Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2)

Sponsor

Constellation Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04603495

Collaborator

(none)

400

Enrollment

132

Locations

Arms

76.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A Phase 3, randomized, blinded study comparing pelabresib (CPI-0610) and ruxolitinib with placebo and ruxolitinib in myelofibrosis (MF) patients that have not been previously treated with Janus kinase inhibitors (JAKi). Pelabresib is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis Post-essential Thrombocythemia Myelofibrosis	Drug: Pelabresib Drug: Ruxolitinib Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

This study has a double-blind design in which patients and investigators are blinded to study drug; study drugs will be packaged identically. All patients will be randomly assigned to either treatment group in a 1:1 ratio. The blind should only be broken in the case of emergency.

Primary Purpose:

Treatment

Official Title:

A Phase 3, Randomized, Double-blind, Active-Control Study of Pelabresib (CPI-0610) and Ruxolitinib vs. Placebo and Ruxolitinib in JAKi Treatment Naive MF Patients

Actual Study Start Date :

Nov 19, 2020

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Apr 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pelabresib + ruxolitinib Pelabresib monohydrate tablets + ruxolitinib phosphate tablets	Drug: Pelabresib Double-blind treatment (pelabresib or matching placebo) will be administered daily for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Pelabresib is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF. Drug: Ruxolitinib Ruxolitinib is a JAK inhibitor and a current, approved treatment option for MF.
Active Comparator: Placebo + ruxolitinib Matching placebo tablets + ruxolitinib phosphate tablets	Drug: Ruxolitinib Ruxolitinib is a JAK inhibitor and a current, approved treatment option for MF. Drug: Placebo Placebo tablets are designed to match pelabresib tablets. Each placebo tablet contains no active pharmaceutical ingredient and is visibly identical to experimental drug in size, shape, and packaging. Placebo dosing follows the same dosing conventions as pelabresib.

Arm

Intervention/Treatment

Experimental: Pelabresib + ruxolitinib

Pelabresib monohydrate tablets + ruxolitinib phosphate tablets

Drug: Pelabresib

Double-blind treatment (pelabresib or matching placebo) will be administered daily for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Pelabresib is a small molecule inhibitor of BET proteins with a novel mechanism of action and potential for disease-modifying effects in MF.

Drug: Ruxolitinib

Ruxolitinib is a JAK inhibitor and a current, approved treatment option for MF.

Active Comparator: Placebo + ruxolitinib

Matching placebo tablets + ruxolitinib phosphate tablets

Drug: Ruxolitinib

Ruxolitinib is a JAK inhibitor and a current, approved treatment option for MF.

Drug: Placebo

Placebo tablets are designed to match pelabresib tablets. Each placebo tablet contains no active pharmaceutical ingredient and is visibly identical to experimental drug in size, shape, and packaging. Placebo dosing follows the same dosing conventions as pelabresib.

Outcome Measures

Primary Outcome Measures

Splenic response at Week 24 [24 weeks of treatment]
The primary endpoint of the study is splenic response, defined as a ≥35% reduction from baseline in spleen volume as measured by magnetic resonance imaging (MRI) or computerized tomography (CT), at Week 24.

Secondary Outcome Measures

Total Symptom Score response at Week 24 [24 weeks of treatment]
The key secondary endpoint of the study is Total Symptom Score response, defined as a ≥50% decrease from baseline in Total Symptom Score as measured by the Myelofibrosis Symptom Assessment Form v4.0, at Week 24. A higher Total Symptom Score indicates a higher disease burden and thus a worse outcome.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged ≥ 18 years
Confirmed diagnosis of myelofibrosis (primary, post-polycythemia vera, or post essential thrombocythemia)
Adequate hematologic, renal, and hepatic function
Have at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0
Prognostic risk-factor score of Intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system
Spleen volume of ≥ 450 cm^3
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

Exclusion Criteria:

Splenectomy or splenic irradiation in the previous 6 months
Chronic or active conditions and/or concomitant medication use that would prohibit treatment
Had prior treatment with any JAKi or BET inhibitor for treatment of a myeloproliferative neoplasm

