Chemosaturation TherapyPercutaneous Hepatic Perfusion (PHP)

Compared with Best Available Care (BAC) for

Metastatic Melanoma in the Liver

Exploratory Survival Analysisof BAC Cross-over

VersusNon-Cross-over Patients

For thePH-III Randomized US

Multi-Center TrialInvestigators

APCCVIR 2012; Abstract #00131

PHASE 3 STUDY INVESTIGATORSMarybeth Hughes, National Cancer Institute, Bethesda, MD

H. Richard Alexander, U. of Maryland School of Medicine, Baltimore, MD

Mark Faries, John Wayne Cancer Institute, Santa Monica, CA

James F. Pingpank, U. of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA

Jonathan S. Zager, Moffitt Cancer Center, Tampa, FL

Sanjiv Agarwala, St Luke’s Hospital and Health Network, Bethlehem, PA

Charles W. Nutting, Swedish Medical Center, Englewood, CO

Richard Royal, U. of Texas, MD Anderson Cancer Center, Houston, TX

Gary Siskin, Albany Medical Center Hospital, Albany NY

Eric Whitman, Atlantic Melanoma Center, Morristown, NJ

CHEMOSATURATION Therapy (CS-PHP)

IsolationSaturation

Filtration

A PERCUTANEOUS ALTERNATIVE to IHP

Filtration Procedure Chemo Filtration

CircuitChemo Isolation &

Delivery Circuit

MELPHALAN A bi-functional alkylating agent (nitrogen mustard) Not cell-cycle specific – binds DNA strands Cytotoxic effects are related to concentration and duration

of exposure Non-toxic to normal hepatocytes Track record with surgical IHP

• Conducted under Special Protocol Assessment (SPA) of US-FDA:• Primary Endpoint: Hepatic Progression Free Survival (hPFS)• Cross-Over: of BAC patients at hepatic progression

• Stratification: Cutaneous vs. Ocular• Lead Center: National Cancer Institute (NIH)

• Accrual: 93 patients/10 Institutions• Melphalan dose = 3.0 mg/kg (from Phase 1 Trial)• Key Secondary Endpoints :

• Response rate & Duration of Response• Overall Survival• Safety & Tolerability

• Staging Scans: Evaluation by RECIST Criteria

• Conducted under Special Protocol Assessment (SPA) of US-FDA:• Primary Endpoint: Hepatic Progression Free Survival (hPFS)• Cross-Over: of BAC patients at hepatic progression

• Stratification: Cutaneous vs. Ocular• Lead Center: National Cancer Institute (NIH)

• Accrual: 93 patients/10 Institutions• Melphalan dose = 3.0 mg/kg (from Phase 1 Trial)• Key Secondary Endpoints :

• Response rate & Duration of Response• Overall Survival• Safety & Tolerability

• Staging Scans: Evaluation by RECIST Criteria

PHASE III: CS-PHP VS. BACSTUDY DESIGN ELEMENTS

PHASE III: PHP-CS VS. BACSTATISTICAL ANALYIS PLAN

• Sample size: 46 patients per arm• Alpha: p≤0.05 (2-sided )• Power: 80% to detect a difference of 4 months Hepatic PFS

• Expected Hepatic PFS (used for sample size determination)• PHP (Treatment): 7.73 months• Best Alternative Care (Control): 4 months

• Response Rate (CR+PR) Detection: 88% power to detect a difference

• Analysis of Results by Intent-to-Treat (ITT)• Statistical Significance: p < 0.05

• Sample size: 46 patients per arm• Alpha: p≤0.05 (2-sided )• Power: 80% to detect a difference of 4 months Hepatic PFS

• Expected Hepatic PFS (used for sample size determination)• PHP (Treatment): 7.73 months• Best Alternative Care (Control): 4 months

• Response Rate (CR+PR) Detection: 88% power to detect a difference

• Analysis of Results by Intent-to-Treat (ITT)• Statistical Significance: p < 0.05

PHP-CS Arm Treatment Schema

Treatments 1 through 6

- Melphalan

- Angiogram (Celiac, SMA)

- GDA assessment (Treatment #1)

4-5 Weeks

24-30 weeks

On Study Evaluation/Randomization

Interval Evaluation* (Baseline, 6-weeks, 12 weeks, 20 weeks, 28 weeks, 36 weeks)

Post Treatment Follow-up

4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks

*Scan Evaluation (hPFS) using RECIST Criteria

PHASE III

PRELIMINARY RESULTS*

MELANOMAMETASTATIC

TO LIVER(N = 93)

PHP ARM(N= 44)

BAC ARM(N = 49)

HEPATIC

PROGRESSION

Cross over to CHEMOSATURATICHEMOSATURATI

OIN PHPOIN PHP(n=28, 57%)

Randomization and Treatment Schematic

R A N D O

M I Z E

1:1

FOLLOW-UP

FOLLOW-UP

Total Accrual: 93 patients (PHP: 44; BAC: 49, Crossover: 28)

Scan Evaluation (hPFS) using RECIST CriteriaPingpank JF, et al. ECCO-ESMO 2011

Baseline Characteristic

Category PHPN=44 (%)

BACN=49 (%)

P value*

Age (years) Mean 55 55 NS

Gender MaleFemale

23 (52)21 (48)

22 (45)27 (55)

