Rituximab and Acalabrutinib in Newly Diagnosed B Cell Post Transplant Lymphoproliferative Disorder

Study Overview
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Brief Summary
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The purpose of this study is to evaluate how effective rituximab and acalabrutinib are when given as a combination treatment for newly diagnosed B cell post transplant lymphoproliferative disorder (PTLD). Currently there is no approved therapy for PTLD. Rituximab alone is commonly used and works in some cases, but not others. In addition, participants with PTLD have trouble tolerating therapies with large amounts of side effects due to their health conditions and medications for their transplant. Due to these reasons the study team is looking for a new treatment with novel targeted agents in order to improve outcomes and to minimize toxicity. Based on emerging data of clinical efficacy of acalabrutinib in B cell malignancies and an unmet need for novel therapies in PTLD, this study will investigate the use of rituximab and acalabrutinib in participants with newly diagnosed B cell PTLD.

Detailed Description
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This is a non-randomized phase II study of acalabrutinib plus rituximab in newly diagnosed B-cell PTLD in participants with both solid organ transplant (SOT) and Bone marrow transplant (BMT). Acalabrutinib is an inhibitor of Bruton Tyrosine Kinase (BTK). BTK is important in B cells and plays a role in the development of PTLD. Acalabrutinib is approved in the US for the treatment of adult participants with indolent lymphoma, mantle cell lymphoma, and is being evaluated to treat other lymphomas. Rituximab has been approved for treatment of B cell non-Hodgkin lymphoma (NHL). While not approved for PTLD, it has become the mainstay of treatment. The primary objective of this study is to determine the overall response rate to combination treatment with rituximab and acalabrutinib in patients with PTLD. The secondary objectives of this study is to determine response rates, survival, failure rates, and safety elements in participants with PTLD treated with combination rituximab and acalabrutinib.

Official Title
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Phase II Study of Rituximab and Acalabrutinib in Newly Diagnosed B Cell Post Transplant Lymphoproliferative Disorder (PTLD)

Conditions
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Post-transplant Lymphoproliferative Disorder

Intervention / Treatment
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* Drug: Rituximab
* Drug: Acalabrutinib
* Diagnostic Test: CT scans


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a biopsy confirmed newly diagnosed CD20 positive B cell PTLD. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. ECOG 3 will be permitted if the decline in performance status is due to lymphoma. [See Appendix 1] Subjects must have adequate hematologic, hepatic, and renal function as defined below: Hemoglobin ≥ 8 gm/dL Absolute neutrophil count ≥500/mcL (unless documented bone marrow involvement with lymphoma) Platelet count ≥50000/mcL (unless there is documented bone marrow involvement with lymphoma) Prothrombin time/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of Lupus anticoagulant) < 2x ULN. Total bilirubin ≤1.5X upper limit of normal (ULN) Creatinine ≤2.5X upper limit of normal (ULN) Alanine aminotransferase/aspartate aminotransferase (ALT/AST) < 2.5 X or ≤5X ULN for patients with document hepatic involvement with lymphoma Women of childbearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) during treatment and for 12 months after last dose of study treatment. Women who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. Subjects must be willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty Subjects must have the 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: Prior treatment with any BTK inhibitor Subjects receiving any other investigational agents or participating in another therapeutic clinical trial. Subjects with active (treated or untreated) brain metastases/ central nervous system (CNS) disease (including but not limited to CNS PTLD) will be excluded from this clinical trial 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, early stage prostate cancer or other cancer from which the subject has been disease free for ≥ 3 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 in the study. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease that would limit absorption of oral medication. Known history of infection with HIV. HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with acalabrutinib. Patients with uncontrolled concurrent illness like active infection (eg, bacterial, viral, or fungal) requiring IV antibiotics or psychiatric illness/social situations that would limit compliance with study requirements Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or rituximab (including active product or excipient components). Active bleeding, history of bleeding diathesis (eg, 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 or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study. 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 28 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. Hepatitis B or C serologic status: 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. History of progressive multifocal leukoencephalopathy (PML) Breastfeeding or pregnant. Pregnant or breastfeeding women are excluded from this study because it is unknown how acalabrutinib and rituximab can affect the fetus or infant. Rituximab can cross the placenta and is found in breast milk. Acalabrutinib has been found in the breast milk of animals and there is not significant data regarding its effect during pregnancy. Vaccination with live virus vaccines is not allowed within 4 weeks of study treatment of or during treatment.

