nda 21-600

P-1

NDA 21-600NDA 21-600

Marqibo

(Vincristine Sulfate Liposomes Injection)

Treatment of patients with aggressive non-Hodgkin’s lymphoma previously treated with at least two combination

chemotherapy regimens

P-2

External ConsultantsExternal Consultants

Fernando Cabanillas, MD Clinician andClinical Professor of Medicine PresenterMD Anderson Cancer Center

Medical DirectorAuxilio Mutuo Cancer Center

Jane Winter, MD ClinicianProfessor of Medicine 2nd largest site Department of Hematology/OncologyNorthwestern University

P-3

External ConsultantsExternal Consultants(Continued)(Continued)

Randy Gascoyne, MD Lymphoma Pathologist and Clinical Professor PathologistBritish Columbia Cancer Agency

Scott Gazelle, MD, MPH, Ph.D Radiologist, Associate Professor Independent ReviewMassachusetts General Hospital Panel

Sandra Chica, MD RadiologistMedical Director - RadiologistPerceptive Informatics, Inc. (Parexel)

P-4

External ConsultantsExternal Consultants(Continued)(Continued)

Shayne Gad, Ph.D, DABT, AST ToxicologistGad Consulting Services

Jean-Marie Houle, Ph.D Pharmacokineticist Houlemiron BC Enterprises Inc.

Louis Gura, MS StatisticianThree Flags Consulting

P-5

Unmet Medical Need in Aggressive NHLUnmet Medical Need in Aggressive NHL

Fernando Cabanillas, MD

Clinical Professor of Medicine MD Anderson Cancer Center

Medical Director Auxilio Mutuo Cancer Center

P-6

Overview of NHLOverview of NHL

NHLs broadly classified as aggressive vs. indolent

Aggressive NHL– 35-40% of NHL– Diffuse large B-cell lymphoma, peripheral T-cell lymphoma

DLBCL frequently presents with divergent histologies– Treatment is driven by the most aggressive histology– Response is measured the same way

– At relapse, life expectancy measured in months

Indolent NHL– At relapse, life expectancy measured in years

No new agents approved for aggressive NHL in last 17 years

P-7

Overview of Aggressive NHLOverview of Aggressive NHL

First-line therapy– R-CHOP therapy cures 50% of aggressive B-cell NHL

Second-line therapy– If <65 years, 20% cured with high dose chemo and

ASCT (only if response to salvage therapy)– If 65 years or if ASCT not feasible, 10% curable

Median survival 6 months

Response rates and duration drop with each relapse

P-8

Overview of Aggressive NHLOverview of Aggressive NHL(Continued)(Continued)

Third-line or later therapy (indicated population)– 10,000 – 15,000 patient prevalence in 2001– No standard therapy– Bone marrow frequently compromised, thus fewer

options– Reduction in tumor burden associated with symptom

improvement– Results are dismal, complete responses are rarely

achieved and survival is short

P-9

Survival After MIME as 3rd Line Survival After MIME as 3rd Line or Later Therapy for Aggressive NHLor Later Therapy for Aggressive NHL

Survival Time (mos.)

0 5 10 15 20 25 30 35 400.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

By 12 months, 75% are dead

By 2 years, 96% are dead

n =72

Median = 6 months

P-10

FDA Single Agent Papers FDA Single Agent Papers Not Adequate for Comparison to VSLINot Adequate for Comparison to VSLI

Regimen/Authors ORR Histologically

Relevant n

10 Pts

No ORR for Aggressive

NHLa

# Prior

Therapies Not Comparable

b

II-2 (Lauria, n=2) 50% 2 X X

Gemcitabine (Bernell, n=3) 66% 3 X

Oxaliplatin (Germann, n=22) 40% 3 X

Oral Etoposide (Shaklai, n=20) 69% 6 X

Bortezomib (Goy, n=45) 20% 9 X X

Oxaliplatin (Younes, n=25) 24% 13 X

Cytarabinec

(Peters, n=59) 64% 22 X

Methotrexate (Canellos, n=25) 52% 25 X

Idarubicin (Case, n=31) 43% 31 X

a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with 2 regimens. c All patients treated with combination therapy.

