A clinical study to investigate the safety and efficacy of CPI-0610 in patients with myelofibrosis and essential thrombocythemia

Phase 1

Conditions: Myeloproliferative Neoplasms (Myelofibrosis and Essential Thrombocythemia)
MedDRA version: 20.0Level: PTClassification code 10028537Term: MyelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.0Level: LLTClassification code 10015494Term: Essential thrombocythemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2018-000579-34-GB

Lead Sponsor: Constellation Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 297

Inclusion Criteria

Prior JAKi:
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 cm3 by CT or MRI for Cohorts 1B and 2B OR RBC transfusion dependent (defined as an average of =2 units of RBC transfusions per month over the 12 weeks prior to enrollment for Cohorts 1A and 2A
e. Peripheral blood blast count <10%
f. At least 2 symptoms measurable (score = 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 2 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 = 2.
4. Serum direct bilirubin = 1.5 x ULN (upper limit of normal)
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x ULN. The AST and /or ALT may be elevated up to 5 x ULN if the elevation can be reasonably ascribed to liver involvement.
6. Calculated or measured creatinine clearance (CrCl) = 45 ml/min (either measured or estimated by the Cockcroft-Gault formula).
7. Patients must have fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy (residual CTCAE grade 1 toxicity, e.g., grade 1 peripheral neuropathy, and residual alopecia are allowed).
8. Male and female patients with reproductive potential must agree to use highly effective contraceptive methods while on study therapy and for 3 months after the last dose of CPI-0610. NOTE: Male patients should be informed of the risk of testicular toxicity and provided with adequate advice regarding sperm preservation.

JAKi Naive Arm 3:
1. Adult (aged = 18 years)
2. Patients with confirmed diagnosis of MF who meet all of the following criteria:
a. DIPSS (see Appendix 3) risk category of intermediate-1 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 = 450 cm3 by CT/MRI
e. Peripheral blood blast count <10%
f. At least 2 symptoms measurable (score = 3) or a total score of = 10 using the MFSAF v4.0
g. No prior treatment with JAKi allowed
3. ECOG performance status = 2.
4. Life expectancy of >24 weeks
5. Serum direct bilirubin < 2.0 x ULN
6. AST and ALT = 2.5 x ULN. The AST and /or ALT may be elevated up to 5 x ULN if the elevation can be reasonably ascribed to liver involvement.
7. Calculated or measured CrCL = 45 ml/min (either measured or estimated by the Cockcroft-Gault formula).
8. Patients with a history of transfusions must have a documented transfusion record during the 12 weeks prior to the first dose of study drug
9. Patients must have fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy (residual CTCAE grade 1 toxicity, e.g., grade 1 peripheral neuropathy, and residu

Exclusion Criteria

Prior JAKi Arm 1 and Add-on to Jaki Arm 2
1. Patients in Cohorts 1B and 2B: Patients who have had prior splenectomy
2. Patients in Cohorts 1B and 2B: Patients who have had splenic irradiation within 3 months of starting study drug
3. Current known active or chronic infection with HIV, Hepatitis B or Hepatitis C
4. Patients with active clinically significant infection will not be eligible for enrolment until recovery for at least 2 weeks prior to the first dose of study drug.
5. Patients wih anemia from iron deficiency, B12 and folate deficiencies hemoyltic anemia, or infection.
6. Serum ferritin level < lower limit of normal (LLN) as per institutional standards
7. Patient with a major bleeding event causing a decrease in hemoglobin of = 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. GI function or GI disease that could significantly alter the absorption of CPI-0610 and/or ruxolitinib
10. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
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) before the first dose of CPI-0610
14. Any investigational agent >2 weeks (or 5 half-lives) 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
For further exclusion criteria for Arm 1 & 2 and details please refer to the protocol)

JAKi Naive Arm 3:
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 drug
4. Current known active or chronic infection with HIV, Hepatitis B or Hepatitis C
5. 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
6. Patients with anemia from iron deficiency, B12 and folate deficiencies, hemolytic anemia or infection
7. Serum ferritin level < LLN as per institutional standards
8. Patient with a major bleeding event causing a decrease in Hgb of = 2g/dL or leading to transfusion of =2 units of packed red cells in the last 6 months prior to enrollment
9. Patients with Child-Pugh Class B or C
10. Impairment of GI function or GI disease that could significantly alter the absorption of CPI-0610 and/or ruxolitinib
11. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or patients with hypersensitivity to any ingredient in the formulation of ruxolitinib
12. Patients who have or have had PML
13. Impaired cardiac function or cl

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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