Phase I trial of PEG-interferon and recombinant IL-2 in patients with metastatic renal cell carcinoma.

PURPOSE: Pegylated interferon alpha-2b (PEG-Intron) is a conjugate of polyethylene glycol (PEG) and interferon alpha-2b, has a prolonged half-life, and an increased area under the curve (AUC) for interferon alpha-2b. The combination of PEG-Intron with recombinant interleukin-2 (rIL-2) was investigated in a phase 1 trial. To determine the maximal tolerable dose (MTD) and preliminary efficacy of concurrent subcutaneous (SC) administration of PEG-Intron and rIL-2 in patients with metastatic renal cell carcinoma (RCC). METHODS: Cohorts of 3-6 patients received escalating doses of PEG-Intron (I-1.5, II- 1.5, III-3.0, IV-3.0, V-4.5 microg/kg SC) given weekly in combination with rIL-2 administered three times weekly (TIW) for 6 weeks. rIL-2 dose levels were escalated in weeks 1 and 4 (I-10.0, II-15.0, III-15.0, IV-20.0, V-20.0 MIU/m(2) SC), and 5.0 MIU/m(2) SC TIW was administered during weeks 2, 3, 5 and 6. RESULTS: Thirty-four patients (24 men; 10 women) were accrued at dose levels I (n = 4), II (n = 4), III (n = 6), IV (n = 14), and V (n = 6) between October 2000 and October 2002. All but one patient had prior nephrectomy (n = 33) and all but one patient (97%) had received no prior systemic therapy. Patients received a median of four cycles of treatment (range 1-9). Dose limiting toxicity occurred at dose level V and included grade 4 neutropenia and hypoxemia. A partial response was found in 5 pts (15%). Median progression-free and overall survival were 9.0 (95% C.I. 5.6-13.1 months) and 31.9 months (95% C.I. 17.2-61.9 months), respectively. CONCLUSION: The combination of PEG-Interferon and SC rIL-2 can be administered with acceptable toxicity.

Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study.

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 (IFNalpha-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 micro g/kg/wk of pegylated IFNalpha-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 micro g/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 IFNalpha-2b at 12 weeks was 6.0 micro g/kg/wk. One year of 6.0 micro g/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNalpha-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 IFNalpha-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 micro g/kg/wk.

Evolving role of pegylated interferons in metastatic renal cell carcinoma.

Interferon (IFN)-alpha has demonstrated antitumor activity in a variety of solid and hematologic malignancies, including metastatic renal cell carcinoma. Pegylation, the process of combining a polyethylene glycol moiety to a biologic protein, substantially changes the pharmacokinetic profile of a drug, resulting in prolongation in half-life, increased area under the curve and, in some cases, improved efficacy. Pegylated IFN-alpha has been evaluated in chronic hepatitis C, chronic myelogenous leukemia and most recently in metastatic renal cell carcinoma. Registrational studies of pegylated IFN-alpha2a (PEGASYS) and pegylated IFN-alpha2b (PEG Intron) in patients with hepatitis C demonstrated greater efficacy with similar safety and tolerability to nonpegylated IFNs, with the advantage of less frequent administration. Studies evaluating these agents in the treatment of metastatic renal cell carcinoma and other cancers are ongoing.

New and modified interferon alfas: preclinical and clinical data.

Recombinant human interferon (IFN)-alpha was the first biotherapeutic agent approved by the US Food and Drug Administration for the treatment of a human malignancy. Its efficacy has also been demonstrated for treatment of several viral diseases. The human genome codes for 12 IFN-alpha proteins, with IFN alpha-1 and IFN alpha-2 accounting for the majority of the naturally occurring IFN-as. However, only subspecies of IFN alpha-2, recombinant human IFN alpha-2a and IFN alpha-2b, are commercially available in the United States. Other species of IFN-a may demonstrate equivalent or improved efficacy and have more tolerable side effects. This article describes ongoing preclinical and clinical studies of several new and modified IFN-alphas. A current phase I trial of a human recombinant IFN alpha-1 is described. Basic pharmacokinetics and clinical studies of polyethylene glycol (PEG) IFN alpha-2b are reviewed as well. Lastly, two novel types of IFN-a, one gene shuffled and one hybridized with human albumin, are summarized.

Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation.

