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

• ClinicalTrials.gov Identifier: NCT02195869
• Recruitment Status: Completed
• First Posted: July 21, 2014
• Results First Posted: July 11, 2019
• Last Update Posted: July 11, 2019
• Sponsor: Pharmacyclics LLC.
• Information provided by (Responsible Party): Pharmacyclics LLC.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Graft Versus Host Disease	Drug: Ibrutinib	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease
• Actual Study Start Date: July 14, 2014
• Actual Primary Completion Date: September 15, 2017
• Actual Study Completion Date: September 15, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Phase 1b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD. [ Time Frame: 28 treatment days after last subject enrolled in Phase 1 dose level(s). ]
   Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib
2. Phase 2: Overall Response Rate as the Percentage of Participants With Response [ Time Frame: Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. ]
   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).

Secondary Outcome Measures :

1. Sustained Response Rate as the Percentage of Participants With Sustained Response [ Time Frame: Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. ]
   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.
2. To Evaluate the Clinical Efficacy of Ibrutinib in Steroid Dependent/Refractory cGVHD by Measuring: Duration of Response (DOR) [ Time Frame: Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. ]
   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.
3. Corticosteroid Requirement Changes Over Time [ Time Frame: Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. ]
   Average daily corticosteroid dose assessed each week.
4. Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Summary Score [ Time Frame: Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. ]

   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.

5. Phase 2b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD [ Time Frame: From first dose with study drug until 30 days after the last dose of study drug, up to 36.7 months ]
   Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

City of Hope Medical Center

Duarte, California, United States, 91010

University of California, San Francisco

San Francisco, California, United States, 94143

Stanford University

Stanford, California, United States, 94305

United States, Georgia

Emory University, Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Tennessee

Vanderbilt University Medical Center, Henry-Joyce Cancer Clinic

Nashville, Tennessee, United States, 37232

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Pharmacyclics LLC.

Investigators

• Study Director: Lori Styles, MD; Pharmacyclics LLC.

  Study Documents (Full-Text)

Documents provided by Pharmacyclics LLC.:

Study Protocol  [PDF] October 21, 2015

Statistical Analysis Plan  [PDF] August 31, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Pharmacyclics LLC.
• ClinicalTrials.gov Identifier: NCT02195869
• Other Study ID Numbers: PCYC-1129-CA
• First Posted: July 21, 2014
• Results First Posted: July 11, 2019
• Last Update Posted: July 11, 2019
• Last Verified: June 2019

Keywords provided by Pharmacyclics LLC.:

PCYC1129; PCYC1129CA; graft versus host disease; chronic graft versus host disease; 1129; Ibrutinib; PCI32765; IMBRUVICA; Pharmacyclics; PCYC; GVHD; Steroid dependent; refractory; chronic; immunology

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases