None listed
Conditions
Brief summary
The purpose of this study is to assess the safety and immune system response to treatment with Tislelizumab in patients with Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL). Who is it for? You may be eligible to join this study if you are aged 45 years or older and have been diagnosed with EBV-associated DLBCL, without immunosuppression. Study details All patients enrolled in this study will receive treatment based on 21-day cycles, with 4 stages: 1. "Induction" stage, involving intravenous Tislelizumab (200mg) and Rituximab (375mg/m2) on day 1 of each cycle over 3 cycles (9 weeks total). 2. "Combination" stage, involving Tislelizumab (200mg), Rituximab (375mg/m2), Cyclophosphamide (750mg/m2), Doxorubicin (50mg/m2), Vincristine (1.4mg/m2, up to a maximum of 2mg) on day 1 of each cycle; and oral tablet Prednisolone (100mg) daily on days 1 to 5 of each cycle. There are 6 cycles for this stage (18 weeks total). 3. "Cell Therapy" stage, involving intravenous Epstein-Barr Virus (EBV) virus specific T-cells (Auto-EBV-VST). Two infusions of 3x10^7/m2 each will be given a week apart. Six weeks after the 2nd infusion, patients will have a PET/CT scan to assess if the cancer has disappeared. If so, the patient will move to the next stage, "Maintenance". (However, if the cancer has not disappeared, the patient will be withdrawn from the treatment phase of this trial.) 4. "Maintenance" stage, involving intravenous Tislelizumab (400mg) on day 1 of every second cycle over 16 cycles (48 weeks total). Overall, the study will take 83 weeks. Other testing that will be performed includes serology, blood tests, bone marrow assessment and ECHO scans (at baseline and end of treatment). It is hoped that the research will provide evidence for the safety of this immune-based approach, and lead to better outcomes for EBV-associated DLBCL lymphoma patients.
Interventions
Summary of treatment regimen:
There are 4 phases in the treatment regiment for this trial:
1. induction
2. combination
3. cell therapy
4. maintenance
Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team.
Induction
200mg Tislelizumab given (intravenously) IV and 375mg/m2 Rituximab delivered IV given on day 1 of every week in the 21 day cycle. There are 3 cycles in this induction period.
Summary of treatment regimen: There are 4 phases in the treatment regiment for this trial: 1. induction 2. combination 3. cell therapy 4. maintenance Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team. Induction 200mg Tislelizumab given (intravenously) IV and 375mg/m2 Rituximab delivered IV given on day 1 of every week in the 21 day cycle. There are 3 cycles in this induction period. Patients are monitored for at least 60 minutes (Cycles 1 and 2) or 30 minutes (cycle 3) afterward in an area with resuscitation equipment and emergency agents. Combination Six cycles of combination therapy, each cycle is 3 weeks (21 days). The drugs received are: *200mg Tislelizumab IV D1 *Rituximab 375mg/m2 IV D1 *Cyclophosphamide 750mg/m2 IV D1 *Doxorubicin 50mg/m2 IV D1 *Vincristine 1.4mg/m2 (max 2mg) IV D1 *Prednisolone 100mg orally (tablet) on D1-5 inclusive Cell Therapy Two infusions of autologous EBV virus specific T cells (VST) will be given a week a part. The infusions will be given IV by a member of the medical or nursing staff trained in the administration of cellular products. Each infusion of VST will be administered at a dosage of 3x10^7/m2. Maintenance Eight cycles of maintenance will be delivered, each cycle is 6 weeks duration. 400mg Tislelizumab IV will be delivered on day 1 of each cycle.
Sponsors
Australasian Leukaemia and Lymphoma Group
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Local histological diagnosis (on core or excision biopsy) of de-novo systemic CD20+ EBV-associated DLBCL by EBER-ISH (positive is equals to or greater than 50% of lymphoma cells) without immunosuppression. (Immunosuppression includes lymphomas occurring after methotrexate, in patients with HIV, or following solid organ or haematopoietic stem cell transplant, and patients with inherited immunodeficiencies). 2. Stages II-IV (or I with bulk equal to or greater than 7.5cm or systemic ‘B’ symptoms). 3. Aged greater than 45 years 4. Adequate major organ function defined as a. ANC (segs + bands) equal to or greater than 1.0 x 10^9/L (can be supported by G-CSF). b. Platelet count equal to or greater than 75 x 10^9/L (or 50 if bone marrow is involved) c. Total bilirubin equal to or less than 1.5 x ULN (unless rise in bilirubin is due to Gilbert’s syndrome or of non-hepatic origin d. ALT and AST equal to or less than 3 x ULN e. Creatinine clearance equal to or greater than 30ml / min / 1.73m2 (Cockcroft-Gault formula) f. LVEF within institutional normal limits (determined either by echocardiography or gated heart pool scan). 5. ECOG status 0-2 (2 if related to lymphoma) 6. Written informed consent. 7. Life expectancy at least 3 months 8. Men who are sexually active with women of child-bearing potential, and women of child-bearing potential, must use any highly effective contraceptive method during the study (failure rate greater then 1% per year) and for a period of 120 days after the last dose of therapy. Should pregnancy occur during therapy or before 120 days, the treating physician should be informed immediately. 9. PET/CT avid disease at baseline. 10. Positive EBV IgG serology. 11. Subjects must agree not to donate blood, semen or sperm while on study treatment and for least 120 days after treatment discontinuation 12. Subjects must agree not to share their medication and to return unused supplies 13. To take part in the PRO component of the study the subject must be able to read/write in English. Patients who do not meet this criteria can participate in the rest of the trial.
