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

NCT04603495 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 3 other identifiers: CDAK539A123012023-507954-34-00CPI 0610-04
• Study Type: interventional
• Target: 430
• Locations: 21 countries
• Sites: 152

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

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

Keywords

Pelabresib; Ruxolitinib

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Splenic Response by Central Radiology Reads at Week 24

  Splenic response was characterized by a reduction of at least 35% in spleen volume from baseline (SVR35), as determined by magnetic resonance imaging (MRI) or computerized tomography (CT), and evaluated through a blinded central radiology review at Week 24.

  Week 24

Secondary Outcomes (24)

• Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24

  Baseline, Week 24

• Key Secondary: Number of Participants With TSS50 Response at Week 24

  Week 24

• Percent Change From Baseline in Total Symptom Score (TSS) at Week 24

  Baseline, Week 24

• Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24

  Baseline, Week 24

• Number of Participants With Splenic Response by Central Radiology Reads at Week 48

  Week 48

Study Arms (2)

Pelabresib + ruxolitinib

EXPERIMENTAL

Pelabresib monohydrate tablets + ruxolitinib phosphate tablets

Drug: Pelabresib; Drug: Ruxolitinib

Placebo + ruxolitinib

ACTIVE COMPARATOR

Matching placebo tablets + ruxolitinib phosphate tablets

Drug: Ruxolitinib; Drug: Placebo

Interventions

Pelabresib 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.

Pelabresib + ruxolitinib

Ruxolitinib DRUG

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

Pelabresib + ruxolitinib; Placebo + ruxolitinib

Placebo 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.

Placebo + ruxolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (156)

University of Alabama at Birmingham

Birmingham, Alabama, 35294-3300, United States

Location

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

Chandler, Arizona, 85224, United States

Location

UC San Diego Moores Cancer Center

La Jolla, California, 92093, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

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

Decatur, Illinois, 62526, United States

Location

Franciscan Health/Indiana blood and Marrow Transplantation

Indianapolis, Indiana, 46237, United States

Location

Norton Cancer Institute, St. Matthews Campus

Louisville, Kentucky, 40207, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Weill Cornell Medical College- New York Presbyterian Hospital

New York, New York, 10065, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center - San Antonio

San Antonio, Texas, 78229, United States

Location

Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Icon Cancer Centre

Brisbane, Queensland, 4101, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Monash Health

Clayton, Victoria, 3168, Australia

Location

Peninsula Private Hospital Clinical Trials Unit

Frankston, Victoria, 3199, Australia

Location

USC Clinical Trials Centre Sunshine Coast Haematology and Oncology Clinic

Buderim, QLD 4556, Australia

Location

One Clinical Research PTY LTD

Nedlands, 6009, Australia

Location

LKH - Universitätsklinikum Graz; Abteilung für Hämatologie

Graz, A-8036, Austria

Location

Krankenhaus der Elisabethinen Linz

Linz, 4020, Austria

Location

Kepler University Hospital

Linz, 4021, Austria

Location

University Hospital Salzburg

Salzburg, 5020, Austria

Location

ZNA

Antwerp, Belgium

Location

Cliniques universitaires Saint-Luc

Brussels, 1200, Belgium

Location

Hôpital de Jolimont

La Louvière, 7100, Belgium

Location

UZ Leuven

Leuven, Belgium

Location

Domaine Universitaire du Sart Tilman

Liège, 4000, Belgium

Location

Tom Baker Cancer Centre

Calgary, Alberta, T2N 4N2, Canada

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7, Canada

Location

London Health Sciences Center - Victoria Hospital

London, Ontario, N6A 5W9, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 2M9, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Fakultni nemocnice Hradec Kralove

Hradec Králové, 500 05, Czechia

Location

University Hospital Olomouc

Olomouc, 779 00, Czechia

Location

Amiens South Hospital univerisy - Hopital Sud

Amiens, 80054, France

Location

Centre Hospitalier

Le Mans, 72000, France

Location

Hôpital l'Archet 1

Nice, 06202, France

Location

Gard Cancer Institute

Nîmes, 30029, France

Location

Centre Hospitalier Lyon Sud Secteur 1G

Pierre-Bénite, 69310, France

Location

Chu Pontchaillou - Service Hematologie

Rennes, 35033, France

Location

Institut de Cancérologie Lucien Neuwirth

Saint-Priest-en-Jarez, 42271, France

Location

Hôpital Bretonneau

Tours, 37044, France

Location

Chru Brabois

Vandœuvre-lès-Nancy, 54500, France

Location

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89081, Germany

Location

Hämatologisch-Onkologische Praxis Augsburg

Augsburg, Bavaria, 86151, Germany

Location

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

Halle, Saxony, 06120, Germany

Location

Universitätsklinikum Jena, Klinik für Innere Medizin II

Jena, Thuringia, 07747, Germany

Location

University Hospital Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Laiko General Hospital

