Myeloproliferative Neoplasms (bone marrow cancer)
Conditions
Interventions
Phase 2 (MF expansion):
The expansion arm doses for myelofibrosis (MF) patients previously treated (or
ineligible to receive treatment with) or currently treated with a JAK inhibitor
(Prior JAKi) o
1 cycle = 21 days)
- Arm 2: Add-on to JAKi Combination Arm (MF patients treated with CPI-0610 in
combination with ruxolitinib): CPI-0610 at initial dose of 125 mg QD for 14
days followed by a 7-day
ruxolitinib at dose
patient is taking at the time of screening (1 cycle = 21 days)
NOTE: There are 2 cohorts within Arm 1: Cohort 1A (transfusion dependent [TD])
and Cohort 1B (non-TD) and 2 cohort
ruxolitinib at initial dose dependent
on applicable approved package insert with upward titration allowed (1 cycle =
21 days).
Phase 2 (ET-expansion)
- Arm 4: ET patients treated with CPI-0610 alon
1 cycle = 21 days)
Sponsors
Constellation Pharmaceuticals
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Phase 2 (MF Expansion - Prior JAKi Arm 1 and Add-on to JAKi Arm 2) Inclusion criteria Patients must meet all of the following criteria to be enrolled in this study:, 1. Adult (aged >= 18 years) 2. Patients with confirmed diagnosis of MF who meet all of the following criteria: a. Dynamic International Prognostic Scoring System (DIPSS) risk category of intermediate-2 or higher. b. Platelet count >= 75 x 10^9 /L without the assistance of thrombopoietic factors or transfusions c. ANC >= 1 x 10^9 /L without the assistance of granulocyte growth factors d. Spleen volume of >= 450 cm^3 by CT or MRI for Cohorts 1B and 2B OR RBC TD transfusions (defined as an average of >= 2 units of RBC transfusions per month [total of >= 6 RBC transfusions over the 12 wks] prior to enrollment) for Cohorts 1A and 2A e. Peripheral blood blast count = 1) using the MFSAF v4.0 g. Monotherapy Arm (Arm 1) patients only: Previously treated with a JAKi and be intolerant, resistant, refractory or lost response to the JAKi; have not received the JAKi within 42 weeks prior to start of study drug, or are ineligible to be treated with a JAKi h. Combination Arm (Arm 2) patients only: Must have received ruxolitinib for at least 6 months and be on a stable ruxolitinib dose for a minimum 8 weeks (prior to start of study drug) 3. ECOG performance status = 45 ml/min 7. Patients must have fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy 8. Male and WOBCP and partners of patients with reproductive potential must agree to use highly effective contraceptive methods for 94 days after the last dose of pelabresib for male patients and male partners of female patients and for 184 days after the last dose of study drug for WOCBP and female partners of male patients 9. Patients must give written informed consent to participate in this study before the performance of any study-related procedure, Phase 2 (MF Expansion - JAKi Naive Arm 3) Inclusion criteria, Patients must meet all of the following criteria to be enrolled in this study:, 1. Adult (aged >= 18 years) 2. Patients with confirmed diagnosis of MF who meet all of the following criteria: a. DIPSS risk category of intermediate-2 or higher b. Platelet count >= 100 x 10^9 /L without the assistance of thrombopoietic factors or transfusions c. ANC >= 1 x 10^9 /L without the assistance of granulocyte growth factors d. Spleen volume of >= 450 cm^3 by CT/MRI e. Peripheral blood blast count = 3) or a total score of >= 10 using the MFSAF v4.0 g. No prior treatment with JAKi allowed 3. ECOG performance status 24 weeks 5. Serum direct bilirubin = 45 ml
Exclusion criteria
Exclusion criteria: Phase 2 (MF Expansion - Prior JAKi Arm 1 and Add-on to JAKi Arm 2) Exclusion criteria Patients who meet any of the following criteria will not be enrolled in the study:, 1. Patients in Cohorts 1B and 2B only: Patients who have had prior splenectomy 2. Patients in Cohorts 1B and 2B only: Patients who have had splenic irradiation within 3 months of starting study drug 3. Current known active or chronic infection with human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C. 4. Patients with active clinically significant infection will not be eligible for enrollment until recovery for at least 2 weeks prior to the first dose of study drug. 5. Patients with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia, or infection 6. Serum ferritin level = 2g/dL or leading to transfusion of >= 2 units of packed red cells in the last 6 months prior to enrollment. 