1 march 2003 odac: doxil ®, ovarian cancer odac discussion on accelerated approval march 12-13,...

11March 2003 ODAC: DOXILMarch 2003 ODAC: DOXIL®®, Ovarian Cancer, Ovarian Cancer

ODAC Discussion on ODAC Discussion on Accelerated ApprovalAccelerated Approval

March 12-13, 2003March 12-13, 2003

DOXILDOXIL®®

(doxorubicin HCl liposome injection)(doxorubicin HCl liposome injection)

Treatment of Treatment of Advanced, Metastatic Ovarian CancerAdvanced, Metastatic Ovarian Cancer


Individuals Available for QuestionsIndividuals Available for Questions

Sponsor RepresentativesSponsor Representatives

Martine George, MD Martine George, MD

Steven Hamburger, PhD Steven Hamburger, PhD

Surya Mohanty, PhD Surya Mohanty, PhD

April Teitelbaum, MD April Teitelbaum, MD

Margaret Tonda, PharmD Margaret Tonda, PharmD

Alex Zukiwski, MD Alex Zukiwski, MD


Ovarian Cancer IndicationOvarian Cancer Indication

DOXILDOXIL®® (doxorubicin HCl liposomal injection) (doxorubicin HCl liposomal injection) is indicated for:is indicated for:

““The treatment of metastatic carcinoma of the ovary in The treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both patients with disease that is refractory to both paclitaxel- and platinum-based chemotherapy paclitaxel- and platinum-based chemotherapy regimens. Refractory disease is defined as disease that regimens. Refractory disease is defined as disease that has progressed while on treatment, or within 6 months has progressed while on treatment, or within 6 months of completing treatment.”of completing treatment.”


Phase IV Status UpdatePhase IV Status Update

Original Phase IV commitment trial (30-49)Original Phase IV commitment trial (30-49)

– CompletedCompleted

– Planned final survival analysis underwayPlanned final survival analysis underway

Second Phase IV commitment trial (SWOG: SO200)Second Phase IV commitment trial (SWOG: SO200)

– Enrollment ongoingEnrollment ongoing


Challenges Surrounding Challenges Surrounding the Phase IV Commitment Trialsthe Phase IV Commitment Trials

The time to reach survival endpoint in original Phase IV The time to reach survival endpoint in original Phase IV commitment trial commitment trial

Multiple parties involved in finalization and implementation Multiple parties involved in finalization and implementation of the second Phase IV commitment trialof the second Phase IV commitment trial

Competition for accrual Competition for accrual

DOXILDOXIL®® can be prescribed to patients with ovarian can be prescribed to patients with ovarian cancer outside of a clinical study cancer outside of a clinical study

November 1998November 1998 Orphan drug designationOrphan drug designation

December 1998December 1998 sNDA submitted ovarian cancer indicationsNDA submitted ovarian cancer indication

Ovarian Cancer TimelineOvarian Cancer Timeline

Orphan Orphan DrugDrug

DesignationDesignation

sNDAsNDASubmittedSubmitted

DecDec

NovNov

66

19971997 19981998 19991999 20002000 20012001 20022002 20032003

March 2003 ODAC: DOXILMarch 2003 ODAC: DOXIL®®, Ovarian Cancer, Ovarian Cancer

June 1999: ODAC Meeting and Accelerated Approval June 1999: ODAC Meeting and Accelerated Approval sNDA contained data from:sNDA contained data from:

– 3 Phase II non-comparative studies in relapsed or refractory ovarian cancer 3 Phase II non-comparative studies in relapsed or refractory ovarian cancer (primary endpoint response rate)(primary endpoint response rate)• n = 176 patientsn = 176 patients

– Ongoing Phase III DOXILOngoing Phase III DOXIL®® vs. topotecan trial (Study 30-49) vs. topotecan trial (Study 30-49) • Data from interim analysis Data from interim analysis


