Slide 1 Doxil ® (doxorubicin HCl liposome injection) Doxil in the Treatment of Advanced, Metastatic...

Doxil®

(doxorubicin HCl liposome injection)

Doxil in the Treatment of Advanced, Metastatic Ovarian Cancer

Oncologic Drugs Advisory Committee MeetingJune 8, 1999

Proposed New Indication

Doxil (doxorubicin HCl liposomal injection) is indicated for:

The treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens and who may also be refractory to topotecan. Refractory is defined as a patient having progressive disease while on treatment, or within 6 months of treatment.

Agenda

Unmet Medical Need: Maurie Markman, MD, DirectorCleveland Clinic Taussig

Cancer Center

STEALTH® Technology Frank Martin, PhD,and Doxil Pharmacology: Principal Scientist

Efficacy of Doxil: Ed Schnipper, MD, VP, Clinical Research

Safety of Doxil: Ken Cunningham, MD, VP, European Clinical

Research

Risk/Benefit: Ed Schnipper, MD, VP, Clinical Research

Experts Available for Questions

ConsultantsAlan Gordon, MD, Sammons Cancer Center, DallasWilliam McGuire, MD, University of MississippiFranco Muggia, MD, NYU Medical Center

Sponsor RepresentativesMartin O’Connell, PhD, Sr Dir, BiostatisticsRandy Allred, Dr PH, Dir, BiostatisticsPeter Working, PhD, VP, Nonclinical ResearchTim Sharpington, Assoc Dir, Clinical ResearchTom Tarlow, Director, Regulatory Affairs

Agenda

Unmet Medical Need: Maurie Markman, MD, Cleveland Clinic Taussig

Cancer Center

Overview of Ovarian Cancer

• 25,200 patients diagnosed in US in 1999• 14,500 deaths• 70% present with advanced disease

– Standard treatment is with platinum and paclitaxel

• Despite improvements with combination therapy– >20% fail to respond to first-line chemotherapy– 80% ultimately relapse

Patient Population Definitions for“second line therapy”

• Sensitive patients (those who have a durable response >6 months) likely to respond to retreatment

• Refractory patients (those who progressed while on or within 6 months of treatment) unlikely to respond

to retreatment

Chemotherapy Agents Approved for Second Line Treatment in Ovarian Cancer

• Paclitaxel (Taxol)• Altretamine (Hexalen)• Topotecan (Hycamtin)

Response Rates of Approved Agents in Second Line Treatment

Platinum/Platinum/ Platinum/ Paclitaxel/

Paclitaxel Topotecan Topotecan Agent Failure* Failure* Refractory

Topotecan 9.4% - -

Paclitaxel - 2.7% -

Altretamine - - -

* Does not necessarily meet strict definition of refractory

Factors Affecting Response

• Patients are less likely to respond if they:– Progress while receiving platinum therapy– Progress after receiving multiple regimens

Patients with Ovarian Cancer

• Relapse common• Long survival• Good Performance Status

Medical Need

• Need for options and alternative treatments for patients who experienced toxicity on prior therapy:– Neurotoxicity– Bone marrow toxicity– Nausea/Vomiting

Quality of Life

• Patients treated for long periods• Need for agents which are well tolerated and

convenient for patients

Agenda


Cancer Center


Structure of Doxil

DoxorubicinDoxorubicin

Lipid Membrane Lipid Membrane (Phospholipid +(Phospholipid +

Cholesterol)Cholesterol)

Polyethylene Polyethylene GlycolGlycol

85-100 nm85-100 nm

Plasma Levels of Total and Liposome-Encapsulated Doxorubicin after Doxil

Days After Infusion0 1 2 3 4 5 6 7

0.25

0.50

2.50

5.00

25.00

1.00

10.00Total Doxorubicin

Encapsulated Doxorubicin

Do

xoru

bic

in (g

/mL

)

Single 50 mg/m2 dose of DoxilMean values ± SD for 14 patients, mixed histologiesGabizon et al, Cancer Res (1994)

Doxorubicin Levels in Prostate Carcinoma Xenograft

Vaage J, et al. Cancer, 1994

µg

Dru

g/gm

Tum

or

Hours100 150 20050

Doxil

Adriamycin

4

6

8

2

0

Doxil AUC = 919

Adriamycin AUC = 36.5

Gamma Scan of Kaposi’s Sarcoma Patient

4 hr. 24 hr. 48 hr. 96 hr.

