Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor
Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor
Hepatocellular cancer, one of the world's most deadly tumors, is associated with chronic
 liver injury and cirrhosis. With the increasing occurrence of viral hepatitis, the incidence
 of this cancer in the United States continues to rise. Surgical resection offers the only
 hope for cure; but sadly, few patients are candidates for surgery due to their liver disease.
 Liver transplant can be an effective treatment, but due to a scarcity of organs, most
 patients do not qualify for this therapy either. Patients who are not candidates for these
 procedures have very few therapeutic options as chemotherapy and radiation have little
 efficacy. New therapies are desperately needed.

 Opioid Growth Factor (OGF) inhibits the growth of a number of cancer lines in vitro by a
 receptor-mediated mechanism. In pancreatic cancer this phenomenon has been well defined not
 only in vitro but in animal models. Based upon these findings, a phase I trial has been
 conducted demonstrating that OGF can be administered safely to patients with pancreatic
 cancer. The investigators hypothesize that administration of OGF will inhibit the course of
 cancer progression in human subjects with unresectable hepatocellular cancer and cirrhosis.
 As a first step in testing this hypothesis, the investigators propose a phase I trial to
 study the toxicity and pharmacokinetics of this therapy in patients suffering from inoperable
 hepatocellular cancer and cirrhosis.
STUDY OBJECTIVES Hepatocellular cancer (HCC) is one of the most prevalent cancers in the
 world. About 19,160 new cases are anticipated to occur in the US in 2007. Any form of chronic
 liver injury and cirrhosis predisposes to the development of this malignancy. Worldwide, the
 most common risk factor is viral hepatitis; in the United States other sources of chronic
 liver injury such as cirrhosis related to alcohol use are important, but the incidence of
 viral hepatitis continues to increase. Regardless of the etiology, the only known cure for
 HCC is surgical resection. Unfortunately, due to associated liver disease and stage of tumor
 progression at the time of diagnosis, very few patients are candidates for surgical therapy.
 Chemotherapy has shown very little efficacy in this disease, and radiation is of little value
 due to associated liver toxicity. New therapies are desperately needed.

 Research examining the mechanisms involved in the growth of human cancer has shown that the
 peptide [Met5]-enkephalin, Opioid Growth Factor (OGF), inhibits growth of a number of cancer
 lines in vitro. In pancreatic cancer this phenomenon has been well defined not only in vitro
 but in vivo after transfer of human tumors into nude mice. The suppressive effect on growth
 by this peptide is by a receptor-mediated mechanism. Based upon these findings, a phase I
 trial has been conducted studying the effects of OGF in patients with pancreatic cancer. We
 hypothesize that administration of OGF will inhibit the course of carcinogenic events in
 human subjects with unresectable hepatocellular cancer and cirrhosis. In order to test this
 hypothesis we propose a phase I trial to study the toxicity of this therapy in patients
 suffering from liver disease and cirrhosis addressing the following specific aims:

 Specific Aim 1: Determine the maximum-tolerated dose (MTD) of OGF after an intravenous
 infusion in patients suffering from HCC. While the MTD has been determined for patients
 suffering from pancreatic cancer, it is unclear that these results will hold true in patients
 with HCC who suffer from liver insufficiency and cirrhosis. For this reason we will conduct a
 dose-finding trial that contains dose-escalation of OGF. Dose-limiting toxicities will be
 determined by monitoring liver function, pupillary size & response, respiration, vital signs
 (orthostatic blood pressure and pulse), gastrointestinal distress, cutaneous flushing, and
 effects on blood count, glucose and electrolytes.

 Specific Aim 2: Study the pharmacokinetics and metabolism of OGF in patients with HCC and
 cirrhosis by monitoring plasma OGF levels. Blood samples will be collected prior to and at
 designated intervals after an infusion of the MTD of OGF in cancer patients. OGF plasma
 levels will be analyzed by performing radioimmunoassay.

 The long-term objectives of our research team are to understand the effects of peptide growth
 factors in patients with HCC and cirrhosis. This phase I trial will be useful in determining
 the appropriate dose and expected toxicities of OGF in these patients. Our study employs the
 use of a naturally occurring opioid peptide, which has been shown to inhibit growth of
 pancreatic cancer in preclinical studies, and to be safely administered to patients with
 pancreatic cancer.

 BACKGROUND AND SIGNIFICANCE Hepatocellular carcinoma (HCC) is the fifth most common
 malignancy in the world; five hundred thousand people succumb to this malignancy annually.
 The incidence and mortality rates are almost equal, which demonstrates that very few patients
 are cured. Any form of chronic liver injury and cirrhosis predisposes to the development of
 this malignancy. The major risk factors for HCC are chronic hepatitis B virus infection,
 chronic hepatitis C virus (HCV) infection, and alcoholic cirrhosis.

