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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Primary Myelofibrosis; Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
• Intervention / Treatment: Drug: Pelabresib; Drug: Ruxolitinib; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 430
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Buderim, Australia, QLD 4556
    • USC Clinical Trials Centre Sunshine Coast Haematology and Oncology Clinic
  • Nedlands, Australia, 6009
    • One Clinical Research Pty Ltd
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Icon Cancer Centre
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Frankston, Victoria, Australia, 3199
      • Peninsula Private Hospital Clinical Trials Unit
• Austria
  • Graz, Austria, A-8036
    • LKH - Universitätsklinikum Graz; Abteilung für Hämatologie
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz
  • Linz, Austria, 4021
    • Kepler University Hospital
  • Salzburg, Austria, 5020
    • University Hospital Salzburg
• Belgium
  • Antwerp, Belgium
    • ZNA
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • La Louvière, Belgium, 7100
    • Hopital De Jolimont
  • Leuven, Belgium
    • UZ Leuven
  • Liège, Belgium, 4000
    • Domaine Universitaire du Sart Tilman
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center - Victoria Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Center
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• Czechia
  • Hradec Králové, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove
  • Olomouc, Czechia, 779 00
    • University Hospital Olomouc
• France
  • Amiens, France, 80054
    • Amiens South Hospital univerisy - Hopital Sud
  • Le Mans, France, 72000
    • Centre hospitalier
  • Nice, France, 06202
    • Hôpital l'Archet 1
  • Nîmes, France, 30029
    • Gard Cancer Institute
  • Pierre-Bénite, France, 69310
    • Centre Hospitalier Lyon Sud Secteur 1G
  • Rennes, France, 35033
    • Chu Pontchaillou - Service Hematologie
  • Saint-Priest-en-Jarez, France, 42271
    • Institut de Cancérologie Lucien Neuwirth
  • Tours, France, 37044
    • Hôpital Bretonneau
  • Vandœuvre-lès-Nancy, France, 54500
    • Chru Brabois
• Germany
  • Hamburg, Germany, 20246
    • University Hospital Hamburg-Eppendorf
  • Baden-Wurttemberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitatsklinikum Ulm
  • Bavaria
    • Augsburg, Bavaria, Germany, 86151
      • Hämatologisch-Onkologische Praxis Augsburg
  • Saxony
    • Halle, Saxony, Germany, 06120
      • Universitätsklinikum Halle (Saale), Krukenberg-Krebszentrum Halle (KKH)
  • Thuringia
    • Jena, Thuringia, Germany, 07747
      • Universitätsklinikum Jena, Klinik für Innere Medizin II
• Greece
  • Athens, Greece
    • Laiko General Hospital
  • Ioannina, Greece, 455 00
    • UGH of Ioannina
  • Rio, Greece, 26504
    • University General Hospital of Patras
• Hong Kong
  • Kowloon
    • Hong Kong, Kowloon, Hong Kong
      • Princess Margaret Hospital
  • New Territories
    • Hong Kong, New Territories, Hong Kong
      • Prince of Wales Hospital
• Hungary
  • Nyíregyháza, Hungary
    • Szabolcs Szatmár Bereg Megyei Kórházak és Egyetemi Oktatókórház; Jósa András Oktatókórház, Hematológia
  • Pecs
    • Pécs, Pecs, Hungary, 7624
      • : Pecs University, 1st Department of Medicine
• Israel
  • Beersheba, Israel, 84101
    • Soroka Medical Center
  • Be’er Ya‘aqov, Israel, 60930000
    • Shamir Medical Center
  • Haifa, Israel, 3109601
    • Rambam Health Corporation
  • Haifa, Israel, 3436212
    • Lady Davis Carmel Medical Center
  • Holon, Israel
    • Wolfson Medical Center
  • Jerusalem, Israel, 9590300
    • Hadassah University Hospital-ein Kerem
  • Nahariya, Israel, 2210001
    • Shaarei Zedek
  • Petah Tikva, Israel, 49100
    • Rabin Medical Center - Beilinson Campus,
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII
  • Bologna, Italy, 40138
    • A.O.U. Policlinico S. Orsola-Malpighi
  • Brescia, Italy, 25123
    • Regional Hospital Spedali Civili di Brescia
  • Ferrara, Italy
    • Azienda Ospedaliera Universitaria Arcispedale Sant'Anna
  • Florence, Italy
    • Azienda Ospedaliera Universitaria Careggi
  • Meldola, Italy
    • IRCCS Istituto Romagnolo per lo studio dei tumori "Dino Amadori"
