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

• Status: Recruiting
• Trial end date: 2028-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborator: AstraZeneca
• Treatments: Acalabrutinib; Isavuconazole

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