Doxorubicin in KS Lesions and Normal Skin (Biopsy at 48 Hrs. after Doxil)

1 2 3 4 5 6 7

0

5

10

15

20

25

Do

xoru

bic

in C

on

cen

tra

tion

(g

/g)

Patient Number

K S LesionNormal Skin

Doxil Activity in Kaposi’s Sarcoma

Doxil vs ABV

Doxil vs BV

Doxil vs Doxil + BV

N

133125

121120

6264

Response

46%25%

59%23%

79%80%

Northfelt et al, JCO (1998)

Stewart et al, JCO (1998)

Mitsuyasu et al, Proc ASCO (1997)

All PatientsPrior Adria

N

4223

Response

48%52%

Product Label

Randomized Trials

Non-comparative Results in Refractory Patients

Doxil Activity in Ovarian Carcinoma Xenograft (HEY)

Vaage J, et al, Cancer (1993) Days After Tumor Implantation

0 7 14 21 28 35 42 49

Me

an

Tu

mo

r V

olu

me

(m

m)3

0

20

40

60

80

100

120

140Saline control

Adriamycin(6 mg/Kg)

Doxil(6 mg/Kg)

Rationale for Exploring Ovarian Indication

• Preclinical activity superior to Adriamycin• Activity in heavily pretreated ovarian patients in

Phase I trial (Muggia et al, JCO 1995)

– 1 PR– 3 minor responses (CA125 , tumor shrinkage <50%)– 1 disease stabilization

Agenda


Cancer Center



Doxil Regulatory History in Ovarian Cancer

• Clinical development program initiated 8/94

• Orphan designation 11/98

• sNDA (50-718, 006) inadvanced ovarian cancer 12/98

• Priority review 3/99

Doxil in Refractory Ovarian Cancer

• Doxil is active

• Doxil is generally well tolerated

• Doxil is convenient

Program Overview

• Phase II non-comparative studies– 3 studies in relapsed or refractory ovarian cancer

• 30-22, 30-47, and 30-47E

• Phase III randomized comparative trial (study 30-49)– Doxil vs Topotecan– Second line following failure of platinum containing

regimen

Design of Phase II Studies

• Three multicenter non-comparative studies• All contained relapsed or refractory patients• Refractory defined as disease progression while

receiving, or within 6 months of receiving prior therapy– Plat/Pac Refractory - patients refractory to both Plat/Pac Refractory - patients refractory to both

platinum and paclitaxelplatinum and paclitaxel– Plat/Pac/Topo Refractory - patients refractory to Plat/Pac/Topo Refractory - patients refractory to

platinum, paclitaxel, and topotecanplatinum, paclitaxel, and topotecan

Endpoints of Phase II Studies

• Primary endpoint was response rate– All responses based on measurable disease (SWOG criteria)

– All responses confirmed

– Independent radiological review

• Secondary endpoints – Time to progression

– Duration of response

– Survival

– Safety

Dosing in Phase II Studies

Study Initial Dosing Regimen

30-22 50 mg/m2 q 3 weeks

30-47 50 mg/m2 q 4 weeks

30-47E 50 mg/m2 q 4 weeks

Median dose received in all 3 studies

was 50 mg/m2 q 4 weeks

Demographics of Phase II Studies

Study 30-22 Study 30-47 Study 30-47E(n = 35) (n = 89) (n = 52)

Sites 2 (US) 18 (US) 14 (Europe)

Median age 62.5 61 53.5

Patients Plat/Pac 28 49 26

refractory

Patients Plat/Pac/Topo - 33 10refractory

Demographics of Phase II Studies

Study 30-22 Study 30-47 Study 30-47E(n = 35) (n = 89) (n = 52)

Months from 2.1 1.7 3.7prior regimen

No. of prior regimens1 22.9% 14.6% 19.2%2 40.0% 52.8% 63.5%3 22.9% 32.6% 17.3%4 11.4% - -5 2.9% - -

Study 30-22 - Response Data

Plat/Pac(n = 28)

Responders 6 (21.4%)

Complete 1 (3.6%)Partial 5 (17.9%)

95% CI (6.2%, 36.6%)

Stable disease 10 (35.7%)

