A Study Of Oral GW572016 In Advanced Or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study was designed to evaluate and compare the efficacy of two dose schedules of an oral investigational drug for the treatment of advanced or metastatic non-small cell lung cancer.

Official Title
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A Phase 2 Multicenter Trial Comparing Two Schedules of GW572016 as First or Second Line Monotherapy in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer With Either Bronchioloalveolar Carcinoma or No Smoking History

Conditions
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Lung Cancer, Non-Small Cell

Intervention / Treatment
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* Drug: GW572016 (lapatinib)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent; Subjects must have histologically confirmed advanced (incurable stage IIIB or IV according to the International Staging System, [Mountain, 1997] Non-Small Cell Lung Cancer (NSCLC) at primary diagnosis or relapsed after curative-intent surgery. Only patients with either (1) the histological subtypes of adenocarcinoma with BAC (Bronchioloalveolar) features or pure BAC (as defined by the 1999 World Health Organization criteria) or, (2) never smokers (i.e. smoked <100 cigarettes in lifetime) with any histology of NSCLC (squamous, adenocarcinoma, lifetime) with any histology of NSCLC (squamous, adenocarcinoma, Patients can have had a maximum of 1 prior systemic therapy (chemotherapy or biologic therapy) for NSCLC that ended at least 3 weeks prior to enrollment. Patients that have had adjuvant cytotoxic chemotherapy that ended at least 3 months prior to enrollment are eligible. Prior surgery and radiotherapy are permitted. Patients should recover from acute side effects of radiation before enrollment (3-4 weeks). Concurrent radiotherapy is prohibited; Archived tumor tissue available for evaluation of genetic and intra-tumoral protein or mRNA expression levels of relevant biomarkers. A minimum of 10 slides of archived tumor tissue is required; however, 15 slides should be sent, if available. For patients diagnosed on the basis of pleural effusions, efforts should be made to provide as many slides as possible made with cells obtained from pleural aspirates. Results of biomarkers will not be used to determine subject eligibility for the study; Measurable lesion(s) according to RECIST (e.g., ≥15 mm with conventional techniques (medical photograph [skin or oral lesion], palpation, plain X-ray, CT, MRI, or ≥10 mm with spiral CT scan); At least 1 measurable lesion located outside of the prior radiation field or, if located within the prior field of irradiation, is increasing in size; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; Life expectancy of ≥ 12 weeks; ≥ 18 years old; A female is eligible to enter and participate in this study if she is of: • Non-childbearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation, women who had a hysterectomy, women who are post-menopausal, or women who have had both ovaries surgically removed); or • Childbearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhea (even severe), women who are perimenopausal, and young women who have begun to menstruate. Women of childbearing potential must have a negative serum pregnancy test at screening, and agree to 1 of the following: a Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of GW572016 until 28 days after the final dose of GW572016; or b Consistent and correct use of 1 of the following acceptable methods of birth control: 1. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; or 2. Implants of levonorgestrel 3. Injectable progestogen 4. Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or 5. Oral contraceptives (either combined or Progestogen only) 6. Barrier methods including diaphragm or condom with a spermicide Able to swallow and retain oral medication; Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram. Subjects with known history of uncontrolled or symptomatic echocardiogram. Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are not eligible; Have adequate organ function as defined in Table 1 Baseline Laboratory Values for Inclusion; Subjects must complete all screening assessments as outlined in the protocol. Exclusion Criteria: Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible; Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety; Unresolved or unstable, serious toxicity from prior administration of another investigational drug; Active or uncontrolled infection; Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; Uncontrolled angina, arrhythmias, or congestive heart failure. Patients whose symptoms are under control are eligible. Known history of or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis except for individuals who have previously treated CNS metastases, are asymptomatic, and have had no requirement for steroids or antiseizure medication for ≥ 3 months prior to study enrollment. Routine screening with CNS imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the subject has a history of CNS metastases; Concurrent cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, and tumor embolization). Concurrent treatment with an investigational agent or participation in another clinical trial Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of GW572016; Prior therapy with any ErbB1 and/or ErbB2 inhibitor; The subject has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GW572016. Has taken/received the following inhibitors of CYP3A4 within the specified number of days prior to the first dose of study medication: Seven (7) days: antibiotics (clarithromycin, erythromycin, troleandomycin), antiretrovirals (delavirdine), protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir), systemic antifungals (itraconazole, ketoconazole, voriconazole, fluconazole (doses of 200 mg/day and above)), antidepressants (nefazodone, fluovoxamine), calcium channel blockers (verapamil, diltiazem), gastrointestinal (cimetidine, aprepitant), and grapefruit or its juice. Six (6) months: amiodarone. Has taken/received the following inducers of CYP3A4 within fourteen (14) days prior to the first dose of study medication: glucocorticoids (dexamethasone or dexamethasone equivalent dose > 1.5mg/day (see chart in Section 7.2 for conversion), anticonvulsants (phenytoin, carbamazepine, phenobarbital), efavirenz, nevirapine, antibiotics (rifampin (rifampicin), rifabutin, rifapentine), St. John's Wort and modafinil.