1

Oncologic Drugs Oncologic Drugs Advisory Committee MeetingAdvisory Committee Meeting

NDA 21-236NDA 21-236

Cisplatin/Epinephrine Injectable Gel for Cisplatin/Epinephrine Injectable Gel for the Treatment of Squamous Cell the Treatment of Squamous Cell

Carcinoma of the Head and NeckCarcinoma of the Head and Neck

Matrix Pharmaceutical, Inc.

2

Introduction

Stephen B. Howell, M.D.Professor of Medicine

Director, Cancer Pharmacology University of California San Diego

Cancer Center

3

Presentation

Glenn Mills, M.D., Professor of Medicine, Head of Aerodigestive Malignancy Program, LSU

Summary of Risks and Benefits

Richard D. Leavitt, M.D., Senior Vice President, Medical Affairs

Clinical Study Results

Glenn Mills, M.D., Professor of Medicine, Head of Aerodigestive Malignancy Program, LSU

Current Management of Recurrent Head and Neck Cancer

Stephen B. Howell, M.D.,Professor of Medicine, UCSD

Pharmacologic Rationale; Assessment of Clinical Benefit

Stephen B. Howell, M.D., Professor of Medicine, UCSD

Discussion of Clinical Benefit Issues

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• Independent ExpertsEverett E. Vokes, M.D., John F. Ultmann Professor, Director, Section of

Hematology/Oncology, University of Chicago; Sub-Chair, Head and Neck Cancer Committee, RTOG

Barry L. Wenig, M.D., M.P.H., Professor of Otolaryngology – Head and Neck Surgery; Chief, Division of Head and Neck Surgery, Evanston Northwestern Healthcare

John Mackowiak, Ph.D., Director of Research, Center for Outcomes Research,Chapel Hill, NC

John R. Durant, M.D., Former Director, Fox Chase Cancer Center and University of Alabama Cancer Center; Chair of Clinical Cooperative Group; Past Chief Executive ASCO

Robert F. Woolson, Ph.D., Professor and Past Chair of Biostatistics, University of Iowa School of Public Health

• Matrix Pharmaceutical StaffLaurence Elias, M.D., Medical DirectorMorgan E. Stewart, Ph.D., Senior Director, Biostatistics & Data ManagementRobert Tressler, Ph.D., Senior Director, Biological Sciences

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Current Management of Recurrent Head and Neck Cancer

Glenn Mills, M.D.Professor of Medicine

Director of Clinical Research and Head of Aerodigestive Malignancy Program

Principal Investigator SWOG Feist-Weiller Cancer Center, LSUHSC-Shreveport

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Scope of the Problem

• In 2001, 50,000 new cases in the US– 20,000 relapses and 15,000 deaths

• Local disease in >50-65% who die– 7500-10,000 patients

• Risk factors – Tobacco

– Alcohol

• Concomitant diseases– Vascular disease; COPD; malnutrition

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Standard Therapy

• Early-stage disease (I, II & III)– Surgery ± radiation therapy – relapse 20-30%

• Late-stage (bulky III & IV)– Radiation ± chemotherapy – relapse 70-80%

– Local relapse a persistent problem (40-65%)

• Chemotherapy– CDDP/5FU – response rate 30-35%

– Reduced effectiveness in radiated/surgical field*

*Forastiere, A.A., et al., JCO 19:1088-95, 2001

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Locally Recurrent HNSCC

• Highly debilitating– Intractable pain

– Compromised airway

– Swallowing dysfunction

– Ulceration – cosmetic and bleeding

• Local problems may predominate even with systemic metastasis

• Median survival 4-6 months

• Quality of life is poor

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Unmet Needs in Local Recurrence

• Post XRT/surgery– Re-irradiation

• Cisplatin relapsed patients– No approved drugs

– Methotrexate, gemcitabine, and taxanes

• New agents and modalities– Better/unique activity

– Reduced toxicity

• Improve palliative care options

• Reduce risk of impending catastrophic event

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Locally Recurrent Head and Neck Cancer