P-11

FDA Papers for Comparison to VSLIFDA Papers for Comparison to VSLI

Histologically

Eligible Patients 10

No ORR for

Aggressive NHLa

Prior Therapies

Not Comparableb

Total

Comparable Papers

Single agent papers (11)

5 1 5 2

Combination therapy papers (35)

2 9 27 5

a ORR includes ineligible histologies, e.g., indolent and mantle cell. b Median number of priors <2 or ORR not analyzed for patients with 2 regimens.

P-12

Single Agent Rituximab in Aggressive NHLSingle Agent Rituximab in Aggressive NHL

Parameter Rothe (n=21)

Tobinai Histologic Subgroup

(n=50)

Coiffier Histologic Subgroup

(n=30)

Median prior regimens

2

(38% 1st relapse)

2a

(32% 1st relapse)

2a

(17% untreated, 31% 1st relapse)

CR+PR (%) 38 34 37

CR (%) 5 — —

TTP (mos) 3.8 2.0a >3.5a

a Median for entire study, not for subgroup.

P-13

Combination Regimens as 3Combination Regimens as 3rdrd Line Line or Later Therapyor Later Therapy

Publication Median # of Priors

ORR CR

IIVP-16 (Engert, n=38) 2 47 21

FLUDAP (Child, n=33) 2 39 15

CEPP(B) (Chao, n=20) 2 45 15

DHAP (Press, n=26) 3 65 —

Ifosfamide, hydroxyurea and etoposide (Gasser, n=19)

3 53 5

P-14

Unmet Clinical NeedsUnmet Clinical Needs

Patients who don’t qualify for aggressive combination regimens or who have relapsed after ASCT– Poor marrow function– Age >65– Poor performance status– No response to pre-transplant salvage therapy– Co-morbidities

Patients with compromised marrow function– Rituximab no longer a viable alternative

No compelling literature evidence for “available therapy” after 2nd relapse

Need an agent that can provide clinically meaningful benefit without excessive toxicity

P-15

Pharmacology PresentationPharmacology Presentation

Tom Madden, Ph.D

Senior Director, Technology Development and Licensing

Inex Pharmaceuticals Corporation

P-16

Vincristine Sulfate Liposomes InjectionVincristine Sulfate Liposomes Injection(VSLI)(VSLI)

Active agent: vincristine sulfate

Liposome composition: sphingomyelin/cholesterol

Liposome size: 115 nm, contains approximately 10,000 drug molecules/vesicle

Aqueous corewith vincristine

Liposomal bilayer

P-17

VSLI: Product RationaleVSLI: Product Rationale

VSLI Increases Tumor Exposure to Vincristine

• Higher vincristine tumor levels due to preferential delivery

• Longer duration of exposure due to slow vincristine release

P-18

VSLI Accumulates in Tumor Tissue by VSLI Accumulates in Tumor Tissue by Extravasation Across Tumor VasculatureExtravasation Across Tumor Vasculature

Tumor tissue demonstrating accumulation of VSLI in

interstitial space

Normal tissue showing VSLI in blood vessels with no evidence

of extravasation

P-19

Vincristine Activity is Dependent on Vincristine Activity is Dependent on Duration of ExposureDuration of Exposure

Duration of Exposure (hr)

Via

ble

Cel

ls

Reproduced from Jackson and Bender, Cancer Res. 39: 4346-9, 1979.

P-20

Vincristine is Slowly Released from VSLI Vincristine is Slowly Released from VSLI in Vivo (Rat Plasma)in Vivo (Rat Plasma)

0

20

40

60

80

100

0 20 40 60 80Time (h)

Re

lea

sed

Vin

cris

tin

e (%

)VSLI provides prolonged exposure to vincristine

P-21

Antitumor Activity of VSLI Is Significantly Antitumor Activity of VSLI Is Significantly Greater Than VCR in the Namalwa Lymphoma Greater Than VCR in the Namalwa Lymphoma

Xenograft ModelXenograft Model

Day Post-Implantation

0 10 20 30 40 50

Mea

n T

um

or

Vo

lum

e (m

m3 )

0

500

1000

1500

VSLI (4.5 mg/m2)

VCR (4.5 mg/m2)PBS Control

P-22

Plasma Vincristine Concentration-time Plasma Vincristine Concentration-time Profiles for VSLI and VCR in PatientsProfiles for VSLI and VCR in Patients

0.1

1

10

100

1000

10000

0 10 20 30 40 50

Time (h)

To

tal V

incr

isti

ne

Co

nce

ntr

atio

n (

ng

/mL

) VSLI (2.0 mg/m2, n=26)

VCR (1.2 mg/m2, n=4, Nelson 1982)

P-23

VSLI Nonclinical SummaryVSLI Nonclinical Summary

Compared to conventional vincristine– VSLI provides increased tumor exposure – VSLI provides increased antitumor activity in

nonclinical studies– VSLI elicits the same toxicities

P-24

Clinical Efficacy and SafetyClinical Efficacy and Safety

Alexandra Mancini, MSc.

