BOREAS: KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment

Sponsor

Kartos Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03662126

Collaborator

(none)

385

Enrollment

156

Locations

Arms

83.5

Anticipated Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Myelofibrosis (PMF) Post-Polycythemia Vera MF (Post-PV-MF) Post-Essential Thrombocythemia MF (Post-ET-MF)	Drug: KRT-232 Drug: Best Available Therapy (BAT)	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

385 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

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

Actual Study Start Date :

Jan 15, 2019

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A Cohort 1 KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)	Drug: KRT-232 KRT-232, administered by mouth
Experimental: Part A Cohort 2 KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)	Drug: KRT-232 KRT-232, administered by mouth
Experimental: Part A Cohort 3 KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)	Drug: KRT-232 KRT-232, administered by mouth
Experimental: Part A Cohort 4b KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)	Drug: KRT-232 KRT-232, administered by mouth
Experimental: Part B Arm 1 KRT-232 KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)	Drug: KRT-232 KRT-232, administered by mouth
Active Comparator: Part B Arm 2 Best Available Therapy Best available therapy at the discretion of the investigator, on a 28-day cycle.	Drug: Best Available Therapy (BAT) Best available therapy options include: hydroxyurea chemotherapy or supportive care (including but not limited to corticosteroids and androgens; JAK inhibitors not allowed).

Outcome Measures

Primary Outcome Measures

(Part A Only) Spleen Volume Reduction (SVR) [24 weeks]
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
(Part B Only) Spleen Volume Reduction (SVR) [24 Weeks]
The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)

Secondary Outcome Measures

(Part A only) Improvement in Total Symptom Score (TSS) [48 weeks]
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
(Part B only) Improvement of Total Symptom Score (TSS) [24 Weeks]
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
(Part B only) Overall Survival (OS) [48 months]
Time from randomization to death from any cause
(Part B only) Progression free survival (PFS) [48 months]
Time from randomization to either first occurrence of disease progression or death due to any cause
(Part B Only) Overall Spleen Volume Reduction (SVR) [48 months]
The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
(Part B Only) Spleen Response Duration [48 months]
Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
(Part B Only) Rate of conversion from RBC transfusion dependent to independent [24 weeks]
The proportion of subjects who have RBC transfusion independence at week 24

