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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7660-7668 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.0933 Pegylated Arginine Deiminase Treatment of Patients With Metastatic Melanoma: Results From Phase I and II StudiesFrom the Pascale National Cancer Institute, Naples, Italy; Phoenix Pharmacologics, Inc; University of Kentucky, Lexington, KY; Hematology and Oncology Division, University of Miami; Miami Veterans Affairs Medical Center, Miami, FL; and Hematology and Oncology Division, Indiana University, Indianapolis, IN. Address reprint requests to John S. Bomalaski, MD, Phoenix Pharmacologics, Inc, 115 John Robert Thomas Dr, Exton, PA 19341; e-mail: jbomalaski{at}phoenixpharmaco.com
PURPOSE: Individuals with metastatic melanoma have a poor prognosis. Many human melanomas are auxotrophic for arginine, and arginine is not an essential amino acid in humans. We hypothesized that this auxotrophy may be therapeutically exploited. A novel amino acid–degrading enzyme (arginine deiminase) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) was used to lower plasma arginine in individuals with metastatic melanoma. PATIENTS AND METHODS: Two cohort dose-escalation studies were performed. A phase I study in the United States enrolled 15 patients, and a phase I to II study in Italy enrolled 24 patients. The Italian patients also received two subsequent cycles of treatment, each consisting of four once-weekly injections of 160 U/m2. The goals of these studies were to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and the antitumor activity of ADI-SS PEG 20,000 mw. RESULTS: PK and PD studies indicated that a dose of 160 U/m2 lowered plasma arginine from a resting level of approximately 130 µmol/L to less than 2 µmol/L for at least 7 days; nitric oxide levels also were lowered. There were no grade 3 or 4 toxicities directly attributable to the drug. Six of 24 phase I to II patients responded to treatment (five partial responses and one complete response; 25% response rate) and also had prolonged survival. CONCLUSION: Elimination of all detectable plasma arginine in patients with metastatic melanoma was well tolerated and may be effective in the treatment of this cancer. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with metastatic melanoma is warranted.
Malignant melanoma is becoming a more prevalent cancer, and the death rate has doubled in the last 35 years. The reasons for this epidemic are not entirely clear.1-5 Patients with stage IV metastatic melanoma have a life expectancy of approximately 4 to 9 months. Chemotherapy, either as a single agent or in combination, has not resulted in prolonged survival, although tumor responses have been observed.1,6-10 Combination chemotherapy is no better. Biologic therapy with interferon alfa or interleukin-2 has also demonstrated limited success, with single-agent response rates of 15% to 20% in selected patients.1,6,7,11-14 Therefore, although clinical responses have been observed with current therapies, this has not translated into major improvement in patient survival, and a more effective, safer treatment is clearly needed. Amino acid deprivation therapy is an effective means of treatment of some cancers. The best known of these treatments uses asparaginase to lower circulating levels of asparagine, a nonessential amino acid. This treatment is particularly effective for acute lymphoblastic leukemia because these cells require asparagine.15 In contrast, most normal human cells do not require asparagines, and elimination of this amino acid is well tolerated. Thus, there is precedence for the use of an amino acid–degrading enzyme as an effective treatment for specific forms of cancer that are auxotrophic for nonessential amino acids. Arginine is another nonessential amino acid for humans and mice.16,17 It can be synthesized from citrulline in two steps via the urea cycle enzymes argininosuccinate synthetase (ASS) and argininosuccinate lyase.18 ASS catalyzes the conversion of citrulline and aspartic acid to argininosuccinate, which is then converted to arginine and fumaric acid by argininosuccinate lyase. Several murine and human melanomas are unable to synthesize arginine. Therefore, it has been suggested that an arginine-degrading enzyme may prove effective in controlling arginine-requiring cancers.19-29 We have shown that all available human melanoma cell lines from the American Type Culture Collection and a large number of human melanoma biopsies do not express ASS, the rate-limiting enzyme in the conversion of citrulline into arginine.23,30 Thus, human melanoma cells are auxotrophic for arginine. Recently, we reported that a number of hepatocellular carcinoma (HCC) cell lines were auxotrophic for arginine and initiated testing of a novel arginine-degrading enzyme–based drug, ADI-SS PEG 20,000 mw, as a treatment for HCC.23,31 This therapy seemed to be well tolerated in individuals with HCC and was effective as a treatment for this disease.32,33 Because the human data indicated this drug to be well tolerated and in vitro and murine data suggested that this therapy may be effective in the treatment of metastatic melanoma, it was decided to evaluate this drug in patients with stage IV metastatic melanoma.
