Clinical trials of arginine deprivation therapy in cancer
The first case of a patient treated with ADI-PEG20 was presented in 2003.42
The patient, who had idiopathic cirrhosis and unresectable HCC, was treated with escalating doses of ADI-PEG20. At a dose of 160 IU/m2
, the serum α-fetoprotein level was decreased and the tumor was reduced in size to allow surgical treatment, while the patient suffered no significant adverse events. This report led to a Phase I/II trial (n = 19) of ADI-PEG20 in patients with nonresectable HCC.43
The optimum biological dose of ADI-PEG20 injected intramuscularly was 160 IU/m2
, which lowered the plasma arginine concentration to an undetectable level (<2 μmol/L) for more than 7 days. The response rate was 47% (two complete responses and seven partial responses), and the rate of stable disease was 37% among 19 enrolled patients. The median survival was 410 days, and no significant toxicity was observed. There was no grade 4 toxicity and the only grade 3 adverse events were the elevated serum lipase and amylase level in one patient each.
In a two-cohort, dose-escalation Phase I/II study of ADI-PEG20 in patients with metastatic melanoma, the optimum biological dose to reduce the blood arginine level to a nondetectable level (<2 mmol/L) for at least 7 days was determined to be 160 IU/m2
There were no grade 3–4 toxic effects directly attributable to the drug. Among six patients treated with 640 IU/m2
of ADI-PEG20 via intramuscular injection once a week, no significant toxic effects were noted except grade 1 injection site pain. Other common adverse events were the elevated serum amylase, lipase, and transaminases, and hypotension, which were all grade 1–2. The maximum tolerated dose was not reached at 640 IU/m2
/week. Six (25%) of 24 patients showed a response to treatment (five partial responses and one complete response), and an additional six patients (25%) had stable disease of at least 3 months duration. All these patients received ADI-PEG20 at a dose of 160 IU/m2
or higher. The median overall survival duration was 15 months in these patients with stage IV disease. None of the plasma samples from any of the 39 patients showed measurable enzyme-neutralizing activity.
In another Phase II study of ADI-PEG20 in patients with melanoma,30
36 patients were treated weekly with ADI-PEG20 at 160–320 IU/m2
intramuscularly. Ten (28%) of the patients had a clinical benefit (partial response, minor response, or stable disease). Including mixed response, 14 (39%) of 36 patients showed antitumor effects. Twenty patients whose disease showed no response to 160 IU/m2
/week were treated with 320 IU/m2
/week, and four of them had a response. This result suggests that 320 IU/m2
/week is the appropriate dosage for future trials. This dose was well tolerated, but further dose escalation is limited by the large volume of intramuscular injection of ADI-PEG20. Pretreatment tumor samples from 26 patients were analyzed for ASS expression. Interestingly, among the 16 patients whose tumors did not express ASS, three (29%) had a clinical response and eight (50%) had some clinical benefit (clinical response or stable disease). In contrast, only one of ten patients whose tumor expressed ASS had clinical benefit (P
= 0.01). This finding suggests that ASS expression status, which can be determined either by immunohistochemical staining or reverse-transcription polymerase chain reaction analysis for messenger ribonucleic acid expression may be a useful predictive marker for ADI-PEG20 treatment efficacy.14
It must be noted that no grade 3–4 toxic effects could be directly attributed to ADI-PEG20 in melanoma patients.30
Therefore, this drug is likely be combined safely with other treatment modalities, such as chemotherapeutic or immunotherapeutic drugs.
ADI-PEG20 treatment also resulted in a dose-dependent decrease of the plasma level of nitric oxide,44
which is biosynthesized by inducible nitric oxide synthase and exerts growth-promoting and proangiogenic effects in tumors, including melanoma.45
This finding suggests that one of the mechanisms of action of ADI-PEG20, and possibly other arginine deprivation therapies, is inhibition of nitric oxide synthesis.
ADI-PEG20 is being tested in a clinical trial setting in other cancer types. After the first Phase I/II trial of ADI-PEG20 in patients with unresectable HCC, two parallel Phase II studies were conducted. In one trial, 80 patients who had unresectable metastatic HCC were treated with 80 IU/m2
or 160 IU/m2
of ADI-PEG20 weekly for up to 6 months.48
This trial yielded an objective response rate of 2.6% and a disease control rate (which included complete and partial responses and stable disease) of 65%. The median overall survival was 11.4 months. Two patients (2.6%) were withdrawn from the study because of immunogenic-related adverse events. Most toxic effects were grade 1–2 (with some grade 3), and there were no deaths attributed to ADI-PEG20. The common side effects were skin irritation or discomfort at the site of injection, fever, anemia, abnormal serum sodium and potassium levels, and decreased fibrinogen. Although there was grade 1–2 transient and reversible encephalopathy, it was not clear if the encephalopathy was related to the drug or the preexisting hepatic dysfunction. After approximately 60 days of treatment, the antibody titer of ADI-PEG20 was steadily increased, and serum arginine levels returned to baseline level.48
In the other Phase II study, 71 Asian patients with advanced HCC received weekly intramuscular injection of ADI-PEG20 at doses of 160 IU/m2
or 320 IU/m2
There were no complete or partial responses. The disease control rate was 31%, and the median overall survival was 7.3 months. The major treatment-related adverse events were grade 1–2 local and/or allergic reactions, hyperuricemia, pruritus, fatigue, hyperammonemia, fever, and diarrhea.49
A randomized double-blind Phase III trial of ADI-PEG20 in patients with advanced HCC is now underway (NCT 01287585). Phase II studies are ongoing in patients with ASS-negative MPM (NCT 01279967) and in patients with relapsed small-cell lung cancer (NCT 01266018).
Results of a Phase I study of recombinant human arginase I (rhArgI[Mn]-PEG5000) in 15 patients with advanced HCC were recently reported.50
Weekly doses of rhArgI(Mn)-PEG5000 ranged from 500–3500 IU/kg, and the maximum tolerated dose was determined to be 1600 IU/kg. The most common adverse effect was diarrhea (14%), and the dose-limiting toxic effect was grade 3 prolonged elevation of serum bilirubin in two patients who received doses of 2500 IU/kg. Among eight patients who were evaluated for tumor response, four (50%) had stable disease for more than 8 weeks. The median time to progression was 2.8 months, and the median overall survival was 5.1 months.
Co-ArgI-PEG has been produced under good manufacturing practice for a Phase I clinical study in advanced cancer (including melanoma) patients in the fall of 2012 (Frankel, unpublished data, 2012).