Lung Cancer
Conditions
Keywords
stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer
Brief summary
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib, paclitaxel, and carboplatin together with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase I/II trial is studying the best dose of erlotinib and the side effects of erlotinib, paclitaxel, and carboplatin when given together with radiation therapy and to see how well they work in treating patients who are undergoing surgery for stage III non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * Assess the safety and feasibility of erlotinib hydrochloride, paclitaxel, and carboplatin in combination with accelerated hyperfractionated radiotherapy in patients with stage IIIA or IIIB non-small cell lung cancer. * Determine the maximum tolerated dose and recommended phase II dose of erlotinib hydrochloride in these patients. * Assess the safety and tolerability of long-term maintenance erlotinib hydrochloride after completion of adjuvant chemoradiotherapy in these patients. Secondary * Evaluate the clinical and pathological response rate in these patients after neoadjuvant erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy. * Assess the impact of erlotinib hydrochloride on disease-free survival, overall survival, locoregional control, and distant metastatic control in these patients. OUTLINE: This is an open-label, phase I dose-escalation study of erlotinib hydrochloride followed by a non-randomized phase II study. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. * Phase I: * Neoadjuvant chemoradiotherapy: Patients receive oral erlotinib hydrochloride once daily on days 1-28 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, and 15 in the absence of disease progression or unacceptable toxicity. Patients concurrently undergo radiotherapy twice daily on days 1-5 and 8-12. Patients with complete response, partial response, or stable disease proceed to surgery. Patients who develop a medical contraindication to surgery (i.e., medically unresectable) receive a second course of erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy as above within 2 weeks after completion of neoadjuvant chemoradiotherapy. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. * Surgery: Within 4 weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgical resection and then proceed to adjuvant chemoradiotherapy. * Adjuvant chemoradiotherapy: Within 6-8 weeks after surgery, patients receive a second course of erlotinib hydrochloride, paclitaxel, carboplatin, and radiotherapy as in neoadjuvant chemoradiotherapy. * Maintenance therapy: All patients receive oral erlotinib hydrochloride once daily for 2 years in the absence of disease progression or unacceptable toxicity. * Phase II: Patients receive treatment as in phase I with erlotinib hydrochloride at the MTD. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.
Interventions
DRUGcarboplatin
AUC2 weekly x 3 weeks
DRUGErlotinib
Daily
DRUGpaclitaxel
50mg/m2/weekly x 3 weeks
PROCEDUREconventional surgery
conventional surgery
RADIATIONradiation therapy
150 cGy bid
Sponsors
National Cancer Institute (NCI)
Nathan Pennell, MD, PhD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed non-small cell lung cancer * Surgically determined stage IIIA or IIIB disease * Histology from an involved mediastinal or supraclavicular lymph nodes alone will be allowed if a separate distal primary lesion is clearly evident on radiographs * Histological or cytological proof of mediastinal nodal involvement by mediastinoscopy, Chamberlain procedure, thoracoscopy, thoracotomy, or CT-guided biopsy is required except for cases of paralysis of left true vocal cord with separate left lung primary distinct from enlarged nodes \> 1 cm in the anterior-posterior window seen on the CT scan * Patients with N3 or T4 status must be evaluated and deemed potentially resectable after induction chemotherapy and radiation therapy * Measurable and evaluable disease * No malignant pleural effusion except for effusion visible only on CT scan and deemed too small to tap * No pericardial effusion * No small or mixed small cell/non-small cell lung cancer * No massive lesions requiring radiation to the entire lung * No metastatic cancer to the lungs PATIENT CHARACTERISTICS: * ECOG performance status 0-1 * WBC ≥ 3,000/mm\^3 * Platelet count \> 100,000/mm\^3 * Serum creatinine ≤ 2.0 mg/dL * Alkaline phosphatase, AST, and ALT \< 2 times upper limit of normal * Albumin \> 3.0 g/dL * Serum bilirubin \< 1.5 mg/dL * Adequate pulmonary function * No clinical evidence of another uncontrolled malignancy * No requirement for urgent therapy for severe local symptoms such as post-obstructive pneumonia PRIOR CONCURRENT THERAPY: * No prior chemotherapy, radiation therapy, or immunotherapy for lung cancer * No prior surgery to treat the cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | 2 weeks after surgery | The Phase I portion of this study is to determine the Maximum Tolerated Dose (MTD) of combining OSI-774 with the paclitaxel-carboplatin chemoradiation protocol and to assess the safety and feasiblity of this combination. |