Pt. 1795 Pt. 2736

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Pharmacologic Rationale and Challenges Associated with

Demonstration of Clinical Benefit

Stephen B. Howell, M.D.Professor of Medicine

Director, Cancer Pharmacology University of California San Diego

Cancer Center

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Indication Refined Since NDA Filing

• When HNSCC recurs, all patients should be considered for additional surgery, systemic chemotherapy, or re-irradiation

• CDDP/epi gel is indicated for patients with locally dominant problematic lesions– Not surgical candidates

• Lesion not resectable; resection would destroy function; surgical risk too high

– Not candidates for systemic chemotherapy• Failed multiple prior regimens; co-morbid disease

– Not candidates for re-irradiation• Risk too high; no access to radiation experts/facilities

– Refused other modalities

• Orphan indication; orphan status granted

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Product Description

Viscous injectable gel containing cisplatin and epinephrine– Cisplatin 4 mg/mL – Established role in the treatment of

HNSCC

– Epinephrine 0.1 mg/mL – Provides vasoconstriction

– Collagen gel – Ensures physically stable dispersion of cisplatin and facilitates accurate placement of drug

Cisplatin

Epinephrine

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Pharmacologic Rationale for Intratumoral Treatment

• Intratumoral CDDP/epi gel results in high tumor CDDP exposure with very little systemic exposure

• Median dose of CDDP per treatment visit 10 mg/m2

Reaction with plasma proteinsRenal excretion

Plasma Compartment

CDDP

Tumor Compartment

CDDP/epi gel

CDDP

Intratumoral Injection

Plasma Compartment

CDDP

Reaction with plasma proteinsRenal excretion

Tumor Compartment

CDDP

CDDP

Intravenous Injection

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Retention of Platinum in Murine RIF Tumors Following Administration of 195Pt-CDDP

4 h 24 h 72 h8 h5 min 1 h 48 h

Murine RIF-1 tumors, dermal, ~ 900 mm3

CDDP/epi gel (CDDP 4 mg/mL, epi 0.1 mg/mL) 50 µL intratumoral. CDDP suspension (CDDP 4 mg/mL)50 µL intratumoral CDDP solution (CDDP 1 mg/mL) 200 µL intravenous

195Pt 300 nCi/mouse

0 .0 33>3 0 0 .0 0 30 .3 < 0. 0 0 3

P t Co n ce n tra tio n (m M )

Murine SCCVII tumors

1 cm

Murine RIF-1 tumors, dermal, ~900 mm2

CDDP/epi gel (CDDP 4 mg/mL, epi 0.1 mg/mL) 50 μL i.tCDDP suspension (CDDP 4 mg/mL) 50 μL i.t.CDDP solution (CDDP 1 mg/mL) 200 μL i.t.195Pt 300 n Ci/mouse

CDDP Epi/Gel

CDDPSuspension

Intratumoral 195Pt-CDDP

>30

3

0.3

0.03

0.003

<0.003

Pt

Co

nce

ntr

atio

n (

mM

)

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Ability of Repeated Injection to Attain Good Drug Distribution

• Dose based on tumor volume: 0.25 mL gel/cm3 tumor, maximum dose 40 mg

• CDDP intratumoral distribution improves as tumor is destroyed

Week 1 Week 2 Week 3

Initial CDDP distribution

to viable tumor

BetterCDDP distribution

to viable tumor

Best CDDP distribution

to viable tumor

= viable tumor = dead tumor

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Challenge: Trial Design and Sequence of Events

• Original design– Primary endpoint: response rate of “Most Troublesome

Tumor” (MTT)– Collect information on clinical benefit:

• Improvement in symptoms• Prevention of catastrophic complications

• Pivotal trials powered on MTT response rate

• Increased emphasis on clinical benefit as an endpoint since trials started– FDA requested analysis of “Patient Benefit” as an additional

primary endpoint

• Problem – Many different kinds of symptoms– Impossible to accrue enough patients

• Integrated analysis required to increase power

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Challenge: Assessing Clinical Benefit

• Heterogeneity of symptoms– Many different kinds of symptoms– Variation in the number of symptoms per patient– Some symptoms are more important than others

• Palliation versus prevention– Both important

• Dichotomous yes/no answer on clinical benefit preferable– How to combine measures of palliation and prevention?

