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Conrad Notes
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S.E. Nielsen, MD, Copenhagen University Hospital, Denmark, studied the safety and potential efficacy of a novel fusion protein (NFP) in 20 cancer patients. Activation of T-cells by NFP leads to cytokines toxic to tumor cells. Patient baseline antibody titers to a portion of NFP correlated with induced systemic concentrations of interleukin (IL)-2 and tumor necrosis factor (TNF) beta. Additional studies are planned with NFP also known as PNU-214565.

T-cell activation by NFP Genetic fusion of superantigen staphylococcal enterotoxin A (SEA) with the Fab fragment of the monoclonal antibody C242 produces NFP. The protein targets gastrointestinal adenocarcinomas. Activated T-cells release cytokines such as IL-2, IL-6, IL-10, gamma interferon and TNF -- all toxic to tumor cells.

Demography of study patients Eleven males and 9 females having a median age of 60.5 years entered this Phase I dose-ranging safety study. Primary tumor sites consisted of 11 colorectum, 5 pancreas, and 4 others of gastrointestinal origin. Prior therapy included surgery, 17; chemotherapy, 2; and radiotherapy, 2. At baseline, all patients showed a WHO performance status of 0 or 1.

Dose-ranging safety protocol The study used an intravenous infusion of NFP at 2 mL/hr for 3 hours on 4 consecutive days. Initially, 2 or 3 patients per group received doses of 0.5, 1.5, or 4.0 ng/kg. Later, the dose was 2.75 ng/kg for 12 patients. Vital signs, routine clinical laboratory tests, and cytokine estimates were performed during treatment with NFP. Patients left the hospital on Day 5 and returned as outpatients for follow-up on Day 7 and 28.

Toxicity with NFP All patients in the 0.5 and 1.5 ng/kg groups experienced mild adverse reactions. The maximally tolerated dose (MTD) was 2.75 ng/kg. At this dose, only 1 of 12 patients developed dose-limiting toxicity (DLT) of grade 4 hypotension which was easily managed with dopamine, according to Nielsen.

The 4.0 ng/kg dose of NFP led to DLT in both patients in this group. One patient developed transient grade 4 vomiting, thrombocytopenia, leukopenia, hyperbilirubinemia, and acute renal failure requiring dialysis. The other patient showed a grade 4 hepatotoxicity and thrombocytopenia which lasted 5 days.

Predicting a safe dose of NFP Nielsen found a significant correlation between baseline anti-SEA antibody titers and systemic cytokines such as IL-1 and TNF beta following NFP infusions (p<0.05). Is it possible to assign a safe dose of NFP that will produce an increase in cytokines? Additional data from Phase I studies are needed to define the MTD of the fusion protein and refine the predictive value of baseline anti-SEA titers.

Investigator conclusions NFP was generally well-tolerated with transient toxicities. The estimated MTD was 2.75 ng/kg following repeated infusions. Pretreatment concentrations of anti-SEA antibodies correlated with NFP dosage, systemic cytokine release, and dose-limiting toxicity

For professional correspondence, please contact Dr. Nielsen by Fax at: 45 35 456 966

Eugene A. Conrad

Presented at The European Cancer Conference (ECCO 9), September 14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
Send comments to: ConradNote@aol.com

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