Protocol Number: 04-C-0273

Title:

A Phase II Study of Hepatic Arterial Infusion of Melphalan with Venous Filtration via Peripheral Hepatic Perfusion (PHP) for Unresectable Primary and Metastatic Cancers of the Liver

Number:

04-C-0273

Summary:

Background:

-The chemotherapy drug melphalan has been used with some success in treating cancer in the liver.

-Melphalan is less toxic if given directly into the blood vessels in the liver instead of through an IV line, and can therefore be given in higher, more effective doses. However, the drug can be given only once this way, because this method requires major surgery.

-A different method of giving chemotherapy directly to the liver without a major operation is called peripheral hepatic perfusion (PHP). Special catheters (plastic tubes) called the DelCath system are positioned in the blood vessels going into and out of the liver through small puncture holes in the skin and the melphalan is given through these catheters.

Objectives:

-To determine if the DelCath system is effective in treating liver tumors.

-To determine the number and severity of side effects using the DelCath system.

Eligibility:

-Patients 16 years of age and older with either primary liver cancer or another cancer that has spread to the liver and cannot be treated surgically.

-Patients with colorectal cancer that has spread to the liver must have completed first and second line chemotherapy (including CPT-11 and oxaliplatin).

Design:

-Participants are admitted to the hospital for PHP, done under general anesthesia. Catheters are placed into the large artery and vein that supply blood to and from the liver, creating a separate circulation for the liver. Melphalan is then infused into the liver for 30 minutes. The circulation to the liver remains separate and the blood is filtered through the DelCath system for another 30 minutes after the drug is given to remove as much of it as possible from the blood coming out of the liver. After the procedure, patients are monitored in the intensive care unit for about 24 hours and remain in the hospital for 3 to 5 days.

-Patients are evaluated 3 weeks after the procedure. Those who have recovered from side effects of the first treatment undergo a second treatment. About 4 weeks after the second treatment, patients whose tumor is responding may be offered two more treatments.

-Follow-up visits are scheduled 4 weeks after the fourth treatment, then every 3 months for the first 2 years and every 4 months for the third year for a physical examination, blood tests, and scans.

-A maximum of 100-105 patients will be enrolled in the study over 4-5 years.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Patients must be greater than or equal to than 16 years of age.

Histologically or cytologically proven cancer, predominantly in the parenchyma of the liver with one of the following histologies: adenocarcinoma of the GI tract, neuroendocrine tumor (with the exceptioin of gastrinoma), primary hepatic malignancy (hepatocellular cancer or intra-hepatic cholangiocarcinoma), or cutaneous or ocular melanoma (patients must have received prior regional melphalan therapy). Evidence of limited unresectable extrahepatic disease on preoperative radiological studies is acceptable if the life-limiting component of progressive disease is in liver. Examples of limited extrahepatic disease that may be commonly encountered and may be considered acceptable include, but are not necessarily limited to up to four pulmonary nodules each less than 1 cm in diameter, retroperitoneal lymph nodes less than 3 cm in diameter, skin or subcutaneous metastases that are fewer than 10 in number and less than 1 cm in diameter, asymptomatic bone metastases that have been or can be palliated with external beam radiation therapy, or a solitary metastasis to any site that can be resected. Patients with hepatic metastases from colorectal tumors must have been treated with first and second line chemotherapy (including irinotecan and oxaliplatin) prior to being treated on this phase II trial. Patients with pancreatic cancer must have received first line chemotherapy.

Patients previously treated with IHP (with or without hepatic arterial infusion using FUDR) or PHP will be eligible if they had a radiographic partial response of 3 months duration to the therapy.

Patients must have had no chemotherapy, radiotherapy, or biologic therapy for their malignancy in the month prior to treatment and must have recovered from all side effects.

Patients must have an ECOG performance standard of less than 3 at on study and on the day prior to treatment.

Patients must have a platelet count greater than or equal to 75,000/mm(3), Hgb greater than 9 gm/dl (correctable with transfusion), an ANC greater than or equal to 1.3 microL and a creatinine less than or equal to 1.5 mg/dL unless the measured creatinine clearance is greater than 60mL/min/1.73m(2).

Patients must have adequate hepatic function as evidence by a total serum bilirubin less than or equal to 2.0 mg/dL and a PT within 2 seconds of the upper normal limit. AST/ALT must be less than or equal to 10 times upper limit of normal.

NCI Laboratory of Pathology will confirm Pathology.

Patients must be aware of the neoplastic nature of his/her illness, the experimental nature of the therapy, alternative treatments, potential benefits, and risks. The patient must be willing to sign an informed consent.

Women who are premenopausal (have had a period within the past 12 months) must be willing to undergo hormonal suppression during treatment.

EXCLUSION CRITERIA:

Patients with Childs B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies will be excluded.

Patients with a history of congestive heart failure with an LVEF less than 40 percent will be excluded.

Patients with COPD or other chronic pulmonary disease with PFT's indicating an FEV1 less than 30 percent or a DLCO less than 40 percent predicted for age will be excluded.

Patients must be greater than 35 kg because of size limitations with respect to percutaneous catheterization of the femoral artery and vein using this system.

Pregnant patients and nursing mothers will be excluded because of the unknown effects of this therapy on the fetus or nursing mothers.

Patients taking immunosuppressive drugs or requiring ongoing chronic anticoagulation will not be eligible.

Patients with active infections are not eligible.

Patients with severe allergic reactions to iodine contrast which can not be controlled by premedication with antihistamines and steroids are not eligible as a hepatic angiogram is needed for this procedure.

Patients with a known prior hypersensitivity reaction to melphalan will be excluded.

Patients with resectable tumor(s) of the liver will be excluded.

Patients with a documented latex allergy.

Patients with a history of hypersensitivity to heparin in the presence of heparin induced thrombocytopenia (HIT) antibodies.

Patients with a history of bleeding disorders (e.g. nose bleeds, bleeding ulcers) or evidence or intracranial abnormalities which would put them at risk for bleeding with anticoagulation (e.g., stroke, active metastases).

Patients with a history of gastrinoma or who have undergone a Whipple procedure.

Special Instructions:

Currently Not Provided

Keywords:

Regional Chemotherapy

Response Rate

Duration of Response

Disease Free Survival

Stratification

Recruitment Keyword(s):

Liver Cancer

Liver Tumor

Hepatic Tumor

Condition(s):

Liver Cancer

Metastases

Investigational Drug(s):

Melphalan

Investigational Device(s):

Delcath System

Intervention(s):

Drug: Melphalan

Device: Delcath System

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.

Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6.

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