Journal of Clinical Oncology, Vol 15, 1994-2007, Copyright © 1997 by American Society of Clinical Oncology
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
BJ Giantonio, RK Alpaugh, J Schultz, C McAleer, DW Newton, B Shannon, Y Guedez, M Kotb, L Vitek, R Persson, PO Gunnarsson, T Kalland, M Dohlsten, B Persson and LM Weiner
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
PURPOSE: To establish the maximum-tolerated dose (MTD) and define the
toxicities of a single-dose infusion of PNU-214565, a recombinant
Escherichia 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 resulting
in cytokine production and tumor regression. PATIENTS AND METHODS:
Twenty-one patients (age range, 39 to 76 years; median, 64; 12 men, nine
women; 18 colorectal, three pancreatic cancers) were treated with a single
3-hour infusion of PNU-214565, with doses ranging from 0.01 to 1.5 ng/kg.
All patients had prior chemotherapy and a good performance status Eastern
Cooperative Oncology Group [ECOG] performance status [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%): four of 21 (19%) with grade 2 and two
of 21 (9.5%) with grade 3. Hypotension 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 necrosis factor alpha (TNF alpha) induction
correlated with toxicity. In the 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. Transient, > or = 50% decreases in circulating
monocytes were observed in 17 of 21 patients as early as 0.5 hours (median
time, 2 hours) from the start of infusion. Decreases (mean 33%) in
circulating lymphocytes were observed in seven of 21 patients. All three
patients with grade 3 toxicity were treated at the 0.5-ng/kg dose. The
significance of baseline anti-SEA, human antimouse antibody (HAMA),
CA242-soluble antigen levels, and T-cell receptor variable beta region (TCR
V beta) subsets and histocompatibility leukocyte antigen-DR (HLA-DR)
genotypes was assessed as possible predictors of toxicity. All toxicities
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 doses 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.
