Dcth isolation perfusion

James F. Pingpank, Jr., MD, FACSAssociate Professor of Surgery

Division of Surgical Oncology, Department of SurgeryUniversity of Pittsburgh, Pittsburgh, PA

June 10, 2010WCIO Annual Meeting- Philadelphia PA

The Evolution of Modern Isolated Hepatic Perfusion for Patients with Unresectable Hepatic Metastases

Thursday, March 31, 2011

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)


Unresectable Hepatic Cancers-Therapeutic Options-

Systemic TreatmentsRegional Therapies

Local ablative therapyCryotherapyRadiofrequency ablationEtOH injection

Infusional therapyHepatic Artery Infusion (HAI)HAI with hemofiltrationChemoembolizationIsolated Hepatic PerfusionSelective Internal Radiation


Rationale for Regional TherapyRegional 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


Treatment of Hepatic MetastasesRegional 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.


Schematic of IHP Circuit and Operative Dissection (290 procedures)

Retro-Hepatic IVC

Supra-Hepatic IVC

Porta Hepatis Dissection


Improved Technique – Combined Percutaneous and Open Procedure

OR Time 12.5 hours

LOS 12 days

OR Time 4.5 hours

LOS 7 days


Background: Isolated Hepatic PerfusionColorectal 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


Percutaneous Hepatic Perfusion

Melphalan Phase I MTD: 3.0 mg/kg (based upon IBW)Thursday, March 31, 2011

Protocol Schema

Treatments 1 and 2

- Melphalan

- Angiogram (Celiac, SMA)

- GDA assessment (Treatment #1)

4-5 Weeks

16 weeks

On Study Evaluation

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

Treatments 3 and 4

- Melphalan

- Angiogram (Celiac, SMA)

- GDA assessment

Interval Evaluation Post Treatment Evaluation


Chemotherapy Levels During TherapyIHP vs PHP

Isolated Hepatic Perfusion Percutaneous Hepatic Perfusion

3.0 mg/kg

1.5 mg/kg


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 100Site 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


MelanomaMetastatic

to liver(n = 93)

PHP Arm(n= 44)

BAC Arm(n = 49)

HEPATIC

PROGRESSION

Cross over to PHP(n=27)

Randomization and Treatment Schema

R A N D O M I Z E

1:1

Follow-up

Follow-up


Phase III Random-Assignment PHP vs. Best Available Care

Accrual goal: 92 patients (Cross-over at Hepatic progression) 12 InstitutionsTotal Accrual: 93 patients (PHP: 44, BAC: 49, Crossover: 27)Melphalan dose: 3.0 mg/kg

Stratification: Cutaneous vs. OcularPrimary endpoint: Hepatic PFS

Secondary endpoints: 1. Response rates, DFS with best available therapy 2. Response rates for patients treated with PHP


Results: Primary Endpoint -Hepatic Progression Free Survival (ITT) -

Hazard Ratio: 0.301 (CI: 0.183-0.497)


Results: Secondary Endpoint-Overall Progression Free Survival (ITT)-

Hazard Ratio: 0.404 (CI: 0.252-0.648)


Results: Secondary Endpoint-Overall Survival (ITT)-

Hazard Ratio: 0.920 (CI: 0.524-1.615)


Metastatic Ocular Melanoma

Pre-PHP: Baseline

Post Treatment: 9 months (active)


PHP Patient Demographics Neuroendocrine Tumors (n=23)

Median no. of hepatic lesions 15Mean diameter of largest lesion 4.8 cmExtrahepatic 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


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

-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

Max

imum

resp

onse

Patients


Hepatic Progression-Free Survival After PHP Metastatic Neuroendocrine Tumor (n=20)

Median: 39 months20 Treated

Censored for death from extra-hepatic disease (n=4)

Not Evaluable due to hepatic toxicity (n=1)On Active Treatment (n=2)


PHP#1 PHP#2

Metastatic Glucagonoma54 year-old female

Metastatic pancreatic neuroendocrine tumor

Primary in place, treated post PHP with XRT

XRT Pancreas BedThursday, March 31, 2011

Metastatic Glucagonoma

Pre-Treatment

April 2003

Post-PHP x 2

November 2003

Follow-up (22m)

March 2005


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.


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


James F. Pingpank, Jr., MD, FACSAssociate Professor of Surgery

Division of Surgical Oncology, Department of SurgeryUniversity of Pittsburgh, Pittsburgh, PA

June 10, 2010WCIO Annual Meeting- Philadelphia PA

The Evolution of Modern Isolated Hepatic Perfusion for Patients with Unresectable Hepatic Metastases


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Dcth isolation perfusion