Phase I/II Study of Chemoprevention With EGFR and COX-2 Inhibitor
Study Details
Study Description
Brief Summary
Evaluate effect on cells and patient response to study medications, assess side effects of these medications, and evaluate chemicals in cells that may tell how the drug works, before, and after receiving the study medications.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
The purpose of this study is to evaluate the effect on cells and patient response to study medications, assess the side effects of these medications, and to evaluate chemicals in the cells that may tell how the drug works, before, and after receiving the study medications.
Approximately 61 patients will participate at Emory Winship Cancer Institute and Emory Crawford W. Long Hospital in Atlanta, Georgia.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Erlotinib & Celecoxib
|
Drug: Erlotinib & Celecoxib
Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion.
Celecoxib given 400 mg orally BID continuously for 6 months.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Dose Escalation and Toxicity: Toxicities Including Grades 1 to 4 [12 months from time of enrollment]
Participants received a fixed dose of celecoxib 400 mg orally BID continuously for 6 months. Erlotinib was dose escalated at 3 dose levels of 50, 75, and 100 mg orally every day for 6 months. Dose escalation followed a standard 3+3 escalation design.
- Clinical Outcome: Documented Progression [12 months from time of enrollment]
Response evaluation was based on pathologic examination of the degree of dysplasia observed and recorded by an expert head and neck pathologist. Pathologic complete response was defined as complete disappearance of dysplasia from the epithelium. Pathologic partial response was defined as improvement of dysplasia by at least one degree (i.e., severe dysplasia becomes moderate dysplasia). Pathologic minor response or stable disease was defined as minor focal improvement without change of degree of dysplasia (i.e., focal improvement from moderate to mild dysplasia with still moderate dysplasia overall) or no pathologic changes after treatment. Pathologic progressive disease was defined as worsening by at least one degree of dysplasia (i.e., mild to moderate dysplasia) or development of invasive cancer on or following treatment.
- Clinical Outcome: Progression to a Higher-grade Dysplasia or Carcinoma [Up to 55 months from initiation of therapy. Median duration of follow-up was 36 months.]
Response evaluation was based on pathologic examination of the degree of dysplasia observed and recorded by an expert head and neck pathologist. Pathologic complete response was defined as complete disappearance of dysplasia from the epithelium. Pathologic partial response was defined as improvement of dysplasia by at least one degree (i.e., severe dysplasia becomes moderate dysplasia). Pathologic minor response or stable disease was defined as minor focal improvement without change of degree of dysplasia (i.e., focal improvement from moderate to mild dysplasia with still moderate dysplasia overall) or no pathologic changes after treatment. Pathologic progressive disease was defined as worsening by at least one degree of dysplasia (i.e., mild to moderate dysplasia) or development of invasive cancer on or following treatment.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participants must have premalignant lesions.
-
Lesion sites include oral cavity, oropharynx, and larynx.
-
Must have at least a >20 pack-year history of smoking.
-
Must have a Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status of 0-1.
-
Participants must be 18 years of age or older.
-
No contraindications for laryngoscopy and biopsy.
-
Adequate liver function.
-
Must have hemoglobin and hematocrit levels at or above the lower limit of the normal range.
-
Participants must have prothrombin time (PT)/partial thromboplastin time (PTT) levels at or above the lower limit of the normal range.
-
Women of child-bearing potential must have a negative serum pregnancy test within 72 hours of receiving treatment.
-
Must be able to swallow the oral dose of erlotinib and celecoxib.
-
Participants must be disease free.
-
Final eligibility will be determined by the health professionals conducting the trial.
Exclusion Criteria:
-
Participants with acute intercurrent illness or those who had surgery within the preceding 4 weeks unless they have fully recovered.
-
History of previous malignancies unless the cancer was stage I or II and rendered free of disease more than 1 year.
-
Pregnant or breast feeding.
-
Not practicing adequate contraception if the participants are of child bearing potential.
-
Female patients who have a positive pregnancy test.
-
History or recent myocardial infarction.
-
Hypertension not adequately controlled by medication.
-
Documented history of coagulopathy.
