Neoplasms

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Carcinoma, Hepatocellular

Liver Cirrhosis

Liver Neoplasms

Carcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Analgesics

Central Nervous System Depressants

All Drugs and Chemicals

Analgesics, Opioid

Mitogens

Enkephalins

Neurotransmitter Agents

Volunteers will be treated with an intravenous infusion of opioid growth factor(OGF) starting at 100 µg/kg with a 50 µg/kg dose escalation with each succeeding group. The investigational drug, OGF, will be diluted in sterile saline to its appropriate concentration based upon the body weight of the volunteer and administered in a volume of 60 ml over 45 minutes (rate of 2 ml/min)

Infusion of opioid growth factor

Eric T Kimchi, MD

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.

Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor

Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor: a Phase I Study

primary outcome variable is toxicity and or tolerance to opioid growth factor in patients with hepatocellular cancer

Study the biological kinetics and metabolism of opioid growth factor (OGF) by monitoring plasma OGF levels

Penn State University

University of Missouri-Columbia

Associate Professor of Surgical Oncology

Gland and Hormone Related Diseases

Rare Diseases

Pancreatic Neoplasms

Recurrence

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Amino Acids

Enkephalin, Methionine

Narcotics

Methionine

DRUG All subjects treated with met-enkephalin (also called OGF) 250 ug/kg iv weekly over 45 minutes

OGF was administered in saline at 250 ug/kg intravenously over 45 minutes

opioid growth factor

metenkephalin, OGF-opioid growth factor

Jill P. Smith, MD

RATIONALE: Opioid growth factor may stop the growth of pancreatic cancer by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying how well opioid growth factor works in treating patients with advanced pancreatic cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

* Determine the growth inhibitory effects of opioid growth factor (\[Met\^5\]-enkephalin) in patients with advanced unresectable pancreatic cancer.

Secondary

* Determine the pharmacokinetics of this drug in these patients.
* Determine the quality of life of patients treated with this drug.
* Determine the pain control, depression, and nutritional status of patients treated with this drug.

OUTLINE: This is an open-label study.

Patients receive opioid growth factor (\[Met\^5\]-enkephalin) IV over 45 minutes once weekly. Treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 4 weeks during study treatment, and at the completion of study treatment.

Patients are followed weekly for survival.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Opioid Growth Factor in Treating Patients With Advanced Pancreatic Cancer That Cannot Be Removed By Surgery

Treatment of Advanced Pancreatic Cancer With Opioid Growth Factor (OGF): Phase II

Milton S. Hershey Medical Center

Antineoplastic Agents

Gastrointestinal Agents

Gemcitabine

Pancrelipase

Pancreatin

Antimetabolites

Opioid Growth factor 250 ug/kg IV once a week. Gemcitabine 1000 mg/m2 weekly for 7 out of 8 weeks induction then every 3 out of 4 week cycles.

1000mg/m2, IV (in the vein) over 30 minutes after treatment with OGF; first cycle is consecutive seven weeks and one week off; subsequent cycles are three weeks on and one week off.

Initial treatment is 150ug/kg (based on body weight of the patient) in a volume of 50ml sterile saline, IV (in the vein) over 45 minutes; subsequent treatments at dose of 250ug/kg

Opioid Growth Factor (OGF)

Jill P Smith, MD

It is hypothesized that OGF biotherapy may be safely administered in combination with gemcitabine to individuals with unresectable pancreatic cancer. The study includes two aims, the first is to evaluate the safety and toxicity of the combination of OGF and gemcitabine chemotherapy. The second aim of the trial is to study the efficacy of OGF and gemcitabine when used in combination.

Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States with a median survival of 3-6 months and a five-year survival rate of 1% making it the worse of all gastrointestinal malignancies. The reason for the poor prognosis is related to failure to diagnose this cancer in early stages and the unresponsiveness of pancreatic cancer to conventional chemotherapy and radiation therapy. Gemcitabine has become the standard of care in treatment of advanced pancreatic cancer; however, the mean survival with gemcitabine is reported at only 5.6 months. Our research team has discovered a novel biotherapy called Opioid Growth Factor (OGF) that inhibits growth of pancreatic cancer in vitro, in animals, and in human subjects. A Phase 1 study with OGF has been completed and the maximum tolerated dose, safety and toxicity evaluated. Currently a Phase 2 trial is in progress to study the efficacy of OGF monotherapy in those who have not responded to standard treatment. Recent experiments from our basic science laboratories indicate a marked additive benefit in cancer inhibition when OGF is combined with gemcitabine. Additionally, animals receiving the combination regime were healthier than those treated with gemcitabine alone suggesting perhaps a protective effect of OGF to chemotherapy toxicity. It is hypothesized that OGF may be safely administered in combination with gemcitabine to individuals with unresectable pancreatic cancer. In order to test this hypothesis 22 eligible naïve patients with pancreatic cancer will be prospectively treated with standard doses of gemcitabine. Concomitantly, OGF will be administered weekly starting at 150 μg/kg and increasing to the Maximum tolerated dose of 250 μg/kg in order to determine the following specific aims: 1) evaluate the safety and toxicity of the combination of OGF biotherapy and gemcitabine; 2) determine whether the combination therapy alters the pharmacokinetics of either agent; and 3) study the efficacy of combination therapy on tumor size, patient survival, and time to progression of disease. The long-term goal of our research team involves translation of novel discoveries from the basic science laboratory into clinical practice with the ultimate goal of improving survival of patients with this devastating disease.

Opioid Growth Factor (OGF) and Gemcitabine: Novel Treatment for Pancreatic Cancer

OGF & Gemcitabine: Novel Treatment for Pancreatic Cancer Phase I, A Safety and Toxicity Study

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Squamous Cell

Endorphins

Opioid Peptides

Opioid Growth Factor

David Goldenberg, MD

This study will investigate the efficacy of opioid growth factor (OGF) on tumor size and survival in patients with head and neck cancer who have failed standard therapy.

The major focus of the study will involve assessment of tumor response, patient survival, tolerance to drug, quality of life, depression, pain management and nutrition. During the study we will begin to study the kinetics of opioid growth factor (OGF) exogenous administration and the relationship between plasma OGF levels, stage of disease and length of treatment. Apart from potentially having growth inhibitory action on cancer, OGF may have some psychological and other biological effects which may prove to be beneficial in the patient's treatment. Presently there is no effective therapy or quality of life adjuvants for the 30,000 Americans who develop head and neck cancer yearly.

Treatment of Advanced Head and Neck Cancer

Treatment of Advanced Head and Neck Cancer With Opioid Growth Factors: Phase II

Associate Professor of Medicine and Surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treatment of Unresectable Hepatocellular Cancer With Opioid Growth Factor	NCT00706576	Hepatocellular ...	Infusion of opi...	18 Years -	University of Missouri-Columbia
Opioid Growth Factor in Treating Patients With Advanced Pancreatic Cancer That Cannot Be Removed By Surgery	NCT00109941	Pancreatic Canc...	opioid growth f... metenkephalin, ...	18 Years - 80 Years	Milton S. Hershey Medical Center
Opioid Growth Factor (OGF) and Gemcitabine: Novel Treatment for Pancreatic Cancer	NCT00783172	Pancreatic Canc...	Gemcitabine Opioid Growth F...	18 Years -	Milton S. Hershey Medical Center
Treatment of Advanced Head and Neck Cancer	NCT00982696	Carcinoma, Squa...	Opioid Growth F...	18 Years -	Milton S. Hershey Medical Center
Treatment of Advanced Head and Neck Cancer	NCT00982696	Carcinoma, Squa...	Opioid Growth F...	18 Years -	Milton S. Hershey Medical Center

Spots Global Cancer Trial Database for opioid growth factor