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

Phase 1

Active, not recruiting

• Conditions: Myelofibrosis; Leukemia, Myelocytic, Acute; Myelodysplastic/Myeloproliferative Neoplasm; Precancerous Conditions; Neoplasms; Leukemia; Primary Myelofibrosis; Bone Marrow Disease; Hematological Disease; Myeloproliferative Disorders
• Interventions: Drug: Pelabresib (CPI-0610); Drug: Ruxolitinib

• Registration Number: NCT02158858
• Lead Sponsor: Constellation Pharmaceuticals

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-06-05
• Study First Submitted QC: 2014-06-05
• Study First Posted: 2014-06-09
• Study Start: 2014-07-16
• Status Verified: 2024-03
• Last Update Submitted: 2024-10-31
• Last Update Posted: 2024-11-04
• Primary Completion: 2025-01
• Study Completion: 2025-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 336

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

Read More

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.

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm (MF patients treated with pelabresib alone)	Pelabresib (CPI-0610)	* 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)
Arm 2: Prior JAKi Combination Arm	Pelabresib (CPI-0610)	* 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)
Arm 2: Prior JAKi Combination Arm	Ruxolitinib	* 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)
Arm 3: JAKi Naïve Combination Arm	Pelabresib (CPI-0610)	Open to patients with MF who have not previously received a JAKi (pelabresib + Ruxolitinib) and have DIPSS risk category Intermediate-2 or higher
Arm 4: Essential Thrombocythemia (ET) Monotherapy Arm	Pelabresib (CPI-0610)	Open to high-risk patients with ET who are resistant or intolerant to hydroxyurea (HU)
Arm 3: JAKi Naïve Combination Arm	Ruxolitinib	Open to patients with MF who have not previously received a JAKi (pelabresib + Ruxolitinib) and have DIPSS risk category Intermediate-2 or higher

Primary Outcome Measures

Name	Time	Method
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 (Cohorts 1B and 2B and Arm 3): Evaluate the spleenic response	By imaging after 24 weeks
Phase 2 (Arm 4): Evaluate the complete hematological response rate	1 cycle (21 days)

Secondary Outcome Measures

Name	Time	Method
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 (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): maximum observed plasma concentration (Cmax)	Assessed during Cycle 1 (first 21 days on study)

Trial Locations

Locations (48)

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

UZ Leuven - Campus Gasthuisberg; 🇧🇪 Leuven, Viaams Braban, Belgium

ICAHN School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States

Washington University School of Medicne Neuromuscular Division Department of Neurology Research; 🇺🇸 Saint Louis, Missouri, United States

Weill Medical College and New York Presbyterian Hospital; 🇺🇸 New York, New York, United States

CHU - Hopital Saint Louis - Centre D'Investigations Clinique; 🇫🇷 Paris, France

UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

Northwestern University - Lurie Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

Maastricht University Medical Center; 🇳🇱 Maastricht, Limburg, Netherlands

Institut de cancérologie du Gard - Hematologie clinique; 🇫🇷 Nîmes, Gard, France

The Christie Hospital; 🇬🇧 Manchester, United Kingdom

AOU Maggiore della Carità; 🇮🇹 Novara, Italy

University of Michigan Medical Center; 🇺🇸 Ann Arbor, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan; 🇧🇪 Brugge, West-Vlaanderen, Belgium

ZNA Stuyvenberg Antwerpen; 🇧🇪 Antwerpen, Belgium

Froedtert & Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University of Alberta Hospital; 🇨🇦 Edmonton, Alberta, Canada

Princess Margaret Cancer Centre; 🇨🇦 Toronto, Ontario, Canada

St. Paul's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

Juravinski Cancer Centre; 🇨🇦 Hamilton, Ontario, Canada

Jewish General Hospital; 🇨🇦 Montreal, Quebec, Canada

Institut Gustave Roussy; 🇫🇷 Villejuif, Ile-de-France, France

CHRU de Lille - Hopital Claude Huriez; 🇫🇷 Toulouse, Haute-Garonne, France

CHRU de Lille - Hopital Claude Huriez - Maladies du Sang; 🇫🇷 Lille, Nord-Pas-de-Calais, France

Universitätsklinikum Leipzig AöR; 🇩🇪 Leipzig, Sachsen, Germany

Institue of Hematology "L. and A. Seràgnoli"; 🇮🇹 Bologna, Emilia-Romagna, Italy

Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini; 🇮🇹 Rimini, Emilia-Romagna, Italy

AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can; 🇮🇹 Genova, Liguria, Italy

IRCCS Policlinico San Matteo, Università degli studi di Pavi; 🇮🇹 Pavia, Lombardia, Italy

Azienda Ospedaliero-Universitaria Careggi; 🇮🇹 Firenze, Italy

Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda; 🇮🇹 Milano, Lombardia, Italy

Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon; 🇮🇹 Varese, Lombardia, Italy

Erasmus Universitair Medisch Centrum Rotterdam; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

VUmcResearch B.V.; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Instytut Hematologii i Transfuzjologii w Warszawie; 🇵🇱 Warszawa, Mazowieckie, Poland

Uniwersyteckie Centrum Kliniczne; 🇵🇱 Gdańsk, Pomorskie, Poland

Oxford University Hospitals; 🇬🇧 Headington, Oxford, United Kingdom

Belfast City Hospital; 🇬🇧 Belfast, United Kingdom

University College London Hospital's NHS foundation Trust; 🇬🇧 London, United Kingdom

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

University Hospital of Wales; 🇬🇧 Cardiff, United Kingdom

Guys and St Thomas' Hospital - Haematology; 🇬🇧 London, United Kingdom

Universitätsklinikum Bonn; 🇩🇪 Bonn, Nordrhein-Westfalen, Germany

University of Cambridge; 🇬🇧 Cambridge, United Kingdom

Mayo Clinic Jacksonville; 🇺🇸 Jacksonville, Florida, United States