| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028537 |
| E.1.2 | Term | Myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074689 |
| E.1.2 | Term | Post polycythemia vera myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074690 |
| E.1.2 | Term | Post essential thrombocythemia myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077161 |
| E.1.2 | Term | Primary myelofibrosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the efficacy of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib
- To characterize the effects of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib in the bone marrow
- To determine the effect of CPI-0610 + ruxolitinib on the durability of splenic response compared with placebo + ruxolitinib
- To determine the effect of CPI-0610 + ruxolitinib on the durability of TSS response compared with placebo + ruxolitinib
- To determine the effect of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib on the rate of RBC transfusion over the first 24 weeks of treatment
- To determine the effect of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib on RBC transfusion dependence rate at Week 24
- To determine the effect of CPI-0610 + ruxolitinib compared with placebo + ruxolitinib on conversion from RBC transfusion dependence to independence
and further as described in the protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all of the following criteria apply:
Age
1. ≥ 18 years of age at the time of signing the informed consent
Type of Patient and Disease Characteristics
2. Have a confirmed diagnosis of MF (PMF or PPV-MF or PET-MF) in accordance with the 2016 WHO criteria (Section 10.4)
3. Require therapy for MF in the opinion of the Investigator and are eligible for treatment with ruxolitinib
4. Have DIPSS risk category Intermediate-1 or higher (Section 10.5)
5. Have spleen volume of ≥ 450 cm3 by MRI or CT scan (either local or central read)
6. Have completed the MFSAF v4.0 (Section 10.6) at least 5 of 7 days prior to randomization
7. Have at least 2 symptoms with an average score ≥ 3 over the 7-day period prior to randomization or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0 (Section 10.6)
8. Have acceptable laboratory assessments obtained within 28 days prior to the first dose of study medication:
• ANC ≥ 1 × 109/L in the absence of growth factors or transfusions for the previous 4 weeks
• Platelet count ≥ 100 × 109/L in the absence of growth factors or transfusions for the previous 4 weeks
• Peripheral blood blast count < 5%
• AST and ALT ≤ 2.5 × ULN (≤ 5 × if the elevation can be ascribed to liver involvement; e.g., presence of hepatomegaly)
• Serum direct bilirubin < 2.0 × ULN
• Calculated or measured CrCl of ≥ 45 mL/min
9. ECOG performance status of ≤ 2
10. Life expectancy > 24 weeks per Investigator assessment
11. Have fully recovered from major surgery, intervention, and from the residual Grade 1 toxicity from prior MF-specific therapy (grade 1 peripheral neuropathy and alopecia are allowed).
12. Male and female patients with reproductive potential must agree to use highly effective contraceptive methods (i.e., condoms or sexual abstinence if the preferred and usual lifestyle of the patient for males and oral, intravaginal, transdermal inhibitors of ovulation that contain estrogen and progesterone; oral, injectable or implantable inhibitors of ovulation that contain progesterone; IUD; IUS; bilateral tubal occlusion; vasectomized partner; sexual abstinence if the preferred and usual lifestyle of the patient for females) while on study therapy and for 3 months after the last dose of study drug. NOTE: Male patients should be informed of the risk of testicular toxicity and provided with adequate advice regarding sperm preservation.
Informed Consent
13. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol |
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| E.4 | Principal exclusion criteria |
1. Had splenic irradiation within 6 months of starting study drug
2. Had prior splenectomy
3. Are a candidate for, and willing to undergo allogeneic HSCT, and, in the opinion of the Investigator, the benefit of proceeding to an allogeneic HSCT prior to treatment with a JAK2 inhibitor outweighs its risks
4. Have current known active or chronic infection with HIV, hepatitis B, or hepatitis C. Screening of patients with serologic testing for these viruses is not required. However, patients who have a past history of viral hepatitis or in whom there is a current suspicion of viral hepatitis should have serologic testing for hepatitis B and hepatitis C performed to determine whether there is any current evidence for ongoing infection with these viruses. Patients considered to be at risk for HIV infection should have HIV testing performed.
5. Have an active infection. Patients will not be eligible for enrollment until recovery to ≤ Grade 1 for at least 2 weeks prior to the first dose of study drug.
6. Have impaired gastrointestinal function or gastrointestinal disease, including active IBD, that could significantly alter the absorption of study drug, including any unresolved nausea, vomiting, or diarrhea > Grade 1
7. Have known hypersensitivity to the investigational agent or ruxolitinib, or its metabolites or formulation excipients
8. Have a history of progressive multifocal leukoencephalopathy
9. Have impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to starting study drug
• QTcF > 500 msec on the screening ECG
• New York Heart Association Class III or IV congestive heart failure
• Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded)
-Patients with a history of coronary artery disease and revascularization are not excluded.