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Kirklin Clinic of UAB Hospital	Birmingham	Alabama	United States	35294
2	University of Southern California Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	Stanford Cancer Center - Palo Alto	Stanford	California	United States	94305
4	Innovative Clinical Research Institute	Whittier	California	United States	90603
5	University Cancer Institute	Boynton Beach	Florida	United States	33426
6	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
7	University of Illinois at Chicago	Chicago	Illinois	United States	60612
8	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
10	Brookdale University Hospital and Medical Center	Brooklyn	New York	United States	11212
11	New York Presbyterian/Weill Cornell Medical Center	New York	New York	United States	10021
12	Mt. Sinai	New York	New York	United States	10029
13	Gabrail Cancer Center	Canton	Ohio	United States	44718
14	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
15	Oregon Health and Science University	Portland	Oregon	United States	97239
16	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
17	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37203
18	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
19	Medical College of Wisconsin - Froedtert Hospital	Milwaukee	Wisconsin	United States	53226
20	Sanatorio de la Mujer	Rosario	Santa Fe	Argentina	S2000ORE
21	Instituto Medico Alexander Fleming	Buenos Aires		Argentina
22	Centro Medico San Luis	Caba		Argentina	1425
23	Monash Medical Centre	Clayton	Victoria	Australia	3168
24	Royal Adelaide Hospital	Adelaide		Australia
25	The Alfred Hospital	Melbourne		Australia
26	South Eastern Private Hospital	Noble Park		Australia	3174
27	Icon Cancer Center	South Brisbane		Australia
28	Hospital Erasto Gaertner	Curitiba	Parana	Brazil	81520
29	UNICAMP - Universidade Estadual de Campinas Hemocentro	Campinas	São Paulo	Brazil	13083
30	Hospital das Clínicas UFG	Goiânia		Brazil	74605
31	Fundacao Doutor Amaral Carvalho	Jau		Brazil	17210-120
32	Hospital de Clinicas de Porto Alegre - Centro de Pesquisa Clinica	Porto Alegre		Brazil	90035-903
33	Associação Educadora São Carlos AESC - Hospital Mãe de Deus - Centro de Pesquisa	Porto Alegre		Brazil	90880-480
34	Instituto de Ensino e Pesquisa São Lucas	Sao Paulo		Brazil	01236-030
35	Hospital das Clínicas da Universidade de São Paulo	Sao Paulo		Brazil	05403-000
36	Instituto D'or de Pesquisa e Ensino	São Paulo		Brazil	04502-001
37	Instituto COI São Paulo	São Paulo		Brazil	1321001
38	University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven	Pleven		Bulgaria
39	University Multiprofile Hospital for Active Treatment Sveti Georgi, Plovdiv	Plovdiv		Bulgaria
40	Acibadem City Clinic Tokuda Hospital, Sofia	Sofia		Bulgaria
41	Specialized Hospital for Active Therapy of Hematological Disorders	Sofia		Bulgaria
42	University Multiprofile Hospital for Active Treatment Alexandrovska, Sofia	Sofia		Bulgaria
43	University Multiprofile Hospital for Active Treatment Saint Ivan Rilski, Sofia	Sofia		Bulgaria
44	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 2M9
45	General Hospital Sibenik	Sibenik		Croatia	22000
46	Clinical Hospital Centre Osijek	Zagreb		Croatia	10000
47	FN Hradec Kralove	Králová		Czechia	500 05
48	Vseonecma fakultni nemocrince V Praze	Nové Město		Czechia
49	Fakultní Nemocnice Olomouc	Olomouc		Czechia	779 00
50	Centre Hospitalier Universitaire D'Amiens (Hopital Sud) - Hématologie Clinique	Amiens		France	80054
51	Center Hospitalier Universitaire d'Angers	Angers		France	49933 Cedex 09
52	C.H de la Côte Basque - Serviv	Bayonne		France	64100
53	Centre Hospitalier Regional Universitaire Brest Hopital Morvan	Brest Cedex		France	29609
54	Centre Hospitalier Universitaire of Caen Normandie - Côte de Nacre	Caen		France	14000
55	Centre Hospitalier Le Mans	Le Mans		France
56	Centre Hospitalier Universitaire de Nîmes	Nîmes		France	30029 Cedex 9
57	Hôpital Saint-Louis	Paris		France	75010
58	Centre Hospitalier Universitaire de Poitiers	Poitiers		France
59	Institut Universitaire du Cancer de Toulouse Oncopole	Toulouse		France	31059
60	Hopital Paul Brousse - Aphp Hôpitaux Universitaires Paris Su	Villejuif		France	94800
61	Klinikum Rechts der Isar der Technischen Universität München Apotheke	München	Bayern	Germany	81675
62	Universitätsklinikum Aachen	Aachen	Nordrhein-Westfalen	Germany	52074
63	Universitaetsklinikum Essen	Essen	Nordrhein-Westfalen	Germany	45147
64	Universitätsklinikum Halle	Halle	Sachsen-Anhalt	Germany	06120
65	Gemeinschaftspraxis Haematologie - Onkologie - Hauptstelle	Dresden	Sachsen	Germany	01307
66	Technische Universität Dresden	Dresden	Sachsen	Germany	01307
67	Universitätsklinikum Jena	Jena	Thuringen	Germany	07747
68	Charité Universitätsmedizin Berlin	Berlin		Germany	13353
69	UKE - Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20251
70	Universitätsmedizin der Johannes Gutenberg Universität Mainz	Mainz		Germany
71	Stauferklinikum Schwäbisch Gmünd	Mutlangen		Germany	73557
72	Praxis für Hämatologie und Onkologie	Saarbrücken		Germany	66113
73	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár	Somogy	Hungary	7400
74	Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház	Nyíregyháza	Szabolcs-Szatmar-Bereg	Hungary	4400
75	Markusovszky Egyetemi Oktatókórház	Szombathely	Vas	Hungary	H-9700
76	Semmelweis Egyetem	Budapest		Hungary	1083
77	Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet	Budapest		Hungary
78	Debreceni Egyetem Orvos es Egeszsegtudomanyi Centrum	Debrecen		Hungary	4032
