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

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

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

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.

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

• Platelets > 100,000/mm^3

• Hemoglobin > 10g/dl

• Plasma creatinine of < 1.6mg/dl

• Total bilirubin < 1.5 x the upper limit of normal

• Serum ALT < 1.5 x the upper limit of normal

• Serum AST < 1.5 x the upper limit of normal

• ECOG performance status 0-1

• Women of child-bearing potential and men taking study drug must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation

• Ability to understand, as well as sign the written informed consent document

• If a woman is of child-bearing potential, she must have a negative pregnancy test prior to study entry; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately

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
• Any medical or psychosocial condition that could jeopardize the subject's participation in and compliance to the study
• Participants who are taking any other investigational pharmaceutical agents
• Previous history of sensitivity to erlotinib, Iressa, or Erbitux, such as a rash that is uncontrollable by topical steroids and/or antibiotics