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AzTrials

MyelofibrosisPhase 3MANIFEST-2NCT04603495

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

A Phase 3 study testing Pelabresib and Ruxolitinib in people with Myelofibrosis and Primary Myelofibrosis, run by Novartis Pharmaceuticals at 156 sites in 22 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pelabresib and Ruxolitinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
430 participants
Where
156 sitesin 22 countries
Study dates
9 Apr 2021to 30 Jun 2027
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

156 sites in 22 countries.

156 sites in 22 countries

United States20 sites

  • University of Michigan Medical Center

    Ann Arbor, Michigan, 48109

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294-3300

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

    Chandler, Arizona, 85224

  • Cleveland Clinic Taussig Cancer Center

    Cleveland, Ohio, 44195

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

    Decatur, Illinois, 62526

  • MD Anderson Cancer Center

    Houston, Texas, 77030

  • Franciscan Health/Indiana blood and Marrow Transplantation

    Indianapolis, Indiana, 46237

  • Mayo Clinic

    Jacksonville, Florida, 32224

  • UC San Diego Moores Cancer Center

    La Jolla, California, 92093

  • USC/Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • UCLA Medical Center

    Los Angeles, California, 90095

  • Norton Cancer Institute, St. Matthews Campus

    Louisville, Kentucky, 40207

  • Yale University School of Medicine

    New Haven, Connecticut, 06510

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • Weill Cornell Medical College- New York Presbyterian Hospital

    New York, New York, 10065

  • University of Texas Health Science Center - San Antonio

    San Antonio, Texas, 78229

  • Center for Blood Disorders and Cellular Therapy, Swedish Cancer Institute

    Seattle, Washington, 98104

  • Washington University

    St Louis, Missouri, 63110

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

South Korea16 sites

  • Inje University Haeundae Paik Hospital

    Busan, 48108

  • Pusan National University Hospital

    Busan, 49241

  • Inje University Busan Paik Hospital

    Busan

  • Kyungpook National University Hospital

    Daegu, 41944

  • Daegu Catholic University Medical Center

    Daegu

  • The Catholic University Of Korea St. Vincent Hospital

    Gyeonggi-do

  • Gachon University Gil Medical Center

    Incheon

  • Jeonbuk National University Hospital

    Jeonju, 54907

  • Gyeongsang National University Hospital

    Jinju, Gyeongsangnam-do

  • Severance Hospital, Yonsei University Health System

    Seoul, 03722

  • Samsung Medical Center

    Seoul, 135-710

  • Korea University Anam Hospital

    Seoul

  • Seoul National University Hospital

    Seoul

  • The Catholic University of Korea

    Seoul

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

    Seoul

  • Ulsan University Hospital

    Ulsan

Other trials in South Korea

Italy15 sites

  • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII

    Bergamo, 24127

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

    Bologna, 40138

  • Regional Hospital Spedali Civili di Brescia

    Brescia, 25123

  • Azienda Ospedaliera Universitaria Arcispedale Sant'Anna

    Ferrara

  • Azienda Ospedaliera Universitaria Careggi

    Florence

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

    Meldola

  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

    Milan

  • Azienda Ospedaliera San Gerardo di Monza

    Monza

  • University Hospital Maggiore della Carità

    Novara, 28100

  • AOU S.Luigi Gonzaga

    Orbassano

  • University Hospital of Padova

    Padova, 35128

  • University Hospital 'Paolo Giaccone' Polyclinic

    Palermo, 90127

  • Ospedale Sant'Eugenio

    Rome

  • Hospital Ordine Mauriziano of Turin

    Turin, 10128

  • Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi

    Varese

Other trials in Italy

Spain12 sites

  • ICO Badalona - Hospital Universitari Germans Trias i Pujol

    Badalona, 8916

  • Hospital Clinic de Barcelona

    Barcelona

  • Vall d'Hebron Institute of Oncology

    Barcelona

  • Hospital San Pedro de Alcantara

    Cáceres, 10003

  • Hospital Universitario de Gran Canaria Dr. Negrin

    Las Palmas de Gran Canaria, 35010

  • Quirónsalud Madrid University Hospital

    Madrid, 28223

  • Morales Meseguer General University Hospital

    Murcia, 30008

  • Hospital Universitario Central de Asturias

    Oviedo, Principality of Asturias, 33011

  • Hospital Universitario de Salamanc

    Salamanca, 37007

  • Hospital Virgen Macarena

    Seville

  • University Hospital of Toledo

    Toledo, 45007

  • Hospital Clínico Universitario de Valencia

    Valencia, 46010

Other trials in Spain

Turkey (Türkiye)10 sites

  • Ankara University Faculty of Medicine Cebeci Research and Application Hospital

    Ankara

  • Dr. Abdurrahman Yurtaslan Oncology Health Application and Research Center

    Ankara

  • Antalya Medstar Hospital

    Antalya

  • Edirne Trakya University Faculty of Medicine Hospital

    Edirne

  • Gaziantep University Sahinbey Research and Application Center Hospital

    Gaziantep

  • Izmir Ege University Faculty of Medicine Hospital

    Izmir

  • Erciyes University Faculty of Medicine Hospital

    Kayseri, 8039

  • Kocaeli University Application

    Kocaeli

  • Mersin University

    Mersin

  • Samsun 19 Mayıs University Health Application Research Hospital

    Samsun

Other trials in Turkey (Türkiye)

