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

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ClinicalTrials.gov Identifier: NCT02158858
Recruitment Status : Recruiting
First Posted : June 9, 2014
Last Update Posted : August 27, 2019
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Constellation Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE June 5, 2014
First Posted Date  ICMJE June 9, 2014
Last Update Posted Date August 27, 2019
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2018)
  • Phase 2 Part: Evaluate spleen response [ Time Frame: By imaging after 24 weeks ]
  • Phase 2 Part: 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
Frequency of dose-limiting toxicities (DLTs) associated with CPI-0610 administration during the first cycle (first 21 days) of treatment [ Time Frame: DLTs asessed during Cycle 1 (first 21 days on study) ]
Change History Complete list of historical versions of study NCT02158858 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2018)
  • Phase 2 Part: Evaluate the duration of spleen response by imaging [ Time Frame: By palpation and imaging after 24 weeks ]
  • Phase 2 Part: Evaluate response category rate [ Time Frame: Rate of response by IWG-MRT after 24 weeks ]
  • Phase 2 Part: 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 ]
  • Phase 2 Part: Evaluate the rate of RBC transfusion and the RBC transfusion dependence rate [ Time Frame: Average number of RBC units per subject-month ]
  • Phase 2 Part: Pharmacokinetic parameters of CPI-0610 and ruxolitinib: AUC and Cmax [ Time Frame: Assessed during cycle 1 (first 21 days on study) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2014)
  • Safety and tolerability of CPI-0610 as assessed by: frequency of adverse events and serious adverse events; changes in hematology and clinical chemistry values; changes in physical examination, vital signs, electrocardiogram, ECHO and ECOG score [ Time Frame: Assessed from Day 1 of Cycle 1 through 30 days after patient's last dose of study drug ]
  • Pharmacokinetic parameters of CPI-0610: AUC(0-t), AUC(0-inf), AUCtau,ss, Tmax, Cmax, Ctrough, T1/2, Vd/F, CL/F [ Time Frame: Assessed during cycle 1 (first 21 days on study); and on cycle 2, day 1 ]
  • Pharmacodynamic effects of CPI-0610: Changes in the expression of MYC and other genes in leukemic cells; changes in cellular proliferation and in the extent of apoptosis [ Time Frame: Assessed during cycle 1 (first 21 days on study); and on cycle 2, day 1 ]
    This is a composite outcome measure
  • Changes in the expression of a set of genes in peripheral blood mononuclear cells (PBMCs) that are sensitive to BET inhibition [ Time Frame: Assessed during cycle 1 (first 21 days on study) ]
  • Anti-leukemia, anti-myelodysplastic syndrome, or anti-myelodysplastic/myeloproliferative neoplasm activity associated with CPI-0610 treatment [ Time Frame: Assessed after every 2 cycles of treatment for the first 6 cycles, and after every 4 cycles thereafter; assessed up to approximately 12 months ]
    Leukemia, MDS and MDS/MPN will be assessed using the 2013 NCCN criteria for ALL, the 2003 Cheson criteria for AML, and the 2006 modified International Working Group (IWG) criteria for MDS and MDS/MPN
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis
Official Title  ICMJE A Phase 1/2 Study of CPI-0610, a Small Molecule Inhibitor of BET Proteins: Phase 1 (in Patients With Hematological Malignancies) and Phase 2 (Dose Expansion of CPI-0610 With and Without Ruxolitinib in Patients With Myelofibrosis)
Brief Summary

Phase 1 Part (Complete): Open-label, sequential dose escalation study of CPI-0610 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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelofibrosis
  • Leukemia, Myelocytic, Acute
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myelodysplastic Syndrome (MDS)
Intervention  ICMJE
  • Drug: CPI-0610
  • Drug: Ruxolitinib
Study Arms  ICMJE
  • Experimental: Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm
    • 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.(CPI-0610 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)
    Intervention: Drug: 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. (CPI-0610 + 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)
    Interventions:
    • Drug: CPI-0610
    • Drug: Ruxolitinib
  • Experimental: Arm 3: JAKi Naïve Combination Arm
    • Open to patients with MF who are anemic (i.e., Hemoglobin (Hgb) <10g/dL) and who have not previously received a JAKi. (CPI-0610 + Ruxolitinib)
    Interventions:
    • Drug: CPI-0610
    • Drug: Ruxolitinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 9, 2018)
169
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2014)
36
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

  • Adult (aged ≥ 18 years)
  • Phase 2 part: Patients with confirmed diagnosis of MF who meet all of the following criteria:

    • Dynamic International Prognostic Scoring System (DIPSS; see Appendix 3) risk category of intermediate-1 or higher.
    • 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
  • 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:

  • Palpable spleen ≥ 5 cm that is below the costal margin on physical examination OR RBC transfusion dependent (defined as an average of ≥2 units of RBC transfusions per month over the 12 weeks prior to enrollment)
  • 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
  • Monotherapy Arm (Arm 1): Previously treated with a JAK inhibitor and be intolerant, resistant, refractory or lost response to the JAK inhibitor
  • Combination Arm (Arm 2): Must have received single agent ruxolitinib and be on a stable dose for a minimum 8 weeks

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

  • Platelet count ≥ 100 x 10^9/L without the assistance of thrombopoietic factors or transfusions
  • Palpable spleen ≥ 5 cm that is below the costal margin on physical examination
  • Anemic, defined as a hemoglobin < 10g/dL
  • At least 2 symptoms measurable (score ≥ 3) or a total score of ≥ 10 using the MFSAF v4.0
  • No prior treatment with JAKi allowed

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 CPI-0610 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Debbie Johnson 617-714-0555 debbie.johnson@constellationpharma.com
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02158858
Other Study ID Numbers  ICMJE 0610-02
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Constellation Pharmaceuticals
Study Sponsor  ICMJE Constellation Pharmaceuticals
Collaborators  ICMJE The Leukemia and Lymphoma Society
Investigators  ICMJE
Study Director: Debbie Johnson Constellation Pharmaceuticals
PRS Account Constellation Pharmaceuticals
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP