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Journal of Clinical Oncology, Vol 19, Issue 5 (March), 2001: 1312-1319
© 2001 American Society for Clinical Oncology

Phase I Trial of 40-kd Branched Pegylated Interferon Alfa-2a for Patients With Advanced Renal Cell Carcinoma

By Robert J. Motzer, Ashok Rakhit, Michelle Ginsberg, Karen Rittweger, Jacqueline Vuky, Richard Yu, Scott Fettner, Leon Hooftman

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, and Department of Medical Imaging, Memorial Sloan-Kettering Cancer Center, New York, NY; and Hoffmann-La Roche, Inc, Nutley, NJ, and Welwyn, United Kingdom.

Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Pegylated (40 kd) interferon alfa-2a (IFN{alpha}2a) (PEGASYS, Hoffman-La Roche, Nutley, NJ; PEG-IFN) is a modified form of recombinant human IFN{alpha}2a with sustained absorption and prolonged half-life after subcutaneous administration. A phase I study of PEG-IFN with pharmacokinetic and pharmacodynamic evaluations was conducted in previously untreated patients with advanced renal cell carcinoma (RCC).

PATIENTS AND METHODS: Twenty-seven patients were enrolled onto cohorts of three or six patients. PEG-IFN was administered on a weekly basis by subcutaneous injection. The dose was escalated from 180 µg/wk to a maximum of 540 µg/wk in 90-µg increments. Serial venous blood samples were drawn to assess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2'-5' oligoadenylate synthetase (OAS).

RESULTS: The maximum-tolerated dose was determined as 540 µg/wk, because two patients experienced dose-limiting toxicity within 28 days of starting treatment. One developed serum grade 3 ALT elevation, and a second developed grade 3 fatigue. Six patients were treated at 450 µg/wk without dose-limiting toxicity. Over the course of treatment, the side-effect profile was mostly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite. Five patients (19%) achieved a partial response. The mean maximum serum concentration increased from 5.0 to 27 ng/mL, and mean area under the curve increased from 247 to 2,981 ng/h/mL, with dose escalation from 180 µg/wk to 540 µg/wk. Serum concentration of PEG-IFN was sustained at close to peak during the dosing interval, and steady-state was achieved in approximately 5 weeks. The immunologic surrogates, neopterin and OAS, were induced at all doses with a sustained concentration profile similar to PEG-IFN.

CONCLUSION: PEG-IFN is a modified form of IFN{alpha}2a with distinct pharmacokinetic advantages and immunomodulatory and antitumor activity for patients with advanced RCC. A dose of 450 µg/wk by subcutaneous administration was determined as a suitable dose for further study. PEG-IFN is more convenient to administer than IFN{alpha} and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity of PEG-IFN will be further assessed in clinical trials and compared with IFN{alpha}.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ANTITUMOR ACTIVITY of interferon against renal cell carcinoma (RCC) was initially reported in 1983 with a partially purified human recombinant human interferon alfa (IFN{alpha}) preparation.1,2 Two preparations, recombinant IFN{alpha}2a (Roferon-A; Hoffmann-La Roche Inc, Nutley, NJ) and recombinant IFN{alpha}2b (Intron A; Schering Corp, Kenilworth, NJ), are commercially available and represent standard preparations used in clinical practice. The overall tumor response rate in 1,042 patients treated with either of these preparations was 12%.3 Both of the commercially available IFN{alpha} preparations are characterized by a relatively short plasma half-life and require frequent dosing.

IFN{alpha}2a is chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance pharmacokinetic characteristics and reduce immunogenicity. The first generation of pegylated IFN{alpha}2a demonstrated a greater than two-fold increase in serum half-life as a result of this chemical modification when evaluated against IFN{alpha} in healthy subjects.4 The second generation of pegylated IFN{alpha}2a, PEGASYS (PEG-IFN), is chemically modified by the covalent attachment of a branched methoxy-PEG moiety of larger molecular weight (40 kd) than that attached to the first-generation (5 kd linear PEG) pegylated IFN{alpha}2a. Unlike a prodrug, this covalent attachment in PEGASYS is expected to remain intact and act as an analog of IFN{alpha}2a.

PEG-IFN is expected to have major improvement in pharmacokinetic properties and allow delivery of a more convenient once-weekly dose of IFN{alpha}2a. The rationale for weekly dosing was confirmed by pharmacokinetic and pharmacodynamic data obtained from animals (rat and monkey) and a phase I study in healthy volunteers. A phase II trial for patients with chronic active hepatitis suggested a suitable dose of 180 µg given once weekly.5 Experiments with A-498–bearing nude mice showed that PEG-IFN was more active than IFN{alpha} in inhibiting renal cell tumor growth (unpublished data). Herein, we report on a phase I trial of PEG-IFN for patients with advanced RCC. Serial venous blood samples were drawn to assess concentrations of PEG-IFN and two immunologic surrogates, neopterin and 2'-5' oligoadenylate synthetase (OAS).6,7


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between June 1998 and May 1999, 27 patients with advanced RCC entered this trial, which was approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center (MSKCC). Eligibility criteria included age >= 18 years; informed consent; measurable disease; Karnofsky performance status >= 80%; and adequate hematologic, renal, and hepatic function. The latter criteria included the following: WBC count >= 3,000 cells/mm3, granulocytes >= 1,500 cells/mm3, platelet count >= 100,000 cells/mm3, and hemoglobin >= 10 g/dL; serum bilirubin <= 1.5 times upper range of normal and transaminase levels and alkaline phosphatase <= 2.5 times upper range of normal; and a serum creatinine concentration of <= 1.5 times normal. Exclusion criteria included active brain metastases, history of psychiatric disabilities, history of seizure requiring anticonvulsant therapy, clinically significant cardiac abnormalities, or poor medical condition because of nonmalignant organ or systemic disease. Prior chemotherapy, immunotherapy, or hormonal therapy for RCC was not allowed.

Dose and Treatment Schedule
PEG-IFN was supplied by Hoffmann-La Roche Inc, Nutley, NJ, as a ready-to-use solution in single-dose glass vials containing 90, 180, 270, 360, 450, or 540 µg per 1 mL of solution in 2-mL-size vials. PEG-IFN was administered by subcutaneous injection once weekly for 24 weeks. Each cycle lasted 28 days and consisted of outpatient subcutaneous injections on days 1, 8, 15, and 22. On the basis of results of tumor size assessment after cycle 2, patients with stable disease or greater response received additional cycles of therapy until evidence of progression or unacceptable toxicity.

Cohorts were treated in sequence with a fixed dose of PEG-IFN at planned dose levels of 180, 270, 360, 450, and 540 µg. Cohorts included three patients per dose level. When one patient or none had a dose-limiting toxicity during the first 28 days of therapy, then three patients were added to that cohort. If no additional patients experienced dose-limiting toxicity, accrual continued at the next higher dose level. If two or more patients in a full cohort of six developed dose-limiting toxicity, accrual stopped, and this dose was considered the maximum-tolerated dose (MTD). Dose-limiting toxicity was defined as grade 3 or 4 nonhematologic toxicity except fever, chills, and flu-like symptoms, grade 3 or 4 thrombocytopenia, and grade 4 neutropenia.

Patients were continued at the assigned dose for the duration of therapy, with dose modification made according to toxicity. Treatment was withheld for grade 3 or 4 nonhematologic toxicity, then restarted at the next lower dose when toxicity improved to grade 1 or better; it was discontinued at the discretion of the treating physician if grade 4. Treatment was withheld for grade 3 or 4 neutropenia or thrombocytopenia, then restarted at the next lower dose level when toxicity had improved. For grade 2 nonhematologic toxicity, treatment could be withheld until grade 1 or better and then restarted at the same dose.

Patients were monitored with regular physical examinations, complete blood count, and serum chemistry. Each patient had a reassessment of measurable disease after 8 weeks of treatment, then every 8 weeks thereafter. Response was assessed according to World Health Organization criteria and toxicity according to National Cancer Institute common toxicity criteria.

Pharmacodynamic and Pharmacokinetic Sample Collection
Serial venous blood samples (3 mL) for serum PEG-IFN determination were drawn by direct venipuncture or through an indwelling catheter in the arm contralateral to the site of subcutaneous injection. Sera were stored at -20°C until assay. Serial venous blood samples were collected in a similar manner for immunologic marker (neopterin and OAS) determinations. Serum samples were obtained before treatment and 6, 48, 72, 96, 120, 144, and 168 hours after injection on weeks 1 and 25 of treatment. Serum samples were also obtained before treatment on day 1 of weeks 5, 9, 13, 17, 21, and 25.

Measurement of Serum PEG-IFN
The assay developed at Hoffmann-La Roche is a quantitative sandwich enzyme-linked immunoassay (ELISA) that uses two distinct mouse monoclonal antihuman IFN{alpha} antibodies that recognize different epitopes of IFN{alpha}2a. In a one-step immunoreaction, PEG-IFN is bound to the peroxidase-conjugated antihuman IFN{alpha} antibody. The complex binds via the capture of anti-IFN{alpha} antibody to the multiprotein layer–covered surface of the microtiter plate. Unbound complexes are removed by washing. Tetramethylbenzidine substrate solution is then added. Conversion of tetramethylbenzidine by peroxidase to a colored product allows the reaction to be observed spectrophotometrically, as the absorbance at 450 nm is directly correlated to the concentration of PEG-IFN in the sample. The analytic sensitivity is 125 pg/mL of PEG-IFN in human serum. The intra-assay variation of the quality control samples is between 0.8% and 12.0%, whereas the interassay variation was between 4.5% and 18.3%. PEG-IFN was stable in serum over three freeze-thaw cycles. Samples stored at -20°C were stable over 5 months.

Measurement of Serum Neopterin
The serum concentration of neopterin was measured with a commercial radioimmunoassay kit (HENNING test, BRAHMS Diagnostica GmbH, Berlin, Germany) consisting of a single incubation step and using a double-antibody phase separation technique. In brief, 125I-neopterin tracer and the premix of the first antibody (specific to neopterin) and a second antibody (antisheep immunoglobulin G) were pipetted to the study sample as described in the kit. After being thoroughly mixed, the samples were incubated in darkness for 1 hour at between 20°C and 25°C. When the immunoreaction was complete, the tubes were centrifuged, the supernatants aspirated, and the pellets counted in a gamma-counter for 5 minutes. The amount of radioactivity remaining in the pellet was inversely proportional to the concentration of the neopterin found in the sample. The limit of quantitation was 3 nmol/L with a 50-µL sample. The intra-assay and between-assay variabilities ranged from 1.8% to 6.5%.

Measurement of OAS
The OAS enzyme activity in serum samples was measured by radioimmunoassay with 125I-labeled tracer and a second antibody used as the bound/free separating agent (Eiken Chemical Co, Tokyo, Japan). First, the OAS in the sample was adsorbed and activated by using poly (I) poly (C) agarose. OAS was produced during a 1-hour reaction by using adenosine triphosphate as substrate. Next, a mixture of 125I-labeled 2',5'-oligoadenylate, anti-2',5'-oligoadenylate antiserum and the second antibody was added. The mixture was incubated and separated by centrifugation. The supernatant was removed by aspiration to perform the bound/free separation, and the radioactivity of the precipitate was measured in a gamma counter. The limit of quantitation in serum was 240 pM/h. The intra-assay variability ranged between 3.6% and 11.7%. The samples were stable for at least 2 months at -20°C and more than 6 months at -70°C.

Measurement of Serum Antibody to PEG-IFN
Anti-IFN{alpha} antibodies were measured in serum at baseline and periodically during treatment-free follow-up by using a one-step immunoreaction ELISA method developed at Hoffmann-La Roche. The anti-IFN{alpha} antibody ELISA is based on the double-antigen enzyme immunoassay system. In a one-step procedure, microtiter plates coated with recombinant IFN{alpha} are incubated with sample or standard and the IFN{alpha} peroxidase conjugate. Antibodies are captured by the immobilized IFN{alpha} and detected by means of their free combining site to the IFN{alpha} conjugate. After the washing step, the peroxidase bound to the complex is reacted with tetramethylbenzidine as a substrate, and the color developed is determined photometrically with an ELISA plate reader. The developed color is proportional to the concentration of anti-IFN{alpha} antibodies. The sensitivity limit of the assay is 0.24 U/mL, with a measurement range of 0.24 to 10.5 U/mL. Interassay variability was 6.5% to 14%. The recovery of spiked anti-IFN{alpha} antibody standard in human sera was more than 94%.

Pharmacokinetic and Pharmacodynamic Data Analysis
Serum concentration (or activity)-versus-time data were analyzed for PEG-IFN, neopterin, and OAS by noncompartmental pharmacokinetic methods. The highest observed concentration and the corresponding sampling time were defined as Cmax and tmax, respectively. The area under the concentration-versus-time curve (AUC(0-{tau})) was calculated by use of the trapezoidal rule over the dosing interval of 1 week.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Twenty-seven patients were treated with PEG-IFN ( Table 1). The median age was 62 years. Fourteen (54%) had a prior nephrectomy. Assignment to MSKCC risk group on the basis of pretreatment clinical features8 showed that all but two patients had favorable- or intermediate-risk clinical features.


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  		Table 1. Patient Characteristics
 
Treatment Administered and Toxicity
The dose was escalated among cohorts from 180 to 540 µg/wk. Six patients were treated at all dose levels except the 270-µg/kg level, which included three patients. The median duration of therapy given to 27 patients was 6 months (range, 1 to 18 or more months), and three patients remain on treatment with PEG-IFN.

Dose-limiting toxicity was defined according to the first 28 days of therapy. One of six patients treated at 180 µg/wk had grade 4 neutropenia. Three patients, six patients, and six patients were treated at 270, 360, and 450 µg/wk, respectively, without dose-limiting toxicity. Two patients experienced dose-limiting toxicity at the dose of 540 µg/wk, which became the MTD. One patient had grade 3 serum ALT elevation, and the other developed grade 3 fatigue within 28 days of starting treatment.

Over the course of treatment, the side-effect profile was mostly mild to moderate in intensity. Adverse events included fatigue, fever, headache, myalgia, nausea, and decreased appetite ( Table 2). Grade 3 or 4 toxicities that occurred within (dose-limiting toxicity) or after 28 days of therapy were fatigue, headache, hepatic toxicity, and leukopenia. Eleven patients required dose reductions, including five of six patients treated at the 540 µg, two patients treated at the 450 µg, one patient at the 270 µg, and three patients at the 180 µg/wk dose level. One patient was removed from study after 15 months of treatment because of toxicity in the absence of progressive disease. This patient developed idiopathic thrombocytopenia, which improved on cessation of PEG-IFN treatment plus treatment with oral corticosteroids.


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  		Table 2. Toxicity According to Dose of PEG-IFN
 
Response and Survival
All patients were evaluated for tumor response. Five patients (19%) in 180, 270, 450, and 540 µg groups achieved a partial response ( Table 3). One patient treated with 180 µg had complete resolution of lung metastases and partial regression of the primary renal tumor. She underwent a posttreatment nephrectomy but progressed with a solitary brain metastasis 12 months after start of therapy. This was resected, and the patient remains disease-free nearly 1 year after nephrectomy. A second patient with a partial response (at 450 µg) progressed after 13 months of therapy. Three patients with partial response (one at 270 µg and two at 540 µg) continue treatment and remain progression free at more than 13 and 19 months. Four of five responders had their primary kidney tumor in place. One had favorable-risk and four had intermediate-risk features by MSKCC model.8


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  		Table 3. Characteristics of Five Patients With Partial Response
 
Best response in the remaining patients was stable disease for 13 (48%) and progression for nine patients (33%); all patients with a best response of stable disease have since progressed. Eighteen of 27 patients remain alive, including one who is disease free. The proportion of patients alive at 6 and 12 months is 89% and 78%, respectively. The proportion of patients who are alive and progression free at 6 and 12 months is 37% and 22%, respectively.