Study 30-47 - Response Data

Plat/Pac Plat/Pac/Topo (n = 49) (n = 33)

Responders 9 (18.4%) 6 (18.2%)

Complete 0 1 (3.0%)Partial 9 (18.4%) 5 (15.2%)

95% CI (7.5%, 29.2%) (5.0%, 31.3%)

Stable disease 16 (32.6%) 15 (45.5%)

Study 30-47E - Response Data

• Refractory patients - no responders

Comparative Demographics ofRefractory Patients

Studies Study30-47 and 30-22 30-47E

Median CA-125 176 1005

Median bulky disease 18.84 32.35

Median duration of treatment (days) 57 29.5

Summary of Response Ratesin ITT Refractory Patients

CombinedStudy Plat/Pac Plat/Pac/Topo Refractory

30-22 21.4% - 21.4% 30-47 18.4% 18.2% 18.3%30-47E 0% 0% 0%

Total 14.6% 14.0% 14.4%

95% CI (7.8% - 21.4%) (3.6% - 24.3%) (8.7% - 20.1%)

(n = 103) (n = 43) (n= 146)

Response Rate by Time to Progression on Platinum Therapy

Response Rate on Doxil

Patients who progressed:

on treatment (n = 70) 10%

<3 months after treatment (n = 20) 25%

3-6 months after treatment (n = 50) 18%

Duration of Response

Prob

abili

ty100

80

60

40

20

00 7 14 21 28 35 42 49 56 63

Weeks Since First Dose

Median duration of response = 39.4 weeks

Combined refractory, n=21

Time to Progression

Prob

abili

ty100

80

60

40

20

00 15 30 45 60 75 90 105 120


Median TTP = 15.9 weeks

Combined refractory, n=146

Time to Progression and Time to Decrease in Karnofsky Score Combined Refractory, (n=146)

0 10 20 30 40 50 60 70 80 90 100 110

100

90

80

70

60

50

40

30

20

10

0

Time to ProgressionTime to Decrease in Karnofsky Score


Pro

bab

ilit

y

Slide 40

Phase III Randomized Comparative Trial (Study 30-49)

• Study design– Second line study following failure of

platinum-containing regimen– Patients randomized to receive

• Doxil 50 mg/m2 q 4 weeks or

• Topotecan 1.5 mg/m2 x 5 d q 3 weeks

– Patients with measurable disease– Primary endpoint — time to progression– Secondary endpoints — response rate, duration of

response, survival, and safety

Study 30-49

• 90 sites in US and Europe• Target of 460 patients accrued • First planned interim analysis• 200 evaluable patients (237 ITT) with at least

6 months follow-up• Patients stratified as platinum refractory or sensitive • Subset of 81 patients met the definition of

Plat/Pac refractory

Interim Response Data - Study 30-49 Plat/Pac refractory patients

Doxil Topotecan

(n = 44) (n = 37)

Responders 6 (13.6%) 3 (8.1%)

Complete 0 0Partial 6 (13.6%) 3 (8.1%)

95% CI (3.5%, 23.8%) (0.0%, 16.9%)

Stable disease 15 (34.1%) 16 (43.2%)

Percentage Reduction in Lesion Area in Combined Refractory Patients (Studies 30-22, 30-47, 30-49, n=27)

0 2 4 6 8 10

No. of Responders

50-59

60-69

70-79

80-89

90-99

100

Per

cen

t

Efficacy Summary from Phase II Studies

• Response 14.4% in refractory patients

• Duration of response 39.5 weeks

• TTP 15.9 weeks

Agenda


Cancer Center




Research

Safety Population

• 5 studies in ovarian cancer– Total patients 408

• 16 studies in a variety of solid tumors– Total patients 772

• Kaposi’s sarcoma– Total patients 1721

Drug Exposure

Summary of Dosing Informationfor Ovarian Patients (n = 408)

• Median cycle dose 50.0 mg/m2

• Median cycle length 29.5 days

• Cumulative dose– Median 149.8 mg/m2

– Range (24.3 - 1049.8)

Mean Dose Intensity per Week in Ovarian Patients (n=408)

12.5

10

7.5

5

2.5

01 2 3 4 5 6 7 8

Cycle

IntendedActual

mg

/m2/w

eek

Adverse Events

Percent of Patients by Severity of Adverse Events (Ovarian Patients, n=396)

