Erlotinib Hydrochloride in Preventing Cancer in Patients With Precancerous Lesions of the Lung

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01013831
First received: November 13, 2009
Last updated: February 17, 2015
Last verified: April 2014
  Purpose

This phase I trial studies the side effects and best dose of erlotinib hydrochloride in preventing cancer in patients with precancerous lesions of the lung. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Dysplasia
Metaplasia
Pulmonary Precancerous Condition
Drug: Erlotinib Hydrochloride
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Phase I Study of Erlotinib in Patients With Premalignant Lesions of the Lung

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in the ratio of p-EGFR to total EGFR [ Time Frame: Baseline up to 90 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in the expression of p-Akt [ Time Frame: Baseline up to 90 days ] [ Designated as safety issue: No ]
    Analyzed using an analysis-of-variance (ANOVA) on the change from baseline expression level with a factor for dose (75, 50, 25 or 100). All tests will be two-sided and tested at level alpha=0.05. If the overall comparison is significant, pairwise comparisons will be done using straight Bonferroni adjustments.

  • Change in the expression of p-Erk [ Time Frame: Baseline up to 90 days ] [ Designated as safety issue: No ]
    Analyzed using an ANOVA on the change from baseline expression level with a factor for dose (75, 50, 25 or 100). All tests will be two-sided and tested at level alpha=0.05. If the overall comparison is significant, pairwise comparisons will be done using straight Bonferroni adjustments.

  • Change in the expression of Ki67 [ Time Frame: Baseline up to 90 days ] [ Designated as safety issue: No ]
    Analyzed using an ANOVA on the change from baseline expression level with a factor for dose (75, 50, 25 or 100). All tests will be two-sided and tested at level alpha=0.05. If the overall comparison is significant, pairwise comparisons will be done using straight Bonferroni adjustments.

  • Incidence of toxicities, graded according to Common Toxicity Criteria, version 3.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • PK/PD parameters [ Time Frame: Up to 90 days ] [ Designated as safety issue: No ]
  • Pharmacogenomic profile [ Time Frame: Up to 90 days ] [ Designated as safety issue: No ]

Enrollment: 60
Study Start Date: October 2009
Study Completion Date: June 2013
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prevention (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO QD for 90 days in the absence of disease progression or unacceptable toxicity.
Drug: Erlotinib Hydrochloride
Given PO
Other Name: Cp-358,774
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the lowest dose of erlotinib (erlotinib hydrochloride) that will decrease the ratio of phosphorylated to total epidermal growth factor receptor (EGFR) (phosphorylated EGFR [pEGFR]/EGFR) by at least 20% in subjects with premalignant lesions of the lung. This will be accomplished by implementing a dose de-escalation trial of erlotinib (i.e., 75, 50, and 25 or 100 mg by mouth daily for a 3-month period), and determining the pEGFR/EGFR ratio in premalignant lesions of the lung epithelium by immunohistochemistry. Changes in the pEGFR/EGFR ratio will be assessed by comparing the pre-treatment (baseline) ratio to that of the post-treatment (3 month) ratio, measured in paraffin embedded biopsy specimens.

SECONDARY OBJECTIVES:

I. To determine the effect of erlotinib on the following biomarkers of potential biological relevance in paraffin embedded lung biopsies, p-v-akt murine thymoma viral oncogene homolog 1 (Akt), p-mitogen-activated protein kinase 1 (Erk), and marker of proliferation Ki-67 (Ki67).

II. To characterize the toxicity profile of erlotinib in this cohort of subjects.

III. To analyze and model erlotinib's pharmacokinetic/pharmacodynamic (PK/PD) profile. Serial blood samples will be drawn at the beginning and at the end of erlotinib treatment, and pharmacokinetic parameters will be determined. The status of EGFR genotype (and that of others genes linked to erlotinib PK/PD) clinical toxicity, and dose will be examined as possible other influential covariates by comparing them to experimentally measured PK profiles, and PD profiles (in particular, the pEGFR/EGFR ratio). The goal of these studies will be to determine the optimal biologic concentration (OBC) of Erlotinib that is associated with the lowest toxicity and highest effect, for a given subject's pharmacogenomic profile.

OUTLINE:

Patients receive erlotinib hydrochloride orally (PO) once daily (QD) for 90 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

  Eligibility

Ages Eligible for Study:   40 Years to 79 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of a premalignant lung lesion (metaplasia or dysplasia) on autofluorescent bronchoscopy (AFB) within 1 month
  • Participants must have a >= 10 pack year lifetime smoking history; current and former smokers only are eligible for this trial
  • No contraindications for treatment with erlotinib or additional bronchoscopies
  • Absolute neutrophil count (ANC) of >= 1.5 x 10^9/L
  • Platelet count of >= 100 x 10^9/L
  • Creatinine level of less than 1.5 mg/dL
  • Total bilirubin =< 2.0 mg/dl
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN)
  • Alkaline phosphatase =< 2.5 x ULN
  • Must meet Eastern Cooperative Oncology Group (ECOG) performance status criteria of 0-1
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) throughout the duration of the study and for 1 month following cessation of study drug; females must begin adequate contraception immediately following screening pregnancy test; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately; if she is pregnant, she will be immediately withdrawn from the study
  • Ability to understand and the willingness to sign a written institutional review board (IRB) approved informed consent document

Exclusion Criteria:

  • Subjects with life-threatening medical conditions that would preclude the treatment intervention and bronchoscopy, including, but not limited to, unstable pulmonary function, acute cardiac failure, which is unstable despite medication use; uncontrolled hypertension; uncontrolled diabetes mellitus; unstable coronary artery disease; acute or chronic liver disease, ongoing or active infection; or psychiatric illness/social situations that would limit compliance with study requirements
  • Participants with evidence of an active cancer or carcinoma in situ, are not eligible
  • Participants currently taking medications that induce or inhibit the cytochrome P450, family 3, subfamily A, polypeptide 4-7 (CYP3A4-7) enzymes
  • Participants may not be receiving any other investigational agents within 3 months
  • Participants taking warfarin
  • History of allergic reactions attributed to erlotinib, a known hypersensitivity to erlotinib, or agents with a similar chemical or biological composition to erlotinib
  • Women who are pregnant or lactating are excluded from the study because based on the proposed mechanism of tyrosine kinase inhibition of erlotinib; erlotinib should be assumed to cause fetal harm when administered to a pregnant woman; there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with erlotinib
  • History of interstitial lung disease (ILD)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01013831

Locations
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
United States, Massachusetts
Boston University School of Medicine
Boston, Massachusetts, United States, 02118
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Investigators
Principal Investigator: Seema Khan Northwestern University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01013831     History of Changes
Other Study ID Numbers: NCI-2013-00750, NCI-2013-00750, RPCI-I-121507, NU-NWU08-11-01, STU00012618, NCI 08-11-01, NWU08-11-01, P30CA060553, N01CN35157
Study First Received: November 13, 2009
Last Updated: February 17, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Metaplasia
Precancerous Conditions
Neoplasms
Pathologic Processes
Erlotinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on May 29, 2015