Pharmacokinetics
Serum concentration of PEG-IFN increased rapidly after the subcutaneous injection, with measurable concentrations appearing at 6 hours, the first time point of determination ( Table 4 and Fig 1). Cmax appeared as early as 48 hours and was sustained at close to peak from day 3 (48 hours) to day 8 (168 hours), the time of next dose. Both peak serum concentration and AUC during dosing interval (AUC0-{tau}) on week 1 increased with dose (180 µg v 540 µg dose, mean ± SD: Cmax, 5 ± 3 v 27 ± 22 ng/mL; AUC0-{tau}, 247 ± 126 v 2,981 ± 2,620 ng/h/mL). There was large interpatient variability in levels of PEG-IFN at all doses.


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  		Table 4. Mean ± SEM Pharmacokinetic Parameters of PEG-IFN*
 


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  		Fig 1. Mean pegylated PEG-IFN concentrations versus time—week 1 (data points represent timing of sample collection).

 
Serum concentrations of PEG-IFN increased with chronic dosing ( Fig 2). There was a three- to five-fold serum concentration accumulation of PEG-IFN on chronic weekly dosing. Trough levels, however, were found to maintain a steady-state starting at approximately week 5.



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  		Fig 2. Predose levels of PEG-IFN on chronic dosing. Mean data were collected from at least two patients (data points represent timing of sample collection).

 
Pharmacodynamics
Significant induction of both neopterin and OAS was observed at all doses studied ( Figs 3 and 4). The evaluation of percentage of changes in serum concentrations and activities of both surrogates over time showed profiles similar to concentration profiles of PEG-IFN. Maximum induction was observed starting at approximately 48 hours and maintained during the rest of the dosing interval ( Table 5). There was a trend for increased induction of neopterin with dose, which seemed to reach a plateau at doses of 450 and 540 µg. Induction of OAS was comparable at doses ranging from 180 to 450 µg/wk, and induction at 540 µg was higher than that at 450 µg. The interpatient variability was large for both surrogates. Immunologic induction was maintained on chronic dosing over 6 months, with little accumulation of serum markers after week 1 ( Figs 5 and 6).



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  		Fig 3. Mean percentage of change in neopterin concentrations versus time—week 1.

 

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  		Table 5. Mean ± SEM Pharmacodynamic Parameters for Neopterin and 2',5'-OAS After Various Doses of PEG-IFN (week 1 unless otherwise specified)
 


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  		Fig 5. Mean percentage of change in neopterin troughs. Mean data are presented only when data were available from at least two patients and no dosing changes occurred.

 


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  		Fig 4. Mean percentage of change in OAS activity versus time—week 1.

 


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  		Fig 6. Mean percentage of change in OAS troughs. Mean data are presented only when data were available from at least two patients and no dosing changes occurred.

 
Concentration–Toxicity Outcome Relationship
Predose (or steady-state) serum concentrations of PEG-IFN were evaluated for their relationship with selected laboratory abnormalities. Figures 7 and 8 demonstrate the relationship between PEG-IFN steady-state concentration level and the worst laboratory test results in National Cancer Institute common toxicity criteria grading for serum ALT levels and neutrophil counts during the postbaseline study period. Data points are connected on the basis of median bands by using a cubic spline to depict the relationship for each laboratory parameter. The graphs show that higher PEG-IFN concentration was associated with worse toxicities. Similar observations were made between trough PEG-IFN concentrations and several other selected laboratory parameter–based adverse events (WBC, AST). The median drug levels for grades 0 to 3 neutropenia were 11, 39.5, 64, and 51 ng/mL, respectively, suggesting higher grades of neutropenia related to increased systemic exposure of PEG-IFN. Corresponding values for grades 0 to 3 serum ALT elevation were 5, 39.5, 46, and 63 ng/mL.



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  		Fig 7. A median band using a cubic spline demonstrating relationship between serum trough concentrations of PEG-IFN and outcomes of liver function (serum ALT).AQ

 


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  		Fig 8. A median band using a cubic spline demonstrating relationship between serum trough concentrations of PEG-IFN and outcomes of neutropenia.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Two recent randomized trials reported a small but significant improvement in survival with IFN{alpha} therapy for patients with advanced RCC.9,10 In one, IFN{alpha} was compared with medroxyprogesterone and resulted in improvement in a median survival of 3 months.9 In the second, IFN{alpha} plus vinblastine was compared with vinblastine alone, and the combination showed a benefit in a median survival of 6 months for IFN{alpha} therapy.10 Although the response rate is low and the survival benefit is modest, IFN{alpha} represents a systemic therapy shown to increase survival in phase III randomized trials for this highly refractory malignancy. Therefore, the investigation of IFN{alpha} analogs such as PEG-IFN, with a potentially improved therapeutic or safety profiles, is warranted for patients with advanced RCC.

This phase I trial established the MTD and toxicity profile of PEG-IFN administered as a once-weekly subcutaneous injection to patients with advanced RCC. The toxicity profile was consistent with that of IFN{alpha} therapy without any toxicity unique to the pegylated analog. Dose-limiting toxicities were neutropenia, elevated liver function values, and fatigue. Two patients experienced dose-limiting toxicity at a dose of 540 µg/wk, and this was defined as the MTD. Five of six patients treated at this dose level required dose reduction at some time during treatment. None of six patients treated at 450 µg/wk had dose-limiting toxicity, and this dose is recommended for subsequent trials. Antitumor activity against metastatic RCC was identified in 19% of the patients who achieved a partial response. Several responses remain continuous, and 78% of patients were still alive at 1 year of treatment in this study. The efficacy and toxicity of PEG-IFN is being assessed further in clinical trials and compared with IFN{alpha}.

Subcutaneous administration of PEG-IFN led to rapid absorption from the injection site, with maximum serum concentrations reached at approximately 48 hours. Serum concentration remained close to peak level for the next 5 days of the dosing interval, providing a close to sustained-release delivery of PEG-IFN for 1 week. As the dose was increased for subsequent patient cohorts, both peak serum drug concentration and AUC(0-{tau}) increased with dose, suggesting a linear pharmacokinetics of PEG-IFN at the dose range studied. On repeated administration, serum predose levels of PEG-IFN increased on multiple dosing with an accumulation factor of 2.5 (range, 1 to 5). The predose levels seemed to reach a steady-state by approximately week 5 and then maintained for more than 6 months when monitored in patients with stable disease or a partial response.

Serum profiles of neopterin and OAS increased gradually after drug administration, with peak concentrations appearing at approximately 48 hours, and maintained levels close to peak for the remainder of the dosing interval. Induction of serum neopterin was dose dependent across lower dose levels but did not increase as dose was escalated from 450 to 540 µg/wk. OAS activity was increased at all doses starting at 180 µg, but induction was not increased with dose in the dose range of 180 to 450 µg. There was maintenance of immunologic induction on long-term treatment, which may be important to successful immunotherapy. The PEG-IFN data contrast with prior experience with interleukin-12, a cytokine we recently studied in patients with advanced RCC.11 Loss of interleukin-12 activity on multiple dosing was demonstrated because of potential immunologic feedback inhibition of cytokine response.12 No such feedback inhibition was observed on long-term treatment with PEG-IFN, as determined by maintenance of neopterin induction and OAS concentrations during 6 months of treatment.

The relationship between serum concentration of PEG-IFN and toxicity was also assessed. Drug exposure–related toxicity was observed for reductions in WBC and elevations of liver transaminases, suggesting a predictable relationship between serum drug concentration and these adverse events. Despite a limited number of patients studied, a trend was observed in this phase I study for these adverse events. In contrast, steady-state serum concentrations of PEG-IFN in five patients with partial response had wide ranges, with median concentration of 45 ng/mL ranging from 17 to 63 ng/mL. Considering the large range of effective drug concentrations and predictable adverse events with increased serum drug concentration, we hypothesize that a therapeutic concentration of less than 60 ng/mL may provide optimal safety and efficacy for this drug in future studies.

