Clinical trial NCT02158858: A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelofibrosis
Leukemia, Myelocytic, Acute
Myelodysplastic/Myeloproliferative Neoplasm
Myelodysplastic Syndrome (MDS)
Preleukemia
Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Disease
Hematological Disease
Precancerous Conditions
Neoplasms
Leukemia
Neoplasms by Histologic Type
Essential Thrombocytosis
Keywords: Phase 1
Phase 2
Oncology
BET Inhibitor
Ruxolitinib
Pelabresib
Lead sponsor: Constellation Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2014-06-09
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate the spleenic response
timeFrame: By imaging after 24 weeks
measure: Phase 2 (Cohorts 1A and 2A): Evaluate the RBC (Red Blood Cell) transfusion independence rate
timeFrame: Absence of RBC transfusion and no hemoglobin level below 8 g/dL in the prior 12 weeks
measure: Phase 2 (Arm 4): Evaluate the complete hematological response rate
timeFrame: 1 cycle (21 days)
Secondary outcomes:
measure: Phase 2 (Arms 1, 2, and 3): Evaluate the duration of the spleenic response by imaging
timeFrame: Through study completion or end of treatment, up to 24 weeks and beyond
measure: Phase 2 (all arms): Evaluate the change in patient reported outcomes
timeFrame: Changes from baseline in the total symptom score (MFSAF v4.0) and PGIC after 24 weeks
measure: Phase 2 (all arms): area under the curve (AUC)
timeFrame: Assessed during Cycle 1 (first 21 days on study)
measure: Phase 2 (all arms): maximum observed plasma concentration (Cmax)
timeFrame: Assessed during Cycle 1 (first 21 days on study)
Other outcomes:
measure: Phase 2 (Arms 1, 2, and 3): Evaluate response category rate
timeFrame: Rate of response by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria after 24 weeks
measure: Phase 2 (Arms 1, 2, and 3): Evaluate the rate of RBC transfusion and the RBC transfusion dependence rate
timeFrame: Average number of RBC units per subject-month, up to 24 weeks and beyond
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Los Angelas
country: United States
facility: UCLA Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Chicago
country: United States
facility: Northwestern University - Lurie Comprehensive Cancer Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicne Neuromuscular Division Department of Neurology Research
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: ICAHN School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Weill Medical College and New York Presbyterian Hospital
state: New York
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert & Medical College of Wisconsin
state: Wisconsin
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg
state: Viaams Braban
city: Brugge
country: Belgium
facility: AZ Sint-Jan Burgge-Oostende AV- Campus Sint-Jan
state: West-Vlaanderen
city: Antwerpen
country: Belgium
facility: ZNA Stuyvenberg Antwerpen
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Nîmes
country: France
facility: Institut de cancérologie du Gard - Hematologie clinique
state: Gard
city: Toulouse
country: France
facility: CHRU de Lille - Hopital Claude Huriez
state: Haute-Garonne
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Ile-de-France
city: Lille
country: France
facility: CHRU de Lille - Hopital Claude Huriez - Maladies du Sang
state: Nord-Pas-de-Calais
city: Paris
country: France
facility: CHU - Hopital Saint Louis - Centre D'Investigations Clinique
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
state: Sachsen
city: Bologna
country: Italy
facility: Institue of Hematology "L. and A. Seràgnoli"
state: Emilia-Romagna
city: Rimini
country: Italy
facility: Servizio Sanitario Regionale Emilia-Romagna - Azienda Unita Sanitaria Locale (AUSL) di Rimini - Ospedale Infermi di Rimini
state: Emilia-Romagna
city: Genova
country: Italy
facility: AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can
state: Liguria
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico, Fondazione IRCCS Ca' Granda
state: Lombardia
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo, Università degli studi di Pavi
state: Lombardia
city: Varese
country: Italy
facility: Ospedale di Circolo, PO Varese, AO Ospedale di Circolo e Fon
state: Lombardia
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Novara
country: Italy
facility: AOU Maggiore della Carità
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Amsterdam
country: Netherlands
facility: VUmcResearch B.V.
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Universitair Medisch Centrum Rotterdam
state: Zuid-Holland
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii w Warszawie
state: Mazowieckie
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
state: Pomorskie
city: Headington
country: United Kingdom
facility: Oxford University Hospitals
state: Oxford
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Cambridge
country: United Kingdom
facility: University of Cambridge
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: University College London Hospital's NHS foundation Trust
city: London
country: United Kingdom
facility: Guys and St Thomas' Hospital - Haematology
city: Manchester
country: United Kingdom
facility: The Christie Hospital
Study officials:
References:
citation: 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.