NDA 50-772NDA 50-772 TLC D-99TLC D-99

Doxorubicin HCL LiposomeDoxorubicin HCL Liposome

The Liposome Company, Inc.The Liposome Company, Inc.Proposed Indication: Proposed Indication:

““First line treatment of metastatic First line treatment of metastatic breast cancer in combination with breast cancer in combination with

cyclophosphamide”cyclophosphamide”

TLC D-99 Review TeamTLC D-99 Review Team

Discipline Primary Reviewer Team Leader

Medical Patricia Cortazar Grant Williams

Biometrics Ning Li Gang Chen,

Chemistry Yung-Ao Hsieh Rebecca Wood

Pharmacology Doo-Young Lee-Ham Paul Andrews

Biopharmaceutics Lydia Kieffer Atiqur Rahman

Project Manager Dianne Spillman Dotti Pease

DSI Gurston Turner Bette L. Barton

Administrative HistoryAdministrative History

11/24/8711/24/87 IND # 30,894 submitted IND # 30,894 submitted

2/4/942/4/94 End of Phase II meetingEnd of Phase II meeting

6/30/986/30/98 Guidance meetingGuidance meeting(Study 2 closed)(Study 2 closed)

11/3/9811/3/98 Study 3 included as a Study 3 included as a supportive supportive trialtrial

12/14/9812/14/98 NDA submittedNDA submitted

In 1994 the Agency In 1994 the Agency agreed to:agreed to:

Utilize response rate as the primary basis Utilize response rate as the primary basis of efficacy comparison.of efficacy comparison.

Utilize proportional analyses rather than Utilize proportional analyses rather than absolute increments (15%). absolute increments (15%).

Evaluate response rates using 95% C.I. of Evaluate response rates using 95% C.I. of the odds ratio.the odds ratio.

Utilize 1-sided C.I. for this response Utilize 1-sided C.I. for this response comparison.comparison.

Utilize a lower bound of this C.I. (R = 0.75) Utilize a lower bound of this C.I. (R = 0.75)

Administrative HistoryAdministrative History

June 30,1998June 30,1998 Guidance meeting Guidance meeting (Study 2 (Study 2

closed)closed)

Nov 3, 1998Nov 3, 1998 Study 3 included Study 3 included as a as a

supportive trialsupportive trial

Dec 14, 1998Dec 14, 1998 NDA submittedNDA submitted

Study Design and Study Design and EndpointsEndpoints

Study (Protocol) Study 1

92CE32-0652

Study 2

92CE32-0589

Study 3

80-301

Number of patients 297 224 160

Arm 1: TLC D-99 CPA

Arm 2: Doxorubicin Epirubicin CPA

(n= 142)60

600

(n= 155)60

600

(n= 105)75

(n= 118)75

(n= 76)75

600

(n= 78)

75600

Cycles q 3 weeks q 3 weeks q 3 weeks

Dose escalation No Yes No

Primary Endpoints Response RateCardiotoxicity

Response RateCardiotoxicity

Response Rate

The dose of epirubicin used in study The dose of epirubicin used in study 3 has not been established 3 has not been established

equivalent to doxorubicin for the equivalent to doxorubicin for the following reasons:following reasons:

Doses of 100 to 120 mg/mDoses of 100 to 120 mg/m22 have been used in have been used in combination therapy and were more effective combination therapy and were more effective than the lower doses.than the lower doses.

Epirubicin may be not equivalent to Epirubicin may be not equivalent to doxorubicin on a mg per mg basis. doxorubicin on a mg per mg basis.

Epirubicin at 75 mg/mEpirubicin at 75 mg/m22 has not been has not been demonstrated to be a standard treatment for demonstrated to be a standard treatment for first line metastatic breast cancer. first line metastatic breast cancer.

Survival CurveSurvival CurveEpirubicin Study Epirubicin Study

Efficacy ResultsEfficacy Results Studies 1 and 2Studies 1 and 2

Study Study 1(N=297)

Study 2(N=224)

Treatment Arm TLC/C(N=142)

Dox/C(N=155)

TLC(N=105)

Dox(N=118)

62/142(44%)

67/155(43%)

28/108(26%)

30/116(26%)Response rate

P > 0.9 P > 0.9Ratio ofResponse Rates*

1.01 (0.78-1.34) 1.003 (0.62-1.68)

*Relative Risk, with one-sided testing 95% C.I.