In summary, PEG-IFN is a modified form of IFN{alpha} with distinct pharmacokinetic advantages, a tolerable and predictable side-effect profile, and documented immunomodulatory and antitumor activity for patients with advanced RCC. PEG-IFN is more convenient to administer than IFN{alpha} and has potential for increased efficacy, less toxicity, or both. The efficacy and toxicity in patients with advanced RCC will be further addressed in multicenter phase II and III trials.


   ACKNOWLEDGMENTS
 
We thank Lucy Dantis and Patricia Fischer for nursing support and Carol Pearce for her review of the manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Quesada JR, Swanson DA, Trindade A, et al: Renal cell carcinoma: Antitumor effects of leukocyte interferon. Cancer Res 43: 940-943, 1983[Abstract/Free Full Text]

2. deKernion JB, Sarna JB, Fignlin R, et al: The treatment of renal cell carcinoma with human leukocyte alpha-interferon. J Urol 130: 1063-1066, 1983[Medline]

3. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 163: 408-417, 2000[Medline]

4. Nieforth KA, Nadeau R, Patel I, et al: Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol modified derivative in healthy subjects. Clin Pharmacol Ther 59: 636-646, 1996[Medline]

5. Reindollar R, Purdum P, Thompson E, et al: Community-based treatment of patients with chronic hepatitis C using peginterferon {alpha}-2a (PEG-IFN): One center’s experience. Hepatology 30: 615A, 1999 (abstr)

6. Huber C, Batchelor JR, Fuchs D, et al: Immune response-associated production of neopterin: Release from macrophages primarily under control of interferon-gamma. J Exp Med 160: 310-316, 1984[Abstract/Free Full Text]

7. Samuel C: Antiviral actions of interferon. Virology 183: 1-11, 1991[Medline]

8. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17: 2530-2540, 1999[Abstract/Free Full Text]

9. Medical Research Council and Collaborators: Interferon-alpha and survival inmetastatic renal carcinoma: Early results of a randomised controlled trial. Lancet 353: 14-17, 1999[Medline]

10. Pyrhonen S, Salminen E, Ruutu M, et al: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in advanced renal cell carcinoma. J Clin Oncol 17: 2859-2867, 1999[Abstract/Free Full Text]

11. Motzer RJ, Rakhit A, Schwartz LH, et al: Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res 4: 1183-1191, 1998[Abstract]

12. Rakhit A, Yeon MM, Ferrante J, et al: Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice. Clin Pharmacol Ther 65: 615-629, 1999[Medline]

Submitted August 8, 2000; accepted November 9, 2000.


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R. J. Motzer, A. Rakhit, J. Thompson, H. Gurney, P. Selby, R. Figlin, S. Negrier, S. Ernst, M. Siebels, M. Ginsberg, et al.
Phase II trial of branched peginterferon-{alpha} 2a (40 kDa) for patients with advanced renal cell carcinoma
Ann. Onc., November 1, 2002; 13(11): 1799 - 1805.
[Abstract] [Full Text] [PDF]

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R. Bukowski, M. S. Ernstoff, M. E. Gore, J. J. Nemunaitis, R. Amato, S. K. Gupta, and C. L. Tendler
Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study
J. Clin. Oncol., September 15, 2002; 20(18): 3841 - 3949.
[Abstract] [Full Text] [PDF]

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S. Tedjarati, C. H. Baker, S. Apte, S. Huang, J. K. Wolf, J. J. Killion, and I. J. Fidler
Synergistic Therapy of Human Ovarian Carcinoma Implanted Orthotopically in Nude Mice by Optimal Biological Dose of Pegylated Interferon {alpha} Combined with Paclitaxel
Clin. Cancer Res., July 1, 2002; 8(7): 2413 - 2422.
[Abstract] [Full Text] [PDF]

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