  • Milan, Italy
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Monza, Italy
    • Azienda Ospedaliera San Gerardo di Monza
  • Novara, Italy, 28100
    • University Hospital Maggiore della Carita
  • Orbassano, Italy
    • AOU S.Luigi Gonzaga
  • Padua, Italy, 35128
    • University Hospital Of Padova
  • Palermo, Italy, 90127
    • University Hospital 'Paolo Giaccone' Polyclinic
  • Rome, Italy
    • Ospedale Sant'Eugenio
  • Turin, Italy, 10128
    • Hospital Ordine Mauriziano of Turin
  • Varese, Italy
    • Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi
• Malaysia
  • Kota Kinabalu, Malaysia, 88586
    • Hospital Queen Elizabeth
  • Johor
    • Johor Bahru, Johor, Malaysia, 80100
      • Hospital Sultanah Aminah
  • Kedah
    • Alor Star, Kedah, Malaysia, 05460
      • Hospital Sultanah Bahiyah
  • Pulau Pinang
    • George Town, Pulau Pinang, Malaysia, 10450
      • Hospital Pulau Pinang
  • Selangor
    • Ampang, Selangor, Malaysia, 68000
      • :Hospital Ampang
    • Petaling Jaya, Selangor, Malaysia, 47500
      • Sunway Medical Centre
• Netherlands
  • Amsterdam, Netherlands, 1081
    • Amsterdam UMC
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University Medical Center
• Poland
  • Biała Podlaska, Poland, 21-50
    • Wojewodzki Szpital Specjalistyczny w Bialej Podlaskiej
  • Gdansk, Poland, 80-293
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland
    • Pratia Onkologia Katowice
  • Skorzewo, Poland, 60-185
    • Centrum Medyczne Pratia
  • Torun, Poland, 87-100
    • Nasz Lekarz Przychodnie Medyczne
• South Korea
  • Busan, South Korea, 49241
    • Pusan National University Hospital
  • Busan, South Korea, 48108
    • Inje University Haeundae Paik Hospital
  • Busan, South Korea
    • Inje University Busan Paik Hospital
  • Daegu, South Korea, 41944
    • Kyungpook National University Hospital
  • Daegu, South Korea
    • Daegu Catholic University Medical Center
  • Gyeonggi-do, South Korea
    • The Catholic University of Korea St. Vincent Hospital
  • Incheon, South Korea
    • Gachon University Gil Medical Center
  • Jeonju, South Korea, 54907
    • Jeonbuk National University Hospital
  • Seoul, South Korea, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, South Korea
    • Korea University Anam Hospital
  • Seoul, South Korea
    • Seoul National University Hospital
  • Seoul, South Korea, 135-710
    • Samsung Medical Center
  • Seoul, South Korea
    • The Catholic University of Korea
  • Seoul, South Korea
    • The Catholic University of South Korea Seoul St. Mary's Hospital
  • Ulsan, South Korea
    • Ulsan University Hospital
  • Gyeongsangnam-do
    • Jinju, Gyeongsangnam-do, South Korea
      • Gyeongsang National University Hospital
• Spain
  • Badalona, Spain, 8916
    • ICO Badalona - Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain
    • Hospital Clinic De Barcelona
  • Barcelona, Spain
    • Vall d'Hebron Institute of Oncology
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcantara
  • Las Palmas de Gran Canaria, Spain, 35010
    • Hospital Universitario de Gran Canaria Dr. Negrin
  • Madrid, Spain, 28223
    • Quirónsalud Madrid University Hospital
  • Murcia, Spain, 30008
    • Morales Meseguer General University Hospital
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanc
  • Seville, Spain
    • Hospital Virgen Macarena
  • Toledo, Spain, 45007
    • University Hospital of Toledo
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Principality of Asturias
    • Oviedo, Principality of Asturias, Spain, 33011
      • Hospital Universitario Central de Asturias
• Taiwan
  • Chiayi City, Taiwan
    • Chang Gung Memorial Hospital Chiayi
  • Chiayi City, Taiwan
    • China Medical University Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
• Thailand
  • Hat Yai District
    • Songkhla, Hat Yai District, Thailand, 90110
      • Songklanagarind Hospital
  • Lak Si
    • Bangkok, Lak Si, Thailand, 10210
      • Chulabhorn Hospital
  • Mueang Khon Kaen District
    • Khon Kaen, Mueang Khon Kaen District, Thailand, 40002
      • Srinagarind hospital,Khon Kaen University
  • Pathumwan
    • Bangkok, Pathumwan, Thailand, 10330
      • King Chulalongkorn Memorial Hospital
  • Ratchathewi District
    • Bangkok, Ratchathewi District, Thailand, 10400
      • Rajavithi Hospital
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye)
    • Ankara University Faculty of Medicine Cebeci Research and Application Hospital
  • Ankara, Turkey (Türkiye)
    • Dr. Abdurrahman Yurtaslan Oncology Health Application and Research Center
  • Antalya, Turkey (Türkiye)
    • Antalya Medstar Hospital
  • Edirne, Turkey (Türkiye)
    • Edirne Trakya University Faculty of Medicine Hospital
  • Gaziantep, Turkey (Türkiye)
    • Gaziantep University Sahinbey Research and Application Center Hospital
  • Izmir, Turkey (Türkiye)
    • Izmir Ege University Faculty of Medicine Hospital
  • Kayseri, Turkey (Türkiye), 8039
    • Erciyes University Faculty of Medicine Hospital
  • Kocaeli, Turkey (Türkiye)
    • Kocaeli University Application
  • Mersin, Turkey (Türkiye)
    • Mersin University
  • Samsun, Turkey (Türkiye)
    • Samsun 19 Mayıs University Health Application Research Hospital
• United Kingdom
  • Boston, United Kingdom, PE21 9QS
    • Pilgrim Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust
  • Liverpool, United Kingdom, L7 8YA
    • The Clatterbridge Cancer Centre
  • London, United Kingdom, W12 0HS
    • Imperial College Healthcare NHS Trust, Hammersmith Hospital
  • London, United Kingdom
    • University College London Hospitals
  • London, United Kingdom, SE1 9RT
    • Guy's & St Thomas NHS Foundation Trust
  • Oxford, United Kingdom
    • Oxford University Hospitals NHS Foundation Trust, Department of Haematology, Cancer and Haematology Centre, Churchill Hospital
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Western General Hospital
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Physicians P.C. dba Ironwood Cancer and Research Centers
  • California
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Center of Decatur/Cancer Care Specialists of IL
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Franciscan Health/Indiana blood and Marrow Transplantation
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute, St. Matthews Campus
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10065
      • Weill Cornell Medical College- New York Presbyterian Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center - San Antonio
  • Washington
    • Seattle, Washington, United States, 98104
      • Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Key Secondary: Absolute Change From Baseline in Total Symptom Score (TSS) at Week 24	The Total Symptom Score (TSS) at Week 24, compared to baseline, was measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represented the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflected a greater disease burden and therefore a worse outcome. The baseline TSS was calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week was determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores were available for a given week, the weekly TSS was considered missing.	Baseline, Week 24
Key Secondary: Number of Participants With TSS50 Response at Week 24	The probability of a TSS response at Week 24 was estimated by calculating the TSS response rate, defined as the percentage of patients who achieved a TSS50 response at Week 24 in each of the two treatment groups. The Total Symptom Score (TSS) response was defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0.	Week 24
Percent Change From Baseline in Total Symptom Score (TSS) at Week 24	Percent Change From Baseline in Total Symptom Score (TSS) at Week 24 measured the change in a patient's symptoms after 24 weeks of treatment, relative to baseline. A negative value indicates symptom improvement, and a reduction of ≥50% is typically considered a meaningful clinical response.	Baseline, Week 24
Number of Participants With Improvement From Baseline in Bone Marrow Fibrosis of at Least 1 Grade at Week 24	Improvement in bone marrow fibrosis by at least 1 grade, as assessed by central read compared to baseline, was analyzed by treatment group and overall. The improvement in bone marrow fibrosis grade was defined as a decrease by at least 1 grade in bone marrow fibrosis grade when compared to baseline, where a grade of MF-3 was the most severe, and MF-0 was the least severe.	Baseline, Week 24