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-3300
2	Ironwood Physicians P.C. dba Ironwood Cancer and Research Centers	Chandler	Arizona	United States	85224
3	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
4	USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
5	UCLA Medical Center	Los Angeles	California	United States	90095
6	Yale University School of Medicine	New Haven	Connecticut	United States	06510
7	Georgetown University	Washington	District of Columbia	United States	20007
8	Mayo Clinic	Jacksonville	Florida	United States	32224
9	University of Miami Hospital	Miami	Florida	United States	33136
10	Moffitt Cancer Center	Tampa	Florida	United States	33612
11	Northwestern	Chicago	Illinois	United States	60611-5975
12	University of Chicago Medical Center	Chicago	Illinois	United States	60637
13	Decatur Memorial Hospital Cancer Care Center of Decatur/Cancer Care Specialists of IL	Decatur	Illinois	United States	62526
14	Loyola University - Cardinal Bernardin Cancer Center	Maywood	Illinois	United States	60153
15	Franciscan Health/Indiana blood and Marrow Transplantation	Indianapolis	Indiana	United States	46237
16	Norton Cancer Institute, St. Matthews Campus	Louisville	Kentucky	United States	40207
17	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
18	Washington University	Saint Louis	Missouri	United States	63110
19	Cancer Care Specialists	Reno	Nevada	United States	89511
20	Summit Medical Group - Cancer Center	Florham Park	New Jersey	United States	07932
21	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
22	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
23	Weill Cornell Medical College- New York Presbyterian Hospital	New York	New York	United States	10065
24	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
25	Oregon Health and Science University	Portland	Oregon	United States	97239
26	MD Anderson Cancer Center	Houston	Texas	United States	77030
27	Mays Cancer Center at UT Health San Antonio MD Anderson	San Antonio	Texas	United States	78229
28	Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute	Seattle	Washington	United States	98104
29	Sydney Adventist Hospital	Wahroonga	New South Wales	Australia	2076
30	Icon Cancer Centre	Brisbane	Queensland	Australia	4101
31	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
32	Monash Health	Clayton	Victoria	Australia	3168
33	Peninsula Private Hospital Clinical Trials Unit	Frankston	Victoria	Australia	3199
34	USC Clinical Trials Centre Sunshine Coast Haematology and Oncology Clinic	Buderim		Australia	QLD 4556
35	One Clinical Research PTY LTD	Nedlands		Australia	6009
36	Calvary North Adelaide Hospital	North Adelaide		Australia
37	Calvary North Adelaide Hospital	North Adelaide		Australia
38	LKH - Universitätsklinikum Graz; Abteilung für Hämatologie	Graz		Austria	A-8036
39	Krankenhaus der Elisabethinen Linz	Linz		Austria	4020
40	ZNA	Antwerpen		Belgium
41	AZ Sint-Jan	Brugge		Belgium
42	Cliniques universitaires Saint-Luc	Brussel		Belgium	1200
43	UZ Brussel	Jette		Belgium	1090
44	Hôpital de Jolimont	La Louvière		Belgium	7100
45	UZ Leuven	Leuven		Belgium
46	Domaine Universitaire du Sart Tilman	Liège		Belgium	4000
47	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
48	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
49	London Health Sciences Center - Victoria Hospital	London	Ontario	Canada	N6A 5W9
50	Princess Margaret Cancer Center	Toronto	Ontario	Canada	M5G 2M9
51	Jewish General Hospital	Montréal	Quebec	Canada	H3T 1E2
52	Hôpital Maisonneuve-Rosemont	Montréal		Canada	H1T 2M4
53	The Ottawa Hospital General Campus	Ottawa		Canada	K1H 8L6
54	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
55	University Hospital Olomouc	Olomouc		Czechia	779 00
56	CHU Amiens Picardie	Amiens		France	80054
57	CHU Henri-Mondor	Créteil		France	94010 Cedex
58	CHU Henri-Mondor	Créteil		France	94010
59	Centre Hospitalier	Le Mans		France	72000
60	Hopital de la Conception	Marseille		France	13385
61	Hôpital l'Archet 1	Nice		France	06202
62	CHU DE NIMES _Institut de Cancérologie du Gard	Nîmes		France
63	Centre d'Investigations Cliniques	Paris		France
64	Centre Hospitalier Lyon Sud Secteur 1G	Pierre-Bénite		France	69310
65	Chu Pontchaillou - Service Hematologie	Rennes		France	35033
66	Institut de Cancérologie Lucien Neuwirth	Saint-Priest-en-Jarez		France	42271
67	Hôpital Bretonneau	Tours		France	37044
68	Chru Brabois	Vandœuvre-lès-Nancy		France	54500
