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

Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02158858
• Other study ID #: 0610-02
• Secondary ID: 2018-000579-34
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: July 16, 2014
• Est. completion date: October 31, 2024

Study information

• Verified date: March 2024
• Source: Constellation Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 336
• Est. completion date: October 31, 2024
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bone Marrow Disease
• Bone Marrow Diseases
• Essential Thrombocytosis
• Hematologic Diseases
• Hematological Disease
• Leukemia
• Leukemia, Myelocytic, Acute
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm
• Myelofibrosis
• Myeloproliferative Disorders
• Neoplasms
• Neoplasms by Histologic Type
• Precancerous Conditions
• Preleukemia
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• Pelabresib (CPI-0610)

• Ruxolitinib

Locations

Country	Name	City	State
Belgium	ZNA Stuyvenberg Antwerpen	Antwerpen
Belgium	AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan	Brugge	West-Vlaanderen
Belgium	UZ Leuven - Campus Gasthuisberg	Leuven	Viaams Braban
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
France	CHRU de Lille - Hopital Claude Huriez - Maladies du Sang	Lille	Nord-Pas-de-Calais
France	Institut de cancérologie du Gard - Hematologie clinique	Nîmes	Gard
France	CHU - Hopital Saint Louis - Centre D'Investigations Clinique	Paris
France	CHRU de Lille - Hopital Claude Huriez	Toulouse	Haute-Garonne
France	Institut Gustave Roussy	Villejuif	Ile-de-France
Germany	Universitätsklinikum Bonn	Bonn	Nordrhein-Westfalen
Germany	Universitätsklinikum Leipzig AöR	Leipzig	Sachsen
Italy	Institue of Hematology "L. and A. Seràgnoli"	Bologna	Emilia-Romagna
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can	Genova	Liguria
Italy	Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda	Milano	Lombardia
Italy	AOU Maggiore della Carità	Novara
Italy	IRCCS Policlinico San Matteo, Università degli studi di Pavi	Pavia	Lombardia
Italy	Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini	Rimini	Emilia-Romagna
Italy	Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon	Varese	Lombardia
Netherlands	VUmcResearch B.V.	Amsterdam	Noord-Holland
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Erasmus Universitair Medisch Centrum Rotterdam	Rotterdam	Zuid-Holland
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk	Pomorskie
Poland	Instytut Hematologii i Transfuzjologii w Warszawie	Warszawa	Mazowieckie
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	University of Cambridge	Cambridge
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Oxford University Hospitals	Headington	Oxford
United Kingdom	Guys and St Thomas' Hospital - Haematology	London
United Kingdom	University College London Hospital's NHS foundation Trust	London
United Kingdom	The Christie Hospital	Manchester
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Northwestern University - Lurie Comprehensive Cancer Center	Chicago	Illinois
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	UCLA Medical Center	Los Angeles	California
United States	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin
United States	ICAHN School of Medicine at Mount Sinai	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Weill Medical College and New York Presbyterian Hospital	New York	New York
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Washington University School of Medicne Neuromuscular Division Department of Neurology Research	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Constellation Pharmaceuticals	The Leukemia and Lymphoma Society

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate the spleenic response		By imaging after 24 weeks
Primary	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
Primary	Phase 2 (Arm 4): Evaluate the complete hematological response rate		1 cycle (21 days)
Secondary	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
Secondary	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
Secondary	Phase 2 (all arms): area under the curve (AUC)		Assessed during Cycle 1 (first 21 days on study)
Secondary	Phase 2 (all arms): maximum observed plasma concentration (Cmax)		Assessed during Cycle 1 (first 21 days on study)