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Journal of Clinical Oncology, Vol 20, Issue 18 (September), 2002: 3841-3949
© 2002 American Society for Clinical Oncology

Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study

By Ronald Bukowski, Marc S. Ernstoff, Martin E. Gore, John J. Nemunaitis, Robert Amato, Samir K. Gupta, Craig L. Tendler

From the Cleveland Clinic Cancer Center, Cleveland, OH; the Dartmouth Hitchcock Medical Center, Norris Cotton Cancer Center, Lebanon, NH; the Royal Marsden Hospital, London, England; the Dallas Research Center, Dallas, and Baylor College of Medicine, Texas Medical Center, Houston, TX; and Schering-Plough Research Institute, Kenilworth, NJ.

Address reprint requests to Ronald M. Bukowski, MD, Director, Experimental Therapeutics Program, Cleveland Clinic Cancer Center/T40, 9500 Euclid Ave, Cleveland, OH 44195-5237; email: bukowsr{at}cc.ccf.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFN{alpha}-2b) in patients with advanced solid tumors (primarily RCC).

PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 µg/kg/wk of pegylated IFN{alpha}-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 µg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression.

RESULTS: The MTD for pegylated IFN{alpha}-2b at 12 weeks was 6.0 µg/kg/wk. One year of 6.0 µg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFN{alpha}-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months.

CONCLUSION: Pegylated IFN{alpha}-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 µg/kg/wk.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
INTERFERON ALFA (IFN{alpha}) is a potent biologic agent with demonstrated antitumor activity against a variety of solid tumors, including renal cell carcinoma (RCC), melanoma, and superficial bladder carcinoma, as well as against chronic myelogenous leukemia (CML). In patients with metastatic RCC, single-agent IFN{alpha} (the most common dose schedule is 5 to 10 million international units [MIU]/m2 intramuscularly or subcutaneously [SC] three times per week [TIW]) yields objective tumor response rates of 11% to 29%.1-10 Similarly, in metastatic melanoma, the objective response (OR) rate for single-agent IFN{alpha} is approximately 15% (range, 6% to 27%).10 However, because IFN{alpha} is rapidly cleared from circulation, it requires frequent dosing, which is cumbersome and poorly tolerated.

Pegylated IFN{alpha}-2b (PEG-Intron; Schering Corporation, Kenilworth, NJ) was developed to reduce the clearance of IFN{alpha}-2b. Attachment of a single polyethylene glycol (PEG; molecular weight 12 kd) moiety to IFN{alpha}-2b does not alter the volume of distribution compared with nonpegylated IFN{alpha}-2b, but it reduces the renal clearance of pegylated IFN{alpha}-2b, resulting in approximately a 10-fold increase in the elimination half-life (approximately 40 hours v 4 hours for IFN{alpha}-2b).11,12 The maximal serum concentration is achieved between 15 and 44 hours after administration and is maintained for 48 to 72 hours. A single dose of pegylated IFN{alpha}-2b (>= 1.0 µg/kg) remains in circulation for more than 168 hours (7 days), whereas a single dose of nonpegylated IFN{alpha}-2b (3 MIU) is cleared by the body within 24 hours.13 The prolonged half-life of pegylated IFN{alpha}-2b significantly increases exposure to IFN{alpha}-2b, which may translate into improved efficacy compared with nonpegylated IFN{alpha}-2b. In addition, pegylated IFN{alpha}-2b is compatible with convenient weekly dosing, compared with a minimum of TIW dosing required for nonpegylated IFN{alpha}-2b.

The safety and efficacy of pegylated IFN{alpha}-2b have been established in patients with chronic hepatitis C and CML. In patients with chronic hepatitis C, pegylated IFN{alpha}-2b (>= 0.5 µg/kg/wk) significantly improved antiviral activity and sustained virologic response compared with IFN{alpha}-2b (3 MIU TIW).14 Furthermore, pegylated IFN{alpha}-2b demonstrated a similar safety profile compared with nonpegylated IFN{alpha}-2b. A phase I study in patients with CML established 6.0 µg/kg/wk as the maximum-tolerated dose (MTD).15 Patients with chronic-phase CML who were intolerant to IFN{alpha} or did not respond to prior IFN{alpha} therapy received 0.75 to 9.0 µg/kg/wk of pegylated IFN{alpha}-2b. A complete hematologic or improved cytogenetic response was observed in 48% of patients.

On the basis of these results, this study was initiated to establish the MTD of pegylated IFN{alpha}-2b given weekly for 12 weeks in patients with progressive metastatic solid tumors (including RCC and melanoma) and to establish the safety profile and preliminary efficacy of pegylated IFN{alpha}-2b in RCC when administered over 1 year.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Patients were eligible if they had a measurable, histologically documented solid tumor, including metastatic melanoma and RCC, that was unresponsive to initial treatment. Prior surgical excision was acceptable but was not required. Eligibility included an Eastern Cooperative Oncology Group performance status of 0 or 1; age 18 to 70 years; more than a 12-week life expectancy; and adequate hepatic, renal, and hematologic function (including absolute neutrophil count >= 3,000 cells/µL, platelet count >= 100,000/µL, hemoglobin >= 9.0 g/dL, serum creatinine <= 2.0 mg/dL or calculated creatinine clearance of >= 50 mL/min, serum bilirubin <= 1.5 times the upper limit of normal [ULN] unless due to disease infiltration, ratio of serum ALT to serum AST <= 1.5 times ULN unless due to disease infiltration, and normal serum calcium). Patients who had received prior IFN- or interleukin-2–containing regimens were eligible. Patients were ineligible if they had received more than two prior systemic treatments, including chemotherapy or immunotherapy, or if they had evidence of CNS metastases, a history of hypersensitivity or intolerance to IFN{alpha}, a history of hospitalization because of neuropsychiatric disorders, severe cardiovascular disease, refractory thyroid dysfunction, uncontrolled diabetes, active hepatitis, or a life-threatening second active malignancy. All patients provided informed written consent.

Dose and Treatment
This multicenter, open-label trial consisted of two phases: a 12-week dose-ranging phase (core phase) to assess the MTD and a 1-year extension phase to evaluate the preliminary efficacy and overall tolerability. In the core phase, previously treated patients were enrolled sequentially into cohorts of three to six patients and were treated with escalating dose levels of pegylated IFN{alpha}-2b (0.75, 1.5, 3.0, 4.5, 6.0, and 7.5 µg/kg body weight) administered SC once weekly for 4 weeks. Patients received 500 to 1,000 mg of acetaminophen 30 minutes before the pegylated IFN{alpha}-2b injection. Patients who discontinued treatment other than for dose-limiting toxicity (DLT) before completing 4 weeks of therapy were not considered assessable. To assess the activity of pegylated IFN{alpha}-2b at the MTD in previously untreated RCC patients, the protocol was amended to allow accrual of additional patients at the two highest dose levels (6.0 and 7.5 µg/kg/wk for <= 12 weeks). Additional patients were enrolled by using a two-stage design (15 patients in the first stage and 10 in the second stage). It was estimated that a maximum of 25 patients at each dose level would be required to determine whether the true response rate was <= 10% v >= 30%. This statistical hypothesis has an error rate of less than 5% with a power of 80%.

Patients who completed the initial 12 weeks of treatment and exhibited stable disease, a partial response (PR), or a complete response (CR) were eligible to continue pegylated IFN{alpha}-2b treatment on a separate extension protocol at the same dose level received in the core phase. Pegylated IFN{alpha}-2b was administered weekly until disease progression or completion of 1 year of treatment. As in the core phase, patients were pretreated with acetaminophen. This study complied with the ethical standards of the local institutional review boards of each study center and with the Helsinki Declaration of 1975, as revised in 1983.

Toxicity and Response Assessments
Toxicities were graded according to the National Cancer Institute’s common toxicity criteria. Patients were monitored for toxicity every 8 weeks. Thyroid function was assessed only at baseline. No formal neuropsychiatric evaluations were performed, but patients were closely monitored for neuropsychiatric adverse events such as depression and impaired concentration. The DLT was reached when two patients at any dose level experienced DLT, defined as any grade 4 hematologic toxicity or the occurrence of any grade 3 or 4 nonhematologic adverse event, with the exception of grade 3 fever (in the absence of infection) or flu-like symptoms (eg, anorexia, fatigue/malaise, chills or rigors, myalgias, and arthralgias). The MTD was then taken to be the next lower dosage level.

Patients who completed >= 8 weeks of treatment were evaluated objectively for tumor response (per World Health Organization criteria). Tumor response was assessed by physical examination, radiologic evaluation, chest radiographs, and appropriate scans (eg, computed tomography and magnetic resonance imaging) at weeks 8 and 12. In the extension protocol, tumor response was evaluated every 8 weeks. A CR required complete disappearance of all clinically detectable malignant disease at two follow-up visits >= 4 weeks apart. A PR denoted a reduction of >= 50% in the sum of the largest diameters of all lesions as determined at two follow-up visits >= 4 weeks apart. A reduction of less than 50% or an increase of less than 25% in the sum of the products of the largest perpendicular diameters of all measurable lesions was considered stable disease.

Dose Modifications
Dose modifications were made if a patient experienced any grade 3 or 4 adverse event. The pegylated IFN{alpha}-2b dose was withheld until toxicity resolved. If the toxicity resolved to grade 0 to 1 within 2 weeks, pegylated IFN{alpha}-2b could be restarted at the next lower dose level and the patient could continue study treatment. If DLT occurred at the lower dose, pegylated IFN{alpha}-2b was discontinued.

Pharmacokinetics
Blood samples (5 mL) were collected at predose (hour 0) and at 24, 48, 72, and 168 hours postdose during week 1 and week 4. These time points have been shown to provide a reasonable estimate of pegylated IFN{alpha}-2b area under the curve (AUC) in patients with chronic hepatitis C.11 Serum pegylated IFN{alpha}-2b concentrations were determined by using a validated electrochemiluminescence assay with a lower limit of quantitation of 50 pg/mL. The assay was linear and reproducible between 50 and 2,000 pg/mL.16 Individual serum pegylated IFN{alpha}-2b concentration-time data were used for pharmacokinetic (PK) analysis with model-independent methods.17 The AUC from 0 to 168 hours was calculated by using the linear trapezoidal method.17 The accumulation factor was determined by using the ratio of the AUC for week 4 divided by the AUC for week 1.

Pretreatment and posttreatment (2 weeks after the end of the study or treatment discontinuation) samples were also assayed to determine the presence of serum neutralizing antibodies capable of binding to and inactivating pegylated IFN{alpha}-2b. Samples were screened with the anti-IFN{alpha} antibody enzyme-linked immunosorbent assay (A4-203 microtiter plate version) from ANAWA Laboratorien Ag (Wangen Zürich, Switzerland).

Statistics
Statistical analyses for response rates and adverse events were descriptive. Survival rates were estimated with the Kaplan-Meier method.18


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Seventy patients with advanced metastatic disease were enrolled between October 1997 and June 2001. The majority (81%) had RCC; overall, 66% had lung metastases. A number had received prior surgery (71%), radiation (27%), or immunotherapy (24%). The median age was 57.5 years, and 56% had been diagnosed within 1 year of study entry. Baseline patient and disease characteristics are listed in Table 1.


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  		Table 1. Patient Characteristics
 
Treatment Administered
Thirty-five previously treated patients were enrolled onto the initial 12-week dose-escalation phase. The MTD for pegylated IFN{alpha}-2b was identified as 6.0 µg/kg/wk on the basis of the initial cohort of 35 previously treated patients who were treated at this dose level. To more fully assess the tolerability of pegylated IFN{alpha}-2b, an additional 35 previously untreated RCC patients were subsequently accrued to the two highest dose levels (6.0 and 7.5 µg/kg/wk) and treated for 12 weeks. Because 7.5 µg/kg/wk was well tolerated among patients with good baseline performance status, 13 of the 35 previously untreated RCC patients were treated at that dose. All patients (n = 70) in the core phase received at least one full dose of pegylated IFN{alpha}-2b, except one patient in the 6.0-µg/kg/wk group who did not receive any study drug and one patient in the 7.5-µg/kg/wk group who received a partial first dose of pegylated IFN{alpha}-2b.

Thirty-three patients completed the 12-week core phase (Table 2), with 23 receiving the full dose through week 12. Twenty-nine patients (23 with RCC, two with melanoma, and four with other malignancies) were eligible for treatment on the extension protocol. The majority (76%; n = 22) of these patients received 6.0 or 7.5 µg/kg/wk. Patients in the 6.0- and 7.5-µg/kg/wk dose groups received a mean delivered dose of 5.3 and 6.2 µg/kg/wk, respectively, with a median treatment duration of 7 months. Eight patients (five with RCC, two with melanoma, and one with adrenal carcinoma) completed the 1-year extension phase, and one RCC patient treated with 1.5 µg/kg/wk who had stable disease continued treatment after study completion, through week 96.


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  		Table 2. Patient Enrollment and Completion
 
Safety
The most frequently reported adverse events during the 12-week core phase are listed by treatment group in Table 3. Overall, there was an apparent trend toward a dose-related increase in the incidence of some adverse events, notably fatigue, diarrhea, myalgia, and asthenia. Among the 70 core phase patients, 10 adverse events were classified as grade 3 and two as grade 4: one patient receiving 3.0 µg/kg/wk reported grade 4 chills, and one patient receiving 7.5 µg/kg/wk experienced a grade 4 increase in bilirubin that was considered not related to the study drug. Serious laboratory abnormalities were rare. There were four reports of dose-limiting grade 4 laboratory abnormalities among patients treated with 7.5 µg/kg/wk: one neutropenia (absolute neutrophil count < 0.5 x 109/L), one increase of serum glutamic oxaloacetic transaminase (> 20.0 x ULN), and two increases in bilirubin (> 3.0 x ULN). Grade 3 neutropenia was reported in two patients receiving 6.0 µg/kg. There were no reports of grade 3 or 4 thrombocytopenia at any dose level studied except for one grade 3 at 7.5 µg/kg/wk.


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  		Table 3. Most Frequently Reported Treatment-Emergent Adverse Events (all grades) by Pegylated IFN{alpha}-2b Dose Cohort Over 12 Weeks (core phase)
 
Core phase patients were also tested for the presence of anti–IFN{alpha}-2b antibodies. Serum samples were available for 49 patients, and posttreatment samples were available for 21 of these patients. No patient tested positive for serum neutralizing antibodies during treatment.

Thirty-seven patients discontinued pegylated IFN{alpha}-2b during the 12-week core phase. The primary reason for discontinuation was progressive disease (23 patients). In addition, 12 patients (11 in the 6.0- or 7.5-µg/kg/wk groups) discontinued treatment because of adverse events, primarily flu-like symptoms. There were two deaths during the 12-week core phase because of disease progression.

The most frequently reported adverse events in the 1-year extension phase of the study (n = 29) are listed in Table 4. Grade 3 or 4 adverse events were reported in eight (28%) patients. One serious adverse event was reported in each of the following categories: aggravated insomnia, arthralgia, convulsions, fever, headache, rigors, myocardial infarction, pain, rash, and sinusitis. In addition, there were two reported serious cases of syncope. Grade 3 or 4 laboratory abnormalities were reported in six patients: three developed grade 3 or 4 neutropenia, two developed grade 3 leukopenia, and one developed grade 3 thrombocytopenia.


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  		Table 4. Most Frequently Reported Treatment-Emergent Adverse Events by Severity (n = 29) Over 1 Year (extension phase)
 
During the 1-year extension phase, 21 patients discontinued treatment: three treated with 7.5 µg/kg/wk discontinued because of adverse events; one experienced fatigue and anorexia; one experienced fatigue, weight loss, and aggravated insomnia; and one experienced arthralgia, arthritis, and rash. Additionally, 15 discontinued because of progressive disease after a median treatment duration of 7 months.

