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Erlotinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Mouth or Throat Cancer

Primary Purpose

Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage II Squamous Cell Carcinoma of the Oropharynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
erlotinib hydrochloride
cisplatin
intensity-modulated radiation therapy
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients with clinical findings consistent with a diagnosis of squamous cell carcinoma of the OC or OP, as determined by the head and neck surgeon, may be recruited to the study prior to diagnostic biopsy; patients must have a histologically confirmed diagnosis of squamous cell carcinoma of OC or OP prior to proceeding with treatment Oropharyngeal sites include base of tongue, tonsil, soft palate, and oropharyngeal wall Oral cavity sites include oral tongue, buccal mucosa, floor of mouth, retromolar trigone, alveolar ridge, hard palate and mucosal lip Patients must be AJCC stage II (T2N0) or III (T1-2N1) (AJCC fifth edition, 1997) for part A of the study, and must be AJCC stage III (T3N 0-1) or IV (T1-4N2-3M0, T4N0-1M0) for part B of the study Priority for study entry will be given to patients with easily accessible tumor and who consent to repeat biopsy; study entry will not be restricted to patients who agree to further biopsies; if a patient enrolls on study and later refuses biopsy (excluding diagnostic), he/she may remain on study Patients with operable or inoperable tumors will be eligible No prior therapy for the tumor, including chemotherapy, radiation therapy, immunotherapy, EGFR targeted therapies, or any other investigational agents Prior malignancies of sites other than the head and neck are allowed if disease free interval >= 3 years; basal cell carcinomas of the skin and in situ cervical dysphagias are allowed within this three year interval if completely resected Documentation of evaluable tumor less than or equal to four weeks before treatment start ECOG performance status = 0, 1 or 2 (Karnofsky >= 60%) Life expectancy of greater than or equal to 6 months Leukocytes >= 3,000 Absolute neutrophil count >= 1,500 Platelets >= 100,000 Total bilirubin within normal institutional limits unless due to hemolysis or Gilbert's syndrome AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal APTT/INR within normal institutional limits; patients who have abnormalities in APTT/INR that are correctable after administration of vitamin K are eligible No uncontrolled diabetes mellitus as glucose must be within a consistently normal range for each patient in order to standardize PET scan interpretations No known malabsorption syndrome G-tube dependent patients are eligible The effects of OSI-774 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with known brain involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive 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 or other agents used in study Major surgery or significant traumatic injury occurring within 28 days prior to treatment Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjögren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Gastrointestinal tract disease resulting in an inability to take oral or enteral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, untreated or new 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 epidermal growth factor inhibitor with the potential for teratogenic or abortifacient effects based on the data suggesting that EGFR expression is important for normal organ development; 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 OSI-774 Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with OSI-774; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Patients on Coumadin are excluded from the study because of reports of interactions between the study drug and Coumadin

Sites / Locations

  • Johns Hopkins University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Regimen A (erlotinib hydrochloride, IMRT)

Regimen B (erlotinib hydrochloride, cisplatin, IMRT)

Arm Description

Patients receive oral erlotinib once daily. Beginning on day 15, patients also undergo IMRT once daily 5 days a week for 7 weeks. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients receive oral erlotinib and undergo IMRT as in regimen A. Patients also receive cisplatin IV over 20 minutes on each day of radiotherapy. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) of cisplatin, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v3.0
Summarized using descriptive statistics.

Secondary Outcome Measures

Time to progression
Pharmacokinetics in terms of steady state concentration (Css, min)
Relationships between cisplatin and erlotinib hydrochloride steady-state concentrations and toxicity and epidermal growth factor receptor (EGFR) inhibition will be assessed using univariate and multivariate statistical methods.
Percent change in standardized uptake value (SUV) corrected for lean body mass
The pre and post treatment scans will be compared by use of Wilcoxon signed rank test. The relationship between metabolic response and clinical response will be evaluated by use of chi square test or Fisher's exact test as appropriate.
Biological response for each individual patient as defined by determination of the proportional variation of each biomarker
Both pharmacokinetic and pharmacodynamic parameters will be calculated and their relationship fit with flexible regression models.
Relationship between time to treatment failure versus variations in the biomarkers
Analyzed by the Kaplan Meier method or Cox regression models, and tested with a logrank test.
Effect of erlotinib hydrochloride on the EGFR activation and signaling
Descriptive statistics (mean +/- standard deviation [SD]) will be used to summarize the data. Differences between pre and post treatment immunohistochemistry (IHC) scored will be compared with a paired-t test.

