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Phase II Study of Phenylacetate in Patients With Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report

From the University of California Medical Center, San Francisco, CA; University of Texas Health Science Center, Dallas, TX; University of Texas, South Western, Dallas, TX; University of Washington Medical Center, Seattle, WA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; Montefiore University Hospital, Pittsburgh, PA; and Southwest Oncology Group Statistical Center, Seattle, WA.

Address reprint requests to Susan M. Chang, MD, 533 Parnassus Ave, Suite U107, San Francisco, CA 94143-0372; email changs@ neuro.ucsf.edu.

	ABSTRACT

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PURPOSE: To determine the response rate, time to treatment failure, and toxicity of phenylacetate in patients with recurrent malignant glioma and to identify plasma concentrations achieved during repeated continuous infusion of this agent.

PATIENTS AND METHODS: Adult patients with recurrent malignant glioma were treated with phenylacetate. The schedule consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off). A starting dose of 400 mg/kg total body weight per day of phenylacetate was initially used and subsequently changed to 400 mg/kg/d based on ideal body weight. Intrapatient dose escalations were allowed to a maximum of 450 mg/kg ideal body weight/d. Tumor response was assessed every 8 weeks. The National Cancer Institute common toxicity criteria were used to assess toxicity. Plasma concentrations achieved during the patients' first two 14-day infusions were assessed.

RESULTS: Forty-three patients were enrolled between December 1994 and December 1996. Of these, 40 patients were assessable for toxicity and response to therapy. Reversible symptoms of fatigue and somnolence were the primary toxicities, with only mild hematologic toxicity. Thirty (75%) of the 40 patients failed treatment within 2 months, seven (17.5%) had stable disease, and three (7.5%) had a response defined as more than 50% reduction in the tumor. Median time to treatment failure was 2 months. Thirty-five patients have died, with a median survival of 8 months. Pharmacokinetic data for this dose schedule showed no difference in the mean plasma concentrations of phenylacetate between weeks 1 and 2 or between weeks 5 and 6.

CONCLUSION: Phenylacetate has little activity at this dose schedule in patients with recurrent malignant glioma. Further studies with this drug would necessitate an evaluation of a different dose schedule.

	INTRODUCTION

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THE MEDIAN SURVIVAL for a patient with a progressive glioma, despite therapeutic modalities, including surgery, radiation therapy, and chemotherapy with accepted agents, such as nitrosoureas or procarbazine, remains dismal at 4 to 12 months. Experimental in vitro and in vivo data suggest that phenylacetate is a potentially active agent in the treatment of malignant glioma.^1-4 Phenylacetate is a product of phenylalanine metabolism and is normally present in the mammalian circulation at low concentrations. Phenylacetate conjugates to glutamine-associated nitrogen with a concomitant decrease in the levels of serum ammonia. Because of this mechanism, phenylacetate has been administered to children with inborn errors of urea synthesis for the treatment of hyperammonemia,^5,6 as well as in other clinical scenarios such as portal systemic encephalopathy⁷ and chemotherapy-induced hyperammonemia.⁸ The clinical experience among all age groups treated with acute or chronic administration of phenylacetate has shown that it is well tolerated. The majority of the side effects are reversible central neurotoxicity, characterized by irritability, lethargy, and somnolence. At lethal doses, coma can occur. Nausea and vomiting and peripheral edema have also been noted.

The long-term administration of phenylacetate has been shown to be not only well tolerated but also effective in reducing plasma glutamine levels.⁹ This is attractive for cancer intervention strategies, given the unique dependence of tumor cells on circulating glutamine. Glutamine is a substrate for energy in rapidly dividing normal and tumor cells and is a major nitrogen source for nucleic acid and protein synthesis.^10,11 Tumor cells, however, operate with limited levels of glutamine, rendering them more sensitive to glutamine depletion. Strategies using glutamine-depleting enzymes or antiglutamine metabolites have not been successful because of unacceptable toxicities.¹² Phenylacetate, in contrast, represents a relatively nontoxic approach to glutamine depletion that is clinically feasible.