Athens, Greece

Location

UGH of Ioannina

Ioannina, 455 00, Greece

Location

University General Hospital of Patras

Rio, 26504, Greece

Location

Princess Margaret Hospital

Hong Kong, Kowloon, Hong Kong

Location

Prince of Wales Hospital

Hong Kong, New Territories, Hong Kong

Location

: Pecs University, 1st Department of Medicine

Pécs, Pecs, 7624, Hungary

Location

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

Nyíregyháza, Hungary

Location

Soroka Medical Center

Beersheba, 84101, Israel

Location

Shamir Medical Center

Be’er Ya‘aqov, 60930000, Israel

Location

Rambam Health Corporation

Haifa, 3109601, Israel

Location

Lady Davis Carmel Medical Center

Haifa, 3436212, Israel

Location

Wolfson Medical Center

Holon, Israel

Location

Hadassah University Hospital-Ein Kerem

Jerusalem, 9590300, Israel

Location

Shaarei Zedek

Nahariya, 2210001, Israel

Location

Rabin Medical Center - Beilinson Campus,

Petah Tikva, 49100, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 6423906, Israel

Location

Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII

Bergamo, 24127, Italy

Location

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

Bologna, 40138, Italy

Location

Regional Hospital Spedali Civili di Brescia

Brescia, 25123, Italy

Location

Azienda Ospedaliera Universitaria Arcispedale Sant'Anna

Ferrara, Italy

Location

Azienda Ospedaliera Universitaria Careggi

Florence, Italy

Location

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

Meldola, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

Location

Azienda Ospedaliera San Gerardo di Monza

Monza, Italy

Location

University Hospital Maggiore della Carità

Novara, 28100, Italy

Location

AOU S.Luigi Gonzaga

Orbassano, Italy

Location

University Hospital of Padova

Padua, 35128, Italy

Location

University Hospital 'Paolo Giaccone' Polyclinic

Palermo, 90127, Italy

Location

Ospedale Sant'Eugenio

Rome, Italy

Location

Hospital Ordine Mauriziano of Turin

Turin, 10128, Italy

Location

Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi

Varese, Italy

Location

Hospital Sultanah Aminah

Johor Bahru, Johor, 80100, Malaysia

Location

Hospital Sultanah Bahiyah

Alor Star, Kedah, 05460, Malaysia

Location

Hospital Pulau Pinang

George Town, Pulau Pinang, 10450, Malaysia

Location

:Hospital Ampang

Ampang, Selangor, 68000, Malaysia

Location

Sunway Medical Centre

Petaling Jaya, Selangor, 47500, Malaysia

Location

Hospital Queen Elizabeth

Kota Kinabalu, 88586, Malaysia

Location

Amsterdam UMC

Amsterdam, 1081, Netherlands

Location

Maastricht University Medical Center

Maastricht, 6229 HX, Netherlands

Location

Wojewódzki Szpital Specjalistyczny w Bialej Podlaskiej

Biała Podlaska, 21-50, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-293, Poland

Location

Pratia Onkologia Katowice

Katowice, Poland

Location

Centrum Medyczne Pratia

Skorzewo, 60-185, Poland

Location

Nasz Lekarz Przychodnie Medyczne

Torun, 87-100, Poland

Location

Gyeongsang National University Hospital

Jinju, Gyeongsangnam-do, South Korea

Location

Inje University Haeundae Paik Hospital

Busan, 48108, South Korea

Location

Pusan National University Hospital

Busan, 49241, South Korea

Location

Inje University Busan Paik Hospital

Busan, South Korea

Location

Kyungpook National University Hospital

Daegu, 41944, South Korea

Location

Daegu Catholic University Medical Center

Daegu, South Korea

Location

The Catholic University Of Korea St. Vincent Hospital

Gyeonggi-do, South Korea

Location

Gachon University Gil Medical Center

Incheon, South Korea

Location

Jeonbuk National University Hospital

Jeonju, 54907, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Samsung Medical Center

