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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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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 / Treatment
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* Drug: Pelabresib (CPI-0610)
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Prior JAKi (JAK inhibitor) Monotherapy Arm (MF patients treated with pelabresib alone)<br>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)<br> <br> |
| Experimental: Arm 2: Prior JAKi Combination Arm<br>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)<br> <br> Drug: Ruxolitinib<br> <br> |
| Experimental: Arm 3: JAKi Naïve Combination Arm<br>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)<br> <br> Drug: Ruxolitinib<br> <br> |
| Experimental: Arm 4: Essential Thrombocythemia (ET) Monotherapy Arm<br>Open to high-risk patients with ET who are resistant or intolerant to hydroxyurea (HU) | Drug: Pelabresib (CPI-0610)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2 (Cohorts 1B and 2B and Arm 3): Evaluate the spleenic response |  | By imaging after 24 weeks | 
| 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 | 
| Phase 2 (Arm 4): Evaluate the complete hematological response rate |  | 1 cycle (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Phase 2 (all arms): area under the curve (AUC) |  | Assessed during Cycle 1 (first 21 days on study) | 
| Phase 2 (all arms): maximum observed plasma concentration (Cmax) |  | Assessed during Cycle 1 (first 21 days on study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Phase 2, Oncology, BET Inhibitor, Ruxolitinib, Pelabresib