10. Have ongoing uncontrolled hypertension (resting systolic blood pressure >160 mmHg and resting diastolic blood pressure >100 mmHg) despite maximal treatment with at least 2 anti-hypertensive agents
11. Have ongoing uncontrolled blood glucose increase (HbA1c ≥9%) despite maximal treatment with oral and/or injectable anti-hyperglycemic agents
12. Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years
13. Have any other concurrent severe and/or uncontrolled concomitant medical condition which acc. to the Investigator could compromise participation in the study or analysis of study data. This includes but is not limited to clinically significant pulmonary disease or neurological disorders.
14. Had prior treatment with any JAKi or BET inhibitor for treatment of a myeloproliferative neoplasm
15. Had systemic anti-cancer treatment other than hydroxyurea and anagrelide less than 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug. NOTE: Hydroxyurea and anagrelide are permitted up to 24 hours prior to start of study drug.
16. Had any investigational agent (whether as cancer treatment or not) less than 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug
17. Had 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
18. Had a strong CYP3A4 inhibitor or inducer within 2 weeks prior to the first dose of study drug (Section 10.8), including St. John’s wort. Initiation of treatment or concomitant use of a strong CYP3A4 inhibitor or inducer during study treatment is prohibited.
19. Require systemic corticosteroids of ≥10 mg QD prednisolone or equivalent 4 weeks before the first dose of study drug. Patients who received topical, nasal, intra-articular, or inhaled corticosteroids are eligible.
20. Women who are lactating or pregnant females as documented by a serum β-hCG pregnancy test consistent with pregnancy, obtained within 72 hours prior to first dose . Female patients with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor’s Medical Monitor, after pregnancy has been excluded. Female patients of non-child bearing potential (see protocol for conditions) do not require a serum pregnancy test.
21. Are unwilling or unable to comply with this study protocol or study requirements. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Splenic response at Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- TSS response at Week 24
- Improvement in bone marrow fibrosis by at least 1 grade compared to baseline at Week 24
- Duration of splenic response, defined as the time from onset of splenic response until progressive disease (a ≥25% increase in spleen volume from baseline, as confirmed by the central review) or death, whichever comes first
- Duration of TSS response, defined as the time from onset of TSS response until a ≥25% increase in TSS from baseline or death, whichever comes first
- Rate of RBC transfusions, defined as the average number of units of RBC transfusion per month (4 weeks), over the first 24 weeks of treatment
- Conversion from RBC transfusion dependence (≥6 units of RBC transfusion during the 12-week baseline period prior to dosing) to independence (no RBC transfusions during any 12-week period post baseline)
- Duration of RBC transfusion independence post conversion, defined as time from the onset of conversion from RBC transfusion dependence to independence until the first occurrence of RBC transfusion
- RBC transfusion dependence, defined as ≥ 6 units of RBC transfusion during the prior 12 weeks, at Week 24
- Hemoglobin response, defined as a ≥ 1.5 g/dL increase in hemoglobin from baseline in the absence of RBC transfusion during the previous 12 weeks
- PGIC at Week 24
- Change from baseline to Week 24 in EQ-5D™
- Splenic and TSS response at Week 24
- IWG-MRT response (e.g., complete and partial remission, clinical improvement, stable disease, progressive disease, and relapse) at Week 24, based on the revised 2013 IWG-MRT response criteria(Section 10.7)
- PFS, defined as the time from randomization until documented progression (see definition of progression in Section 7.1), or until death from any cause for patients without documented progression
- OS, defined as the time from randomization until death from any cause
- Conversion from MF to AML
- AEs and SAEs and changes in physical examinations, vital signs, ECGs, and laboratory results
- PK of CPI-0610: AUC0-t, AUC0-α, AUCtau,ss, Tmax, Cmax, Ctrough, T1/2, Vd/F, CL/F
- PK of ruxolitinib: AUC0-t, AUC0-α, AUCtau,ss, Tmax, Cmax, Ctrough,T1/2, Vd/F, CL/F
EXPLORATORY ENDPOINTS
- Change from baseline in peripheral blood blast percent
- Assessment of post-treatment transcriptional changes from baseline and changes in signaling pathway activity assessed by measuring levels of mRNA and/or protein
- Post-treatment changes from baseline in circulating concentrations of cytokines
- Post-treatment changes from baseline in the ratio of mutant to wild type JAK2, CALR, and other MF-relevant alleles
- Assessment of MF or BET biology-related features associated with response |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The key secondary endpoint of the study is TSS response, defined as a ≥ 50% decrease from baseline in TSS as measured by the MFSAF v4.0, at Week 24.
For other secondary endpoints and exploratory endpoints the evaluation will be performed at
timepoints as indicated in the protocol and above. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Crossover is possible for control arm after double-blind treatment |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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