 The only known cure for HCC is surgical resection. The patient's degree of cirrhosis and the
 anatomic location of tumor determine if partial hepatectomy can be performed. Even at high
 volume centers specializing in the procedure, operative mortality has been shown to increase
 from 1% to 14% in the presence of cirrhosis (1). For this reason, resection is usually
 reserved for patients with Child's A liver function. Multiple lesions do not preclude
 resection. Intraductal tumors causing obstructive jaundice can be successfully resected. In
 this situation, it is important to distinguish obstruction from underlying liver disease as
 the cause of the patient's jaundice.

 Total hepatectomy followed by orthotropic liver transplantation is a sensible strategy to
 treat patients with cirrhosis and cancer, and experience is growing with this approach. As
 expected, the best results have been recorded in patients who had small HCC discovered
 incidentally at transplantation performed for liver failure. Lesions smaller than 5 cm
 treated by transplantation have a significantly better prognosis, and, because organs are
 scarce, transplantation for HCC us usually limited to this setting. Mazzaferro et al have
 reported liver transplantation as an effective treatment for small, unresectable HCC in
 patients with cirrhosis, with 4-year recurrence-free survival of 83%.

 Unfortunately, 90% of patients are not suitable for resection or transplantation with a
 curative intent (2-6), and these patients have very few therapeutic options of proven
 efficacy. In this setting the prognosis is extremely poor, with median survivals as low as 3
 months in high-incidence areas (5-8). No systemic chemotherapeutic regimens have demonstrated
 significant efficacy. Response rates to single-agent and multidrug protocols, with or without
 biologic response modifiers, are no better than 20% to 30% (9-12)and randomized trials do not
 demonstrate a clear survival benefit (13, 14). Recently, sorafenib was shown to increase
 overall survival, from 7.9 months to 10.7 months, in Child's A patients with hepatocellular
 cancer (15). External radiation therapy for HCC is ineffective even for palliation (9, 16,
 17)because the dose of radiation that can be delivered to the tumor is limited by radiation
 hepatitis (18, 19). Hepatic intraarterial infusion of cytotoxic agents, aimed at increasing
 the local concentration of drugs and reducing systemic toxicity (20), and intraarterial
 embolization, which causes ischemic necrosis of the tumor (21), have been used as palliative
 treatment either alone or in combination. Chemoembolization is most often employed on the
 basis of reports of decrease in tumor size in nonrandomized trials (22-26); however, the
 results of a multi-center randomized trial showed no improvement in overall survival, and
 significant morbidity with this therapeutic approach (27). Clearly new therapeutic strategies
 are needed to treat this deadly disease.

 Endogenous opioid systems participate in the growth of developing cells and tissues,
 micro-organisms, tissues that undergo cellular renewal, and in neoplastic cells and tissues
 (28, 29). A thorough examination of the effects of opioid peptides in pancreatic cancer cells
 growing in tissue culture revealed that [Met5]- enkephalin, a pentapeptide was the most
 potent peptide influencing DNA synthesis and growth; in view of its growth factor action,
 [Met5]-enkephalin has been termed opioid growth factor (OGF). OGF interacts with the OGFr
 receptor zeta (OGFr) to influence growth. Unlike other opioid receptors, the function (e.g.,
 growth), distribution (neural and non-neural), transient appearance during ontogeny, ligand
 specificity (i.e., [Met5]- enkephalin), competitive inhibition profile, subcellular location
 (i.e., nucleus), and the fact that ligands for other known opioid receptors do not influence
 growth have provided a unique set of characteristics that distinguish the OGFr from other
 opioid receptors. It has been demonstrated that opioids function as inhibitory growth factors
 in human pancreatic cancer, both in vitro and in vivo (28, 30).

 [Met5]-enkephalin has been safely used in several pilot studies to treat human subjects with
 cancer. Wybran and Schandene (31) administered [Met5]-enkephalin intravenously to seven
 previously untreated patients with lung cancer and found significant increases in T-cell
 immunity (i.e., OK1 0 cells. Leu11 cells, and natural killer cells). Plotnikoff and
 colleagues (32) administered [Met5]-enkephalin over a period of several months by intravenous
 infusions at doses of 10 to 60 pg/kg body weight three times weekly to human subjects with
 advanced melanoma. Plotnikoff and coworkers (33) and Wybran and coworkers (31) have reported
 improvement in the size and coloration of Kaposi's sarcoma nodules in AIDS patients. In
 addition, [Met5]-enkephalin increased the number of cytotoxic T-cells and NK cells involved
 in tumor surveillance. The tumor response in these human studies has been attributed to
 [Met5]-enkephalin's action on the immune system (31, 34). Most recently, a phase I study has
 demonstrated that OGF can be delivered safely to patients suffering from advanced pancreatic
 cancer (30) and is now being given in a phase II trial.

