SUPERANTIGEN-BASED IMMUNOTHERAPY - A PHASE-I TRIAL OF PNU-214565, A MONOCLONAL-ANTIBODY STAPHYLOCOCCAL-ENTEROTOXIN A RECOMBINANT FUSION PROTEIN, IN ADVANCED PANCREATIC AND COLORECTAL-CANCER

Purpose: To establish the maximum-tolerated dose (MTD) and; define the toxicities of a single-dose infusion of PNU-214565, a recombinant Esc herichia coli-derived fusion protein of Staphylococcal enterotoxin A ( SEA) and the Fab-fragment of the C242 monoclonal antibody in patients with advanced colorectal and pancreatic carcinomas. To investigate the capability of PNU-214565 to induce a superantigen (SAg) response resu lting in cytokine production and tumor regression. Patients and Method s: Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine women; 18 colorectal, three pancreatic cancers) were treated wit h a single 3-hour infusion of PNU-514565, with doses ranging from 0.01 to 1.5 ng/kg. All patients had prior chemotherapy and a good performa nce status Eastern Cooperative Oncology Group [ECOG] performance statu s [PS] = 0 [n = 10]; PS = 1 [n = 11]), 10 had prior radiation, and 18 had prior surgery. Results: Fever and hypotension were the most common toxicities. Fever of any grade occurred in 16 of 21 patients (76%): f our of 21 (19%) with grade 2 and two of 21 (9.5%) with grade 3. Hypote nsion of any grade occurred in 13 of 21 (62%): four of 21 with grade 2 and one of 21 (5%) with grade 3. Interleukin-2 (IL-2) and tumor necro sis factor alpha (TNF alpha) induction correlated with toxicity. In th e two patients with grade 3 fever, peak IL-2 and TNF alpha levels were 2.9 IU/mL and 165 pg/mL, and 8.3 IU/mL and 245 pg/mL, respectively. T ransient, greater than or equal to 50% decreases in circulating monocy tes were observed in 17 of 21 patients as early as 0.5 hours (median t ime, 2 hours) from the start of infusion, Decreases (mean 33%) in circ ulating lymphocytes were observed in seven of 21 patients. All three p atients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The significance of baseline anti-SEA, human antimouse antibody (HAMA), CA 242-soluble antigen levels, and T-cell receptor variable beta region ( TCR V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-D R) genotypes was assessed as possible predictors of toxicity, All toxi cities were transient and easily managed. No grade 3 toxicity occurred at the higher dose levels. Conclusion: PNU-214565, a SAg-based tumor targeted therapy, is safe when given as a single 3-hour infusion at do ses up to 1.5 ng/kg. The MTD for a single dose was not determined. The safety of a repeated dose schedule is currently under investigation, beginning with doses determined to be safe in this trial. (C) 1997 by American Society of Clinical Oncology.