Acalabrutinib for the Treatment of Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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This phase II trial studies how well acalabrutinib works in treating patients with chronic graft versus host disease. Acalabrutinib may be an effective treatment for graft-versus-host disease caused by a stem cell transplant.

Detailed Description
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OUTLINE: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 6 cycles with an option to continue for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then periodically thereafter.

Official Title
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Acalabrutinib for Chronic Graft-Versus-Host Disease

Conditions
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Recurrent Moderate-Severe Chronic Graft Versus Host Disease, Hematopoietic and Lymphoid Cell Neoplasm

Intervention / Treatment
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* Drug: Acalabrutinib
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥ 18 years of age Moderate-severe chronic GVHD, diagnosed per the 2014 National Institutes of Health (NIH) criteria Progression or recurrence of active chronic GVHD signs/symptoms after treatment with steroids Karnofsky performance status >= 70% Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of acalabrutinib Men must refrain from sperm donation during the study Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information Exclusion Criteria: Hospitalization for evaluation or management of an infection within the last 8 weeks Change in immunosuppressive regimen within the 2 weeks prior to enrollment Noncompliance Treatment of chronic GVHD with ibrutinib Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug Recurrent or prior malignancy (or any other malignancy that requires active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for >= 2 years Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication Received a live virus vaccination within 28 days of first dose of study drug Known history of infection with human immunodeficiency virus (HIV) Uncontrolled, active significant infection (e.g., bacterial, viral, fungal or progressive multifocal leukoencephalopathy) Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components) Active bleeding, history of bleeding diathesis (e.g., hemophilia or von Willebrand disease) Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer Requires warfarin or equivalent vitamin K antagonist History of significant cerebrovascular disease or event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug Major surgical procedure within 30 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug Subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded Child-Pugh score of C for hepatic impairment Total bilirubin > 2 mg/dL or alanine aminotransferase (ALT) > 2 x upper limit of normal, unless abnormalities are due to liver GVHD, in which case total bilirubin > 3 mg/dL or ALT 5 x upper limit of normal are exclusions Absolute neutrophil count < 1.0 x 10^9/L or use of myeloid growth factors within the past 2 weeks Platelet count < 50 x 10^9/L or platelet transfusion or thrombomimetic agent within the past 2 weeks Glomerular filtration rate < 50 mL/min/1.73 m^2 Breastfeeding or pregnant Concurrent participation in another clinical trial and receiving a non-Food and Drug Administration (FDA) approved medication

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (acalabrutinib)<br>Patients receive acalabrutinib 100 mg PO BID on days 1-28. Treatment repeats every 28 days for up to 6 cycles with an option to continue for up to 24 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Acalabrutinib<br>* Given PO<br>* Other names: Bruton Tyrosine Kinase Inhibitor ACP-196;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best response (complete and partial response [CR + PR]) | The composite outcome of CR and PR, calculated according to the proposed response definitions of the 2014 National Institutes of Health Consensus Conference. Exact 95% confidence intervals (CI) will be calculated for the objective response rate using the Clopper and Pearson method. Will also compare the observed best ORR with the published efficacy of ibrutinib (67%) and provide the 95% CI for the difference. | Within the first 6 months of treatment when the best response rate is known for each patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Defined as grade 3 and above according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and all serious AEs (SAEs) described for the population receiving at least one dose of acalabrutinib at least from the time of consent through the safety follow-up period. Any AE/SAE at least possibly related to acalabrutinib therapy will be reported for the duration of the study. | Up to 30 days following the last dose of acalabrutinib | 
| Duration of response (DOR) | Will be described for the group achieving at least a PR, defined as the number of weeks the subject maintains a PR or CR. Will be estimated using the Kaplan-Meier method. Approximate 95% CIs for median DOR will be computed using the formula proposed by Brookmeyer and Crowley. | From the date the PR is documented until loss of the response or start of another systemic immunosuppressive treatment for chronic graft versus host disease (GVHD), whichever occurs first, assessed up to 3 years | 
| Change in patient-reported outcomes: Lee Chronic GVHD Symptom Scale score | Will be assessed by the Lee Chronic GVHD Symptom Scale score. Scores will be calculated based on published algorithms with absolute changes and clinically meaningful changes described for the population as a whole and based on CR + PR versus stable disease (SD) + mixed response (MR) + progressive disease (PD). | Baseline up to 3 years | 
| Change in patient-reported outcomes: Patient-Reported Outcomes Measurement Information System-29 | Will be assessed by the Patient-Reported Outcomes Measurement Information System-29. Scores will be calculated based on published algorithms with absolute changes and clinically meaningful changes described for the population as a whole and based on CR + PR versus stable disease (SD) + mixed response (MR) + progressive disease (PD). | Baseline up to 3 years | 
| Failure-free survival | Will be defined as the duration of relapse-free survival without adding any other systemic treatment for chronic GVHD. Will be estimated with the composite event of death from any cause, relapse and addition of secondary immune suppressive agents using the Kaplan-Meier method. Systemic immune-suppressive agents include orally or intravenously administered systemically active immune-suppressive drugs, as well as procedures including extra-corporeal photopheresis. | At 6 months and 1 year | 
| Organ-specific response rates | Response rates by organ will also be calculated and reported as ORR (CR+PR) versus all other categories (SD, PD, MR). | Up to 3 years |