Eligibility Only patients with inoperable stage IV metastatic melanoma with measurable disease (  20 mm) who had experienced treatment failure with conventional therapy were enrolled onto this study. None of these patients had chemotherapy or surgery either 30 days before this study or during this study. All patients were more than 18 years old, had a Karnofsky performance score 80 (United States) or 40 (Italy), and were treated as outpatients at Indiana University (Indianapolis, IN), the University of Miami (Miami, FL), or the G. Pascale National Cancer Institute (Naples, Italy). All patients were advised of the risks associated with their participation and provided informed consent according to the Declaration of Helsinki.
Treatment Protocol Italian phase I to II study. Patients were sequentially enrolled onto one of six cohorts. The first four cohorts were composed of three patients, and each cohort was treated with one cycle consisting of a dose level of 40, 80, 160, or 320 U/m2. Six patients received one cycle at a dose level of 640 U/m2. The first cycle consisted of three IM treatments administered on days 1, 15, and 22. In addition, six patients were enrolled onto a final cohort in which each patient received three cycles consisting of four once-weekly IM treatments at the OBD. All of the patients were then eligible to receive two additional cycles of treatment consisting of four once-weekly treatments at the OBD (160 U/m2) provided they had stable disease or better. As in the US study, PK, PD, and antibody titers to ADI-SS PEG 20,000 mw were determined. Any antitumor effect that ADI-SS PEG 20,000 mw had was measured using direct measurement (skin lesions), ultrasound, or computed tomography (CT) scans (performed before entry onto the study and after each cycle of treatment), according to what was most suitable for the individual patient. The total number of patients to be enrolled was determined as described by Simon et al34,35 and previously applied to the evaluation of ADI-SS PEG 20,000 mw treatment of patients with HCC.33 Thus, during the course of this study, several of the first 12 patients responded to ADI-SS PEG 20,000 mw treatment, and by the time four patients had been observed to respond to treatment, a total of 24 patients had been enrolled onto the study. At this point, further enrollment was terminated. During treatment, patients were seen weekly by a physician for history, physical examination, and toxicity assessment. The National Cancer Institute Common Toxicity Criteria (version 2.0) was used to grade all toxicities observed. Tumor response was determined using standard WHO criteria. Complete response was defined as disappearance of all radiologic evidence of disease for at least 4 weeks. Partial response was a more than 50% reduction in bidimensional tumor measurements without the appearance of any new lesions for at least 4 weeks. Progressive disease was defined as a 25% increase in the bidimensional measurements of all tumors, 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. Imaging modalities were standardized in the radiology department at each institution, and the results of all imaging studies were confirmed by a single independent radiologist.
PD
PK
Testing for Antibodies to ADI-SS PEG 20,000 mw
Measurement of Nitric Oxide Synthesis
Patient Characteristics The US phase I study was performed from February 4, 2002, to March 11, 2003. The Italian phase I to II study was performed between July 7, 2002, and April 20, 2004. A total of 15 and 24 patients were enrolled onto the US and Italian studies, respectively. The characteristics of the patients enrolled onto the studies are listed in Table 1.
Compliance Of the 15 patients enrolled onto the US phase I study, 14 completed the study. Of the 24 patients enrolled onto the Italian phase I to II study, 12 completed all cycles of treatment. All 12 of the patients who did not complete the study were taken off treatment because of progressive disease. The average number of treatments per patient in the phase I to II study was 8.7 (range, three to 12 treatments). At no time did any of the patients ask to be removed from the studies.
Observations Related to Safety Two patients developed hypotension within 20 to 40 minutes after treatment. One of these patients had a history of hypertension and diabetes mellitus and was receiving five medications for those conditions. This patient had a more than three-fold increase in D-dimer. Although this patient did not have visible thrombi on CT scan, the etiology of the hypotension remains unknown, and this patient did not receive subsequent treatments with ADI-SS PEG 20,000 mw. A second patient had a hypotensive response shortly after receiving the fourth IM treatment. This patient was then re-treated six additional times without further adverse events. None of the patients developed shortness of breath after treatment. Several clinical laboratory abnormalities were noted after ADI-PEG 20,000 mw injection and are listed in Table 2. However, except for the elevation in uric acid, none correlated with the dose of ADI-SS PEG 20,000 mw administered and, thus, were not likely attributed to the treatment, although they may possibly be related to treatment. The most common laboratory abnormalities observed after treatment with ADI-SS PEG 20,000 mw were mild increases in fibrinogen that did not correlate with dose or time of dosing. However, this increase did not manifest itself in coagulopathies in any of the 39 patients, and this clinical laboratory observation is not graded according to the National Cancer Institute Common Toxicity Criteria.
