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A Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects with Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD)

A Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants with Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD)

19

Of the 19 subjects enrolled, 63.2% were men and 36.8% were women. The median age at baseline was 40.0 (range: 13 to 64) years, which included 1 adolescent subject. The median time from transplant to initial cGVHD diagnosis was 8.31 (range: 3.4 to 22.8) months, and the median time from initial cGVHD diagnosis to study entry was 21.36 (range: 5.1 to 158.0) months. At baseline, 10 subjects (52.6%) had moderate cGVHD and 9 subjects (47.4%) had severe cGVHD. Subjects had a median number of 2 (range: 1 to 3) prior cGVHD treatment regimens. All subjects were required to continue corticosteroids at baseline. The median daily steroid dose per weight at baseline was 0.27 (range: 0.1 to 1.8) mg/kg/day. The majority of subjects (94.7%) had 2 or more organs involved at baseline, with the most commonly involved organs being mouth (15/19 [78.9%] subjects), skin (14/19 [73.7%] subjects), muscles, fascia, and joints (10/19 [52.6%] subjects), and eyes (9/19 [47.4%] subjects). The median dose intensity of ibrutinib was 409.88 (range: 157.8 to 420.0) mg/day.

A total of 26 subjects were screened and 19 cGVHD subjects requiring continuous systemic corticosteroid therapy were enrolled in the study after the diagnosis of steroid dependent/refractory disease and received ibrutinib; of which 7/19 (36.8%) subjects completed the study treatment and 12/19 (63.2%) subjects had discontinued ibrutinib at the time of final analysis. The most common reason for ibrutinib discontinuation were AEs and physician decision (3/19 [15.8%] subjects each), progressive disease (cGVHD) and withdrawal by subject (2/19 [10.5%] subjects each). A total of 11/19 (57.9%) subjects completed the study participation, and 8/19 (42.1%) subjects terminated the study. The reasons for the study termination were death (7/19 [36.8%] subjects) and withdrawal by subject (1/19 [5.3%] subject). Primary analysis was conducted at a protocol-planned timepoint (when the last subject completed the efficacy assessments at Week 37 or discontinued treatment before Week 37); final analysis was conducted at the end of the study when the last scheduled study assessment of the last subject was completed. The median time on study was extended from 11.93 (range: 1.9 to 16.7) months at primary analysis to 31.11 (range: 1.9 to 38.6) months at final analysis, and the median duration of ibrutinib exposure from 9.63 (range: 0.6 to 16.7) months to 16.33 (range: 0.6 to 36.2) months.

All results, unless otherwise specified, are based on the final analysis. - Of the 19 treated subjects, all subjects had at least 1 TEAE reported. The most common treatment-emergent adverse events (TEAEs) (>=20.0% of subjects) during the study were pneumonia and stomatitis (9/19 [47.4%] subjects each), upper respiratory tract infection, platelet count decreased and cellulitis (6/19 [31.6%] subjects each), nausea (5/19 [26.3%] subjects), pruritus, oedema peripheral, cataract, purpura, headache and constipation (4/19 [21.1%] subjects each). - TEAEs of Grade 3 or higher were reported in 17/19 (89.5%) subjects. The most common (>=10.0% of subjects) Grade 3 or higher TEAEs reported during the study included pneumonia (6/19 [31.6%] subjects), platelet count decreased and cellulitis (3/19 [15.8%] subjects each), cataract, neutrophil count decreased, anemia, renal impairment and stomatitis (2/19 [10.5%] subjects each). - Treatment-emergent SAEs were reported in 12/19 (63.2%) subjects. The most common (>=10.0% of subjects) treatment-emergent SAEs were pneumonia (7/19 [36.8%] subjects), cellulitis (3/19 [15.8%] subjects) and renal impairment (2/19 [10.5%] subjects). - No new TEAEs leading to death, treatment discontinuation, or dose reduction was reported from primary to final analysis. o Three of 19 (15.8%) subjects died due to TEAEs: 1 subject had multiple organ dysfunction syndrome (considered ibrutinib-related), 1 subject had pneumonia fungal (considered ibrutinib-related), and 1 subject had subarachnoid hemorrhage (considered not ibrutinib-related). o Treatment-emergent AEs leading to treatment discontinuation were reported in 3/19 (15.8%) subjects (1 with Grade 3 stomatitis, 1 with fatal multiple organ dysfunction syndrome, and 1 with fatal subarachnoid hemorrhage). o Treatment-emergent AEs leading to dose reduction were reported in 2/19 (10.5%) subjects (1 with Grade 3 stomatitis and 1 with Grade 3 gastrointestinal hemorrhage). - At primary analysis, major hemorrhage was reported in 3/19 (15.8%) subjects and no new subject reported major hemorrhage after primary analysis. Of the 3/19 (15.8%) subjects with major hemorrhage, 1 subject had Grade 3 gastrointestinal hemorrhage and Grade 4 immune thrombocytopenia, and another subject had Grade 5 subarachnoid hemorrhage. The other subject had Grade 3 traumatic hemorrhage, whose preferred term was changed to joint injury at the final analysis. - One of 19 (5.3%) subject reported serious Grade 2 atrial flutter (cardiac arrythmia events). - Infections (defined as TEAEs in the infections and infestations SOC [system organ class]) were reported in 15/19 (78.9%) subjects. The most common infections were pneumonia (9/19 [47.4%] subjects), cellulitis and upper respiratory tract infection (6/19 [31.6%] subjects each). The most common Grade 3 or higher infection was pneumonia (6/19 [31.6%] subjects).

