|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2007.14.5193 on March 17 2008 © 2008 American Society of Clinical Oncology. Phase I Study of Recombinant Interleukin-21 in Patients With Metastatic Melanoma and Renal Cell Carcinoma
From the University of Washington; ZymoGenetics Inc, Seattle, WA; Providence Portland Medical Center, Portland, OR; University of Michigan Health System, Ann Arbor, MI; University of Southern California, Los Angeles, CA; and the University of Pittsburgh Cancer Institute, Pittsburgh, PA Corresponding author: John A. Thompson, MD, Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023; e-mail: jat{at}u.washington.edu
Purpose A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21). Patients and Methods Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 µg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles. Results Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 µg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD). Conclusion Outpatient therapy with rIL-21 at 30 µg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.
Modulation of the immune system using interleukin-2 (IL-2) and interferon may induce objective responses in some patients with malignant melanoma (MM) and renal cell carcinoma (RCC), but the utility of these agents is limited by low response rates and treatment-associated toxicities. New immunomodulatory agents with improved efficacy and safety profiles are therefore needed. Interleukin-21 (IL-21) is a class I cytokine that affects both innate and adaptive immunity. Effects of IL-21 include activation, increased proliferation, and prolonged survival of tumor-specific CD8+ cytotoxic T lymphocytes1; enhancement of T-cell dependent B cell proliferation and antibody production2; and terminal differentiation and activation of natural killer cells.2,3 Unlike IL-2, IL-21 renders CD4+ T cells resistant to regulatory T cell suppression and does not enhance proliferation of regulatory T cells4; IL-21 may also lead to enhanced generation of memory T cells. IL-21 has been reported to have antitumor effects in various preclinical cancer models.1,5-9 Treatment of cynomolgus monkeys with recombinant IL-21 (rIL-21) was associated with dose-dependent increases in soluble CD25 (sCD25), a marker of T and natural killer cell activation. Transient decreases in circulating lymphocytes were observed, followed by rebound lymphocytosis, consistent with the predicted biologic effects of rIL-21 on lymphocyte activation.10,11 The primary toxicities observed in cynomolgus monkeys included reversible anemia, thrombocytopenia, and transient fever; capillary leak syndrome was not observed. To further evaluate the potential of rIL-21 as a novel immunotherapeutic cytokine, a two-part phase I study was performed in patients with MM and RCC to estimate the maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
Patients Eligibility requirements included metastatic cutaneous MM or RCC of predominantly clear-cell histology; age  18 years; disease measurable by computed tomography or magnetic resonance imaging; life expectancy 12 weeks; Eastern Cooperative Oncology Group performance status  1; no prior history of brain metastases unless stable after treatment; no antitumor treatment or systemic corticosteroids within 3 weeks of study enrollment; and liver function tests grade 1, creatinine lower than 2.0 mg/dL, hemoglobin higher than 12 g/dL, absolute neutrophil count higher than 1,500 cells/mm3, and platelets higher than 100,000/mm3. The institutional review boards of participating medical centers approved the protocol, and patients gave written informed consent before study-specific procedures began.
Study Design
Dose escalation was conducted using a standard 3 + 3 design,12 with a starting rIL-21 dose of 3 µg/kg and escalation planned in half-log increments. Toxicities were evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0. Dose-limiting toxicity (DLT) was defined as toxicity Serum samples for evaluation of rIL-21 pharmacokinetics were obtained at selected time points and concentrations of rIL-21 were determined using a validated custom enzyme-linked immunosorbent assay (ELISA). Noncompartmental pharmacokinetics parameters were calculated using WINNonlin (Scientific Consultant, Apex, NC; Pharsight Inc, Cary, NC). The pharmacologic effects of rIL-21 were assessed by measuring the serum concentration of sCD25 with a validated custom ELISA. Serum specimens were collected before dosing on day 1 of each cycle and at the end of each treatment course to evaluate antibodies to rIL-21. Samples were screened for binding antibodies by ELISA13; samples containing specific and measurable binding antibodies were further evaluated for neutralizing activity by cell-based bioassay. Computed tomography or magnetic resonance imaging evaluations for tumor restaging per Response Evaluation Criteria in Solid Tumors (RECIST)14 were performed at the end of each treatment course. Patients with stable disease (SD) or better at the time of tumor restaging could be eligible for re-treatment with rIL-21.
Patients Forty-three patients were treated with rIL-21 in this study (24 MM; 19 RCC), 15 patients during dose escalation (nine MM; six RCC) and 28 during the cohort expansion (15 MM; 13 RCC; Table 1). Of the RCC patients, 15 had undergone prior nephrectomy. Twenty-five patients had received prior therapy for metastatic disease (11 MM; 14 RCC). Of these, 14 had received IL-2 (eight RCC; six MM) and four additional MM patients had received adjuvant treatment with interferon.
Thirty-nine of 43 patients treated in this study received at least eight of 10 scheduled doses during the first treatment course, and 12 patients received up to five additional treatment courses. Five patients discontinued the study prematurely, four due to disease progression and one due to pleural effusion considered probably not related to rIL-21.
Safety Experience: Dose Escalation Four patients treated at a dose level of 30 µg/kg or higher experienced DLTs, primarily transient grade 3 laboratory abnormalities that did not meet the per-protocol definition of adverse events. At 30 µg/kg, one of six patients experienced transient grade 3 ALT elevation. At 100 µg/kg, two of two patients experienced DLTs consisting of grade 3 hyponatremia in one patient, and grade 3 thrombocytopenia, leukopenia, hyperbilirubinemia, hypophosphatemia, and grade 4 lymphopenia in the other patient. At 50 µg/kg, the single subject treated experienced transient grade 3 neutropenia without associated fever or infection. This event was not considered clinically significant, and the patient was subsequently re-treated without recurrence of neutropenia. The MTD was estimated to be 30 µg/kg, and this dose level was recommended for cohort expansion. Overall, a total of 34 patients were treated at the 30 µg/kg dose level (including six patients from the dose escalation phase).
Safety Experience: First Treatment Course
During the first treatment course, all 34 patients treated at the 30 µg/kg dose level experienced at least one adverse event. The maximum severity was grade 1 for nine patients (26%), grade 2 for 21 patients (62%), and grade 3 for the remaining four patients (12%). Three patients experienced grade 3 events considered related to rIL-21 (abdominal pain, thrombocytopenia, and hypophosphatemia). One patient experienced a serious adverse event consisting of overnight hospitalization for grade 2 fever without associated infection; this event was also considered related to rIL-21 treatment. Three serious adverse events not considered related to rIL-21 were reported for three subjects: hemoptysis associated with disease progression, grade 3 cerebral edema due to tumor regrowth in a patient with prior brain metastasis (the patient who had grade 3 abdominal pain), and grade 3 bilateral pleural effusions thought to be due to underlying cardiac disease. Laboratory abnormalities were usually grade 1 or 2 in severity and returned to baseline within 3 weeks after rIL-21 dosing. Decreases in hemoglobin, neutrophil counts, and/or platelet counts were commonly observed. Lymphopenia occurred in 88% of patients (including four patients [9%] with grade 4 lymphopenia). Other common abnormalities included increases in ALT, bilirubin, or triglycerides and decreases in albumin, calcium, magnesium, phosphorus, or sodium.
Safety Experience: Re-Treatment Re-treatment with rIL-21 was not associated with increased toxicity, with the exception of one patient who experienced a serious adverse event of grade 4 hepatoxicity. This patient tolerated the first treatment course of rIL-21 without notable toxicity other than transient grade 1 to 2 elevations in ALT. Within 4 days after completion of the second treatment course of rIL-21, the patient developed intermittent epigastric pain and was hospitalized with grade 4 hepatotoxicity, including an AST of 2,261 U/L, ALT of 5,225 U/L, bilirubin of 188 µmol/L, and prothrombin time of 30.5 seconds. A liver biopsy showed hepatonecrosis consistent with toxic injury. The patient was discharged from the hospital after 4 days, as hepatic enzymes and prothrombin time began to decrease. After discharge, all values returned to baseline.
Pharmacokinetics, Pharmacodynamics, and Immunogenicity of rIL-21
Pharmacodynamic effects of rIL-21 included dose-dependent increases in serum concentration of sCD25 and changes in lymphocyte counts. In patients treated at 30 µg/kg, an eight-fold increase over baseline was observed for sCD25 at the end of each five-day dosing interval; mean lymphocyte count decreased to 47% of baseline during dosing and rebounded to 139% above baseline after completion of dosing (Fig 2).
