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

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ClinicalTrials.gov Identifier: NCT04548648
Recruitment Status : Recruiting
First Posted : September 14, 2020
Last Update Posted : July 15, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Lymphoma Drug: Acalabrutinib Drug: Isavuconazole Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: The study is designed as an open label, single arm phase II study to provide preliminary data about its efficacy before proceeding to a larger two arm study.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LCCC1841: A Phase 2 Trial of Acalabrutinib in Relapsed/Refractory Primary and Secondary CNS Lymphomas
Estimated Study Start Date : July 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2028


Arm Intervention/treatment
Open-label, single-arm
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 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.
Drug: Acalabrutinib
Acalabrutinib at 100 mg is taken orally approximately every 12 hours until disease progression or unacceptable toxicity.
Other Names:
  • ACP-196
  • CALQUENCE

Drug: Isavuconazole
Prophylactic treatment with isavuconazole includes loading dose of 372 mg (2 capsules) administered orally every 8 hours for 6 doses (48 hours), followed by maintenance administration of 372 mg (2 capsules) once daily as long as the subject is on study treatment.
Other Name: Cresemba




Primary Outcome Measures :
  1. Overall response rate [ Time Frame: 2 years ]
    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 :
  1. Number of different types of toxicities [ Time Frame: 3 years ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

  2. Progression-free survival (PFS) [ Time Frame: 5 years ]
    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.

  3. Complete response (CR) rate [ Time Frame: 2 years ]
    Complete Response (CR) is defined using the International Primary CNS Lymphoma Collaborative Group response assessment criteria for primary CNS lymphoma.

  4. Duration of response (DoR) [ Time Frame: 2 years ]
    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.

  5. Overall Survival (OS) [ Time Frame: 5 years ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04548648


Contacts
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Contact: Lynn Ruffin 9193081724 Lynn_ruffin@med.unc.edu
Contact: Jana Hall 9198433550 jana_hall@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Christopher Dittus    919-966-4431    chris_dittus@med.unc.edu   
Contact: Jana Hall    9198433550    jana_hall@med.unc.edu   
Levine Cancer Institute, Carolinas Health Care System Not yet recruiting
Charlotte, North Carolina, United States, 28204
Principal Investigator: Nilanjan Ghosh, MD, PhD         
Wake Forest University Comprehensive Cancer Center Recruiting
Winston-Salem, North Carolina, United States, 27157-1096
Principal Investigator: David Hurd, MD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
AstraZeneca
Investigators
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Principal Investigator: Christopher Dittus UNC Lineberger Comprehensive Cancer Center
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04548648    
Other Study ID Numbers: LCCC1841
First Posted: September 14, 2020    Key Record Dates
Last Update Posted: July 15, 2021
Last Verified: July 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
CNS Lymphoma
Additional relevant MeSH terms:
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Neoplasms by Histologic Type
Neoplasms
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Isavuconazole
Acalabrutinib
Antineoplastic Agents
Antifungal Agents
Anti-Infective Agents