ll 19 subjects treated with ibrutinib were included in the efficacy, safety, and PK analyses. At the primary analysis with the median follow-up period of 11.93 months, - The best overall response rate (BORR) (CR+PR) defined based on the 2014 NIH Consensus Development Project Criteria was 73.7% (14/19 subjects; 95% CI: 48.8%, 90.9%) in all treated analysis set. The lower bound of the 95% Confidence Interval (CI) exceeded 25% (the prespecified threshold of efficacy); therefore, the primary objective of the study was met. - Among 14 responders, 2 subjects had CR and 12 subjects had PR. - Responses were seen across the involved organs for cGVHD. At the final analysis with the median follow-up period of 31.11 months, - The best overall response rate (BORR) (CR+PR) defined based on the 2014 NIH Consensus Development Project Criteria was 84.2% (16/19 subjects; 95% CI: 60.4%, 96.6%) in all treated analysis set. - After primary analysis, additional 1 subject has reached CR and 1 reached PR. The BORR of CR and PR was observed in 3/19 (15.8%) subjects and 13/19 (68.4%) subjects, respectively, at the final analysis. - Responses were seen across the involved organs for cGVHD. The organ response rate (PR/CR) was increased from primary to final analysis for skin (35.7% to 57.1%), eye (11.1% to 22.2%), mouth (35.7% to 40.0%) and esophagus (40.0% to 60.0%).