Preclinical studies of phenylacetate have shown tumor growth suppression and the promotion of differentiation of various hematopoietic and solid tumors, including prostatic carcinoma and glioblastoma multiforme.^13-16 The conditions that demonstrated antitumor activity were continuous exposure to concentrations of at least 275 µg/mL for at least 2 weeks. The dose proposed in this study on the basis of phase I data^17,18 was found to be tolerable and associated with a plasma level shown to be necessary for growth arrest in in vitro tumor systems. The dose-limiting toxicity was neurotoxicity, which was rapidly reversible once the drug was discontinued. According to the phase I reports, antitumor activity was noted in one patient with a recurrent glioblastoma (stabilization of disease), and in one patient with a recurrent anaplastic astrocytoma (partial response). Given the preclinical data as well as some antitumor activity seen in the phase I study of phenylacetate, this phase II study was initiated.

We report on the efficacy of phenylacetate in patients with recurrent malignant glioma and present further information on the toxicity and plasma levels achieved at a dose schedule of a 2-week continuous infusion followed by a 2-week rest period.

	PATIENTS AND METHODS

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Patient Eligibility
Adult patients (minimum age, 16 years) with a recurrent malignant glioma after radiation therapy were eligible for the study. Patients with recurrent tumors whose initial pathologic diagnosis was glioblastoma multiforme, anaplastic astrocytoma, anaplastic mixed oligoastrocytoma, anaplastic oligodendroglioma, or malignant astrocytoma not otherwise specified were eligible. Pathology was verified by central review. For patients with glioblastoma multiforme, one prior chemotherapy regimen, administered either as an adjuvant or at recurrence, was allowed. For patients with other histologies, two prior regimens were allowed. Prior chemotherapy within less than 4 weeks (for non-nitrosourea agents) or 6 weeks (for nitrosoureas) of starting phenylacetate was not allowed. Biopsies were not required at recurrence.

Other required criteria for eligibility included radiographically measurable, progressive disease on computed tomographic or magnetic resonance imaging examination, obtained while the patient was receiving a stable dose of corticosteroids; a Southwest Oncology Group performance score of 0 to 2; and adequate hematologic, renal, and hepatic function. Informed consent was obtained from a patient or responsible relative. Radiation therapy had to have been completed more than 6 weeks before therapy with phenylacetate was started. Patients could not have received prior therapy with phenylacetate. Patients with any serious medical illness expected to compromise the ability to tolerate phenylacetate, including major difficulties with peripheral edema or severe cardiac disease, were excluded.

Drug Regimen
Phenylacetate (supplied by the National Cancer Institute) was administered as a continuous intravenous infusion initially at a dose of 400 mg/kg/d, but because of neurotoxicity, this regimen was modified to a dose of 400 mg/kg/d using the lesser of calculated ideal body weight (IBW) versus actual patient weight. A treatment cycle was 8 weeks in duration and consisted of a continuous infusion of phenylacetate for 14 consecutive days followed by a 14-day break, and then repetition of that pattern. If the first infusion was tolerated, intrapatient dose escalation was allowed to a maximum of 450 mg/kg IBW/d. Central venous access was required for the administration of phenylacetate, which could be given on an outpatient basis. Response was assessed after each 8-week cycle of therapy. Supportive measures such as corticosteroids or anticonvulsants were used as necessary. Administration of growth factors was not allowed to support the WBC count during the therapy, except that in the case of febrile neutropenia, use of growth factors was permissible at the discretion of the investigator. The National Cancer Institute common toxicity guidelines were used. Patients were removed from study because of progressive disease, unacceptable toxicity, or a delay of more than 28 days measured from the last day of the preceding infusion.

