| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 Pelabresib + ruxolitinib compared with placebo + ruxolitinib |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the effect of pelabresib + ruxolitinib on the absolute
change in TSS at Week 24 vs Baseline compared with placebo +
ruxolitinib
- To determine the efficacy of pelabresib + ruxolitinib compared with
placebo + ruxolitinib
- To determine the effect of pelabresib + ruxolitinib on the percent
change in TSS at Week 24 vs Baseline compared with placebo +
ruxolitinib
- To characterize the effects of pelabresib + ruxolitinib compared with
placebo + ruxolitinib in the bone marrow
- To determine the effect of pelabresib + ruxolitinib on the durability of
splenic response compared with placebo + ruxolitinib
- To determine the effect of pelabresib + ruxolitinib on the durability of
TSS response compared with placebo + ruxolitinib
And further as described in the protocol (this includes the new exploratory objective):
- To evaluate leukemia free survival in patients treated with pelabresib + ruxolitinib compared with placebo + ruxolitinib |
|
| 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%
• Isolated elevation of AST and/or ALT ≤ 2.5 × ULN of the local reference interval (≤ 5 × if the elevation can be ascribed to liver involvement, e.g., presence of hepatomegaly)
• Isolated elevation of serum direct bilirubin < 2.0 × ULN of the local reference interval
• 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. Both male and female patients and partners of patients, with reproductive potential, must agree to use at least one highly effective contraceptive method (preferably low user dependency contraception methods, as in Section 6.9, in particular when contraception is introduced as a result of participation in a clinical study) while on study therapy and for 94 days after the last dose of study drug for male patients and male partners of female patients, and for 184 days after the last dose of study drug for female patients and female partners of male patients. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. NOTE: Patients may consider seeking information from the study investigator regarding donation and cryopreservation of germ cells prior to treatment. 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
*Equation used for calculating the estimated creatinine clearance will be captured in the eCRF |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria 1.-3. did not change. Please see protocol section 5.2. page 27.
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. Testing for COVID-19 is not mandatory during the screening for this study. However, based on the local epidemiologic situation and
each patient's individual COVID-19 exposure risk and/or vaccination status, investigators should consider testing and in the case
of COVID-19 positivity consider delaying the start of the study treatment until the infection is resolved.
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 (QTcF interval is not relevant in patients with pacemaker-controlled arrythmia)
• New York Heart Association Class III or IV congestive heart failure
• Uncontrolled clinically significant cardiac arrhythmia (patients with rate-controlled arrhythmias 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/uncontrolled diabetes (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 with the exception of hormonal therapy, 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. Consult the Medical
Monitor with questions if needed.
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, inhaled, and other forms of corticosteroids without systemic activity are eligible.
20. Had a live vaccination within 30 days prior to the first dose of study drug (Czech Republic only).
and further as described in the protocol (Other Exclusions) |
|
| 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) |
• Absolute change in TSS at Week 24 compared to baseline
• TSS50 response at Week 24
• Improvement in bone marrow fibrosis by at least 1 grade at Week 24 compared to baseline
• Splenic response at Week 48
• TSS50 response at Week 48
• Absolute change in TSS at Week 24 compared to baseline
• Rate of RBC transfusion over the first 24 weeks of treatment
• Conversion from RBC transfusion at baseline dependence to independence
• Categorical change of PGIC at Week 24 compared to Baseline
• PFS
• OS
• Proportion of patients with transformation to blast phase (AML)
• AEs of all grades and SAEs
• Population PK assessment incl. determination of exposure metrics and secondary parameter (ie, AUC0-t, tmax, Cmax, T1/2, Vd/F, CL/F)
• Descriptive assessment of ruxolitinib plasma concentrations in the presence or absence of pelabresib and further as described in the protocol (exploratory endpoints)
• Duration of splenic response,
• Modified TSS50 response at Week 24 (TSS score without the fatigue sub-domain).
• Duration of TSS50 response,
and further as described in the protocol (this includes the new exploratory endpoint):
• Leukemia free survival |
|
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 178 |
| 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 |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Türkiye |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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