DCTH James Pingpank presentation 2010 WICO

1. The Evolution of Modern Isolated
Hepatic Perfusion for Patients with
Unresectable Hepatic Metastases
James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology, Department of Surgery
University of Pittsburgh, Pittsburgh, PA
June 10, 2010
WCIO Annual Meeting- Philadelphia PA
Thursday, March 31, 2011

2. Disclosures
James F. Pingpank, Jr., MD
Scientific Advisory Board (Delcath Systems, Inc; New York, NY)
Research Support (Delcath Systems, Inc; New York, NY)
All participating institutions received research support from study
sponsor, Delcath Systems, Inc (New York, NY)
Intra-arterial melphalan and Delcath double balloon catheter under
IND (FDA)
Thursday, March 31, 2011

3. Unresectable Hepatic Cancers
-Therapeutic Options-
Systemic Treatments
Regional Therapies
Local ablative therapy
Cryotherapy
Radiofrequency ablation
EtOH injection
Infusional therapy
Hepatic Artery Infusion (HAI)
HAI with hemofiltration
Chemoembolization
Isolated Hepatic Perfusion
Selective Internal Radiation
Thursday, March 31, 2011

4. Rationale for Regional Therapy
Regional therapy allows dose escalation to the
cancer-bearing region or organ of the body while
minimizing systemic exposure and toxicity, via
complete separation of the regional and systemic
circulation
Eliminates or significantly reduces systemic toxicity,
and dose escalation of therapeutic agents is
limited largely by the tissue tolerance of the
perfused organ/limb
- Improved efficacy/tumor response
Based on its unique vascular anatomy the liver is a
favorable site for delivery of regional therapy
- Established tumors in liver derive
the majority of blood flow from the
arterial tree (tumors: 100% versus
normal liver: 25%)
Potential for delivery of clinically relevant levels of
hyperthermia or biologic agents
Thursday, March 31, 2011

5. Treatment of Hepatic Metastases
Regional Therapy
Unresectable cancers (primary or metastases)
confined to liver are a significant clinical problem:
Colorectal cancer: 30,000/yr
Hepatocellular carcinoma: 16,000/yr
Ocular melanoma: 2,000/yr
Neuroendocrine tumors: 2,000/yr
Other histologies:
?
Therapeutic options are limited and survival after
diagnosis of liver metastases is short.
Morbidity and mortality in this setting is invariably
secondary to disease progression in the liver.
Thursday, March 31, 2011

6. Schematic of IHP Circuit and Operative
Dissection (290 procedures)
Supra-Hepatic IVC
Retro-Hepatic IVC
Porta Hepatis Dissection
Thursday, March 31, 2011

7. Improved Technique – Combined Percutaneous and
Open Procedure
 OR Time 12.5  OR Time 4.5
hours hours
 LOS 12 days  LOS 7 days
Thursday, March 31, 2011

8. Background: Isolated Hepatic Perfusion
Colorectal Metastases
n=120 pts
RR: 60%, Median OS: 17.4m
SSO2007 (Abstract 14)
Ocular Melanoma Metastases
n=29 pts
RR:62%, Median OS: 12.1 m
Clin Cancer Res 2003 15;9(17):6343-9.
Neuroendocrine Metastases
n=13 pts
RR: 50%, Median OS: 48 m
Thursday, March 31, 2011

9. Percutaneous Hepatic Perfusion
Melphalan Phase I MTD: 3.0 mg/kg (based upon IBW)
Thursday, March 31, 2011

10. Protocol Schema
On Study Evaluation Interval Evaluation Post Treatment Evaluation
Treatments 1 and 2 Treatments 3 and 4
- Melphalan - Melphalan
- Angiogram (Celiac, SMA) - Angiogram (Celiac, SMA)
- GDA assessment (Treatment #1) - GDA assessment
4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks
16 weeks
Thursday, March 31, 2011

11. Chemotherapy Levels During Therapy
IHP vs PHP
Isolated Hepatic Perfusion Percutaneous Hepatic Perfusion
1.5 mg/kg
3.0 mg/kg
Thursday, March 31, 2011

12. Phase I PHP: Metastatic Melanoma
Radiographic Treatment Response
(n=16)
Response n % Duration
Overall 8 50
Complete 2 13 10, 15
Partial 6 37.5 2+,8, 8, 12, 15, 16
Stable Disease 4 25 7, 7, 8, 8+
Progressive Disease 4 25
Not Evaluable 2 13 (vascular anomaly)
Follow-up Status
DOD (Dead of disease) 16 100
Site of Disease Recurrence/Progression (n=12 responders)
Hepatic 6 50
Systemic 4 33
Both 2 17
+ censored with stable or responding hepatic disease with systemic progression
Finalized June 2007
Thursday, March 31, 2011