• How to deal with situation where most critical symptom gets better but others worsen?

• How to adjust palliation scores for differences in importance of the symptom to the patient?

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Clinical Reality

• Achieving any kind of improvement is very difficult– Recurrent/refractory

– Far advanced

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Approaches Taken to Assess Clinical Benefit

• Tumor shrinkage– Value often obvious to patient and physician– Fundamentally different from tumors at less critical sites– Shrinkage is reasonable direct measure of clinical benefit

• Palliation– Identified “Most Troublesome Tumor” and most important

symptom– 4 point scales– Tracked progress toward goals prospectively and

independently selected by patient and physician

• Prevention– Identified critical structures threatened– Measured success in avoiding anticipated complication

• Patient Benefit Algorithm developed to provide yes/no answer

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Clinical Study Results

Richard D. Leavitt, M.D.Senior Vice President, Medical Affairs

Matrix Pharmaceutical, Inc.

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Study Schema: Studies 414 and 514

CDDP/epi gel

Placebo gel

Evaluate

Follow-up monthly

Randomize 2:1

*At progression any time after 3 blinded treatments

Crossover to active drug*

Open-LabelDouble-Blind

Q 1 W x 6

• Identical study design• All ITT analyses • Simultaneous study unblinding

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Efficacy

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All Patients First Considered for Standard Therapy

•89% previously received multiple therapeutic modalities

•89% of MTTs in a previously radiated field

ISE T-006.1 for no. of MTTs in prev. irrad. field,

ISE E-4 for Venn diagram

44%44% Radiation & Radiation &

SurgerySurgery

39%39% Radiation, Radiation, Surgery, &Surgery, &

ChemotherapyChemotherapy

46%46% ChemotherapyChemotherapy(n = 82)(n = 82)

94%94% RadiationRadiation(n = 168)(n = 168)

87%87% SurgerySurgery

(n = 155)(n = 155)

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Objective Response Rate of Most Troublesome Tumor (MTT)

CDDP/epi gel Placebo gel p-value1

Study 414

CR + PR 34% (21/62) 0% (0/24) < 0.001

CR 23% (14/62) 0% (0/24)

PR 11% (7/62) 0% (0/24)

Study 514

CR + PR 25% (14/57) 3% (1/35) <0.007

CR 16% (9/57) 3% (1/35)

PR 9% (5/57) 0% (0/35)

Combined Results

CR + PR 29% (35/119) 2% (1/59) <0.001

CR 19% (23/119) 2% (1/59)

PR 10% (12/119) 0% (0/59)1Exact Cochran-Mantel-Haenszel

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All Partial Responses in Blinded Phase79% - 99%

79%

83%83%

87%

88%88%

95%

96%96%

98%

99%

99%

0 20 40 60 80 100

179721102688

549451105133

549625415372

177227531992

Pa

tie

nt

ID

Percent Reduction in Tumor Volume

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Prompt and Durable Objective Response

35 Responders* Days Range (days)

Time to response (median) 21 7 - 162

Duration of response (median) 78 30+ - 554+

*33 of 35 responders still responding at time of study exit or censoring

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Time to Tumor Progression

Time to Tumor Progression

CDDP/Epi Gel Placebo Gel

Median (days) 149 35

Range (days) 5 - 564+ 5 - 263+

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High Objective Response After Crossover from Placebo to CDDP/Epi Gel

Studies 414 & 514 Combined

Objective Response 27% (11/41)

CR 17% (7/41)

PR 10% (4/41)

Mean size increased from 5.7 to 10.8 cm3 from baseline to crossover

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High Objective Response in Patients with Prior Systemic Platinum Therapy

