| 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 |
| Immune Thrombocytopenia, a chronic, autoimmune disease that is associated with bleeding risk due to low platelet levels in the blood. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| 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 |
Part A:
• To characterize the safety and tolerability of up to four dose levels of rilzabrutinib in patients with ITP
• To explore the clinical activity of up to four dose levels of rilzabrutinib in relapsed/refractory patients with ITP
• To identify a potential dose regimen to use in future studies of rilzabrutinib in patients with ITP
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP
Part B:
• To characterize the safety and tolerability of 400 mg BID dose of rilzabrutinib in patients with ITP
• To further explore the clinical activity and durability of response of the selected dose of 400 mg BID of rilzabrutinib in patients with ITP who have relapsed or have an insufficient response to prior therapies
• To evaluate the predictive value of platelet response to rilzabrutinib therapy in the first 8 weeks of active treatment for the achievement of the primary endpoint
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP
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|
| E.2.2 | Secondary objectives of the trial |
Part A:
• Effect of rilzabrutinib on platelet autoantibody levels
• Effect of rilzabrutinib on markers of hemolysis
• Effect of rilzabrutinib on thrombopoietin (TPO) levels
• Effect of rilzabrutinib on quality of life (QoL) using the Euro-QoL 5-Dimension Visual Analog Scale (EQ-5D VAS)
• Plasma metabolite analysis of rilzabrutinib
Part B:
• To explore effect of rilzabrutinib on markers of hemolysis
• To explore effect of rilzabrutinib on thrombopoietin (TPO) levels
• To explore effect of rilzabrutinib on IgG, IgG1, IgG4, IgM, IgE levels
• To explore effect of rilzabrutinib on quality of life (QOL) using the EQ-5D VAS and Immune Thrombocytopenic Purpura Patient Assessment Questionnaire (ITP-PAQ) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A:
1. Male and female patients, aged 18 to 80 years old (Czech Republic and Norway only: aged 18 to 65 years old)
2. Immune-related ITP (both primary and secondary)
3. Refractory or relapsed patients with no available and approved therapeutic options with a platelet count of count <30,000/µL on two occasions no sooner than 7 days apart in the 15 days before treatment begins
4. A history of response (two or more platelet counts ≥50,000/μL with an increase of at least 20,000/μL) to at least one prior line of therapy (with splenectomy being considered a line of therapy)
5. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 × 109/L, hemoglobin [Hgb] >9 g/dL, AST/ALT ≤1.5 × ULN, albumin ≥3 g/dL, total bilirubin ≤1.5 × ULN, estimated glomerular filtration rate [eGFR] > 60 mL/min (Cockcroft and Gault method) (C1D1 pre-dose may be checked up to Day -3 prior to C1D1)
6. Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use a highly effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, sexual abstinence when this is in line with the preferred and usual lifestyle of the patient). Unless surgically sterile, postmenopausal females should have menopause confirmed by FSH testing
7. Able to provide written informed consent and agreeable to the schedule of assessments
Part B:
1. Male or female patients, aged 18 to 80 years old
2. Patients with immune-related ITP (both primary and secondary) as defined by current guidelines with at least 3 months duration
3. Patients who had a response (achievement of platelet count ≥ 50,000/μL) to IVIg/anti-D or corticosteroid that was not sustained and failed at least one other ITP therapy (that was not IVIg or corticosteroid)
4. Patients with a platelet count of < 30,000/μL on two occasions no less than 7 days apart in the 15 days before treatment begins, and no platelet count above 35,000/μL on Study Day 1.
5. Patients with adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5 × 109/L, Hgb >9 g/dL, AST/ALT ≤1.5 × ULN, albumin ≥3 g/dL, total bilirubin ≤1.5 × ULN, eGFR >50 mL/min (Cockcroft and Gault method) (pre-dose may be checked up to Day -3)
6. Female patients who are of reproductive potential must agree for the duration of active treatment in the study to use a highly effective means of contraception (hormonal contraception methods that inhibits ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomized partner, or true abstinence; when this is in line with the preferred and usual lifestyle of the patient). Unless surgically sterile, postmenopausal females should have menopause confirmed by follicle-stimulating hormone (FSH) testing.
