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

NCT ID: NCT04603495

Last Updated: 2025-12-17

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 430 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-09
• Study Completion Date: 2027-06-30

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.

Conditions

Myelofibrosis; Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Pelabresib + ruxolitinib

Pelabresib monohydrate tablets + ruxolitinib phosphate tablets

Group Type: EXPERIMENTAL

Pelabresib

Intervention Type: DRUG

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.

Ruxolitinib

Intervention Type: DRUG

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

Placebo + ruxolitinib

Matching placebo tablets + ruxolitinib phosphate tablets

Group Type: ACTIVE_COMPARATOR

Ruxolitinib

Intervention Type: DRUG

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

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Ruxolitinib

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

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Ironwood Physicians P.C. dba Ironwood Cancer and Research Centers

Chandler, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States

UCLA Medical Center

Los Angeles, California, United States

Yale University School of Medicine

New Haven, Connecticut, United States

Mayo Clinic

Jacksonville, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Decatur Memorial Hospital Cancer Care Center of Decatur/Cancer Care Specialists of IL

Decatur, Illinois, United States

Franciscan Health/Indiana blood and Marrow Transplantation

Indianapolis, Indiana, United States

Norton Cancer Institute, St. Matthews Campus

Louisville, Kentucky, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

Washington University

St Louis, Missouri, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Weill Cornell Medical College- New York Presbyterian Hospital

New York, New York, United States

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States

MD Anderson Cancer Center

Houston, Texas, United States

University of Texas Health Science Center - San Antonio

San Antonio, Texas, United States

Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute

Seattle, Washington, United States

Icon Cancer Centre

Brisbane, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Monash Health

Clayton, Victoria, Australia

Peninsula Private Hospital Clinical Trials Unit

Frankston, Victoria, Australia

USC Clinical Trials Centre Sunshine Coast Haematology and Oncology Clinic

Buderim, , Australia

One Clinical Research PTY LTD

Nedlands, , Australia

LKH - Universitätsklinikum Graz; Abteilung für Hämatologie

Graz, , Austria

Krankenhaus der Elisabethinen Linz

Linz, , Austria

Kepler University Hospital

Linz, , Austria

University Hospital Salzburg

Salzburg, , Austria

ZNA

Antwerp, , Belgium

Cliniques universitaires Saint-Luc

Brussels, , Belgium

Hôpital de Jolimont

La Louvière, , Belgium

UZ Leuven

Leuven, , Belgium

Domaine Universitaire du Sart Tilman

Liège, , Belgium

Tom Baker Cancer Centre

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

London Health Sciences Center - Victoria Hospital

London, Ontario, Canada

Princess Margaret Cancer Center

Toronto, Ontario, Canada

Jewish General Hospital

Montreal, Quebec, Canada

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

University Hospital Olomouc

Olomouc, , Czechia

Amiens South Hospital univerisy - Hopital Sud

Amiens, , France

Centre Hospitalier

Le Mans, , France

Hôpital l'Archet 1

Nice, , France

Gard Cancer Institute

Nîmes, , France

Centre Hospitalier Lyon Sud Secteur 1G

Pierre-Bénite, , France

Chu Pontchaillou - Service Hematologie

Rennes, , France

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, , France

Hôpital Bretonneau

Tours, , France

Chru Brabois

Vandœuvre-lès-Nancy, , France

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, Germany

Hämatologisch-Onkologische Praxis Augsburg

Augsburg, Bavaria, Germany

Universitätsklinikum Halle (Saale), Krukenberg-Krebszentrum Halle (KKH)

Halle, Saxony, Germany

Universitätsklinikum Jena, Klinik für Innere Medizin II

Jena, Thuringia, Germany

University Hospital Hamburg-Eppendorf

Hamburg, , Germany

Laiko General Hospital

Athens, , Greece

UGH of Ioannina

Ioannina, , Greece

University General Hospital of Patras

Rio, , Greece

Princess Margaret Hospital

Hong Kong, Kowloon, Hong Kong

Prince of Wales Hospital

Hong Kong, New Territories, Hong Kong

: Pecs University, 1st Department of Medicine

Pécs, Pecs, Hungary

Szabolcs Szatmár Bereg Megyei Kórházak és Egyetemi Oktatókórház; Jósa András Oktatókórház, Hematológia

