Clinical Trials /

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

NCT04337827

Description:

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.

Related Conditions:
  • Post-Transplant Lymphoproliferative Disorder
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CASE3419
  • NCT ID: NCT04337827

Conditions

  • Post-transplant Lymphoproliferative Disorder

Interventions

DrugSynonymsArms
RituximabRituxan, MabtheraRituximab and Acalabrutinib
AcalabrutinibACP-196Rituximab and Acalabrutinib

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Rituximab and AcalabrutinibExperimentalParticipants 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.
  • Rituximab
  • Acalabrutinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 8 weeks after treatment
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Complete response rate (CRR)
Time Frame:at 6 months after treatment
Safety Issue:
Description:CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria
Measure:Complete response rate (CRR)
Time Frame:at 12 months after treatment
Safety Issue:
Description:CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria
Measure:Complete response rate (CRR)
Time Frame:at 24 months after treatment
Safety Issue:
Description:CRR is defined as all patients that achieve a CR based on end of treatment scans, using the Lugano Criteria
Measure:Partial response rate (PRR)
Time Frame:at 6 months after treatment
Safety Issue:
Description:PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria.
Measure:Partial response rate (PRR)
Time Frame:at 12 months after treatment
Safety Issue:
Description:PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria.
Measure:Partial response rate (PRR)
Time Frame:at 24 months after treatment
Safety Issue:
Description:PRR is defined as all patients that achieve a PR based on end of treatment scans, using the Lugano Criteria.
Measure:Duration of response (DOR)
Time Frame:Up to 3 years after treatment
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:at 6 months after treatment
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:at 12 months after treatment
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:at 24 months after treatment
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Up to 3 years after treatment
Safety Issue:
Description: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.
Measure:Time to treatment failure (TTF)
Time Frame:Up to 3 years after treatment
Safety Issue:
Description: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.
Measure:number of participants with a grade 3 Adverse Event (AE) or higher
Time Frame:Up to 3 years after treatment
Safety Issue:
Description:Safety as defined by number of participants with a grade 3 AE or higher

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Deepa Jagadeesh

Last Updated

April 7, 2020