7. Able to provide written informed consent and agreeable to the schedule of assessments |
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| E.4 | Principal exclusion criteria |
Part A:
1. Pregnant or lactating women
2. ECG findings of QTcF > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities
3. History of current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the trial, with the exception of non-melanoma skin cancer
4. Transfusion with blood or blood products or plasmapheresis within 2 weeks before Day 1
5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to Day 1 (more than 10% variation from Day 1 daily doses)
6. Use of rescue medications other than corticosteroids or TPO in Exclusion Criterion #5 in the two weeks before Day 1
7. Immunosuppressant drugs other than corticosteroids – these drugs should be discontinued for at least 14 days before Day 1
8. Treatment with rituximab or splenectomy within the 3 months prior to Day 1
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to Day 1)
10. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of Day 1
11. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives (whichever is longer) of study drug dosing including, but not limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine
12. Planned or concomitant use of any anticoagulants and platelet aggregation inhibiting drugs such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), thienopyridenes (within 14 days of planned dosing through end of follow-up)
13. Has received any investigational drug within the 30 days before receiving the first dose of study medication, or at least 5 times elimination half-life of the drug(whichever is longer); patient should not be using an investigational device at the time of dosing
14. Current drug or alcohol abuse
15. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate study drug absorption
16. History of solid organ transplant
17. Positive for screening for HIV, hepatitis B (surface antigen and core antibodies unrelated to vaccination), or hepatitis C (anti-HCV antibody confirmed with HCV RNA)
18. History of serious infections requiring intravenous therapy within the last 3 months before Day 1
19. Clinically significant cognitive dysfunction (≥ Grade 1) or medical history suggestive of increased risk for cognitive dysfunction during the study
20. Live vaccine within 28 days prior to Day 1 or plan to receive one during the study
21. Planned surgery in the time frame of the dosing period
22. Any other clinically significant disease, condition, or medical history that, in the opinion of the Investigator, would interfere with patient safety, study evaluations, and/or study procedures
Part B:
1. Pregnant or lactating women
2. ECG findings of QTcF > 450 msec (males) or > 470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats/min on ECG), or other clinically significant abnormalities
3. History (within 5 years of SD1) or current, active malignancy requiring or likely to require chemotherapeutic or surgical treatment during the trial, with the exception of non-melanoma skin cancer
4. Transfusion with blood, blood products, IVIg, or plasmapheresis within 2 weeks before SD1
5. Change in corticosteroid and/or TPO agonist dose within 2 weeks prior to SD1 (more than 10% variation)
6. Use of rescue medications in the 4 weeks before SD1
7. Treatment with immunosuppressant drugs other than corticosteroids within 2 weeks prior to SD1
8. Treatment with rituximab or splenectomy within the 3 months prior to SD1
• Patients treated with rituximab within 6 months from screening will have normal B-cell counts prior to enrollment
9. Ongoing need for the use of proton pump inhibitor drugs such as omeprazole and esomeprazole (it is acceptable to change patient to H2 receptor blocking drugs prior to SD1)
10. Concomitant use of known strong-to-moderate inducers or inhibitors of CYP3A within 3 days or 5 half-lives (whichever is longer) of SD1
11. Use of CYP3A-sensitive substrate drugs with a narrow therapeutic index within 3 days or 5 half-lives(whichever is longer) of study drug dosing including, but not limited to, alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or terfenadine
Please, refer to protocol for further exclusion criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Outcome Measures of the Study: Part A:
Primary Safety endpoints:
Safety will be assessed by the incidence, severity and relationship of TEAEs, including clinically significant changes in physical examination, laboratory tests, and vital signs.