-
Documented history of congestive heart failure (CHF) greater than New York Heart Association (NYHA) Grade II.
-
Participants who were taking COX-2 inhibitors or EGFR tyrosine kinase inhibitors within 3 months of study entry.
-
Documented history or interstitial lung disease.
-
Known connective tissue disease.
-
History of nonsteroidal antiinflammatory drug (NSAID)-induced ulcers or those who are at risk for a GI ulcer.
-
Participated in a clinical trial of an investigational drug within 12 months prior to enrollment.
-
Final eligibility will be determined by the health professionals conducting the trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University Winship Cancer Institute | Atlanta | Georgia | United States | 30322 |
Sponsors and Collaborators
- Emory University
- National Institutes of Health (NIH)
Investigators
- Principal Investigator: Dong Shin, MD, Emory University Winship Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
- IRB00024922
Study Results
Participant Flow
| Recruitment Details | Between October 24, 2006, and June 28, 2012, 36 subjects with documented premalignant lesions, including mild (mild-D), moderate, or severe oral leukoplakia, and carcinoma in situ (CIS) were screened. Lesion sites included oral cavity oropharynx, and the larynx. |
|---|---|
| Pre-assignment Detail | Seventeen subjects were enrolled on the study, 3 of whom withdrew consent (one male of 69 years of age, and two females of 43 and 42 years of age). Two patients who signed informed consent were deemed to be screen failures, one secondary to prior history of oral squamous cell carcinoma and the other secondary to a history of cardiac arrhythmias. |
| Arm/Group Title | Erlotinib & Celecoxib |
|---|---|
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. |
| Period Title: Overall Study | |
| STARTED | 12 |
| COMPLETED | 7 |
| NOT COMPLETED | 5 |
Baseline Characteristics
| Arm/Group Title | Erlotinib & Celecoxib |
|---|---|
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. |
| Overall Participants | 12 |
| Age, Customized (participants) [Number] | |
| 40-49 years old |
4
33.3%
|
| 50-59 years old |
2
16.7%
|
| 60-69 years old |
4
33.3%
|
| 70-79 years old |
1
8.3%
|
| 80-89 years old |
1
8.3%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
8
66.7%
|
| Male |
4
33.3%
|
Outcome Measures
| Title | Dose Escalation and Toxicity: Toxicities Including Grades 1 to 4 |
|---|---|
| Description | Participants received a fixed dose of celecoxib 400 mg orally BID continuously for 6 months. Erlotinib was dose escalated at 3 dose levels of 50, 75, and 100 mg orally every day for 6 months. Dose escalation followed a standard 3+3 escalation design. |
| Time Frame | 12 months from time of enrollment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib & Celecoxib |
|---|---|
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. |
| Measure Participants | 7 |
| Abdominal cramping, Grade 1 |
2
16.7%
|
| Alopecia, Grade 1 |
2
16.7%
|
| Anemia, Grade 1 |
2
16.7%
|
| Anemia, Grade 2 |
1
8.3%
|
| Anxiety, Grade 1 |
2
16.7%
|
| Decreased protein, Grade 1 |
2
16.7%
|
| Leukopenia, Grade 1 |
1
8.3%
|
| Leukopenia, Grade 2 |
1
8.3%
|
| Depression, Grade 1 |
3
25%
|
| Diarrhea, Grade 1 |
5
41.7%
|
| Dry eyes, Grade 1 |
4
33.3%
|
| Dry skin, Grade 1 |
6
50%
|
| Elevated LDH, Grade 1 |
3
25%
|
| Elevated serum creatinine, Grade 1 |
4
33.3%
|
| Elevated serum creatinine, Grade 2 |
1
8.3%
|