Senior Vice President, Clinical and Regulatory Affairs

Inex Pharmaceuticals Corporation

P-25

Efficacy Trials in Relapsed Efficacy Trials in Relapsed Aggressive NHLAggressive NHL

Supportive Phase IIa Study (DM97-162)– NHL or ALL– Investigator-sponsored at MD Anderson Cancer Center– 92 patients with relapsed aggressive NHL

Primary Phase IIb Study (CA99002)– International multicenter: 42 sites enrolled– 119 patients enrolled

Two largest trials in multiply relapsed aggressive NHL

Similar study designs and response criteria

Consistent results in 211 patients

P-26

Randomized Controlled TrialRandomized Controlled Trial

Post-approval commitment to confirm clinical benefit – 3 meetings and SPA comments from FDA– Revised protocol to be resubmitted shortly– Study to start in first half 2005

P-27

Study Conduct Issues Raised by FDA

P-28

Study Conduct Issues Raised by FDAStudy Conduct Issues Raised by FDA

Low Number of Eligible Patients

Numerous protocol amendments and exemptions

Low histologic eligibility rate

Incomplete staging in 19% of patients

Conduct of Independent Review Panel (IRP)

Wording of response criteria

Operations of core imaging lab

Amendments to IRP Charter

P-29

Protocol AmendmentsProtocol Amendments

Protocol Version Number of Patients

Enrolled

5.0 7 6.0 8 7.0 9 8.0 54 9.0 41

P-30

Protocol Version 5.0Protocol Version 5.0

Key Inclusion Criteria

Patients with a CR or CRu to 1st line chemotherapy

Patients with at least a PR to most recent therapy

A poorer prognosis population

7.07.0

at least a minor response

deleted

P-31

Other AmendmentsOther Amendments

Version 7.0 8.0

Peripheral T-cell lymphoma (1 pt)

Anaplastic large null-/T-cell lymphoma (2 pts)

Transformed NHL (11 pts)

No further changes in eligibility criteria

With each amendment FDA agreed that trial population suitable for accelerated approval


P-32

Protocol AmendmentsProtocol Amendments

Version 8.0 to 9.0

Additional CT scans scheduled 4 weeks after first response instead of the original 8 weeks

A clarification changed wording that these confirmatory CT scans “should” instead of “must” be obtained

P-33

Enrollment ExemptionsEnrollment Exemptions

Careful to not allow exemptions that would have enhanced apparent VSLI response rate


P-34

Histologic EligibilityHistologic Eligibility

19% ineligible by retrospective Central Review – Mostly indolent lymphomas

FDA excluded additional 7 patients described as ‘probably eligible’ by Central Review

Not protocol violations or due to amendments– Site pathology defined them as eligible for enrollment

P-35

Histologic Eligibility by Central Histologic Eligibility by Central Pathology Review (ITT)Pathology Review (ITT)

Histologic Eligibility

SWOG 8516 (n=1128)a 79%

SWOG 9240 (n=112)a 81%

Coiffier (2002) (n=399)a 86%

SWOG 9125 (n=100)a 90% VSLI Phase IIb (n=119) 81%

a Newly diagnosed patients

P-36

Other FDA Eligibility ExclusionsOther FDA Eligibility Exclusions

Number of Patients

CTs incomplete at study entry 3

Bone marrow biopsies >8 weeks before study or not done

9

Missing LDH at study entry 1

Missing neuro exams at study entry

13

Stage of disease was not an eligibility criterion

0

0

0

1

P-37

Response Criteria WordingResponse Criteria Wording

In some situations the criteria are ambiguous or silent

These clarifications were undertaken to uphold the rigor of the criteria

To ensure consistent interpretation in this multicenter study

P-38

Response Criteria WordingResponse Criteria Wording

April 3, 2000 Meeting with FDA

Protocol Version 5.0 with clarified response criteria wording

FDA agreed with the protocol wording

No changes to response criteria since that meeting

P-39

Operations of Core Imaging LabOperations of Core Imaging Lab

FDA review noted that procedures manual was dated 1 year after review of images began