77

ODACODAC

JunJun

AcceleratedAcceleratedApproval Approval

19971997 19981998 19991999 20002000 20012001 20022002 20032003





Phase IV commitment: Completion of Study 30-49 Phase IV commitment: Completion of Study 30-49

May 1997May 1997 First patient enrolled First patient enrolled

March 1999March 1999 Last patient enrolledLast patient enrolled

Phase IV Commitment Study 30-49


88

19971997 19981998 19991999 20002000 20012001 20022002 20032003

MarMar

FirstFirstPatientPatient

EnrolledEnrolled

LastLastPatientPatient

EnrolledEnrolled

DecDecMayMay


JunJun




Phase III Randomized Study of DOXILPhase III Randomized Study of DOXIL®® vs. vs. Topotecan in Ovarian Cancer Topotecan in Ovarian Cancer

Objective:Objective: Compare efficacy and safetyCompare efficacy and safety

Population:Population: Patients with relapsed ovarian cancer following Patients with relapsed ovarian cancer following failure with platinum-based chemotherapy (n = 474)failure with platinum-based chemotherapy (n = 474)

Stratification:Stratification: Platinum-sensitivity and bulk of diseasePlatinum-sensitivity and bulk of disease

Treatments:Treatments: DOXIL 50 mg/mDOXIL 50 mg/m22 q 4 wk q 4 wk

Topotecan 1.5 mg/mTopotecan 1.5 mg/m22 x 5 d q 3 wk x 5 d q 3 wk

Outcomes:Outcomes: Primary Primary –– TTP TTP

Secondary Secondary –– ORR, response duration, ORR, response duration, survival, safetysurvival, safety

Original Design:Original Design: Non-inferiority Non-inferiority

Study 30-49 Study 30-49

June 2000: Meeting with the FDA after End of Planned Treatment Analysis June 2000: Meeting with the FDA after End of Planned Treatment Analysis was provided for Study 30-49 was provided for Study 30-49 Analysis did not demonstrate superiority in TTP Analysis did not demonstrate superiority in TTP Significant survival advantage of DOXILSignificant survival advantage of DOXIL®® compared to topotecan in the compared to topotecan in the

platinum-sensitive groupplatinum-sensitive group ~50% of patients were alive~50% of patients were alive



1010

End ofEnd ofPlannedPlanned

TreatmentTreatmentMeetingMeeting

JunJun


EnrolledEnrolled


19971997 19981998 19991999 20002000 20012001 20022002 20032003



EnrolledEnrolled



End of Planned Treatment:End of Planned Treatment:Time to ProgressionTime to Progression


DOXILDOXIL®® TopotecanTopotecan PP

All Patients All Patients 18.418.4

n = 239n = 239

18.318.3

n = 235n = 2350.6320.632

Platinum-SensitivePlatinum-Sensitive29.929.9

n = 109n = 109

26.726.7

n = 111n = 1110.3870.387

Platinum-RefractoryPlatinum-Refractory9.19.1

n = 130n = 130

14.314.3

n = 124n = 1240.9410.941

Median (wks)Median (wks)


End of Planned Treatment:End of Planned Treatment:SurvivalSurvival


Median (wks)Median (wks)

DOXILDOXIL®® TopotecanTopotecan PP

All PatientsAll Patients58.758.7

n = 239n = 239

56.756.7

n = 235n = 2350.9640.964

Platinum-SensitivePlatinum-Sensitive110.7110.7

n = 109n = 109

84.784.7

n = 111n = 1110.0270.027

Platinum-RefractoryPlatinum-Refractory34.634.6

n = 130n = 130

41.441.4

n = 124n = 1240.1260.126


Percent of Patients by Severity of Percent of Patients by Severity of Adverse EventsAdverse Events


0

20

40

60

80

100

Grade I Grade II Grade III Grade IV

DOXIL® Topotecan

0

20

40

60

80

100

Grade I Grade II Grade III Grade IV

DOXIL® Topotecan

June 2000: Outcome of FDA Meeting for End of Planned Treatment AnalysisJune 2000: Outcome of FDA Meeting for End of Planned Treatment Analysis

