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4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

BACKGROUND Abnormal p53 function commonly defines high-risk CNS tumors, but functional restoration has eluded investigators. SGT-53 is a targeted nanomedicine encapsulating a plasmid DNA encoding wild-type human p53 with a transferrin receptor-targeting scFv on the nanocomplex surface resulting in efficient delivery across the BBB and robust tumor binding/uptake. Data generated by collaborators demonstrated synergy with irradiation and chemotherapy. REPORT: Two children with recurrent CNS malignancies have been treated with SGT-53, each receiving greater than 50 infusions in combination with irradiation and chemotherapy with no grade 3/4 AEs positively attributed to SGT-53. The first was an 11yo male with recurrent disseminated p53+ SHH medulloblastoma, with bulky intracranial/thoracolumbar disease. He received irradiation followed by biweekly doses of SGT-53 and temozolomide, bevacizumab and irinotecan given one week out of four. This patient exhibited a complete response of all disease on his first follow-up scan 8 weeks after therapy initiation and remained in remission for 8 months. The second patient was a 3yo male with disseminated recurrent choroid plexus carcinoma. He received CSI with SGT-53, followed by SGT-53, temozolomide and irinotecan as described above, again with no related grade 3/4 AEs. He experienced a partial response to all sites of disease and completed therapy after six months, progressing 7.8 months after initiating treatment. CONCLUSIONS SGT-53 was well tolerated in two heavily-pretreated patients despite aggressive combinatorial strategies. The majority of the AEs experienced were mild and manageable. Each patient had significant responses, suggesting that SGT-53 should be evaluated in a clinical trial for similar patients.

Background: Development of gene therapy has been limited by our inability to systemically administer treatment which selectively targets tumor tissue. We developed an SGT-RB94 nanocomplex composed of cationic liposome encapsulating plasmid DNA encoding the RB94 gene which had previously been shown to selectively kill cancer cells but not non-transformed human cells. The surface of the liposome is decorated with a single chain antibody fragment to the transferrin receptor to target the nanocomplex to cancer cells. Methods: We performed a phase I trial of single agent SGT-RB94 in patients with previously treated metastatic cancer. Treatment with SGT-RB94 was administered twice a week for 3 weeks out of four using a fixed at a fixed DNA dose of 0.6, 1.2, or 2.4 mg pDNA. Radiographic imaging was performed every 2 cycles to evaluate for response. When possible, a biopsy of a metastatic site was performed, after beginning treatment to evaluate for targeting of the gene product. PCR was performed to show expression of SGT-94 in RB+ tumors, RB94 protein production was confirmed using Western blotting. Results: Thirteen patients were treated with 11 clinically evaluable for response. Dose-limiting toxicity was not observed at the 2.4 mg dose. A total of 181 doses of SGT-94 were administered. The treatment was well tolerated with the most frequent treatment related toxicities being Grade 1-2 fever and chills (27%), thrombocytopenia (45%), neutropenia (18%), and hypotension (18%). The only grade 3-4 toxicity were lymphopenia (9%), and neutropenia (9%). The fever/chills and hypotension most typically occurred after the first dose, and responding with steroids. The neutropenia and thrombocytopenia were also transient and improved with continued dosing. There was evidence of clinical activity with a complete response in a lung metastases; this patient was retreated upon progression, and had a partial response in his peritoneal implants. Two patients continued to have stable disease after 4-5 cycles of treatment. Two patients had RB- tumors by immunohistochemistry. One had a post-treatment biopsy showing evidence of cytoplasmic staining for the RB protein with extensive tumor necrosis following treatment, but this tumor ultimately progressed. One patient with stable disease had surgical consolidation with wedge resection of his lung metastases which showed RB94 expression by PCR, and protein production by Western blot in two separate tumors, but not in his normal lung tissue. Conclusions: Systemic delivery of SGT-RB94 was well tolerated with evidence of clinical activity and selective targeting of tumor tissue, overcoming a major limitation to current gene therapy strategies. Further development of SGT-RB94 as a treatment modality is warranted. Citation Format: Arlene Siefker-Radtke, Xin-qiao Zhang, Kathleen F. Pirollo, Esther H. Chang, Chris P. Leung, Charles Guo, Randall E. Millikan, William F. Benedict. Systemic administration using targeted gene delivery with SGT-RB94 shows evidence of tumor targeting and anticancer activity: a phase I first-in-man trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT059.

RB-94 is a truncated form of the RB tumor suppressor gene which has shown marked cytotoxicity in every human tumor type tested to date without affecting normal cells. A systemically administered, tumor-targeted nanocomplex for systemic gene delivery (termed SGT) has been developed. In the SGT nanocomplex, the payload is encapsulated within a cationic liposome. The surface of the liposome is decorated with an anti-transferrin receptor (TfR) single chain antibody fragment (scFv) designed to target cancer cells by binding to the TfR which is highly expressed on tumor cells. Here we describe the results of a DNA dose escalating first-in-man Phase l study of SGT encapsulated RB-94 (SGT-94) for the treatment of metastatic genitourinary tumors. The majority of the cancers treated in this study were bladder cancers. Treatment with SGT-94 was well tolerated with minimal side effects observed. Moreover, among the 11 evaluable patients of 13 treated, a complete remission (CR) in a lung metastasis, two partial remissions (PRs) and three incidences of stable disease (SD) were observed. The CR and PRs occurred at the highest dose (2.4 mg DNA) tested. In addition, there is strong evidence for tumor-specific targeting including data from two resected lung metastases. In these metastatic lesions, the presence of RB94 was documented by both PCR and Western blotting in the tumors. However, RB94 was absent in contiguous normal lung tissue. Therefore, this Phase I study demonstrates not only the safety, but also the anti-cancer potential of the SGT-94 nanocomplex and suggests that additional studies using SGT-94 alone or in combination with chemotherapy, radiation or other modalities are warranted.