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MANIFEST-2, A GLOBAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL STUDY OF PELABRESIB (CPI-0610) AND RUXOLITINIB VS PLACEBO AND RUXOLITINIB IN JAK INHIBITOR-NAÏVE MYELOFIBROSIS PATIENTS
Author(s): ,
Claire Harrison
Affiliations:
Guy's and St Thomas' NHS Foundation Trust,London,Royaume-uni;Guy's and St Thomas' NHS Foundation Trust,London,Vereinigtes Königreich;Guy's and St Thomas' NHS Foundation Trust,London,Regno Unito;Guy's and St Thomas' NHS Foundation Trust,London,United Kingdom;Guy's and St Thomas' NHS Foundation Trust,London,Reino Unido;Guy's and St Thomas' NHS Foundation Trust,London,Verenigd Koninkrijk;Guy's and St
,
Raajit K Rampal
Affiliations:
Memorial Sloan-Kettering Cancer Center,New York, NY,États-unis;Memorial Sloan-Kettering Cancer Center,New York, NY,Vereinigte Staaten;Memorial Sloan-Kettering Cancer Center,New York, NY,Stati Uniti;Memorial Sloan-Kettering Cancer Center,New York, NY,United States;Memorial Sloan-Kettering Cancer Center,New York, NY,Estados Unidos;Memorial Sloan-Kettering Cancer Center,New York, NY,Verenigde Staten;
,
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Kanada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canadá;Princess Margaret Cancer Centre, University of Tor
,
Srdan Verstovsek
Affiliations:
Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,États-unis;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Vereinigte Staaten;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,Stati Uniti;Leukemia Department, University of Texas MD Anderson Cancer Center,Houston, TX,United States;Leukemia Department, Univers
,
Moshe Talpaz
Affiliations:
University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,États-unis;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Vereinigte Staaten;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Stati Uniti;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,United States;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Estados Unidos;Univ
,
Jean-Jacques Kiladjian
Affiliations:
Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Frankreich;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,Frankrijk;Hôpital Saint-Louis, Université de Paris,Paris,França;Hôpital Saint
,
Ruben Mesa
Affiliations:
Mays Cancer Center at UT Health San Antonio MD Anderson Cencer Center,San Antonio, TX,États-unis;Mays Cancer Center at UT Health San Antonio MD Anderson Cencer Center,San Antonio, TX,Vereinigte Staaten;Mays Cancer Center at UT Health San Antonio MD Anderson Cencer Center,San Antonio, TX,Stati Uniti;Mays Cancer Center at UT Health San Antonio MD Anderson Cencer Center,San Antonio, TX,United States;
,
Andrew Kuykendall
Affiliations:
Mofitt Cancer Center,Tampa, FL,États-unis;Mofitt Cancer Center,Tampa, FL,Vereinigte Staaten;Mofitt Cancer Center,Tampa, FL,Stati Uniti;Mofitt Cancer Center,Tampa, FL,United States;Mofitt Cancer Center,Tampa, FL,Estados Unidos;Mofitt Cancer Center,Tampa, FL,Verenigde Staten;Mofitt Cancer Center,Tampa, FL,Estados Unidos;Mofitt Cancer Center,Tampa, FL,United States;Mofitt Cancer Center,Tampa, FL,USA
,
Alessandro Vannucchi
Affiliations:
Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italie;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italien;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italia;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italy;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Floren
,
Francesca Palandri
Affiliations:
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italie;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italien;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologna,Italia;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli',Bologn
,
Sebastian Grosicki
Affiliations:
Medical University of Silesia in Katowice,Katowice,Pologne;Medical University of Silesia in Katowice,Katowice,Polen;Medical University of Silesia in Katowice,Katowice,Polonia;Medical University of Silesia in Katowice,Katowice,Poland;Medical University of Silesia in Katowice,Katowice,Polonia;Medical University of Silesia in Katowice,Katowice,Polen;Medical University of Silesia in Katowice,Katowice,
,
Timothy Devos
Affiliations:
University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgique;University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgien;University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven,Leuven,Belgio;University Hospitals Leuven and Laboratory of Molecular Immunology (Re