Yes No

29% (14/48) 30% (21/71)

Prior Cisplatin or Carboplatin

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Patient BenefitTreatment Goal Questionnaire

• The Instrument

• The Results

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Treatment Goals Questionnaire

• Assesses patient-specific benefit of local therapy

• Prospectively selected treatment goals– Primary goals

– Other selected goals – “secondary”

– Palliative goals• 4-point scale• Benefit required 28-day duration• Worsening scored after 7-day decline

– Preventive goals• Scored as met for ≥ 28 days or not met

• Independently validated by Center for Outcomes Research

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One-Point Difference Is Clinically MeaningfulPain Control

Level 4: Pain cannot be relieved by any medication

Level 3: Prescription medication required to relieve pain (e.g. narcotics, piroxicam)

Level 1: No medication required

Level 2: Over-the-counter medication relieves pain (e.g. aspirin, acetaminophen)

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Determination of Patient Benefit

• Patient Benefit Algorithm based solely on primary treatment goals prospectively selected by patient and investigator

YES = If either goal is met and neither worsens

NO = If neither goal is met or if either goal worsens

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Achievement of Patient Benefit

1Exact Cochran-Mantel-Haenszel

Study CDDP/Epi Gel Placebo p-value1

414 (n = 86) 34% (21/62) 17% (4/24) 0.18

514 (n = 92) 19% (11/57) 9% (3/35) 0.24

Combined(n = 178)

27% (32/119) 12% (7/59) 0.046

• Of the 41 patients randomized to placebo who crossed over to open label CDDP/epi gel, 11 (27%) achieved Patient Benefit

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Association of Tumor Response and Patient Benefit

Exact Cochran-Mantel-Haenszel

p = 0.006

Combined 414/514

Responder Non-responder

Benefitter 47% (17/36) 15% (22/142)

Non-benefitter 53% (19/36) 85% (120/142)

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Patients and Investigators Attained Prospectively Selected Palliative Goals

CDDP/Epi Gel Placebo GelOdds Ratio p-value1

Prospectively Selected Primary Palliative Goal

13% (13/99) 4% (2/51) 3.7 0.081

Any Prospectively Selected Palliative Goal

18% (20/111) 6% (3/54) 3.7 0.032

1Exact Cochran-Mantel-Haenszel

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Attainment of Palliative Goals or Unforeseen Benefits

CDDP/Epi Gel Placebo GelOdds Ratio

p-value1

Prospectively-Selected Primary Palliative Goal

13% (13/99) 4% (2/51) 3.7 0.081

Any Prospectively-Selected Palliative Goal

18% (20/111) 6% (3/54) 3.7 0.032

Any Palliative Goal or Unforeseen Benefit

34% (40/119) 8% (5/59) 5.5 < 0.001

1Exact Cochran-Mantel-Haenszel

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Association Between Tumor Response and Achievement of Palliative Goals or Unforeseen Benefits

RespondersNon-

Respondersp-value1

Prospectively-Selected Primary Palliative Goal

28% (8/29) 7% (5/70) 0.009

Any Prospectively-Selected Palliative Goal

33% (11/33) 12% (9/78) 0.007

Any Palliative Goal or Unforeseen Benefit

54% (19/35) 25% (21/84) 0.005

1Exact Cochran-Mantel-Haenszel

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Prevention of Major Complications Is Central to the Management of Patients with HNSCC

• Invasion of vital structures is devastating

• Airway obstruction directly threatens life

• Impaired swallowing compromises nutrition and quality of life

Success in achieving preventive goals can be clinically meaningful

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Structures Specified by Investigators as Threatened

Prevent Obstruction n = 26 goals Trachea, airway, etc. 13 Mouth/nose 4 Pharynx/oropharynx 3

Esophagus 2

Major vessels 2

Eye/vision 1 Not stated 1Prevent Invasion n = 50 goals Major vessels 31 Eye/vision 4 Skull/brain/vertebra 2 Trachea, airway, etc. 4 Mouth, nose 2