| Elevated alkaline phosphatase, Grade 1 |
3
25%
|
| Elevated ALT, Grade 1 |
5
41.7%
|
| Elevated AST, Grade 4 |
4
33.3%
|
| Fatigue, Grade 1 |
6
50%
|
| Hyperbilirubinemia, Grade 1 |
2
16.7%
|
| Hypercholesterolemia, Grade 1 |
2
16.7%
|
| Hyperglycemia, Grade 1 |
7
58.3%
|
| Hyperglycemia, Grade 2 |
2
16.7%
|
| Hypoalbuminemia, Grade 1 |
3
25%
|
| Hypoalbuminemia, Grade 2 |
1
8.3%
|
| Hypocalcemia, Grade 1 |
4
33.3%
|
| Hypoglycemia, Grade 1 |
1
8.3%
|
| Hypoglycemia, Grade 2 |
1
8.3%
|
| Hypokalemia, Grade 1 |
2
16.7%
|
| Hyponatremia, Grade 1 |
3
25%
|
| Mouth sores, Grade 1 |
9
75%
|
| Mouth sores, Grade 2 |
3
25%
|
| Mucositis, Grade 1 |
3
25%
|
| Mucositis, Grade 3 |
1
8.3%
|
| Nausea, Grade 1 |
4
33.3%
|
| Neuropathy, Grade 1 |
3
25%
|
| Pruritis, Grade 1 |
2
16.7%
|
| Rash, Grade 1 |
8
66.7%
|
| Rash, Grade 3 |
2
16.7%
|
| Shortness of breath, Grade 1 |
3
25%
|
| Strep throat, Grade 2 |
1
8.3%
|
| Urosepsis, Grade 3 |
1
8.3%
|
| Vomiting, Grade 1 |
2
16.7%
|
| Title | Clinical Outcome: Documented Progression |
|---|---|
| Description | Response evaluation was based on pathologic examination of the degree of dysplasia observed and recorded by an expert head and neck pathologist. Pathologic complete response was defined as complete disappearance of dysplasia from the epithelium. Pathologic partial response was defined as improvement of dysplasia by at least one degree (i.e., severe dysplasia becomes moderate dysplasia). Pathologic minor response or stable disease was defined as minor focal improvement without change of degree of dysplasia (i.e., focal improvement from moderate to mild dysplasia with still moderate dysplasia overall) or no pathologic changes after treatment. Pathologic progressive disease was defined as worsening by at least one degree of dysplasia (i.e., mild to moderate dysplasia) or development of invasive cancer on or following treatment. |
| Time Frame | 12 months from time of enrollment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib & Celecoxib |
|---|---|
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. |
| Measure Participants | 7 |
| Complete remission (CR) |
3
25%
|
| Partial remission (PR) |
1
8.3%
|
| Progressive disease (PD) |
1
8.3%
|
| Stable disease (SDi) |
2
16.7%
|
| Title | Clinical Outcome: Progression to a Higher-grade Dysplasia or Carcinoma |
|---|---|
| Description | Response evaluation was based on pathologic examination of the degree of dysplasia observed and recorded by an expert head and neck pathologist. Pathologic complete response was defined as complete disappearance of dysplasia from the epithelium. Pathologic partial response was defined as improvement of dysplasia by at least one degree (i.e., severe dysplasia becomes moderate dysplasia). Pathologic minor response or stable disease was defined as minor focal improvement without change of degree of dysplasia (i.e., focal improvement from moderate to mild dysplasia with still moderate dysplasia overall) or no pathologic changes after treatment. Pathologic progressive disease was defined as worsening by at least one degree of dysplasia (i.e., mild to moderate dysplasia) or development of invasive cancer on or following treatment. |
| Time Frame | Up to 55 months from initiation of therapy. Median duration of follow-up was 36 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Erlotinib & Celecoxib |
|---|---|
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. |