Dose Reductions
If any interruption of the phenylacetate infusion occurred, the rest period always started on day 15 regardless of the duration of the interruption period. Dose reductions by 50-mg/kg/d increments were specified for neurotoxicity, hematologic toxicity, and other toxicities. The minimum dose allowed was 250 mg/kg IBW/d. Grade 1 or higher nonreversible neurotoxicity, grade 3 or 4 nonreversible hematologic toxicity, a decrease of the absolute neutrophil count to less than 500/µL or platelets to less than 50,000/µL, or two episodes of febrile neutropenia were criteria for removal from the study.

Treatment Response
Patients were evaluated for tumor response every 8 weeks using clinical and radiographic criteria. Only one assessment of response was necessary for classification as stable disease or better. A complete response was defined by disappearance of all disease, and partial response was defined as a greater than 50% reduction in the manual cross-sectional area of the tumor. Progressive disease was defined as a greater than 25% increase in the size of the tumor or any new lesion. Stable disease was any other response. To be classified as responders by radiographic evaluation, patients must have been at least clinically stable and receiving at least the same or lower dose of dexamethasone than at the time of the baseline tumor measurement.

Statistical Considerations
The primary end point of the study was confirmed radiographic response (complete or partial) to phenylacetate. A true response rate to phenylacetate of 20% or more was considered of interest, whereas further testing was not to be pursued if the response rate was 5% or lower. The study design called for 20 patients to be accrued. If none of these 20 patients achieved a confirmed partial or complete response, the study would terminate with the conclusion that the regimen does not warrant further investigation. Otherwise, an additional 20 patients would be accrued. The study achieved the criterion for continuation after the first 20 patients were tested. This design had a significance level (probability of falsely declaring an agent with a 5% response probability to warrant further study) of .05 and power (probability of correctly declaring an agent with a 20% response probability to warrant further study) of 92%. Forty patients were sufficient to estimate the true response rate, toxicity rate, and 4-month treatment failure rate to within ±16% at most. Any toxicity that occurred with at least 5% probability was likely to be seen at least once (with an 87% chance).

Survival was measured from the day of registration onto the study until death from any cause. Time to treatment failure was measured from the day of registration onto the study until the date of first observation of progressive disease, death from any cause, or discontinuation of treatment. The distributions of survival and treatment failure were estimated by the method of Kaplan and Meier.¹⁹

Pharmacokinetic Studies and Analysis
Pharmacokinetic data were obtained for the first cycle of therapy. Blood samples were obtained before the infusion was given on days 1 and 29. Additional samples were drawn on days 7, 14, 36, and 42. If the infusion was discontinued for toxicity, blood was obtained for analysis both at the end of the infusion and when symptoms had resolved. Reverse-phase high-performance liquid chromatography was used for the detection of phenylacetate and phenylglutamine, as previously described.¹⁸

	RESULTS

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Patients
From December 1994 to December 1996, 43 patients were enrolled. Three were ineligible because of ineligible pathology (one patient) or insufficient time between prior radiation (one patient) or chemotherapy (one patient) and treatment with phenylacetate. Clinical characteristics of the eligible patients are listed in Table 1.

Response
All eligible patients were assessable for response. The median time to treatment failure was 2 months for all patients (95% confidence interval, 1 to 2 months). There were no complete responses. Three (7.5%) of the 40 patients had a partial response (95% confidence interval, 2% to 20%). Seventy-five percent (30 of 40 patients) failed treatment by 8 weeks, and 17.5% had stable disease (95% confidence interval, 7% to 33%). Of the 10 patients with stable disease or better, six failed treatment within 3.5 months and three failed at 5.5, 9.5, and 12.0 months. One responding patient remained on study for 24 months. Thirty-five patients have died, with a median survival of 8 months (95% confidence interval, 6 to 9 months). Figures 1 and 2 show the Kaplan-Meier curves for treatment failure and survival.