69	Debreceni Egyetem Klinikai Kozpont, Belgyogyaszati Klinika, Hematologia	Debrecen		Hungary	4032
70	Szabolcs Szatmár Bereg Megyei Kórházak és Egyetemi Oktatókórház; Jósa András Oktatókórház, Hematológia	Nyíregyháza		Hungary
71	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII	Bergamo		Italy	24127
72	A.O.U. Policlinico S. Orsola-Malpighi	Bologna		Italy	40138
73	AOU Policlinico G. Rodolico - San Marco	Catania		Italy
74	Azienda Ospedaliera Universitaria Arcispedale Sant'Anna	Ferrara		Italy
75	Azienda Ospedaliera Universitaria Careggi	Florence		Italy
76	Ospedale Policlinico San Martino IRCCS	Genova		Italy
77	IRCCS Istituto Romagnolo per lo studio dei tumori "Dino Amadori"	Meldola		Italy
78	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano		Italy
79	Azienda Ospedaliera San Gerardo di Monza	Monza		Italy
80	AOU S.Luigi Gonzaga	Orbassano		Italy
81	Ospedale Sant'Eugenio	Rome		Italy
82	Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi	Varese		Italy
83	Inje University Haeundae Paik Hospital	Busan		Korea, Republic of	48108
84	Pusan National University Hospital	Busan		Korea, Republic of	49241
85	Inje University Busan Paik Hospital	Busan		Korea, Republic of
86	Kyungpook National University Hospital	Daegu		Korea, Republic of	41944
87	Daegu Catholic University Medical Center	Daegu		Korea, Republic of
88	Keimyung University Dongsan Hospital	Daegu		Korea, Republic of
89	Cha Bundang Medical Center Cha University	Gyeonggi-do		Korea, Republic of
90	The Catholic University Of Korea St. Vincent Hospital	Gyeonggi-do		Korea, Republic of
91	Gachon University Gil Medical Center	Incheon		Korea, Republic of
92	Jeonbuk National University Hospital	Jeonju		Korea, Republic of	54907
93	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
94	Korea University Guro Hospital	Seoul		Korea, Republic of	08307
95	Samsung Medical Center	Seoul		Korea, Republic of	135-710
96	Hanyang University Medical Center	Seoul		Korea, Republic of
97	Korea University Anam Hospital	Seoul		Korea, Republic of
98	Seoul National University Hospital	Seoul		Korea, Republic of
99	The Catholic University of Korea	Seoul		Korea, Republic of
100	The Catholic University of South Korea Seoul St. Mary's Hospital	Seoul		Korea, Republic of
101	Ulsan University Hospital	Ulsan		Korea, Republic of
102	Amsterdam UMC	Amsterdam		Netherlands	1081
103	Maastricht University Medical Center	Maastricht		Netherlands	6229 HX
104	Wojewódzki Szpital Specjalistyczny w Bialej Podlaskiej	Biała Podlaska		Poland	21-50
105	Uniwersyteckie Centrum Kliniczne	Gdańsk		Poland	80-293
106	Pratia Onkologia Katowice	Katowice		Poland
107	Centrum Medyczne Pratia	Skorzewo		Poland	60-185
108	Nasz Lekarz Przychodnie Medyczne	Toruń		Poland	87-100
109	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
110	ICO Badalona - Hospital Universitari Germans Trias i Pujol	Badalona		Spain	8916
111	Hospital Clinic de Barcelona	Barcelona		Spain
112	Vall d'Hebron Institute of Oncology	Barcelona		Spain
113	Hospital San Pedro de Alcantara	Caceres		Spain	10003
114	ICO Girona - Hospital Universitari de Girona	Girona		Spain
115	Hospital Universitario de Gran Canaria Dr. Negrin	Las Palmas de Gran Canaria		Spain	35010
116	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
117	Complejo Hospitalario de Navarra	Pamplona		Spain	31008
118	Hospital Universitario de Salamanc	Salamanca		Spain	37007
119	Hospital Virgen Macarena	Sevilla		Spain
120	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010
121	Chang Gung Memorial Hospital Chiayi	Chiayi City		Taiwan
122	China Medical University Hospital	Chiayi City		Taiwan
123	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan
124	Taichung Veterans General Hospital	Taichung		Taiwan
125	National Taiwan University Hospital	Taipei		Taiwan
126	Western General Hospital	Edinburgh	Scotland	United Kingdom	EH4 2XU
127	University Hospital of Wales	Cardiff	Wales	United Kingdom	CF14 4XW
128	Pilgrim Hospital	Boston		United Kingdom	PE21 9QS
129	Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust	Cambridge		United Kingdom	CB2 0QQ
130	Imperial College Healthcare NHS Trust, Hammersmith Hospital	London		United Kingdom	W12 0HS
131	University College London Hospitals	London		United Kingdom
132	Oxford University Hospitals NHS Foundation Trust, Department of Haematology, Cancer and Haematology Centre, Churchill Hospital	Oxford		United Kingdom