Seoul, 135-710, South Korea

Location

Korea University Anam Hospital

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

The Catholic University of Korea

Seoul, South Korea

Location

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

Seoul, South Korea

Location

Ulsan University Hospital

Ulsan, South Korea

Location

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, 33011, Spain

Location

ICO Badalona - Hospital Universitari Germans Trias i Pujol

Badalona, 8916, Spain

Location

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Vall d'Hebron Institute of Oncology

Barcelona, Spain

Location

Hospital San Pedro de Alcantara

Cáceres, 10003, Spain

Location

Hospital Universitario de Gran Canaria Dr. Negrin

Las Palmas de Gran Canaria, 35010, Spain

Location

Quirónsalud Madrid University Hospital

Madrid, 28223, Spain

Location

Morales Meseguer General University Hospital

Murcia, 30008, Spain

Location

Hospital Universitario de Salamanc

Salamanca, 37007, Spain

Location

Hospital Virgen Macarena

Seville, Spain

Location

University Hospital of Toledo

Toledo, 45007, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Chang Gung Memorial Hospital Chiayi

Chiayi City, Taiwan

Location

China Medical University Hospital

Chiayi City, Taiwan

Location

Taichung Veterans General Hospital

Taichung, Taiwan

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

Songklanagarind Hospital

Songkhla, Hat Yai District, 90110, Thailand

Location

Chulabhorn Hospital

Bangkok, Lak Si, 10210, Thailand

Location

Srinagarind hospital,Khon Kaen University

Khon Kaen, Mueang Khon Kaen District, 40002, Thailand

Location

King Chulalongkorn Memorial Hospital

Bangkok, Pathumwan, 10330, Thailand

Location

Rajavithi Hospital

Bangkok, Ratchathewi District, 10400, Thailand

Location

Ankara University Faculty of Medicine Cebeci Research and Application Hospital

Ankara, Turkey (Türkiye)

Location

Dr. Abdurrahman Yurtaslan Oncology Health Application and Research Center

Ankara, Turkey (Türkiye)

Location

Antalya Medstar Hospital

Antalya, Turkey (Türkiye)

Location

Edirne Trakya University Faculty of Medicine Hospital

Edirne, Turkey (Türkiye)

Location

Gaziantep University Sahinbey Research and Application Center Hospital

Gaziantep, Turkey (Türkiye)

Location

Izmir Ege University Faculty of Medicine Hospital

Izmir, Turkey (Türkiye)

Location

Erciyes University Faculty of Medicine Hospital

Kayseri, 8039, Turkey (Türkiye)

Location

Kocaeli University Application

Kocaeli, Turkey (Türkiye)

Location

Mersin University

Mersin, Turkey (Türkiye)

Location

Samsun 19 Mayıs University Health Application Research Hospital

Samsun, Turkey (Türkiye)

Location

Western General Hospital

Edinburgh, Scotland, EH4 2XU, United Kingdom

Location

University Hospital of Wales

Cardiff, Wales, CF14 4XW, United Kingdom

Location

Pilgrim Hospital

Boston, PE21 9QS, United Kingdom

Location

Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

Location

The Clatterbridge Cancer Centre

Liverpool, L7 8YA, United Kingdom

Location

Guy's & St Thomas NHS Foundation Trust

London, SE1 9RT, United Kingdom

Location

Imperial College Healthcare NHS Trust, Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

University College London Hospitals

London, United Kingdom

Location

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

Oxford, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 35950489 RESULT

• 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.

  PMID: 40065169 RESULT

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

ruxolitinib

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2020
• First Posted: October 26, 2020
• Study Start: April 9, 2021
• Primary Completion: August 23, 2023
• Study Completion (Estimated): June 30, 2027
• Last Updated: December 17, 2025
• Results First Posted: October 28, 2024

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

DE (5); TH (5); AU (6); HU (2); US (20); GR (3); NL (2); PL (5); MY (6); IT (15); BE (5); TW (4); CZ (2); ES (12); KR (16); IL (9); HK (2); GB (9); CA (5); FR (9); TU (10)