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of time to treatment failure in assessable patients treated with phenylacetate.

View larger version (12K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of overall survival in assessable patients treated with phenylacetate.

Toxicity
All 40 eligible patients were assessable for toxicity. Treatment was generally well tolerated. One patient died of a central venous catheter–related infection and sepsis. There were no grade 4 toxicities. In Table 2 are listed the most common toxicities associated with phenylacetate administration. Fatigue, reversible disorientation, nausea, and peripheral edema were the side effects noted most frequently. Three patients were removed from study because of toxicity.

Pharmacokinetic Data
For the patients who received a dose of phenylacetate at 400 mg/kg/d based on their actual weight (four patients) or based on their IBW (21 patients), the average concentration of phenylacetate and its metabolite phenylacetylglutamine during week 1 was 164 µg/mL (± 61 µg/mL SD) and 135 µg/mL (± 42 µg/mL SD), respectively. For 18 patients who received 400 mg/kg IBW/d of phenylacetate during week 2, the average phenylacetate concentration was 160 µg/mL (± 82 µg/mL SD). There was no apparent evidence of autoinduction of the metabolism of phenylacetate during these 2 weeks for these patients. Eight patients continued on the same dose schedule during weeks 5 and 6 with an average phenylacetate concentration of 168 µg/mL (± 113 µg/mL SD). The 2-week rest period did not seem to alter the clearance of phenylacetate. Six patients received an initial dose of 400 mg/kg IBW/d at weeks 1 and 2 and then received an escalated dose of 450 mg/kg IBW/d at weeks 5 and 6. For these patients, the average phenylacetate concentration for weeks 1 and 2 was 156 µg/mL (± 44 µg/mL SD) and for weeks 5 and 6 was 195 µg/mL (± 77 µg/mL SD), confirming the higher concentrations achieved at this dose level.

Unfortunately, owing to the ambulatory nature of the study and the time at which plasma samples were drawn in relationship to the onset and resolution of symptoms of neurotoxicity, definite correlations could not be made. For example, one of the initial patients dosed at 400 mg/kg based on his total body weight complained of "somnolence and trouble walking." The infusion was stopped and later restarted at a dose of 350 mg/kg. A phenylacetate level drawn 30 minutes after discontinuation of the infusion was 557 µg/mL. This was well below the established level associated with neurotoxicity (800 µg/mL), but it certainly could have been much higher if drawn during the infusion. Additionally, after patients were treated at the dose based on IBW rather than total body weight, the infusions were generally well tolerated, and patients were discontinued from therapy mainly because of lack of efficacy rather than toxicity.

	DISCUSSION

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In vivo and in vitro studies have shown that phenylacetate can inhibit tumor growth while sparing normal tissue and can induce phenotypic reversion and differentiation of malignant cells.^20,21 The mechanisms of phenylacetate action on tumor cell biology are unknown, and several have been postulated. The depletion of glutamine, a major nitrogen source for nucleic acid and protein synthesis, is thought to be one mechanism. Tumor cells operate at limiting levels of glutamine and are potentially more sensitive to glutamine depletion.^10,11 Inhibition of the mevalonate pathway in glioma cells by the inhibition of sterol and isoprenoid synthesis may be another mechanism that affects the growth of tumor cells.²² Other potential mechanisms are modulation of gene expression and subsequent effects on cell phenotype. The ras gene family is thought to play a central role in signal transduction and maintenance of the malignant phenotype. Shack et al²⁰ showed that phenylacetate suppressed the growth of ras-transformed cells, through interference with p21^ras isoprenylation, with subsequent phenotypic reversion. Gorospe et al¹³ also demonstrated enhanced expression of the inhibitor of cyclin-dependent kinases, p21^Waf1/Cip1, when breast carcinoma cells were exposed to phenylacetate, resulting in growth arrest. The bcl-2 oncogene has been shown to inhibit apoptosis. Using cell culture and animal model assays, Adam et al²³ demonstrated that there is downregulation of Bcl-2 oncoprotein synthesis after exposure to phenylacetate. Both a differentiation process and apoptotic death were shown. Another interesting effect may be on lipid metabolism and cell growth. Pineau et al²⁴ demonstrated the activation of the peroxisomal proliferator–activated nuclear receptor, a transcription factor shown to regulate the expression of genes controlling lipid metabolism.

