This study has been transitioned to CTIS with ID 2023-509397-39-00 check the CTIS register for the current data. Part A: Safety:• To characterize the safety and tolerability of up to four dose levels of rilzabrutinibin patients with ITPEfficacy:• To…
ID
Source
Brief title
Condition
- Platelet disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 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.
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.
Secondary outcome
Secondary Endpoints
Safety Endpoints
In addition, safety will be assessed by the following 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)
Background summary
Rilzabrutinib is a high-affinity, inhibitor of BTK. Pertinent to the treatment
of ITP, Rilzabrutinib treatment in profoundly inhibited human B cell activation
and blocked antibody- (IgG, IgE) mediated activation of immune cells via Fc
receptor signaling. In nonclinical studies, Rilzabrutinib demonstrated a
significant dose-dependent reduction of platelet-loss in a mouse model of
immune thrombocytopenia. Rilzabrutinib also showed rapid and significant
anti-inflammatory effects in rat collagen-induced arthritis model, rat
antibody-mediated arthus model, and spontaneous canine pemphigus disease.
The proposed study is a dose-finding study that uses an intrapatient
dose-escalation design to explore a range of potential biologically active
doses within each patient, starting with an expected *no effect dose.* This
design allows for evaluation of a full range of potentially active doses in all
patients in the study and accounts for the biological variation in response in
each patient. Compared to a parallel dose-response study, this design will
expose fewer patients to ineffective dose levels and is appropriate to the
planned population. The dose-finding portion of the study (Part A) is complete
and all newly-admitted patients are initiating active treatment at the
recommended dose of 400 mg rilzabrutinib twice daily (B.I.D.)
Study objective
This study has been transitioned to CTIS with ID 2023-509397-39-00 check the CTIS register for the current data.
Part A:
Safety:
• To characterize the safety and tolerability of up to four dose levels of
rilzabrutinib
in patients with ITP
Efficacy:
• 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
Pharmacokinetics:
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP
Exploratory:
• To explore effect of rilzabrutinib on platelet autoantibody levels
• To explore effect of rilzabrutinib on markers of hemolysis
• To explore effect of rilzabrutinib on thrombopoietin (TPO) levels
• To explore effect of rilzabrutinib on quality of life (QOL) using the Euro-QoL
5-Dimension Visual Analog Scale (EQ-5D VAS)
• To characterize plasma metabolites of rilzabrutinib
Part B:
Safety:
To characterize the safety and tolerability of the selected dose of 400 mg BID
of rilzabrutinib in patients with ITP
Efficacy:
• 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
Pharmacokinetics:
• To characterize the pharmacokinetics of rilzabrutinib in patients with ITP
Exploratory:
• 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)
Study design
This is an adaptive, open-label, dose-finding study of rilzabrutinib in
patients with ITP who are refractory or relapsed with no available and approved
therapeutic options, with a platelet count <30,000/µL on two counts no sooner
than 7 days apart in the 15 days before treatment begins.
The active treatment period is 24 weeks and the post-treatment follow-up period
is 4 weeks.
Intervention
Part A:
PRN1008 100 mg, 300 mg and 400 mg tablets. Tablets should be taken with a glass
(~8 oz.) of water and may be taken with or without food.
Part B:
PRN1008 400 mg tablets. Tablets should be taken with a glass (~8 oz.) of water
and may be taken with or without food.
Study burden and risks
Possible risks / burden related to the IMP:
Possible Adverse Events (AE) such as diarrhea or *loose stools*, nausea,
abdominal distension, vomiting, abdominal discomfort, lab abnormalities,
headache, abdominal pain or bloating, change in immune system and allergic
reaction risks
Possible risks / burden associated with blood collection:
Discomfort, pain, irritation, infection, light-headedness or fainting, a
feeling of weakness accompanied by sweating, slowing of heart beat, and a
decrease in blood pressure.
55 Corporate Drive .
Bridgewater NJ 08807
US
55 Corporate Drive .
Bridgewater NJ 08807
US
Listed location countries
Age
Inclusion criteria
Part A
Inclusion Criteria:
1. Male or female patients, aged 18 to 80 years old (Czech Republic and Norway
only: 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 <30,000/µL on two occasions no less than 7 days apart
in
the 15 days prior to beginning study treatment.
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, 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
Part B
Inclusion Criteria:
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 FSH testing.
7. Able to provide written informed consent and agreeable to the schedule of
assessments
Exclusion criteria
Part A:
Exclusion Criteria:
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 screening for human immunodeficiency virus (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
12. Planned or concomitant use of any anticoagulants and platelet aggregation
inhibiting drugs such as aspirin with the exception of up to 100 mg/day doses,
NSAIDs, thienopyridenes (within 2 weeks 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 • Patients who previously received treatment with BTK inhibitors
within
30 days before receiving the first dose of study medication or who have
previously received rilzabrutinib are not eligible for the study
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 at screening for HIV, hepatitis B (surface antigen, core
antibodies),
or hepatitis C (anti-HCV antibody confirmed with HCV RNA).
• Patients who are HBV surface antigen (HBsAg) positive will not be eligible.
• Patients who are HBsAg negative and HBV core antibody (HBcAb) positive
will be tested for HBV surface antibody (HBsAb) and HBV DNA. If HBV
DNA is negative, and HBsAb titer is >100 IU/L, patients may be enrolled.
Monthly HBV DNA monitoring will be required while on treatment and for 6
months after the last dose of the study drug. Positive HBV DNA results will
be managed appropriately as per local standard of care.
• Patients who are HBcAb positive, HBsAg negative with HBsAb titer
<100 IU/L or negative, are not eligible.
18. History of recurring (2 or more) serious infections requiring intravenous
antibiotic
therapy within the last 3 months before SD1 or active serious or moderate
infection ongoing on the day of the planned first dose of study drug
19. Myelodysplastic syndrome
20. Live vaccine within 28 days prior to SD1 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509397-39-00 |
| EudraCT | EUCTR2017-004012-19-NL |
| CCMO | NL68745.078.19 |
| Other | PRN1008-010 (DFI17124) |