Earlier version in place before reviews began

No changes to core lab procedures for entire IRP process

P-40

Amendments to IRP CharterAmendments to IRP Charter

No changes to conduct of IRP radiology and oncology reviews

Amendments in place before reviews began

A few clarifications for situations not previously anticipated requested by Dr. Scott Gazelle– Amendments documented what was done

All images read in chronologic sequence and locked

P-41

Conclusions Regarding Conclusions Regarding Study Conduct IssuesStudy Conduct Issues

Protocol amendments and exemptions defined a population with a poorer prognosis

Histologic eligibility comparable to literature rates

Only 9 patients (8%) ineligible for efficacy evaluation due to protocol violations

IRP process was well conducted

Well defined and reliable assessment of objective response in the indicated population

Adequate and well-controlled trial

P-42

Pivotal Study Presentation

P-43

Key Eligibility CriteriaKey Eligibility Criteria

Aggressive de novo or transformed NHL

At least 2 prior combination regimens including an anthracycline

At least a minor response to 1st line therapy

P-44

Key Eligibility CriteriaKey Eligibility Criteria(Continued)(Continued)

No maximum number of prior regimens

No requirement of response to prior salvage therapies

No upper limit on age

ECOG PS 0-3 accepted

Grade 1-2 neuropathy permitted

Granulocytes0.5 x 109/L

Platelets 50 x 109/L

P-45

2 mg/m2 without dose capping, 1hr IV infusion

Repeat every 2 weeks

12 cycles maximum, 2 cycles after CR

VSLI Monotherapy RegimenVSLI Monotherapy Regimen

2 mg/m2 without dose capping, 1hr IV infusion

Repeat every 2 weeks

12 cycles maximum, 2 cycles after CR

At least 2x dose intensity of vincristine

P-46

Efficacy Endpoints and PopulationsEfficacy Endpoints and Populations

Efficacy Endpoints

Primary– Objective response rate (CR + CRu + PR)

Secondary– Duration of response– Time to progression – Overall survival

Efficacy Populations

Intent-to-Treat Population (ITT) (n=119)

Per-Protocol Population (PP) (n=77)

P-47

Efficacy EvaluationsEfficacy Evaluations

International Workshop Criteria (Cheson et al 1999)– CTs of chest, abdomen, pelvis– 6 indicator lesions– Response does not require confirmation

Independent Review Panel (IRP)– Primary efficacy assessment– Blinded to site opinion of response – Independent selection of indicator lesions

P-48

Patient Population

P-49

Extent of Prior Therapy (ITT)Extent of Prior Therapy (ITT)

25%23%

33%

19%

1%0

5

10

15

20

25

30

35

1 2 3 4 5-10

# of Regimens

% o

f P

atie

nts

(n

=11

9)

• Mean: 3.8; Median: 3 • 33% had prior ASCT

• Predominantly at 4th-5th line

P-50

Response to Prior TherapyResponse to Prior Therapy

CR+PR

(%)

CR (%)

Response Duration

(mos)

First line 92 50 8

Second line 41 20 5

Last line 35 13 5

75% received a combination regimen as last therapy

P-51

Sensitivity to Last Qualifying Therapy (ITT)Sensitivity to Last Qualifying Therapy (ITT)

% of Patients

(n=119)

Resistant 67 Refractory (no response) 50 Early relapse (response duration <3

months) 17

Sensitive (response duration 3 months) 33

P-52

Efficacy Data (ITT)

P-53

Objective Response Rate (ITT) Objective Response Rate (ITT) by IRPby IRP

Best Tumor Response Number (%) of

Patients (n=119)

Responders (ORR) 30 (25) CR, CRu 8 (7) PR 22 (18)

Nonresponders SD 31 (26) PD 32 (27) UE 26 (22)

P-54

Objective Response Rate ComparisonsObjective Response Rate Comparisons

% of Patients

Best Response

ITT

(n=119)

Per Protocol (n=77)

FDA

Eligible (n=65)

ORR 25 27 22

[95% CI] [18, 34] [18, 39] [12, 34]

CR 3 1 2

CRu 3 4 2

PR 18 22 18

SD 26 29 —

P-55

Is Objective Response Likely to Predict Clinical Benefit?

