| 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 efficacy of pelabresib + ruxolitinib 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
- To determine the effect of pelabresib + ruxolitinib compared with placebo + ruxolitinib on the rate of RBC transfusion over the first 24 weeks of treatment
- To determine the effect of pelabresib + ruxolitinib compared with placebo + ruxolitinib on RBC transfusion dependence rate at Week 24
- To determine the effect of pelabresib + ruxolitinib compared with placebo + ruxolitinib on conversion from RBC transfusion dependence to independence
- To evaluate the PGIC at Week 24
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%
• 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.
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 |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria 1.-4. did not change. Please see protocol section 5.2.
page 27.
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)
Note that 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 that in the opinion of 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.
Prior Therapy
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 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.
21. Females who are breastfeeding or pregnant (as documented by a
highly sensitive urine or serum β-hCG pregnancy test consistent with
pregnancy, obtained within 72 hours prior to the first dose of study
drug) or expecting to conceive or males expecting to father children
within the projected duration of the trial, starting with the screening
visit through 184 days after the last dose of study drug. Female patients
of non-child bearing potential (post-menopausal for more than 1 year;
underwent a hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy) do not require a serum pregnancy test.
22. 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
compared to baseline
• Splenic response at Week 48
• TSS response at Week 48
• Rate of RBC transfusion over the first 24 weeks of treatment
• Conversion from RBC transfusion dependence to independence
• Category 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, defined as the time from onset of splenic response until progressive disease (a > or =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 (> or = 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 > or = 6 units of RBC transfusion during the prior 12 weeks, at Week 24
- Hemoglobin response, defined as a > or = 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 > or = 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 | 4 |
| 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 States |
| Turkey |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| United Kingdom |
|
| 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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