Lung Cancer
Conditions
Keywords
stage II non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Celecoxib may stop the growth of tumor cells by stopping blood flow to the tumor and may make the tumor cells more sensitive to radiation therapy. PURPOSE: Phase I/II trial to study the effectiveness of combining celecoxib with radiation therapy in treating patients who have locally advanced non-small cell lung cancer.
Detailed description
OBJECTIVES: * Determine the maximum tolerated dose and the recommended phase II dose of concurrent celecoxib and limited-field radiotherapy in intermediate-prognosis patients with locally advanced non-small cell lung cancer. * Determine the efficacy and toxicity of this regimen in these patients. * Determine how the predictors of mortality in the general population (i.e., comorbid conditions, functional status, quality of life, and psychological status) influence prognosis, toxicity, and outcomes of therapy in patients treated with this regimen. * Correlate circulating levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL8) with survival in patients treated with this regimen. * Correlate circulating levels of interleukin-1 (IL1), interleukin-6 (IL6), and transforming growth factor-beta (TGFB) with pulmonary toxicity in patients treated with this regimen. OUTLINE: This is a phase I dose-escalation study of celecoxib followed by a phase II, multicenter study. * Phase I: Patients receive oral celecoxib twice daily. Beginning on day 6, patients undergo thoracic radiotherapy 5 days a week for 3-6.5 weeks . Patients continue to receive celecoxib for up to 2 years in the absence of disease progression or unacceptable toxicity. * Phase II: If fewer than 3 of the first 6 patients experience dose-limiting toxicity, then the dose of celecoxib is escalated for all patients in the study, including those in the first cohort. Quality of life is assessed at baseline and at 3, 6, and 12 months after start of therapy. Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 6-12 patients will be accrued for the phase I portion of this study and a total of 116 patients will be accrued for the phase II portion of this study within 25 months.
Interventions
DRUGcelecoxib
RADIATIONradiation therapy
Sponsors
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
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 * Inoperable stage IIB OR * Unresectable stage IIIA or IIIB * No evidence of hematogenous metastases PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Zubrod 2 AND more than 5% weight loss over the past 3 months OR * Zubrod 0-1 AND less than 5% weight loss over the past 3 months and refuses chemotherapy or are medically unable to tolerate combined modality therapy Life expectancy * Not specified Hematopoietic * Not specified Hepatic * Bilirubin no greater than 2 times upper limit of normal * International Normalized Ratio (INR) no greater than 3.0 if taking warfarin Renal * Creatinine clearance at least 50 mL/min Other * No active gastrointestinal ulcers or bleeding within the past 3 months * No other malignancy within the past 3 years except nonmelanoma skin cancer * No known hypersensitivity to celecoxib * No prior allergic-type reactions to sulfonamides * No prior asthma, urticaria, or allergic-type reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * No prior neoadjuvant chemotherapy * No concurrent chemotherapy Endocrine therapy * No concurrent corticosteroids Radiotherapy * No prior thoracic radiotherapy Surgery * No prior complete or subtotal tumor resection Other * No concurrent NSAIDs, lithium, furosemide, or angiotensin-converting enzyme inhibitors * Concurrent aspirin (325 mg/day) for cardioprotection allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Celecoxib Combined With Radiation Therapy (RT) | Start of treatment to 90 days | Patients were followed for at least 90 days from start of RT and carefully evaluated with respect to treatment morbidity. A dose limiting toxicity (DLT) was defined as grade 3 or 4 nonhematologic (excluding nausea, vomiting, and alopecia) and grade 4 hematologic toxicities. Six patients were to be accrued at each dose level. If no more than three of the six patients experienced a DLT then that dose level was considered acceptable and dose escalation occurred by accruing six more patients at the next dose level. Otherwise, the preceding dose level, if any, would be declared the MTD. The MTD would be used for the Phase II arm. At a given dose, the probability of halting dose escalation when the true toxicity is 50% or higher is at least 66% (power). In addition, if the true DLT rate is instead 20%, there will still be a 10% probability of halting dose escalation at a given dose level (type I error). Rating scale: 0 = not the MTD, 1 = MTD |
| Overall Survival | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 12 months. | Because only 21 patients (18 analyzable) out of 128 planned were accrued on this study, all analyzable patients were combined to report overall survival. The original study design planned for a comparison to a historical control, but due to the small number of patients, survival time is only reported, not tested. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Phase I: Celecoxib 200mg BID + RT COX-2 Inhibitor: Celecoxib 200 mg b.i.d, 7 days/week begins 5 days prior to start of radiation therapy (RT). Once RT begins, Celecoxib a.m. dose 1-2 hours prior to RT. Administer for 2 years or until disease progression.
