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Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 1815-1822 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.120 Pegylated Arginine Deiminase Treatment of Patients With Unresectable Hepatocellular Carcinoma: Results From Phase I/II StudiesFrom the Pascale National Cancer Institute, Naples, Italy; Phoenix Pharmacologics Inc, and University of Kentucky, Lexington, KY; and M.D. Anderson Cancer Center, University of Texas, Houston, TX. Address reprint requests to Steven Curley, MD, Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 444, Houston, TX 77030; e-mail: scurley{at}mdanderson.org
PURPOSE: Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid–degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study. PATIENTS AND METHODS: Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m2 was sufficient to lower plasma arginine from a resting level of approximately 130 µmol/L to below the level of detection (< 2 µmol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose. RESULTS: This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (> 680 days). CONCLUSION: Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted.
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world.1–4 The international yearly incidence is approximately 1 million cases. In the United States, approximately 20,000 new cases are diagnosed annually, with more than 18,700 deaths annually. Thus the incidence and mortality rates are almost equal. Current therapy for HCC is inadequate.1–6 Fewer than 10% of HCC patients are candidates for surgical resection or transplantation. Even those who undergo resection have a poor long-term prognosis, as most relapse within 2 to 3 years with hepatic and/or systemic metastatic disease.3,4,6 Systemic chemotherapy, either as a single agent or in combination, has not resulted in prolonged long-term survival rates. Hepatic arterial infusion of chemotherapy has yielded some increased long-term response rates, but this therapy as well as radiotherapy and hepatic arterial embolization have limited and most often only palliative benefit. Despite all forms of current treatment, most patients die within 1 year of diagnosis. Median life expectancy of patients with nonresectable disease has been historically reported as 1.4 to 3 months.3,4,7–10 Arginine is one of the nonessential amino acids for humans.11 Normal cells and tissues synthesize arginine from citrulline in two steps using the urea cycle enzymes argininosuccinate synthase (ASS) and argininosuccinate lyase. Some human cancers do not express ASS and thus are unable to synthesize arginine from citrulline. Therefore, it has been suggested that an arginine-degrading enzyme may prove effective in the eradication or control of arginine auxotrophic cancers.12–18 We have shown that all available human HCC cell lines from the American Type Culture Collection do not express ASS and thus are auxothrophic for arginine.17 Various HCC cell lines have been shown to be killed in vitro and in vivo by arginine deiminase (ADI).14,17 However, this form of therapy has two major disadvantages. First, ADI is not produced by mammals and must be derived from microbes. As a consequence, nascent ADI is strongly antigenic in mammals. Second, ADI has a short circulating half-life in mammals (approximately 5 hours) and must be administered in large daily doses to inhibit tumors implanted into mice.13,19 ADI was formulated with polyethylene glycol (PEG) to produce ADI-SS PEG 20,000 mw.19 This formulation of ADI is less antigenic in experimental animals and has a much longer circulating half-life and is thus much more effective as an antitumor agent.17,19 Toxicology testing of ADI-SS PEG 20,000 mw indicated it was safe in mice. More recently, results obtained from the testing of this drug in a single patient with HCC treated as a single patient exemption to our investigational new drug indicated that this therapy was well tolerated and produced an antitumor response.20 Here we report the first results obtained with this drug in a larger patient population.
Eligibility Only patients with advanced or metastatic inoperable HCC were admitted to this study. None of these patients had any chemotherapy within 30 days before or during this study and all were older than 18 years, had a Karnofsky performance status (KPS)  40% and were treated as outpatients at the G. Pascale National Cancer Institute in Naples, Italy. This phase I/II protocol was conducted under approval of the Italian Health Ministry and the institutional review board at the G. Pascale National Cancer Institute in Naples, Italy. All patients were advised of the risks associated with their participation in this study and provided informed consent according to the Declaration of Helsinki.
