KEYNOTE-B79 phase 1b trial to evaluate the allogeneic CAR T-cells CYAD-101 and pembrolizumab in refractory metastatic colorectal cancer patients.

Abstract

TPS227 Background: The allogeneic chimeric antigen receptor (CAR) T-cell treatment CYAD-101 utilizes the NKG2D receptor that targets eight ligands expressed on tumor cells and also on stromal and immunosuppressive immune cells of the tumor microenvironment. CYAD-101 co-expresses a T-cell receptor (TCR) inhibitory peptide with the aim to eliminate the potential of graft versus host disease (GvHD), the main safety risk associated with engineered cells of allogeneic origin. In the previous alloSHRINK trial (NCT03692429), CYAD-101 was administered post FOLFOX preconditioning chemotherapy to 15 patients with progressive metastatic colorectal cancer (mCRC) who were previously treated with FOLFOX. Overall, the treatment was well tolerated with no evidence of GvHD. The disease control rate was 73.3% with two patients presenting a confirmed partial response per RECIST’s criteria (4 months and 8 months of duration from first CYAD-101 infusion) and nine had stable disease with a median duration of 4.6 months. Evidence of increase in the TCR repertoire and modulation of the cytokine profile post-treatment with CYAD-101 were observed implying that CYAD-101 may also be modulating the immune suppressive environment in patients mirroring what was demonstrated in pre-clinical models. We considered that a sequential therapy with the anti-PD1 monoclonal antibody pembrolizumab to further release the anti-tumor potential of this expanded T-cell population may drive deeper, more durable and new clinical responses beyond that currently demonstrated with the CAR T-cells alone. Methods: The phase 1b KEYNOTE-B79 trial (NCT04991948) will evaluate, according to a Simon’s two stage study design, the safety and clinical activity of three consecutive infusions of CYAD-101 (1x109 cells per infusion) post FOLFOX preconditioning chemotherapy with two-week interval between cycles, followed by pembrolizumab treatment (200 mg administered every three weeks for up to two years) in microsatellite stable/mismatch-repair proficient mCRC patients with recurrent/progressing disease after at least one metastatic line of therapy, which must include FOLFOX chemotherapy. The pembrolizumab treatment will be initiated 3 weeks after the last CYAD-101 infusion to fall outside the classical time window of potential CAR T-cell toxicities (e.g., cytokine release syndrome). The co-primary endpoints of the trial are the occurrence of dose-limiting toxicities (DLTs) at any time from the first FOLFOX preconditioning treatment up to 3 weeks after the first pembrolizumab treatment and the objective response rate (ORR) at the tumor assessment planned 6 weeks after the first pembrolizumab treatment administration. The KEYNOTE-B79 study will be initiated in Q4-2021 in five sites in USA and Europe. Clinical trial information: NCT04991948.