Individualized patient dosing in phase I clinical trials: The role of Escalation with Overdose Control in PNU-214936

Jonathan D. Cheng, James S. Babb, Corey Langer, Steinar Aamdal, Francisco Robert, Lars Rupert Engelhardt, Olov Fernberg, Joan Schiller, Goran Forsberg, R. Katherine Alpaugh, Louis M. Weiner, André Rogatko

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


Purpose: A patient-specific dose-escalation scheme using a Bayesian model of Escalation with Overdose Control (EWOC) was conducted to establish the maximum tolerated dose (MTD) of PNU-214936 in advanced non-small-cell lung cancer (NSCLC). PNU-214936 is a murine Fab fragment of the monoclonal antibody 5T4 fused to a mutated superantigen staphylococcal enterotoxin A (SEA). Patients and Methods: Seventy-eight patients with NSCLC were treated with an individualized dose of PNU-214936 calculated using EWOC, based on their anti-SEA antibody level, and given as a 3-hour infusion on 4 consecutive days. Results: Fever (82%; grade 3 to 4, 2.6%) and hypotension (57%; grade 3 to 4, 9%) were the most common toxicities. Eight dose-limiting toxicities occurred, as defined as any grade 4 toxicity occurring within the first 5 days. The MTD was defined as a function of pretreatment anti-SEA antibody level. MTD ranged from 103 ng/kg for patients with anti-SEA concentrations ≤ 10 pmol/mL, to 601 ng/kg for patients with anti-SEA concentrations of 91 to 150 pmol/mL. A minor tumor response was demonstrated in five of 66 assessable patients. Conclusion: EWOC determined phase I doses of PNU-214936 that were adjusted for patient anti-SEA antibody level, while safeguarding against overdose. Furthermore, the method permitted the construction of a dosing algorithm that would allow patients in subsequent clinical investigations to be treated with a dose of PNU-214936 that is tailored to their specific tolerance for the agent, as reflected by their pretreatment anti-SEA.

Original languageEnglish (US)
Pages (from-to)602-609
Number of pages8
JournalJournal of Clinical Oncology
Issue number4
StatePublished - 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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