Inclusion
1. Histologically confirmed EBV+ve B cell NHLs or Hodgkin Lymphoma occurring in the immunosuppressed (acquired e.g. HIV, iatrogenic e.g. PTLD, methotrexate, primary e.g. inherited, congenital). If Hodgkin Lymphoma, then the rituximab is recommended but not mandated, in patients with PTLD (to assist with reduction in iatrogenic immunosuppression). Methodology for detection of EBV within the biopsy is not mandated, but it is expected will typically be EBER in situ hybridization. Other methodologies will need to be confirmed with the investigative team on a case-by-case basis.
2. Systemic and/or CNS lymphoma, including ocular lymphoma.
3. Patient has relapsed/refractory or (at physician’s discretion) unsuitable for standard first-line treatments.
4. At least 1 measurable site of disease according to the 2014 Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non Hodgkin Lymphoma – the Lugano Classification. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement. Any clinical stage permitted.
5. Age greater than or equal to 18 years.
6. Provision by patient or legally acceptable representative of informed consent indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.
7. ECOG performance status 0-3.
8. Minimum life expectancy of 3 months.
9. Haematology values must be within the following limits:
a. Absolute neutrophil count (ANC) greater than or equal to 0.75x109/L independent of growth factor support
b. Platelets greater than or equal to 75x109/L or greater than or equal to 50x109/L if bone marrow involvement independent of transfusion support in either situation.
10. Biochemical values within the following limits:
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =less than or equal to 3 x upper limit of normal (ULN).
b. Total bilirubin less than or equal to 2.0 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin.
c. > 30 mL/min creatinine clearance permitted. Patients on dialysis are permitted irrespective of renal function and in these patients pharmacokinetics assays and guidance are mandated.
11. Patients requiring treatment with moderate CYP3A inhibitors (see Appendix 6) are permitted, but are recommended to commence with lower ibrutinib dosing, and then escalate as tolerated. Ibrutinib pharmacokinetic assays are available, if requested, to all patients, including those requiring treatment with moderate CYP3A inhibitors. Patients are ineligible from accrual if they are on a strong CYP3A4 inhibitor (see Appendix 6) unless an alternative medication can be found. The exception to this is posaconazole, as the investigative team have previously administered ibrutinib (420mg, then stepped to 560mg) without toxicity. In that scenario, pharmacokinetic monitoring and guidance is mandated. Patients requiring a strong CYP3A4 inhibitor at a later point during the course of the study, must cease ibrutinib. It can be restarted once the CYP3A4 inhibitor has ceased. If the CYP3A4 inhibitor is to be continued, ibrutinib can be restarted at a lower dose at physicians discretion. In this scenario, pharmacokinetic monitoring and guidance is mandated.
12. Patients that are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree not to donate sperm during and after the study.
13. HIV+ patients are permitted, providing patients have CD4 counts greater than or equal to 350m3, agree to adhere to ongoing combination antiretroviral therapy, and have an HIV RNA viral load <400 copies/ml. Strong CYP3A4 inhibitor anti-retrovirals are not permitted and patients will need to be switched to an alternative agent.
14. Patients with resolved (HBsAg negative, HBcAb positive) HBV are permitted providing they have prophylaxis with entecavir or equivalent and monitored with HBV markers (HBV serology/HBV viral load) 3 monthly.
a. Patients with occult HBV (HBsAg negative, detectable HBV viral load) are permitted but should have prophylaxis with entecavir or equivalent and monitored with HBV markers (HBV serology/HBV viral load) 3 monthly.
Duration of prophylaxis will be at least 18 months post completion of ibrutinib therapy.
b. Patients with chronic HBV (HBsAg positive, detectable HBV viral load) should have HBV treatment with entecavir and can only enter trial if viral load undetectable.
All patients meeting criteria 14.a-c should be referred to a hepatology specialist.
15.
a. Patients with past HCV (HCV antibody positive but HCV RNA viral load negative) are eligible.
b. Patients with chronic HCV (HCV antibody positive, HCV RNA viral load detectable) are eligible if they have completed HCV therapy and if they have a sustained undetectable viral load.
All patients meeting criteria 15.a-b should be referred to a hepatology specialist.
Exclusion
1. Primary Effusion, Burkitt’s, and ENKT lymphomas.
2. Contraindication to any drug in the proposed regimen.
3. Serious active co-morbid disease according to the investigator’s decision.
4. Poor hepatic function, defined as Alanine aminotransferase (ALT) and aspartate.
aminotransferase (AST) > 3 x upper limit of normal (ULN) and/or total bilirubin > 2.0 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin.
5. History of malignancy during the past 2 years, with the exception of non-melanoma skin cancers or stage 0 (in situ) carcinoma.
6. Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy.
7. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.
8. Requires treatment with fish oil.
9. History of stroke or intracranial haemorrhage within 6 months of enrolment.
10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
11. Known severe bleeding disorders (e.g. severe von Willebrand’s disease).
12. Major surgery within 4 weeks of enrolment.
13. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
14. 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 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
15. Any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
16. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment.
17. HIV+ patients with a CD4 T cell count <350m3 and/or cannot commit to adhere to ongoing combination antiretroviral therapy, and/or have an HIV RNA viral load greater than or equal to 400 copies/ml. Strong CYP3A4 inhibitor anti-retrovirals are not permitted and patients will need to be switched to an alternative agent.
18. Women who are pregnant or lactating.
19. Previous severe adverse reaction to rituximab, ibrutinib, or 3rd Party EBV-specific CTL.
20. Participation in ongoing other therapeutic studies except for studies with a non-medical intervention.
21. Patients requiring anti-tuberculosis medication at time of study entry.
22. Patients are ineligible from accrual if they are on a strong CYP3A4 inhibitor (see eligibility criteria point 11) unless an alternative medication can be found. The exception to this is posaconazole, as the investigative team have previously administered ibrutinib (420mg, then stepped to 560mg) without toxicity. In that scenario, pharmacokinetic monitoring and guidance is mandated. Patients requiring a strong CYP3A4 inhibitor at a later point during the course of the study, must cease ibrutinib. It can be restarted once the CYP3A4 inhibitor has ceased. If the CYP3A4 inhibitor is to be continued, ibrutinib can be restarted at a lower dose at physicians discretion. In this scenario, pharmacokinetic monitoring and guidance is mandated.