A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis

A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (Dose Escalation of CPI-0610 in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis and Essential Thrombocytopenia)

Phase 1 Part (Complete): Open-label, sequential dose escalation study of pelabresib in patients with previously treated Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasms, and Myelofibrosis.

Phase 2 Part: Open-label study of CPI-0610 with and without Ruxolitinib in patients with Myelofibrosis.

CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.

Study Overview

• Status: Active, not recruiting
• Conditions: Neoplasms; Neoplasms by Histologic Type; Leukemia; Preleukemia; Primary Myelofibrosis; Myeloproliferative Disorders; Myelofibrosis; Precancerous Conditions; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic Syndrome (MDS); Leukemia, Myelocytic, Acute; Bone Marrow Disease; Hematological Disease; Essential Thrombocytosis
• Intervention / Treatment: Drug: Pelabresib (CPI-0610); Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Actual): 336
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuyvenberg Antwerpen
  • Viaams Braban
    • Leuven, Viaams Braban, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg
  • West-Vlaanderen
    • Brugge, West-Vlaanderen, Belgium, 8000
      • AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2A5
      • St. Paul's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• France
  • Paris, France, 75010
    • CHU - Hopital Saint Louis - Centre D'Investigations Clinique
  • Gard
    • Nîmes, Gard, France, 30029
      • Institut de cancérologie du Gard - Hematologie clinique
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • CHRU de Lille - Hopital Claude Huriez
  • Ile-de-France
    • Villejuif, Ile-de-France, France, 94805
      • Institut Gustave Roussy
  • Nord-Pas-de-Calais
    • Lille, Nord-Pas-de-Calais, France, 59037
      • CHRU de Lille - Hôpital Claude Huriez - Maladies du Sang
• Germany
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • Universitätsklinikum Bonn
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitätsklinikum Leipzig AöR
• Italy
  • Firenze, Italy, 50134
    • Azienda Ospedaliero-Universitaria Careggi
  • Novara, Italy, 28100
    • AOU Maggiore della Carità
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Institue of Hematology "L. and A. Seràgnoli"
    • Rimini, Emilia-Romagna, Italy, 47923
      • Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini
  • Liguria
    • Genova, Liguria, Italy, 16132
      • AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
    • Pavia, Lombardia, Italy, 27100
      • IRCCS Policlinico San Matteo, Università degli studi di Pavi
    • Varese, Lombardia, Italy, 21100
      • Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon
• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Maastricht University Medical Center
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • VUmcResearch B.V.
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 AA
      • Erasmus Universitair Medisch Centrum Rotterdam
• Poland
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-776
      • Instytut Hematologii i Transfuzjologii w Warszawie
  • Pomorskie
    • Gdańsk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Belfast City Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • University of Cambridge
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, NW1 2PG
    • University College London Hospital's NHS foundation Trust
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas' Hospital - Haematology
  • Manchester, United Kingdom, M20 4BX
    • The Christie Hospital
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 7LE
      • Oxford University Hospitals
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University - Lurie Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicne Neuromuscular Division Department of Neurology Research
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Weill Medical College and New York Presbyterian Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The University Of Texas MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Phase 2 part: Patients with confirmed diagnosis of MF who meet all of the following criteria:

• ANC ≥ 1 x 10^9/L without the assistance of granulocyte growth factors
• Peripheral blood blast count <10%
• ECOG performance status ≤ 2.
• Adequate hematological, renal, hepatic, and coagulation laboratory assessments
• No prior treatment with a BET inhibitor
• Patients must give written informed consent to participate in this study before the performance of any study-related procedure.

For Arm 1 and 2 the following criteria should be considered:

• Patients with confirmed diagnosis of MF who meet all of the following criteria
• Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-2 or higher
• Spleen volume ≥ 450 cm^3 by MRI or CT for Cohorts 1B and 2B OR RBC transfusion dependent (defined as an average of ≥2 units of RBC transfusions per month (total of greater than 6 RBC transfusions) over the 12 weeks prior to enrollment for Cohorts 1A and 2A)
• At least 2 symptoms measurable (Score ≥ 1) using the Myelofibrosis Symptom Assessment Form Version 4.0 (MFSAF v4.0)
• Platelet count ≥ 75 x 10^9/L without the assistance of thrombopoietic factors or transfusions for at least 14 days
• Arm (Arm 1): Previously treated with a JAK inhibitor and be intolerant, resistant, refractory, or lost response to the JAK inhibitor; have not received the JAK inhibitor within 2 weeks prior to the start of study drug, or are ineligible to be treated with a JAK inhibitor
• Combination Arm (Arm 2): Must have received single agent ruxolitinib and be on a stable dose for a minimum 8 weeks but have disease that is not being adequately controlled by ruxolitinib

For Arm 3 (JAK inhibitors naïve) the following criteria should be considered:

• Patients with confirmed diagnosis of MF who meet all of the following criteria
• Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-2 or higher
• Platelet count ≥ 100 x 10^9/L without the assistance of thrombopoietic factors or transfusions
• Spleen volume ≥ 450 cm^3 by MRI/CT
• At least 2 symptoms measurable (Score ≥ 3) or a total score of ≥ 10 using the Myelofibrosis Symptom Assessment Form Version 4.0 ( MFSAF v4.0)
• No prior treatment with JAKi allowed

For Arm 4 (ET Expansion) the following criteria should be considered:

