NCT00063895

Completed

Phase 1

A Pharmacogenetic and Pharmacodynamic Study of Erlotinib (OSI-774) Toxicity in Patients With Advanced Solid Tumors

National Cancer Institute (NCI)1 site in 1 country80 target enrollmentApril 2003

Interventionserlotinib hydrochloride pharmacological study pharmacogenomic studies laboratory biomarker analysis

Drugserlotinib hydrochloride

Overview

Phase: Phase 1
Intervention: erlotinib hydrochloride
Conditions: Recurrent Non-small Cell Lung Cancer
Sponsor: National Cancer Institute (NCI)
Enrollment: 80
Locations: 1
Primary Endpoint: Rate of diarrhea and skin rash across the short, medium, and long genotype frequencies of the CA polymorphism
Status: Completed
Last Updated: 13 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This phase I/II trial is studying the side effects of erlotinib and to see how well it works in treating patients with metastatic or unresectable non-small cell lung cancer, ovarian cancer, or squamous cell carcinoma (cancer) of the head and neck. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth

Detailed Description

PRIMARY OBJECTIVES: I. To determine if a significant correlation exists between the length of the CA dinucleotide repeat polymorphism in the EGFR gene and observed toxicity in patients treated with OSI-774. SECONDARY OBJECTIVES: I. To study the pharmacodynamic effects of OSI-774 on EGFR activity and MAP kinase signaling using skin as a surrogate tissue. II. To determine if interindividual variation of OSI-774 pharmacokinetics is related to a previously described CYP3A5 genetic polymorphism. III. To evaluate whether toxicity or inhibition of EGFR phosphorylation correlates with OSI-774 AUC in patients treated with OSI-774. IV. To describe the observed anti-tumor response and toxicities in patients with advanced solid tumors treated with single agent fixed dose of OSI-774. OUTLINE: This is a multicenter study. Patients are stratified according to length of CA dinucleotide repeat polymorphism (short vs medium vs long). Patients receive oral erlotinib on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Registry

clinicaltrials.gov

Start Date

April 2003

End Date

October 2005

Last Updated

13 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

National Cancer Institute (NCI)

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Patients must have histologically or cytologically confirmed metastatic or unresectable non-small cell lung cancer, squamous cell carcinoma of the head and neck, or ovarian cancer
•Eligible patients must have been off previous anticancer therapy including chemotherapy, radiotherapy, biological therapy, or other investigational therapy for at least 4 weeks before study entry (6 weeks if prior therapy included nitrosoureas or mitomycin C)
•ECOG performance status =\< 2 (Karnofsky \>= 60%)
•Life expectancy of greater than 12 weeks
•Leukocytes \>= 3,000/ul
•Absolute neutrophil count \>= 1,500/ul
•Platelets \>= 100,000/ul
•Total bilirubin within normal institutional limits
•Creatinine within normal institutional limits OR creatinine clearance \> 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
•Patients must have measurable or assessable disease

Exclusion Criteria

•Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; patients with prior treatment with small molecule inhibitors of EGFR, including erlotinib and gefitinib, are not eligible for this study
•Patients may not be receiving any other investigational agents
•Patients with uncontrolled brain metastasis; patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 4 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-774
•Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
•Pregnant women are excluded from this study because OSI-774 is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with OSI-774, breastfeeding should be discontinued if the mother is treated with either agent
•HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with OSI-774 or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
•Patients with significant ophthalmologic abnormalities, including: severe dry eye syndrome, kerato-conjunctivitis sicca, Sjogren's syndrome, severe exposure keratopathy, disorders that might increase the risk for epithelium-related complications (e.g. bullous keratopathy, aniridia, severe chemical burns, neutrophilic keratitis); patients with mild forms of any of the above, an asymptomatic history, or a normal ophthalmologic examination may be considered for inclusion at the discretion of the investigator; an ophthalmologic exam is not needed prior to this study unless clinically indicated; patients with treatable conditions (e.g. infectious keratitis/conjunctivitis, allergic conjunctivitis) may be reevaluated for study eligibility after treatment or resolution of the condition; use of contact lenses during the course of this trial may increase the risk of corneal complications and will be strongly discouraged
•Serious, non-healing wound ulcer, or bone fracture
•Major surgical procedure, open biopsy or significant traumatic injury within 14 days prior to Day 1; following such procedures or injuries, wound healing should be evident prior to initiation of therapy

Arms & Interventions

Treatment (erlotinib hydrochloride)

Patients receive oral erlotinib on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: erlotinib hydrochloride

Treatment (erlotinib hydrochloride)

Patients receive oral erlotinib on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: pharmacological study

Treatment (erlotinib hydrochloride)

Patients receive oral erlotinib on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: pharmacogenomic studies

Treatment (erlotinib hydrochloride)

Patients receive oral erlotinib on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: laboratory biomarker analysis

Outcomes

Primary Outcomes

Rate of diarrhea and skin rash across the short, medium, and long genotype frequencies of the CA polymorphism

Time Frame: Week 6

Compared using Armitage's test for a trend in proportions. In the event that the relationship between toxicity and length of the polymorphism is not monotone, a two degree-of-freedom chisquare test will be used in place of the trend test. The number of CA repeats treated as a continuous variable by averaging the number of repeats on each chromosome. Logistic regression analysis will then be performed to model the probability of toxicity as a function of the average length.

Secondary Outcomes

All observed toxicities(Up to 4 years)
Pharmacodynamic effects of erlotinib hydrochloride on EGFR activity and MAP kinase signaling(Week 1)
Observed anti-tumor responses(Up to 4 years)
Erlotinib hydrochloride AUC(Baseline, 0.5, 1, 2, 4, and 6 h after initiation, and pre-treatment days 15 and 29)