Full Information

First Posted
November 12, 2002
Last Updated
September 27, 2013
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00049166
Brief Title
Erlotinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Mouth or Throat Cancer
Official Title
A Phase I Study of OSI-774 in Combination With Standard Fractionation Radiation Therapy in Patients With Oral Cavity or Oropharyngeal Cancer Stage II or III and in Combination With Standard Fractionation Radiation Therapy and Low Dose Daily Cisplatin in Patients With Oral Cavity or Oropharyngeal Cancer Stage III and IV
Study Type
Interventional

2. Study Status

Record Verification Date
September 2013
Overall Recruitment Status
Completed
Study Start Date
October 2002 (undefined)
Primary Completion Date
July 2007 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
Phase I trial to study the effectiveness of combining erlotinib with radiation therapy with or without cisplatin in treating patients who have advanced mouth or throat cancer. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining erlotinib with radiation therapy with or without cisplatin may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. Determination of the maximally tolerated dose (MTD) of the combination of daily oral OSI-774 and standard fractionation external beam radiation therapy in patients with oral cavity (OC) or oropharyngeal (OP) squamous cell carcinoma (SCC), stage II and III. II. Determination of the MTD of daily oral OSI-774, low dose daily cisplatin at 6 mg/m^2/day and standard fractionation external beam radiation therapy in patients with oral cavity or oropharyngeal SCC stage III and IV. III. Determination of the safety of chronic oral dosing of OSI-774 after radiation therapy. SECONDARY OBJECTIVES: I. Determination of biological markers of activity of OSI-774 in tumor biopsy specimens from patients with SCC of OC and OP pre and post therapy. II. Determination of the ability of (18F)-FDG-PET scan to demonstrate biological activity of OSI-774 in previously untreated patients with SCC of the OC and OP and to predict for clinical response. OUTLINE: This is a multicenter, dose-escalation study of erlotinib. Patients are assigned to 1 of 2 regimens according to disease stage. Regimen A (patients with stage II [T2, N0] or III [T1-2, N1] disease): Patients receive oral erlotinib once daily. Beginning on day 15, patients also undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 7 weeks. Regimen B (patients with stage III [T3, N0-1] or IV [T1-4, N2-3, M0 or T4, N0-1, M0] disease): Patients receive oral erlotinib and undergo IMRT as in regimen A. Patients also receive cisplatin IV over 20 minutes on each day of radiotherapy. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 30 days and then every 3 months for up to 2 years. PROJECTED ACCRUAL: A total of 24-48 patients (12-24 per regimen) will be accrued for this study within 6-24 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage II Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage II Squamous Cell Carcinoma of the Oropharynx, Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage III Squamous Cell Carcinoma of the Oropharynx, Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IV Squamous Cell Carcinoma of the Oropharynx

