CALGB 30801: Randomized Phase III Placebo Controlled Trial of COX-2 Inhibition in Stage IIIb/IV COX-2 Overexpressing NSCLC...
COX-2 in Lung Cancer <ul><li>Overexpressed in NSCLC and pre-neoplasia  </li></ul><ul><li>A marker of poor prognosis in NSC...
CALGB 30203:Gemcitabine/ Carboplatin  + Eicosanoid Modulators <ul><li>Randomized phase II trial accrued 140 pts in 9 month...
COX-2: Prognostic and Predictive Marker <ul><li>COX-2 – negative prognostic marker </li></ul><ul><li>COX-2 – positive pred...
Other Evidence for the importance of COX-2 Overexpression in Therapy <ul><li>Lung cancer </li></ul><ul><ul><li>Rush Univer...
Stage IIIB (pleural effusion), IV NSCLC PS 0-1 Adequate organ fcn A Carboplatin AUC =5.5 Gemcitabine(squamous) 1000 mg/m2 ...
Objectives <ul><li>Primary:  </li></ul><ul><ul><li>Determine if the addition of celecoxib to standard chemotherapy will in...
Statistical Assumptions: COX-2 Endpoint <ul><li>The following assumptions are made for power analysis  </li></ul><ul><li>M...
Correlative Study: Urinary PGEM as a Biomarker <ul><li>Hypothesis: Urinary PGE-M may be a marker for COX-2 dependent disea...
Other Correlative Studies <ul><li>-765G/C polymorphism in  PTGS2  and COX-2  expression in NSCLC </li></ul><ul><ul><li>Hyp...
Toxicity of COX-2 Inhibitors <ul><li>Well known potential cardiovascular issues </li></ul><ul><ul><li>Increased cardiovasc...
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Edelman- NCI

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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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Edelman- NCI