Concurrent Radiation Therapy: 2 Gy daily, 30-33 fractions, 5 days/week for 6-7 weeks, for a total dose of 60-66 Gy; or 3 Gy daily, 15 fractions, 5 days/week for 3-4 weeks for a total dose of 45 Gy. | 7 |
| Experimental: Phase I/II: Celecoxib 400mg BID + RT COX-2 Inhibitor: Celecoxib 400 mg b.i.d, 7 days/week begins 5 days prior to start of radiation therapy (RT). Once RT begins, Celecoxib a.m. dose 1-2 hours prior to RT. Administer for 2 years or until disease progression.
Concurrent Radiation Therapy: 2 Gy daily, 30-33 fractions, 5 days/week for 6-7 weeks, for a total dose of 60-66 Gy; or 3 Gy daily, 15 fractions, 5 days/week for 3-4 weeks for a total dose of 45 Gy. | 11 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible / No protocol treatment | 0 | 2 |
| Overall Study | Withdrawal of consent | 1 | 0 |
Baseline characteristics
| Characteristic | Experimental: Phase I: Celecoxib 200mg BID + RT | Experimental: Phase I/II: Celecoxib 400mg BID + RT | Total |
|---|---|---|---|
| Age, Continuous | 73 years | 71 years | 72 years |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 8 / 11 |
| serious Total, serious adverse events | 1 / 7 | 1 / 11 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Celecoxib Combined With Radiation Therapy (RT)
Patients were followed for at least 90 days from start of RT and carefully evaluated with respect to treatment morbidity. A dose limiting toxicity (DLT) was defined as grade 3 or 4 nonhematologic (excluding nausea, vomiting, and alopecia) and grade 4 hematologic toxicities. Six patients were to be accrued at each dose level. If no more than three of the six patients experienced a DLT then that dose level was considered acceptable and dose escalation occurred by accruing six more patients at the next dose level. Otherwise, the preceding dose level, if any, would be declared the MTD. The MTD would be used for the Phase II arm. At a given dose, the probability of halting dose escalation when the true toxicity is 50% or higher is at least 66% (power). In addition, if the true DLT rate is instead 20%, there will still be a 10% probability of halting dose escalation at a given dose level (type I error). Rating scale: 0 = not the MTD, 1 = MTD
Time frame: Start of treatment to 90 days
Population: The first six eligible patients who started protocol treatment at each dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Celecoxib 200mg BID + RT | Maximum Tolerated Dose (MTD) of Celecoxib Combined With Radiation Therapy (RT) | 0 units on a scale |
| Phase I: Celecoxib 400mg BID + RT | Maximum Tolerated Dose (MTD) of Celecoxib Combined With Radiation Therapy (RT) | 1 units on a scale |
Primary
Overall Survival
Because only 21 patients (18 analyzable) out of 128 planned were accrued on this study, all analyzable patients were combined to report overall survival. The original study design planned for a comparison to a historical control, but due to the small number of patients, survival time is only reported, not tested.
Time frame: From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 12 months.
Population: Eligible patients who started protocol treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Celecoxib 200mg BID + RT | Overall Survival | 10.0 years |