| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Myeloproliferative Neoplasms (Myelofibrosis and Essential
Thrombocythemia)
|
|
| E.1.1.1 | Medical condition in easily understood language |
Group of blood cancers (Myelofibrosis and Essential Thrombocythemia)
|
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 | 10015494 |
| E.1.2 | Term | Essential thrombocythemia |
| 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 |
Prior JAK Inhibitor (JAKi) Arms 1 & Add-on to JaKi Arm 2 - Transfusion Dependent (TD) Cohorts: Cohort 1A (Monotherapy TD) and Cohort 2A (Combination therapy TD)
To evaluate the rate of conversion from red blood cell (RBC) TD to RBC transfusion independence (TI)
Prior JAKi Arm 1 & Add-on to JaKi Arm 2 - non-TD Cohorts: Cohort 1B (Monotherapy non-TD) and Cohort 2B (Combination therapy non-TD)
To evaluate splenic response rate by imaging after 24 weeks of treatment
JAKi Naïve (Arm 3)
To evaluate splenic response rate by imaging after 24 weeks of treatment
ET Expansion Arm 4:
To evaluate the complete hematological response rate
Please refer to the protocol for further details |
|
| E.2.2 | Secondary objectives of the trial |
Prior and Add-on to JaKi TD Cohorts (1A and 2A)
Early anemic response rate
Overall splenic response rate at 12 and 24 weeks, duration
Prior and Add-on to JaKi non-TD Cohorts (1B and 2B)
Anemic response rate in TI patients
RBC transfusion rate
JAKi Naïve Arm 3
Splenic response rate by imaging at 12 weeks
Rate, time and duration of anemic response in TI patients
Overall splenic response rate and duration
All arms
Response categories per rev 2013 IWG-MRT criteria
Change in PROs, rate and time to ≥50% reduction in TSS after 12 and 24 weeks
ET Expansion Arm 4:
To assess symptom improvement
To evaluate the partial hematological response rate
(For further details please refer to the protocol) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Prior JAKi Arm 1 and Add-on to JAKi Arm 2:
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; see Appendix 3) risk category of intermediate-2 or higher
b. Platelet count ≥ 75 x 109/L without the assistance of thrombopoietic factors or transfusions
c. ANC ≥ 1 x 109/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 TD (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 <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 WOBCP and partners of patients with reproductive potential must agree to use highly effective contraceptive methods while on study therapy and 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 WOBCP and female partners of male patients. 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-2 or higher
b. Platelet count ≥ 100 x 109/L without the assistance of thrombopoietic factors or transfusions
c. ANC ≥ 1 x 109/L without the assistance of granulocyte growth factors
d. Spleen volume of ≥ 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 residual alopecia are allowed)
10. Male and WOCBP and partners of patients with reproductive potential must agree to use highly effective contraceptive methods while on study therapy and 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. NOTE: Male patients should be informed of the risk of testicular toxicity and provided with adequate advice regarding sperm preservation.
Arm 4 (ET Expansion):
1. Adult (aged ≥ 18 years)
2. A confirmed diagnosis of ET according to the 2016 WHO criteria
3. High-risk disease, defined as meeting at least one of the following criteria:
- Age > 60 years
- Platelet count > 1500 × 109 /L (at any point during the patient’s disease)
- Previously documented thrombosis (including Transient Ischemic Attack [TIA]), erythromelalgia, or migraine (severe, recurrent, requiring medications, and felt to
be secondary to the MPN) either after diagnosis or within 10 years before diagnosis and considered disease-related
- Previous hemorrhage related to ET
- Diabetes or hypertension requiring pharmacological therapy for > 6 month
(For further inclusion criteria for all Arms and details please refer to the protocol) |
|
| E.4 | Principal exclusion criteria |
Prior JAKi Arm 1 and Add-on to JAKi Arm 2:
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 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. 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
7. Patients with Child-Pugh Class B or C
8. GI function or GI disease that could significantly alter the absorption of pelabresib and/or ruxolitinib
9. Impaired cardiac function or clinically significant cardiac diseases
10. Ongoing uncontrolled hypertension despite maximal antihypertensive treatment
11. 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
12. 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 pelabresib.