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Regimen A (erlotinib hydrochloride, IMRT)
Arm Type
Experimental
Arm Description
Patients receive oral erlotinib once daily. Beginning on day 15, patients also undergo IMRT once daily 5 days a week for 7 weeks. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Arm Title
Regimen B (erlotinib hydrochloride, cisplatin, IMRT)
Arm Type
Experimental
Arm Description
Patients receive oral erlotinib and undergo IMRT as in regimen A. Patients also receive cisplatin IV over 20 minutes on each day of radiotherapy. Patients in both regimens continue to receive erlotinib until the last day of IMRT (patients already in the maintenance phase of this study as of 5/11/04 continue to receive erlotinib once daily for up to 2 years) in the absence of disease progression or unacceptable toxicity. In both regimens, cohorts of 3-6 patients receive escalating doses of erlotinib until the MTD is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
Intervention Type
Drug
Intervention Name(s)
erlotinib hydrochloride
Other Intervention Name(s)
CP-358,774, erlotinib, OSI-774
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
cisplatin
Other Intervention Name(s)
CACP, CDDP, CPDD, DDP
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
intensity-modulated radiation therapy
Other Intervention Name(s)
IMRT
Intervention Description
Undergo intensity modulated radiation therapy
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) of cisplatin, graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) v3.0
Description
Summarized using descriptive statistics.
Time Frame
Up to 7 weeks
Secondary Outcome Measure Information:
Title
Time to progression
Time Frame
Up to 2 years
Title
Pharmacokinetics in terms of steady state concentration (Css, min)
Description
Relationships between cisplatin and erlotinib hydrochloride steady-state concentrations and toxicity and epidermal growth factor receptor (EGFR) inhibition will be assessed using univariate and multivariate statistical methods.
Time Frame
Up to 10 weeks
Title
Percent change in standardized uptake value (SUV) corrected for lean body mass
Description
The pre and post treatment scans will be compared by use of Wilcoxon signed rank test. The relationship between metabolic response and clinical response will be evaluated by use of chi square test or Fisher's exact test as appropriate.
Time Frame
Up to 14 days
Title
Biological response for each individual patient as defined by determination of the proportional variation of each biomarker
Description
Both pharmacokinetic and pharmacodynamic parameters will be calculated and their relationship fit with flexible regression models.
Time Frame
Up to 2 years
Title
Relationship between time to treatment failure versus variations in the biomarkers
Description
Analyzed by the Kaplan Meier method or Cox regression models, and tested with a logrank test.
Time Frame
Up to 2 years
Title
Effect of erlotinib hydrochloride on the EGFR activation and signaling
Description
Descriptive statistics (mean +/- standard deviation [SD]) will be used to summarize the data. Differences between pre and post treatment immunohistochemistry (IHC) scored will be compared with a paired-t test.
Time Frame
Up to day 120

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with clinical findings consistent with a diagnosis of squamous cell carcinoma of the OC or OP, as determined by the head and neck surgeon, may be recruited to the study prior to diagnostic biopsy; patients must have a histologically confirmed diagnosis of squamous cell carcinoma of OC or OP prior to proceeding with treatment Oropharyngeal sites include base of tongue, tonsil, soft palate, and oropharyngeal wall Oral cavity sites include oral tongue, buccal mucosa, floor of mouth, retromolar trigone, alveolar ridge, hard palate and mucosal lip Patients must be AJCC stage II (T2N0) or III (T1-2N1) (AJCC fifth edition, 1997) for part A of the study, and must be AJCC stage III (T3N 0-1) or IV (T1-4N2-3M0, T4N0-1M0) for part B of the study Priority for study entry will be given to patients with easily accessible tumor and who consent to repeat biopsy; study entry will not be restricted to patients who agree to further biopsies; if a patient enrolls on study and later refuses biopsy (excluding diagnostic), he/she may remain on study Patients with operable or inoperable tumors will be eligible No prior therapy for the tumor, including chemotherapy, radiation therapy, immunotherapy, EGFR targeted therapies, or any other investigational agents Prior malignancies of sites other than the head and neck are allowed if disease free interval >= 3 years; basal cell carcinomas of the skin and in situ cervical dysphagias are allowed within this three year interval if completely resected Documentation of evaluable tumor less than or equal to four weeks before treatment start ECOG performance status = 0, 1 or 2 (Karnofsky >= 60%) Life expectancy of greater than or equal to 6 months Leukocytes >= 3,000 Absolute neutrophil count >= 1,500 Platelets >= 100,000 Total bilirubin within normal institutional limits unless due to hemolysis or Gilbert's syndrome AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal APTT/INR within normal institutional limits; patients who have abnormalities in APTT/INR that are correctable after administration of vitamin K are eligible No uncontrolled diabetes mellitus as glucose must be within a consistently normal range for each patient in order to standardize PET scan interpretations No known malabsorption syndrome G-tube dependent patients are eligible The effects of OSI-774 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients with known brain involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive 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 or other agents used in study Major surgery or significant traumatic injury occurring within 28 days prior to treatment Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjögren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Gastrointestinal tract disease resulting in an inability to take oral or enteral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, untreated or new 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 epidermal growth factor inhibitor with the potential for teratogenic or abortifacient effects based on the data suggesting that EGFR expression is important for normal organ development; 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 OSI-774 Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with OSI-774; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Patients on Coumadin are excluded from the study because of reports of interactions between the study drug and Coumadin
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maura Gillison
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287-8936
Country
United States

12. IPD Sharing Statement

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Erlotinib and Radiation Therapy With or Without Cisplatin in Treating Patients With Mouth or Throat Cancer

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