SurvivalSurvival Studies 1 and 2Studies 1 and 2

Study 1(n=297)

Study 2(n=224)

Treatment Arm TLC/C(n=142)

DOX/C(n=155)

TLC(n=108)

DOX(n=116)

Overall Survival

Median (mo)

21.2 16.4 14.6 20.1

Hazard Ratio 1.01 0.75

95% CI

(Two-sided)

0.71 – 1.43 0.54 – 1.03

p-value >0.9 0.07

Study 1Study 1SurvivalSurvival

Study 2Study 2Survival Survival

Study 2Study 2Multivariate analysisMultivariate analysis

Prognostic factors for covariate adjustment : (J Clin Oncol 16:2401-2408, 1998)

– Disease Free Interval – AST level – Liver metastases – Previous adjuvant chemotherapy

Treatment effect with covariates: Risk Ratio: 0.70 p-value :0.034

Covariates adjustment for progesterone and estrogen receptors: p-value 0.05

Time to ProgressionTime to Progression Studies 1 and 2Studies 1 and 2

Study 1(n=297)

Study 2(n=224)

Treatment Arm TLC/C

(n=142)

DOX/C

(n=155)

TLC

(n=108)

DOX

(n=116)

Time toProgression

Median (mo)

5.6 6.0 3.8 4.3

Hazard Ratio 1.07 0.91

95% CI for

H. R. Two-sided

0.81 – 1.41 0.66 – 1.26

Log-rank p-value 0.65 0.58

Efficacy ResultsEfficacy ResultsStudy 3Study 3

Study 3(n=160)

Treatment Arm TLC/C

(n=80)

EPI/C

(n=80)

37/80

(46)

31/80

(39)

Response Rate

0.4

Ratio of ResponseRates*

1.19

95% C.I. one-sided 0.81 – 1.84

95% C.I. two-sided 0.76 – 1.97

Response duration 10 7.8

* Relative Risk

SurvivalSurvival Study 3Study 3

Study 3(n=160)

Treatment Arm TLC/C

(n=80)

EPI/C

(n=80)

Overall Survival

Median (months)

18.5 16

Hazard Ratio 1.25

95% C.I. two-sided 0.79 – 1.98

Log-rank p-value 0.35

Time to ProgressionTime to ProgressionStudy 3Study 3

Study 3(n=160)

Treatment Arm TLC/C(n=80)

EPI/C(n=80)

Time to ProgressionMedian (mo)

7.7 6.3

Hazard Ratio 1.4595% CI(Two-sided)

0.97 – 2.16

p-value 0.07

SummarySummaryStudy 3Study 3

Similar response rates and survivalSimilar response rates and survival

Trend toward longer TTP for TLC Trend toward longer TTP for TLC

armarm

Relatively low dose of EpirubicinRelatively low dose of Epirubicin

Small study stopped prematurelySmall study stopped prematurely

CardiotoxicityCardiotoxicity

Study Study 1 Study 2

Cardiotoxicity TLC/C Dox/C TLC Dox

9/142

(6%)

32/154

(21%)

18/105

(17%)

43/118

(36%)

Cardiac Event

p=0.0002 p=0.002

CHF 0/142 5/154 2/105 9/118

> 15.2 9.8 9.8 6.9Median Time toCardiac Event(mo)

p=0.0005 p = 0.0007

Summary of Summary of ToxicitiesToxicities

Study 1 Study 2 Study 3

Toxicity TLC/C60

n=142

Dox/C60

n=154

p-value*

TLC75

n=105

Dox75

n=118

p-value*

TLC/C75

n=76

Epi/C75

n=78

p-value*

Neutropenic fever 14 (10) 23 (15) 0.220 15 (14) 12 (10) 0.413 6 (8) 1 (1) 0.062

Thrombocytopenia 72 (51) 73 (47) 0.642 87 (83) 89 (75) 0.191 41 (54) 21 (27) 0.001

Stomatitis 57 (40) 86 (56) 0.008 59 (56) 82 (69) 0.051 27 (35) 9 (11) 0.001

Vomiting

Grade> 3

19 (13) 24 (15) 0.624 14 (13) 28 (24) 0.059 16 (21) 15 (19) 0.842

Diarrhea 40 (28) 59 (38) 0.084 27 (26) 50 (42) 0.011 16 (21) 15 (19) 0.842

*Fisher’s Exact Test

Regulatory issuesRegulatory issues

Studies 1 and 2 showed less Studies 1 and 2 showed less cardiotoxicity TLC armcardiotoxicity TLC arm

Non-inferiority (Ratio of Response Non-inferiority (Ratio of Response Rates):Rates):– Study 1: 0.78 Study 1: 0.78 – Study 2: 0.62Study 2: 0.62

Regulatory issuesRegulatory issues

Overall survival:Overall survival:

Study 1: HR: 1.01 95% CI: 0.71 Study 1: HR: 1.01 95% CI: 0.71

Study 2: p= 0.07 HR: 0.75 95% CI: Study 2: p= 0.07 HR: 0.75 95% CI: 0.540.54

The comparator arm on Study 3 is not The comparator arm on Study 3 is not adequateadequate

Reviewer ConclusionsReviewer Conclusions

Insufficient evidence to support TLC D-99 Insufficient evidence to support TLC D-99 for first line treatment of metastatic for first line treatment of metastatic breast cancerbreast cancer– Non-inferior R.R in Study 1Non-inferior R.R in Study 1– Negative Survival trend Study 2Negative Survival trend Study 2– Study 3 inadequate comparatorStudy 3 inadequate comparator

TLC D-99 less cardiotoxic, but this TLC D-99 less cardiotoxic, but this endpoint alone does not support the endpoint alone does not support the proposed indicationproposed indication