A Phase IIa Randomized, Double-Blind Trial of Erlotinib in Inhibiting EGF Receptor Signaling in Aberrant Crypt Foci of the Colon
Overview
- Phase
- Phase 2
- Intervention
- erlotinib hydrochloride
- Conditions
- Adenomatous Polyp
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 45
- Locations
- 3
- Primary Endpoint
- Change in ACF pERK Levels
- Status
- Completed
- Last Updated
- 11 years ago
Overview
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 Description
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 of study treatment, patients are followed up for 4 to 9 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants with one or more of the following criteria will be eligible to participate:
- •History of Stage I-III colorectal cancer, not treated in the past 6 months with no anticipated treatment in the next 3 months
- •Adenoma ≥ 1 cm in size
- •3 or more adenomas (of any size) removed at one colonoscopy within past 6 years
- •Sessile serrated adenoma ≥ 5 mm in size
- •Adenoma (of any size) with villous features (villous, tubulovillous)
- •Adenoma (of any size) with high grade dysplasia
- •Participants are eligible for randomization into the treatment phase of the trial if they are found to have ≥ 4 ACFs at either baseline colonoscopy or baseline flexible sigmoidoscopy
- •Blood tests at screening which meet the following criteria:
- •WBC \> 3000/mm\^3
Exclusion Criteria
- •History of Inflammatory Bowel Disease (IBD)
- •History of interstitial lung disease or chronic lung disease
- •Smoking within the past 3 months
- •Increased bleeding risk from rectal biopsy (Patients receiving aspirin or plavix can be enrolled)
- •Patients receiving warfarin or coumadin
- •Uncontrollable diarrhea of any cause
- •Patients, including rectal cancer patients, that have received prior radiation to the rectum or pelvis
- •Participants taking a known significant CYP 3A4 inducer or inhibitor; known significant inducers/inhibitors include: amprenavir, aprepitant, atazanavir, carbamazepine, clarithromycin, conivaptan, diltiazem, darunavir/ritonavir, dronedarone, erythromycin, fluconazole, fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, phenytoin, posaconazole, rifampin, ritonavir, St. John's wort, saquinavir, telithromycin, tipranavir/ritonavir, verapamil, voriconazole
- •Women who are pregnant or breast-feeding
- •Active keratoconjunctivitis, or corneal surgery in the past three weeks
Arms & Interventions
Erlotinib Hydrochloride (25 mg)
Patients receive 25mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.
Intervention: erlotinib hydrochloride
Erlotinib Hydrochloride (25 mg)
Patients receive 25mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.
Intervention: placebo
Erlotinib Hydrochloride (25 mg)
Patients receive 25mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.
Intervention: laboratory biomarker analysis
Erlotinib Hydrochloride (50 mg)
Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.
Intervention: erlotinib hydrochloride
Erlotinib Hydrochloride (50 mg)
Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.
Intervention: placebo
Erlotinib Hydrochloride (50 mg)
Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.
Intervention: laboratory biomarker analysis
Erlotinib Hydrochloride (100 mg)
Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.
Intervention: erlotinib hydrochloride
Erlotinib Hydrochloride (100 mg)
Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.
Intervention: placebo
Erlotinib Hydrochloride (100 mg)
Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Change in ACF pERK Levels
Time Frame: From baseline to post-treatment (up to 30 days)
Quantification will be performed by Western blot analysis. Tested using paired t-test with a two-sided significance level of 0.05.
Secondary Outcomes
- Change in EGF-inducible Markers - Total EGFR in Normal Mucosa(From baseline to post-treatment (up to 30 days))
- ACF: Normal Mucosa pERK Ratio(Up to day 30)
- Change in EGF-inducible Markers - pEGFR in ACF(From baseline to post-treatment (up to 30 days))
- Change in EGF-inducible Markers - Total EGFR in ACF(From baseline to post-treatment (up to 30 days))
- Plasma OSI-420 Concentration (ng/mL)(Up to day 30)
- Normal Mucosa Erlotinib Concentration (ng/mg)(Up to day 30)
- Number of Participants Reported at Least 1 Rash Side Effect During the Study(Up to 9 weeks)
- Change in EGF-inducible Markers - pEGFR in Normal Mucosa(From baseline to post-treatment (up to 30 days))
- Number of Participants Reported at Least 1 Diarrhea Side Effect During the Study(Up to 9 weeks)
- Plasma Erlotinib Concentration (ng/mL)(Up to day 30)
- Normal Mucosa OSI-420 Concentration (ng/mg)(Up to day 30)
- Number of Participants Reported at Least 1 Side Effect During the Study(Up to 9 weeks)