Exclusion criteria
1. T cell lymphoma, transformed or 3B Follicular Lymphoma 2. CNS / meningeal / spinal cord involvement with lymphoma 3. Prior anti-PD-1 mAb 4. Active autoimmunity that might deteriorate when receiving an immunostimulatory agent. Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Controlled Type I diabetes b. Hypothyroidism (provided it is managed with hormone replacement therapy only) c. Controlled celiac disease d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia) e. Any other disease that is not expected to recur in the absence of external triggering factors 5. Chronic prednisolone is greater than 10mg (or equivalent). Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses is equal to 10 mg or 10 mg equivalent prednisone per day. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable. 6. Uncontrolled systemic infection, including active Hepatitis B/C. Patients with Hep B core Ab positive and Hep B surface antigen negative are permitted in the trial only if they have negative HBV DNA and must be on HBV prophylaxis (choice of prophylaxis is at physician’s discretion, with local guidance). Patients who are Hep B surface antigen positive are NOT allowed. Prior treated Hep C is allowed, provided HCV RNA is not detected. 7. As there is ‘chemo-free’ induction, patients requiring urgent cyto-reductive therapy for life-threatening disease are excluded. Requirement for urgent treatment due to life-threatening complications include for example: Compressive symptoms due to disease (which may or may not be bulky), such as superior vena caval obstruction; significant organ involvement causing compromise of organ function (including but not limited to liver, renal obstruction), malignant, symptomatic hypercalcaemia 8. Anticipated to be unable to receive full-dose R-CHOP 9. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal, squamous cell skin cancer, low risk melanoma, superficial bladder cancer, localised cancer of the prostate cancer, cervix, or breast 10. Immunosuppression related lymphoma (e.g. PTLD, HIV, methotrexate).(Immunosuppression related lymphomas include those occurring after methotrexate, in patients with HIV, or following solid organ or haematopoietic stem cell transplant, and patients with inherited immunodeficiencies). 11. Previous treatment for current lymphoma (including chemotherapy, radiotherapy or investigational drug). Prior treatment for a histologically distinct lymphoma is permitted. 12. No concurrent uncontrolled medical condition as determined by investigator 13. Prior immune checkpoint blockade therapy 14. Use of pre-phase corticosteroids is discouraged (but permitted) due to the potential for reduction in Tislelizumab activity. However, if patients have received pre-phase steroids for symptom relief prior to screening they are not excluded. 15. Prior organ transplantation including allogeneic stem cell transplantation 16. Past history of interstitial lung disease (a rare side-effect of PD-1 blockade), non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.) 17. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3 NCI-CTCAE v6), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) 18. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of enrolment and/or if the subject has not fully recovered from the surgery within 4 weeks of enrolment 19. Pregnancy or lactation. 20. Serious active co-morbid disease according to investigator’s discretion. 21. Previous adverse reaction to the trial drugs. 22. Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, within 28 days (inclusive) before first dose of study drug b. Pulmonary embolism within 28 days (inclusive) before first dose of study drug c. Any history of acute myocardial infarction within 6 months (inclusive) before or first dose of study drug d. Any history of heart failure meeting New York Heart Association (NYHA Classification III or IV within 6 months (inclusive) before or first dose of study drug e. Any event of ventricular arrhythmia greater than or equal to Grade 2 in severity within 6 months (inclusive) before first dose of study drug f. Any history of cerebrovascular accident within 6 months (inclusive) before first dose of study drug g. Uncontrolled hypertension: systolic pressure greater than or equal to 160 mmHg or diastolic pressure greater than or equal to 100 mmHg despite anti-hypertension medications within 28 days (inclusive) before first dose of drug h. Any episode of syncope or seizure within 28 days (inclusive) before first dose of study drug 23. Was administered a live vaccine within 4 weeks (inclusive) before first dose of study drug. COVID vaccines and seasonal vaccines for influenza are allowed.
Outcome results
None listed