Specific binding antibodies to rIL-21 were identified in six of 43 treated patients. All six antibody-positive patients received 30 µg/kg rIL-21, and five developed antibody after re-treatment with rIL-21. Evidence of neutralizing activity was observed in a cell proliferation bioassay for three of these patients (during course 1, during course 3, and after course 5). There was no association of antibody development with specific adverse events.
Antitumor Effect
This phase I trial explored the use of rIL-21 in an outpatient treatment regimen for patients with metastatic MM and RCC. Therapy with rIL-21 was well tolerated at doses of 30 µg/kg or lower. The most common adverse events, including flu-like symptoms and rash, were mild to moderate in severity. Laboratory abnormalities, such as cytopenias and increased hepatic enzymes, were similar to those observed with other cytokine therapies, such as interferon-  , interleukin (IL)-2, IL-6, IL-12, and IL-18.15-21 No capillary leak syndrome or mood disturbances were observed. Although the MTD was estimated to be 30 µg/kg, treatment at a higher dose may be feasible, as the DLT experienced by the one patient treated at 50 µg/kg consisted only of grade 3 neutropenia that did not recur with re-treatment. The observed increase in serum sCD25 may reflect dose-dependent activation of lymphocyte subsets by rIL-21 and the transient lymphopenia may reflect adherence and/or migration of activated lymphocytes; lymphopenia also is seen with other immunostimulatory cytokine therapies.15,17-20 Promising antitumor activity was observed in this trial, with best overall responses of SD or better in 29 (67%) of 43 patients. In some patients, repeat treatment with rIL-21 was associated with progressive shrinkage of tumors. Decrease in tumor mass was seen in disease sites that included lymph node, lung, and visceral sites, including pancreas and liver. Approximately half of the patients in this trial had received prior biologic therapy, which may have biased against response to rIL-21. One of the hallmarks of therapy with high-dose IL-2 is the achievement of durable responses in some patients. This study was not designed to assess duration of response, although responses lasting between 6 and 18 months were observed in four of five patients who achieved a PR or better. Additional clinical trials and longer follow-up will be needed to better assess the durability of the responses induced by rIL-21. The immunomodulatory effects of IL-2 are highly dependent on the dose, route, and schedule of administration. Whether this will also hold true for rIL-21 has yet to be determined, especially as some in vitro effects of IL-2 and IL-21 differ, including effects on T cells, memory cells, and regulatory T cells. The dosing regimen used in this study was adapted from the US Food and Drug Administration–approved regimen for high-dose IL-2 and tailored to enable outpatient administration. Alternate dosing regimens and schedules may also be feasible. Davis et al22 recently conducted an open-label, two-arm phase I dose escalation study evaluating two different dosing regimens of rIL-21 in 29 patients with unresectable metastatic melanoma. Recombinant IL-21 was administered intravenously in an outpatient setting at doses between 1 and 100 µg/kg either three times per week for 6 weeks, or as three cycles of daily dosing for 5 days. The overall safety profile and DLTs were similar to the results observed in this study, and the MTD was also estimated to be 30 µg/kg. Although the primary focus of the Davis et al study was safety, preliminary evidence of antitumor effects was observed: 10 of 23 patients assessable for disease response per RECIST achieved SD or better (nine SD and one CR). In conclusion, this phase I study documented the toxicity profile, immunomodulatory effects, and pharmacokinetics of rIL-21 in patients with metastatic MM and RCC. The study demonstrated that repeated courses of rIL-21 can be administered in an outpatient setting with an acceptable safety profile and may be associated with promising antitumor effects. In light of the tolerability of rIL-21 therapy and evidence of antitumor activity in RCC, where 17 of 19 patients achieved SD or better on study (four with PR, 13 with SD), rIL-21 may be an appropriate candidate for combination with other agents. Additional studies have been initiated to test the use of rIL-21 as a single agent for first-line treatment of MM, in combination with signal transduction inhibitors (including sunitinib and sorafenib) in patients with metastatic RCC, and in combination with antibodies such as rituximab in patients with non-Hodgkin's lymphoma.