0

20

40

60

80

100

Grade I Grade II Grade III Grade IV Fatal

Pe

rce

nt

of

Pa

tie

nts

Drug Related Adverse Events Reported in >10% of Ovarian Patients (n=396)

0

5

10

15

20

25

30

35

40

45

Grade I/II Grade III/IV

PPE Nausea Rash Alopecia Mucositis Diarrhea

Stomatitis Asthenia Vomiting Constipation Anorexia

Per

cen

t o

f P

atie

nts

Hematologic Laboratory Data, Ovarian Patients (n=408)

Grade III Grade IV Comment

Neutropenia 19.6% 8.6% Growth Factor 4.1%

Anemia 23.5% 16.4% RBC Trans14.0%

Epo 4.3%

Thrombocytopenia 0.5% 0.7% Platelet Trans0.5%

Withdrawals Due to Drug-Related AEs,Ovarian Patients (n=396)

Total withdrawals 11.0%

Five most common AEs

PPE or other skin toxicity 3.5%

Cardiovascular disorder 1.0%

Stomatitis 0.8%

Asthenia 0.8%

Infusion reactions 0.5%

Palmar-Plantar Erythrodysesthesia (PPE)

Management

PPE - Grading and Management

Symptoms Dose Adjustment

Grade I Mild erythema Redose, unless previous Grade III/IV

Grade II Erythema with Delay 1-2 weeks or until desquamation resolved to Grade 0-I

Grade III Blistering Delay 1-2 weeks or untilresolved to Grade 0-I. Then redose at 75%

Grade IV Diffuse As for Grade III

Cardiotoxicity

Cardiotoxicity

• 0.8% (6/772) withdrew due to cardiotoxicity related to Doxil– 5 asymptomatic LVEF declines– 1 CHF (after 22 cycles — 944.3 mg/m2)

• 5 additional drug related cardiac events, all Grade I

Cardiac Safety

• Doxil PK mimics continuous infusion of doxorubicin• Preclinical - Less cardiotoxic1

• Biopsies in 10 KS patients (469 to 860 mg/m2) show minimal cardiotoxicity (Billingham scores 0-1.5; median 0.3)2

• Biopsies in 4 solid tumor patients (675 to 1680 mg/m2) show minimal cardiotoxicity (Billingham scores 0-1.5)

1 Working et al, JPET (1999)2 Berry, et al, Ann Oncol (1998)

Phase III Randomized Comparative Trial(Study 30-49)

• Doxil - 50 mg/m2 every 4 weeks

• Topotecan - 1.5 mg/m2 x 5 days every 3 weeks

Terminations and Dose Modifications(Study 30-49)

Doxil Topotecan(n = 135) (n = 132)

Patient still on study 45.2% 40.2%

Termination due to adverse events 6.7% 9.1%

Delayed, interrupted or reduced doses % Patients 44.4% 65.9% % Cycles 32.1% 49.9%

Percent of Patients by Severity of Adverse Events(Study 30-49)

0

20

40

60

80

100

Grade I Grade II Grade III Grade IV

Pe

rce

nt

of

Pa

tie

nts

Doxil Topotecan

0

10

20

30

40

50

60

70

80

Pe

rce

nt

Pat

ien

ts

Doxil’s 5 Most Frequent Drug-Related Adverse Events (Study 30-49)

Grade I, II

Grade III, IV

Doxil Topotecan

StomatitisPPE Anemia Asthenia Nausea

Topotecan’s 5 Most Common Drug-Related Adverse Events (Study 30-49)

0

10

20

30

40

50

60

70

80P

erce

nt

Pat

ien

ts

Neutropenia

ThrombocytopeniaAnemia

Alopecia Leukopenia

Grade I, II

Grade III, IV

Doxil Topotecan

Safety Summary

• Generally well tolerated

• PPE is the most common adverse event and is manageable

• Adverse event profile is predictable

Agenda


Cancer Center




Research

Risk/Benefit: Ed Schnipper, MD, VP, Clinical Research

Summary

• No approved therapy

• Objective response rate of 14.4%

• Duration of response of 39.4 weeks

• Generally well tolerated

• Convenient monthly dosing

Conclusions

• Doxil is active in patients with ovarian cancer who are refractory to platinum and paclitaxel and who may also be refractory to Topotecan

• Doxil represents a valuable addition to the treatment options for these patients

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