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1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar  Pharmacia & Upjohn First-Line Therapy of Metastatic Colorectal.

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Presentation on theme: "1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar  Pharmacia & Upjohn First-Line Therapy of Metastatic Colorectal."— Presentation transcript:

1 1 (Irinotecan, CPT-11) Oncologic Drugs Advisory Committee Review March 16, 2000 Camptosar  Pharmacia & Upjohn First-Line Therapy of Metastatic Colorectal Cancer

2 2 Presentation Agenda  Background  2 Pivotal Phase III Controlled Clinical Trials –Improved Tumor Control –Improved Survival  Summary and Conclusions  Q&A

3 3 CPT-11 Presentation Team FunctionNameAffiliation MedicalLangdon Miller, MDP&U Paula Locker, MSP&U Gabriela Gruia, MDAventis BiostatisticalNicoletta Pirotta, MSP&U Gary Elfring, MSP&U Lucile Awad, MSAventis PharmacologyLarry Schaaf, PhDP&U InvestigatorsLeonard Saltz, MDMSKCC Jean-Yves Douillard, MD C Gauducheau Hanjochen Wilke, MDK Essen-Mitte

4 4 Background

5 5  Development of metastases: –20% of patients have metastatic disease at presentation –40% of all patients will ultimately develop metastases  Deaths due to metastatic disease: 57,000 patients  Standard first-line treatment: 5-fluorouracil (5-FU) Colorectal Cancer in 2000  US Incidence: 130,000 patients –95,000 with colon cancer –35,000 with rectal cancer American Cancer Society. Cancer Facts & Figures 2000.

6 6 Survival (median) 5-FU Therapy: With and Without LV Adding LV to 5-FU significantly improves response rate but not survival Meta-analysis Group in Cancer. J Clin Oncol. 1992;10:896-903 Meta-analysis of 9 randomized trials (N=1,381) Response Rate

7 7 5-FU Therapy: Infusional vs Bolus Infusional 5-FU significantly increases response rate but median survival remains 12 months Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Meta-analysis of 6 randomized trials (N=1,219) Response Rate Survival (median)

8 8  Novel agent with a new mechanism of action needed CPT-11 Therapy of Colorectal Cancer  CPT-11 offers: –Topoisomerase I inhibition –Consistent activity in colorectal cancer

9 9 First-Line, Single-Agent CPT-11 Therapy CPT-11 offers similar activity to that of 5-FU/LV *Conti. J Clin Oncol. 1996;14:709-715. ^Pitot. J Clin Oncol. 1997;15:2910-2919. Results of US phase II trials (N=72) Response Rate Survival (median)

10 10 RANDOMIZATION CPT-11: 350 mg/m 2 every 3 weeks Best Supportive Care Prior5-FU Second-Line CPT-11 Therapy (V301) Cunningham et al. Lancet. 1998; 352:1413-18..

11 11 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821 Months Probability Second-Line Survival (V301) p=0.0001* * log-rank test CPT-11 BSC

12 12 RANDOMIZATION CPT-11: 350 mg/m 2 every 3 weeks Infusional 5-FU-based regimen Prior5-FU Second-Line CPT-11 Therapy (V302) Rougier et al. Lancet. 1998; 352:1407-12.

13 13 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 036912151821 Months Probability Second-Line Survival (V302) p=0.04* * log-rank test CPT-11 Infusional 5-FU

14 14  Different mechanism of action from 5-FU Rationale for First-Line CPT-11 Combination Therapy Hypothesis: First-line combination of CPT-11 with 5-FU/LV will further improve tumor control and survival  Active as first-line, single-agent therapy  Extends survival when used as second-line therapy

15 15 *Saltz. J Clin Oncol. 1996;14:2959-2967.  Weekly bolus regimen (Saltz -- Study 0007) Phase I Combination Dose-Finding and Pharmacokinetic Studies  Every-2-week infusional regimen (de Gramont -- Study F106) †Ducreux. J Clin Oncol. 1999;17:2901-2908.  Weekly infusional regimen (AIO -- Study G101) ‡Vanhoefer. J Clin Oncol. 1999;17:907-913. Addition of CPT-11 to existing schedules of 5-FU/LV

16 16 Pivotal Phase III Trials Study Design and Conduct

17 17 Pivotal First-Line Trials Two independent, phase III, prospective, randomized, controlled, international studies CPT-11/Infusional 5-FU/LV vs Infusional 5-FU/LV Aventis Study V303 CPT-11/Bolus 5-FU/LV vs Bolus 5-FU/LV vs ( CPT-11 alone) Pharmacia & Upjohn Study 0038

18 18 Entry Criteria (0038)  Histologically proven colorectal cancer  Unresectable measurable metastases  Performance status 0, 1 or 2  No prior chemotherapy for metastatic disease  >12 months since completion of adjuvant 5-FU  No prior pelvic radiotherapy permitted  Adequate hematologic, renal, and hepatic function

19 19 Entry Criteria (V303)  Histologically proven colorectal cancer  Unresectable measurable metastases  Performance status 0, 1 or 2  No prior chemotherapy for metastatic disease  >6 months since completion of adjuvant 5-FU  Prior pelvic radiotherapy permitted  Adequate hematologic, renal, and hepatic function

20 20 Treatment (0038)  Treatment continued until tumor progression or unacceptable toxicity  Supportive care for all study arms included: –Atropine for the treatment of cholinergic symptoms –Loperamide for the treatment of late diarrhea –Antiemetics for the prophylaxis of nausea and vomiting  Second-line, post-study chemotherapy permitted

21 21 Treatment (V303)  Treatment continued until tumor progression or unacceptable toxicity  Supportive care for all study arms included: –Atropine for the treatment of cholinergic symptoms –Loperamide for the treatment of late diarrhea –Antiemetics for the prophylaxis of nausea and vomiting –Fluoroquinolone antibiotic for diarrhea in association with –Fluoroquinolone antibiotic for diarrhea in association with grade 4 neutropenia or neutropenic fever  Second-line, post-study chemotherapy permitted

22 22 Endpoints (0038)  Time to tumor progression (primary)  Tumor response rate  Survival  Safety  Quality of life (EORTC QLQ-C30)

23 23 Endpoints (V303)  Time to tumor progression  Tumor response rate (primary)  Survival  Safety  Quality of life (EORTC QLQ-C30)

24 24 Patient Evaluation (0038)  On-study assessments – Tumor measurements (q 6 weeks x 4, then q 12 weeks) – Performance status, weight, quality of life, chemistries (Day 1 of each cycle) – Adverse events, CBCs (weekly)  Follow-up –Post-study chemotherapy – Survival

25 25 Patient Evaluation (V303)  On-study assessments – Tumor measurements (q 6-7 weeks) – Performance status, weight, quality of life, chemistries (Day 1 of each cycle) – Adverse events, CBCs (weekly)  Follow-up –Post-study chemotherapy – Survival

26 26 Sample Size Calculation (0038)  Primary endpoint assumptions –40% improvement in TTP  Statistical test –  = 0.05 and 1-  = 0.85 –Unstratified log-rank  Sample size –220 patients per treatment arm

27 27 Sample Size Calculation (V303)  Primary endpoint assumptions –40% improvement in response rate  Statistical tests –  = 0.05 and 1-  = 0.80 –Unstratified chi-square  Sample size –169 patients per treatment arm

28 28 RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION Stratification:  PS (0 vs 1, 2)  Age ( 65 yr)  Time from initial diagnosis ( 6 mo)  Prior adjuvant therapy (yes vs no) CPT-11:125 mg/m 2 /wk x 4 wks, q 6 wks 5FU:500 mg/m 2 /wk x 4 wks, q 6 wks LV: 20 mg/m 2 /wk x 4 wks, q 6 wks 5FU:425 mg/m 2 /d x 5 d, q 4 wks 5FU:425 mg/m 2 /d x 5 d, q 4 wks LV: 20 mg/m 2 /d x 5 d, q 4 wks 5-FU dose intensity= 531 mg/m 2 /wk 5-FU dose intensity= 333 mg/m 2 /wk Treatment Arms (0038)

29 29 CPT-11: 80 mg/m 2 /wk x 6 wks, q 7 wks 5-FU: 2.3 gm/m 2 /wk x 6 wks, q 7 wksAIO LV:500 mg/m 2 /wk x 6 wks, q 7 wks or CPT-11: 180 mg/m 2 d1 q 2 wks 5-FU:400 IV/600 CI mg/m 2 d1, 2 q 2 wksde Gramont LV:200 mg/m 2 d1, 2 q 2 wks 5-FU: 2.6 gm/m 2 /wk x 6 wks, q 7 wksAIO LV:500 mg/m 2 /wk x 6 wks, q 7 wks or 5-FU:400 IV/600 CI mg/m 2 d1, 2 q 2 wksde Gramont LV:200 mg/m 2 d1, 2 q 2 wks RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION Treatment Arms (V303)

30 30 Study Enrollment and Follow-Up (0038)  Principal Investigator:Dr. Leonard Saltz  Number of sites:71 (Primarily North America)  Accrual period: May 1996 - May 1998  Survival cut-off: December 1999 (19-month follow-up)

31 31 Study Enrollment and Follow-Up (V303)  Principal Investigator:Dr. Jean-Yves Douillard  Number of sites:83 (Primarily Europe)  Accrual period: May 1997 - February 1998  Survival cut-off: October 1999 (20-month follow-up)

32 32 Pivotal Phase III Trial Results Patient Characteristics and Treatment Administration

33 33 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 Intent-to-treat population 231226226 Never treated 4 8 4 Treated on another arm 2 1 1 As-treated population 225219223 Patient Enrollment (0038)

34 34 CPT-11/5-FU/LV 5-FU/LV CPT-11/5-FU/LV 5-FU/LV [AIO][de Gramont] [AIO][de Gramont] Randomized199188 Never treated 1 1 Full-analysis population198187 [53] [145][44][143] Treated on other arm 0 1 As-treated population 199186 [54] [145][43][143] Patient Enrollment (V303)

35 35 CPT-11/5-FU/LV5-FU/LV CPT-11 N=231N=226N=226 Median age (yrs)626161 [range][25-85][19-85][30-87] Gender (% of pts) M66 5564 M66 5564 F344534. F344534. Performance status (% of pts) 0394246  1615854 Demographics (0038)

36 36 CPT-11/5-FU/LV5-FU/LV N=198N=187 Median age (yrs)6261 [range][27-75][25-75] Gender (% of pts) M67 53 F3347. F3347. Performance status (% of pts) 05251  14849 Demographics (V303)

37 37 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 N=231N=226N=226 Primary site (% of pts) Colon818584 Rectum171415 Number of involved organ sites (% of pts) 1646662 >2363438 Liver involvement (% of pts)828283 Disease Characteristics (0038)

38 38 CPT-11/5-FU/LV 5-FU/LV CPT-11/5-FU/LV 5-FU/LV N=198N=187 Primary site (% of pts) Colon5565 Rectum4536 Number of involved organ sites (% of pts) 16263 >23837 Liver involvement (% of pts)7780 Disease Characteristics (V303)

39 39 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 N=231N=226N=226 Median time from initial diagnosis (mo) 1.9 1.7 1.8 [range][0.1-161][0.1-203][0.1-186] Prior adjuvant 5-FU 11810 (% of pts) Pelvic radiotherapy 211 (% of pts) Disease History (0038)

40 40 CPT-11/5-FU/LV 5-FU/LV CPT-11/5-FU/LV 5-FU/LV N=198N=187 Median time from initial diagnosis (mo) 4.5 2.7 [range][0.1-88][0.1-104] Prior adjuvant 5-FU2624 (% of pts) Radiotherapy2016 (% of pts) Disease History (V303)

41 41 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 N=231N=226N=226 Abnormal baseline value (% of pts) Hgb <11 g/dL262526 WBC  8x10 9 /L525351 LDH >ULN605653 Bilirubin >ULN 7 410 CEA  100 ng/mL403937 Baseline Laboratory Abnormalities (0038) *ULN = upper limit of normal

42 42 CPT-11/5-FU/LV 5-FU/LV CPT-11/5-FU/LV 5-FU/LV N=198N=187 Abnormal baseline value (% of pts) Hgb <11 g/dL1621 WBC  8x10 9 /L4738 LDH >ULN4044 Bilirubin >ULN 7 7 CEA  100 ng/mL3532 Baseline Laboratory Abnormalities (V303) *ULN = upper limit of normal

43 43 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 N=225N=219N=223 Median duration (mo)5.54.13.9 [range][0.3-33][0.4-22][0.2-18]. Median dose intensity (mg/m 2 /wk) [Median relative dose intensity*] 5-FU236 [0.71]457 [0.86]-- CPT-11 60 [0.72]--62 [0.75] Treatment Administration (0038) *Ratio of actual dose intensity relative to planned dose intensity

44 44 CPT-11/5-FU/LV 5FU/LV CPT-11/5-FU/LV 5FU/LV N=199 N=186 N=199 N=186 AIOde Gramont AIOde Gramont N=54N=145N=43N=143 Median duration (mo) 5.55.74.84.2 Median duration (mo) 5.55.74.84.2 [range][0.5-14.8] [0.5-15.7] [0.2-10.6][0.5-11.5] [range][0.5-14.8] [0.5-15.7] [0.2-10.6][0.5-11.5] Median relative dose intensity * CPT-110.820.93 ---- 5-FU 0.810.920.900.96 Treatment Administration (V303) *Ratio of actual dose intensity relative to planned dose intensity

45 45 Pivotal Phase III Trial Results Efficacy and Safety

46 46 CPT-11/5-FU/LV5-FU/LVCPT-11 N=(231,198)N=(226,187)N=226 Study 003839%21%18% Study V303 35% 22% Confirmed Response Rates (0038,V303) Responses confirmed  4 weeks after initial objective response *Chi-square test p<0.005* p<0.0001*

47 47 CPT-11/5-FU/LV5-FU/LVCPT-11 N=(231,198)N=(226,187)N=226 Median (0038) 7.0 mo4.3 mo4.2 mo Median (V303) 6.7 mo 4.4 mo *Log-rank test Time to Tumor Progression (0038,V303) p=0.004* p<0.001*

48 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 03691215182124 Months Probability CPT-11/5-FU/LV (N=231) 5-FU/LV (N=226) * log-rank test p=0.004* Time to Tumor Progression (0038)

49 49 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 03691215 Months Probability CPT-11/5-FU/LV (N=198) 5-FU/LV (N=187) Time to Tumor Progression (V303) p<0.001* * log-rank test

50 50 Hazard Ratio Factor Value[95% CI]p-value Factor Value[95% CI]p-value LDH  UNL vs >UNL 0.600.0001 [0.47-0.76] Organ sites1 vs  2 sites0.63 0.0001 [0.50–0.80] PS0 vs  10.74 0.0088 [0.59–0.93] Bilirubin  UNL vs >UNL 0.56 0.0132 [0.35–0.89] Hemoglobin< 11 vs  11 g/dL0.740.0157 [0.58–0.95] Age  65 vs <65 years0.78 0.0315 [0.63–0.98] TreatmentCPT-11/5-FU/LV0.640.0001 vs 5-FU/LV [0.51–0.79] vs 5-FU/LV [0.51–0.79] *ULN=upper limit of normal Cox Regression Analysis: TTP (0038)

51 51 Hazard Ratio Factor Value[95% CI]p-value Factor Value[95% CI]p-value Organ sites1 vs  2 sites0.73 0.0001 [0.57–0.94] LDH  UNL vs >UNL 0.640.0012 [0.48-0.84] TreatmentCPT-11/5-FU/LV0.590.0001 vs 5-FU/LV [0.46–0.76] vs 5-FU/LV [0.46–0.76] Cox Regression Analysis: TTP (V303)

52 52 CPT-11/5-FU/LV5-FU/LVCPT-11 N=(231,198)N=(226,187)N=226 Median (0038)14.8 mo12.6 mo12.0 mo Median (V303)17.4 mo 14.1 mo Survival (0038,V303) *Log-rank test p=0.042* p=0.032*

53 53 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 06121824303642 Months CPT-11/5-FU/LV (N=231) 5-FU/LV (N=226) Survival (0038) p=0.042* Probability * log-rank test

54 54 Survival (V303) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0612182430 Months Probability CPT-11/5-FU/LV (N=198) 5-FU/LV (N=187) p=0.032* * log-rank test

55 55 Hazard Ratio Factor Value[95% CI]p-value Factor Value[95% CI]p-value LDH  UNL vs >UNL 0.470.0001 [0.37-0.60] PS0 vs  10.57 0.0001 [0.45–0.71] WBC <8 vs  8 x 10 9 /L 0.640.0001 [0.51–0.80] Organ sites1 vs  2 sites0.67 0.0004 [0.54–0.84] Bilirubin  UNL vs >UNL 0.55 0.0051 [0.35–0.86] TreatmentCPT-11/5-FU/LV0.800.0372 vs 5-FU/LV [0.64–0.99] vs 5-FU/LV [0.64–0.99] Cox Regression Analysis: Survival (0038)

56 56 Hazard Ratio FactorValue[95% CI]p-value LDH  UNL vs >UNL 0.550.0001 [0.42-0.72] PS0 vs  10.52 0.0001 [0.41–0.67] Time from  1 vs < 1 mo.630.0005 Metastatic Dx [0.49-0.82] Organ sites1 vs  2 sites0.73 0.0127 [0.57–0.94] TreatmentCPT-11/5-FU/LV0.770.0365 [vs 5-FU/LV] [0.61–0.98] [vs 5-FU/LV] [0.61–0.98] Cox Regression Analysis: Survival (V303)

57 57 CPT-11/5-FU/LV5-FU/LV CPT-11 N=205N=203N=195 Patients with any 52%70%79% post-study therapy CPT-11-based 1%38% 3% CPT-11+5-FU-based13%18% 9% 5-FU-based30%10% 64% Other therapy 8% 4% 3% Patients not treated48%30%21% Post-Study Therapy (0038) 56% 

58 58 CPT-11/5-FU/LV5-FU/LV N=167N=171 Patients with any 49%65% post-study therapy CPT-11-based 2%28% CPT-11+5-FU-based 4% 6% 5-FU-based32%21% Other therapy11%10% Patients not treated51%35% Post-Study Therapy (V303) 34% 

59 59 CPT-11/5-FU/LV 5-FU/LV CPT-11 CPT-11/5-FU/LV 5-FU/LV CPT-11 Event (% of pts) N=225N=219N=223 Diarrhea, grade 3/4231331 Grade 315 618 Grade 4 8 713 Vomiting, grade 3/410 412 Mucositis, grade 3/4 2 17 2 Neutropenia, grade 4244312 Neutropenic fever 715 6 Neutropenic infection 2 0 2 Discontinuations 8 612 Drug-related deaths 0.9 1.40.9 Adverse Events (0038)

60 60 CPT-11/5-FU/LV 5-FU/LV CPT-11/5-FU/LV 5-FU/LV Event (% of pts) N=199N=186 Diarrhea, grade 3/42311 Grade 317 7 Grade 4 6 4 Vomiting, grade 3/4 6 3 Mucositis, grade 3/4 3 3 Neutropenia, grade 4 9 1 Neutropenic fever 5 1 Neutropenic infection 2 0 Discontinuations 9 3 Drug-related deaths 0.5 0 Adverse Events (V303)

61 61 Quality of Life Pivotal Phase III Trial Results  Study 0038 primary endpoints –Global health status –Role functioning –Pain  Study V303 primary endpoint –Global health status

62 62 Global Health Status Subscale -20 -15 -10 -5 0 5 10 15 20 048121620242832 Weeks Better Worse Mean Change (  se) EORTC QLQ-C30 Quality of Life (0038) CPT-11/5-FU/LV 5-FU/LV

63 63 -20 -15 -10 -5 0 5 10 15 20 048121620242832 EORTC QLQ-C30 Quality of Life (0038) Weeks Better Worse Mean Change (  se) Role Functioning Subscale CPT-11/5-FU/LV 5-FU/LV

64 64 -20 -15 -10 -5 0 5 10 15 20 048121620242832 Weeks Worse Better Mean Change (  se) Pain Subscale EORTC QLQ-C30 Quality of Life (0038) CPT-11/5-FU/LV 5-FU/LV

65 65 Global Health Status Subscale -20 -15 -10 -5 0 5 10 15 20 048121620242832 Weeks Better Worse Mean Change (  se) EORTC QLQ-C30 Quality of Life (V303) CPT-11/5-FU/LV 5-FU/LV

66 66 Summary and Conclusions Two independent, phase III, prospective, randomized, controlled, multinational studies

67 67  Significantly lengthens time to tumor progression Efficacy Summary  Significantly improves response rate First-line combination CPT-11/5-FU/LV  Significantly prolongs survival

68 68 Safety Summary  Predictable and manageable side effect profile First-line combination CPT-11/5-FU/LV  Similar incidence of grade 4 diarrhea relative to 5-FU/LV  Low rates of grade 3/4 vomiting, mucositis, neutropenia, and febrile neutropenia

69 69 Quality of Life Summary  Prolongs life without compromising quality of life First-line combination CPT-11/5-FU/LV

70 70Conclusion  CPT-11-based combination therapy sets  CPT-11-based combination therapy sets a new standard in the first-line treatment of metastatic colorectal cancer

71 71 Proposed New Indication   CPT-11 should be indicated as a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum   Recommended CPT-11/5-FU/LV regimens: – –Saltz – –de Gramont

72 72 Q & A


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