Number of Participants With Splenic Response by Central Radiology Reads at Week 48	Splenic response is 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 48.	Week 48
Number of Participants With TSS50 Response at Week 48	The probability of a TSS response at Week 48 is estimated by calculating the TSS response rate, defined as the percentage of patients who achieve a TSS50 response at Week 48 in each of the two treatment groups. The Total Symptom Score (TSS) response is defined as a ≥50% reduction from baseline in TSS, as measured by the Myelofibrosis Symptom Assessment Form v4.0.	Week 48
Absolute Change From Baseline in Total Symptom Score (TSS) at Week 48	The Total Symptom Score (TSS) at Week 48, compared to baseline, is measured using the Myelofibrosis Symptom Assessment Form v4.0. This score represents the sum of seven individual symptom items, each rated on a 0-10 scale, resulting in a possible total daily score ranging from 0 to 70. A higher TSS reflects a greater disease burden and therefore a worse outcome. The baseline TSS is calculated as the average of non-missing daily total symptom scores over the seven-day period preceding the day of randomization. The TSS for each treatment week is determined as the average of non-missing daily total symptom scores for that week. However, if fewer than four daily scores are available for a given week, the weekly TSS is considered missing.	Baseline, Week 48
Rate of Red Blood Cell (RBC) Transfusion Over First 24 Weeks of Treatment	The rate of RBC transfusions was defined as the average number of RBC units transfused per patient month (4 weeks) during the first 24 weeks of treatment. The average number of RBC units per patient-month was calculated by dividing the total (ie, for all patients) number of RBC units in the whole exposure time by the sum of patient-months.	Week 24
Number of Participants Who Transitioned From Red Blood Cell (RBC) Transfusion Dependence to Transfusion Independence	Transfusion dependence (TD) was defined as having received ≥6 units of RBCs during the 12-week baseline period prior to dosing and Transfusion independence (TI) was defined as the absence of RBC transfusions during any continuous 12-week period of the double-blind treatment phase. The conversion from TD to TI was evaluated and defined as the proportion of patients who transitioned from transfusion dependence to transfusion independence. Patients who remained in the double-blind treatment period and had not received any RBC transfusions during the most recent 12 weeks were considered responders. Patients who discontinued from the double-blind treatment before Week 12 were classified as non-responders.	From 12-week baseline period prior to dosing to any 12-week period post baseline, up to 24 weeks
Category Change From Baseline of Patient Global Impression of Change (PGIC) at Week 24	The Patient Global Impression of Change (PGIC) was a single-item measure of the patient's perceived change in MF symptoms since starting treatment. Patients responded to: "Since beginning this study treatment, your myelofibrosis symptoms were: (1) Very much improved, (2) Much improved, (3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) Very much worse."	Baseline, Week 24
Progression-Free Survival (PFS)	Progression-Free Survival (PFS), defined as the time from randomization until documented progression, or until death from any cause for patients without documented progression	Through study completion, an average of 6 years
Overall Survival (OS)	OS, defined as the time from randomization until death from any cause	Through study completion, an average of 6 years
Proportion of Patients With Transformation to Blast Phase (AML)	Patients are categorized as having transformed to Acute Myelogenous Leukemia (AML) when the peripheral blood blast percentage increases to ≥20% and this elevation persists for at least two weeks, or when leukemic transformation is confirmed through disease status assessment.	Through study completion, an average of 6 years