Early phase I clinical data^17,18 showed that the drug was well tolerated and that the dose-limiting toxicity was rapidly reversible neurotoxicity. This occurred consistently when the peak serum levels of phenylacetate exceeded 800 µg/mL. Two of 13 patients with primary brain tumors had either a decrease in tumor size or stabilization of growth. Because of the laboratory and early clinical data suggesting activity in malignant glioma as well as the tolerability of the drug, this phase II study was initiated.

Despite the theoretical rationale for the antitumor effect of phenylacetate and preclinical data supporting its efficacy in animal model systems, our results using comparable dosing schedules failed to demonstrate a substantial therapeutic efficacy in patients with recurrent malignant glioma. The time to treatment failure was short, and the response rate was only 7.5%. Disease stabilization was seen in an additional 17.5% of patients. There were no complete responses. Although this agent readily penetrates into the CSF,²⁵ the concentrations achieved at this dose schedule may partially account for the lack of significant activity. The average plasma concentration of phenylacetate achieved at 400 mg/kg IBW/d was 164 µg/mL, somewhat lower than the preclinical concentration of 275 µg/mL that demonstrated antitumor activity. The clinical relevance of this concentration is unclear, because the three patients who had partial responses in this study had plasma concentrations of phenylacetate ranging from 128 to 406 µg/mL, respectively. Similarly, Thibault et al^17,18 reported steady-state plasma concentrations of 108 and 135 µg/mL in the two patients who achieved responses in their study.

Phenylacetate is conjugated with glutamine by the hepatic enzyme phenylacetyl-coenzyme A:glutamine acyltransferase to yield the metabolite phenylacetylglutamine.²⁶ It is reasonable to speculate that corticosteroids and/or anticonvulsants may have altered the clearance of phenylacetate. The majority of the patients in this trial were receiving corticosteroids and/or anticonvulsants. Therefore, we were not able to examine the effects of anticonvulsants on the elimination of phenylacetate. However, Thibault et al¹⁸ found no association between specific drugs, including anticonvulsants, and an increase in the clearance of phenylacetate. The levels of phenylacetate achieved (164 µg/mL) in this study are not markedly different from those previously reported. Thibault et al¹⁸ reported serum concentrations of phenylacetate ranging from 80 to 100 164 µg/mL in a patient receiving a continuous infusion of phenylacetate at a dose of 250 mg/kg/d. This equates proportionally to 128 to 160 µg/mL at 400 mg/kg/d. Thibault also found average concentrations of 171 ± 58 164 µg/mL in 18 patients receiving 350 mg/kg IBW/d of phenylacetate as a continuous infusion (A. Thibault, personal communication, September 1998).

Plasma concentrations remained relatively stable over the treatment courses. Autoinduction of the metabolism of phenylacetate has been previously reported.¹⁸ The difference in sampling times may account for our not observing an initial decrease. The 2-week rest period did not affect the subsequent plasma concentrations of the drug in patients receiving the same dose for the second 2-week infusion.

Although the drug was well tolerated with expected side effects, further studies of single-agent phenylacetate using this treatment schedule in patients with recurrent malignant glioma are not warranted. A more intense treatment schedule of 12 days on followed by 2 days off is currently being evaluated. Other potential roles for this agent include the evaluation of its ability to modulate radiation response, as demonstrated in vitro,²⁷ and the use of an oral analog, phenylbutyrate.²⁸

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

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Submitted June 5, 1998; accepted November 3, 1998.

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