Chemosaturation TherapyPercutaneous Hepatic Perfusion (PHP)

Compared with Best Available Care (BAC)

For Un-resectable Metastatic Melanoma in the Liver

PH-III Randomized US Multi-Center Trial

Investigators

APCCVIR 2012; Abstract #00136

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

Drug Levels During Therapy

Pingpank JF, et al. J Clin Oncol 2005;23:3465–74

• 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 Randomization

Patient Demographics

Pingpank JF, et al. ASCO 2010

Therapy CS-PHP N=44 (%)

BACN=49 (%)

AllN=93 (%)

P Value*

Radiation (primary tumor)

23(52)

24(49)

47(51)

NS

Chemotherapy 7(16)

6(12)

13(14)

NS

Immunotherapy 6(14)

7(14)

13(14)

NS

Image Directed Local Therapy

2(5)

3(6)

5(5)

NS

Unknown 0(0)

1(2)

1(1)

NS

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

No differences between two groupsNo differences between two groups

Therapy Prior to Randomization

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 2011

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

Secondary Endpoint: Hepatic Response Rate

Disease Control Rate (CR+PR+SD): CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%)

Disease Control Rate (CR+PR+SD): CS-PHP: 39 (88.6%) versus BAC: 14 (30.6%)

Pingpank JF, et al. ECCO-ESMO 2011

Treatment Related Toxicity*, Grade 3-4 and Grade 5, (116 treatments)

Hematologic Grade 3-4, n(%) Grade 5, n(%) Neutropenia 71 (61) 1 (<1) Thrombocytopenia 86 (74) 1 (<1) Anemia 54 (47)

Hepatic Elevated AST 14 (12) Elevated ALT 6 (5) Hyperbilirubinemia 8 (7) 1 (<1) Increased alk. phos. 6 (5)

*Percentages Per Cycle

Phase III: Treatment Related Toxicities of CS-PHP

Pingpank JF, et al. ASCO 2010

44 Patients, 116 Treatments44 Patients, 116 Treatments

PHASE 3 MELANOMA STUDY: SAFETY

Most common grade 3/4 AEs (peri-procedure)o thrombocytopenia, anemia and hypoalbuminemia

Melphalan-related neutropenia, leukopenia (in cycle)o febrile neutropenia in 6 (15%) patients

Transient peri-procedural transaminitis and hyper-bilirubinemia (10 - 30%)

Non-hematological toxicities infrequent Three patients died of treatment-related events

o hepatic failure, n=1 (99% liver replaced with tumor at autopsy; prophylactic allopurinol)

o neutropenia, n=1o pancytopenia, n=1

Conclusions

• Significant improvement in hPFS (INV)– 6.4 months at median: HR 0.35 (p < 0.0001)

• Consistent with IRC (incl. secondary endpoints)• No difference in mOS due to cross-over (ITT)

– 55% crossover from BAC to PHP-melphalan

• Transient LFT elevations – no Rx required• Expected & manageable toxicities of melphalan• Patients still alive as of April 30, 2012

– 2 BAC and 8 CS-PHP

Thank you