Clinical Trials /

LCCC1841: A Phase 2 Trial of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas

NCT04548648

Description:

The purpose of this study is to see if acalabrutinib is effective in treating a type of cancer call central nervous system (CNS) lymphoma. Acalabrutinib has not been approved by the Food and Drug Administration (FDA) for the treatment of CNS lymphoma. However, FDA has approved its use for treatment of another type of lymphoma called mantle cell lymphoma. Currently, there are no standard FDA approved treatments for treatment of CNS lymphoma. Acalabrutinib acts similar to another cancer drug called ibrutinib. Ibrutinib was tested in several research trials for management of CNS lymphomas, and the results were promising. Acalabrutinib and ibrutinib attack a similar target found in CNC lymphoma. Research studies show that acalabrutinib does a better job in attacking this target than ibrutinib, and this might be beneficial for using this drug in treating CNS lymphoma. The purpose of this study is test whether giving acalabrutinib is safe and could help controlling with CNS lymphoma. The study doctors will be looking to see if acalabrutinib can shrink the cancer. In this research study, participants will be given acalabrutinib and isavuconazol, because it helps in preventing fungal infections. Fungal infection is a common side effect of acalabrutinib. Treatment with acalabrutinib and isavuconazole will continue unless the cancer progresses or participants experience bad side effects.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Central Nervous System Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: LCCC1841: A Phase 2 Trial of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas
  • Official Title: LCCC1841: A Phase 2 Trial of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: LCCC1841
  • NCT ID: NCT04548648

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, CALQUENCEOpen-label, single-arm
IsavuconazoleCresembaOpen-label, single-arm

Purpose

The purpose of this study is to see if acalabrutinib is effective in treating a type of cancer call central nervous system (CNS) lymphoma. Acalabrutinib has not been approved by the Food and Drug Administration (FDA) for the treatment of CNS lymphoma. However, FDA has approved its use for treatment of another type of lymphoma called mantle cell lymphoma. Currently, there are no standard FDA approved treatments for treatment of CNS lymphoma. Acalabrutinib acts similar to another cancer drug called ibrutinib. Ibrutinib was tested in several research trials for management of CNS lymphomas, and the results were promising. Acalabrutinib and ibrutinib attack a similar target found in CNC lymphoma. Research studies show that acalabrutinib does a better job in attacking this target than ibrutinib, and this might be beneficial for using this drug in treating CNS lymphoma. The purpose of this study is test whether giving acalabrutinib is safe and could help controlling with CNS lymphoma. The study doctors will be looking to see if acalabrutinib can shrink the cancer. In this research study, participants will be given acalabrutinib and isavuconazol, because it helps in preventing fungal infections. Fungal infection is a common side effect of acalabrutinib. Treatment with acalabrutinib and isavuconazole will continue unless the cancer progresses or participants experience bad side effects.

Detailed Description

      LCCC 1841 is a multicenter open-label, single-arm, phase 2 study designed to investigate the
      antitumor effects of acalabrutinib in subjects with relapsed primary central nervous system
      lymphoma (PCNSL), and relapsed secondary CNS lymphoma (SCNSL) with no evidence of current
      systemic disease. Subjects with the following histological subtypes of lymphoma will be
      included in the study: diffuse large B-cell lymphoma (DLBCL, all subtypes); mantle cell
      lymphoma (MCL, all subtypes); plasmablastic lymphoma, and lymphoplasmacytic lymphoma. Up to
      32 subjects will receive acalabrutinib at the dose of 100 mg approximately every 12 hours. A
      Simon two-stage design will be used to minimize the expected sample size if the regimen has
      low activity. In the first stage, 15 evaluable subjects will be enrolled and treated. If =8
      subjects have an overall response of stable disease or better as determined by the
      International Primary CNS Lymphoma Collaborative Group Response Assessment Criteria , an
      additional 13 subjects will be enrolled and treated in the second stage of the study for a
      total of 28 evaluable subjects treated on the trial. The study will accrue up to 32 subjects
      to ensure data from 28 evaluable subjects. If <8 subjects have an overall response of stable
      disease or better as determined by the International Primary CNS Lymphoma Collaborative Group
      Response Assessment Criteria, the study will be closed to accrual and no additional subjects
      will be enrolled. If the study shows a positive effect of acalabrutinib in treating CNS
      lymphomas, acalabrutinib could become the standard relapsed CNS lymphoma regimen, not only
      for PCNSL, but also in certain subtypes of SCNSL. Any complete responses to acalabrutinib
      treatment will be clinically notable as spontaneous remissions do not occur.