Treatment-emergent adverse events in the post treatment follow-up period will also be assessed and examined for possible relationship to the prior rilzabrutinib treatment. Adverse events (AEs) will be categorized as treatment emergent after the first dose of rilzabrutinib has been received.
Primary Efficacy Endpoint:
Proportion of patients able to achieve two or more consecutive platelet counts, separated by at least 5 days, of ≥50,000/μL AND an increase of platelet count of ≥20,000/μL from baseline, by dose level, without use of rescue medication in the 4 weeks prior to the latest elevated platelet count.
Outcome Measures of the Study: Part B:
Primary Safety endpoints:
Safety will be assessed by the incidence, severity and relationship of TEAEs, including clinically significant changes in physical examination, laboratory tests, and vital signs. Bleeding TEAEs will be tabulated and a proportion of patients with a Grade 2 or higher bleeding event will be provided.
Primary Efficacy endpoint:
Proportion of patients able to achieve platelet counts ≥50,000/μL on at least 8 out of the last 12 weeks of the 24-week treatment period without the use of rescue medication after 10 weeks of active treatment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 1, Day 15, Day 29, Day 57, Day 85, Day 113, Day 141, hematology weekly visits between clinic visits of each cycle, Day 169 (last day of active treatment) and Day 197 (FUV End of study)
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| E.5.2 | Secondary end point(s) |
Safety Endpoints:
• Proportion of patients receiving rescue medication at each dosing level and overall
• Proportion of patients with a Grade 2 or higher bleeding event at each dosing level and overall
• Bleeding scale (ITP-BAT) at the end of treatment period for each dosing level
Efficacy Endpoints:
Part A:
• Percent of weeks with platelet counts ≥ 50,000/μL by dose level and overall
• Proportion of patients with 4 out of the final 8 platelet counts ≥ 50,000/μL across all dose levels
• Change from baseline to the average of the post Day 1 platelet counts by dose level and overall for patients who had >4 weeks of study drug on that given dose level
• Number of weeks with platelet counts ≥ 50,000/μL across all dose levels
• Number of weeks with platelet counts ≥ 30,000/μL across all dose levels
• Time to first platelet count ≥ 50,000/μL across all dose levels
Part B:
• Number of weeks with platelet count ≥50,000/μL OR ≥30,000/μL and doubling the baseline in the absence of rescue therapy (platelet counts will be censored for 4 weeks after the use of rescue medication, if given)
• Proportion of all treated patients able to achieve two or more consecutive platelet counts, separated by at least 5 days, of ≥50,000/μL AND an increase of platelet count of ≥20,000/μL from baseline without use of rescue medication in the 4 weeks prior to the latest elevated platelet count
• Number of weeks with platelet counts ≥ 30,000/μL and doubling from baseline over the 24-week treatment period (platelet counts will be censored for 4 weeks after the use of rescue medication, if given)
• Proportion of patients receiving rescue medication
• Change from baseline in ITP Bleeding Assessment Tool (ITP-BAT)
Pharmacokinetic Outcome Measures:
Plasma PK parameters (maximum observed plasma concentration [Cmax], Tmax, area under the plasma concentration-time curve [AUC], elimination half-life [t½], apparent volume of distribution of the drug after oral administration [V/F], apparent total clearance of the drug from plasma after oral administration [CL/F]) of rilzabrutinib in ITP patients will be evaluated in each patient based on frequent sampling on Day 1 of a new, higher dosing level and reported by dose
(Part A only) and, if relevant, overall. Results will be reported by descriptive statistics.
Exploratory analyses will pool these data with the data from other studies of rilzabrutinib. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As specified within the list of endpoints |
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| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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.8.3 |
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 | 10 |
| 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 |
| Bulgaria |
| Canada |
| Czechia |
| Netherlands |
| Norway |
| United Kingdom |
| United States |
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| 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
|
| The end of the study is defined as the date of the final safety follow-up visit after the last participant’s last visit (LPLV). |
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| 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 | 8 |
| 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 | 8 |
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