A Phase I Study Of OSI-774 (NSC #718781)-Based Multimodality Therapy For Inoperable Stage III Non Small Cell Lung Cancer
A Phase I Study Of OSI-774 (NSC #718781)-Based Multimodality Therapy For Inoperable Stage III Non Small Cell Lung 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 work in different ways to stop tumor cells from dividing so they stop growing or die. Combining erlotinib and radiation therapy with combination chemotherapy may kill more tumor cells. Phase I trial to study the effectiveness of combining erlotinib and radiation therapy with combination chemotherapy in treating patients who have inoperable stage III non-small cell lung cancer
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose of erlotinib that can be administered with chest radiotherapy in combination with cisplatin and etoposide or carboplatin and paclitaxel in patients with inoperable stage III non-small cell lung cancer.
II. Determine the dose-limiting toxicity of these regimens in these patients. III. Assess the clinical response (complete response, partial response, progressive disease, or stable disease) in patients treated with these regimens.
IV. Determine levels of tumor epidermal growth factor expression in patients treated with these regimens.
OUTLINE: This is a multicenter, dose-escalation study of erlotinib. Patients are assigned to 1 of 2 treatment groups.
GROUP 1: Patients receive cisplatin IV over 2 hours on days 1, 8, 29, and 36; etoposide IV over 1 hour on days 1-5 and 29-33; and oral erlotinib once daily on days 1-49. Patients undergo concurrent radiotherapy 5 days a week for 7 weeks beginning on day 1. Patients receive consolidation therapy comprising docetaxel IV over 1 hour on days 50, 71, and 92. Some patients may also receive oral erlotinib once daily on days 50-112.
GROUP 2: Patients receive induction chemotherapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21. Patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 43, 50, 57, 64, 71, 78, and 85 and oral erlotinib once daily on days 43-91. Patients undergo radiotherapy concurrently with consolidation therapy 5 days a week for 7 weeks beginning on day 43.
In both groups, cohorts of 3-6 patients receive escalating doses of erlotinib during concurrent chemoradiotherapy until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 2 of 6 patients experience dose-limiting toxicity. At least 12 patients from each group are treated at the MTD.
Patients are followed at 8 weeks.
PROJECTED ACCRUAL: A total of 24-48 patients (12-24 per treatment group) will be accrued for this study within 6-12 months.
Inclusion Criteria:
Histologically confirmed non-small cell lung cancer
Stage IIIA (T1 or T2, N2) or IIIB disease not amenable to resection or surgery
T3, N2 or T4, N0-N2 disease also allowed if based on the closeness to the carina, invasion of the mediastinum, or invasion of the chest wall
T3, N0-N1 disease allowed provided the disease is not amenable for surgical resection
No M1 disease
No disease invasion of a vertebral body
Contralateral mediastinal disease (N3) allowed if all gross disease can be encompassed in the radiotherapy boost field
Pleural effusion that is transudative, cytologically negative, and non-bloody allowed if the tumor can be encompassed in a reasonable field of radiotherapy
Measurable or evaluable disease
Pleural effusions are not considered measurable or evaluable
Measurable disease is defined as any mass in 2 perpendicular diameters by CXR, CT scan, or MRI
Evaluable disease includes lesions apparent on CXR or CT scan that are:
Performance status - ECOG 0-1
Performance status - Karnofsky 70-100%
More than 6 months
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Bilirubin normal
AST and ALT no greater than 1.5 times upper limit of normal (ULN) and alkaline phosphatase normal
AST and ALT normal and alkaline phosphatase no greater than 2.5 times ULN
Creatinine normal
Creatinine clearance at least 50 mL/min
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
No history of cornea abnormalities (e.g., dry-eye syndrome, Sjögren's syndrome)
No congenital abnormality (e.g., Fuch's dystrophy)
No abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose)
No abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test)
No gastrointestinal tract disease resulting in the inability to take oral medications
No required IV alimentation
No peptic ulcer disease
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No history of allergy to compounds of similar chemical or biologic composition to erlotinib or other study agents
No significant traumatic injury within the past 21 days
No other uncontrolled concurrent illness
No ongoing or active infection
No psychiatric illness or social situation that would preclude study compliance
No other active malignancy within the past 6 months except non-melanoma skin cancer
No concurrent colony-stimulating factors (filgrastim [G-CSF] or sargramostim [GM-CSF]) with radiotherapy
No prior chemotherapy for lung cancer
See Disease Characteristics
No prior chest radiotherapy
See Disease Characteristics
At least 7 days since prior mediastinoscopy
More than 3 weeks since prior formal exploratory thoracotomy
More than 3 weeks since prior major surgery
No prior surgical procedures affecting absorption
No prior epidermal growth factor receptor-targeting therapies
No other concurrent investigational or commercial agents or therapies directed at malignancy
No concurrent combination antiretroviral therapy for HIV-positive patients