PHASE II STUDY OF AN OPTIMIZED 5FU-OXALIPLATIN STRATEGY (OPTIMOX2) WITH CELECOXIB IN METASTATIC COLORECTAL CANCER: A GERCOR STUDY. T André, F Maindrault-Goebel, L Mineur, M Flesch, M Mabro, G Ganem, M Hebbar, D Avenin, R Mokhtar, A de Gramont. ABSTRACT Background: In the OPTIMOX study (André et al, ASCO 2003), 6 cycles of Folfox7 followed by simplified LV5FU2 maintenance were administered to decrease the neurotoxicity and to later allow FOLFOX7 reintroduction. Celecoxib is an anti-cox2 compound with anti-neoplastic properties such as angiogenic inhibition and apoptosis induction. We evaluated a new strategy exploring 1) the stop and go procedure (6 cycles of Folfox7 then stop and reintroduction Folfox7 at progression); 2) the addition of celecoxib during Folfox7 and chemotherapy-free interval (CFI). Methods: Patients (pts) with non resectable metastatic colorectal adenocarcinoma were treated in first-line by Folfox7: oxaliplatin 130 mg/m2 day (d1), and folinic acid 400 mg/m2 d1, and 5FU 46h 2400 mg/m2 every two weeks for 6 cycles. Chemotherapy was then interrupted and reintroduced at progression. Celecoxib 400 mg BID per os was administered during Folfox7 and CFI intervals until Folfox7 discontinuity for progression or limiting toxicity. 44 pts included, 42 eligible: Performance status (%) 0/1/2 = 45/40/15, median age 60 [31-76]. Half of patients had one metastatic site. Results: 42 pts are evaluable for safety and 38 for response. Grade 3-4 toxicity per pts (%) were neutropenia 7%, thrombocytopenia 19%, diarrhea 7%, nausea-vomiting 7%, neuropathy 9.5%, (maximal gr 3-4 toxicity 31%). During follow-up period (median 44 weeks), 2 pts presented grade 1-2 epigastralgia without ulcers,1 digestive hemorrhage with gastritis and one a renal toxicity grade 4. 2 CR, 16 PR (RR 47%; 95% CI: 31%-63%), 13 SD (34.2%) and 7 PD (18.4%) were obtained. Median PFS 1 was 26 weeks. 31/42 had a CFI (11 pts not evaluable for CFI: 7 PD at 2-3 months of therapy, 3 for personal choice and 1 out of protocol for toxicity). Median CFI 1duration was 76 days (range 59-219) with 58% with PD at the end of CFI 1. Conclusion: In this phase II study, celecoxib combined with FOLFOX 7 is associated with a good safety and a response rate of 47%. RR seems not increased by addition of celecoxib in comparison with results of OPTIMOX1 study (Arm FOLFOX7-sLVF5U2: RR 58.5%). In this strategy phase II study with Chemotherapy Free Interval and celecoxib, PFS of 6 months is lower (non comparative phase III study) as PFS obtained with simplified LV5FU2 in maintenance therapy after 6 FOLFOX7 (OPTIMOX1 study: Arm FOLFOX7-sLVF5U2: PFS 9 months). OPTIMOX2 celecoxib: RATIONAL In the OPTIMOX study (André et al, ASCO 2003; de Gramont, ASCO 2004), 6 cycles of FOLFOX7 followed by simplified LV5FU2 maintenance were administered to decrease the cumulative neurotoxicity of oxaliplatin and to later allow FOLFOX7 reintroduction. Celecoxib is an anti-cox2 compound with anti-neoplastic properties such as angiogenic inhibition and apoptosis induction We evaluated a new strategy exploring the stop and go procedure (6 cycles of FOLFOX7 then stop and reintroduction FOLFOX7 at progression) which avoids cumulative toxicity (oxaliplatin), decreases the risk of resistance, improves QoL, and decreases the cost the addition of celecoxib during FOLFOX7 and chemotherapy-free interval (CFI) STUDY DESIGN (PHASE II) Surgery then Simplified LV5FU2 (12 cycles + celecoxib) CFI* = CT Free Interval 2 months CFI* CR, PR 2 months CFI* Celocoxib Celocoxib FOLFOX 7 X 6 FOLFOX 7 X 6 Out of protocol Celocoxib H0 H2 H24 H48 5-FU 2400 Oxali 130 Cycles every 14 days, Dose mg/m2 Evaluation by CT scan at C4, C6 and then every 2 months Out of protocol POPULATION Multicenter phase II study, 44 patients were enrolled after informed consent, between 12/2002 and 6/2003, 2 patients were ineligible Inclusion criteria: – Histologically proven adenocarcinoma of the colon or rectum – Non resectable metastatic disease – Mesurable disease (Recist criteria) – No prior CT except adjuvant CT if ended ? 6 months before study entry – 18 – 75 years and WHO PS ? 2 – Adequate hematological, renal and liver functions (Bili < 1.5 ULN and Ph Alc < 3 ULN) Exclusion criteria:
– Treatment by fluconazole, warfarin, lithium or corticosteroids