8. Patients with Child-Pugh Class B or C 9. Impairment of GI function or GI disease that could significantly alter the absorption of CPI-0610 and/or ruxolitinib, including any unresolved nausea, vomiting, or diarrhea > CTCAE grade 1 10. Impaired cardiac function or clinically significant cardiac diseases, including any of the following: a. Acute myocardial infarction or unstable angina pectoris 500 msec on the screening ECG c. Uncontrolled clinically significant cardiac arrhythmia 11. Ongoing uncontrolled hypertension despite maximal antihypertensive treatment 12. Any other concurrent severe and/or uncontrolled concomitant medical condition that in the opinion of the investigator could compromise participation in the study or analysis of study data. 13. Systemic anti-cancer treatment (other than ruxolitinib for the Combination Arm [Arm 2]; see inclusion criterion #2) other than hydroxyurea and anagrelide less than 2 weeks (or 5 half-lives, whichever is longer) before the first dose of CPI-0610. 14. Any investigational agent less than 2 weeks (or 5 halflives, whichever is longer) before the first dose of CPI-0610 15. Prior treatment with a BET inhibitor 16. Hematopoietic growth factor (granulocyte growth factor, erythropoiesis stimulating agent, thrombopoietin mimetic) or androgenic steroids less than 4 weeks before the first dose of study drug 17. Patients in the Combination Arm (Arm 2) who are receiving treatment with fluconazole. 18. Systemic corticosteroids at daily doses >= 10 mg of oral prednisone or equivalent within 2 weeks before the first dose of study drug. 19. Women who are lactating or pregnant females as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 72 hours prior to the first dose of CPI-0610. 20. Patients unwilling or unable to comply with this study protocol Phase 2 (MF Expansion - JAKi Naive Arm 3) Exclusion criteria Patients who meet any of the following criteria will not be enrolled in the study: 1. Prior treatment with a BET inhibitor 2. Patients who have had a prior splenectomy 3. Patients who have had splenic irradiation within 3 months of starting study <b
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 2 (MF Expansion-Prior JAKi Arm 1 and Add-on to JAKi Arm 2) Primary Endpoints: - The splenic response rate is defined as the proportion of patients who achieve a >= 35% reduction from baseline spleen size by imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) after 24 weeks of treatment (Cycle 9, Day 1) - The conversion rate is defined as the proportion of patients who convert from TD to TI, where TD is defined as receiving an average of >= 2 RBC transfusions per month during the 12 weeks prior to enrollment and TI is defined as absence of RBC transfusions over any consecutive 12 week period Phase 2 (MF Expansion - JAKi Naïve Arm 3) Primary Endpoint: - The splenic response rate is defined as the proportion of patients who achieve a >= 35% reduction from baseline spleen size by imaging (MRI or CT) after 24 weeks of treatment (Cycle 9, Day 1) Phase 2 (ET Expansion Arm 4) The proportion of patients who meet the criteria for a CHR, as assessed by modified ELN criteria (5) • Normalization of platelet count ( | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 2 (MF Expansion-Prior JAKi Arm 1 and Add-on to JAKi Arm 2) Secondary Endpoints: - PROs will be evaluated using the Myelofibrosis Symptom Assessment Form Version 4.0 (MFSAF v4.0) and the Patient Global Impression of Change (PGIC). Changes from baseline in the TSS from the MFSAF v4.0 and PGIC will be described. The proportion of patients who achieve a >=50% reduction in TSS after 12 weeks (Cycle 5, Day 1) and 24 weeks of treatment (Cycle 9, Day 1) will also be reported. - Time to conversion is defined as the time from the first dose of CPI-0610 until the first day of TI - The duration of TI is defined as the time from the first onset date of TI to the earliest onset date of loss of TI - The early anemic response rate is defined as the proportion of patients who achieve a hemoglobin (Hgb) increase of >=1g/dL from baseline over any consecutive 8 week period in the absence of RBC transfusions - The anemic response rate is defined as the proportion of patients who enroll as TI and achieve >= 1.5 g/dL Hgb increase from baseline over any consecutive 12 week period in the absence of RBC transfusions - The overall splenic response rate is the proportion of patients who achieve a >= 35% reduction from baseline spleen size by imaging (MRI or CT); The reduction in spleen size from baseline by imaging (MRI or CT) after 12 weeks (Cycle 5, Day 1) and 24 weeks of treatment (Cycle 9, Day 1) will also be evaluated. - Duration of the spleen response is defined as the time when splenic response criteria are first met (a >= 35% reduction from baseline spleen size) until the time at which an increase of >= 25% in spleen volume by imaging compared to baseline is documented - Rate of response categories (such as complete response/remission (CR), partial response/remission (PR), clinical improvement (CI), stable disease (SD), progressive disease (PD) and relapse) after 24 weeks of treatment and every 6 months thereafter based on the revised 2013 IWG-MRT res | — |
Countries
Netherlands
Outcome results
None listed