Erlotinib Hydrochloride in Treating Patients With Stage I-III Colorectal Cancer or Adenoma
Primary Purpose
Adenomatous Polyp, Recurrent Colon Cancer, Recurrent Rectal Cancer
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
erlotinib hydrochloride
placebo
laboratory biomarker analysis
Sponsored by
About this trial
This is an interventional prevention trial for Adenomatous Polyp
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
- 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
Sites / Locations
- VA Long Beach Healthcare System
- Chao Family Comprehensive Cancer Center
- University of Illinois at Chicago
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Erlotinib Hydrochloride (25 mg)
Erlotinib Hydrochloride (50 mg)
Erlotinib Hydrochloride (100 mg)
Arm Description
Patients receive 25mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.
Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.
Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.
Outcomes
Primary Outcome Measures
Change in ACF pERK Levels
Quantification will be performed by Western blot analysis. Tested using paired t-test with a two-sided significance level of 0.05.
Secondary Outcome Measures
Change in EGF-inducible Markers - pEGFR in Normal Mucosa
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
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
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
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
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)
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Plasma OSI-420 Concentration (ng/mL)
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Normal Mucosa Erlotinib Concentration (ng/mg)
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Normal Mucosa OSI-420 Concentration (ng/mg)
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
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
Described for each arm using frequencies.
Number of Participants Reported at Least 1 Diarrhea Side Effect During the Study
Described for each arm using frequencies.
Full Information
NCT ID
NCT00754494
First Posted
September 17, 2008
Last Updated
December 22, 2014
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00754494
Brief Title
Erlotinib Hydrochloride in Treating Patients With Stage I-III Colorectal Cancer or Adenoma
Official Title
A Phase IIa Randomized, Double-Blind Trial of Erlotinib in Inhibiting EGF Receptor Signaling in Aberrant Crypt Foci of the Colon
Study Type
Interventional
2. Study Status
Record Verification Date
March 2014
Overall Recruitment Status
Completed
Study Start Date
July 2008 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
September 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenomatous Polyp, Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage I Colon Cancer, Stage I Rectal Cancer, Stage IIA Colon Cancer, Stage IIA Rectal Cancer, Stage IIB Colon Cancer, Stage IIB Rectal Cancer, Stage IIC Colon Cancer, Stage IIC Rectal Cancer, Stage IIIA Colon Cancer, Stage IIIA Rectal Cancer, Stage IIIB Colon Cancer, Stage IIIB Rectal Cancer, Stage IIIC Colon Cancer, Stage IIIC Rectal Cancer
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Erlotinib Hydrochloride (25 mg)
Arm Type
Experimental
Arm Description
Patients receive 25mg of erlotinib hydrochloride PO and one 100 mg of placebo and one 25 mg of placebo PO QD.
Arm Title
Erlotinib Hydrochloride (50 mg)
Arm Type
Experimental
Arm Description
Patients receive 50 mg of erlotinib hydrochloride PO and one 100 mg of placebo PO QD.
Arm Title
Erlotinib Hydrochloride (100 mg)
Arm Type
Experimental
Arm Description
Patients receive 100 mg of erlotinib hydrochloride PO and two 25 mg of placebo PO QD.
Intervention Type
Drug
Intervention Name(s)
erlotinib hydrochloride
Other Intervention Name(s)
CP-358,774, erlotinib, OSI-774
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
placebo
Other Intervention Name(s)
PLCB
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Change in ACF pERK Levels
Description
Quantification will be performed by Western blot analysis. Tested using paired t-test with a two-sided significance level of 0.05.
Time Frame
From baseline to post-treatment (up to 30 days)
Secondary Outcome Measure Information:
Title
Change in EGF-inducible Markers - pEGFR in Normal Mucosa
Description
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.
Time Frame
From baseline to post-treatment (up to 30 days)
Title
Change in EGF-inducible Markers - Total EGFR in Normal Mucosa
Description
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.
Time Frame
From baseline to post-treatment (up to 30 days)
Title
Change in EGF-inducible Markers - pEGFR in ACF
Description
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.
Time Frame
From baseline to post-treatment (up to 30 days)
Title
Change in EGF-inducible Markers - Total EGFR in ACF
Description
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.
Time Frame
From baseline to post-treatment (up to 30 days)
Title
ACF: Normal Mucosa pERK Ratio
Description
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.
Time Frame
Up to day 30
Title
Plasma Erlotinib Concentration (ng/mL)
Description
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Time Frame
Up to day 30
Title
Plasma OSI-420 Concentration (ng/mL)
Description
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Time Frame
Up to day 30
Title
Normal Mucosa Erlotinib Concentration (ng/mg)
Description
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Time Frame
Up to day 30
Title
Normal Mucosa OSI-420 Concentration (ng/mg)
Description
Will be quantified in biopsy samples using appropriate descriptive statistics (means and standard deviations).
Time Frame
Up to day 30
Title
Number of Participants Reported at Least 1 Side Effect During the Study
Description
Described for each arm using frequencies. The onset of adverse events is between randomization date and off-study date.
Time Frame
Up to 9 weeks
Title
Number of Participants Reported at Least 1 Rash Side Effect During the Study
Description
Described for each arm using frequencies.
Time Frame
Up to 9 weeks
Title
Number of Participants Reported at Least 1 Diarrhea Side Effect During the Study
Description
Described for each arm using frequencies.
Time Frame
Up to 9 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Timothy Morgan
Organizational Affiliation
Chao Family Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
VA Long Beach Healthcare System
City
Long Beach
State/Province
California
ZIP/Postal Code
90822
Country
United States
Facility Name
Chao Family Comprehensive Cancer Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of Illinois at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Erlotinib Hydrochloride in Treating Patients With Stage I-III Colorectal Cancer or Adenoma
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