FDA agreed to a final survival analysis to be performed when a FDA agreed to a final survival analysis to be performed when a percentage of the 474 randomized and treated patients died or were lost percentage of the 474 randomized and treated patients died or were lost to follow-up to follow-up – 90% events chosen to provide adequate power for survival analysis90% events chosen to provide adequate power for survival analysis– Protocol amended accordinglyProtocol amended accordingly

A second protocol to prove clinical benefit was required A second protocol to prove clinical benefit was required



1414



JunJun


EnrolledEnrolled


19971997 19981998 19991999 20002000 20012001 20022002 20032003



EnrolledEnrolled


July 2000July 2000

ALZA submitted a second Phase IV draft protocol ALZA submitted a second Phase IV draft protocol

– DOXILDOXIL®® and carboplatin vs. carboplatin in platinum-sensitive and carboplatin vs. carboplatin in platinum-sensitive patients with recurrent epithelial ovarian carcinoma after failure patients with recurrent epithelial ovarian carcinoma after failure of initial, platinum-based chemotherapy of initial, platinum-based chemotherapy



Second Phase IV Commitment StudySecond Phase IV Commitment Study

1515

SecondSecondPhase IV Phase IV ProtocolProtocol

SubmittedSubmitted

JulJul

End of PlannedEnd of PlannedTreatmentTreatmentMeetingMeeting


EnrolledEnrolled


19971997 19981998 19991999 20002000 20012001 20022002 20032003



EnrolledEnrolled




September – December 2000 September – December 2000

Dialogue between ALZA and FDA regarding protocol design of the Dialogue between ALZA and FDA regarding protocol design of the second Phase IV Commitment Trialsecond Phase IV Commitment Trial

Second Phase IV Commitment StudySecond Phase IV Commitment Study

1616

Dialogue Dialogue BetweenBetween

ALZA & FDAALZA & FDA

Sept-DecSept-Dec


SubmittedSubmitted


EnrolledEnrolled


19971997 19981998 19991999 20002000 20012001 20022002 20032003



EnrolledEnrolled





January – November 2001January – November 2001 Discussions between SWOG and ALZA to conduct this study Discussions between SWOG and ALZA to conduct this study

December 2001December 2001 ALZA submits SWOG protocol SO200 to FDAALZA submits SWOG protocol SO200 to FDA



Second Phase IV Commitment Study SO200Second Phase IV Commitment Study SO200

1717

DiscussionsDiscussionsbetween between SWOG & SWOG &

ALZAALZA

SWOG ProtocolSWOG ProtocolSubmitted to Submitted to

FDAFDA

DecDec

Jan-NovJan-Nov

Dialogue Dialogue BetweenBetween

ALZA & FDAALZA & FDA


SubmittedSubmitted


EnrolledEnrolled


19971997 19981998 19991999 20002000 20012001 20022002 20032003



EnrolledEnrolled






*SWOG, GOG, CALGB, ECOG, NCCTG, NCI / CTSU*SWOG, GOG, CALGB, ECOG, NCCTG, NCI / CTSU

SWOG SO200 Ovarian CancerSWOG SO200 Ovarian Cancer

Objectives:Objectives: Compare between the two treatment groups:Compare between the two treatment groups:• Primary endpoint: Overall survival • Primary endpoint: Overall survival • Secondary endpoints: PFS, confirmed CRs, TTF, toxicity• Secondary endpoints: PFS, confirmed CRs, TTF, toxicity

Population:Population: Patients with recurrent disease or disease Patients with recurrent disease or disease progression with a progression-free and platinum-progression with a progression-free and platinum-free interval of 6 to 24 months after completion of free interval of 6 to 24 months after completion of first line platinum-based chemotherapy (n = 900)first line platinum-based chemotherapy (n = 900)

Study Design:Study Design: Randomized, intergroup*, open-label study Randomized, intergroup*, open-label study