 Our research team has demonstrated both the presence and the function of the Opioid Growth
 Factor (OGF)-OGF receptor (OGFr) system in human hepatocellular carcinoma. First,
 immunohistochemistry staining of human hepatocellular cell lines SK-Hep-1 and HepG2 cells
 revealed specific distribution of both OGF and OGFr. Second, OGFr was detected in receptor
 binding studies, and found to have specific and saturable binding of a single binding site,
 with binding capacity (Bmax) values of 12.1 +/- 2.7 fmol/mg protein and 9.4 +/- 1.9 fmol/mg
 protein and binding affinity (Kd) values of 6.1 +/- 1.1 nM and 5.8 +/- 1.5 nM for SK-Hep-1
 and HepG2, respectively. Third, in functional assays that monitored the effects of OGF on
 cell number of human hepatocellular carcinoma cells, a statistically significant suppression
 in cell growth was found in vitro when SK-Hep-1 cell were cultured in the presence of OGF
 (appendix 10.7). Based on the previous in vitro and in vivo evidence in pancreatic cancer, as
 well as with colon cancer, neuroblastoma, and squamous cell carcinoma of the head and neck,
 as well as the successful Phase I trial of OGF in pancreatic cancer patients, these
 preliminary data with hepatocellular carcinoma cells are consistent and provide the rationale
 to test OGF therapy in patients with hepatocellular carcinoma and cirrhosis.
Inclusion Criteria:

 -  In this acute dose-finding section of the study, we will enroll patients with HCC and
 cirrhosis.

 -  Both male and female patients 18 years of age or older will be eligible.

 -  Patients with cancer must have a Karnofsky performance rating of at least 50%.

 -  Patients must have HCC and cirrhosis that is not amenable to current therapies
 including liver resection, tumor ablation, or liver transplant.

 -  Patients must be mentally alert and able to give informed consent.

 -  Female patients who are menopausal, or of childbearing age who are surgically sterile
 or practicing birth control (chemical or mechanical) are eligible.

 -  All females of childbearing potential must have a serum pregnancy test upon entry into
 the study and must take precautions to not become pregnant during the study (from the
 time of enrollment until 1 week after the infusion of OGF). No corticosteroid or
 narcotic therapy 24 hrs prior to infusion.

 -  Volunteers must refrain from alcoholic beverages for 24 hours before, and 24 hours
 after, the day of infusion.

 -  If patients have received sorafenib, at least 4 weeks must pass from the last dose.

 -  At least four weeks must pass from significant surgery and the subject must be
 physically recovered.

 Exclusion Criteria:

 -  Patients with asthma, chronic obstructive pulmonary disease, unstable cardiovascular
 diseases (congestive heart failure, symptoms of coronary artery disease, cardiac
 arrhythmias, poorly controlled hypertension, have suffered a myocardial infarction in
 the preceding year or have an abnormal EKG) will not be allowed.

 -  Patients with poorly controlled diabetes, seizure disorders, primary central nervous
 system (CNS) tumors or known brain metastases are excluded.

 -  A clinical judgment will be made based on the other criteria and performance status as
 to the patient's ability to tolerate therapy.

 -  Serum total bilirubin and international normalized ratio (INR) will be used as markers
 of liver function in the exclusion criteria as defined in Table 1 (see below).

 -  Pregnant or nursing women are not eligible.

 -  Patients requiring antibiotics in the preceding week for a serious infection are not
 eligible.

 -  Volunteers may have on the morning of the study one 8 ounce glass of water or juice
 and toast.

 -  EKG and laboratory tests will be reviewed to evaluate whether any exclusion criteria
 are met.

 -  Those who are not eligible will be notified.

 Table 1: Exclusion Criteria

 -  Leukocyte Count < 3500/μl

 -  Hemoglobin < 8500/μl

 -  Blood urea nitrogen (BUN) > 30mg/dl (hydrated)

 -  Creatinine > 2 mg/dl

 -  Platlet Count < 55,000/mm3

 -  INR (unless on coumadin) > 2

 -  Total Bilirubin > 3.5mg/dl

 -  Sodium < 130 mmol/L

 -  Potassium <3.2 mmol/L

 -  Glucose > 300 or < 60 mg/dl