Pharmacokinetics
The mean serum concentration-time data and PK parameters of pegylated IFN{alpha}-2b at weeks 1 and 4 are listed in Table 5 and Fig 1. After administration, pegylated IFN{alpha}-2b was readily absorbed. In addition, pegylated IFN{alpha}-2b serum concentrations increased in a dose-related manner at weeks 1 and 4. The maximum serum concentration and time of maximal concentration could not be determined because of the limited number of serum samples collected in the study. The AUC at weeks 1 and 4 demonstrated a dose-related but not dose-proportional increase over the 0.75- to 7.5-µg/kg dose range (data not shown). The overall trend of accumulation across dose groups was similar, suggesting no dose-related changes in the accumulation of pegylated IFN{alpha}-2b (Table 5).


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  		Table 5. Mean Pharmacokinetics of Pegylated IFN{alpha}-2b
 


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  		Fig 1. Pegylated IFN{alpha}-2b concentration-time profiles at weeks 1 and 4 with subcutaneous, once-weekly dosing in patients with solid tumors.

 
Response
At week 12, 29 (42%) of 69 treated patients (including one who received a partial dose) achieved an OR or stable disease and continued treatment on the extension protocol. The best response in the 1-year extension phase was a CR in four patients and a PR in five patients (Table 6). Therefore, among all 69 patients, nine (13%) had an OR at 1 year. Of the four CRs, two were observed in RCC patients and two in melanoma patients with visceral metastases. Additionally, three of the four CRs occurred in patients treated with 6.0 µg/kg/wk. Seven responses were ongoing at last follow-up, and two CRs were durable beyond 1 year (Table 7). Objective tumor responses were observed in patients with several types of primary tumors and at both visceral and nonvisceral sites of disease (Table 7). Computed tomography scans of the kidneys and lungs of a 56-year-old man with clear-cell carcinoma of the left kidney and lung involvement are shown in Fig 2. The patient had a PR when treated with 6.0 µg/kg/wk and, after nephrectomy, remained in complete remission beyond 1 year.


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  		Table 6. Best Objective Response in Patients With Metastatic Disease Treated With Pegylated IFN{alpha}-2b
 

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  		Table 7. Details of Best Responses in Patients Treated on the Extension Protocol
 


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  		Fig 2. Computed tomography scans of the kidney (A) and lung (B) of a 56-year-old patient with a PR to treatment with 6.0 µg/kg/wk of pegylated IFN{alpha}-2b.

 
Among the 69 treated patients in the study (core and extension phase), the 1- and 2-year survival rates were 52% (95% confidence interval [CI], 39% to 63%) and 29% (95% CI, 18% to 40%), respectively, and the median survival was 12.7 months. Among the 29 extension phase patients, the 1- and 2-year survival rates were 86% (95% CI, 73% to 99%) and 58% (95% CI, 38% to 76%), respectively, and the median survival was 27.1 months (Fig 3A).



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  		Fig 3. Kaplan-Meier estimate of survival for (A) extension protocol patients (n = 29) and for (B) all RCC patients (n = 57).

 
Among the 57 RCC patients (35 previously untreated), 23 had an OR or stable disease at week 12 and were eligible for the extension phase. At 1 year, six (11%) of 57 RCC patients had an OR (two CRs and four PRs). The 1-year survival rate was 50%, and the median survival was 13.2 months (Fig 3B).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This phase I/II study was initiated to determine the MTD and PK of pegylated IFN{alpha}-2b given weekly for 12 weeks to patients with progressive metastatic solid tumors and to establish the safety, tolerability, and preliminary efficacy of pegylated IFN{alpha}-2b when administered over 1 year of therapy. On the basis of the initial dose-escalation phase, the MTD was considered to be 6.0 µg/kg/wk. Patients treated with 7.5 µg/kg/wk developed dose-limiting hematologic and liver toxicity; however, 7.5 µg/kg/wk was tolerated by patients with good baseline performance status and by patients who had received limited prior therapy. The adverse events profile was generally similar to that reported previously for pegylated IFN{alpha}-2b and IFN{alpha}-2b14,15,19; no unexpected adverse events were observed. The incidence of adverse events was dose related. The most commonly reported adverse events were nausea, anorexia, fatigue, and rigors. Most adverse events were mild or moderate in severity, and grade 3 or 4 events were uncommon. Clinical laboratory changes were also primarily mild to moderate in severity.