Nyíregyháza, , Hungary

Soroka Medical Center

Beersheba, , Israel

Shamir Medical Center

Be’er Ya‘aqov, , Israel

Rambam Health Corporation

Haifa, , Israel

Lady Davis Carmel Medical Center

Haifa, , Israel

Wolfson Medical Center

Holon, , Israel

Hadassah University Hospital-Ein Kerem

Jerusalem, , Israel

Shaarei Zedek

Nahariya, , Israel

Rabin Medical Center - Beilinson Campus,

Petah Tikva, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII

Bergamo, , Italy

A.O.U. Policlinico S. Orsola-Malpighi

Bologna, , Italy

Regional Hospital Spedali Civili di Brescia

Brescia, , Italy

Azienda Ospedaliera Universitaria Arcispedale Sant'Anna

Ferrara, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

IRCCS Istituto Romagnolo per lo studio dei tumori "Dino Amadori"

Meldola, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Azienda Ospedaliera San Gerardo di Monza

Monza, , Italy

University Hospital Maggiore della Carità

Novara, , Italy

AOU S.Luigi Gonzaga

Orbassano, , Italy

University Hospital of Padova

Padua, , Italy

University Hospital 'Paolo Giaccone' Polyclinic

Palermo, , Italy

Ospedale Sant'Eugenio

Rome, , Italy

Hospital Ordine Mauriziano of Turin

Turin, , Italy

Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi

Varese, , Italy

Hospital Sultanah Aminah

Johor Bahru, Johor, Malaysia

Hospital Sultanah Bahiyah

Alor Star, Kedah, Malaysia

Hospital Pulau Pinang

George Town, Pulau Pinang, Malaysia

:Hospital Ampang

Ampang, Selangor, Malaysia

Sunway Medical Centre

Petaling Jaya, Selangor, Malaysia

Hospital Queen Elizabeth

Kota Kinabalu, , Malaysia

Amsterdam UMC

Amsterdam, , Netherlands

Maastricht University Medical Center

Maastricht, , Netherlands

Wojewódzki Szpital Specjalistyczny w Bialej Podlaskiej

Biała Podlaska, , Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, , Poland

Pratia Onkologia Katowice

Katowice, , Poland

Centrum Medyczne Pratia

Skorzewo, , Poland

Nasz Lekarz Przychodnie Medyczne

Torun, , Poland

Gyeongsang National University Hospital

Jinju, Gyeongsangnam-do, South Korea

Inje University Haeundae Paik Hospital

Busan, , South Korea

Pusan National University Hospital

Busan, , South Korea

Inje University Busan Paik Hospital

Busan, , South Korea

Kyungpook National University Hospital

Daegu, , South Korea

Daegu Catholic University Medical Center

Daegu, , South Korea

The Catholic University Of Korea St. Vincent Hospital

Gyeonggi-do, , South Korea

Gachon University Gil Medical Center

Incheon, , South Korea

Jeonbuk National University Hospital

Jeonju, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Korea University Anam Hospital

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

The Catholic University of Korea

Seoul, , South Korea

The Catholic University of South Korea Seoul St. Mary's Hospital

Seoul, , South Korea

Ulsan University Hospital

Ulsan, , South Korea

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, Spain

ICO Badalona - Hospital Universitari Germans Trias i Pujol

Badalona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Vall d'Hebron Institute of Oncology

Barcelona, , Spain

Hospital San Pedro de Alcantara

Cáceres, , Spain

Hospital Universitario de Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, , Spain

Quirónsalud Madrid University Hospital

Madrid, , Spain

Morales Meseguer General University Hospital

Murcia, , Spain

Hospital Universitario de Salamanc

Salamanca, , Spain

Hospital Virgen Macarena

Seville, , Spain

University Hospital of Toledo

Toledo, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Chang Gung Memorial Hospital Chiayi