Treatments:Treatments: Carboplatin AUC = 5 q 4 wks plus Carboplatin AUC = 5 q 4 wks plus DOXILDOXIL®® 30 mg/m 30 mg/m22 q 4 wks q 4 wks

Carboplatin AUC = 5 q 4 wksCarboplatin AUC = 5 q 4 wks



August 2002August 2002 SWOG activates protocolSWOG activates protocol

September 2002September 2002 First patient enrolled First patient enrolled

SeptSept

19971997 19981998 19991999 20002000 20012001 20022002 20032003




EnrolledEnrolledsNDAsNDA

SubmittedSubmitted




DialogueDialogueBetweenBetweenALZA &ALZA &

FDAFDA

FirstFirstPatient Patient

EnrolledEnrolledSWOGSWOG

ProtocolProtocolActivatedActivated

SWOG SWOG ProtocolProtocol

Submitted Submitted to FDAto FDA

AugAug


ALZAALZA



EnrolledEnrolled


SubmittedSubmitted


19971997 19981998 19991999 20002000 20012001 20022002 20032003






EnrolledEnrolledsNDAsNDA

SubmittedSubmitted




90%90%Survival Survival AnalysisAnalysis(30-49)(30-49)

MarMar

DialogueDialogueBetweenBetweenALZA &ALZA &

FDAFDA

FirstFirstPatient Patient

EnrolledEnrolledSWOGSWOG

Protocol Protocol ActivatedActivated

SWOG SWOG ProtocolProtocol

Submitted Submitted to FDAto FDA

June 2000June 2000 FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized FDA agreed to a final survival analysis from Study 30-49 performed when 90% of the 474 randomized

and treated patients had died or were lost to follow-upand treated patients had died or were lost to follow-up

March 2003March 2003 Analysis of final survival results for Study 30-49 is ongoing Analysis of final survival results for Study 30-49 is ongoing

JunJun


ALZAALZA


EnrolledEnrolled



SubmittedSubmitted



Issues Surrounding Issues Surrounding Phase IV Commitment TrialsPhase IV Commitment Trials

After the end of planned treatment analysis, the primary endpoint for After the end of planned treatment analysis, the primary endpoint for Study 30-49 was modified to become overall survival Study 30-49 was modified to become overall survival

– The time to reach the 90% event endpoint in Study 30-49 The time to reach the 90% event endpoint in Study 30-49 was > 3.5 yearswas > 3.5 years

Finalization and implementation of the second Phase IV SO200 Finalization and implementation of the second Phase IV SO200 commitment trial commitment trial

– Multiple parties involved (SWOG, other cooperative groups, Multiple parties involved (SWOG, other cooperative groups, NCI, FDA and Sponsor) NCI, FDA and Sponsor)

– Transfer of clinical responsibilitiesTransfer of clinical responsibilities

Competition for accrual Competition for accrual

– Ongoing clinical trialsOngoing clinical trials

– DOXILDOXIL®® can be prescribed to patients with ovarian cancer can be prescribed to patients with ovarian cancer outside of a clinical studyoutside of a clinical study


SummarySummary

Conversion from Accelerated Approval to Full Approval:Conversion from Accelerated Approval to Full Approval:

Original Phase IV commitment study (30-49)Original Phase IV commitment study (30-49)

– Study started before NDA submissionStudy started before NDA submission

– Design agreed with FDADesign agreed with FDA

– Enrollment completed prior to approvalEnrollment completed prior to approval

– Planned final survival analysis underwayPlanned final survival analysis underway

Second Phase IV commitment study (SWOG: SO200)Second Phase IV commitment study (SWOG: SO200)

– Study design acceptable to FDAStudy design acceptable to FDA

– Currently enrolling patients Currently enrolling patients

1 march 2003 odac: doxil ®, ovarian cancer odac discussion on accelerated approval march 12-13,...

Documents

ovarian cancer phase

ovarian cancer challenges

ovarian cancer odac

ovarian cancer indication

commitment study

patient enrolled phase

commitment trial swog

commitment trial competition