All results, unless otherwise specified, are based on the final analysis. Efficacy Results: - The rate of sustained response for >=20 weeks was 68.8% (11/16 responders, 95% CI: 41.3%, 89.0%). - The median DOR was not reached (range: 1.0 to 34.5+). The Kaplan-Meier estimate for DOR at 30-months was 56.2% (95% CI: 26.9%, 77.6%). - The cGVHD response rate for all treated analysis set was 52.6% (10/19 subjects) at Week 25, 47.4% (9/19 subjects) at Week 49, and 31.6% (6/19 subjects) at Week 97. - The median daily corticosteroid dose requirement tended to decrease over time for all treated analysis set; the median dose was 0.27 (range: 0.08 to 1.77) mg/kg/day at baseline, 0.25 (range: 0.08 to 0.87) mg/kg/day at Week 24, 0.15 (range: 0.06 to 0.64) mg/kg/day at Week 48, 0.14 (range: 0.01 to 0.59) mg/kg/day at Week 96. - The improvement rate in the Lee cGVHD Symptom Scale total summary score was 52.6% (10/19 subjects; 95% CI: 28.9% ,75.6%) for all subjects. Subjects who had improvement included both responders and non-responders. - The median FFS (range: 1.9 to 37.3+) and median OS (range: 1.9 to 37.3+) were not reached, with the 30-months FFS and OS of 62.7% (95% CI: 37.2%, 80.2%) and 62.0% (95% CI: 36.3%, 79.8%), respectively. One of the 19 (5.3%) subject discontinued all the concomitant immunosuppressants including corticosteroids during the study. Pharmacokinetic Results: Pharmacokinetic data are based on the primary analysis. Four subjects who received voriconazole had 280 mg ibrutinib once daily while 15 remaining subjects received 420 mg ibrutinib once daily. The plasma exposure of ibrutinib was evident after the first dose (Week 1 Day 1) and at steady-state (Week 2 Day 1). Ibrutinib was rapidly absorbed after oral administration with a tmax of approximately 4.00 hours on both PK collection days. The apparent terminal t1/2 was similar on Week 1 Day 1 and at steady-state (Week 2 Day 1), where median values were 4.9 and 4.4 hours, respectively. The mean accumulation ratios of ibrutinib after 8 days of repeated dosing were 1.00 based on Cmax and 1.13 based on AUC0-24h. After the first dose of ibrutinib (Week 1 Day 1), the mean ibrutinib Cmax and AUClast values were 1.63- and 2.79-fold higher, respectively, in subjects who received fluconazole (n=8) than subjects who did not receive CYP3A inhibitors (n=7). At steady-state (Week 2 Day 1), the mean ibrutinib Cmax, AUC0-24h, and AUClast values were 2.47-, 2.93-, and 2.97-fold higher, respectively, in subjects who received fluconazole (n=8) than subjects who did not receive CYP3A inhibitors (n=7). After the first dose of ibrutinib (Week 1 Day 1), the mean ibrutinib Cmax and AUClast values that were 1.03- and 2.22-fold higher, respectively, in subjects who received voriconazole (n=4) than subjects who did not receive CYP3A inhibitors. Similarly, at steady-state (Week 2 Day 1), the mean ibrutinib Cmax, AUC0-24h, and AUClast values that were 1.57-, 1.41-, and 1.39-fold higher, respectively, in subjects who received voriconazole than subjects who did not receive CYP3A inhibitors (n=7). Pharmacodynamic results: The mean BTK occupancy (coefficient of variation %), regardless of the ibrutinib daily dose, was found to be 88.1% (20.2%) as early as 4 hours after the first dose of ibrutinib. These occupancy levels were maintained throughout the assessment period at 91.8%, 88.3%, and 91.2%, at week 1 day 2, predose; week 2 day 1, predose; and week 13 day 1, predose, respectively. ITK binding occupancy was measured, but the signal-to-noise ratio was inadequate for a quantitative analysis to return precise occupancy.

The results showed a positive benefit-risk profile of ibrutinib at a dosing regimen of 420 mg/day in Japanese subjects with steroid dependent/refractory cGVHD. - The study met its primary efficacy objective. Clinically meaningful results were demonstrated for BORR (CR+PR) and sustained response, with a trend of overall reduction in the use of steroids. - Ibrutinib had an acceptable safety profile in this population, and no new safety signals for ibrutinib were observed.

June. 06, 2021

https://pubmed.ncbi.nlm.nih.gov/34102349/

Yes

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Janssen Pharmaceutical K.K.

Janssen Pharmaceutical K.K.

+81-120-183-275 付時間 9：00～17：40（土・日・祝日および会社休日を除く）

completed

June. 19, 2018

Interventional

No Masking Single Group Assignment

treatment purpose

3

- Steroid dependent/refractory chronic graft versus host disease (cGVHD) defined as modified National Institutes of Health (NIH) criteria (2014) below at any time post-hematopoietic cell transplant (post-HCT):

a) Dependent disease, defined as, when glucocorticoid (prednisolone doses greater than or equal to [>=] 0.25 milligram per kilogram per day (mg/kg/day)or >=0.5 milligram per kilogram (mg/kg) every other day) are needed to prevent recurrence or progression of manifestations as demonstrated by unsuccessful attempts to taper the dose to lower levels on at least 2 occasions, separated by at least 8 weeks. In case of inability to taper the dose to less than or equal to (<=)0.25 mg/kg/day or <=0.5 mg/kg every other day (prednisolone doses) due to recurrence or progression of cGVHD manifestations, it is considered as steroid-dependent disease if the lowest tapering dose of the second occasion is equal or higher than the lowest tapering dose of the first occasion;

b) Refractory disease, defined as, when cGVHD manifestations progress despite the use of a regimen containing glucocorticoid (prednisolone at >=1 mg/kg/day for at least 1 week) or persist without improvement despite continued treatment with glucocorticoid (prednisolone at >=0.5 mg/kg/day or 1 mg/kg every other day) for at least 4 weeks

