Lung Adenocarcinoma, Lung Adenosquamous Carcinoma, Malignant Pericardial Effusion, Malignant Pleural Effusion, Minimally Invasive Lung Adenocarcinoma, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Non-Small Cell Cancer AJCC v7
Conditions
Keywords
A Phase II Randomized Study of OSI-774
Brief summary
This randomized phase II trial studies how well erlotinib hydrochloride with or without carboplatin and paclitaxel works in treating patients with stage III-IV non-small cell lung cancer. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving erlotinib hydrochloride together with carboplatin and paclitaxel may kill more tumor cells than giving either drug alone.
Detailed description
PRIMARY OBJECTIVES: I. To determine the distribution of progression-free survival (PFS) in patients with previously untreated advanced adenocarcinoma of the lung who are never or light former smokers treated with either OSI-774 (erlotinib) (erlotinib hydrochloride) alone (arm A) or in combination with carboplatin/paclitaxel (arm B). SECONDARY OBJECTIVES: I. To determine the radiographic response rate in patients with previously untreated advanced adenocarcinoma of the lung who are never or light former smokers treated with either OSI-774 (erlotinib) alone (arm A) or in combination with carboplatin/paclitaxel (arm B). II. To determine the frequency of epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) mutations and anaplastic lymphoma kinase (ALK) translocations in patients with previously untreated advanced adenocarcinoma of the lung who are never or light former smokers. III. To determine the response rate and time to progression in patients with and without EGFR mutations treated with either OSI-774 (erlotinib) alone (arm A) or in combination with carboplatin/paclitaxel (arm B). IV. To determine the response rate and time to progression in patients with and without K-ras mutations treated with either OSI-774 (erlotinib) alone (arm A) or in combination with carboplatin/paclitaxel (arm B). V. To determine the median and overall survival of patients with previously untreated advanced adenocarcinoma of the lung who are never or light former smokers treated with either OSI-774 (erlotinib) alone (arm A) or in combination with carboplatin/paclitaxel (arm B). VI. To estimate the response rate, progression-free, and overall survival of patients with echinoderm microtubule associated protein like (EML)4-ALK translocation who received OSI-774 erlotinib alone (arm A) or in combination with carboplatin/paclitaxel (arm B). OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive erlotinib hydrochloride as in Arm I. Patients also receive paclitaxel intravenously (IV) over 1-3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of 6 cycles of treatment, patients may continue to receive erlotinib hydrochloride alone as above. After completion of study treatment, patients are followed at least every 3 months for 1 year and then every 6 months for up to 2 years.
Interventions
DRUGCarboplatin
Given IV
DRUGErlotinib
Given PO
DRUGErlotinib Hydrochloride
Given PO
DRUGPaclitaxel
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic documentation of primary lung adenocarcinoma including any variant thereof such as pure or mixed bronchioloalveolar carcinoma or adenosquamous cell carcinoma; patients with non-small cell lung cancer (NSCLC) not otherwise specified (NOS) are not eligible * Pathology block or unstained slides from initial or subsequent diagnosis must be available for sequencing of EGFR, K-ras, Erb-2 and B-raf; patients need to have had at least a core biopsy; patients whose diagnosis was made through a fine needle aspirate will not have sufficient material for mutational analysis and are not eligible * Select stage IIIB with cytologically documented malignant pleural or pericardial effusion OR stage IV disease * Patients must be chemotherapy naïve; they may not have received neo-adjuvant or adjuvant chemotherapy * No prior exposure to OSI-774 (erlotinib) or other treatments targeting the human epidermal growth factor receptor (HER) family axis (e.g., trastuzumab, gefitinib, cetuximab, lapatinib, etc.) * No uncontrolled central nervous system metastases (i.e., any known central nervous system \[CNS\] lesion which is radiographically unstable, symptomatic and/or requiring corticosteroids); patients must be \>= 3 weeks beyond completing cranial irradiation and off corticosteroid therapy * \>= 3 weeks since prior radiation therapy * \>= 3 weeks since prior major surgery * No treatment with an investigational agent currently or within the last 28 days * Non-smoker or former light smoker; non-smoker is defined as a person who smoked =\< 100 cigarettes in their lifetime while a former light smoker is a patient who smoked between \> 100 cigarettes AND =\< 10 pack years AND quit \>= 1 year ago; this must be documented on the On-study Form (C-1405) * Eastern Cooperative Oncology Group (ECOG) 0 or 1 * Non-pregnant and non-nursing * No dysphagia or active gastrointestinal disease or disorder that alters gastrointestinal motility or absorption; no lack of integrity of the gastrointestinal tract (e.g., a significant surgical resection of the stomach or small bowel); patients unable to swallow intact tablets must be able to swallow tablets dissolved in water * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral computed tomography (CT) scan; lesions that are considered non-measurable include the following: * Bone lesions * Leptomeningeal disease * Ascites * Pleural/pericardial effusion * Lymphangitis cutis/pulmonis * Abdominal masses that are not confirmed and followed by imaging techniques * Cystic lesions * Granulocyte \>= 1,500/mcl * Platelet count \>= 100,000/mcl * Hemoglobin \>= 9.0 g/dL * Total bilirubin =\< upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 x ULN * Creatinine =\< 1.5 mg/dl