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: lapatinib<br>Randomized, open-label, parallel group, 2-stage study to evaluate and compare 2 dose schedules (1500 mg once daily and 500 mg twice daily) of oral lapatinib. | Drug: GW572016 (lapatinib)<br>* tyrosine kinase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response in the Targeted Population Through the End of Treatment | Disease progression and tumor response (number of participants achieving a complete response [CR] or partial response [PR]), using standardized criteria (Response evaluation criteria in solid tumors). CR, disappearance of all target lesions; PR, 30% decrease in the sum of the longest diameter of target lesions; progressive disease, 20% increase in the sum of the longest diameter of target lesions; stable disease, small changes that do not meet above criteria. Disease assessment was done at baseline and then every 8 weeks after starting treatment, until the participant discontinued treatment. | Baseline and then every 8 weeks through end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) at Four Months in the Targeted Population | Percentage of participants in the Targeted Population, at 4 months after starting study drug, who were alive and without disease progression. | From randomization and then every 8 weeks up to four months | 
| Progression-free Survival (PFS) at Four Months in the Non-Targeted Population | Percentage of participants in the Non-Targeted Population, at 4 months after starting study drug, who were alive and without disease progression. | From randomization and then every 8 weeks up to four months | 
| The Number of Participants Who Showed Certain Biomarkers in Their Serum or Tumor Tissue | To further characterize the participant population, these biomarkers could be tested: serum levels of ErbB1 and ErbB2; intra-tumoral expression of ErbB1, ErbB2, etc.; mutations in ErbB1, ErbB2, and k-ras. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, serum biomarkers were not analyzed. | From randomization to disease progression (for serum biomarkers) or until analyses of tumor tissue samples | 
| Pharmacokinetics (PK) of Lapatinib | To characterize the PK (absorption, distribution, metabolism, and excretion) of the study drug lapatinib in the participant population. PK is defined as the concentration of drug in a participant's blood at certain time points after the drug was taken by mouth. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, pharmacokinetics were not analyzed. | From randomization to time of PK period completed: Day 1 (first dose) and Days 2, 28, and 29 while participant was on study drug | 
| Pharmacogenetics (PgX) | To (1) investigate the relationship between genetic variants in specific genes and the absorption, distribution, metabolism, and excretion (pharmacokinetics) of lapatinib, and to (2) investigate the relationship between genetic variants in select genes in DNA and the response (safety, efficacy, and tolerability) to lapatinib. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, pharmacogenetics were not analyzed. | From randomization at every 4-week assessment through end of treatment | 
| Quality of Life | Standard survey forms were completed by the participant at scheduled assessments to find out how the participant felt while on study. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, quality of life was not analyzed. | Baseline and then every 4 weeks through end of treatment | 
| Time to Response | Time from randomization until first documented evidence of partial or complete tumor response, measured using standard criteria (RECIST). Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, time to response was not analyzed. | From randomization and then every 8 weeks to time of response to study drug | 
| Duration of Response | For those participants who show a complete or partial response, duration of response would be time from first documented evidence of response (complete or partial response by RECIST) until disease progression or death, if sooner. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, duration of response was not analyzed. | Time from first documented evidence of response to study treatment and then every 8 weeks until disease progression or death | 
| Time to Tumor Progression | Time from randomization until the first documented sign of disease progression or death due to any cause, if sooner. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, time to tumor progression was not analyzed. | From randomization and then every 8 weeks to disease progression or death | 
| Overall Survival | Overall survival is measured as the time from randomization until death due to any cause. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, overall survival was not analyzed. | From randomization and then every 8 weeks while on study drug and then every 3 months as follow-up until death | 
| Review of Non-small Cell Lung Cancer (NSCLC) Histology (Cell Type) Using an Independent Review | Comparison of the specific cell type (histology) of non-small cell lung cancer from participant's tissue samples, as determined by local pathologist, to the type determined by an independent pathologist. Based on the interim analysis at the end of Stage 1, and predefined stopping rules for futility, further enrollment into the study was stopped due to lack of efficacy on both treatment arms; therefore, NSCLC histology was not analyzed. | Anytime from Baseline through end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, ErbB1, ErbB2, metastatic, lapatinib, Her-2/neu, protein kinase inhibitor, BAC, GW572016, Advanced, NSCLC