Clinical Trial to Assess The Efficacy and Safety of the Combination of Tisagenlecleucel And Ibrutinib in Mantle Cell Lymphoma

Inclusion criteria

• Patients must meet all the following criteria for study entry:

• Written informed consent prior to screening procedures
• Be ≥18 years of age on the day of signing informed consent
• Have a confirmed diagnosis of MCL according to World Health Organization (2016) criteria
• Have sufficient fresh or archival material available for central review
• At least one site of radiographically assessable disease not previously irradiated (lymph node with largest diameter ≥1.5cm, or unequivocal evaluable hepatomegaly/splenomegaly or marrow phase disease)
• Meet at least one of the following disease criteria:

• Have relapsed, or progressed following at least 1 prior line of systemic chemoimmunotherapy for MCL (may include ibrutinib or other BTK-inhibitor in combination)
• Be refractory to at least one prior line of chemoimmunotherapy (refractory is defined as less than a conventional PR following 2 cycles of anthracycline or cytarabine-containing therapy)
• Have achieved <CR on PET imaging following 2 cycles of anthracycline or cytarabine-containing therapy in the presence of aberrations of p53; or <CR post autologous stem cell transplantation
• Failure to achieve CR following at least 6 months of an ibrutinib or BTK inhibitor -containing front-line regimen, or failure to achieve PR following 8 weeks of a BTK inhibitor
• Have a life expectancy of ≥ 3 months, as judged by the investigator
• Have acceptable haematological function within 7 days prior to registration, defined as:

• Absolute neutrophil count ≥1x10^9/L (may be supported by growth)
• Absolute lymphocyte count ≥0.3x10^9/L or absolute CD3+ fraction > 0.15x 10^9/L
• Platelets >50x 10^9/L unless explained by lymphoma at the discretion of the CPI
• Haemoglobin ≥ 80 g/L (may be transfusion supported)
• Have acceptable organ function within 7 days prior to registration, defined as:

• Serum creatinine ≤1.5 x ULN, or a calculated creatinine clearance of at least 50 mL/min using the Cockcroft-Gault equation (see appendix 1) or a 24-hour urine collection
• AST or ALT ≤3.0 x ULN
• Bilirubin ≤ 1.5 x ULN (with the exception of patients with Gilbert's syndrome. Patients with Gilbert's syndrome may be included if their total bilirubin is ≤3.0 x ULN and direct bilirubin ≤1.5 x ULN).
• aPTT and PT ≤ 1.5x ULN
• Adequate pulmonary function defined as:
• No or mild dyspnea (≤ grade 1)
• Oxygen saturation measured by pulse oximetry ≥ 90 percent on room air 10. Female patients of childbearing potential and non-sterile male patients (with partners of childbearing potential) must agree to use highly effective methods of contraception from registration on the study to 30 days after the last dose of ibrutinib and 12 months after Tisagenlecleucel infusion and until Tisagenlecleucel is no longer present by qPCR on two consecutive tests (whichever is later):

• Total abstinence from sexual intercourse when this is in line with the preferred and usual life style of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks prior to registration. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment
• Male sterilisation (at least 6 months prior to screening). For female patients on the study, the vasectomised male partner should be the sole partner for that patient
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before enrolment into this study.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.

• Female patients of childbearing potential must have a negative serum (beta-human chorionic gonadotropin (β-hCG) or urine pregnancy test within 7 days of registration 12. Sexually active male patients must use a condom during intercourse and must agree to refrain from sperm donation, from registration on the study until 30 days after the last dose of ibrutinib or 12 months after Tisagenlecleucel infusion and until Tisagenlecleucel is no longer present by qPCR on two consecutive tests

Exclusion criteria

• Patients who meet any of the following criteria will be excluded from study entry:

• Prior allogeneic transplantation
• Autologous transplantation within 6 weeks prior to registration
• Active and uncontrolled autoimmune cytopenias
• Active central nervous system involvement with MCL
• Previous treatment with adoptive T-cell therapy
• Receipt of a non BTK-inhibitor investigational medical product within the last 30 days prior to planned leukapheresis
• Receipt of a non-anti CD20- monoclonal antibody with anti-neoplastic intent within 30 days prior to planned leukapheresis
• Receipt of steroids >20mg prednisolone or equivalent in the fortnight prior to planned leukapheresis
• Requirement for ongoing therapy with:

• Potent CYP3A inhibitors (e.g. indinavir, ketoconazole, clarithromycin)
• Potent CYP3A inducers (e.g. rifampin, phenytoin, carbamazepine)
• Vitamin K antagonists (e.g. warfarin or equivalent)
• Antiretroviral medications
• Consumption within 3 days prior to registration:

• Grapefruit or grapefruit products
• Seville oranges
• Star fruit
• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of screening or class III to IV cardiac disease as defined by the New York Heart Association Functional Classification
• Active neurological disorders of clinical relevance (e.g. epilepsy, severe brain injury, dementia, Parkinson's disease or autoimmune/inflammatory disorders (e.g. Guillain-Barre syndrome, motor neurone disease, chronic inflammatory demyelinating polyneuropathy)
• Other significant life-threatening illness or medical condition which, in the investigator's opinion, could compromise the subject's safety, interfere with absorption or metabolism of study drug, or put the study outcomes at undue risk
• History of other active malignancy, with the exception of:

• Adequately treated in situ carcinoma of the cervix or breast
• Adequately treated basal cell carcinoma of skin or localised squamous cell carcinoma of the skin
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and without evidence of recurrence for at least 2 years prior to registration
• History of human immunodeficiency (HIV) or active hepatitis C virus or active hepatitis B virus. NOTE: Serology must be repeated at the pre-conditioning stage prior to infusion with Tisagenlecleucel.
• Clinically significant active infection confirmed by clinical evidence, imaging or positive laboratory tests (e.g. blood cultures, viral DNA/RNA by PCR)
• Receipt of live, attenuated vaccines within 4 weeks of registration
• Major surgery within 4 weeks prior to registration
• Pregnant or nursing (lactating) women. Note: Women of child-bearing potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion (if performed) and prior to Tisagenlecleucel infusion.
• Known hypersensitivity to the excipients of Tisagenlecleucel or to any product to be given to the patient as per the study protocol (e.g. tocilizumab and lymphodepleting agents)