P-56

8 patients with CR or CRu– 3 patients asymptomatic– Remaining 5 patients either had resolution of

symptoms or improved ECOG PS

22 patients with PR– 15 had improvements in symptoms or ECOG PS

Symptom Improvement in RespondersSymptom Improvement in Responders

P-57

Time-to-Event Endpoints

P-58

Duration of Response Duration of Response

Kaplan-Meier Analysis

IRP Review

(n=30)

FDA Analysis (n=30)

Median duration of response (days)

>85a

72

95% CI [72, —]b [37, —]b

a Probability of ongoing response 52% at last event of PD. b Upper limit cannot be calculated.

P-59

Time to Progression (ITT)Time to Progression (ITT)by IRPby IRP

Kaplan-Meier Analysis ITT

(n=119) Responders

(n=30)

Median TTP (days) 89 >127a

95% CI [64, 217] [113, —]b

a Progression-free probability 45% at last event of PD. b Upper limit cannot be calculated.

P-60

Survival (ITT)Survival (ITT)

119 68 47 41 35 26 15 5 0

Patients at Risk

Censored Observations

Median 6.7 months

25% alive at 2 years

P-61

Subgroup Analyses

P-62

ORR by Number of Prior Regimens and ORR by Number of Prior Regimens and Sensitivity to Last Qualifying RegimenSensitivity to Last Qualifying Regimen

ORR (% of Patients)

2 Regimensa(n=24) 46

Sensitivea(n=11) 64

Resistant (n=13) 31

>2 Regimens (n=95) 20

Sensitive (n=28) 32

Resistant (n=67) 15

a Includes one patient (sensitive) who had

only one prior regimen and responded to VSLI.

P-63

Consistent Results in Both Studies (n=211)Consistent Results in Both Studies (n=211)

ORR (% of Patients)

Combined Studies Phase

IIb

Phase IIa

Combined

2 Regimens (n=49) 46 52 49

Sensitive (n=28) 64 65 64

Resistant (n=21) 31 25 29

>2 Regimens (n=161) 20 24 22

Sensitive (n=43) 32 47 37

Resistant (n=118) 15 18 16

P-64

Univariate AnalysesUnivariate AnalysesObjective Response RateObjective Response Rate

Subgroup ORR

(% of Patients) 95% CI

Prior ASCT

Yes (n=39) 26 [13, 42]

No (n=80) 25 [16, 36]

Age

60 years (n=60) 25 [15, 38]

>60 years (n=59) 25 [15, 38]

>70 years (n=28) 36 [19, 56]

P-65

VSLI Efficacy Compared to VSLI Efficacy Compared to Single-Agent RituximabSingle-Agent Rituximab

Parameter Rothe (n=21)

Tobinai

Subgroup (n=50)

Coiffier

Subgroup (n=30)

Phase IIb Subgroup

(n=24)

Phase IIb (n=119)

Median prior regimens

2

(38% 1st relapse)

2a (32% 1st relapse)

2a (17% untreated, 31% 1st relapse)

2b 3

CR+PR (%) 38 34 37 46 25

CR (%) 5 — — 0 7

Duration of response (mos)

— — — 2.0 3.0

TTP (mos) 3.8 2.0a >3.5a 3.0 3.0

a Median for entire study, not for subgroup.

b 1 patient had only 1 prior regimen.

P-66

Objective Tumor Response by IRP Objective Tumor Response by IRP Single-Agent Rituximab as Last TherapySingle-Agent Rituximab as Last Therapy

Number (%) of Patients

(n=20)

Best Tumor Response

Rituximab VSLI

ORR 5 (25) 8 (40)

CR 0 (0) 2 (10)

CRu 0 (0) 1 (5)

PR 5 (25) 5 (25)

MR+SD 4 (20) 4 (20)

PD+UE 11 (55) 8 (40)

P-67

Safety Data

P-68

Extent of Treatment with VSLI (ITT)Extent of Treatment with VSLI (ITT)

(n=119)

Number of Cycles Received Mean 4.6 Median (range) 4.0 (1-20)