BACKGROUND: PEG Intron (pegylated interferon-alpha-2b [IFN-alpha-2b]; Schering-Plough, Kenilworth, NJ) has demonstrated delayed clearance and increased area under the curve compared with native IFN-alpha-2b. Studies in patients with chronic hepatitis C infection and malignancies have demonstrated both biologic and clinical activity of PEG Intron and have provided empiric data to compare the pharmacokinetics (PK) and pharmacodynamics of PEG Intron and IFN-alpha-2b. METHODS: The authors conducted a review of the available data comparing the PK and pharmacodynamic effects of PEG Intron and IFN-alpha-2b. Safety and efficacy data from Phase I/II studies of PEG Intron in patients with chronic myelogenous leukemia (CML) and solid tumors were also reviewed. RESULTS: Data from patients with chronic hepatitis C infection suggest that exposure to IFN at a PEG Intron dose of 0.25 microg/kg per week is similar to that observed after administration of IFN-alpha-2b at a dose of 3 million International Units, three times per week. PEG Intron at doses up to 6 microg/kg per week was well tolerated and demonstrated clinical activity in patients with CML and solid tumors, including metastatic melanoma and renal cell carcinoma. CONCLUSIONS: Dose intensification can be achieved safely in patients with CML and solid tumors using PEG Intron, which could improve efficacy. These results provide useful dosing guidelines to clinicians investigating the antitumor activity of PEG Intron in patients with malignancies. More data are needed to determine the optimal dose in various oncologic indications. However, these results provide a sound rationale for further investigation of PEG Intron.

A Phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma.

BACKGROUND: Multiple myeloma remains an incurable disease. New agents are needed to improve therapy for patients with this disease. Previous investigators evaluated in vitro sensitivity of myeloma cells to polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) using the human tumor clonogenic assay. Of the 19 myeloma samples evaluated, 63% were inhibited at 0.075 IU/mL, and 74% were inhibited at 0.75 IU/mL. PEG-L-asparaginase is a form of Escherichia coli-derived L-asparaginase that is bound covalently to polyethylene glycol. Compared with the native form, it has a longer half-life and is less likely to cause allergic reactions. METHODS: The authors conducted a Phase I-II trial using PEG-L-asparaginase as a single agent in patients with recurrent and/or refractory multiple myeloma. RESULTS: Twenty-two patients received a median of two doses of PEG-L-asparaginase. In the 17 patients who are evaluable for response, a complete response was observed in one patient after four doses, and stable disease was observed in eight patients. Progression of disease was the reason for termination from study in the remaining eight patients. The median survival was 31.7 months, with four patients who were alive at 72 months after the start of therapy. Grade 3-4 toxicity was noted by the PEG-L-asparaginase 2000 mg/m(2) level. Severe allergic reactions were noted only at the highest dose level. CONCLUSIONS: Current data suggest that the maximal tolerated dose for single agent PEG-L-asparaginase in relapse/refractory multiple myeloma patients is 1000 mg/m(2) every 4 weeks. We could not identify any correlation between dose, plasma level and response. In this advanced group of patients we noted stable disease and/or response in 52% of evaluable patients. PEG-L-asparaginase has lower tolerance when used in the standard dosage as a single agent in this group of patients. We therefore recommend further studying of PEG-L-asparaginase dose of 1000 mg/m(2) on alternate weeks with steroids and/or other immune modulators.

A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients.

BACKGROUND: Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, a low plasma cell labeling index, and multidrug resistance (the primary cause of chemotherapy failure). MM patients receiving the vincristine, doxorubicin, and dexamethasone (VAD) regimen develop resistance and cardiac and steroid toxicity. Pegylated liposomal doxorubicin (Doxil/CAELYX) could potentially extend the duration of malignant plasma cell exposure to therapeutic levels of doxorubicin. This Phase II study evaluates combination pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone in MM patients. METHODS: Thirty-three newly diagnosed patients with MM received intravenous pegylated liposomal doxorubicin (40 mg/m(2)), vincristine (2.0 mg, Day 1), and oral or intravenous dexamethasone (40 mg per day for 4 days) every 4 weeks for six or more cycles and/or for two cycles after the best response. RESULTS: The overall response rate was 88%: 4 (12%) patients achieved a complete response, 18 (55%) a major response, and 7 (21%) a minor response. Three patients (9%) had stable and one (3%) had progressive disease. The median time to progression was 23.1 months, with 2-year and 3-year progression-free survival rates of 42% and 23%, respectively. The patient survival rate at 3 years was 67%. No patients discontinued treatment due to adverse events. Myelosuppression was manageable. The most common toxicities were Grade 3 palmar-plantar erythrodysesthesia, mucositis, and neutropenia. Only one patient experienced cardiotoxicity. CONCLUSIONS: Substituting pegylated liposomal doxorubicin for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in patients with MM improve the safety profile and convenience of the treatment regimen without compromising efficacy.