Optimizing Lymphodepletion to Improve Outcomes in Patients Receiving Cell Therapy With Kymriah

Patients will be enrolled in two stages: the dose escalation stage to assess the safety and tolerability of a modified LD regimen, and once the maximum tolerated dose (MTD) is determined, a cohort expansion phase to further characterize the toxicity and efficacy profile and determine the recommended phase 2 dose (RP2D). The study will enroll approximately 20-40 patients in the dose escalation stage (Part 1), and approximately 20 further patients at cohort expansion (Part 2). There will be six dose escalation cohorts, in three study arms. There are two dosing cohorts in each study arm. Patients in Arm 1 will receive the JULIET chemotherapy LD regimen with or without TLI, and in Arms 2 and 3, intermediate doses of Cy with a fixed dose of Flu, with or without TLI, will be given. The cohorts in Arm 1 will enroll concurrently, and enrollment into Arm 2 will begin after Arm 1 has enrolled all patients and data review by the Trial Steering Committee (TSC). Similarly, enrollment into Arm 3 will only commence once Arm 2 has accrued and relevant safety data has been reviewed. For accrual into Cohort 2, Arm 1, there will be a 15-day staggered enrollment for the first 2 patients. Staggered enrollment with another 15-day delay may be considered for enrollment into relevant cohorts in Arms 2 and 3, after review by the TSC. Following completion of accrual to Arm 1, a 30 day dose limiting toxicity (DLT) window will be observed, prior to review by the TSC and commencement of patient enrollment into Arm 2. The same procedure and DLT window will be followed prior to patient enrollment into Arm 3. One DLT window will be observed during this study: 30 days post infusion of tisagenlecleucel.