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

• ClinicalTrials.gov Identifier: NCT02158858
• Recruitment Status: Active, not recruiting
• First Posted: June 9, 2014
• Last Update Posted: March 6, 2024
• Sponsor: Constellation Pharmaceuticals
• Collaborator: The Leukemia and Lymphoma Society
• Information provided by (Responsible Party): Constellation Pharmaceuticals

Tracking Information

• First Submitted Date: June 5, 2014
• First Posted Date: June 9, 2014
• Last Update Posted Date: March 6, 2024
• Actual Study Start Date: July 16, 2014
• Estimated Primary Completion Date: October 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 5, 2022)

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

• Original Primary Outcome Measures (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) ]

Current Secondary Outcome Measures (submitted: December 5, 2022)

• 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 ]
• 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 ]
• Phase 2 (all arms): area under the curve (AUC) [ Time Frame: Assessed during Cycle 1 (first 21 days on study) ]
• Phase 2 (all arms): maximum observed plasma concentration (Cmax) [ Time Frame: Assessed during Cycle 1 (first 21 days on study) ]

Original Secondary Outcome Measures (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 (submitted: August 23, 2021)

• 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 ]
• 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 ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)

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 Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• Drug: Pelabresib (CPI-0610)
• Drug: Ruxolitinib

Study Arms

• 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)
  Intervention: 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)
  Interventions:

  • 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
  Interventions:

  • 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)
  Intervention: Drug: Pelabresib (CPI-0610)

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 23, 2024): 336
• Original Estimated Enrollment (submitted: June 5, 2014): 36
• Estimated Study Completion Date: October 31, 2024
• Estimated Primary Completion Date: October 31, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, Italy, Netherlands, Poland, United Kingdom, United States

Administrative Information

• NCT Number: NCT02158858
• Other Study ID Numbers: 0610-02; 2018-000579-34 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Constellation Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Constellation Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: The Leukemia and Lymphoma Society
• Investigators: Not Provided
• PRS Account: Constellation Pharmaceuticals
• Verification Date: March 2024