NS

Race WhiteNon-White

44 (100)0 (0)

48 (98)1 (2)

NS

ECOG Missing01

3 (7)37 (84)

4 (9)

4 (8)42 (86)

3 (6)

NS

Primary Tumor OcularCutaneous

39 (89)5 (11)

43 (88)6 (12)

NS

*Fisher’s Exact Test. Two-sided PR <= P

Well-Balanced RandomizationWell-balanced for Prior Therapies

Well-Balanced RandomizationWell-balanced for Prior Therapies

Patient Demographics

Pingpank JF, et al. ASCO 2010

PH-III Randomized US Trial

Primary End Point

Hepatic Progression-free Survival (ITT)

Hazard Ratio: 0.35 (CI: 0.23-0.54)

0 5 10 15 20 25 30 350 5 10 15 20 25 30 35Months

CS-PHP

BAC

8.01.6

p<0.0001

1.01.0Survival probabilitySurvival probability

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Pingpank JF, et al. ECCO-ESMO 20113/31/11

PH-III Randomized US Trial

Secondary End Points

Overall Progression-free Survival (ITT)

Hazard Ratio: 0.36 (CI: 0.23-0.57)

0 5 10 15 20 25 30 350 5 10 15 20 25 30 35Months

CS-PHP

BAC

6.71.6

p<0.0001

1.01.0Survival probabilitySurvival probability

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Pingpank JF, et al. ECCO-ESMO 2011

Overall Survival (ITT)

Hazard Ratio: 1.08 (CI: 0.69-1.68)

0 5 10 15 20 25 30 35 40 45 50 550 5 10 15 20 25 30 35 40 45 50 55Months

CS-PHP

BAC

9.89.9

p=0.74

1.01.0Survival probabilitySurvival probability

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

55% crossover

Pingpank JF, et al. ECCO-ESMO 20113/31/11

Factors Associated with Survival

Pingpank JF, et al. ASCO 2010

Survival was Highly Associated with Use of Melphalan with CS-PHP

Survival was Highly Associated with Use of Melphalan with CS-PHP

EFFICACY (PATIENTS RANDOMIZED TO CS-PHP VERSUS RANDOMIZED TO BAC)

EndpointCS-PHP(N=44)

BAC(N=49)

HR (95% CI) P value

Median hPFS, months 8.0 1.60.35

(0.23–0.54)p<0.0001

Median OS, months 9.8 9.91.08

(0.69–1.68)p=0.7403

ORR, % 32 2 – p=0.0001

ITT population

Data as of 31 March 2011

EFFICACY (CS-PHP AND BY BAC SUBSET)

Endpoint

CS-PHP randomized

(N=44)BAC only

(N=21)

BAC-to-PHP crossover

(n=28)

Median hPFS, months 8.0 1.6 8.8

HR (crossover vs BAC-only) 0.32

Median overall survival, months 9.8 4.1 13.1

HR (crossover vs BAC-only) 0.33

Still alive as of 31 March 2011 4 3* 7

Follow-up: 9.7–53.5 months

*1 patient crossed over but never received PHPBAC-only patients: chemoembolization, HAI nab-paclitaxel, temozolomide

ITT population

Data as of 31 March 2011

Overall survival (ITT population)

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

12 360 24 48 60

4.1

PHP randomized

BAC crossover*

BAC only*

Censored observations

PHP randomized v PHP crossover v BAC only

9.8 13.1

Pro

po

rtio

n o

f s

ub

jec

ts s

urv

ivin

g

* Similar patient characteristics and demographics between BAC crossover and BAC only

Pro

po

rtio

n o

f s

ub

jec

ts s

urv

ivin

gOverall survival (ITT population)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

12 360 24 48 60

11.4

Total PHP incl. crossover

BAC only

Censored observations

Time (months)

Total PHP versus BAC only

4.1

Overall Survival Tail For Treated Patients

PHASE III RESULTS & CONCLUSIONS*

Primary endpoint exceeded,o P = 0.0001, Hazard Ratio = 0.35 o CS/PHP median hPFS of 8.0 months compared to 1.6

months for BAC o Five times gain in hPFS

o 86% overall clinical benefit (CR + PR + SD) Gen 1 Safety profile – consistent with currently approved US

labeling for IV melphalano 30-day deaths on PHP: 3/44 patients (6.8%)

1 Neutropenic Sepsis; 1 Hepatic Failure (95% T.B. + allopurinol); 1 Pancytopenia

o 30-day deaths on BAC: 3/49 patients (6.1%)o 116 PHP procedures were performed (3/116 = 2.6%)

* Updated Investigator results presented at 2011 ECCO/ESMO Annual Meeting.

PHASE III RESULTS & CONCLUSIONS*

Secondary endpointsoOS Secondary endpoint – No difference in Kaplan-Meier

curves due to cross over o 9.8 months compared to 10.0 months

oCS/PHP median overall PFS of 6.7 months vs. 1.6 months for BAC

OS exploratory analysisoMedian survival of 9.8 months for treatment arm

compared to 4.1 months non-crossover BAC patientsoMedian survival of 11.4 months for all patients treated

with melphalan, including crossovero8 CS/PHP-treated patients and 2 BAC-treated patients

still alive as of 4/2012

* Updated Investigator results presented at 2011 ECCO/ESMO Annual Meeting.

Thank you