Pharynx/oropharynx 1

Not stated 6

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Attainment of Preventive Goals

CDDP/Epi Gel Placebo GelOdds Ratio

p-value1

Prospectively-Selected Primary Preventive Goal

62% (26/42) 26% (6/23)* 4.6 0.027

*Placebo patients often did not attain a preventive goal when disease progressed and patient was crossed over to CDDP/epi gel or left study

1Exact Cochran-Mantel-Haenszel

43

Challenges in Evaluating Preventive Goals

• FDA correct: Direct comparison between the two arms has limitations

• Difficult to estimate rate of attainment of preventive goals on the placebo arm– Tumors rapidly progressing on placebo arm

(5.7 to 10.8 cm3)

– Not enough placebo patients on study for 28 days

44

Inclusion of Preventive Goals in Assessment of Patient Benefit is Appropriate

• Reasonable to include rate of attainment of preventive goals– Single Patient Benefit outcome pre-specified palliative

and preventive goals

– Investigators believe prevention is crucial

– Algorithm is a valid measure of Patient Benefit

– Completing planned treatment is a valid indirect measure of clinical benefit

• Post-hoc examination of independent contribution of palliation to Patient Benefit should be secondary

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Supportive Efficacy Data

Open Label, Phase II Solid Tumor Studies

Study 403 67 patientsStudy 503 59 patients

Same efficacy endpoints

46

MTT Response in Open-Label Solid Tumor Studies 403 and 503

Study CDDP/Epi Gel95% Confidence

Interval

403 CR + PR 31% (20/65) 20 - 44%

CR 17% (11/65)

PR 14% (9/65)

503 CR + PR 41% (24/59) 28 - 54%

CR 14% (8/59)

PR 27% (16/59)

Combined CR + PR 35% (44/124) 27 - 45%

CR 15% (19/124)

PR 20% (25/124)

47

Patient Benefit and Association of Objective Response of Most Troublesome Tumor

Patient Benefit Rate

Study 403 37% (24/65)

Study 503 25% (15/59)

Association of Benefit & Tumor Response

Responders Non-Responders

403 Benefitters (n = 24) 55% (11/20) 29% (13/45) p = 0.055

503 Benefitters (n = 15) 50% (12/24) 9% (3/35) p = <0.001

Chi-squared test

48

Safety

• Dosing Accuracy

• Adverse Events

• Local Cytotoxic Effects

• Clinically Important Adverse Events

49

Dosing Errors Were Rare in Studies 414 & 514

CDDP/Epi Gel (n = 533)*

Placebo (n = 186)

n (%) n (%)

No discrepancy 317 (59%) 117 (63%)

Tumor unable to accommodate 59 (11%) 28 (15%)

Tumor responded 33 (6%) 0 (0%)

Adverse event 22 (4%) 10 (5%)

Dose calculation error 20 (4%) 12 (6%)

Patient refused treatment or requested delay 8 (2%) 0 (0%)

Reflux 9 (2%) 4 (2%)

Other 65 (12%) 15 (8%)

*Includes 83 visits at which no dose was given

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All Adverse Events, Treatment-Related and Unrelated, Reported in ≥ 8% of Patients

Adverse Event CDDP/Epi Gel (n = 150) Placebo (n = 75)Mild/Moderate Severe Mild/Moderate Severe

Immediate injection effects

Pain 17% (26) 10% (15) 16% (12) 4% (3)Local reactions at treatment site

Pain 18% (27) 12% (18) 11% (8) 7% (5)Facial edema 6% (10) 3% (5) 0 0Infection 6% (10) 1% (2) 1% (1) 0

