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

Graft vs Host Disease Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03474679
• Other study ID #: CR108443
• Secondary ID: 54179060GVH3001
• Status: Completed
• Phase: Phase 3
• Start date: May 1, 2018
• Est. completion date: November 29, 2021

Study information

• Verified date: January 2023
• Source: Janssen Pharmaceutical K.K.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate efficacy of ibrutinib in Japanese participants with steroid dependent/refractory chronic graft versus host disease (cGVHD) by measuring overall cGVHD response (complete response [CR] and partial response [PR] defined by National Institutes of Health [NIH] consensus development project criteria [2014]).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: November 29, 2021
• Est. primary completion date: November 29, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Graft vs Host Disease

Intervention

Drug:
• Ibrutinib
Participants will receive 420 mg (3 * 140 mg capsules) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.

Locations

Country	Name	City	State
Japan	Anjo Kosei Hospital	Anjo-shi
Japan	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyo-ku
Japan	Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital	Hiroshima
Japan	Kobe City Medical Center General Hospital	Hyogo
Japan	Tokai University Hospital	Isehara
Japan	Osaka Women's and Children's Hospital	Izumi
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto-shi
Japan	Kurashiki Central Hospital	Kurashiki
Japan	Gunmaken Saiseikai Maebashi Hospital	Maebashi
Japan	Japanese Red Cross Nagoya Daiichi Hospital	Nagoya
Japan	The Hospital of Hyogo College of Medicine	Nishinomiya
Japan	Okayama University Hospital	Okayama
Japan	Osaka City University Hospital	Osaka
Japan	Hokkaido University Hospital	Sapporo-shi
Japan	National Center for Child Health and Development	Setagaya-ku

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Pharmaceutical K.K.

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) in the absence of new therapy for chronic graft versus host disease (cGVHD) and absence of progression of underlying disease or death based on the National Institutes of Health (NIH) Consensus Development Project Criteria (2014). CR is defined as resolution of all manifestations in each organ or site; PR is defined as improvement in at least 1 organ or site without progression in any other organ or site; and chronic graft versus host disease (cGVHD) progression is defined as clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.	Up to 3 year 6 months
Secondary	Sustained Response Rate	Sustained response rate was defined as percentage of participants with NIH defined CR or PR that was sustained for at least 20 weeks. CR is defined as resolution of all manifestations in each organ or site; PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	Up to 3 year 6 months
Secondary	Duration of Response (DOR)	DOR is defined as the duration from the date of initial response (CR or PR) to the date of progressive cGVHD or death, whichever occurred first. CR is defined as resolution of all manifestations in each organ or site; PR is defined as improvement in at least 1 organ or site without progression in any other organ or site; and cGVHD progression is defined as clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.	Up to 3 year 6 months
Secondary	cGVHD Response Rate at Each Timepoints	cGVHD response rate was defined as percentage of participants with NIH defined CR or PR at each timepoint. CR is defined as resolution of all manifestations in each organ or site; PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	Weeks 5, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157
Secondary	Change in the Amount of Corticosteroid Required Over Time	Change in the amount of corticosteroid required over time was reported.	Baseline, Weeks 24, 48, 96, and 144
Secondary	Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Scale Score	Percentage of participants with overall improvement in Lee cGVHD symptom scale score was reported. Lee cGVHD symptom scale is a patient-reported symptom scale used to measure symptom burden and has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0-Not at all, 1-Slightly, 2-Moderately, 3-Quite a bit, 4-Extremely, with lower values representing a better outcome. A score was calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 with a higher score indicating worse symptoms. An overall score was calculated as the average of these 7 subscales if at least 4 subscales had valid scores. A change of greater than or equal to (>=) 7 points on the Lee cGVHD symptom scale overall score was considered significant and relates to improvement in quality of life (QoL).	Up to 3 year 6 months
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs are adverse events with onset during the treatment phase or that were a consequence of a preexisting condition that has worsened since baseline, and occurred during treatment or within 30 days following the last dose of study treatment, or any adverse event that was considered study treatment-related regardless of the start date of the event.	Up to 3 year 6 months
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC [0-last]) of Ibrutinib	AUC(0-last) is defined as area under the plasma concentration-time curve from time zero to time of last measurable concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC [0-24]) of Ibrutinib	AUC(0-24) is defined as area under the plasma concentration-time curve from time zero to 24 hours of ibrutinib.	0 to 24 hours (Day 1 of Weeks 1 and 2)
Secondary	Maximum Observed Plasma Concentration (Cmax) of Ibrutinib	Cmax is defined as maximum observed plasma concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ibrutinib	Tmax is defined as time to reach the maximum observed plasma concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Elimination Half-Life (t1/2) of Ibrutinib	T1/2 is defined as elimination half-life of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Apparent Clearance (CL/F) of Ibrutinib	CL/F is defined as apparent clearance of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Apparent Volume of Distribution (Vd/F) of Ibrutinib	Vd/F is defined as apparent volume of distribution of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Ibrutinib	AUC(0-infinity) is defined as area under the plasma concentration-time curve from time zero to infinite time of ibrutinib.	Day 1 of Weeks 1 and 2
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC [0-last]) of PCI-45227	AUC(0-last) is defined as area under the plasma concentration-time curve from time zero to time of last measurable concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC [0-24]) of PCI-45227	AUC(0-24) is defined as area under the plasma concentration-time curve from time zero to 24 hours of PCI-45227.	0 to 24 hours (Day 1 of Weeks 1 and 2)
Secondary	Maximum Observed Plasma Concentration (Cmax) of PCI-45227	Cmax is defined as maximum observed plasma concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of PCI-45227	Tmax is defined as time to reach the maximum observed plasma concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Elimination Half-Life (t1/2) of PCI-45227	T1/2 is defined as elimination half-life of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Apparent Clearance (CL/F) of PCI-45227	CL/F is defined as apparent clearance of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Apparent Volume of Distribution (Vd/F) of PCI-45227	Vd/F is defined as apparent volume of distribution of PCI-45227.	Day 1 of Weeks 1 and 2
Secondary	Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of PCI-45227	AUC(0-infinity) is defined as area under the plasma concentration-time curve from time zero to infinite time of PCI-45227.	Day 1 of Weeks 1 and 2