(P 233) DNG64-CAR-V+ REGIMEN SHOWS CLINICAL BENEFIT IN PATIENTS WITH ADVANCED CCNG1 ONCOGENE EXPRESSING SARCOMAS (NCT04091295)

Objective: Targeted gene delivery has long been considered the “Holy Grail” of cancer gene therapy. Off-the-shelf injectable DNG64-CAR-V, a tumor-targeted Chimeric Amphotropic RNA Vector encoding a CCNG1 inhibitor gene, induces apoptosis not only in cancer cells but also in tumor-associated endothelial cells and activated cancer-associated fibroblasts, thereby priming the tumor microenvironment for enhanced innate immune cell and/or drug entry. Expanded access DNG64-CAR-V is currently available for advanced sarcomas (NCT04091295).

Endpoints: Primary: Clinical benefit rate (CBR) defined as the percentage of patients achieving a confirmed or best response of CR, PR, or SD; Secondary: Overall response rate (ORR) and incidence of TRAEs; Collaborative: Correlation of CCNG1 expression level with CBR. The study will use a Simon 2-stage design with Type I error rate = 0.1 and power = 0.8; a CBR ≥ 30% would warrant opening a Phase II study.

Methods: The study site will treat 40 patients with DNG64-CAR-V (1.7 x 10e10 RV copies i.v. 3x weekly, 3 weeks/month) plus FDA approved drugs (“DNG64-CAR-V+ regimen”). Archived tumor samples from all patients will undergo RNA sequencing to determine CCNG1 expression level. The study will use a Simon 2-stage design with Type I error rate = 0.1 and power = 0.8; a CBR ≥ 30% would warrant opening a Phase II study.

Results: Analysis of 6 evaluable patients (1 Extra-skeletal myxoid chondrosarcoma, 1 spindle cell sarcoma, 1 uterine leiomyosarcoma, 1 dedifferentiated liposarcoma, 1 osteosarcoma, 1 synovial sarcoma) treated with DNG64-CAR-V+ regimen demonstrated 83% CBR and 33% ORR (2 PR, 3 SD, 1PD). All tumors showed enhanced CCNG1 expression. Stratified by CCNG1 expression level, high CCNG1 expressors (n=4) had a 75% CBR (1 PR, 2 SD, 1 PD), medium-high expressors (n=1) had a 100% CBR (1 PR), and medium-low expressors (n=1) had a 100% CBR (1 SD). No DNG64-CAR-V related adverse events were reported.

Conclusion: These data demonstrate 83% CBR and 33% ORR. Based on a CBR ≥ 30% for the entire cohort and for each subgroup stratified by CCNG1 expression level, all groups qualify for further studies of efficacy/safety in a Phase II study using the DNG64-CAR-V+ regimen.