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 18 Weeks Progression Free Survival (PFS) Rate | At 18 weeks | The product limit estimator developed by Kaplan Meier will be used to graphically describe progression free survival for patients randomized to each study arm. The 18 week progression-free survival rate was defined as the proportion of patients that were alive progression-free 18 weeks after registration into the study. Disease progression was assessed per modified RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, in either primary or nodal lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of new lesions. Kaplan-Meier estimate of 18-week progression-free survival was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Duration of Study (up to 3 years) | The proportion of patients who respond (completely or partially) to each combination regimen will be estimated. An exact binomial confidence interval will be computed for these estimates. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions |
| Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | Duration of study (up to 3 years) | The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival With KRAS Mutation Status | Duration of study (up to 3 years) | Progression free survival is defined in previous outcome measures. GIven the small number of KRAS mutant participants, the analysis combines data from both arms. |
| Overall Survival | Time from randomization to death (up to 3 years) | Overall survival (OS) is defined as the time from patient randomization (arm assignment) to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method. |
| Overall Response Rate With KRAS Mutational Status | Duration of study (up to 3 years) | Overall response is defined in previous outcome measures. GIven the small number of KRAS mutant participants in each treatment arm, the analysis combines data from both arms. |
| Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status | Duration of treatment (up to 3 years) | PFS was defined as the time from registration until disease progression or death, whichever occurs first. The median PFS with 95% CI was estimated using the Kaplan-Meier method. Progression is defined as in the primary outcome measure. EGFR mutations were performed at the Dana-Farber Cancer Institute using a sensitive heteroduplex method coupled with enzymatic digestion as previously reported (Janne PA, et al: A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res 12:751-758, 2006). All positive findings were independently verified and subjected to sequencing. The mutation analyses were blinded to the participants' clinical outcome. |
| Overall Response Rate by EGFR Mutation Status | Duration of study (up to 3 years) | Response and EGFR mutation status are defined in previous outcome measures. |
Countries
United States
Participant flow
Recruitment details
Between August 2005 and April 2009, 188 participants were enrolled.
Pre-assignment details
Seven participants withdrew consent before initiating study therapy, therefore, 181 participants were randomized to either arm.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Erlotinib Patients receive oral erlotinib once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 81 |
| Arm B: Erlotinib/Carboplatin/Paclitaxel Patients receive erlotinib as in arm I. Patients also receive paclitaxel IV over 1-3 hours and carboplatin IV over 15-30 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses of treatment, patients may continue to receive erlotinib alone as above. | 100 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Alternative therapy | 3 | 3 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Other illness/MD discretion | 3 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Arm B: Erlotinib/Carboplatin/Paclitaxel | Total | Arm A: Erlotinib |
|---|---|---|---|
| Age, Continuous | 60 years | 59 years | 58 years |
| ECOG Performance Status 0 - fully active | 48 participants | 98 participants | 50 participants |
| ECOG Performance Status 1 - minimal symptoms | 52 participants | 83 participants | 31 participants |
| Histology Adenocarcinoma | 84 participants | 155 participants | 71 participants |
| Histology Adenocarcinoma with bronchioloalveolar features | 14 participants | 22 participants | 8 participants |
| Histology Bronhioloalveolar cancer | 2 participants | 4 participants | 2 participants |
| Region of Enrollment United States | 100 participants | 181 participants | 81 participants |
| Sex: Female, Male Female | 58 Participants | 107 Participants | 49 Participants |
| Sex: Female, Male Male | 42 Participants | 74 Participants | 32 Participants |
| Smoking history Light former smoker | 21 participants | 38 participants | 17 participants |
| Smoking history Never smoker | 79 participants | 143 participants | 64 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 78 / 81 | 94 / 99 |
| serious Total, serious adverse events | 21 / 81 | 39 / 99 |
Outcome results
Primary
18 Weeks Progression Free Survival (PFS) Rate
The product limit estimator developed by Kaplan Meier will be used to graphically describe progression free survival for patients randomized to each study arm. The 18 week progression-free survival rate was defined as the proportion of patients that were alive progression-free 18 weeks after registration into the study. Disease progression was assessed per modified RECIST criteria, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, in either primary or nodal lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of new lesions. Kaplan-Meier estimate of 18-week progression-free survival was calculated.