• Patients with a confirmed diagnosis of ET
• High-risk disease, defined as meeting at least one of the following criteria:
• Age > 60 years
• Platelet count > 1500 × 10^9/L (at any point during the patient's disease)
• Previously documented thrombosis, erythromelalgia, or migraine
• Previous hemorrhage related to ET
• Diabetes or hypertension requiring pharmacological therapy for > 6 months

• Have ≥2 symptoms with an average score ≥ 3 over the 7-day period prior to Cycle 1 Day 1 or an average total score of ≥15 over the 7-day period prior to Cycle 1 Day 1 using the using the MPN SAF

  • Platelets > 600 × 10^9/L
  • Resistant or intolerant to HU

Exclusion Criteria:

• Current known active or chronic infection with human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C.
• Impaired cardiac function or clinically significant cardiac diseases
• Patients with Child-Pugh Class B or C
• Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of pelabresib and/or ruxolitinib, including any unresolved nausea, vomiting, or diarrhea that is CTCAE Grade >1
• Prior treatment with a BET inhibitor.
• Pregnant or lactating women
• Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study
• Patients unwilling or unable to comply with this study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm (MF patients treated with pelabresib alone); Cohort 1A: Open to patients with MF who are Transfusion Dependent (TD) and who have previously been treated with a JAKi and are intolerant, resistant, refractory or lost response to the JAKi, or are ineligible to be treated with a JAKi (pelabresib alone); Cohort 1B: Open to patients with MF who are not TD and who have previously been treated with a JAKi and are intolerant, resistant, refractory or lost response to the JAKi, or are ineligible to be treated with a JAKi. (CPI-0610 alone)	Drug: Pelabresib (CPI-0610)
Experimental: Arm 2: Prior JAKi Combination Arm; Cohort 2A: Open to patients with MF who are Transfusion Dependent (TD) and are currently taking ruxolitinib but have disease that is not being adequately controlled by ruxolitinib (pelabresib + Ruxolitinib); Cohort 2B: Open to patients with MF who are not TD and are currently taking ruxolitinib but have disease that is not being adequately controlled by ruxolitinib. (CPI-0610 + Ruxolitinib)	Drug: Pelabresib (CPI-0610); Drug: Ruxolitinib
Experimental: Arm 3: JAKi Naïve Combination Arm; Open to patients with MF who have not previously received a JAKi (pelabresib + Ruxolitinib) and have DIPSS risk category Intermediate-2 or higher	Drug: Pelabresib (CPI-0610); Drug: Ruxolitinib
Experimental: Arm 4: Essential Thrombocythemia (ET) Monotherapy Arm; Open to high-risk patients with ET who are resistant or intolerant to hydroxyurea (HU)	Drug: Pelabresib (CPI-0610)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate the spleenic response	By imaging after 24 weeks
Phase 2 (Cohorts 1A and 2A): Evaluate the RBC (Red Blood Cell) transfusion independence rate	Absence of RBC transfusion and no hemoglobin level below 8 g/dL in the prior 12 weeks
Phase 2 (Arm 4): Evaluate the complete hematological response rate	1 cycle (21 days)

Secondary Outcome Measures

Outcome Measure	Time Frame
Phase 2 (Arms 1, 2, and 3): Evaluate the duration of the spleenic response by imaging	Through study completion or end of treatment, up to 24 weeks and beyond
Phase 2 (all arms): Evaluate the change in patient reported outcomes	Changes from baseline in the total symptom score (MFSAF v4.0) and PGIC after 24 weeks
Phase 2 (all arms): area under the curve (AUC)	Assessed during Cycle 1 (first 21 days on study)
Phase 2 (all arms): maximum observed plasma concentration (Cmax)	Assessed during Cycle 1 (first 21 days on study)

Other Outcome Measures

Outcome Measure	Time Frame
Phase 2 (Arms 1, 2, and 3): Evaluate response category rate	Rate of response by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria after 24 weeks
Phase 2 (Arms 1, 2, and 3): Evaluate the rate of RBC transfusion and the RBC transfusion dependence rate	Average number of RBC units per subject-month, up to 24 weeks and beyond

Collaborators and Investigators

• Sponsor: Constellation Pharmaceuticals
• Collaborators: The Leukemia and Lymphoma Society

Publications and helpful links

General Publications

• Zavidij O, Haradhvala NJ, Meyer R, Cui J, Verstovsek S, Oh S, Mead A, Taverna P. MPN-238 Single-Cell RNA Profiling of Myelofibrosis Patients Reveals Pelabresib-Induced Decrease of Megakaryocytic Progenitors and Normalization of CD4+ T Cells in Peripheral Blood. Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S331-S332. doi: 10.1016/S2152-2650(22)01448-3.

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2014
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 5, 2014
• First Posted (Estimated): June 9, 2014

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Ruxolitinib; Phase 1; Oncology; Phase 2; BET Inhibitor; Pelabresib
• Additional Relevant MeSH Terms: Hemorrhagic Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Neoplasms; Myelodysplastic Syndromes; Primary Myelofibrosis; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Thrombocytosis; Thrombocythemia, Essential; Hematologic Diseases; Bone Marrow Diseases; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Precancerous Conditions; Neoplasms by Histologic Type
• Other Study ID Numbers: 0610-02; 2018-000579-34 (EudraCT Number)