A Study of Rilzabrutinib in Adult Patients With Immune Thrombocytopenia (ITP)

Phase 2Active Not RecruitingNCT03395210

Principia Biopharma, a Sanofi Company86 enrolled

Overview

This was a 2 part (Part A and B) adaptive, open-label, dose-finding study of PRN1008 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 dose-finding portion of the study was completed. Part B treatment dose was 400 mg twice daily.

This was a 2 part (Part A and B) adaptive, open-label, dose-finding study of PRN1008 in approximately 60 patients in Part A and approximately 25 patients in Part B. Part A enrolled patients with ITP who were refractory or relapsed with no available and approved therapeutic options. Eligible patients had 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 was 24 weeks and the post-treatment follow-up period is 4 weeks. In the dose-finding part of the study, each patient enrolled in the study was allowed to up-titrate their dose after 28 days of PRN1008 therapy, if they did not experience a platelet response or a dose-limiting toxicity (DLT) at the last dose level. Patients who responded to PRN1008 per protocol may enter a long term-extension. Part B of the study included approximately 25 patients with ITP who had relapsed or had an insufficient response to prior therapies. Eligible patients had a platelet count \<30,000/µL on two occasions no less than 7 days apart, within 15 days before treatment began and a platelet count of ≤35,000/µL on Study Day 1 (SD1). The study consisted of a 28-day screening period, 24-week active treatment period, and a long-term extension. After the last dose of PRN1008 there was a 4-week safety follow-up period.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Immune Thrombocytopenia

Interventions

RilzabrutinibDRUG

BTK inhibitor

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female patients, aged 18 to 80 years old * Immune-related ITP (both primary and secondary) Exclusion Criteria: * Pregnant or lactating women * Current drug or alcohol abuse * History of solid organ transplant * Positive screening for HIV, hepatitis B, or hepatitis C

Locations (31)

Outcomes

Primary Outcomes

Part A: Percentage of Participants Who Achieved 2 or More Consecutive Platelet Counts by Starting Dose Level and Overall

The percentage of participants who achieved 2 or more consecutive platelet counts, separated by at least 5 days, of \>=50,000/ microliter (μL) and an increase of platelet count of \>=20,000/μL from baseline, by starting dose level and overall, without use of rescue medication in the 4 weeks prior to the latest elevated platelet count. 95% confidence interval (CI) was based on the Clopper-Pearson method. The average of the 2 screening results and the Cycle 1 Day 1 result were used as the baseline value.

Time frame: Up to 24 Weeks

Part B: Percentage of Participants Who Achieved Platelet Counts >=50,000/μL

The percentage of participants who achieved 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. 95% CI was based on the Clopper-Pearson exact method.

Time frame: Up to 24 Weeks

Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment Related Treatment-Emergent Adverse Events

Adverse event (AE): any untoward medical occurrence in participant or clinical study participant, temporally associated with the use of rilzabrutinib, whether or not considered related to rilzabrutinib. TEAEs: AEs that developed or worsened or became serious on or after the first dose administration of rilzabrutinib (Day 1). Any TEAEs are considered treatment-related TEAEs as per Investigator's evaluation of participant's circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an TEAE can be considered as related to the rilzabrutinib.

Time frame: From first dose of rilzabrutinib (Day 1) up to last dose + 1 (up to 294 days)

Part B: Number of Participants With Treatment-Emergent Adverse Events and Treatment Related Treatment-Emergent Adverse Events

AE any untoward medical occurrence in participant or clinical study participant, temporally associated with the use of rilzabrutinib, whether or not considered related to rilzabrutinib. TEAEs: AEs that developed or worsened or became serious during the treatment-emergent period, defined as any time after the first dose administration of rilzabrutinib (Day 1). Any TEAEs are considered treatment-related TEAEs as per Investigator's evaluation of participant's circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an TEAE can be considered as related to rilzabrutinib.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Part A: Percentage of Weeks With Platelet Counts >=50,000/μL by Starting Dose Level and Overall

The percentage of weeks in which participants achieved platelet counts \>=50,000/μL in the treatment period are summarized here.

Time frame: Up to 24 Weeks

Part A: Percentage of Participants With 4 Out of the Final 8 Platelet Counts >=50,000/μL by Starting Dose Level and Overall

The percentage of participants who had at least 4 out of the final 8 platelet counts \>=50,000/μL are summarized here. The final 8 scheduled platelet counts are the measurements performed in the last 8 weeks of rilzabrutinib (depending on treatment duration, not necessarily from Week 19 to Week 24) in the treatment period. 95% CI was based on the Clopper-Pearson method.

Time frame: Up to 24 Weeks

Part A: Change From Baseline to the Average of Post Day 1 Platelet Counts by Dose Level and Overall

Average of post Day 1 platelet count is equivalent to average of (average of each participant's post-Day 1 platelet counts), included platelet counts up to 1 day after the date of last dose of rilzabrutinib and excluded platelet counts on or after date of rescue, if applicable. The average of the 2 screening results and the Cycle 1 Day 1 result measured on different date were used as the baseline value.

Time frame: Baseline and up to 24 Weeks

Part A: Number of Weeks With Platelet Counts >=50,000/μL by Starting Dose Level and Overall

The number of weeks in which participant achieved platelet counts \>=50,000/μL in the treatment period are summarized here. The number of weeks is based on the number of scheduled weekly assessments, by study day.

Time frame: Up to 24 Weeks

Part A: Number of Weeks With Platelet Counts >=30,000/μL by Starting Dose Level and Overall

The number of weeks in which participant achieved platelet counts \>=30,000/μL in the treatment period are summarized here. The number of weeks is based on the number of scheduled weekly assessments, by study day.

