Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma

Mace L. Rothenberg, Bonnie LaFleur, Donna E. Levy, Mary Kay Washington, Sherry L. Morgan-Meadows, Ramesk K Ramanathan, Jordan D. Berlin, Al B. Benson, Robert J. Coffey

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Purpose: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFα). Patients and Methods: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. Results: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. Conclusion: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

Original languageEnglish (US)
Pages (from-to)9265-9274
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number36
DOIs
StatePublished - 2005
Externally publishedYes

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Phase II Clinical Trials
Adenocarcinoma
Epidermal Growth Factor Receptor
Disease-Free Survival
Colorectal Neoplasms
Biopsy
Neoplasms
Transforming Growth Factor alpha
Survival
gefitinib
Proxy
Exanthema
Fatigue
Diarrhea
Phosphotransferases
Survival Rate
Cell Proliferation
Clinical Trials
Therapeutics
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. / Rothenberg, Mace L.; LaFleur, Bonnie; Levy, Donna E.; Washington, Mary Kay; Morgan-Meadows, Sherry L.; Ramanathan, Ramesk K; Berlin, Jordan D.; Benson, Al B.; Coffey, Robert J.

In: Journal of Clinical Oncology, Vol. 23, No. 36, 2005, p. 9265-9274.

Research output: Contribution to journalArticle

Rothenberg, Mace L. ; LaFleur, Bonnie ; Levy, Donna E. ; Washington, Mary Kay ; Morgan-Meadows, Sherry L. ; Ramanathan, Ramesk K ; Berlin, Jordan D. ; Benson, Al B. ; Coffey, Robert J. / Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 36. pp. 9265-9274.
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T1 - Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma

AU - Rothenberg, Mace L.

AU - LaFleur, Bonnie

AU - Levy, Donna E.

AU - Washington, Mary Kay

AU - Morgan-Meadows, Sherry L.

AU - Ramanathan, Ramesk K

AU - Berlin, Jordan D.

AU - Benson, Al B.

AU - Coffey, Robert J.

PY - 2005

Y1 - 2005

N2 - Purpose: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFα). Patients and Methods: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. Results: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. Conclusion: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

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