- Participants must be receiving baseline systemic glucocorticoid therapy for cGVHD at study entry. The dose of steroids must be stable for 14 days prior to starting ibrutinib

- At the time of trial enrollment, participants may be receiving other immunosuppressive therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 14 days prior to starting ibrutinib

- Clinically stable or worsening cGVHD for a minimum of 14 days between screening and Day 1 cGVHD response assessment

- Karnofsky or Lansky (participants less than [<]16 years) performance status >=60

- Active acute graft versus host disease (GVHD)

- More than 3 previous systemic treatments for cGVHD. Treatment with glucocorticoids is considered a treatment for cGVHD and should be included in determining the number of previous treatments

- History of treatment with a tyrosine kinase inhibitor (example [e.g.] imatinib), purine analogs, or other cancer chemotherapy in the 4 weeks prior to starting ibrutinib. Participants may have received ibrutinib pre-transplant for other reasons besides cGVHD such as for the treatment of leukemia or lymphoma

- History of treatment with monoclonal T and B cell antibodies in the 8 weeks prior to starting ibrutinib

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of ibrutinib

Both

Graft vs Host Disease

investigational material(s)
Generic name etc : Ibrutinib
INN of investigational material : Ibrutinib
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Participants will receive 420 milligram (mg) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

efficacy
Percentage of Participants who Achieve Complete Response (CR) or Partial
Response (PR) (i.e. Overall Response Rate [ORR])
Approximately up to 4.5 years

efficacy
Percentage of Participants with Sustained Response that was sustained for at least 20 weeks
Approximately up to 4.5 years
efficacy
Duration of Response (DOR)
From the date of initial documentation of a response to the date of first documented evidence of progressive cGVHD or death, whichever occurs first (approximately up to 4.5 years)
efficacy
Percentage of Participants with cGVHD response at Each Timepoint of Efficacy Evaluation
Screening, Day 1 Weeks 1, 5, 13 and 25, Week 37 and every 12 weeks (q12w) thereafter, Progressive cGVHD Visit, End-of-Treatment and Response Follow-up Visits (until progressive cGVHD) q12w (approximately up to 4.5 years)
efficacy
Change in the Amount of Corticosteroid Required Per Participant Over Time
Screening, Day 1 Weeks 1, 2, 5, 9, 13, 17, 21, 25, Week 37 and q12w thereafter, Progressive cGVHD Visit, End-of-Treatment and Response Follow-up Visits (until progressive cGVHD) q12w (approximately up to 4.5 years)
efficacy
Improvement in Symptom Burden Measured by the Lee cGVHD Symptom Scale
Screening, Day 1 Weeks 1, 5, 13 and 25, Week 37 and q12w thereafter, Progressive cGVHD Visit, End-of-Treatment and Response Follow-up Visits (until progressive cGVHD) q12w (approximately up to 4.5 years)
safety
Number of Participants with Adverse Events (AEs) as a Measure of Safety
From signing Informed Consent Form until 30 days after the last dose of study treatment (approximately up to 4.5 years)
safety
Number of Participants with Clinical Laboratory Abnormalities
Screening, Day 1 Weeks 1, 2, 5, 9, 13, 17, 21, 25, Week 37 and q12w thereafter, Progressive cGVHD Visit, End-of-Treatment (approximately up to 4.5 years)
pharmacokinetics
Area Under the Plasma Concentration-Time Curve from Time Zero to Time of Last Measurable Concentration (AUC [0-last]) of Ibrutinib
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Area Under the Plasma Concentration-Time Curve from Time Zero to 24 Hours (AUC [0-24]) of Ibrutinib
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ibrutinib
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Elimination Half-Life (t1/2) of Ibrutinib
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
AUC (0-last) of Metabolite PCI-45227
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
AUC (0-24) of Metabolite PCI-45227
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Cmax of Metabolite PCI-45227
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
Tmax of Metabolite PCI-45227
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1
pharmacokinetics
t1/2 of Metabolite PCI-45227
Day 1 (Predose, 1 hour [h], 2h, 4h, 6h) Weeks 1 and 2; Day 2 (Predose) Week 1

Mar. 12, 2018