France9 sites

  • Amiens South Hospital univerisy - Hopital Sud

    Amiens, 80054

  • Centre Hospitalier

    Le Mans, 72000

  • Hôpital l'Archet 1

    Nice, 06202

  • Gard Cancer Institute

    Nîmes, 30029

  • Centre Hospitalier Lyon Sud Secteur 1G

    Pierre-Bénite, 69310

  • Chu Pontchaillou - Service Hematologie

    Rennes, 35033

  • Institut de Cancérologie Lucien Neuwirth

    Saint-Priest-en-Jarez, 42271

  • Hôpital Bretonneau

    Tours, 37044

  • Chru Brabois

    Vandœuvre-lès-Nancy, 54500

Other trials in France

Israel9 sites

  • Shamir Medical Center

    Be’er Ya‘aqov, 60930000

  • Soroka Medical Center

    Beersheba, 84101

  • Rambam Health Corporation

    Haifa, 3109601

  • Lady Davis Carmel Medical Center

    Haifa, 3436212

  • Wolfson Medical Center

    Holon

  • Hadassah University Hospital-Ein Kerem

    Jerusalem, 9590300

  • Shaarei Zedek

    Nahariya, 2210001

  • Rabin Medical Center - Beilinson Campus,

    Petah Tikva, 49100

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 6423906

Other trials in Israel

United Kingdom9 sites

  • Pilgrim Hospital

    Boston, PE21 9QS

  • Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust

    Cambridge, CB2 0QQ

  • University Hospital of Wales

    Cardiff, Wales, CF14 4XW

  • Western General Hospital

    Edinburgh, Scotland, EH4 2XU

  • The Clatterbridge Cancer Centre

    Liverpool, L7 8YA

  • Guy's & St Thomas NHS Foundation Trust

    London, SE1 9RT

  • Imperial College Healthcare NHS Trust, Hammersmith Hospital

    London, W12 0HS

  • University College London Hospitals

    London

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

    Oxford

Other trials in United Kingdom

Australia6 sites

  • Royal Adelaide Hospital

    Adelaide, South Australia, 5000

  • Icon Cancer Centre

    Brisbane, Queensland, 4101

  • USC Clinical Trials Centre Sunshine Coast Haematology and Oncology Clinic

    Buderim, QLD 4556

  • Monash Health

    Clayton, Victoria, 3168

  • Peninsula Private Hospital Clinical Trials Unit

    Frankston, Victoria, 3199

  • One Clinical Research PTY LTD

    Nedlands, 6009

Other trials in Australia

Malaysia6 sites

  • Hospital Sultanah Bahiyah

    Alor Star, Kedah, 05460

  • :Hospital Ampang

    Ampang, Selangor, 68000

  • Hospital Pulau Pinang

    George Town, Pulau Pinang, 10450

  • Hospital Sultanah Aminah

    Johor Bahru, Johor, 80100

  • Hospital Queen Elizabeth

    Kota Kinabalu, 88586

  • Sunway Medical Centre

    Petaling Jaya, Selangor, 47500

Other trials in Malaysia

Belgium5 sites

  • ZNA

    Antwerp

  • Cliniques universitaires Saint-Luc

    Brussels, 1200

  • Hôpital de Jolimont

    La Louvière, 7100

  • UZ Leuven

    Leuven

  • Domaine Universitaire du Sart Tilman

    Liège, 4000

Other trials in Belgium

Canada5 sites

  • Tom Baker Cancer Centre

    Calgary, Alberta, T2N 4N2

  • University of Alberta Hospital

    Edmonton, Alberta, T6G 2B7

  • London Health Sciences Center - Victoria Hospital

    London, Ontario, N6A 5W9

  • Jewish General Hospital

    Montreal, Quebec, H3T 1E2

  • Princess Margaret Cancer Center

    Toronto, Ontario, M5G 2M9

Other trials in Canada

Germany5 sites

  • Hämatologisch-Onkologische Praxis Augsburg

    Augsburg, Bavaria, 86151

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

    Halle, Saxony, 06120

  • University Hospital Hamburg-Eppendorf

    Hamburg, 20246

  • Universitätsklinikum Jena, Klinik für Innere Medizin II

    Jena, Thuringia, 07747

  • Universitätsklinikum Ulm

    Ulm, Baden-Wurttemberg, 89081

Other trials in Germany

Poland5 sites

  • Wojewódzki Szpital Specjalistyczny w Bialej Podlaskiej

    Biała Podlaska, 21-50

  • Uniwersyteckie Centrum Kliniczne

    Gdansk, 80-293

  • Pratia Onkologia Katowice

    Katowice

  • Centrum Medyczne Pratia

    Skorzewo, 60-185

  • Nasz Lekarz Przychodnie Medyczne

    Torun, 87-100

Other trials in Poland

Thailand5 sites

  • Chulabhorn Hospital

    Bangkok, Lak Si, 10210

  • King Chulalongkorn Memorial Hospital

    Bangkok, Pathumwan, 10330

  • Rajavithi Hospital

    Bangkok, Ratchathewi District, 10400

  • Srinagarind hospital,Khon Kaen University

    Khon Kaen, Mueang Khon Kaen District, 40002

  • Songklanagarind Hospital

    Songkhla, Hat Yai District, 90110

Other trials in Thailand

Austria4 sites

  • LKH - Universitätsklinikum Graz; Abteilung für Hämatologie

    Graz, A-8036

  • Krankenhaus der Elisabethinen Linz

    Linz, 4020

  • Kepler University Hospital

    Linz, 4021

  • University Hospital Salzburg

    Salzburg, 5020

Other trials in Austria

Taiwan4 sites

  • Chang Gung Memorial Hospital Chiayi

    Chiayi City

  • China Medical University Hospital

    Chiayi City

  • Taichung Veterans General Hospital

    Taichung

  • National Taiwan University Hospital

    Taipei

Other trials in Taiwan

Greece3 sites

  • Laiko General Hospital

    Athens

  • UGH of Ioannina

    Ioannina, 455 00

  • University General Hospital of Patras

    Rio, 26504

Other trials in Greece

Czechia2 sites

  • Fakultni nemocnice Hradec Kralove

    Hradec Králové, 500 05

  • University Hospital Olomouc

    Olomouc, 779 00

Other trials in Czechia

Hong Kong2 sites

  • Princess Margaret Hospital

    Hong Kong, Kowloon

  • Prince of Wales Hospital

    Hong Kong, New Territories

Other trials in Hong Kong

Hungary2 sites