Time frame: At 18 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Erlotinib | 18 Weeks Progression Free Survival (PFS) Rate | 52 percentage of participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | 18 Weeks Progression Free Survival (PFS) Rate | 69 percentage of participants |
Secondary
Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment.
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Erlotinib | Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | 20 participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | 52 participants |
Secondary
Overall Response Rate
The proportion of patients who respond (completely or partially) to each combination regimen will be estimated. An exact binomial confidence interval will be computed for these estimates. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions
Time frame: Duration of Study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Erlotinib | Overall Response Rate | 35 percentage of participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Overall Response Rate | 46 percentage of participants |
Other Pre-specified
Overall Response Rate by EGFR Mutation Status
Response and EGFR mutation status are defined in previous outcome measures.
Time frame: Duration of study (up to 3 years)
Population: EGFR mutation analysis was successfully performed in 164 participants; 17 participants had insufficient material or DNA for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Erlotinib | Overall Response Rate by EGFR Mutation Status | EGFR Mutant | 70 percentage of participants |
| Arm A: Erlotinib | Overall Response Rate by EGFR Mutation Status | EGFR Wild Type | 9 percentage of participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Overall Response Rate by EGFR Mutation Status | EGFR Mutant | 73 percentage of participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Overall Response Rate by EGFR Mutation Status | EGFR Wild Type | 30 percentage of participants |
Other Pre-specified
Overall Response Rate With KRAS Mutational Status
Overall response is defined in previous outcome measures. GIven the small number of KRAS mutant participants in each treatment arm, the analysis combines data from both arms.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Erlotinib | Overall Response Rate With KRAS Mutational Status | 29 percentage of participants |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Overall Response Rate With KRAS Mutational Status | 42 percentage of participants |
Other Pre-specified
Overall Survival
Overall survival (OS) is defined as the time from patient randomization (arm assignment) to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Time frame: Time from randomization to death (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Erlotinib | Overall Survival | 24.6 months |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Overall Survival | 19.8 months |
Other Pre-specified
Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status
PFS was defined as the time from registration until disease progression or death, whichever occurs first. The median PFS with 95% CI was estimated using the Kaplan-Meier method. Progression is defined as in the primary outcome measure. EGFR mutations were performed at the Dana-Farber Cancer Institute using a sensitive heteroduplex method coupled with enzymatic digestion as previously reported (Janne PA, et al: A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res 12:751-758, 2006). All positive findings were independently verified and subjected to sequencing. The mutation analyses were blinded to the participants' clinical outcome.
Time frame: Duration of treatment (up to 3 years)
Population: EGFR mutation analysis was successfully performed in 164 participants; 17 participants had insufficient material or DNA for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: Erlotinib | Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status | EGFR Mutant | 14.1 months |
| Arm A: Erlotinib | Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status | EGFR Wild Type | 2.6 months |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status | EGFR Mutant | 17.2 months |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Progression Free Survival (PFS) by Epidermal Growth Factor Receptor (EGFR) Mutation Status | EGFR Wild Type | 4.8 months |
Other Pre-specified
Progression Free Survival With KRAS Mutation Status
Progression free survival is defined in previous outcome measures. GIven the small number of KRAS mutant participants, the analysis combines data from both arms.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Erlotinib | Progression Free Survival With KRAS Mutation Status | 4 months |
| Arm B: Erlotinib/Carboplatin/Paclitaxel | Progression Free Survival With KRAS Mutation Status | 6.7 months |