Chiayi City, , Taiwan

China Medical University Hospital

Chiayi City, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Songklanagarind Hospital

Songkhla, Hat Yai District, Thailand

Chulabhorn Hospital

Bangkok, Lak Si, Thailand

Srinagarind hospital,Khon Kaen University

Khon Kaen, Mueang Khon Kaen District, Thailand

King Chulalongkorn Memorial Hospital

Bangkok, Pathumwan, Thailand

Rajavithi Hospital

Bangkok, Ratchathewi District, Thailand

Ankara University Faculty of Medicine Cebeci Research and Application Hospital

Ankara, , Turkey (Türkiye)

Dr. Abdurrahman Yurtaslan Oncology Health Application and Research Center

Ankara, , Turkey (Türkiye)

Antalya Medstar Hospital

Antalya, , Turkey (Türkiye)

Edirne Trakya University Faculty of Medicine Hospital

Edirne, , Turkey (Türkiye)

Gaziantep University Sahinbey Research and Application Center Hospital

Gaziantep, , Turkey (Türkiye)

Izmir Ege University Faculty of Medicine Hospital

Izmir, , Turkey (Türkiye)

Erciyes University Faculty of Medicine Hospital

Kayseri, , Turkey (Türkiye)

Kocaeli University Application

Kocaeli, , Turkey (Türkiye)

Mersin University

Mersin, , Turkey (Türkiye)

Samsun 19 Mayıs University Health Application Research Hospital

Samsun, , Turkey (Türkiye)

Western General Hospital

Edinburgh, Scotland, United Kingdom

University Hospital of Wales

Cardiff, Wales, United Kingdom

Pilgrim Hospital

Boston, , United Kingdom

Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust

Cambridge, , United Kingdom

The Clatterbridge Cancer Centre

Liverpool, , United Kingdom

Guy's & St Thomas NHS Foundation Trust

London, , United Kingdom

Imperial College Healthcare NHS Trust, Hammersmith Hospital

London, , United Kingdom

University College London Hospitals

London, , United Kingdom

Oxford University Hospitals NHS Foundation Trust, Department of Haematology, Cancer and Haematology Centre, Churchill Hospital

Oxford, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Czechia; France; Germany; Greece; Hong Kong; Hungary; Israel; Italy; Malaysia; Netherlands; Poland; South Korea; Spain; Taiwan; Thailand; Turkey (Türkiye); United Kingdom

References

Harrison CN, Gupta VK, Gerds AT, Rampal R, Verstovsek S, Talpaz M, Kiladjian JJ, Mesa R, Kuykendall AT, Vannucchi AM, Palandri F, Grosicki S, Devos T, Jourdan E, Wondergem MJ, Al-Ali HK, Buxhofer-Ausch V, Alvarez-Larran A, Patriarca A, Kremyanskaya M, Mead AJ, Akhani S, Sheikine Y, Colak G, Mascarenhas J. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis. Future Oncol. 2022 Sep;18(27):2987-2997. doi: 10.2217/fon-2022-0484. Epub 2022 Aug 11.

Reference Type: RESULT

PMID: 35950489 (View on PubMed)

Rampal RK, Grosicki S, Chraniuk D, Abruzzese E, Bose P, Gerds AT, Vannucchi AM, Palandri F, Lee SE, Gupta V, Lucchesi A, Oh ST, Kuykendall AT, Patriarca A, Alvarez-Larran A, Mesa R, Kiladjian JJ, Talpaz M, Scandura JM, Lavie D, Harris M, Kays SK, Li Q, Boxhammer R, Brown B, Jegg AM, Harrison CN, Mascarenhas J. Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. Nat Med. 2025 May;31(5):1531-1538. doi: 10.1038/s41591-025-03572-3. Epub 2025 Mar 10.

Reference Type: RESULT

PMID: 40065169 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2023-507954-34-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

CPI 0610-04

Identifier Type: OTHER

Identifier Source: secondary_id

CDAK539A12301

Identifier Type: -

Identifier Source: org_study_id