Phase 1/1b study of PRGN-3005 autologous UltraCAR-T cells manufactured overnight for infusion next day to advanced stage platinum resistant ovarian cancer patients.
Authors: Liao John B. , Stanton Sasha E. , Chakiath Marion , Semnani Roshanak , Shah Rutul R. , Tan Tasha , Sabzevari Helen , Lankford Amy , Disis Mary L. 
Published: June 2023

5590 Background: Relapsed or refractory (r/r) ovarian cancer patients (pts) have limited treatment options. PRGN-3005 UltraCAR-T cells express a chimeric antigen receptor (CAR) targeting unshed MUC16, membrane bound IL-15 (mbIL15) and a kill switch with robust activity in preclinical models. UltraCAR-T investigational therapies are manufactured overnight using the proprietary UltraPorator electroporation system at the medical center and administered to patients one day after gene transfer. Methods: The Phase 1/1b study of PRGN-3005 evaluates the safety and recommended Phase 2 dose (RP2D) of PRGN-3005 in pts with r/r ovarian cancer (NCT03907527). In Phase 1, pts received PRGN-3005 without lymphodepletion (LD) via Intraperitoneal (IP) infusion (Cohort 1, C1) or Intravenous (IV) infusion (Cohort 2, C2) at Dose level 1-3. Dose level 3, IV infusion was further evaluated in pts treated with cyclophosphamide LD (60mg/kg/day on days -4 to -3 (IV LD)). As of the February 6, 2023 data cut-off, 25 evaluable pts have been treated in C1 (n = 12), C2 (n = 6), and IV LD (n = 7). Pts had a median age of 64 years (38-76) and were heavily pre-treated with a median of 8 prior regimens (4-11). Pts treated in C1 received 1 to 65.5 x 105 cells/kg, pts treated in C2 received 0.1 to 50 x 105 cells/kg and pts treated in IV LD received 0.1 to 39 x 105 cells/kg. Results: PRGN-3005 was well tolerated at up to 65.5 x 105 cells/kg. There have been no deaths, dose-limiting toxicities, neurotoxicity, grade ≥3 Cytokine Release Syndrome (CRS), or unexpected on-target/off-target toxicities related to PRGN-3005, and no use of the kill switch as of data cut-off. Grade 1 CRS occurred in 3/7 IV LD pts and one pt had transient grade 2 CRS, which resolved in < 24 hours. Plasma levels of IL-15 did not increase with treatment confirming mbIL15 is not shed. A dose dependent increase in PRGN-3005 was observed in peripheral blood of patients even in the absence of LD, and i n vivo persistence of PRGN-3005 could be observed in some patients for up to 9 months post infusion. Response was evaluated per RECIST 1.1, and 20% of all subjects experienced a response in at least 1 target lesion. In the IV LD pts, the disease control rate (DCR) was 85.7% at first restaging, with a decreased target tumor burden in 4/7 (57%), and a 27.4% average decrease in CA125. One pt had a 28% decrease in target tumor burden after receiving a second infusion of PRGN-3005 after 12 months. Conclusions: PRGN-3005 UltraCAR-T targeting MUC16 has been well tolerated with minimal toxicity. PRGN-3005 demonstrated a dose-dependent expansion and persistence in blood with or without LD. Encouraging DCR rates and a reduction in overall tumor burden have been observed in heavily pretreated, ovarian cancer pts treated with LD. The study continues to enroll to the Phase 1b expansion phase and is treating pts at DL3 with LD with an option to receive a second dose. Clinical trial information: NCT03907527 .