The safety profile of pegylated IFN{alpha}-2b (6.0 µg/kg/wk) for 1 year observed in this study compares favorably with that of the high-dose IFN{alpha}-2b regimens used for the treatment of melanoma and RCC. The incidence of fatigue was only 38%, and no patient experienced grade 3 or 4 fatigue with long-term therapy. In contrast, nearly all patients treated with high-dose IFN{alpha}-2b experience fatigue, and grade 3 or 4 fatigue has been reported in up to 25% of patients treated for 1 year with the high-dose IFN{alpha}-2b regimen approved for adjuvant therapy of melanoma.20-22 With long-term therapy, chronic fatigue and anorexia were the major DLTs, but these were observed only at the 7.5-µg/kg/wk dose level.

Serum concentrations of pegylated IFN{alpha}-2b increased in a dose-related manner, and pegylated IFN{alpha}-2b demonstrated a PK profile consistent with decreased clearance and increased AUC compared with IFN{alpha}-2b, as reported previously in chronic hepatitis C patients.11 Pegylated IFN{alpha}-2b has a long serum half-life of approximately 40 hours and remains in circulation for longer than 168 hours (7 days). The clearance of pegylated IFN{alpha}-2b after a single dose is significantly slower than that of IFN{alpha}-2b, which is cleared by the body within 24 hours.11,12 The favorable PK profile of pegylated IFN{alpha}-2b supports once-weekly administration.

PK data from chronic hepatitis C patients have demonstrated that 0.25 µg/kg/wk of pegylated IFN{alpha}-2b results in similar exposure to IFN{alpha} compared with SC administration of 9 MIU/wk of IFN{alpha}-2b (3 MIU TIW) in a given patient.12 Phase I/II studies in patients with CML have demonstrated that dose intensification can be safely achieved with pegylated IFN{alpha}-2b at doses up to 6.0 µg/kg/wk.15 A standard SC dose of IFN{alpha}-2b used in the treatment of metastatic RCC and melanoma is 10 MIU/m2 TIW (45 to 60 MIU/wk).10 There is no direct PK comparison between the 6.0-µg/kg/wk dose of pegylated IFN{alpha}-2b and standard doses of IFN{alpha}-2b used to treat CML (5 MIU/m2/d). However, on the basis of extrapolation of available PK comparability data, the 6.0-µg/kg/wk dose of pegylated IFN{alpha}-2b may achieve exposure comparable with that of 180 MIU/wk of IFN{alpha}-2b.

Nine (13%) of the 69 treated patients had an OR, including four CRs and five PRs, and two responses were durable beyond 1 year. The OR rate among 44 previously untreated RCC patients was 14% (consistent with that observed in previously reported trials of IFN{alpha}-2b).1-10 Although ORs were observed across a range of doses, the majority occurred at the higher doses of pegylated IFN{alpha}-2b (6.0 and 7.5 µg/kg/wk). Responses were also observed at both visceral and nonvisceral sites of disease. These data suggest that pegylated IFN{alpha}-2b at these dose levels has antitumor activity in RCC and other solid tumors. The highest response rates achieved with IFN{alpha} in patients with solid tumors have been observed with uninterrupted schedules at doses of 10 to 50 MIU/m2 TIW or daily by intravenous, intramuscular, or SC injection.1-10 However, at these high doses IFN{alpha} is poorly tolerated. The data presented here suggest that with pegylated IFN{alpha}-2b it is possible to achieve the same or higher exposure to IFN{alpha} as that achieved with high-dose IFN{alpha} regimens without reaching DLT. In addition, weekly dosing with pegylated IFN{alpha}-2b provides greater convenience and will likely improve patient compliance.