Dose Intensity (mg/m2/wk) Median 0.98

P-69

Safety – Major EndpointsSafety – Major Endpoints

14% of patients withdrawn due to associated AEs, mostly neuropathy

No treatment-associated deaths

P-70

Neuropathy

P-71

Prior Neurotoxic Therapies (ITT)Prior Neurotoxic Therapies (ITT)

% of Patients (n=119)

Number of Prior Regimens Containing Neurotoxic Agents

1 14 2 56 3-5 30

Neurologic Abnormality at Baseline 85

P-72

Worst Neuropathy on Study by Grade at Study EntryWorst Neuropathy on Study by Grade at Study Entry(Pain, Paresthesia, Numbness, (Pain, Paresthesia, Numbness,

Weakness, Constipation)Weakness, Constipation)

% of Patients

Worst Grade on Study Study Entry Grade Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Grade 0 (n=39) 8 26 33 26 0

Grade 1 (n=46) 0 24 41 26 4

Grade 2 (n=21) 0 5 38 52 5

P-73

Mean Change from Baseline for Cycles 1 to 6 Mean Change from Baseline for Cycles 1 to 6 for Hand Numbnessfor Hand Numbness

Hand Numbness

n=94 n=81 n=70 n=50 n=33 n=23

0.0

1.0

2.0

C1 C2 C3 C4 C5 C6Cycle

Ch

ang

e fr

om

Bas

elin

e (+

/-

SE

M)

*Significant change from baseline

*

*

*

*

*

*

P-74

Dose to Grade 3 or 4 NeuropathyDose to Grade 3 or 4 Neuropathy(Pain, Paresthesia, Numbness, (Pain, Paresthesia, Numbness,

Weakness, Constipation)Weakness, Constipation)

Kaplan-Meier Analysis (n=115)

Number (%) of patients with Grade 3 or 4 neuropathy

37 (32)

Grade 3 neuropathy 34 (30) Grade 4 neuropathy 3 (3)

Estimated median cumulative dose

21.2 mg/m2

(~11 doses)

• Equivalent to 15 doses of conventional vincristine

P-75

Comparison of Neuropathy in Responders Comparison of Neuropathy in Responders vs. Nonresponders (Numbness)vs. Nonresponders (Numbness)

% of Patients

Grade Changes From Baseline to Worst Value

Parameter No Change

1

Grade

2 Grades

3

Grades

4 Grades

Responders, CR+CRu+PR (n=29)

14 41 24 21 0

Nonresponders, SD+PD+UE (n=74)

55 24 16 4 0

PD or UE only (n=48) 69 19 10 1 0

P-76

Timing of Antitumor EffectTiming of Antitumor Effect vs. Neuropathy vs. Neuropathy

Antitumor activity evident early in patients who responded, usually within 2 weeks (1st dose)– Symptomatic improvements– Reduced palpable adenopathy– Decreased LDH

Development of neuropathy is gradual and predictable

Informed treatment decisions can be made before significant neuropathy develops

P-77

Hematologic Abnormalities

P-78

Hematologic Abnormalities at Study EntryHematologic Abnormalities at Study Entry

% of Patients (n=119)

Hematologic Abnormality At Study Entry

Anemia 78 Neutropenia 15 Thrombocytopenia 40

ANC <1.5 or Platelets <100K 33

P-79

Hematology CTC Grade Changes from Hematology CTC Grade Changes from Baseline to Worst GradeBaseline to Worst Grade

% of Patients

Grade Change

Parameter No Change

1

Grade

2 Grades

3

Grades

4 Grades

Hemoglobin (n=118) 47 40 9 1 0

Neutrophils (n=117) 52 15 11 15 5

Platelet count (n=118) 56 32 6 1 0

P-80

Hematologic ToxicityHematologic Toxicity

Neutropenia

• 8% Grade 4 neutropenia (<0.5 ANC)

• 3% febrile neutropenia

• 2% prophylactic filgrastim usage

Thrombocytopenia

• 1% Grade 4 thrombocytopenia (<10x109/L)

• 6% platelet transfusions

P-81

Patients with Net Clinical BenefitPatients with Net Clinical Benefit

Fernando Cabanillas, MD

Clinical Professor of Medicine MD Anderson Cancer Center

Medical Director Auxilio Mutuo Cancer Center

P-82

Patient Benefit SummariesPatient Benefit Summaries

FDA requested patient benefit summaries to facilitate review for clinical benefit

