Background\nWe have harnessed a novel biological system, the bacterial minicell, to deliver cancer therapeutics\nto cancer cells. Preclinical studies showed that epidermal growth factor receptor\n(EGFR)-targeted, paclitaxel-loaded minicells (EGFRminicellsPac) have antitumor effects in\nxenograft models. To examine the safety of the minicell delivery system, we initiated a firsttime-\nin-human, open-label, phase I clinical study of EGFRminicellsPac in patients with\nadvanced solid tumors.\nMethodology\nPatients received 5 weekly infusions followed by a treatment free week. Seven dose levels\n(1x108, 1x109, 3x109, 1x1010, 1.5x1010, 2x1010, 5x1010) were evaluated using a 3+3 doseescalation\ndesign. Primary objectives were safety, tolerability and determination of the maximum\ntolerated dose. Secondary objectives were assessment of immune/inflammatory\nresponses and antitumor activity.\nPrincipal Findings\nTwenty eight patients were enrolled, 22 patients completed at least one cycle of EGFR mini cells Pac;\n6 patients did not complete a cycle due to rapidly progressive disease. A total of\n236 doses was delivered over 42 cycles, with a maximum of 45 doses administered to a single\npatient. Most common treatment-related adverse events were rigors and pyrexia. No\ndeaths resulted from treatment-related adverse events and the maximum tolerated dose\nwas defined as 1x1010 EGFR mini cells Pac. Surprisingly, only a mild self-limiting elevation in the inflammatory cytokines IL-6, IL-8 and TNF�± and anti-inflammatory IL-10 was observed.\nAnti-LPS antibody titers peaked by dose 3 and were maintained at that level despite repeat\ndosing with the bacterially derived minicells. Ten patients (45%; n = 22) achieved stable disease\nas their best response.\nConclusions/Significance\nThis is the first study in humans of a novel biological system that can provide targeted delivery\nof a range of chemotherapeutic drugs to solid tumor cells. Bispecific antibody-targeted\nminicells, packaged with the chemotherapeutic paclitaxel, were shown to be safe in patients\nwith advanced solid tumors with modest clinical efficacy observed. Further study in Phase II\ntrials is planned.
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