# Presentation: 692822

## Slide 1

## sNDA 20-571

- “Irinotecan as a component of first line treatment of patients with metastatic colorectal cancer.”

## APPROVED SCHEDULES (SINGLE AGENT)

**125 mg/m****2**** wkly x 4 Q6 wks**
**350 mg/m****2**** Q3 wks**

## PROPOSED SCHEDULES(CPT-11 + 5FU/LV)

**CPT-11+ BOLUS**
- CPT-11 + 5FU/LV weekly x 4 (**Saltz**)
- less dose intense “Roswell Park”
**CPT-11+ CONTINUOUS INFUSION**
- CPT-11 + biweekly CIV (**deGramont)**
- CPT-11 + weekly CIV (**AIO)**

## STUDY DESIGN0038 (U.S.)

**STUDY DESIGN****0038 (U.S.)**

**ARM A** :             CPT-11	125 wk x 4 Q 6 wks (n=226)
**ARM B** :             CPT-11	125 wk x 4 Q 6 wks(n=231)               5FU	500 bolus                            LV	        20
**ARM C** :              5FU	425 daily x 5(n=226)               LV	        20

## STUDY DESIGNv303 (EUROPE)

**STUDY DESIGN****v303 (EUROPE)**

## EFFICACY ENDPOINTS(U.S.)

**EFFICACY ENDPOINTS****(U.S.)**

**ARM A**: CPT-11     **ARM B:**: CPT-11       **ARM C**: 5FU
- 	 5FU	   	    LV	  LV

**1****0**** :  TIME TO TUMOR PROGRESSION**
**2****o**** : S****	****URVIVAL**

## STUDY DESIGN(Europe)

**STUDY DESIGN****(Europe)**

**1****0****:  RESPONSE RATE**
**2****0****:  SURVIVAL****      TTP**

## DATA ANALYSIS

- Survival
- Key safety parameters
- Supportiveness of other efficacy endpoints

## INCLUSION CRITERIA

## PATIENT DEMOGRAPHICS(U.S. and Europe)

- Well balanced
- More Rectal Cancer:  Europe

## DEATHS(Europe)

**Enrollment:  May 97 to ****	****	**** Feb 98 **
**Cut-off:         Feb 99****                      Oct 99**

**% DEATHS**

## SURVIVAL v303 (Europe)

- MEDIAN SURVIVAL (Months)
- 	_February 1999_
- 	A (CPT-11+5FU/LV	= 16.8	B (5FU/LV) 	= 14
- 	_October 1999_
- 	A (CPT-11+5FU/LV	= 17.4	B (5FU/LV)	=14.1

- p = 0.028

- p = 0.032

## DEATHS(U.S.)

**Enrollment:  May 96 to ****	****              May 98**
**Cut-off:         Sept 99****                      Dec 99**** **

**% DEATHS**

## SURVIVAL 0038 (U.S.)

- MEDIAN SURVIVAL (Months)
- 	_September 1999_
- 	B 	14.5	C 	12.6
- 	A
- 	_December 1999_
- 	B	14.8	C	12.6
- 	A	12.0

- p = 0.097

- p = 0.042HR = 0.81

## CROSS OVER TO CPT-11

**CROSS OVER TO CPT-11**

**U.S.**
- 		B	CPT-11+5FU/LV
- 		**C****	****5FU/LV ****	****40% CPT-11**
- 		A	CPT-11
**EUROPE**
- 		A	CPT-11+5FU/LV
- 		**B****	****5FU/LV****	****30% CPT-11**

## TIME TO TUMOR PROGRESSION(Months)

## TIME TOTREATMENT FAILURE(Months)

## RESPONSE RATE

## SUMMARY OF EFFICACY

_**STRENGTHS**_
- Consistent survival advantage (Europe)
- Survival advantage in ff-up analysis (US)
- Significant differences in  TTP, TTF and response rate

_**CONCERNS**_
- Which CIV schedule offers “real” advantage (Europe)
- CPT-11+ biweekly?
- CPT-11+ weekly?

## 				# of Patients
ARM A (CPT-11+5FU/LV)
		A1 CPT-11 + weekly CIV			 53
		A2 CPT-11 + biweekly CIV		145
ARM B (5FU/LV)
		B1 weekly CIV		  	44
		B2 biweekly CIV			143

- 				_# of Patients_
**ARM A (CPT-11+5FU/LV)**
- 		A1 CPT-11 + weekly CIV			 **53**
- 		A2 CPT-11 + biweekly CIV		145
**ARM B (5FU/LV)**
- 		B1 weekly CIV		  	**44**
- 		B2 biweekly CIV			143

**ACCRUAL: ****TREATMENT SUBGROUPS**** ****(EUROPE)**

## EFFICACY: TREATMENT SUBGROUPS(EUROPE)

## SAFETY REVIEW

**Europe**  CPT-11+wkly    CPT-11+ biweekly
**U.S.**

## GRADE 3/4 TOCIXITY (Europe)

**Neutropenia**

**Neutropenic Fever**

**Nausea**

**Vomiting**

**Diarrhea**

**Mucositis**

**Asthenia**

**Alopecia**

**Cholinergic Symptoms**

## GRADES 3/4 TOXICITY(CPT-11+5FU/LV Subgroups, Europe)

## GRADE 3/4 TOXICITY  (U.S.)

**Neutropenia**

**Neutropenic Fever**

**Nausea**

**Vomiting**

**Diarrhea**

**Mucositis**

**Asthenia**

**Alopecia**

## DISCONTINUATION2o TO TOXICITY

**EUROPE**
- 	CPT-11+5FU/LV	18 (8%)
- 	5FU/LV	  5 (3%)
**U.S.**
- 	CPT-11+5FU/LV	17 (7%)
- 	5FU/LV	14 (6%)

## SUMMARY OF SAFETYCPT-11+5FU/LV REGIMENS

## CONSIDERATIONS FOR APPROVAL

***Two large, randomized, well-designed, controlled clinical trials***

## 
Significant improvement in survival versus infusional 5FU/LV (AIO and deGramont)

***Significant improvement in survival versus infusional 5FU/LV (AIO and deGramont)***

**CONSIDERATIONS FOR APPROVAL**

***Initial trend, then significant  improvement in survival versus Mayo Clinic Regimen***

**CONSIDERATIONS FOR APPROVAL**

***Acceptable toxicity profile***

## DOSE/ADMINISTRATION SCHEDULES ?

## REVIEW TEAM