Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Chronic Graft Versus Host Disease

A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease

The purpose of this study is to assess the safety and clinical efficacy of ibrutinib in subjects with steroid dependent or refractory Chronic Graft Versus Host Disease.

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Drug: Ibrutinib

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Winship Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center, Henry-Joyce Cancer Clinic
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Steroid dependent or refractory classic chronic GVHD disease.
• No more than 3 previous treatments for cGVHD.
• Receiving baseline systemic glucocorticoid therapy (at stable dose) for cGVHD at study entry.
• Men and women ≥18 years old.
• Karnofsky performance status ≥60.

Exclusion Criteria:

• Known or suspected active acute GVHD.
• Current treatment with sirolimus AND either cyclosporine or tacrolimus.
• History of treatment with a tyrosine kinase inhibitor (eg, imatinib), purine analogs or other cancer chemotherapy in the 4 weeks prior to starting study drug.
• Currently active, clinically significant cardiovascular disease.
• Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines or a recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
• Progressive underlying malignant disease including post-transplant lymphoproliferative disease.
• History of other malignancy (not including the underlying malignancy that was the indication for transplant)
• Concomitant use of warfarin or other Vitamin K antagonists
• Known bleeding disorders or hemophilia.
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV).
• Concurrent use of a strong cytochrome P450(CYP) 3A inhibitor.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b: Dose Level 1; Subjects receive daily dose of 420 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 1b: Dose Level 2; Subjects receive daily dose of 280 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 1b: Dose Level 3; Subjects receive daily dose of 140 mg of Ibrutinib capsules	Drug: Ibrutinib; Other Names: PCI32765
Experimental: Phase 2; Subjects receive daily dose of recommended phase 2 dose	Drug: Ibrutinib; Other Names: PCI32765

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD.	Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib	28 treatment days after last subject enrolled in Phase 1 dose level(s).
Phase 2: Overall Response Rate as the Percentage of Participants With Response	Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site).	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Response Rate as the Percentage of Participants With Sustained Response	For subjects who achieved an NIH-defined CR or PR, the proportion of subjects who achieved CR or PR that was sustained for at least 20 weeks (140 days). Intermittent SD was also acceptable.	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.
To Evaluate the Clinical Efficacy of Ibrutinib in Steroid Dependent/Refractory cGVHD by Measuring: Duration of Response (DOR)	For subjects who achieved an NIH-defined CR or PR, the interval between the date of initial documentation of a response and the date of first documented evidence of PD, death, or date of censoring if applicable.	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.
Corticosteroid Requirement Changes Over Time	Average daily corticosteroid dose assessed each week.	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.
Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Summary Score	Subject reported improvement in symptom burden. The symptom burden will be measured according to the Lee cGVHD Symptom Scale. A change in >7 points on the Lee cGVHD Symptom Scale will be considered significant and relates to improvement in quality of life. A score is 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 scale. A total summary score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. There are 7 subscales (Skin, Energy, Lung, Eye, Nutrition, Mouth and Psychological) with ratings as follow: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely; with a lower values representing a better outcome.	Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months.
Phase 2b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD	Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib	From first dose with study drug until 30 days after the last dose of study drug, up to 36.7 months

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.

Publications and helpful links

General Publications

• Doki N, Toyosaki M, Shiratori S, Osumi T, Okada M, Kawakita T, Sawa M, Ishikawa T, Ueda Y, Yoshinari N, Nakahara S. An Open-Label, Single-Arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease. Transplant Cell Ther. 2021 Oct;27(10):867.e1-867.e9. doi: 10.1016/j.jtct.2021.05.019. Epub 2021 Jun 6.
• Waller EK, Miklos D, Cutler C, Arora M, Jagasia MH, Pusic I, Flowers MED, Logan AC, Nakamura R, Chang S, Clow F, Lal ID, Styles L, Jaglowski S. Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study. Biol Blood Marrow Transplant. 2019 Oct;25(10):2002-2007. doi: 10.1016/j.bbmt.2019.06.023. Epub 2019 Jun 28.
• Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, Li Y, Chang S, Lal I, Dubovsky J, James DF, Styles L, Jaglowski S. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 Nov 23;130(21):2243-2250. doi: 10.1182/blood-2017-07-793786. Epub 2017 Sep 18.

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2014
• Primary Completion (Actual): September 15, 2017
• Study Completion (Actual): September 15, 2017

Study Registration Dates

• First Submitted: July 11, 2014
• First Submitted That Met QC Criteria: July 16, 2014
• First Posted (Estimate): July 21, 2014

Study Record Updates

• Last Update Posted (Actual): July 11, 2019
• Last Update Submitted That Met QC Criteria: June 14, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: chronic; Pharmacyclics; PCYC; Ibrutinib; refractory; GVHD; IMBRUVICA; immunology; graft versus host disease; chronic graft versus host disease; Steroid dependent; PCI32765; PCYC1129; PCYC1129CA; 1129
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease
• Other Study ID Numbers: PCYC-1129-CA