Lung Cancer
Conditions
Keywords
recurrent non-small cell lung cancer, stage IV non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IIIA non-small cell lung cancer
Brief summary
RATIONALE: Celecoxib may stop the growth of tumor cells by blocking some of the enzymes need for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving celecoxib together with docetaxel or pemetrexed may kill more tumor cells. PURPOSE: This phase II trial is studying how well celecoxib given together with docetaxel or pemetrexed works in treating patients with advanced or recurrent non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * To determine the efficacy of celecoxib when administered with standard chemotherapy comprising docetaxel or pemetrexed disodium in patients with advanced, recurrent non-small cell lung cancer (NSCLC) exhibiting cyclooxygenase (COX) dependence. Secondary * To determine the overall response rate and time to progression in patients with COX-dependent recurrent NSCLC treated with celecoxib and docetaxel or pemetrexed disodium. * To determine the effect of celecoxib on the urinary metabolites of PGE\_2 , PGI\_2, and thromboxane in patients with COX-dependent recurrent NSCLC. * To correlate changes in urinary PGE-M and survival with intratumoral expression of COX-2, mPGES, and 15-PGDH as assessed by IHC. OUTLINE: Patients with no prior taxane exposure receive docetaxel IV over 1 hour on day 1; patients with prior taxane exposure or for whom docetaxel treatment is contraindicated receive pemetrexed disodium IV over 10 minutes on day 1. Treatment with docetaxel or pemetrexed disodium repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. All patients receive oral celecoxib twice daily beginning 5-7 days prior to the first docetaxel or pemetrexed disodium infusion and continuing for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo blood and urine sample collection at baseline and periodically during study for biomarker correlative studies. Urine samples are assessed for PGE-M levels. Blood samples are analyzed for serum celecoxib levels, VEGF, endostatin, and cytokine assays. After completing the last dose of celecoxib, patients are followed at 4-6 weeks and then every 3 months thereafter for up to 2 years from study entry.
Interventions
DRUGcelecoxib
600 mg will be taken by mouth twice a day for 6 weeks then 400 mg twice a day for up to a year after chemotherapy is discontinued in the absence of progression.
DRUGDocetaxel
75mg/m2 given through a vein over 90 minutes on day 1 of a 3-week cycle
DRUGpemetrexed disodium
500 mg/m2 through a vein over 90 minutes on day 1 of a 3 week cycle.
OTHERlaboratory biomarker analysis
Blood collection
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria: * Cytologically or histologically confirmed COX dependent non-small cell lung cancer. * COX dependency is defined by change in urinary PGE-M levels following a run-in phase of celecoxib. * Previous treatment with ≤2 different chemotherapy regimens one of which must have been platinum-based (cisplatin or carboplatin) chemotherapy. * Age ≥18 years * ECOG PS 0, 1 or 2. * Measurable or evaluable disease. * At least 3 weeks post major surgery, chemotherapy or radiotherapy & recovered from all toxicities. * Expected survival of at least 2 months. * CNS metastases permitted provided the patient has adequately recovered from radiotherapy includes stereotactic therapy) or surgery. * Adequate renal function: serum creatinine ≤1.8 mg/dl &/or CrCl \>50 cc/min Eligibility According to Liver Function: AST: \</= 1.5 ULN-Docetaxel; \</= 2.5 ULN-Pemetrexed (Liver parameters to be used for pemetrexed in the absence of proven or radiographically suspected liver metastases.); \</= 5.0 ULN-Pemetrexed (Liver parameters to be used for pemetrexed only in the presence of proven or radiographically suspected liver metastases.) Alk Phosphatase: \</= 2.5 ULN-Docetaxel; \</= 2.5 ULN-Pemetrexed (Liver parameters to be used for pemetrexed in the absence of proven or radiographically suspected liver metastases.); \</= 5.0 ULN-Pemetrexed (Liver parameters to be used for pemetrexed only in the presence of proven or radiographically suspected liver metastases.) Total Bilirubin: \</= 1.5 ULN-Docetaxel; \</= 1.5 ULN-Pemetrexed (Liver parameters to be used for pemetrexed in the absence of proven or radiographically suspected liver metastases.); \</= 2.5 ULN-Pemetrexed (Liver parameters to be used for pemetrexed only in the presence of proven or radiographically suspected liver metastases.) * Adequate hematologic function: ANC≥1500/mm3 & platelets ≥100,000/mm3 * Female patients cannot be pregnant and must use contraception if of childbearing age * Lactating women are excluded. * Peripheral neuropathy must be CTC grade ≤2 * Patients must not currently be on non-steroidal anti-inflammatory agents or other COX-2 inhibitors (Must be off for at least ≤7 days) * Written informed consent.