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	A treatment-emergent adverse event (TEAE) for the double-blind treatment period is defined as an AE that has a start date on or after the first dose of the pelabresib/placebo and before 30 days after the last dose of pelabresib/placebo or before the start of alternative (off-study) treatment for MF, whichever occurs first. If the AE has a start date before the date of first dose but increases in severity after first dose and before 30 days post last dose will be considered a TEAE as well. An AE that occurs after the administration of the first dose of open-label pelabresib treatment will be considered treatment-emergent for the crossover treatment period. However, a TEAE for the crossover treatment period that occurs within 30 days after the last dose of pelabresib/placebo will be considered treatment emergent for the double-blind treatment period as well.	Through study completion, an average of 6 years
Pharmacokinetic (PK) Parameters for Pelabresib: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC0-t)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Pharmacokinetic (PK) Parameters for Pelabresib: Time to Reach Maximum (Peak) Plasma Concentration Following Drug Administration (Tmax)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Tmax will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Pharmacokinetic (PK) Parameters for Pelabresib: Maximum (Peak) Plasma Drug Concentration (Cmax)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. AUC0-t will be listed and summarized using descriptive statistics. Cmax will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Pharmacokinetic (PK) Parameters for Pelabresib: Effective Half-Life (T1/2)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. T1/2 will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Volume of Distribution After Non-intravenous Administration (Vd/F)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. Vd/F will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Pharmacokinetic (PK) Parameters for Pelabresib: Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F)	Pharmacokinetic (PK) parameters will be calculated based on Pelabresib plasma concentrations and actual sampling time points. CL/F will be listed and summarized using descriptive statistics.	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Ruxolitinib Plasma Concentrations in the Presence or Absence of Pelabresib	Blood samples (approximately 4 mL each) will be collected at the time points specified in the Schedule of Assessments (SOA) to determine plasma concentrations of Ruxolitinib plasma concentrations in the presence or absence of Pelabresib	Cycle 1 Day 1, Cycle 1 Day 14 and Cycle 9 Day 1: Predose, 30 minutes to 1 hour post-dose, 3 to 4.5 hours post-dose. Cycle 3 and Cycle 7 Day 1: Predose, 5 minutes post ECG assessment. 1 Cycle = 21 days
Duration of the Splenic Response	Duration of splenic response, defined as the time from onset of splenic response until the time at which the patient has a <35% decrease from baseline in spleen volume and a >25% increase from nadir, as confirmed by the central review) or death, whichever comes first	Through study completion, an average of 6 years
Number of Participants With Modified Total Symptom Score (mTSS) Response at Week 24	The modified TSS (mTSS) was defined as TSS without the fatigue sub-domain and with a total scale of 60 points versus 70 points for TSS. Patients were classified as responders if the percentage of change from baseline in mTSS was ≤ -50% at Week 24.	Week 24
Duration of the TSS50 Response	Duration of TSS response, defined as the time from onset of TSS50 response until the time at which the patient has a <50% reduction in TSS from baseline and an increase of ≥25% from nadir	Through study completion, an average of 6 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2021
• Primary Completion (Actual): August 23, 2023
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: October 20, 2020
• First Submitted That Met QC Criteria: October 21, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Estimated): December 17, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Ruxolitinib; Pelabresib
• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Hemic and Lymphatic Diseases; Primary Myelofibrosis; ruxolitinib
• Other Study ID Numbers: CDAK539A12301; CPI 0610-04 (Other Identifier: Constellation Pharmaceuticals); 2023-507954-34-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No