      In a previous study, ibrutinib showed a CR rate of 45% and an ORR of 68% ; in another study
      ], ibrutinib showed a CR rate of 17% and an ORR of 55%. Thus, in order to recommend further
      investigation of acalabrutinib as a regimen for primary CNS lymphoma, acalabrutinib treatment
      must show an overall response rate (ORR) of at least 70%, which would demonstrate that it is
      not inferior to previously approved regimens.
    

Trial Arms

NameTypeDescriptionInterventions
Open-label, single-armOtherA multicenter open-label, single-arm, phase 2 study designed to investigate the antitumor effects of acalabrutinib in subjects with relapsed primary central nervous system lymphoma (PCNSL), and relapsed secondary CNS lymphoma (SCNSL) with no evidence of current systemic disease. Subjects will receive acalabrutinib at the dose of 100 mg every 12 hours. Prophylactic administration of broad spectrum triazole antifungal agent isavuconazole will be performed while subjects receive acalabrutinib.
  • Acalabrutinib
  • Isavuconazole

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent obtained to participate in the study and HIPAA authorization
             for release of personal health information.

          2. Age ≥18 years at the time of consent.

          3. Subject has adequate performance status as defined by ECOG of ≤ 2. (Note: Performance
             status can be assessed after administration of corticosteroids.)

          4. Subject has histological confirmation of biopsy-proven CNS lymphoma OR MRI findings
             consistent with CNS lymphoma if biopsy is not possible (due to inaccessible location).
             Subjects with intra-ocular lymphoma will not be excluded as long as there is also
             parenchymal disease.

          5. Subject has B-cell Non-Hodgkin Lymphoma.

          6. Subject has no evidence of systemic involvement of lymphoma confirmed by CT or PET-CT
             imaging within 28 days prior to first dosing in the study.

          7. Subject must have received at least one prior line of chemotherapy for primary or
             secondary CNS lymphoma. There is no limit on the number of prior treatment regimens.

          8. Subject has adequate organ function as demonstrated by: System Laboratory Value
             Hematological* Absolute Neutrophil Count (ANC) ≥ 1 x 109/L Platelets ≥ 75 x 109/L
             Renal* Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula
             (Appendix B) Hepatic* Bilirubin ≤ 1.5 × upper limit of normal (ULN). Subjects with
             Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their
             conjugated bilirubin is <1.5× ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN
             Alanine aminotransferase (ALT) ≤ 2.5 × ULN Coagulation International Normalized Ratio
             (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤ 2 ×
             ULN (in the absence of lupus anticoagulant)

          9. Subject is able to receive isavuconazole for prophylaxis of invasive aspergillosis
             while subject receives acalabrutinib therapy.

         10. Female subjects of childbearing potential must have a negative serum pregnancy test
             within three days (72 hours) prior to initiating study treatment. Note: Females are
             considered of childbearing potential unless they are surgically sterile (have
             undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they
             are naturally postmenopausal for at least 12 consecutive months. Documentation of
             postmenopausal status must be provided.

        10. Females of childbearing potential must be willing to abstain from heterosexual activity
        or to use 2 forms of effective methods of contraception from the time of informed consent
        until 2 days after the last dose of acalabrutinib. The two contraception methods can be
        comprised of two barrier methods, or a barrier method plus a hormonal method.

        Exclusion Criteria:

        1. Subjects meeting any of the following exclusion criteria will not be able to participate
        in this study 2.Prior cancer treatment that was completed less than 14 days prior to Day 1
        of study dosing or if subject has not recovered from all reversible acute toxic effects of
        the regimen to grade ≤1 or baseline.

        3. Prior brain radiotherapy under the following conditions:

          -  Whole-brain radiotherapy (WBRT) that was completed less than 28 days prior to Day 1 of
             study dosing

          -  Stereotactic radiosurgery (SRS) that was competed less than 14 days prior to Day 1 of
             study dosing.

             3. Currently participating in or has participated in a study of an investigational
             agent within 28 days of first dosing with study treatment.

             4.Subject is pregnant or breastfeeding (Note: breast milk cannot be stored for future
             use while the mother is being treated on study).

             5 Subject has a known additional malignancy that is active and/or progressive
             requiring treatment; exceptions include basal cell or squamous cell skin cancer, in
             situ cervical or bladder cancer, or other cancer for which the subject has been
             disease-free for at least five years.

             6. Subject has active CSF involvement that requires ongoing intrathecal chemotherapy.

             7. Previous exposure to a BTK inhibitor. 8. Subjects with severe hepatic
             insufficiency, as defined by Child-Pugh Score > 6 (Appendix C).