Exclusion criteria
* More than two prior chemotherapy regimens for recurrent or relapsed NSCLC. * COX Independent as defined by change in urinary PGE-M levels following a run-in phase of celecoxib. * Previous treatment with both docetaxel and pemetrexed * History of greater than grade 2 allergic reaction to celecoxib or any other non-steroid anti-inflammatory agent including aspirin, ibuprofen, or indomethacin. * History of allergy to compounds containing boron or mannitol. * History of allergy to sulfonamides. * Concomitant use of Warfarin, but low dose Coumadin allowed for port prophylaxis * Recent (past 4 weeks) coronary artery bypass graft (CABG) surgery. * Inadequate organ function: * Serum creatinine ≥1.8 mg/dl or a calculated CrCl \<45 cc/min. * AST \>1.5 upper limits of normal (ULN); alkaline phosphatase \>2.5 ULN; & bilirubin \>1.5 ULN * ANC\<1500/mm3 & platelets \<100,000/mm3 * Active pregnancy or inability or unwillingness to employ appropriate contraception. * Small cell carcinoma histology. * Prior malignancy within 5 years of diagnosis of NSCLC. Exceptions include basal cell or non-metastatic squamous cell carcinomas of the skin, cervical carcinoma in situ or FIGO stage I cervical carcinoma, or other cancer history considered not clinically significant by the principal investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Survival | 2 years from date of registration | Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | On-treatment date to date of disease progression (assessed at 6 weeks up to 2 years) | Overall response rate is measured by complete response + partial response. Number of patients in each response category, per RECIST v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), \>=30% decrease in sum of longest diameter of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or SD. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD. |
| Time to Progression | 2 years from date of registration | Estimated probable duration from on-study date to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as \>=20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions. |
Other
| Measure | Time frame |
|---|---|
| Effect of Celecoxib on Urinary Metabolites of PGE2, PG12 and Thromboxane | At 1 year |
| Changes in Urinary PGE-M and Survival as Assessed by Immunohistochemistry | At 1 year |
Countries
United States
Participant flow
Recruitment details
This study opened October 2007 and ran to December 2013. All patients were recruited from Vanderbilt-Ingram Cancer Center.
Pre-assignment details
This study included a run-in phase of celecoxib 600 mg BID x 5-7 day, following patient enrollment. Patients with ≥70% decrease in PGE-M level, were considered COX dependent and protocol eligible making them eligible for protocol treatment. Patients with \<70% decrease in PGE-M level were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Either docetaxel or pemetrexed given with celecoxib
celecoxib: 600 mg will be taken by mouth twice a day for 6 weeks then 400 mg twice a day for up to a year after chemotherapy is discontinued in the absence of progression.
Docetaxel: 75mg/m2 given through a vein over 90 minutes on day 1 of a 3-week cycle
pemetrexed disodium: 500 mg/m2 through a vein over 90 minutes on day 1 of a 3 week cycle.
laboratory biomarker analysis: Blood collection | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Alternative Therapy | 1 |
| Overall Study | Death | 3 |
| Overall Study | Disease Progression, relapse | 13 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Treatment Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 63.26 years |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 23 |
| serious Total, serious adverse events | 17 / 23 |
Outcome results
Primary
Median Survival
Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details)
Time frame: 2 years from date of registration
Population: All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where death is an event, with censoring for non-expired patients at greater of off-study date or last known alive date.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Median Survival | 184 days |
Secondary
Overall Response Rate
Overall response rate is measured by complete response + partial response. Number of patients in each response category, per RECIST v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), \>=30% decrease in sum of longest diameter of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or SD. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD.
Time frame: On-treatment date to date of disease progression (assessed at 6 weeks up to 2 years)
Population: All patients with best overall response data; patients are excluded if best overall response data is missing or if the patient is not evaluable for best overall response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Arm | Overall Response Rate | 0 participants |
Secondary
Time to Progression
Estimated probable duration from on-study date to date of disease progression, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under RECIST v1.1 as \>=20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.
Time frame: 2 years from date of registration
Population: All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where progression is an event, with censoring for non-progressed patients at greater of off-study date, last known alive date, or date of death not attributable to disease progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Time to Progression | 89 days |
Other Pre-specified
Changes in Urinary PGE-M and Survival as Assessed by Immunohistochemistry
Time frame: At 1 year
Population: data is not available. no analysis done
Other Pre-specified
Effect of Celecoxib on Urinary Metabolites of PGE2, PG12 and Thromboxane
Time frame: At 1 year
Population: data is not available. no analysis done