13. Any investigational agent >2 weeks (or 5 half-lives) before the first dose of pelabresib
14. Prior treatment with a BET inhibitor
15. 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
16. Patients in the Combination Arm (Arm 2) who are receiving treatment with fluconazole
17. 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. 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
8. Patients with Child-Pugh Class B or C
9. Impairment of GI function or GI disease that could significantly alter the absorption of pelabresib and/or ruxolitinib
10. 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
11. Patients who have or have had PML
12. Impaired cardiac function or clinically significant cardiac diseases
13. Ongoing uncontrolled hypertension despite maximal antihypertensive treatment
14. 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
15. 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 pelabresib
16. 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 pelabresib
17. 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.
(For further exclusion criteria for Arm 3 and details please refer to the protocol)
Arm 4 ( ET Expansion):
1. Prior treatment with a BET inhibitor
2. Current known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
3. 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.
4. Patients with liver cirrhosis Child-Pugh Class B or C.
(For further exclusion criteria for Arm 4 and details please refer to the protocol) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Prior JAKi and Add-on to JaKi Arms -TD Cohorts (Cohorts 1A and 2A):
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 (total of ≥ 6 RBC transfusions during the 12 weeks) prior to enrollment and TI is defined as absence of RBC transfusions over any consecutive 12 week periods
Prior JAKi and Add-on to JaKi Arms -non-TD Cohorts (Cohorts 1B and 2B) and JAK Naive Arm:
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])
ET Expansion Arm 4:
The proportion of patients who meet the criteria for a CHR, as assessed by modified ELN criteria (Barosi et al. 2009)
- Normalization of platelet count (≤ 400 × 109 /L)
- WBC count within normal range (≤ 10 × 109 /L)
- Laboratory results confirmed after 1 cycle (after 3 weeks)
- Normal spleen size (by palpation or imaging) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Prior JAKi and Add-on to JaKi Arms - TD Cohorts:
Throughout duration of treatment
Prior JAKi Arms and Add-on to JaKi Arms - non-TD Cohorts and JAKi Naive Arm:
After 24 weeks of treatment (Cycle 9, Day 1)
ET Expansion Arm 4:
After 1 cycle (3 weeks) |
|
| E.5.2 | Secondary end point(s) |
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 and PGIC will be described. The proportion of patients who achieve a ≥50% reduction in the TSS after 12 weeks (Cycle 5, Day 1) and 24 weeks of treatment (Cycle 9, Day 1) will also be reported.
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 after 24 weeks of treatment (Cycle 9, Day 1) will also be evaluated.
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
Duration of the splenic response is defined as the time when splenic response criteria are first met (a ≥ 35% reduction from baseline spleen size) until the first time spleen volume reduction is < 35% from baseline and is increased by ≥ 25% from nadir in spleen volume by imaging
PK of pelabresib: Cmax, tmax, Ctrough, AUClast, AUC0-8,ss, Cmax,ss, tmax,ss
Pelabresib on PK of ruxolitinib: Cmax, tmax, Ctrough, AUClast, AUC0-8,ss
ET Expansion Arm 4:
The proportion of patients with ≥ 50% reduction from baseline in the MPN-SAF total score. PGIC will also be summarized.
The proportion of patients who meet the following criteria for a partial hematological response:
- Platelets 400-600 × 109 /L
- WBC within normal range (≤ 10 × 109 /L)
- Laboratory results confirmed after 1 cycle (after 3weeks) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are evaluated at the times specified above (after 3, 12, 18 or 24 weeks of treatment) or throughout the duration of the study if a timepoint is not specified. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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