Time frame: Up to 24 Weeks

Part A: Time to First Platelet Count >=50,000/μL Across All Dose Levels

Time to first platelet count \>=50,000/μL during the treatment period in days was calculated as: (date of first occurrence of platelet count \>=50,000/μL - date of first rilzabrutinib dosing) +1.

Time frame: Up to 24 Weeks

Part B: Number of Weeks With Platelet Counts >= 50,000/μL or >= 30,000/μL and Doubling the Baseline

The number of weeks in which participant achieved platelet counts with thresholds as: \>=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) are summarized here. Baseline is defined as the average of 3 platelet counts: 2 qualified screening platelet counts collected in electronic case report form (eCRF) and Week 1 (study day 1) platelet count.

Time frame: Up to 24 Weeks

Part B: Percentage of Participants Who Achieved 2 or More Consecutive Platelet Counts

Percentage of participants who achieved 2 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 are summarized here. Baseline is defined as the average of 3 platelet counts: 2 qualified screening platelet counts collected in eCRF and Week 1 (study day 1) platelet count. 95% CI was based on the Clopper-Pearson exact method.

Time frame: Up to 24 Weeks

Part B: Number of Weeks With Platelet Counts >=30,000/μL and Doubling the Baseline

The number of weeks in which participant achieved platelet counts \>=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) are summarized here. Baseline is defined as the average of 3 platelet counts: 2 qualified screening platelet counts collected in eCRF and Week 1 (study day 1) platelet count.

Time frame: Up to 24 Weeks

Part B: Percentage of Participants Who Received Rescue Medication

Rescue medication is defined as any therapy used to rescue a participant (1 of intravenous immunoglobulin \[IVIG\], high-dose steroids, platelet infusion or anti-D immunoglobulin infusion). Percentage of participants who received rescue medication are summarized here. 95% CI was based on the Clopper-Pearson exact method.

Time frame: Up to 24 Weeks

Part B: Change From Baseline in Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS)

The IBLS is a bleeding assessment score. IBLS comprises of 11 sites for female and 10 sites for male, and each site is scored from 0 (none) to 2 (marked bleeding). The total overall score ranges from 0-22, with higher scores indicating higher presence of marked bleeding. For each participant, an IBLS score at each visit was calculated by taking the average across 11 items (10 for male and postmenopausal women) at 9 anatomical sites (8 for male and postmenopausal women). For each participant, a mean IBLS score was also calculated by taking the average across all post-baseline visits during the 24-week treatment period. IBLS average value ranges from 0 to 2. The smaller the IBLS average value is, the healthier the participants are. For change from baseline, negative value indicates an improvement. The baseline value is defined as the last available value before the first dose rilzabrutinib.

Time frame: Baseline and up to 24 weeks

Part A: Percentage of Participants Who Received Rescue Medication by Dose Levels and Overall

Rescue medication is defined as any therapy used to rescue a participant (1 of IVIG, high-dose steroids, platelet infusion or anti-D immunoglobulin infusion). The percentage of participants who received rescue medication for each dose level and overall are summarized here. 95% CI was based on the Clopper-Pearson method.

Time frame: Up to 24 Weeks

Part A: Percentage of Participants With Grade 2 or Higher Bleeding Event by Dose Level and Overall

The percentage of participants with intensity grade 2 or higher bleeding event are summarized for each dose level and overall. The TEAEs with standardized medical dictionary for regulatory activities (MedDRA) query (SMQ) hemorrhages were medically determined for analysis of bleeding events. 95% CI was based on the Clopper-Pearson method.

Time frame: Up to 24 Weeks

Part A: Number of Participants With Idiopathic Thrombocytopenic Purpura/Immune Thrombocytopenia (ITP) Bleeding Assessment Tool (ITP-BAT) Scale by Dose Level

The ITP-BAT scale comprises of 11 grades from 0 (none) to 2 (marked bleeding), with higher scores indicating higher presence of marked bleeding, assessed at 9 anatomical sites (skin, oral, epistaxis, gastrointestinal \[GI\], urinary, gynecological \[GYN\], pulmonary, intracranial hemorrhage \[HEM\], subconjunctival HEM) by history over the previous week (Hx). In addition, 2 sites (skin and oral), were also assessed by physical examination (PE). The 'worst ever' bleeding experienced at each site was graded using the same system. Here, 0 indicates none; 1 indicates 1-5 bruises and/or scattered petechiae and 2 indicates \>5 bruises with size \>2 centimeter (cm) and/or diffuse petechiae. Each participant summed up the transformed scores across all 11 sites per visit assessment. The total overall score ranges from 0-22 with the higher score indicating worst outcome.

Time frame: Up to 24 Weeks

Part A: Maximum Observed Plasma Concentration (Cmax) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine Cmax of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, 3, and 5 (each cycle 28 days)

Part A: Time of Observed Maximum Plasma Concentration (Tmax) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine tmax of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, 3, and 5 (each cycle 28 days)

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine AUClast of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, 3, and 5 (each cycle 28 days)

Part A: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine AUCinf of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, and 3 (each cycle 28 days)

Part A: Elimination Half-Life (t1/2) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine t1/2 of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, and 3 (each cycle 28 days)

Part A: Apparent Volume of Distribution of the Drug After Oral Administration (Vz/F) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine Vz/F of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, and 3 (each cycle 28 days)

Part A: Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) of Rilzabrutinib

Plasma samples were collected at specified timepoints to determine CL/F of rilzabrutinib.

Time frame: Day 1 of Cycles 1, 2, and 3 (each cycle 28 days)

Part B: Plasma Concentration of Rilzabrutinib

Plasma samples were collected at specified timepoints for evaluation of rilzabrutinib pharmacokinetic (PK) concentrations.

Time frame: Pre-dose and 2 hours post-dose on Days 1, 29, and 57