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

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Abstract

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
Volume22
Issue number4
DOIs
StatePublished - 2004

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Clinical Trials, Phase I
Maximum Tolerated Dose
Non-Small Cell Lung Carcinoma
Antibodies
Superantigens
Immunoglobulin Fab Fragments
Staphylococcal enterotoxin A
Hypotension
Fever
Monoclonal Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cheng, J. D., Babb, J. S., Langer, C., Aamdal, S., Robert, F., Engelhardt, L. R., ... Rogatko, A. (2004). Individualized patient dosing in phase I clinical trials: The role of Escalation with Overdose Control in PNU-214936. Journal of Clinical Oncology, 22(4), 602-609. https://doi.org/10.1200/JCO.2004.12.034

Individualized patient dosing in phase I clinical trials : The role of Escalation with Overdose Control in PNU-214936. / Cheng, Jonathan D.; Babb, James S.; Langer, Corey; Aamdal, Steinar; Robert, Francisco; Engelhardt, Lars Rupert; Fernberg, Olov; Schiller, Joan; Forsberg, Goran; Katherine Alpaugh, R.; Weiner, Louis M.; Rogatko, André.

In: Journal of Clinical Oncology, Vol. 22, No. 4, 2004, p. 602-609.

Research output: Contribution to journalArticle

Cheng, JD, Babb, JS, Langer, C, Aamdal, S, Robert, F, Engelhardt, LR, Fernberg, O, Schiller, J, Forsberg, G, Katherine Alpaugh, R, Weiner, LM & Rogatko, A 2004, 'Individualized patient dosing in phase I clinical trials: The role of Escalation with Overdose Control in PNU-214936', Journal of Clinical Oncology, vol. 22, no. 4, pp. 602-609. https://doi.org/10.1200/JCO.2004.12.034
Cheng, Jonathan D. ; Babb, James S. ; Langer, Corey ; Aamdal, Steinar ; Robert, Francisco ; Engelhardt, Lars Rupert ; Fernberg, Olov ; Schiller, Joan ; Forsberg, Goran ; Katherine Alpaugh, R. ; Weiner, Louis M. ; Rogatko, André. / Individualized patient dosing in phase I clinical trials : The role of Escalation with Overdose Control in PNU-214936. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 4. pp. 602-609.
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abstract = "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.",
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AU - Robert, Francisco

AU - Engelhardt, Lars Rupert

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AU - Forsberg, Goran

AU - Katherine Alpaugh, R.

AU - Weiner, Louis M.

AU - Rogatko, André

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N2 - 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.

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