Tisagenlecleucel for the Treatment of Primary Central Nervous System Lymphoma
This phase I trial studies the side effects of tisagenlecleucel in treating patients with primary central nervous system lymphoma. Tisagenlecleucel is an investigational treatment that uses a patient's own immune cells, called T cells, to try to kill the cancerous cells. T cells fight infections and can also kill cancer cells in some cases. In this study, some T cells will be removed from the blood, changed in a laboratory, and then given back by intravenous infusion. While in the laboratory, new genetic material will be placed into the T cells. T cells that have genetic material added are called genetically changed T cells. If the genetically changed T cells recognize and attach to cancer cells, they may have the ability to become activated and kill them.
Inclusion Criteria
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: New diagnosis of primary CNS lymphoma
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Voluntarily sign informed consent form(s)
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: >= 60 years of age at the time of signing informed consent
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Have failed or are unable to tolerate definitive first-line methotrexate based therapy as defined by: * Grade 3+ acute kidney injury (AKI) and/or transaminitis preventing repeat treatment exposure and/or * Failure to achieve a complete response (per IPCG) following two cycles of first line therapy ** Definitive first-line therapies must include high dose methotrexate-based therapy but may also include temozolomide, high dose cytarabine, pemetrexed, lenalidomide, ibrutinib and rituximab * Whole-brain irradiation, lenalidomide monotherapy and ibrutinib monotherapy are considered first line therapy if patient was not eligible for methotrexate-based chemotherapy at time of initial treatment but now meets study eligibility criteria
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of apheresis
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Absolute neutrophil count (ANC) > 1000 cells/mm^3 without growth factor support within 7 days
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Untransfused platelet count > 50,000 mm^3 within 7 days
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Left ventricular ejection fraction > 40%
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN)
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Direct bilirubin < 1.5 x ULN
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Creatinine clearance > 30 ml/min using the Cockcroft-Gault formula
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: International ratio (INR) or partial thromboplastin time (PTT) < 1.5 x ULN, unless on a stable dose of anticoagulant for a thromboembolic event
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: The effects of tisagenlecleucel T cells on the developing human fetus are unknown. For this reason, women of child-bearing potential and men with partners of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to leukapheresis for at least 1-year post tisagenlecleucel infusion and until CAR T cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men with partners of childbearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to leukapheresis and until 4 months after tisagenlecleucel T cells administration
- PRIMARY CNS LYMPHOMA IN HIGH RISK ELDERLY PATIENTS: Ability and willingness to adhere to the study visit schedule and all protocol requirements
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Diagnosis of relapsed/refractory PCNSL having received at least one prior line of CNS directed therapy
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Voluntarily sign informed consent form(s)
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: >= 18 years of age at the time of signing informed consent
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Adequate absolute lymphocyte count (ALC > 500 cells/ul) within one week of apheresis
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Absolute neutrophil count (ANC) > 1000 cells/mm^3 without growth factor support
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Untransfused platelet count > 50,000 mm^3
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Untransfused hemoglobin > 9 g/dL
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Left ventricular ejection fraction > 40%
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN)
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Direct bilirubin < 1.5 x ULN
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Creatinine clearance > 30 ml/min using the Cockcroft-Gault formula
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: International ratio (INR) or partial thromboplastin time (PTT) < 1.5 x ULN, unless on a stable dose of anticoagulant for a thromboembolic event
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: The effects of tisagenlecleucel T cells on the developing human fetus are unknown. For this reason, women of child-bearing potential and men with partners of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to leukapheresis for at least 1-year post tisagenlecleucel infusion and until CAR T cells are no longer present by qPCR on two consecutive tests. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men with partners of childbearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to leukapheresis and until 4 months after tisagenlecleucel T cells administration
- RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA: Ability and willingness to adhere to the study visit schedule and all protocol requirements
- LYMPHODEPLETION/CELL INFUSION: No active, uncontrolled, systemic bacterial, viral, or fungal infection
- LYMPHODEPLETION/CELL INFUSION: Creatinine clearance > 30 ml/min using the Cockcroft-Gault formula
Exclusion Criteria
- Prior treatment with an any investigational cellular therapy
- Ongoing treatment with chronic immunosuppressants (e.g., cyclosporine). Systemic steroids are allowed up to a dose of dexamethasone 4 mg daily or equivalent
- Ongoing systemic immunosuppression for acute and/or chronic graft versus host (GVH) as a result of previous allogeneic bone marrow transplant
- Significant co-morbid condition or disease which in the judgment of the principal investigator would place the subject at undue risk or interfere with the study; examples include, but are not limited to, cirrhotic liver disease, sepsis, and/or recent significant traumatic injury
- Active, uncontrolled, systemic bacterial, viral, or fungal infection
- Active hepatitis B or hepatitis C infection
- Human immunodeficiency virus (HIV) infection
- Subjects with a history of class III or IV congestive heart failure or non-ischemic cardiomyopathy
- Subjects with second malignancies if the second malignancy has required therapy in the last 3 years or is not in complete remission; exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy other than hormonal therapy
- Pregnant or lactating women
- Live virus vaccines within 2 weeks prior to planned start of lymphodepleting chemotherapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04134117.
PRIMARY OBJECTIVE:
I. To assess the safety of tisagenlecleucel in patients with primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL).
SECONDARY OBJECTIVE:
I. To assess the activity of tisagenlecleucel in patients with primary CNS diffuse large B-cell lymphoma (PCNSL).
EXPLORATORY OBJECTIVES:
I. To evaluate overall, and progression-free survival of patients treated with tisagenlecleucel with PCNSL.
II. Detection and quantification of tisagenlecleucel and tumor specific mutations in the biopsies, the peripheral blood and cerebrospinal fluid (CSF).
III. Assessment of cytokine/chemokine profiling in peripheral blood and CSF.
IV. Longitudinal neurocognitive evaluation as per International PCNSL Collaborative Group (IPCG) guidelines.
V. Assess pre/post tumor samples for gene and immune-profiling.
OUTLINE:
Patients receive cyclophosphamide intravenously (IV) over 30 minutes and fludarabine IV over 30 minutes on days -5 to -3. Patients then receive tisagenlecleucel IV over 30 minutes on day 0. Patients undergo echocardiography or multigated acquisition (MUGA) scan during screening and position emission tomography (PET) scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), lumbar puncture, and blood sample collection throughout the study.
After completion of study treatment, patients are followed up at 2, 4, 7, 10, 14, 21, and 28 days, monthly up to 6 months, quarterly up to 2 years, then up to 15 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorMatthew J Frigault
- Primary ID19-319
- Secondary IDsNCI-2019-08955
- ClinicalTrials.gov IDNCT04134117