79	Szegedi Tudományegyetem	Szeged		Hungary	6725
80	Ha'Emek Medical Center	Afula		Israel	1834111
81	Assuta Ashdod University Hospital	Ashdod		Israel
82	Rambam Medical Centre	Haifa		Israel	31096
83	Carmel MC	Haifa		Israel
84	Hadassah Medical Organisation	Jerusalem		Israel	91120
85	Hematology Institute	Kfar Saba		Israel	44281
86	Western Galilee Hospital - Nahariya	Nahariya		Israel	22100
87	Rabin Medical Center - Beilinson Hospital	Petah Tikva		Israel	49100
88	Tel Aviv Sourasky Medical Center - Oncology	Tel Aviv		Israel	6423906
89	Assuta MC	Tel Aviv		Israel	64239
90	Assaf Harofeh Medical Center - Hematology	Zerifin		Israel	7030000
91	PO Civile SS.Antonio e Biagio	Alessandria		Italy	15121
92	AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi	Ancona		Italy	60123
93	A.O.di Bologna Policl.S.Orsola	Bologna		Italy	41038
94	AO Spedali Civili di Brescia	Brescia		Italy	25123
95	Azienda Ospedaliero Universitaria Policlinico - Vittorio Emanuele	Catania		Italy	95123
96	AOU Careggi	Firenze		Italy	50141
97	Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST IRCCS	Meldola		Italy
98	Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda	Milano		Italy	20122
99	AOU Maggiore della Carità	Novara		Italy	28100
100	Azienda Ospedaliera Ospedali Riuniti Marche Nord - Pesaro	Pesaro		Italy	61121
101	Arcispedale S. Maria Nuova, AO di Reggio Emilia	Reggio Emilia		Italy	42123
102	Policlinico Universitario Agostino Gemelli	Roma		Italy	00168
103	Inje University Busan Paik Hospital	Busan		Korea, Republic of	47392
104	Kyungpook National University Hospital	Daegu		Korea, Republic of	41944
105	Yeungnam University Medical Center	Daegu		Korea, Republic of	42415
106	Keimyung University Dongsan Medical Center	Daegu		Korea, Republic of	42601
107	CHA Bundang Medical Center, CHA University	Seongnam-si		Korea, Republic of	Seongnam-si
108	Seoul National University Hospital	Seoul		Korea, Republic of	03080
109	Samsung Medical Center	Seoul		Korea, Republic of	06351
110	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	6591
111	Hospital of Lithuanian University of Health Sciences Kaunas	Kaunas		Lithuania	LT-50161
112	Instituto Mexicano del Seguro Social	Monterrey		Mexico	64180
113	Sociedad de Metabolismo y Corazón S.C. - Oncology	Veracruz		Mexico	91910
114	Perpetual Succour Hospital - Hemat/Transfusion Med	Cebu City		Philippines	6000
115	University of the Philippines - Philippine General Hospital	Manila		Philippines	1000
116	Dolnośląskie Centrum Transplantacji Komórkowych z Krajowym Bankiem Dawców Szpiku	Wrocław	Dolnoslaskie	Poland	53-439
117	Szpital Specjalistyczny w Brzozowie Podkarpacki Ośrodek Onkologiczny im. Ks. B. Markiewicza	Brzozow	Podkarpackie	Poland	36-200
118	Samodzielny Publiczny Zakład Opieki Zdrowotnej Zespół Szpitali Miejskich	Chorzów	Slaskie	Poland	41-500
119	Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie	Lublin		Poland	20-081
120	SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii	Olsztyn		Poland
121	Szpital Wojewódzki w Opolu	Opole		Poland	45-061
122	Clinical Research Center Spółka z Ograniczoną Odpowiedzialnością Medic-R sp. k.	Poznań		Poland	60-848
123	Wojewodzki Szpital Specjalistyczny im. Janusza Korczaka w Slupsku Sp. z o.o.	Słupsk		Poland	76-200
124	H. Infante Dom Pedro. Centro Hospitalar do Baixo Vouga	Aveiro		Portugal	3814-501
125	Hospital de Braga	Braga		Portugal	4710-243
126	H. São Francisco Xavier-Centro Hospitalar Lisboa Ocidental	Lisboa		Portugal	1495-005
127	Champalimaud Cancer Center	Lisbon		Portugal	1400-038
128	Clinical oncological dispensary	Omsk		Russian Federation	644013
129	Saint-Petersburg SMU I.P.Pavlov	St Petersburg		Russian Federation	197089
130	Oncologic dispensary of Komi Republic	Syktyvkar		Russian Federation	167904
131	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
132	Hospital Universitario de Gran Canaria Doctor Negrin	Las Palmas De Gran Canaria	Las Palmas	Spain	35010
133	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda	Madrid	Spain	28222
134	Hospital Universitario Vall d'Hebrón	Barcelona		Spain	08035
135	Hospital de La Santa Creu i Sant Pau	Barcelona		Spain	8041
136	Hospital Universitario Virgen de la Victoria	Málaga		Spain	29010
137	Hospital Universitario Son Espases	Palma de Mallorca		Spain	07120
138	Complejo Hospitalario de Navarra - H. de Navarra, Hematología C/ de Irunlarrea, 3, Pamplona	Pamplona		Spain	31008
139	Hospital Universitario de Salamanca	Salamanca		Spain	37007
140	Hospital Universitario Doctor Peset	Valencia		Spain	46017
141	H. Quirón Zaragoza	Zaragoza		Spain	50012
142	Ramathibodi Hospital - Mahidol University - Hematology	Bangkok		Thailand	10400
143	Siriraj Hospital	Bangkok		Thailand	10700
144	Thammasat University Hospital	Khlong Luang		Thailand	12120
145	Srinagarind Hospital (KhonKaen University)	Khon Kaen		Thailand	40002
146	Songklanagarind Hospital	Songkhla		Thailand	90110
147	Sakarya Research and Training Hospital	Adapazarı		Turkey	54100
148	Ankara University Faculty of Medicine	Ankara		Turkey	06500
149	Gazi University Medical Faculty	Ankara		Turkey	06500
150	Gaziantep University Faculty of Medicine	Gaziantep		Turkey	27100
151	Inonu University Turgut Ozal Medical Center	Malatya		Turkey	44280
152	Mersin University Medical Faculty	Mersin		Turkey	33110
153	University Hospitals Birmingham NHS Foundation Trust	Birmingham		United Kingdom
154	NHS Greater Glasgow and Clyde	Glasgow		United Kingdom
155	Guy's and Saint Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
156	Oxford University Hospitals NHS Foundation Trust	Oxford		United Kingdom