| Measure Participants | 7 |
| Stage I invasive carcinoma |
1
8.3%
|
| Stage II oral cavity carcinoma |
1
8.3%
|
| Invasive squamous cell carcinoma |
1
8.3%
|
| Recurrent moderate dysplasia |
1
8.3%
|
| Recurrent severe dysplasia |
1
8.3%
|
| Recurrent high-grade dysplasia |
1
8.3%
|
| Complete remission |
1
8.3%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Erlotinib & Celecoxib | |
| Arm/Group Description | Erlotinib & Celecoxib: Erlotinib given orally, once daily (dose escalation from 50 mg, 75 mg, or 100 mg) continuously for 6 months in the phase I portion. Celecoxib given 400 mg orally BID continuously for 6 months. | |
All Cause Mortality |
||
| Erlotinib & Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Erlotinib & Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | 2/12 (16.7%) | |
| Gastrointestinal disorders | ||
| Mucositis (Grade 3) | 1/12 (8.3%) | |
| Infections and infestations | ||
| Urosepsis (Grade 3) | 1/12 (8.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash (Grade 3) | 1/12 (8.3%) | |
Other (Not Including Serious) Adverse Events |
||
| Erlotinib & Celecoxib | ||
| Affected / at Risk (%) | # Events | |
| Total | 12/12 (100%) | |
| Blood and lymphatic system disorders | ||
| Anemia (Grade 1) | 2/12 (16.7%) | |
| Anemia (Grade 2) | 1/12 (8.3%) | |
| Decreased protein (Grade 1) | 2/12 (16.7%) | |
| Elevated Lactate Dehydrogenase (Grade 1) | 3/12 (25%) | |
| Elevated Alkaline Phosphatase (Grade 1) | 3/12 (25%) | |
| Elevated Alanine Aminotransferase (Grade 1) | 5/12 (41.7%) | |
| Elevated Aspartate Aminotransferase (Grade 1) | 4/12 (33.3%) | |
| Hyperbilirubinemia (Grade 1) | 2/12 (16.7%) | |
| Hypercholesterolemia (Grade 2) | 2/12 (16.7%) | |
| Hyperglycemia (Grade 1) | 7/12 (58.3%) | |
| Hyperglycemia (Grade 2) | 2/12 (16.7%) | |
| Hypoalbuminemia (Grade 1) | 3/12 (25%) | |
| Hypoalbuminemia (Grade 2) | 1/12 (8.3%) | |
| Hypocalcemia (Grade 1) | 4/12 (33.3%) | |
| Hypoglycemia (Grade 1) | 1/12 (8.3%) | |
| Hypoglycemia (Grade 2) | 1/12 (8.3%) | |
| Hypokalemia (Grade 1) | 2/12 (16.7%) | |
| Hyponatremia (Grade 1) | 3/12 (25%) | |
| Eye disorders | ||
| Dry Eyes (Grade 1) | 4/12 (33.3%) | |
| Gastrointestinal disorders | ||
| Abdominal cramping (Grade 1) | 2/12 (16.7%) | |
| Diarrhea (Grade 1) | 5/12 (41.7%) | |
| Mucositis (Grade 1) | 3/12 (25%) | |
| Vomiting (Grade 1) | 2/12 (16.7%) | |
| General disorders | ||
| Fatigue (Grade 1) | 6/12 (50%) | |
| Nausea (Grade 1) | 4/12 (33.3%) | |
| Shortness of Breath (Grade 1) | 3/12 (25%) | |
| Immune system disorders | ||
| Leukopenia (Grade 1) | 1/12 (8.3%) | |
| Leukopenia (Grade 2) | 1/12 (8.3%) | |
| Infections and infestations | ||
| Strep Throat (Grade 2) | 1/12 (8.3%) | |
| Nervous system disorders | ||
| Neuropathy (Grade 1) | 3/12 (25%) | |
| Psychiatric disorders | ||
| Anxiety (Grade 1) | 2/12 (16.7%) | |
| Depression (Grade 1) | 3/12 (25%) | |
| Renal and urinary disorders | ||
| Alopecia (Grade 1) | 2/12 (16.7%) | |
| Elevated Serum Creatinine (Grade 1) | 4/12 (33.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Dry Skin (Grade 1) | 6/12 (50%) | |
| Mouth Sores (Grade 1) | 9/12 (75%) | |
| Mouth Sores (Grade 2) | 3/12 (25%) | |
| Pruritis (Grade 1) | 2/12 (16.7%) | |
| Rash (Grade 1) | 8/12 (66.7%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dong Shin, MD |
|---|---|
| Organization | Emory University School of Medicine |
| Phone | 404-778-2980 |
| dmshin@emory.edu |
- IRB00024922