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
Summary
The goal of this clinical research study is to find the recommended safe dose of TGFBR2 KO CAR27/IL-15 NK cells that can be given to patients with relapsed/refractory disease. The safety and effectiveness of this treatment will also be studied.
Detailed 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
Arms & interventions
- DrugDexamethasone
Given Orally
- DrugCyclophosphamide
Given by IV
- DrugFludarabine
Given by IV
- DrugDecitabine
Given by IV
- BiologicalTGFBR2 KO CAR27/IL-15 NK cells
Given by Infusion
Outcome measures
Primary
Safety and Adverse Events (AEs)
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
Time frame: Through study completion; an average of 1 year
Response rates (AML cohort)
Rate of complete remission (CR) + CR with incomplete hematologic recovery (CRi) + CR with CR with partial hematologic recovery (CRh)
Time frame: 30 days from CAR infusion
Response rates (MDS/CMML) cohort
Rate of CR + partial remission (PR) + CR with limited count recovery (CRL), CRh, hematologic improvement (HI) for MDS; rate of CR + PR + marrow CR (mCR) + clinical benefit (CB) for CMML
Time frame: 30 days from CAR infusion
Secondary
CR rate
Time frame: 30 days from CAR infusion
Measurable residual disease (MRD) negativity (AML cohort)
Time frame: 30 days from CAR infusion
Duration of response
Time frame: Through study completion; an average of 1 year
Relapse-free survival
Time frame: Through study completion; an average of 1 year
Overall survival
Time frame: Through study completion; an average of 1 year
Hematologic and non-hematologic toxicities
Time frame: Through study completion; an average of 1 year
Eligibility criteria
Study locations (1)
The University of Texas M. D. Anderson Cancer Center
Houston, Texas, 77030