| Tolerability of Long-term OSI-774 (Phase II) | 2 years | Number of patients who experienced grade \>/= 3 toxicities on maintanance erolotinib (OSI-774) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 3 years | Months from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up |
| Pathological Complete Response Rate | 2 years | Number of participants with an pathological complete response rate using the RECIST criteria. Complete response: Disappearance of all measurable and evaluable disease Partial response: A 30% or greater decline in the sum of the longest diameter of target lesions compared to the baseline measurement. Progressive disease: A 20% or greater increase in the sum of the longest diameter of the target lesions compared to the baseline. Stable disease: Disease that did not meet the criteria for a CR / PR or progressive disease. |
| Distant Control | 2 years | Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years |
| Locoregional Control | 2 years | Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years |
| Overall Survival | 3 years | Percent of participants still alive from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up. |
Countries
United States
Participant flow
Pre-assignment details
9 participants completed the phase I portion of the study. 3 of those subjects continued onto the phase II portion of the study and are included within the 26 participants.
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation All participants that went on study at the three dose levels.
Dose Level A: 50 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin Dose Level B: 100 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin Dose Level C: 150 mg OSI-774/50 mg/m2 Paclitaxel/2 AUC Carboplatin | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase II - Expansion Phase | Adverse Event | 0 | 0 | 2 |
| Phase II - Expansion Phase | Disease progression | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Erlotinib, Paclitaxel, and Carboplatin With Radiation |
|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 2 / 2 | 15 / 26 |
| other Total, other adverse events | 4 / 4 | 2 / 2 | 26 / 26 |
| serious Total, serious adverse events | 2 / 4 | 1 / 2 | 9 / 26 |
Outcome results
Primary
Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I)
The Phase I portion of this study is to determine the Maximum Tolerated Dose (MTD) of combining OSI-774 with the paclitaxel-carboplatin chemoradiation protocol and to assess the safety and feasiblity of this combination.
Time frame: 2 weeks after surgery
Population: participants enrolled in the phase I portion of the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | 150 mg daily |
Primary
Tolerability of Long-term OSI-774 (Phase II)
Number of patients who experienced grade \>/= 3 toxicities on maintanance erolotinib (OSI-774)
Time frame: 2 years
Population: Participants that completed adjuvant chemoradiation and maintenance erolotinib.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Tolerability of Long-term OSI-774 (Phase II) | grade 3 | 4 Participants |
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Tolerability of Long-term OSI-774 (Phase II) | less than grade 3 | 16 Participants |
Secondary
Distant Control
Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years
Time frame: 2 years
Population: Data not collected
Secondary
Locoregional Control
Estimated by the Kaplan-Meier method and summarized at various follow-up points as the number of patients remaining at risk, the event estimate, standard error, and median.From the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up, assessed up to 2 years
Time frame: 2 years
Population: Data not collected
Secondary
Overall Survival
Percent of participants still alive from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up.
Time frame: 3 years
Population: Participants that participated in the phase II of the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Overall Survival | 69 percentage of participants |
Secondary
Pathological Complete Response Rate
Number of participants with an pathological complete response rate using the RECIST criteria. Complete response: Disappearance of all measurable and evaluable disease Partial response: A 30% or greater decline in the sum of the longest diameter of target lesions compared to the baseline measurement. Progressive disease: A 20% or greater increase in the sum of the longest diameter of the target lesions compared to the baseline. Stable disease: Disease that did not meet the criteria for a CR / PR or progressive disease.
Time frame: 2 years
Population: Participants that participated in phase II portion of the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Pathological Complete Response Rate | 6 participants |
Secondary
Progression Free Survival (PFS)
Months from the date of study entry to the date of the corresponding event (recurrence of death) or the date of final follow-up
Time frame: 3 years
Population: Participants that participated in the phase II of the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib, Paclitaxel, and Carboplatin With Radiation | Progression Free Survival (PFS) | 41.8 months |