Celecoxib and Docetaxel or Pemetrexed in Treating Patients With Advanced Recurrent Non-Small Cell Lung Cancer

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.

• celecoxib (Drug): 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 (Drug): 75mg/m2 given through a vein over 90 minutes on day 1 of a 3-week cycle
• pemetrexed disodium (Drug): 500 mg/m2 through a vein over 90 minutes on day 1 of a 3 week cycle.
• laboratory biomarker analysis (Other): Blood collection

Primary outcomes

• 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 outcomes

• 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 outcomes

• 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]

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Median Survival (Primary), Median, days: Treatment Arm 184 (129 to 208)
• Overall Response Rate (Secondary), Number, participants: Treatment Arm 0 (0 to 0.176)
• Time to Progression (Secondary), Median, days: Treatment Arm 89 (42 to 386)
• Effect of Celecoxib on Urinary Metabolites of PGE2, PG12 and Thromboxane (Other pre specified)
• Changes in Urinary PGE-M and Survival as Assessed by Immunohistochemistry (Other pre specified)

Adverse events

Serious adverse events by term

Other adverse events by term

• Leora Horn, MD, Study chair, Vanderbilt-Ingram Cancer Center

NIH grants: P30CA068485