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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02158858
Recruitment Status : Active, not recruiting
First Posted : June 9, 2014
Last Update Posted : December 7, 2022
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Constellation Pharmaceuticals

Study Description
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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.


Condition or disease Intervention/treatment Phase
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 Drug: Pelabresib (CPI-0610) Drug: Ruxolitinib Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 341 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : July 29, 2014
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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)


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

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

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

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02158858


Locations
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Sponsors and Collaborators
Constellation Pharmaceuticals
The Leukemia and Lymphoma Society
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Constellation Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02158858    
Other Study ID Numbers: 0610-02
2018-000579-34 ( EudraCT Number )
First Posted: June 9, 2014    Key Record Dates
Last Update Posted: December 7, 2022
Last Verified: December 2022
Keywords provided by Constellation Pharmaceuticals:
Phase 1
Phase 2
Oncology
 BET Inhibitor
Ruxolitinib
Pelabresib
Additional relevant MeSH terms:
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Leukemia
Neoplasms
Preleukemia
Precancerous Conditions
Neoplasms by Histologic Type
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Primary Myelofibrosis
 Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Hematologic Diseases
Bone Marrow Diseases
Thrombocytosis
Thrombocythemia, Essential
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders