# Presentation: 692819

## (Irinotecan, CPT-11)

**(Irinotecan, CPT-11)**

*Oncologic Drugs Advisory Committee Review*
*March 16, 2000*

***Camptosar*********

**Pharmacia & Upjohn**

**First-Line Therapy of Metastatic Colorectal Cancer**

## Presentation Agenda

- Background
- 2 Pivotal Phase III Controlled Clinical Trials
- Improved Tumor Control
- Improved Survival
- Summary and Conclusions
- Q&A

## CPT-11 Presentation Team

**Function****	****	****Name****	****Affiliation****Medical****	****Langdon Miller, MD****	****	****P&U****	****Paula Locker, MS****	****	****P&U****	****Gabriela Gruia, MD****	****	****Aventis**
**Biostatistical****	****Nicoletta Pirotta, MS****	****	****P&U****	****Gary Elfring, MS****	****	****P&U****	****Lucile Awad, MS****	****	****Aventis**
**Pharmacology****	****Larry Schaaf, PhD****	****	****P&U**
**Investigators****	****Leonard Saltz, MD****	****	****MSKCC****	****Jean-Yves**** Douillard, MD ****	****	****C Gauducheau****	****Hanjochen**** ****Wilke, MD****	****	****K Essen-Mitte**

## Background

## Colorectal Cancer in 2000

- 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. ***

## 5-FU Therapy: With and Without LV

**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)**

## 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)**

## 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

## 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)**

## Second-Line CPT-11 Therapy (V301)

**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**A**
**T**
**I**
**O**
**N**

**CPT-11:  350 mg/m****2**** every 3 weeks**

**Best Supportive Care**

**Prior**
**5-FU**

**Second-Line CPT-11 Therapy ****(V301)**

**Cunningham *****et al.  Lancet*****. 1998; 352:1413-18..**

## Second-Line Survival(V301)

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**Months**

**Probability**

**Second-Line Survival****(V301)**

**p=0.0001***

*** log-rank test**

**CPT-11**

**BSC**

## Second-Line CPT-11 Therapy (V302)

**A**
**N**
**D**
**O**
**M**
**I**
**Z**
**A**
**T**
**I**
**O**
**N**

**CPT-11:  350 mg/m****2**** every 3 weeks**

**Infusional 5-FU-based regimen**

**Prior**
**5-FU**

**Second-Line CPT-11 Therapy ****(V302)**

**Rougier *****et al.  Lancet*****. 1998; 352:1407-12.**

## Second-Line Survival(V302)

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0 **

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**Months**

**Probability**

**Second-Line Survival****(V302)**

**p=0.04***

*** log-rank test**

**CPT-11**

**Infusional****5-FU**

## 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

## Phase I Combination Dose-Finding and Pharmacokinetic Studies

**Phase I Combination Dose-Finding and Pharmacokinetic Studies**

**Addition of CPT-11 to existing schedules of 5-FU/LV**

## Pivotal Phase III Trials

**Study Design and Conduct**

## Pivotal First-Line Trials

**Two independent, phase III, prospective, randomized, controlled, international studies**

## Entry Criteria(0038)

**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

## Entry Criteria(V303)

**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

## Treatment(0038)

**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

## Treatment(V303)

**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 grade 4 neutropenia or neutropenic fever
- Second-line, post-study chemotherapy permitted

## Endpoints(0038)

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

## Endpoints(V303)

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

## 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

## 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

## 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

## 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

## Treatment Arms(0038)

**ZAT**
**ION**

**Stratification:**
**	****	**
** ****	****PS (0 vs 1, 2)****	**
** ****	****Age  ****	****(< 65 yr vs **_**>**_** 65 yr)****	****	**
** ****	****Time from initial ****	****diagnosis****	****(< 6 mo vs **_**>**_** 6 mo)****	****	**
** ****	****Prior adjuvant ****	****therapy ****	****(yes vs no)**

**5-FU dose intensity=****531**** mg/m****2****/wk**

**5-FU dose intensity=****333**** mg/m****2****/wk**

**Treatment Arms****(0038)**

## Treatment Arms(V303)

**	****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 wks****	****AIO**
**	****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 wks****	****de Gramont**
**	****LV:****	****200 mg/m****2**** d1, 2 q 2 wks**
**	****5-FU:****	**** 2.6 gm/m****2****/wk x 6 wks, q 7 wks****	****AIO**
**	****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 wks****	****de Gramont**
**	****LV:****	****200 mg/m****2**** d1, 2 q 2 wks**

**RANDOMI**
**ZAT**
**ION**

**Treatment Arms****(V303)**

## 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)

## 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)

## Pivotal Phase III Trial Results

**Patient Characteristics****and Treatment Administration**

## Patient Enrollment(0038)

**	****	****	**
**Intent-to-treat population ****	****231****	****	****226****	****226**
**Never treated ****	****    4****	****    ****	****    8****	****    4**
**Treated on another arm ****	****    2****	****    ****	****    1****	****    1**
**	****As-treated population ****	****225****	****	****219****	****223**

**Patient Enrollment****(0038)**

## Patient Enrollment(V303)

**	****	****	****[AIO]****	****	****[de Gramont]****	**** ****[AIO]****	****	****[de Gramont]**
** ****	**
**Randomized****	****	****	****199****	****	****	****188**
**Never treated****	****    ****	****	****1****	****    ****	****    ****	****1**
**Full-analysis population****	****	****	****198****	****	****	****187****	****	****	****[53]****	****	****  [145]****	****[44]****	****	****[143]**
**Treated on other arm****	****    ****	****	****0****	****    ****	****    ****	****1****As-treated population ****	****	****	****199****	****	****	****186 ****	****	****	****	****[54]****	****	****  [145]****	****[43]****	****	****[143]**
**	****	****	**
**	****	**

**Patient Enrollment****(V303)**

## Demographics(0038)

**	****	****	****N=231****	****	****N=226****	****N=226**
**Median age (yrs)****	****62****	****	****61****	****61****	****[range]****	****[25-85]****	****	****[19-85]****	****[30-87]**
** **
**Gender (% of pts)****	**
**	****  ****	****M****	****66****	**** ****	****55****	****64**
**	****  ****	****F****	****34****	****	****45****	****34****.**
**Performance status (% of pts)****	****  ****	****0****	****39****	****	****42****	****46**		******1****	****61****	****	****58****	****54**

**Demographics****(0038)**

## Demographics(V303)

**	****	****	****N=198****	****	****N=187****	**
**Median age (yrs)****	****62****	****	****61****	****	****[range]****	****[27-75]****	****	****[25-75]****	**
** **
**Gender (% of pts)****	**
**	****	****M****	****67****	**** ****	****53****	**
**	****  ****	****F****	****33****	****	****47****	****.**
**Performance status (% of pts)****	****  ****	****0****	****52****	****	****51****	**		******1****	****48****	****	****49****	**

**Demographics****(V303)**

## Disease Characteristics(0038)

**	****	****N=231****	****	****N=226****	****N=226**
**Primary site (% of pts)****	****	****	****	**
**	****Colon****	****81****	****	****85****	****84****	****Rectum****	****17****	****	****14****	****15**
**Number of involved****organ sites (% of pts)****	****  1****	****64****	****	****66****	****62****	**_**>**_**2****	****36****	****	****34****	****38**
**Liver involvement (% of pts)****	****82****	****	****82****	****83**

**Disease Characteristics****(0038)**

## Disease Characteristics(V303)

**	****	****N=198****	****	****N=187****	**
**Primary site (% of pts)****	****	****	****	**
**	****Colon****	****55****	****	****65****	****	****Rectum****	****45****	****	****36****	**
**Number of involved****organ sites (% of pts)****	****  1****	****62****	****	****63****	****	**_**>**_**2****	****38****	****	****37****	**
**Liver involvement (% of pts)****	****77****	****	****80****	**

**Disease Characteristics****(V303)**

## Disease History(0038)

**	****	****N=231****	****	****N=226****	****N=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 ****	****11****	****	****8****	****10****	****(% of pts)**
**Pelvic radiotherapy ****	****2****	****	****1****	****1****	****(% of pts)**

**Disease History****(0038)**

## Disease History(V303)

**	****	****N=198****	****	****N=187****	**
**Median time from ****initial diagnosis (mo) ****	****4.5 ****	****	****2.7****	****  ****	****[range]****	****[0.1-88]****	****	****[0.1-104]****	**
**Prior adjuvant 5-FU****	****26****	****	****24****	****(% of pts)**
**Radiotherapy****	****20****	****	****16****	****(% of pts)**

**Disease History****(V303)**

## Baseline Laboratory Abnormalities(0038)

**	****	****N=231****	****	****N=226****	****N=226**
**Abnormal baseline value (% of pts)**
**	****Hgb <11 g/dL****	****26****	****	****25****	****26**
**	****WBC ********8x10****9****/L****	****52****	****	****53****	****51**
**	****LDH >ULN****	****60****	****	****56****	****53**
**	****Bilirubin >ULN****	****  7****	****  ****	****  4****	****10**
**	****CEA ********100 ng/mL****	****40****	****	****39****	****37**

**Baseline Laboratory Abnormalities****(0038)**

***ULN = upper limit of normal**

## Baseline Laboratory Abnormalities(V303)

**	****	****N=198****	****	****N=187****	**
**Abnormal baseline value (% of pts)**
**	****Hgb <11 g/dL****	****16****	****	****21****	**
**	****WBC ********8x10****9****/L****	****47****	****	****38****	**
**	****LDH >ULN****	****40****	****	****44****	**
**	****Bilirubin >ULN****	****  7****	****  ****	****  7****	**
**	****CEA ********100 ng/mL****	****35****	****	****32****	**

**Baseline Laboratory Abnormalities****(V303)**

***ULN = upper limit of normal**

## Treatment Administration(0038)

**	****	****	****N=225****	****	****N=219****	****N=223**
**Median duration (mo)****	****5.5****	****	****4.1****	****3.9**
**	****[range]****	****[0.3-33]****	****	****[0.4-22]****	****[0.2-18]**
**.**
**Median dose intensity (mg/m****2****/wk)  ****[Median relative dose intensity*]**** **
**	****	****5-FU****	****236 ****[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**

## Treatment Administration(V303)

**	****	****	****	****  ****N=199****	****	****	****  N=186**
**	****	****	****AIO****	****	****de Gramont****	**** ****AIO****	****	****de Gramont**
**	****	****	****N=54****	****	****N=145****	****N=43****	****	****N=143**
** ****Median duration (mo) ****	****	****5.5****	****	****5.7****	****4.8****	****	****4.2**
**     ****[range]****	****	****[0.5-14.8]****	****	**** [0.5-15.7] ****	**** [0.2-10.6]****	****	****[0.5-11.5]**
**Median relative dose intensity *****	****	****	****	****	****	**
**	****CPT-11****	****	****0.82****	****	****0.93****	****--****	****	****--****	****	****	****5-FU ****	****	****0.81****	****	****0.92****	****0.90****	****	****0.96**** **
**	**
**	****	****	**
**	****	**

**Treatment Administration****(V303)**

***Ratio of actual dose intensity relative to planned dose intensity**

## Pivotal Phase III Trial Results

**Efficacy and Safety**

## Confirmed Response Rates (0038,V303)

**	****	****N=(231,198)****	****	****N=(226,187)****	****N=226**
**Study 0038****	****39%****	****	****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***

## Time to Tumor Progression (0038,V303)

**	****	****N=(231,198)****	****	****N=(226,187)****	****N=226**
**Median (0038) ****	****7.0 mo****	****	****4.3 mo****	****4.2 mo**
**	**
**Median (V303) ****	****6.7 mo ****	****	****4.4 mo****	****	****	**
**	**
**	****	**
**	****	****	**

***Log-rank test**

**Time to Tumor Progression**** (0038,V303)**

**p=0.004***

**p<0.001***

## Time to Tumor Progression(0038)

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**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)**

## Time to Tumor Progression (V303)

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**3**

**6**

**9**

**12**

**15**

**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**

## Cox Regression Analysis: TTP(0038)

**     ****Factor****	****         Value****	****[95% CI]****	****p-value**
**LDH****	******** UNL vs >UNL ****	****0.60****	****0.0001**
**	****	****[0.47-0.76]**
**Organ sites****	****1 vs ********2 sites****	****0.63 ****	****0.0001 ****	****	****[0.50–0.80]**
**PS****	****0 vs ******** 1****	****0.74 ****	****0.0088 ****	****	****[0.59–0.93]**
**Bilirubin****	******** UNL vs >UNL ****	**** 0.56 ****	****0.0132****	****	****[0.35–0.89]**
**Hemoglobin****	****< 11 vs ******** 11 g/dL****	****0.74****	****0.0157****	****	****[0.58–0.95]**
**Age****	********65 vs <65 years*****	*****0.78 ****	****0.0315****	****	****[0.63–0.98]**
**Treatment****	****CPT-11/5-FU/LV****	****0.64****	****0.0001**
**	**** **** ****vs 5-FU/LV**** ****	**** ****[0.51–0.79]**

***ULN=upper limit of normal**

**Cox Regression Analysis: TTP****(0038)**

## Cox Regression Analysis: TTP(V303)

**     ****Factor****	****         Value****	****[95% CI]****	****p-value**
**Organ sites****	****1 vs ********2 sites****	****0.73 ****	****0.0001 ****	****	****[0.57–0.94]**
**LDH****	******** UNL vs >UNL ****	****0.64****	****0.0012**
**	****	****[0.48-0.84]**
**Treatment****	****CPT-11/5-FU/LV****	****0.59****	****0.0001**
**	****   ****vs 5-FU/LV**** ****	**** ****[0.46–0.76]**

**Cox Regression Analysis: TTP****(V303)**

## Survival (0038,V303)

**	****	****N=(231,198)****	****	****N=(226,187)****	****N=226**
**Median (0038)****	****14.8 mo****	****	****12.6 mo****	****12.0 mo**
**	**
**Median (V303)****	****17.4 mo ****	****	****14.1 mo****	**
**	****	****	**

**Survival ****(0038,V303)**

***Log-rank test**

**p=0.042***

**p=0.032***

## Survival(0038)

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**Months**

**CPT-11/5-FU/LV (N=231)**

**5-FU/LV (N=226)**

**Survival****(0038)**

**p=0.042***

**Probability**

*** log-rank test**

## Survival (V303)

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**0**

**6**

**12**

**18**

**24**

**30**

**Months**

**Probability**

**CPT-11/5-FU/LV (N=198)**

**5-FU/LV (N=187)**

**p=0.032***

*** log-rank test**

## Cox Regression Analysis: Survival(0038)

**     ****Factor****	****        Value****	****[95% CI]****	****p-value**
**LDH****	******** UNL vs >UNL ****	****0.47****	****0.0001**
**	****	****[0.37-0.60]**
**PS****	****0 vs ******** 1****	****0.57 ****	****0.0001 ****	****	****[0.45–0.71]**
**WBC****	**** <8 vs ********8 x 10****9****/L ****	****0.64****	****0.0001****	****	****[0.51–0.80]****	**
**Organ sites****	****1 vs ********2 sites****	****0.67 ****	****0.0004 ****	****	****[0.54–0.84]**
**Bilirubin****	**** ******** UNL vs >UNL ****	****0.55 ****	****0.0051****	****	****[0.35–0.86]**
**Treatment****	****CPT-11/5-FU/LV****	****0.80****	****0.0372**
**	****   ****vs 5-FU/LV**** ****	****[0.64–0.99]****	****	**

**Cox Regression Analysis: Survival****(0038)**

## Cox Regression Analysis: Survival(V303)

**Cox Regression Analysis: Survival****(V303)**

## Post-Study Therapy(0038)

**	****	****N=205****	****	****N=203****	****N=195**
**Patients with any ****	****52%****	****	****70%****	****79%****post-study therapy**
***	*****CPT-11-based****	****  1%****	****	****38%****	****   3%**
**	****CPT-11+5-FU-based****	****13%****	****	****18%****	****   9%**
**	****5-FU-based****	****30%****	****	****10%****	**** 64%**
**	****Other therapy****	****  8%****	****	****  4%****	****   3% **
**Patients not treated****	****48%****	****	****30%****	****21%**
**	**

**Post-Study Therapy****(0038)**

## Post-Study Therapy(V303)

**	****	****N=167****	****	****N=171****	**
**Patients with any ****	****49%****	****	****65%****	****post-study therapy**
***	*****CPT-11-based****	**** 2%****	****	****28%****	**
**	****CPT-11+5-FU-based****	**** 4%****	****	****  6%****	****   **
**	****5-FU-based****	****32%****	****	****21%****	**
**	****Other therapy****	****11%****	****	****10%**
**Patients not treated****	****51%****	****	****35%****	**
**	**

**Post-Study Therapy****(V303)**

## Adverse Events(0038)

**Event (% of pts) ****	****N=225****	****	****N=219****	****N=223****Diarrhea, grade 3/4****	****23****	****	****13****	****31**
**	****Grade 3****	****15****	****  ****	****  6****	****18**
**	****Grade 4****	****  8****	****  ****	****  7****	****13**
**Vomiting, grade 3/4****	****10****	****  ****	****  4****	****12**
**Mucositis, grade 3/4****	****  2 ****	****	****17****	****  2**
**Neutropenia, grade 4****	****24****	****	****43****	****12**
**Neutropenic fever****	****  7****	****	****15****	****  6**
**Neutropenic infection****	****  2****	****	****  0****	****  2**
**Discontinuations****	****  8****	****	****  6****	****12**
**Drug-related deaths****	****   0.9 ****	****  ****	****1.4****	****0.9**

**Adverse Events****(0038)**

## Adverse Events(V303)

**Event (% of pts) ****	****N=199****	****	****N=186****Diarrhea, grade 3/4****	****23****	****	****11**
**	****Grade 3****	****17****	****  ****	****  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)**

## Pivotal Phase III Trial Results

**Pivotal Phase III Trial Results**

- Study 0038 primary endpoints
- Global health status
- Role functioning
- Pain
- Study V303 primary endpoint
- Global health status

## EORTC QLQ-C30 Quality of Life(0038)

**Global Health Status Subscale**

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**20**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**Weeks**

**Better**

**Worse**

**Mean Change (********se)**

**EORTC QLQ-C30 Quality of Life****(0038)**

## EORTC QLQ-C30 Quality of Life(0038)

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**20**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**EORTC QLQ-C30 Quality of Life****(0038)**

**Weeks**

**Better**

**Worse**

**Mean Change (********se)**

**Role Functioning Subscale**

## EORTC QLQ-C30 Quality of Life(0038)

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**20**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**Weeks**

**Worse**

**Better**

**Mean Change (********se)**

**Pain Subscale**

**EORTC QLQ-C30 Quality of Life****(0038)**

## EORTC QLQ-C30 Quality of Life(V303)

**-20**

**-15**

**-10**

**-5**

**0**

**5**

**10**

**15**

**20**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**28**

**32**

**Weeks**

**Better**

**Worse**

**Mean Change (********se)**

**EORTC QLQ-C30 Quality of Life****(V303)**

## Summary and Conclusions

**Two independent, phase III, prospective, randomized, controlled, multinational studies**

## Efficacy Summary

**Efficacy Summary**

- Significantly improves response rate

**First-line combination CPT-11/5-FU/LV**

- Significantly prolongs survival

## Safety Summary

**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

## Quality of Life Summary

**Quality of Life Summary**

- Prolongs life without compromising quality of life

**First-line combination CPT-11/5-FU/LV**

## Conclusion

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

## 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

## Q & A