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

    Nyíregyháza

  • : Pecs University, 1st Department of Medicine

    Pécs, Pecs, 7624

Other trials in Hungary

Netherlands2 sites

  • Amsterdam UMC

    Amsterdam, 1081

  • Maastricht University Medical Center

    Maastricht, 6229 HX

Other trials in Netherlands

About this study

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

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.

Being tested
Pelabresib, Ruxolitinib, Placebo
Keywords
Pelabresib, Ruxolitinib
Medical subject headings
Primary Myelofibrosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PelabresibDrug

    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.

  • RuxolitinibDrug

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

  • PlaceboDrug

    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.

Study groups in NCT04603495
Study groupRoleWhat they receive
Pelabresib + ruxolitinibExperimentalPelabresib monohydrate tablets + ruxolitinib phosphate tablets
Receives: Drug: Pelabresib; Drug: Ruxolitinib
Placebo + ruxolitinibActive comparatorMatching placebo tablets + ruxolitinib phosphate tablets
Receives: Drug: Ruxolitinib; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Week 24

Secondary outcomes (24)

  1. 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.

    Measured: Baseline, Week 24

  2. 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.

    Measured: Week 24

  3. 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.

    Measured: Baseline, Week 24

  4. 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.

    Measured: Baseline, Week 24

  5. 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.

    Measured: Week 48

  6. 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.

    Measured: Week 48

  7. 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.

    Measured: Baseline, Week 48

  8. 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.

    Measured: Week 24

  9. 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.

    Measured: From 12-week baseline period prior to dosing to any 12-week period post baseline, up to 24 weeks

  10. 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."

    Measured: Baseline, Week 24

  11. 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

    Measured: Through study completion, an average of 6 years

  12. Overall Survival (OS)

    OS, defined as the time from randomization until death from any cause

    Measured: Through study completion, an average of 6 years

  13. 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.

    Measured: Through study completion, an average of 6 years

  14. 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.

    Measured: Through study completion, an average of 6 years

  15. 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.

    Measured: 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

  16. 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.

    Measured: 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

  17. 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.

    Measured: 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

  18. 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.

    Measured: 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

  19. 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.

    Measured: 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

  20. 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.

    Measured: 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

  21. 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

    Measured: 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

  22. 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

    Measured: Through study completion, an average of 6 years

  23. 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.

    Measured: Week 24

  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

    Measured: Through study completion, an average of 6 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Oct 2020
  2. Study start9 Apr 2021
  3. Primary completion23 Aug 2023
  4. Study completion30 Jun 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
430 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04603495
Sponsor's protocol ID
CDAK539A12301
Other IDs
2023-507954-34-00, CPI 0610-04, 2023
Acronym
MANIFEST-2
Status last verified
Jul 2026
First submitted
20 Oct 2020
Last updated
17 Jul 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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

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.

    PubMed 35950489

  • 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.

    PubMed 40065169

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Pelabresib and Ruxolitinib in people with Myelofibrosis and Primary Myelofibrosis, run by Novartis Pharmaceuticals at 156 sites in 22 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 17 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 156 sites in United States, South Korea, Italy, Spain, Turkey (Türkiye) and 17 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Splenic Response by Central Radiology Reads at Week 24 (time frame: Week 24). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04603495, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2026.

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