A Phase I/II Study of CAR.70-Engineered IL15-Transduced Cord Blood-Derived NK Cells With TGF-beta Receptor 2 (TGFBR2) Knock Out in Conjunction With Lymphodepleting Chemotherapy for the Management of Relapsed/Refractory Myeloid Malignancies

Description

This is a phase I/II, two-arm, open-label study. The study will have a phase I dose-escalation portion using a standard “BOIN” approach to determine the MTD of the CAR.70/IL15-transduced/TGFBR2KO CB-NK cells, followed by phase II expansions of 2 arms: 1.) patients with relapsed/refractory AML and 2.) patients with MDS/CMML after HMA failure.

Up to 12 patients will be enrolled in the phase I portion of the study. Following determination of the recommended phase 2 dose (RP2D), 20 patients will be enrolled into the AML arm and 10 patients will be enrolled into the MDS/CMML arm (30 patients total in phase II).

The regimen consists of lymphodepleting and priming chemotherapy with dexamethasone, decitabine, fludarabine and cyclophosphamide, followed by a one-time infusion of the CAR.70/IL15-transduced/TGFBR2KO CB-NK cells

Primary Objectives:

* Phase I: To determine the safety and optimal cell dose of TGFBR2 KO CAR27/IL-15 NK cells in patients with relapsed/refractory myeloid malignances
* Phase II: To determine the response rates of TGFBR2 KO CAR27/IL-15 NK cells in patients with relapsed/refractory AML and in patients with MDS or CMML after HMA failure

Secondary Objectives:

* To determine the CR rate in each cohort
* To determine the rate of flow cytometry MRD negativity (AML cohort only)
* To assess duration of response, relapse-free survival (AML cohort only), and overall survival
* To determine hematologic and non-hematologic toxicities

Exploratory Objectives:

* To assess impact of baseline cytomolecular features and CD70 expression on response
* To quantify persistence of the infused CAR product
* To conduct comprehensive immune reconstitution studies