38 patients considered to be responders by either IRP or Investigator

5 patients with SD (minor response) had evidence of clinical benefit

Total of 43 individual patient benefit-risk assessments

P-83

41 Patients Had Evidence of 41 Patients Had Evidence of Net Clinical BenefitNet Clinical Benefit

Improvement in symptoms or ECOG PS

Tumor response to VSLI that permitted stem cell transplant

Durable complete response

Durable PR or prolonged SD

Better response than with prior regimen

Improvement in laboratory parameters

In case studies

P-84

Clinical Benefit: Symptomatic and Clinical Benefit: Symptomatic and ECOG PS ImprovementsECOG PS Improvements

Category of Improvement Number (%) of

Patients (n=43)

Symptomatic improvement (B symptoms or other symptoms)

20 (47)

ECOG PS improved 13 (30)

Symptomatic or ECOG PS improvement

26 (60)

P-85

Clinical Benefit: Stem Cell TransplantClinical Benefit: Stem Cell Transplant

6 patients were able to receive transplants after VSLI study, 5 allogeneic, 1 autologous

Responsiveness to VSLI therapy and maintenance of good performance status enabled consideration for transplant

5 patients alive (1 died at 29 months)– 1 with disease (survival of 28+ months)– 4 with no evidence of disease (27+, 29+, 31+,

39+ months)

P-86

Case Studies ofSelected Patients with Clinical Benefit

P-87

Patient 35-01Patient 35-01

56 y/o F, Stage IV-B, IPI=1

Primary mediastinal DLCL, weight loss, fever, night sweats, anemia

Prior Rx: 1) CHOPPR for 3 months; 2) ESHAPPD; 3) RICEPD

20 cycles VSLI/38 weeks CRu of ~1 yr

Transient Grade 4 neutropenia at Cycle 5

Attained CRu after being refractory to all prior Rx; resolution of B symptoms and anemia

P-88


76 y/o F, DLCL-B, IPI=3

Multiple pulmonary metastases

Low platelets (72k)

Prior Rx: 1) CHOPCR; 2) CTX-VP16-DTIC-Rituxan-PredCR

8 cycles VSLI/14 weeks PR 8+ mos, platelets normalized

No Grade 3-4 toxicities

Residual pulmonary nodules not changed @ 2.5 years (fibrotic tissue?)

Chemo-free interval of 27+ mos, a longer remission than with any prior therapies

P-89


47 y/o M, Stage IV-B, DLCL-B, IPI=1

Mediastinal mass and marrow involvement

Prior Rx: 1) CHOPMR; 2) RICEPD

8 cycles VSLI/14 weeks PR 9+ mos (IRP); CR 14+

mos (INV)

No Grade 3-4 toxicities

Alive with no evidence of disease at 30+ mos, with no subsequent therapies

Attained CR after being refractory to all prior Rx; resolution of B symptoms and anemia

P-90

Benefit-Risk Conclusions

P-91

Summary of Patient PopulationSummary of Patient Population

Median 3 prior regimens 4th-5th line therapy

33% had prior ASCT

33% with low blood counts

50% refractory to last therapy

24% >70 years

66% with elevated LDH

P-92

Summary of VSLI BenefitsSummary of VSLI Benefits

25% ORR in heavily pretreated patients with highly resistant disease and compromised marrow– 46% ORR in those treated on 2nd relapse

Clinically important ORR for this population

22% of patients with symptomatic or ECOG PS improvement

Median duration of response of 3 months, 4 months for time to progression for a population with a median survival of 7 months

P-93

Summary of RisksSummary of Risks

Neuropathy is dose-limiting toxicity– Gradual cumulative development– Only 13% withdrew for neuropathy

Well tolerated compared to other agents– Low incidence of severe myelotoxicity and

hospitalizations– Low incidence of severe nausea and vomiting or

alopecia

P-94

Favorable Benefit-Risk ProfileFavorable Benefit-Risk Profile

Symptomatic improvement and antitumor activity evident early, allowing informed treatment decisions before significant neuropathy develops

Favorable benefit-risk profile for this population with no standard treatment options

P-95

Why Do We Need VSLI?Why Do We Need VSLI?

Effective and well-tolerated agent for– Patients at 3rd line or later– Patients who don’t qualify for aggressive combination

regimens or who have relapsed after ASCT– Patients with compromised marrow function

Benefits 1 in 4 patients with minimal toxicity

nda 21-600

Documents