Lipase and amylase levels were also occasionally slightly 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, and thus, this was solely a laboratory finding. Except for three patients with borderline normal WBC that decreased to less than normal during treatment but then returned to normal, patients did not experience potential hematologic toxicity; WBC differentials did not change.
Several patients did develop significant hyperuricemia after treatment with ADI-SS PEG 20,000 mw. None of these patients had a history of gout. The hyperuricemia was always observed at ADI-SS PEG 20,000 mw dose levels
Immunogenicity of ADI-SS PEG 20,000 mw in Patients With Melanoma
Maximum-Tolerated Dose One of the goals of the Italian phase II study was to determine the maximum-tolerated dose (MTD) of ADI-SS PEG 20,000 mw. The MTD was defined as the dose that resulted in two or more patients of a cohort having a grade 3 or greater toxicity. In animals (mice), we have previously reported the no effect level of this drug to be more than 200 U/m2, with minimal toxicities observed at 800 U/m2.38 Because it has been previously shown that the IM route of administration of protein-based drugs, such as asparaginase, is safer than the intravenous route, the maximum dose that could be administered was limited by the ability to concentrate the drug and by the maximum volume that could be easily administered without undue pain. Six patients were treated with 640 U/m2 of ADI-SS PEG 20,000 mw once a week (an injection volume of 8 to 10 mL). Except for a number of reports of pain associated with these injections (grade 1), no toxicities were noted. Because this was the highest dose that could be easily administered, we conclude that the MTD is greater than the maximum feasible dose that can be administered by this route of injection.
PD
PK PKs 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 3. 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 3. Note that the PK was 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 excellent correlation between the data obtained by both of these assays. Moreover, the PK data (Fig 3) are also consistent with the PD data shown in Figure 2.
ADI-SS PEG 20,000 mw Inhibition of NO NO is thought to be largely synthesized from extracellular arginine.39,40 We have reported that ADI-SS PEG 20,000 inhibits NO synthesis in vitro and in mice.36,37 Because NO plays a role in vascular function and is thought to mediate hypotension, it has been hypothesized that ADI-SS PEG 20,000 mw may inhibit NO production and, thus, adversely affect blood pressure and/or heart rate. Therefore, this was studied in this human study. As can be seen in Figure 4A, ADI-SS PEG 20,000 mw treatment resulted in a dose-dependent decrease in plasma arginine and a concomitant decrease in NO synthesis. Although this treatment significantly decreased NO levels, there was no measurable effect of this treatment on blood pressure or heart rate (Fig 4B).
Effects of ADI-SS PEG 20,000 mw on Melanoma Tumors None of the patients enrolled onto the US phase I study had measurable reduction in any of their tumors, and response was not a goal of the phase I study. However, results from the Italian phase I to II trial included one complete response and five partial responses (six of 24 patients; 25% response rate). Fourteen patients had stable disease for at least one cycle, and six patients had stable disease throughout the 3 months of study. All of the responders and those patients with stable disease were treated at a dose of 160 U/m2 or higher. The CT scans and ultrasounds from several of these patients are shown in Figure 5. The remainder of patients had progressive disease.
Effects of ADI-SS PEG 20,000 mw on Survival of Patients With Metastatic Melanoma The typical patient in the Italian study had experienced treatment failure with three or more chemotherapy/immunotherapy regimens and surgery. After ADI-SS PEG 20,000 mw therapy, as of December 2004, the median survival time was 15 months, with a mean survival time of 19.6 months with stage IV disease. The median survival time of these patients with stage IV disease before study entry was 7 months, with a mean of 12.2 months. Of the five patients with an objective response, the median time to progression was 5 months, and the median survival time was 6 months; two patients are still alive.
