Metabolismo y Corazón S.C. - Oncology | Veracruz | |
| Philippines | Perpetual Succour Hospital - Hemat/Transfusion Med | Cebu City | |
| Philippines | University of the Philippines - Philippine General Hospital | Manila | |
| Poland | Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. Ks. B. Markiewicza | Brzozow | Podkarpackie |
| Poland | Szpital Uniwersytecki nr 2 im dr. Jana Biziela | Bydgoszcz | |
| Poland | Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespól Szpitali Miejskich | Chorzów | Slaskie |
| Poland | Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie | Lublin | |
| Poland | SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii | Olsztyn | |
| Poland | Szpital Wojewódzki w Opolu | Opole | |
| Poland | Clinical Research Center Spólka z Ograniczona Odpowiedzialnoscia Medic-R sp. k. | Poznan | |
| Poland | Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o. | Slupsk | |
| Poland | Dolnoslaskie Centrum Transplantacji Komórkowych z Krajowym Bankiem Dawców Szpiku | Wroclaw | Dolnoslaskie |
| Portugal | H. Infante Dom Pedro. Centro Hospitalar do Baixo Vouga | Aveiro | |
| Portugal | Hospital de Braga | Braga | |
| Portugal | Instituto Português de Oncologia de Coimbra | Coimbra | |
| Portugal | H. São Francisco Xavier-Centro Hospitalar Lisboa Ocidental | Lisboa | |
| Portugal | Champalimaud Cancer Center | Lisbon | |
| Romania | Cen Med de Diagn si Trat Amb NEOMED | Brasov | |
| Romania | Spitalul Clinic Colentina | Bucharest | |
| Romania | Medicover | Bucuresti | |
| Romania | Spitalul Clinic Coltea | Bucuresti | |
| Romania | Institutul Oncologic "Prof. Dr. Ion Chiricuta" | Cluj-Napoca | |
| Romania | Spitalul Clinic Municipal Filantropia Craiova | Craiova | |
| Romania | Institutul Regional de Oncologie Iasi | Iasi | |
| Romania | Spitalul Clinic Judetean de Urgenta Tg Mures | Târgu-Mures | |
| Romania | Oncomed | Timisoara | |
| Romania | Spitalul Clinic Municipal de Urgenta Timisoara | Timisoara | |
| Russian Federation | Clinical oncological dispensary | Omsk | |
| Russian Federation | Saint-Petersburg SMU I.P.Pavlov | St Petersburg | |
| Russian Federation | Oncologic dispensary of Komi Republic | Syktyvkar | |
| Spain | Hospital Universitari Germans Trias i Pujol | Badalona | Barcelona |
| Spain | Hospital de La Santa Creu i Sant Pau | Barcelona | |
| Spain | Hospital Universitario Vall d'Hebrón | Barcelona | |
| Spain | Hospital San Pedro de Alcantara | Cáceres | |
| Spain | Hospital Universitario de Gran Canaria Doctor Negrin | Las Palmas De Gran Canaria | Las Palmas |
| Spain | Hospital Universitario Puerta de Hierro - Majadahonda | Majadahonda | Madrid |
| Spain | Hospital Universitario Virgen de la Victoria | Málaga | |
| Spain | Hospital Universitario Son Espases | Palma de Mallorca | |
| Spain | Complejo Hospitalario de Navarra - H. de Navarra, Hematología C/ de Irunlarrea, 3, Pamplona | Pamplona | |
| Spain | Hospital Universitario de Salamanca | Salamanca | |
| Spain | Hospital Universitario Doctor Peset | Valencia | |
| Spain | H. Quirón Zaragoza | Zaragoza | |
| Taiwan | Chang Gung Medical Foundation - ChiaYi Chang Gung Memorial Hospital - Chiayi Branch | Chiayi City | |
| Taiwan | Kaohsiung Medical University - Chung-Ho Memorial Hospital | Kaohsiung | |
| Taiwan | China Medical University Hospital | Taichung | |
| Taiwan | National Taiwan University Hospital | Taipei City | Taipei |
| Thailand | Ramathibodi Hospital - Mahidol University - Hematology | Bangkok | |
| Thailand | Siriraj Hospital | Bangkok | |
| Thailand | Thammasat University Hospital | Khlong Luang | |
| Thailand | Srinagarind Hospital (KhonKaen University) | Khon Kaen | |
| Thailand | Songklanagarind Hospital | Songkhla | |
| Turkey | Sakarya Research and Training Hospital | Adapazari | |
| Turkey | Ankara University Faculty of Medicine | Ankara | |
| Turkey | Gazi University Medical Faculty | Ankara | |
| Turkey | Pamukkale University | Denizli | |
| Turkey | Gaziantep University Faculty of Medicine | Gaziantep | |
| Turkey | Inonu University Turgut Ozal Medical Center | Malatya | |