Systemic/other local effectsPain 15% (22) 7% (10) 11% (8) 4% (3)Asthenia 9% (14) 5% (8) 7% (5) 4% (3)Facial edema 7% (11) 5% (7) 1% (1) 1% (1)Infection 8% (12) 2% (3) 8% (6) 1% (1)Fever 9% (13) <1% (1) 7% (5) 0Headache 8% (12) <1% (1) 4% (3) 3% (2)Nausea 14% (21) 3% (4) 5% (4) 3% (2)Vomiting 14% (21) 2% (3) 1% (1) 1% (1)Constipation 11% (16) 3% (4) 4% (3) 0Anorexia 8% (12) 3% (4) 1% (1) 0Dysphagia 7% (11) 3% (4) 4% (3) 1% (1)Anemia 6% (10) 4% (6) 5% (4) 1% (1)Dehydration 3% (4) 6% (9) 4% (3) 0Dyspnea 5% (8) 5% (8) 5% (4) 3% (2)

51

Many Patients Had Tumor-Related Tissue Conditions at Study Entry

Baseline

0 20 40 60 80 100

Erythema

Swelling

Bleeding

Erosion

Ulceration

Necrosis

Eschar

Severe

CDDP/epi gel

Placebo gel

Mild/Mod

% of Patients

52

Local Cytotoxic Effects (Randomized Phase)

Worsened from Baseline

0 20 40 60 80 100

Severe

CDDP/epi gel

Placebo gel

Mild/Mod

% of Patients

Erythema

Swelling

Bleeding

Erosion

Ulceration

Necrosis

Eschar

53

Other Clinically Important Adverse Events

• Cerebrovascular events– 6 patients (5 CDDP/epi gel, 1 placebo)

– Most likely caused by carotid artery vasospasm

– No treatment-related events after study amendment

• Cardiovascular events – Nonfatal cardiopulmonary arrest in one patient

– Transient increases in blood pressure and pulse during drug administration

54

Summary of Clinical Efficacy and Safety of CDDP/Epi Gel

• Two adequate, placebo-controlled clinical trials in recurrent advanced HNSCC – confirmatory and complementary

• Effective local control of tumors in patients with recurrent HNSCC

• Patients achieved benefit, palliation of symptoms, and prevention of complications

• Patient Benefit associated with tumor response

• Supportive trials with high response rate and Patient Benefit in other solid tumors

• Side effects manageable with limited systemic effects

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Discussion of Clinical Benefit Issues

Stephen B. Howell, M.D. Professor of Medicine

Director, Cancer Pharmacology University of California San Diego

Cancer Center

56

Rates of Attainment of Primary Goals in Patients Randomized to CDDP/Epi Gel or Placebo Gel, Studies Combined

Selected by Patient Selected by Physician

CDDP/Epi Gel

Placebo Gel

CDDP/Epi Gel

Placebo Gel

Wound care 12% (3/26) 0% (0/9) 13% (3/23) 0% (0/13)

Pain control 11% (4/38) 5% (1/22) 12% (3/26) 0% (0/14)

Obstructive symptom 11% (3/27) 0% (0/11) 8% (2/24) 0% (0/5)

57

FDA Analysis of Palliative Goals

• To score “better” required 28 days; “worse” required 7 days – Conservative scoring– Expect more patients to worsen than improve– CDDP/epi gel expected to produce transient worsening in

some patients

• Patients stayed on CDDP/epi gel arm longer than on placebo (median 41 vs 28 days), and therefore had a greater chance of worsening

Study CDDP/Epi Gel Placebo Gel

414 Better 6% (3/51) 5% (1/20)

Worse 25% (13/51) 10% (2/20)

514 Better 19% (10/54) 3% (1/33)

Worse 22% (12/54) 12% (4/33)

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Analysis of Palliative Goals Over First 28 Days Adjusted for Equal Scoring Intervals

Study CDDP/Epi Gel Placebo Gel414 Better 18% (9/51) 10% (2/20)

Worse 20% (10/51) 10% (2/20)

514 Better 11% (6/53) 3% (1/33)Worse 13% (7/53) 6% (2/33)

Combined Better 14% (15/104) 6% (3/53)Worse 16% (17/104) 8% (4/53)

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All Palliative Goals: Rate of Worsening on Any Scale During Treatment and 1st Month of Follow-up