  1. 1. CALGB 30801: Randomized Phase III Placebo Controlled Trial of COX-2 Inhibition in Stage IIIb/IV COX-2 Overexpressing NSCLC Martin J. Edelman ,MD University of Maryland Greenebaum Cancer Center
  2. 2. COX-2 in Lung Cancer <ul><li>Overexpressed in NSCLC and pre-neoplasia </li></ul><ul><li>A marker of poor prognosis in NSCLC </li></ul><ul><li>Induced by tobacco carcinogens </li></ul><ul><li>Preclinical studies of COX-2 inhibitors suggest antitumor and chemopreventive efficacy </li></ul><ul><li>Epidemiologic data suggest subjects who routinely use NSAIDs have decreased lung cancer risk </li></ul>
  3. 3. CALGB 30203:Gemcitabine/ Carboplatin + Eicosanoid Modulators <ul><li>Randomized phase II trial accrued 140 pts in 9 months. </li></ul><ul><li>Negative overall. </li></ul><ul><li>Preplanned analysis of COX-2 and 5LOX expression </li></ul>Stage IIIB (pleural effusion), IV NSCLC PS 0-2 Adequate organ fcn Brain metastases eligible A Carboplatin AUC =5.5 Gemcitabine 1000 mg/m2 Zileuton 600 mg po qid PD Off study SD, PR CR Eicosanoid modulator until progression B Carboplatin AUC =5.5 Gemcitabine 1000 mg/m2 Celecoxib 400 mg po bid C Carboplatin AUC =5.5 Gemcitabine 1000mg/m2 Zileuton 600 mg po qid Celecoxib 400 mg bid
  4. 4. COX-2: Prognostic and Predictive Marker <ul><li>COX-2 – negative prognostic marker </li></ul><ul><li>COX-2 – positive predictive marker for celecoxib </li></ul><ul><li>5LOX- neither predictive nor prognostic </li></ul>JCO, 2008 HR =2.51 P=.023 HR=.294 P=.004
  5. 5. Other Evidence for the importance of COX-2 Overexpression in Therapy <ul><li>Lung cancer </li></ul><ul><ul><li>Rush University study (Fidler, 2007) </li></ul></ul><ul><ul><li>Vanderbilt (Csiki, 2007) </li></ul></ul><ul><li>Renal cell carcinoma </li></ul><ul><ul><li>COX-2 overexpressing patients had longer survival with IFN/celecoxib (Rini, 2006) </li></ul></ul><ul><li>Breast cancer </li></ul><ul><ul><li>Capecitabine + celecoxib (200 mg bid, continuously) in advanced breast cancer. (Fabi, 2008) </li></ul></ul><ul><li>Colorectal polyps </li></ul><ul><ul><li>Only COX-2 expressing disease suppressed by ASA (Chan 2007) </li></ul></ul><ul><li>Colorectal cancer </li></ul><ul><ul><li>Aspirin reduced risk of death from cancer only in COX-2 expressing pts (HR =.39). Non-COX-2 pts (HR = 1.22) </li></ul></ul>Fabi, 2008 Fidler,Bonomi, 2007
  6. 6. Stage IIIB (pleural effusion), IV NSCLC PS 0-1 Adequate organ fcn A Carboplatin AUC =5.5 Gemcitabine(squamous) 1000 mg/m2 d1,8 OR Carboplatin AUC = 6 Pemetrexed (non-squamous)500mg/m2 d 1 AND Celecoxib 400 mg po bid X 6 21 day cycles PD Off study SD, PR CR CALGB 30801: Randomized Phase III Placebo Controlled Trial of COX-2 Inhibition in Stage IIIb/IV COX-2 Overexpressing NSCLC B Carboplatin AUC =5.5 Gemcitabine 1000 mg/m2 OR Carboplatin AUC = 6 Pemetrexed (non-squamous)500mg/m2 d 1 AND Placebo X 6 21 day cycles Correlates: Urinary PGEM, pk, pharmacogenetics R E G I S T E R COX-2 Index >2 Index >4* No Chemotherapy per investigator, follow for survival Consider CALGB 30607,30702 Yes R A N D O M I Z E Continue celecoxib or placebo *Index > 4 for primary endpoint
  7. 7. Objectives <ul><li>Primary: </li></ul><ul><ul><li>Determine if the addition of celecoxib to standard chemotherapy will increase progression free and overall survival. </li></ul></ul><ul><li>Secondary: </li></ul><ul><ul><li>Confirm the prognostic value of COX-2 expression. </li></ul></ul><ul><ul><li>RR, OS, PFS etc. </li></ul></ul><ul><li>Correlative/Biomarker </li></ul><ul><ul><li>Correlation of urinary PGE-M with COX-2 expression, celecoxib administration and outcome </li></ul></ul><ul><ul><li>Association between the -765G/C polymorphism in PTGS2 and COX-2 expression in non-small cell lung cancer specimens (Maitland) </li></ul></ul><ul><ul><li>Association of CYP2C9 germline polymorphisms and celecoxib metabolism </li></ul></ul>
  8. 8. Statistical Assumptions: COX-2 Endpoint <ul><li>The following assumptions are made for power analysis </li></ul><ul><li>Median PFS for patients on arm receiving COX-2 inhibitor is 6.2 months and for patients receiving placebo is 4.0 months, corresponding to a hazard ratio of is 0.65 under constant hazards; </li></ul><ul><li>792 pts with an accrual period of 40 months needed for 208 tobe randomized for primary endpoint. </li></ul><ul><li>Power to detect difference is > 85%. Power for OS is >80%. </li></ul>
  9. 9. Correlative Study: Urinary PGEM as a Biomarker <ul><li>Hypothesis: Urinary PGE-M may be a marker for COX-2 dependent disease </li></ul><ul><li>PGE-M is a stable urinary metabolite of PGE-2. </li></ul><ul><li>Levels decrease with COX-2 inhibition. </li></ul><ul><li>A possible biomarker for COX-2 sensitive disease </li></ul><ul><li>Suppression of PGE-M correlated with outcome in pts receiving celecoxib. </li></ul>Csiki, I. et al. Clin Cancer Res 2005;11:6634-6640 Reckamp, K et al Proc ASCO, 2007
  10. 10. Other Correlative Studies <ul><li>-765G/C polymorphism in PTGS2 and COX-2 expression in NSCLC </li></ul><ul><ul><li>Hypothesis: There is an association between rs20417 (-765G>C) genotype and the rate of NSCLC tumors with > 4 intensity score for COX-2 protein expression on IHC. </li></ul></ul><ul><li>CYP2C9 germline polymorphisms and celecoxib metabolism </li></ul><ul><ul><li>Hypothesis: Celecoxib metabolism will be affected by germline P450 polymorphisms and this will determine efficacy </li></ul></ul>
  11. 11. Toxicity of COX-2 Inhibitors <ul><li>Well known potential cardiovascular issues </li></ul><ul><ul><li>Increased cardiovascular toxicity on study by Gridelli. </li></ul></ul><ul><ul><li>Not seen in celecoxib studies (but the numbers are small). </li></ul></ul><ul><li>Must be put into the context of other anti-cancer agents </li></ul><ul><ul><li>We are not treating sore knees </li></ul></ul><ul><ul><li>Toxicity profile compares favorably to trastuzamab, doxorubicin etc. </li></ul></ul>

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