Clinical Trial: Erlotinib Hydrochloride in Treating Patients With Stage I-III Colorectal Cancer or Adenoma

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase IIa Randomized, Double-Blind Trial of Erlotinib in Inhibiting EGF Receptor Signaling in Aberrant Crypt Foci of the Colon

Brief Summary: This randomized phase II trial is studying how well erlotinib hydrochloride works in treating patients with stage I-III colorectal cancer or adenoma. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Erlotinib hydrochloride may also stop tumors from growing or coming back

Detailed Summary:

PRIMARY OBJECTIVES:

I. To test the hypothesis that erlotinib (erlotinib hydrochloride) doses as low as 25 mg will decrease aberrant crypt foci (ACF) phosphorylated extracellular signal-regulated kinases (pERK) levels from baseline (pre) to post erlotinib treatment.

SECONDARY OBJECTIVES:

I. To test the hypothesis that additional epidermal growth factor (EGF) inducible biomarkers will decrease from baseline (pre) to post treatment with erlotinib 25 mg, 50 mg or 100 mg orally (PO) once daily (QD) therapy.

II. To determine the mean decrease from baseline of the ACF: normal mucosa pERK ratio pre and post 8-30 days of erlotinib.

III. To determine erlotinib concentration in plasma and colorectal tissue at 25 mg, 50 mg and 100 mg doses after 8-30 days of therapy.

IV. To determine the incidence of rash, diarrhea and other side effects of low dose erlotinib.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.

ARM II: Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.

ARM III: Patients receive 25 mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.

In all arms, treatment continues for 8-30 days in the absence of disease progression or unacceptable toxicity.

After completion
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome: Change in ACF pERK Levels [ Time Frame: From baseline to post-treatment (up to 30 days) ]

Original Primary Outcome: Comparison of decrease in aberrant crypt foci (ACF) pERK levels

Current Secondary Outcome:

• Change in EGF-inducible Markers - pEGFR in Normal Mucosa [ Time Frame: From baseline to post-treatment (up to 30 days) ]
  pEGFR expression levels were quantified by immunoblotting and calculated as the ratio of the pEGFR signals to reference signals. A log-transformation of pEGFR was utilized in primary analyses. The general linear model was used to estimate and compare the relative change in median pEGFR with adjustment for actin as a normalizing factor. The estimated relative change (post:pre) in the median, corresponding 95% confidence interval, and p-value for testing the null hypothesis of equal medians comparing pre- and post-measurements were reported.
• Change in EGF-inducible Markers - Total EGFR in Normal Mucosa [ Time Frame: From baseline to post-treatment (up to 30 days) ]
  Total EGFR expression levels were quantified by immunoblotting and calculated as the ratio of the total EGFR signals to reference signals. A log-transformation of total EGFR was utilized in primary analyses. The general linear model was used to estimate and compare the relative change in median total EGFR with adjustment for actin as a normalizing factor. The estimated relative change (post:pre) in the median, corresponding 95% confidence interval, and p-value for testing the null hypothesis of equal medians comparing pre- and post-measurements were reported.
• Change in EGF-inducible Markers - pEGFR in ACF [ Time Frame: From baseline to post-treatment (up to 30 days) ]
  pEGFR expression levels were quantified by immunoblotting and calculated as the ratio of the pEGFR signals to reference signals. A log-transformation of pEGFR was utilized in primary analyses. The general linear model was used to estimate and compare the relative change in median total EGFR with adjustment for actin as a normalizing factor. The estimated relative change (post:pre) in the median, corresponding 95% confidence interval, and p-value for testing the null hypothesis of equal medians comparing pre- and post-measurements were reported.
• Change in EGF-inducible Markers - Total EGFR in ACF [ Time Frame: From baseline to post-treatment (up to 30 days) ]
  Total EGFR expression levels were quantified by immunoblotting and calculated as the ratio of the total EGFR signals to reference signals. A log-transformation of total EGFR was utilized in primary analyses. The general linear model was used to estimate and compare the relative change in median total EGFR with adjustment for actin as a normalizing factor. The estimated relative change (post:pre) in the median, corresponding 95% confidence interval, and p-value for testing the null hypothesis of equal medians comparing pre- and post-measurements were reported.
• ACF: Normal Mucosa pERK Ratio [ Time Frame: Up to day 30 ]
  Quantification will be performed by Western blot analysis. Tested using analysis of variance with subsequent pairwise comparisons using the Tukey method to adjust for multiple comparisons.
• Plasma Erlotinib Concentration (ng/mL) [ Time Frame: Up to day 30 ]
  Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
• Plasma OSI-420 Concentration (ng/mL) [ Time Frame: Up to day 30 ]
  Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
• Normal Mucosa Erlotinib Concentration (ng/mg) [ Time Frame: Up to day 30 ]
  Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
• Normal Mucosa OSI-420 Concentration (ng/mg) [ Time Frame: Up to day 30 ]
  Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
• Number of Participants Reported at Least 1 Side Effect During the Study [ Time Frame: Up to 9 weeks ]
  Described for each arm using frequencies. The onset of adverse events is between randomization date and off-study date.
• Number of Participants Reported at Least 1 Rash Side Effect During the Study [ Time Frame: Up to 9 weeks ]
  Described for each arm using frequencies.
• Number of Participants Reported at Least 1 Diarrhea Side Effect During the Study [ Time Frame: Up to 9 weeks ]
  Described for each arm using frequencies.

Original Secondary Outcome:

• Change over time for EGF-inducible markers (i.e., pERBB2, pAKT, total EGFR, Ki-67, and cyclin D1)
• Pre- vs post-treatment ACF/normal mucosa pERK ratio
• Erlotinib hydrochloride concentration in plasma and colorectal tissue
• Treatment-related side effects

Dates:
Date Received: September 17, 2008
Date Started: July 2008
Date Completion:
Last Updated: December 22, 2014
Last Verified: March 2014