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: Rituximab and Acalabrutinib<br>Participants will receive treatment of Rituximab weekly for 4 weeks, and Acalabrutinib twice daily for 4 weeks. Response assessment via diagnostic CT scans will dictate further treatment decisions. | Drug: Rituximab<br>* Weekly x 4 weeks. If diagnostic test reveals complete response, then participant will continue with one additional 28 day cycle. If partial response, then proceed with 3 additional 28 day cycles. If stable disease or progression of disease, then go off study treatment and proceed onto Long Term Follow Up (LTFU).<br>* Other names: Mabthera;Drug: Acalabrutinib<br>* 100mg twice per day (BID) x 4 weeks (28 day cycle) If diagnostic test reveals complete response, then participant will continue with one additional 28 day cycle. If partial response, then proceed with 3 additional 28 day cycles. If stable disease or progression of disease, then go off study treatment and proceed onto LTFU.<br>* Other names: ACP-196;Diagnostic Test: CT scans<br>* 2 weeks (day 36 ± 5 days) after end of cycle 1 treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | ORR will be estimated along with 90% Confidence Intervals (CIs), and compared against the null using exact binomial test. Logistic regression model will be used to identify factors associated with response status. | Up to 8 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CRR) | CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria | at 6 months after treatment | 
| Complete response rate (CRR) | CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria | at 12 months after treatment | 
| Complete response rate (CRR) | CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria | at 24 months after treatment | 
| Partial response rate (PRR) | PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria. | at 6 months after treatment | 
| Partial response rate (PRR) | PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria. | at 12 months after treatment | 
| Partial response rate (PRR) | PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria. | at 24 months after treatment | 
| Duration of response (DOR) | DOR is only measured in responders. DOR is defined as the time from documented response (CR or PR) to the time of confirmed disease progression or death due to any cause, whichever occurs first. Subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, have discontinued study, or have initiated other non-protocol anti-tumor therapy (NPT) will be censored at the last tumor assessment when subjects are progression-free. | Up to 3 years after treatment | 
| Progression free survival (PFS) | PFS as defined as the time from first dose to documented disease progression, or death from any cause, whichever occurs first. Data for subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, have discontinued the study, or have initiated NPT will be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 day) Estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model will be used to identify factors associated with survival endpoint. | at 6 months after treatment | 
| Progression free survival (PFS) | PFS as defined as the time from first dose to documented disease progression, or death from any cause, whichever occurs first. Data for subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, have discontinued the study, or have initiated NPT will be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 day) Estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model will be used to identify factors associated with survival endpoint. | at 12 months after treatment | 
| Progression free survival (PFS) | PFS as defined as the time from first dose to documented disease progression, or death from any cause, whichever occurs first. Data for subjects who are still alive and free from progression at the time of data cutoff date, lost to follow-up, have discontinued the study, or have initiated NPT will be censored on last assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 day) Estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model will be used to identify factors associated with survival endpoint. | at 24 months after treatment | 
| Overall survival (OS) | Overall survival (OS) is defined as the time from first dose to death from any cause. Data for subjects who are still alive at the time of data cutoff date, lost to follow-up, have discontinued the study (or, if no post-baseline assessment, at the time of first dose plus 1 day) will be censored on last assessment Estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model will be used to identify factors associated with survival endpoint. | Up to 3 years after treatment | 
| Time to treatment failure (TTF) | TTF is measured from the time from study entry to any treatment failure including discontinuation of treatment for any reason, such as disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death. | Up to 3 years after treatment | 
| number of participants with a grade 3 Adverse Event (AE) or higher | Safety as defined by number of participants with a grade 3 AE or higher | Up to 3 years after treatment |