Treatment Protocol
Because advanced HCC is uniformly fatal, it was decided that all patients should receive three cycles at the OBD, provided that the toxicity was acceptable, to assess tumor response to this therapy. Thus the dose of drug administered on second and subsequent cycles of treatment was increased as shown above. All treatments were administered by intramuscular injection. The initial cycle of treatment consisted of three treatments on days 1, 15, and 22. Subsequent cycles consisted of four treatments on days 1, 8, 15, and 22. Subsequent cycles of treatment were initiated on day 36 of the preceding cycle. The total number of patients to be enrolled was determined as described by Simon.21,22 This protocol design would terminate the study early if a predetermined response rate was not observed. According to this protocol design, in the first stage of the study, a predetermined number of patients were treated and if none of the patients had an antitumor response, then ADI-SS PEG 20,000 mw was to be declared inactive and the study terminated. If, however, the predetermined number of responses had been observed in the first stage of the study, then the recruitment of patients was to be continued until either the predetermined number of responses were observed (in which case ADI-SS PEG 20,000 mw was to be declared active) or the maximum number of patients allowed was reached. We chose a targeted response rate of 20%. Thus, under these statistical considerations, at least one of the first 12 patients to receive treatment at the OBD for 3 months needed to show a response or the study would be terminated and ADI-SS PEG 20,000 mw would be declared inactive. If, however, at least one of the first 12 patients responded to treatment, recruitment of patients would be continued until four patients were observed to respond (and ADI-SS PEG 20,000 mw would be declared active) or a maximum number of 37 patients had been treated for 3 months at the OBD. Before study entry, all patients provided a complete medical history assessment of performance status and underwent physical examination, including medical laboratory studies. In addition, an abdominal computed tomography scan (CT scan) was performed on each patient within 30 days before entry onto study and repeated every 4 weeks to assess response to therapy. CT scans were performed using spiral (helical) techniques.23–25 Patients were examined weekly by a physician for physical examination and toxicity assessment. The National Cancer Institute Common Toxicity Criteria version 2.0 was used to describe all toxicities observed. Tumor response was determined using standard National Cancer Institute criteria, delineated as follows. Complete response was defined as disappearance of all radiologic evidence of disease for at least 4 weeks. Partial response was defined as a greater than 50% reduction in bidimensional tumor measurements without the appearance of any new lesions for at least 4 weeks. Progressive disease was defined as either a 20% increase in the bidimensional measurements of all tumors or the appearance of any new lesion or the reappearance of any lesion that had disappeared. Stable disease was defined as tumor response that was not a complete response, partial response, or progressive disease.
Pharmacodynamics
Pharmacokinetics
Testing for Antibodies to ADI-SS PEG 20,000 mw
Patient Characteristics This study was performed between July 2002 and January 2003. A total of 19 patients were enrolled onto this study. The characteristics of the patients enrolled are listed in Table 2.
Compliance Of the 19 patients entered onto the study, 15 patients (79%) completed all cycles of treatment. Of the four patients who did not complete the study, two were discontinued from treatment because of progressive disease and two others died while on study as a result of complications of their cirrhosis (hemorrhage of esophageal varices). As noted in Table 2, 18 (94.7%) of the 19 patients in this study had biopsy-proven cirrhosis. A total of 240 treatments were scheduled, and 238 treatments (99.1%) were actually administered. The average number of treatments per patient was 12.5 (range, six to 19 treatments).
Observations Related to Safety Several clinical laboratory abnormalities were noted after ADI-PEG 20,000 mw injection and are listed in Table 3. Except for the elevation in uric acid, none of these correlated with the dose of ADI-SS PEG 20,000 mw and thus were not attributed to the treatment. The most common laboratory abnormalities observed after treatment with ADI-SS PEG 20,000 mw were increases in fibrinogen. However, in none of the patients did this increase manifest itself in coagulopathies, and this clinical observation is not graded according to the Common Toxicity Criteria.
Lipase and amylase levels were also occasionally elevated after treatment. However, there was no correlation with the dose of ADI received and the severity or incidence of this clinical laboratory abnormality. None of the patients developed clinical pancreatitis. Several patients did develop hyperuricemia after treatment. Because none of these patients had a history of gout and the hyperuricemia was always observed at ADI-SS PEG 20,000 mw dose levels 80 U/m2, the hyperuricemia was scored as a side effect related to treatment. Interestingly, all patients but one with elevated uric acid exhibited radiographic evidence of tumor necrosis. It was concluded that this was an adverse event associated with the antitumor effectiveness of this therapy. All patients developing hyperuricemia were promptly treated intravenously with urate oxidase (Elitek; Sanofi, Paris, France), and none developed tumor lysis syndrome. There were no other serious adverse events observed in this study. No events were life-threatening, required in-patient hospitalization, or prolongation of existing hospitalization, and no events resulted in persistent or significant disability or incapacity.
Immunogenicity of ADI-SS PEG 20,000 mw in Patients With HCC
Pharmacodynamics The plasma arginine concentration from each of the cohorts of patients is illustrated in Figure 2. Note that a dose of 160 U/m2 was sufficient to eliminate all detectable arginine from the circulation for at least 7 days.
Pharmacokinetics Pharmacokinetics of ADI-SS PEG 20,000 mw were determined using two different assays. The first assay used was a direct measurement of ADI enzyme activity in the plasma. The results from this assay are shown in Figure 3A. To determine whether enzymatically inactive ADI-SS PEG 20,000 mw could remain in the plasma for a longer time, a second assay used an ELISA to quantify the amount of ADI-SS PEG 20,000 mw protein present in the plasma. The results from this assay are shown in Figure 3B. Note the pharmacokinetics were similar irrespective of the assay used. When the specific activity of ADI-SS PEG 20,000 mw (12 U/mg of protein) is compared with the amount of protein detected by ELISA, there is an excellent correlation between the data obtained by both of these assays.
Effects of ADI-SS PEG 20,000 mw on HCC Tumors Results from this radiologic assessment indicated that two patients (10.5%) had a complete response, seven patients (36.8%) had a partial response, seven patients (36.8%) had stable disease, and three patients (15.9%) had progressive disease. Although complete responses to other systemic treatments for HCC have been noted in the medical literature, they are in fact quite unusual, thus the CT scans from those individuals are shown (Fig 4).
The durability of the response was also measured. Durability was defined as time from the start of treatment until progression. The mean durability of the responses noted above to the time of this report is > 400 days (range, 37 to > 680 days). Despite all treatments having been discontinued for approximately 6 months, eight patients continue to have stable disease or better, including the two patients with complete responses. The remaining six patients have developed progressive disease in the 6 months after termination of treatment.
Effects of ADI-SS PEG 20,000 mw on Performance Status and Functional Liver Reserve
It has long been known that arginine is required for growth of some tumors. Gilroy26 first demonstrated that mice fed a diet rich in arginine developed tumors that grew faster and to a larger size than mice fed a normal diet. Conversely, it was later shown that mice fed diets deficient in arginine have reduced tumor growth.27,28 Thus there is a long history of evidence in the nutritional literature indicating a requirement for arginine in the growth of some tumors. These observations prompted several groups to use arginase as a means of decreasing arginine in both animals and in vitro.29–31 These experiments were largely unsuccessful, as this enzyme had a weak affinity for arginine (45 mmol/L) and a nonphysiologic alkaline pH optimum (> 9.0).32 An independent line of evidence also implicated the essential role of arginine in tumor cell growth in that various laboratories noted the deleterious effects of Mycoplasma contamination on the viability of tumor cells (but not normal cells) in culture.33 Kraemer et al34,35 demonstrated that the growth inhibitory effects of Mycoplasma on tumor cells in vitro could be overcome by the addition of excess arginine to the cultures. Schimke et al36 discovered that arginine catalysis by Mycoplasma occurred by a novel enzyme, ADI, which converted arginine into citrulline and ammonia and not ornithine and urea, as does arginase. It was later proven by Simbercoff et al37 that it was ADI from the Mycoplasma that killed the tumor cells in contaminated cultures. We examined a large number of ADIs purified from many different microbes and found that ADI from M. hominus to have the most optimal combination of physiologic pH optimum and highest affinity for arginine (approximately 10-fold greater than other Mycoplasma ADI enzymes). We further tested a large number of PEG formulations and found that ADI formulated with succinimydal succinimide PEG of 20,000 mw (a formulation termed ADI-SS PEG 20,000 mw) has the longest circulating half-life and least immunogenicity.19 This drug was extensively tested both in vitro and in mouse HCC xenograft models and found to have potent antitumor activity. Toxicologic testing also indicated this drug to be safe in experimental animals. This report is the first report of the systematic testing of ADI-SS PEG 20,000 mw in human cancer patients. Analysis of safety data obtained from this study indicated that ADI-SS PEG 20,000 mw treatment was well tolerated, thus confirming the reports of Rose et al38,39 and Snyderman et al, 40 who demonstrated that humans do not require exogenous arginine. There were no instances of ADI-SS PEG 20,000 mw treatment being discontinued or the dose lowered for safety reasons during this study. None of the patients requested cessation of treatment or removal from the protocol. Fourteen (73.7%) of the 19 patients entered onto this study have died to date, and the median survival was 410 days. All deaths were attributed to factors other than ADI-SS PEG 20,000 mw. Two grade 3 toxicities, one grade 2 toxicity, and 24 grade 1 toxicities were observed. However, all were considered unlikely to be related to treatment and more likely related to the severity of the underlying disease, except for the three instances of elevated uric acid, which probably were related to ADI-SS PEG 20,000 mw-induced HCC tumor lysis. Testing for antibody to ADI-SS PEG 20,000 mw indicated that this drug had little immunogenicity; no neutralizing activity was found in any of the patients. These observations were consistent with the absence of any patient developing redness at the injection site, fever, rash, hypotension, shortness of breath, or other symptoms of allergic response after treatment. Our preclinical studies demonstrated that ADI-SS PEG 5000 mw was significantly more immunogenic than the 20,000 mw PEG formulation.41 Furthermore, injection of nonpegylated ADI in our preclinical models produced a marked immune response with a greater than 10-fold increase in anti–ADI antibody titers compared with the levels seen in our patients treated with ADI-SS PEG 20,000 mw.