A pegylated form of IFN{alpha}2a (Pegasys; Hoffman-La Roche, Nutley, NJ) has also recently been studied in patients with solid tumors.23 Pegylated IFN{alpha}2a contains a 40-kd branched PEG molecule, which is substantially larger than the 12-kd linear moiety of pegylated IFN{alpha}-2b. Higher-molecular-weight PEG species result in a longer half-life but may negatively affect biologic activity.24 In fact, pegylated IFN{alpha}2a, which is pegylated primarily on lysines, retains only 7% of the bioactivity of nonpegylated IFN{alpha}2a in a cell culture assay.25 In a phase I study in 27 patients with previously untreated metastatic RCC, treatment with pegylated IFN{alpha}2a (180 to 540 µg/wk) for 6 months yielded five (19%) PRs.23 In comparison, in the trial reported here, six (14%) of 44 previously untreated RCC patients had an OR to pegylated IFN{alpha}-2b, including two CRs. None of the previously treated RCC patients had an OR with pegylated IFN{alpha}-2b. However, this is not surprising given the evidence that patients who do not respond to previous immunotherapy are unlikely to respond to second-line immunotherapy.26

In addition to reduced biologic activity, higher-molecular-weight PEG molecules have a slower rate of absorption into the bloodstream,27,28 which would extend the time to maximum serum concentration and may result in tissue accumulation and an increased potential for toxicity. Furthermore, a 40-kd PEG moiety cannot be excreted by the kidneys and is not quickly metabolized; therefore, the PEG may accumulate in the liver. Significant accumulation in the liver may increase the risk for toxicity, especially with long-term administration. Notably, three patients treated with pegylated IFN{alpha}2a developed grade 3 liver toxicity compared with no patients treated with pegylated IFN{alpha}-2b in this study.23

This study confirms that pegylated IFN{alpha}-2b is safe and well tolerated in patients with advanced solid tumors. In RCC and a variety of other solid tumors, pegylated IFN{alpha}-2b exhibited promising antitumor activity, including durable responses and favorable survival at 1 and 2 years. The PK results presented here also suggest that IFN{alpha} dose intensification can be safely achieved in solid tumors by using pegylated IFN{alpha}-2b. The results of this study provide a strong rationale for randomized trials of pegylated IFN{alpha}-2b in RCC, both as monotherapy and in combination with other agents such as interleukin-2.


   ACKNOWLEDGMENTS
 
We thank Carol Zelinack for data monitoring and technical assistance. We also thank Nancy Crosby, ARNP; Kathleen MacKay, RN; Heidi Wells, RN; Jan Fisher, MA; Mary Waugh; and Debra Truman.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Boccardo F, Rubagotti A, Canobbio L, et al: Interleukin-2, interferon-alpha and interleukin-2 plus interferon-alpha in renal cell carcinoma: A randomized phase II trial. Tumori 84: 534-539, 1998[Medline]

2. De Mulder PH, Oosterhof G, Bouffioux C, et al: EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma: The EORTC Genitourinary Group. Br J Cancer 71: 371-375, 1995[Medline]

3. Fossa SD, Martinelli G, Otto U, et al: Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study. Ann Oncol 3: 301-305, 1992[Abstract/Free Full Text]

4. Kirkwood JM, Harris JE, Vera R, et al: A randomized study of low and high doses of leukocyte alpha-interferon in metastatic renal cell carcinoma: The American Cancer Society collaborative trial. Cancer Res 45: 863-871, 1985[Abstract/Free Full Text]

5. Interferon-alpha and survival in metastatic renal carcinoma: Early results of a randomised controlled trial: Medical Research Council Renal Cancer Collaborators. Lancet 353:14-17, 1999

6. Motzer RJ, Murphy BA, Bacik J, et al: Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18: 2972-2980, 2000[Abstract/Free Full Text]

7. Muss HB, Costanzi JJ, Leavitt R, et al: Recombinant alfa interferon in renal cell carcinoma: A randomized trial of two routes of administration. J Clin Oncol 5: 286-291, 1987[Abstract]

8. Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma: Groupe Francais d’Immunotherapie. N Engl J Med 338: 1272-1278, 1998[Abstract/Free Full Text]

9. Quesada JR, Rios A, Swanson D, et al: Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J Clin Oncol 3: 1522-1528, 1985[Abstract/Free Full Text]

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11. Glue P, Fang JW, Rouzier-Panis R, et al: Pegylated interferon-{alpha}2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther 68: 556-567, 2000[CrossRef][Medline]

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Submitted February 8, 2002; accepted May 24, 2002.


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