A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma

Kristopher J. Kimball, T. Michael Numnum, Tyler O. Kirby, William C. Zamboni, Jacob M. Estes, Mack N. Barnes, Daniela Matei, Kevin M. Koch, Ronald D. Alvarez

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Abstract

Objectives: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. Methods: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. Results: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n = 1), and non-dose limiting G3 neutropenia (n = 3). Of the 11 patients who received ≥ 1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. Conclusions: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

Original languageEnglish
Pages (from-to)95-101
Number of pages7
JournalGynecologic Oncology
Volume111
Issue number1
DOIs
StatePublished - Oct 2008

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Carboplatin
Platinum
Carcinoma
Pharmacokinetics
Neutropenia
Maximum Tolerated Dose
lapatinib
Area Under Curve
Therapeutics
Recurrence
Pharmaceutical Preparations

Keywords

  • EGFR inhibitor
  • HER2 inhibitor
  • Lapatinib
  • Ovarian cancer

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Kimball, K. J., Numnum, T. M., Kirby, T. O., Zamboni, W. C., Estes, J. M., Barnes, M. N., ... Alvarez, R. D. (2008). A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma. Gynecologic Oncology, 111(1), 95-101. https://doi.org/10.1016/j.ygyno.2008.07.001

A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma. / Kimball, Kristopher J.; Numnum, T. Michael; Kirby, Tyler O.; Zamboni, William C.; Estes, Jacob M.; Barnes, Mack N.; Matei, Daniela; Koch, Kevin M.; Alvarez, Ronald D.

In: Gynecologic Oncology, Vol. 111, No. 1, 10.2008, p. 95-101.

Research output: Contribution to journalArticle

Kimball, KJ, Numnum, TM, Kirby, TO, Zamboni, WC, Estes, JM, Barnes, MN, Matei, D, Koch, KM & Alvarez, RD 2008, 'A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma', Gynecologic Oncology, vol. 111, no. 1, pp. 95-101. https://doi.org/10.1016/j.ygyno.2008.07.001
Kimball, Kristopher J. ; Numnum, T. Michael ; Kirby, Tyler O. ; Zamboni, William C. ; Estes, Jacob M. ; Barnes, Mack N. ; Matei, Daniela ; Koch, Kevin M. ; Alvarez, Ronald D. / A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma. In: Gynecologic Oncology. 2008 ; Vol. 111, No. 1. pp. 95-101.
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abstract = "Objectives: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. Methods: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. Results: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n = 1), and non-dose limiting G3 neutropenia (n = 3). Of the 11 patients who received ≥ 1 course of therapy, 3 (27{\%}) had a partial response, and 3 (27{\%}) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. Conclusions: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.",
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AU - Numnum, T. Michael

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AU - Zamboni, William C.

AU - Estes, Jacob M.

AU - Barnes, Mack N.

AU - Matei, Daniela

AU - Koch, Kevin M.

AU - Alvarez, Ronald D.

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N2 - Objectives: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. Methods: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. Results: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n = 1), and non-dose limiting G3 neutropenia (n = 3). Of the 11 patients who received ≥ 1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. Conclusions: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

AB - Objectives: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. Methods: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. Results: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n = 1), and non-dose limiting G3 neutropenia (n = 3). Of the 11 patients who received ≥ 1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. Conclusions: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

KW - EGFR inhibitor

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