| Turkey | Mersin University Medical Faculty | Mersin | |
| Turkey | Ondokuz Mayis University Medical Faculty - Hematology | Samsun | |
| United Kingdom | University Hospitals Birmingham NHS Foundation Trust | Birmingham | |
| United Kingdom | NHS Greater Glasgow and Clyde | Glasgow | |
| United Kingdom | Guy's and Saint Thomas' NHS Foundation Trust | London | |
| United Kingdom | Oxford University Hospitals NHS Foundation Trust | Oxford | |
| United States | The Kirklin Clinic of UAB Hospital | Birmingham | Alabama |
| United States | Dana-Farber Cancer Institute | Boston | Massachusetts |
| United States | University Cancer Institute | Boynton Beach | Florida |
| United States | Brookdale University Hospital and Medical Center | Brooklyn | New York |
| United States | Gabrail Cancer Center | Canton | Ohio |
| United States | Northwestern University Feinberg School of Medicine | Chicago | Illinois |
| United States | University of Illinois at Chicago | Chicago | Illinois |
| United States | The Ohio State University Comprehensive Cancer Center | Columbus | Ohio |
| United States | The University of Texas MD Anderson Cancer Center | Houston | Texas |
| United States | University of Southern California Norris Comprehensive Cancer Center | Los Angeles | California |
| United States | Medical College of Wisconsin - Froedtert Hospital | Milwaukee | Wisconsin |
| United States | Vanderbilt University Medical Center | Nashville | Tennessee |
| United States | Mt. Sinai | New York | New York |
| United States | New York Presbyterian/Weill Cornell Medical Center | New York | New York |
| United States | Oregon Health and Science University | Portland | Oregon |
| United States | Washington University School of Medicine | Saint Louis | Missouri |
| United States | Avera Cancer Institute | Sioux Falls | South Dakota |
| United States | Stanford Cancer Center - Palo Alto | Stanford | California |
| United States | Innovative Clinical Research Institute | Whittier | California |
| Lead Sponsor | Collaborator |
|---|---|
| Kartos Therapeutics, Inc. |
United States, Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Korea, Republic of, Lithuania, Mexico, Philippines, Poland, Portugal, Romania, Russian Federation, Spain, Taiwan, Thailand, Turkey, United Kingdom,
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
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | (Part A Only) Spleen Volume Reduction (SVR) | The proportion of subjects achieving a = 35% spleen volume reduction (SVR) from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan | 24 weeks | |
| Primary | (Part B Only) Spleen Volume Reduction (SVR) | The proportion of subjects achieving SVR of = 35% at Week 24 by MRI/CT scan (central review) | 24 Weeks | |
| Secondary | (Part A only) Improvement in Total Symptom Score (TSS) | The proportion of subjects who have at least a 50% reduction from Baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0 | 48 weeks | |
| Secondary | (Part B only) Improvement of Total Symptom Score (TSS) | The proportion of subjects who have at least a 50% reduction from Baseline to Week 24 in the total symptom score as measured by the MF-SAF v4.0 | 24 Weeks | |
| Secondary | (Part B only) Overall Survival (OS) | Time from randomization to death from any cause | 48 months | |
| Secondary | (Part B only) Progression free survival (PFS) | Time from randomization to either first occurrence of disease progression or death due to any cause | 48 months | |
| Secondary | (Part B Only) Overall Spleen Volume Reduction (SVR) | The proportion of subjects in each arm achieving SVR of = 35% at any time by MRI/CT scan (central review) | 48 months | |
| Secondary | (Part B Only) Spleen Response Duration | Time from initial SVR of = 35% by MRI/CT (central review) until the first occurrence of disease progression | 48 months | |
| Secondary | (Part B Only) Rate of conversion from RBC transfusion dependent to independent | The proportion of subjects who have RBC transfusion independence at week 24 | 24 weeks |
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