13. Randomization and Treatment Schema
H
E
P
A
PHP Arm
T Follow-up
R (n= 44)
I
A
C
N
Melanoma D
Metastatic P
O Cross over to PHP
to liver R
M (n=27)
O
(n = 93) I
G
Z
R
E
E
BAC Arm S Follow-up
1:1 (n = 49) S
I
O
N
Thursday, March 31, 2011

14. Phase III Random-Assignment PHP vs.
Best Available Care
Accrual goal: 92 patients (Cross-over at Hepatic progression)
12 Institutions
Total Accrual: 93 patients (PHP: 44, BAC: 49, Crossover: 27)
Melphalan dose: 3.0 mg/kg
Stratification: Cutaneous vs. Ocular
Primary endpoint: Hepatic PFS
Secondary endpoints:
1. Response rates, DFS with best available therapy
2. Response rates for patients treated with PHP
Thursday, March 31, 2011

15. Results: Primary Endpoint
-Hepatic Progression Free Survival (ITT) -
Hazard Ratio: 0.301
(CI: 0.183-0.497)
Thursday, March 31, 2011

16. Results: Secondary Endpoint
-Overall Progression Free Survival (ITT)-
Hazard Ratio: 0.404
(CI: 0.252-0.648)
Thursday, March 31, 2011

17. Results: Secondary Endpoint
-Overall Survival (ITT)-
Hazard Ratio: 0.920
(CI: 0.524-1.615)
Thursday, March 31, 2011

18. Metastatic Ocular Melanoma
Pre-PHP: Baseline
Post Treatment: 9 months (active)
Thursday, March 31, 2011

19. PHP Patient Demographics
Neuroendocrine Tumors (n=23)
Median no. of hepatic lesions 15
Mean diameter of largest lesion 4.8 cm
Extrahepatic Disease 9 (39%)
Subsequent Resection: n=7
Percentage hepatic replacement
<25% 12 (52%)
25-50% 5
(22%)
>50% 6 (26%)
Primary Tumor Histology
Carcinoid 6
PNET 17
Thursday, March 31, 2011

20. PHP Response: Neuroendocrine Tumors
(n=23)
NE (Toxicity*, Incomplete Tx, OLT) 4
PD at interval evaluation 1
SD/MR 3
PR 13
CR 2
Overall Response Rate (19 patients) 15 (79%)
100
75
50
Maximum response
25
0
-25
-50
-75
-100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Patients
Thursday, March 31, 2011

21. Hepatic Progression-Free Survival After PHP
Metastatic Neuroendocrine Tumor (n=20)
Median: 39 months
20 Treated
Censored for death from extra-hepatic
disease (n=4)
Not Evaluable due to hepatic toxicity (n=1)
On Active Treatment (n=2)
Thursday, March 31, 2011

22. Metastatic Glucagonoma
54 year-old female
Metastatic pancreatic
neuroendocrine tumor
Primary in place, treated
post PHP with XRT
PHP#1 PHP#2 XRT Pancreas Bed
Thursday, March 31, 2011

23. Metastatic Glucagonoma
Pre-Treatment Post-PHP x 2 Follow-up (22m)
April 2003 November 2003 March 2005
Thursday, March 31, 2011

24. Conclusions
High-dose Melphalan, delivered via intra-arterial
administration is effective against hepatic metastases
from ocular melanoma and neuroendocrine tumors
Increased drug delivery achieved through novel regional
therapeutic approaches may increase efficacy of a given
agent (vs. systemic administration) by overcoming a low
therapeutic index.
Metastatic Melanoma
Retreatment of patients with a previous therapeutic
benefit from melphalan appears to be effective (n=5)
A Multi-center Phase III licensing trial is completed and
will be presented at ASCO in June 2010.
Thursday, March 31, 2011

25. Conclusions
High-dose Melphalan, delivered via intra-arterial
administration is effective against hepatic metastases
from ocular melanoma and neuroendocrine tumors
Increased drug delivery achieved through novel regional
therapeutic approaches may increase efficacy of a given
agent (vs. systemic administration) by overcoming a low
therapeutic index.
Neuroendocrine Tumors
Tumor reduction from PHP routinely results in durable
control of hormone-related symptoms
A Multi-center licensing trial is awaiting FDA approval
Thursday, March 31, 2011

26. The Evolution of Modern Isolated
Hepatic Perfusion for Patients with
Unresectable Hepatic Metastases
James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology, Department of Surgery
University of Pittsburgh, Pittsburgh, PA
June 10, 2010
WCIO Annual Meeting- Philadelphia PA
Thursday, March 31, 2011