,
Eric Jourdan
Affiliations:
C.H.U,Nîmes,France;C.H.U,Nîmes,Frankreich;C.H.U,Nîmes,Francia;C.H.U,Nîmes,France;C.H.U,Nîmes,Francia;C.H.U,Nîmes,Frankrijk;C.H.U,Nîmes,França;C.H.U,Nîmes,Франция ;C.H.U,Nîmes,Frankrike
,
Marielle J Wondergem
Affiliations:
Amsterdam University Medical Centers,Amsterdam,Pays-bas;Amsterdam University Medical Centers,Amsterdam,Niederlande;Amsterdam University Medical Centers,Amsterdam,Paesi Bassi;Amsterdam University Medical Centers,Amsterdam,Netherland;Amsterdam University Medical Centers,Amsterdam,Países Bajos;Amsterdam University Medical Centers,Amsterdam,Nederland;Amsterdam University Medical Centers,Amsterdam,Hola
,
Haifa Kathrin Al-Ali
Affiliations:
University Hospital Halle,Halle,Allemagne;University Hospital Halle,Halle,Deutschland;University Hospital Halle,Halle,Germania;University Hospital Halle,Halle,Germany;University Hospital Halle,Halle,Alemania;University Hospital Halle,Halle,Duitsland;University Hospital Halle,Halle,Alemanha;University Hospital Halle,Halle,Германия;University Hospital Halle,Halle,Tyskland
,
Veronika Buxhofer-Ausch
Affiliations:
KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Autriche;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Österreich;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Austria;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Austria;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Austria;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Oostenrijk;KRANKENHAUS DER ELISABETHINEN Linz GmbH,Linz,Áustria;KRANKENHAUS DER ELISAB
,
Alberto Alvarez-Larrán
Affiliations:
Hospital Clínic Barcelona,Barcelona,Espagne;Hospital Clínic Barcelona,Barcelona,Spanien;Hospital Clínic Barcelona,Barcelona,Spagna;Hospital Clínic Barcelona,Barcelona,Spain;Hospital Clínic Barcelona,Barcelona,España;Hospital Clínic Barcelona,Barcelona,Spanje;Hospital Clínic Barcelona,Barcelona,Espanha;Hospital Clínic Barcelona,Barcelona,Испания;Hospital Clínic Barcelona,Barcelona,Spanien
,
Sanjay Akhani
Affiliations:
MorphoSys AG,Planegg,Allemagne;MorphoSys AG,Planegg,Deutschland;MorphoSys AG,Planegg,Germania;MorphoSys AG,Planegg,Germany;MorphoSys AG,Planegg,Alemania;MorphoSys AG,Planegg,Duitsland;MorphoSys AG,Planegg,Alemanha;MorphoSys AG,Planegg,Германия;MorphoSys AG,Planegg,Tyskland
,
Rafael Muñoz-Carerras
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Yury Sheykin
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Gozde Colak
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Morgan Harris
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
John Mascarenhas
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
(Abstract release date: 05/12/22) EHA Library. Harrison C. 06/10/22; 357889; P1030
Prof. Dr. Claire Harrison
Prof. Dr. Claire Harrison
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1030

Type: Poster presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively.

Aims
MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post‑essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment.

Methods
The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 109/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 109/L vs 100–200 × 109/L) and spleen volume (≥1800 cm3 vs <1800 cm3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7‑day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks.

Results
Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020.

Conclusion
MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keyword(s): Clinical trial, Janus Kinase inhibitor, Myelofibrosis

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1030

Type: Poster presentation

Session title: Myeloproliferative neoplasms - Clinical

Background
Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively.

Aims
MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post‑essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment.

Methods
The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 109/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 109/L vs 100–200 × 109/L) and spleen volume (≥1800 cm3 vs <1800 cm3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7‑day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks.

Results
Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020.

Conclusion
MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keyword(s): Clinical trial, Janus Kinase inhibitor, Myelofibrosis

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