Patient Goal

47% (7/15)24% (11/45) Obstructive symptom

21% (6/28)22% (11/51) Pain control

24% (4/17)27% (10/37) Wound care

Physician Goal

43% (20/46)43% (46/107)Total

13% (2/16)28% (11/40) Wound care

11% (2/18)18% (7/39) Pain control

75% (6/8)27% (9/33)Obstructive symptom

Placebo Gel (n = 46)

CDDP/Epi Gel (n = 107)Goal

“Worsening” defined as worsening of at least one scale point from baseline for at least 2 consecutive visits. Assessments for patients randomized to placebo gel obtained after start of open-label CDDP/epi gel are not excluded.

60

Attainment of Prospectively Selected Primary Palliative Goals – Within Patient Analysis

Attained Patient’s and/or Physician’s Primary Palliative Goal*

Attained Primary Palliative Goal But Other Person’s Assessment of Primary Goal Worsened

4% (2/53)

Placebo Gel

0% (0/53)

4% (2/53)

12% (13/104)

CDDP/Epi Gel

0% (0/104)

12% (13/104)Net Primary Palliative Goal

*Denominator does not exclude unattainable goals

61

Attainment of Any Prospectively Selected Palliative Goal – Within Patient Analysis

Attained Any Primary or Secondary Palliative Goal

Attained Any Primary or Secondary Palliative Goal But Another Palliative Goal Worsened

6% (3/54)

Placebo Gel

2% (1/54)

4% (2/54)

18% (20/111)

CDDP/Epi Gel

4% (4/111)

14% (16/111)Net Palliative Goal Attainment

62

Pivotal Trials Provide Substantial Evidence of Clinical Benefit

• Significant difference in MTT response rate in both studies – obvious clinical benefit

• Positive trend for Patient Benefit in both studies; statistical significance in the prospective integrated analysis

• Palliation– Improvement for each type of symptom when examined

individually– Integrated analysis of all primary and secondary palliative

goals significant (p = 0.032)– Analysis of primary and secondary goals and unforeseen

benefits significant in each study individually (414: p = 0.036; 514: p = 0.007)

• Studies 403 and 503 = supportive data– High response rate (35%)– High Patient Benefit rate (31%)

63

Summary of Risks and Benefits

Glenn Mills, M.D.Professor of Medicine

Director of Clinical Research and Head of Aerodigestive Malignancy Program

Principal Investigator SWOG Feist-Weiller Cancer Center, LSUHSC-Shreveport

64

Risks/Benefits of Current Treatment Options for Recurrent Local Disease

• No Therapy – Local – bleeding, airway, pain, nutrition and appearance

– Decline in quality of life

– May shorten patient’s life

• Risks of current treatments– Radiation therapy – ineffective dose if in-field relapse

– Surgery – usually not an option

– Chemotherapy – excessive toxicity*

• Marginal improvement in survival

*Forastiere, A.A., et al., JCO 19:1088-95, 2001

65

Risks and Benefits of CDDP/Epi Gel

• Risks– Side effects – local, manageable

– Systemic effects – uncommon, usually not severe, patient selection

• Benefits– High complete response rate

– Clinical benefit – both palliative and preventive goals

– Prompt responses – short duration of treatment

– Outpatient administration

66

Patient 414-1795

Day 51Day 1

67

Patient 514-2736

Day 1 Day 210

Tumor Uvula

Uvula

Tongue

Tongue

68

Need for CDDP/Epi Gel in the Treatment of Recurrent Local-Regional HNSCC

• Third form of local therapy

• Needed addition to local treatment options

• Effective/beneficial therapy for local disease

69

Oncologic Drugs Oncologic Drugs Advisory Committee MeetingAdvisory Committee Meeting

NDA 21-236NDA 21-236

Cisplatin/Epinephrine Injectable Gel for Cisplatin/Epinephrine Injectable Gel for the Treatment of Squamous Cell the Treatment of Squamous Cell

Carcinoma of the Head and NeckCarcinoma of the Head and Neck

Matrix Pharmaceutical, Inc.