             9. Subject is receiving prohibited medications or treatments as listed in Section 5.3
             of the protocol that cannot be discontinued/replaced by an alternative therapy.
             Subject requires treatment with a strong cytochrome P450 3A4 (CYP3A4)
             inhibitor/inducer other than isavuconazole (please consult Section 5.3). Subjects may
             be eligible if they are medically able to discontinue CYP3A4 inhibitors/inducers at
             least 14 days before the first dose of study treatment.

             10. Subject requires or receiving anticoagulation with warfarin or equivalent vitamin
             K antagonists (e.g., phenprocoumon) within 14 days of first dose of study drug.
             Subjects requires or is taking direct oral anticoagulants (e.g. apixaban, rivaroxaban,
             edoxaban, lovenox) within 7 days of first dose of study drug.

             11. Subject requires treatment with proton pump inhibitors (e.g., 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.

             12. Subject is currently receiving any chemotherapy, anticancer immunotherapy. Note:
             Subjects receiving corticosteroids will be eligible, but corticosteroids are expected
             to be tapered off as soon as possible from a clinical standpoint.

             13. Subject has clinically significant cardiovascular disease such as ventricular
             dysfunction, symptomatic coronary artery disease, 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 (NYHA) Functional Classification (Appendix D) at screening. Subjects with
             controlled, asymptomatic atrial fibrillation during screening can enroll on study.

             14. Subject has familial short QT syndrome. 15. Subject has a history of malabsorption
             syndrome, disease significantly affecting gastrointestinal function, or resection of
             the stomach or small bowel, symptomatic inflammatory bowel disease, partial or
             complete bowel obstruction, or gastric restrictions and bariatric surgery, such as
             gastric bypass that is likely to affect absorption.

             16. Subject has a known history of infection with HIV or any uncontrolled active
             significant infection (e.g., bacterial, viral or fungal).

             17. Subject has a known history of drug-specific hypersensitivity or anaphylaxis to
             acalabrutinib or isavuconazole (including active ingredient or excipient components).

             18. Subject has active bleeding or history of bleeding diathesis (e.g., hemophilia or
             von Willebrand disease).

             19. Subject has a history of uncontrolled AIHA (autoimmune hemolytic anemia) or ITP
             (idiopathic thrombocytopenic purpura).

             20. Subject has a history of significant cerebrovascular disease/event, including
             stroke or intracranial hemorrhage, within 6 months before the first dose of
             acalabrutinib.

             21. Subject had major surgical procedure within 28 days of first dose of
             acalabrutinib. 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 acalabrutinib.

             22. Subject must either have hepatitis B core antibody negative OR if a subject is
             hepatitis B core antibody positive they must have their hepatitis B viral load
             checked. These subjects will be excluded if their viral load is positive. Subject who
             are core antibody positive and viral load negative will be considered eligible, but
             must receive entecavir prophylaxis.

             23. Subjects who are hepatitis C antibody positive must have a negative polymerase
             chain reaction (PCR) result. Those who are hepatitis C PCR positive will be excluded.

             24. Subjects who are unable to swallow oral medications
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate
Time Frame:2 years
Safety Issue:
Description:Overall response rate (ORR; ORR= Partial Response + Complete Response) will be assessed at 2 months as measured by the International Primary CNS Lymphoma Collaborative Group Response assessment criteria in subjects with relapsed/refractory primary and secondary CNS lymphoma receiving acalabrutinib.

Secondary Outcome Measures

Measure:Number of different types of toxicities
Time Frame:3 years
Safety Issue:
Description:Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).
Measure:Progression-free survival (PFS)
Time Frame:5 years
Safety Issue:
Description:Progression-free survival (PFS) is defined from the date of initiating study treatment to the date of disease progression per the International Primary CNS Lymphoma Collaborative Group response assessment criteria or death as a result of any cause.
Measure:Complete response (CR) rate
Time Frame:2 years
Safety Issue:
Description:Complete Response (CR) is defined using the International Primary CNS Lymphoma Collaborative Group response assessment criteria for primary CNS lymphoma.
Measure:Duration of response (DoR)
Time Frame:2 years
Safety Issue:
Description:Duration of response (DoR) is defined as time from documentation of tumor response to disease progression according to the International Primary CNS Lymphoma Collaborative Group response assessment criteria.
Measure:Overall Survival (OS)
Time Frame:5 years
Safety Issue:
Description:OS will be measured from the date of initiating study treatment to the date of death or 5 years (whichever is first). Subjects who have not died by the analysis data cut-off date will be censored at their last date of contact.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • CNS Lymphoma

Last Updated

September 8, 2020