This is an open-label Phase 1 study to estimate the safety and manufacturing feasibility of lentivirally transduced T cells expressing anti-CD38 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in patients with Acute Myeloid Leukemia and Multiple Myeloma. This CAR T cell product will be referred to as "CART-38 cells".
Three dose levels of CART-38 cells will be evaluated using a 3+3 dose escalation design in two parallel disease cohorts as follows:
* Cohort A: Relapsed/Refractory Acute Myeloid Leukemia (AML)
* Cohort B: Multiple Myeloma (MM)
Enrollment in Cohorts A and B may occur in parallel, however subject infusions must be staggered as follows:
* Inter-Cohort Stagger: The first three subjects in the study, irrespective of cohort assignment, must be staggered by a minimum of 28 days.
* Intra-Cohort Stagger: In order to allow for appropriate monitoring/assessment of toxicities, the 1st and 2nd subject infusions at every dose level within each individual disease cohort must be staggered by at least 28 days. If there are no emergent safety concerns identified in the first subject infused, subsequent subject infusions within that disease cohort/dose level do not need to be staggered and may be infused sequentially (e.g. 2nd and 3rd subject infusions may occur in parallel). Formal DLT evaluations will be performed after the 3rd subject in each disease cohort/dose level reaches the Day 28 safety follow-up visit, and will allow for a formal decision regarding dose level progression, expansion, or de-escalation. Formal DLT evaluations will be determined by the Clinical PI and Sponsor Medical Director.
Cohort-specific DLT assessments will be performed after the 3rd evaluable subject at each dose level completes their Day 28 Safety Follow-up Visit. Generally, each cohort/dose level will be evaluated as follows. Please refer to Section 3.1 of the study protocol for complete details:
* If 0 DLTs are observed in the first 3 DLT evaluable subjects at an assigned dose level, the disease cohort will advance to the next dose level. If 0 DLTs are observed in the first 3 DLT evaluable subjects at the highest dose level (Dose Level 3), the disease cohort will add an additional 3 DLT evaluable subjects at this dose level to further evaluate safety.
* If 1 DLT is observed in the first 3 DLT evaluable subjects at an assigned dose level, the disease cohort will enroll an additional 3 evaluable subjects at this dose level to further evaluate safety. If 0 DLTs are observed in the second 3 evaluable subjects at this dose level (or a total of 1 DLT/6 evaluable subjects), the disease cohort will advance to the next dose level.
* If 2 DLTs are observed at an assigned dose level at any time, enrollment into that disease cohort will be stopped and the dose level for that cohort will be de-escalated to the previous dose level. If fewer than 6 DLT evaluable subjects were infused at the previous dose level, up to 6 total evaluable subjects will be infused to establish the maximum tolerated dose (MTD).
* The MTD is defined as the dose at which 0 or 1 DLT occurs in 6 DLT evaluable subjects.
DLT evaluable subjects are those who receive CART-38 cells as per their assigned dose level and either a) complete the DLT evaluation period per protocol, or b) experience a DLT that requires premature study discontinuation during the DLT evaluation period. Subjects that do not qualify as DLT evaluable will be replaced at the same dose level.
Retreatment:
Subjects who have demonstrated clinical benefit after their initial CART-38 infusion may also be eligible to receive retreatment with CART-38 cells at the physician-investigator's discretion. The CART-38 retreatment dose administered must not exceed a CART-38 dose that has been fully explored at previous dose levels and established as safe. Therefore, retreatment will remain closed until the safety of the CART-38 cells has been fully established within Dose Level 1 for that Cohort, and DSMB and FDA approval to open retreatment has been received.
