A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001.

摘要: An attenuated strain of Salmonella typhimurium, designated VNP20009, was generated by deletion the msbB and purl genes. When VNP20009 administered intravenously (IV) to mice bearing spontaneous, syngeneic, or human xenograft tumors, bacteria accumulated preferentially within extracellular components forming tumor-to-normal tissue ratios exceeding 300-1000 1. NVP20009 safely at doses up 2.5 x 10(9) cfu/kg in monkey toxicology studies. Based on preclinical data, entered Phase I clinical trials November 1999, has now been >45 patients IV direct intratumoral injection. By route, a maximum tolerated dose not reached, escalation continues past current level 4 10(7)/m2. Furthermore, persisted injected tumors for least 2 weeks 8/11 treated date. 30-min administration, (MTD) 3 X 10(8) cfu/m2 established. In all date, shed urine stool. further modified chromosomal insertion an E. coli cytosine deaminase (CD) gene deltamsbB locus which, when expressed, converts 5-fluorocytosine (5-FC) 5-fluorouracil (5-FU). The CD containing TAPET-CD VNP20029. had similar efficacy safety murine tumor models profiles animal studies, compared its parent VNP20009. Specifically, reduced virulence >10,000 fold, wild-type strain. It well-tolerated 10(6) cfu/mouse 1 10(10) cfu/monkey. After injection tumor-bearing mice, reached levels as high 10(8)-10(9) cfu/gm. accumulation liver spleen, normal tissues with greatest colonization TAPET-CD, were also caused growth inhibition >90% several models. 5-FC intraperitoneal (IP) once times daily that pre-treated 5-FU (reaching 20-40 microM/g) detected tumor, low undetectable (e.g., liver, etc.). co-administration different enhanced anti-tumor activity significant alone, confirming benefit inserted gene. On basis protocol is proposed which advanced cancer will receive 5-FC. be day given orally q8h beginning toxicities have resolved < = grade 1, continued 14 days. Tumor sampled verify measure concentrations 8. A second sample obtained between 15-17 selected confirm persistence obtain measurement intra-tumoral concentrations. TAPET-CD/5-FC treatment cycle repeated appropriate 29.