– Duodenal or gastric ulcer(s) in the past BASELINE CHARACTERISTICS (N = 42) Median age (range) 60 yrs (31 – 76) Sexe ratio (M / F) Performance status (0 / 1 / 2) 45 / 40 / 15 Site of primary: colon / rectum Prior adjuvant chemotherapy (Yes – No) Alkaline Phos: Normal / between 1 and 3 ULN LDH: N / > ULN / Missing (%) 50 / 33 / 17 Nb metastatic sites: 1 / ? 2 (%) Metastatic sites Liver (%) Other (%) TOXICITY Per patient Per cycle Grade 3/4 (NCI) Neutropenia Thrombocytopenia Nausea-vomiting Diarrhea Alopecia (gr 2) Peripheral neuropathy (gr 3) Maximal (gr 3 - 4) There were no toxic death. Two pts had grade 1-2 epigastralgia without ulcer, one had gastritis with digestive hemorrhage and one presented grade 4 renal toxicity. TUMOR RESPONSE (N = 42) Tumour response was assessed with CT-scan every 2 months (4 cycles) according to RECIST criteria. Complete response Partial response Stable disease Progressive disease Non evaluable OBJECTIVE RESPONSE RATE 18/38 = 47% CHEMOTHERAPY FREE INTERVAL (CFI)= PAUSE CFI number 1 (n=31, 7 pts with PD after 4 or 6 FOLFOX7, 3 out of protocol for personal choice and 1 for toxicity)
– At the evaluation after 2 months CFI: 58% PD, 16% SD, 13% PR, 13% CR
– Median: 76 days (range: 59-219) CFI number 2 (n=14)
– Median: 68 days (range: 29-152)
– At the evaluation after 2 months CFI: 57% PD, 21% SD, 7% PR, 14% CR CFI number 3 (n=8)
– Median: 62 days (range: 36-94)
– At the evaluation after 2 months CFI: 62.5% PD, 12.5% SD, 0% PR, 25% CR CFI number 4 (n=2)
– Median: 83 days (range: 76-91)
– At the evaluation after 2 months CFI: 50% PD, 50% CR OXALIPLATIN REINTRODUCTION 12 pts with oxaliplatin reintroduction (28.6%)
– 1RP, 5SD, 6PD 13 without PD at this time (7 with surgery R0 of metastasis) 17 pts without reintroduction and out of protocol
– 4 with neurotoxity grade 3 and 2 with other toxicity
– 3 personal choice of patients or physician PROGRESSION FREE SURVIVAL Optimox II Celecoxib TDC (42 patients) Optimox II Celecoxib overall survival (42 patients) follow up: Proportions Proportions 0.4 Time (weeks) Time (weeks) At time of analysis, progression At time of analysis, 13 deaths occurred in 36/42 patients occurred in 42 patients Median progression-free Median was not reached survival was 26 semaines IC 95%=[22 -28 weeks] CONCLUSION (1) In this phase II study, celecoxib combined with FOLFOX 7 is associated with a good safety, a response rate of 47% and a disappointing PFS of 6 As most patients have PD after 2 months Chemotherapy Free Interval (CFI) it necessary to prolong CFI and allow FOLFOX reintroduction later than first progression in patient without symptom, especially when progression occurs after a objective response. New criteria for chemotherapy reintroduction are needed. RR seems not increased by addition of celecoxib in comparison with results of OPTIMOX1 study (Arm FOLFOX7-sLVF5U2: RR 58.5%). In this strategy phase II study with Chemotherapy Free Interval and celecoxib, PFS of 6 months is lower (non comparative phase III study) as PFS obtained with simplified LV5FU2 in maintenance therapy after 6 FOLFOX7 (OPTIMOX1 study: Arm FOLFOX7-sLVF5U2: PFS 9 months). CONCLUSION (2) GERCOR OPTIMOX2- Chemotherapy Free Interval (CFI) phase III study is ongoing to evaluate Chemotherapy Free interval OPTIMOX 1 Advanced FOLFOX 7 - CFI - FOLFOX 7 - CFI
In responders and stable disease patients: stop and reintroduce according formula below or in case of tumor- related symptom. Exact formula to anticipate time of reintroduction (for lesions >2cm): ITM =initial tumor measure; TM = tumor measure at present evaluation; TM
= tumor measure expected next evaluation. = (TMP )²/TMP
?ITM, reintroduce; If TM <ITM, do not reintroduce. Other drugs like anti-angiogenic (anti VEGF) or anti-Epidermal Growth Factor should be evaluate in phase III first line advanced CRC in combination with CFI
The Prostate 44:111–117 (2000) Modulating Effect of Estrogen and Testosterone on Prostatic Stromal Cell Phenotype Differentiation Induced by Noradrenaline and Doxazosin Paul Smith,1* Nicholas P. Rhodes,2 Youqiang Ke,1 and Christopher S. Foster1 1Department of Cellular and Molecular Pathology, University of Liverpool, 2Department of Clinical Engineering, University of Liverpool,
PHASE II STUDY OF AN OPTIMIZED 
CONCLUSION (2)