Treatment of patients with unresectable HCC for at least 3 months with the OBD (
One of the strengths of this study is that it was conducted in patients who are representative of most patients with HCC and not a highly selected subgroup of the best patients. Thus these patients all had severe cirrhosis and advanced HCC, which is typical of most patients seen at treatment centers. In fact, more than half of these patients had Child's class B or C cirrhosis, and all but two patients had stage IV (tumor-node-metastasis system) malignant disease. Moreover, nearly half of these patients (eight of 19) had a KPS It is recognized that the data presented here are from a small patient population; nonetheless, the results are encouraging, as are those obtained to date from the ongoing phase II study currently being conducted at the University of Texas M.D. Anderson Cancer Center (Houston, TX). All these data suggest that further testing in a larger patient population is warranted. Another limitation of this study was that all patients only received three cycles of treatment at the OBD. Animal data indicate that the mechanism of this drug is the selective starvation of the tumor. Thus treatment of individuals for a longer time period may result in improved results. Recently, we have described a histochemical method for determining whether a tumor is sensitive to arginine deprivation therapy.42 Analysis of a large number of human tumor biopsies from diverse cancers from various organs indicates that the incidence of arginine auxotrophy may be quite high, and therefore the potential may exist to use ADI-SS PEG 20,000 mw therapy in a variety of cancers in addition to HCC.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: C. Mark Ensor, Frederick W. Holtsberg, John S. Bomalaski, Mike A. Clark, Phoenix Pharmaceuticals.
We thank Marcello Piazza, MD, Guglielmo Borgio, MD, Raffaele Orlando, MD, Fabrizio Scordino, MD, and Grazia Tosone, MD, of the University Federico II of Naples, Luigi Adinolfi, MD, and Enrico Ragone, MD, of the Second University of Naples, and Guiseppe Morelli, MD, of the Cotugno Hospital, Naples, Italy.
Phoenix Pharmacologics provides support for a research nurse to F.I. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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28. Gonzalez GG, Byus CV: Effect of dietary arginine restriction upon ornithine and polyamine metabolism during two-stage epidermal carcinogenesis in the mouse. Cancer Res 51:2932–2939, 1991 29. Varit: Inhibitory effects of arginase on mammary adenocarcinoma transplants in Strain "A" mice. Permanente Foundation Med Bull 9:56–59, 1951 30. Holley RW: Evidence that a rat liver "inhibitor" of the synthesis of DNA in cultured mammalian cells is arginase. Biochim Biophys Acta 145:525–527, 1967[Medline] 31. Bach SJ, Swaine D: The effect of arginase on the retardation of tumour growth. Br J Cancer 19:379–384, 1965[Medline] 32. Dillon BJ, Holtsberg FW, Ensor CM: Biochemical characterization of the arginine deiminase degrading enzymes arginase and arginine deiminase and their effects on nitric oxide production. Med Sci Monit 8:248–253, 2002 33. Tycell E, Neuman RE: Growth response of stable and primary cell cultures to L-ornithine and L-citrulline and L-arginine. Exp Cell Res 20:84–91, 1960[CrossRef][Medline] 34. Kraemer PM, Defendi V, Hayflick L, et al: Mycoplasma (PPLO) strains with lytic activity for murine lymphoma cells in vitro. Proc Soc Exp Biol Med 112:381–387, 1963 35. Kraemer PM: Interaction of mycoplasma (PPLO) and murine lymphoma cell cultures: Prevention of cell lysis by arginine. Proc Soc Exp Biol Med 115:206–212, 1964 36. Schimke RT, Berlin CM, Sweeney EW, et al: The generation of energy by the arginine dihydrolase pathway in Mycoplasma hominis 07. J Biol Chem 241:2228–2236, 1964 37. Simberkoff MS, Thorbecke GJ, Thomas L: Studies on PPLO infection: V. Inhibition of lymphocyte mitosis and antibody formation by mycoplasmal extracts J Exp Med 129:1163–1181, 1969[Abstract] 38. Rose WC: The amino acid requirements of man. Fed Proc 8:546–552, 1949[Medline]
39. Rose WC, Haines WJ, Warner DT: The amino acid requirements of man: V. The role of lysine, arginine, and tryptophan. J Biol Chem 206:421–430, 1954 40. Snyderman SE, Boyer A, Holt LE: Arginine is not a requirement for human infants. Am J Dis Child 97:192–195, 1959 41. Bomalaski JS, Ivett JL, Vegarra M, et al: Comparative toxicity of arginine deiminase formulated with polyethylene glycol 5000 or 20,000 and the effects of arginine. Preclinica 1:284–293, 2003 42. Dillon BJ, Prietro VG, Curley SA, et al: Incidence and distribution of argininosuccinate synthase deficiency in human cancers: A method for identifying cancers sensitive to arginine deprivation. Cancer 100:826–833, 2004[CrossRef][Medline] Submitted November 20, 2003; accepted February 24, 2004. This article has been cited by other articles:
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60%. Previous studies of such significantly affected individuals indicate that none of these patients would have been expected to have survived more than 6 months.