It has long been known that arginine is required for growth of some tumors. Gilroy41 demonstrated more than 70 years ago that mice fed a diet increased 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 had reduced tumor growth.42,43 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 lowering arginine in both animals and in vitro.44-46 However, these experiments were largely unsuccessful because this enzyme has a weak affinity for arginine (45 mmol/L) and a nonphysiologic pH optimum (> 9.0).36 Earlier, we reported the results from the testing of ADI-SS PEG 20,000 mw in patients with HCC.32,33 The results from the PK and PD data obtained in these patients indicated that the OBD was 160 U/m2 and that this drug could be administered once a week. These studies further demonstrated this drug to be well tolerated in this patient population. A reasonable antitumor response rate was observed in patients with HCC, including two complete responses, which are rarely obtained in this disease. Furthermore, prolonged survival occurred. The data reported in these patients with stage IV melanoma is consistent with the HCC data in many respects. Clinical responses and apparent improved survival occurred in both patient populations. Also, the PK and PD data obtained in patients with metastatic melanoma and HCC are remarkably similar. Thus, the underlying cirrhosis that was present in the HCC patient population had little effect on either the circulating half-life of this drug or its effectiveness in lowering plasma arginine levels. This was somewhat surprising because the liver is believed to be the primary organ responsible for arginine synthesis, and it was expected at the outset that it might require more ADI-SS PEG 20,000 mw to lower arginine in patients with normal liver function. Perhaps the most important information to be obtained from the PK and PD studies performed to date is that a once-weekly injection (IM) at a dose level of 160 U/m2 is sufficient to eliminate all detectable arginine from the circulation for at least 7 days, both in patients with normal liver function and with cirrhosis. We have defined this dose to be the OBD for this drug. Because the resting level of arginine in humans is approximately 125 µmol/L and our lower limit of detection of arginine by the methods used was less than 2 µmol/L, this dose of ADI-SS PEG 20,000 mw is clearly capable of a marked reduction in circulating levels of this amino acid. NO is produced by NO synthase catalysis of extracellular arginine. NO is an endothelial product that functions to maintain blood flow by vasodilation and smooth muscle relaxation. ADI-SS PEG 20,000 mw eliminates extracellular arginine and has been shown to inhibit NO production both in vitro and in mice.36,37 Thus, there was an initial concern that one of the toxicities of ADI-SS PEG 20,000 mw treatment would be hypertension. Hence, we monitored NO production and blood pressure and heart rate. Maximal inhibition of endogenous NO occurred when plasma arginine levels were less than the level of detection. It was observed that, when ADI-SS PEG 20,000 mw was administered at the OBD, there was inhibition of NO production, but there was no increased blood pressure or heart rate. Although we and others have hypothesized that the mechanism of action of ADI-SS PEG 20,000 mw is the selective starvation of cancer cells auxotrophic for arginine, the observation that this drug inhibits NO production provides the basis for additional mechanisms of action.24-29,47 For example, there is mounting evidence that endogenous NO is associated with maintenance of tumor blood flow and tumor growth-promoting effects. These data are based on the observations that NO production has been associated with tumor growth and that inhibitors of NO synthesis can inhibit the growth of some tumors in experimental systems.48,49 Perhaps even more relevant to the data obtained in our study is the finding that inhibition of NO synthesis triggers apoptosis in human melanoma cells but not normal melanocytes.50 The authors of this study concluded that melanoma cell survival is, in fact, regulated by endogenous NO produced from inducible NO synthase activity. ADI has been shown to induce apoptosis in leukemia cells.24,29,51 Thus, by inhibiting NO production, it is possible that ADI-SS PEG 20,000 mw may induce apoptosis in human melanoma tumors. In addition, arginine deimination by ADI antagonizes the transcriptional induction mediated by arginine methylation, thus repressing signal transduction.52 Therefore, ADI may inhibit tumors through a variety of mechanisms. In conclusion, data from these studies indicate that an ADI-SS PEG 20,000 mw dose level of 160 U/m2 administered once a week is effective in lowering plasma arginine and that this treatment is well tolerated. Moreover, these studies indicate that ADI-SS PEG 20,000 mw may have antitumor activity and prolong survival of patients with melanoma. Further testing in larger studies is warranted because new effective therapies are urgently needed for this treatment-refractory disease.53
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
We thank the Melanoma Cooperative Group of Naples: P. Aprea, P.A. Ascierto, A.F. Ayal, G. Beneduce, L. Bosco, G. Botti, G. C. Caracò, G. Castello, E. Celentano, M.G. Chiofalo, G. Comella, A. Daponte, M.R. De Marco, F. Graziano, E. Leonardi, M.L. Lombardi, A. Marfella, M. Montella, S. Mori, N. Mozzillo, M. Napolitano, A. Ottaiano, G.F. Peluso, F. Perone, G. Pirozzi, S.M.R. Satriano, S. Scala, E. Simeone, and F. Tatangelo, National Tumor Instutue "G. Pascale"; R.A. Satriano, A. Vozza, V. Ruocco, Second University of Naples, Naples; G. Palmieri, Division of Cancer Genetics, ICB-CNR, Algheo (SS); and A. Cossu and F. Tanda, University of Sassari, Sassari Italy. We also thank M.R. Ventura for data management.
Supported in part by grants from the US Food and Drug Administration and National Institutes of Health to Phoenix Pharmacologics, Inc. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