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Eric L. Sievers, Zymogenetics (C), Seattle Genetics (C); Steven D. Hughes, Zymogenetics (C); Todd A. DeVries, Zymogenetics (C); Diana F. Hausman, Zymogenetics (C) Consultant or Advisory Role: John A. Thompson, Zymogenetics (U); Brendan D. Curti, Zymogenetics (U); Bruce G. Redman, Zymogenetics (U); Sanjiv S. Agarwala, Bayer-Onyx (C) Stock Ownership: Eric L. Sievers, Zymogenetics; Steven D. Hughes, Zymogenetics; Todd A. DeVries, Zymogenetics; Diana F. Hausman, Zymogenetics Honoraria: Jeffrey S. Weber, Zymogenetics; Sanjiv S. Agarwala, Novartis, Bayer-Onyx Research Funding: John A. Thompson, Zymogenetics; Brendan D. Curti, Zymogenetics; Bruce G. Redman, Zymogenetics; Jeffrey S. Weber, Zymogenetics Expert Testimony: None Other Remuneration: None
Conception and design: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Jeffrey S. Weber, Eric L. Sievers, Steven D. Hughes Financial support: Eric L. Sievers Provision of study materials or patients: John A. Thompson, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Sanjiv S. Agarwala Collection and assembly of data: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Eric L. Sievers, Todd A. DeVries Data analysis and interpretation: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Sanjiv S. Agarwala, Eric L. Sievers, Steven D. Hughes, Todd A. DeVries, Diana F. Hausman Manuscript writing: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Sanjiv S. Agarwala, Todd A. DeVries, Diana F. Hausman Final approval of manuscript: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Sanjiv S. Agarwala, Eric L. Sievers, Todd A. DeVries, Diana F. Hausman
We thank Michael Dodds and Jeremy Freeman for assistance in interpreting pharmacokinetic, pharmacodynamic, and antibody data; Pallavur Sivakumar for input regarding interleukin-21 biology; Roberta Connelly for assistance in article preparation (under the sponsorship of ZymoGenetics); and Patty Pedersen and Lily Chan for technical assistance.
published online ahead of print at www.jco.org on March 17, 2008 Supported by ZymoGenetics Inc, Seattle, WA. Presented in part at the International Society for Biological Therapy of Cancer Annual Meeting, Alexandria, VA, November 10-13, 2005; the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; European Organisation for the Research and Treatment of Cancer, Prague, Czech Republic, November 7-10, 2006. ClinicalTrials.gov identifier: NCT00095108 [ClinicalTrials.gov] . Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Moroz A, Eppolito C, Li Q, et al: IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: Comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 173:900-909, 2004 2. Parrish-Novak J, Dillon SR, Nelson A, et al: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57-63, 2000[CrossRef][Medline] 3. Parrish-Novak J, Foster DC, Holly RD, et al: Interleukin-21 and the IL-21 receptor: Novel effectors of NK and T cell responses. J Leukoc Biol 72:856-863, 2002 4. Peluso I, Fantini MC, Fina D,et al: IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178:732-739, 2007 5. Ugai S, Shimozato O, Kawamura K, et al: Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. Cancer Gene Ther 10:187-192, 2003[CrossRef][Medline] 6. Ugai S, Shimozato O, Yu L, et al: Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects. Cancer Gene Ther 10:771-778, 2003[CrossRef][Medline] 7. Wang G, Tschoi M, Spolski R, et al: In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res 63:9016-9022, 2003 8. Di Carlo E, Comes A, Orengo AM, et al: IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. J Immunol 172:1540-1547, 2004 9. Sondergaard H, Frederiksen KS, Thygesen P, et al: Interleukin 21 therapy increases the density of tumor infiltrating CD8(+) T cells and inhibits the growth of syngeneic tumors. Cancer Immunol Immunother 56:1417-1428, 2007[CrossRef][Medline] 10. Hughes SD, Krejsa C, Wagner F, et al: IL-21 enhancement of rituximab-mediated B cell depletion. J Clin Oncol 23:182S, 2005 (suppl; abstr 2568) 11. Hughes SD, Ponce RA, Krejsa C, et al: IL-21 improves rituximab-mediated B cell depletion. Blood 106:345, 2005 (abstr 345) 12. Edler L: Overview of phase I trials, in Crowley J (ed): Handbook of Statistics in Clinical Oncology. New York, NY, Marcel Dekker, 2001, pp 11-14 13. Mire-Sluis AR, Barrett YC, Devanarayan V, et al: Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods 289:1-16, 2004[CrossRef][Medline] 14. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organisation for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 15. Lotze MT, Matory YL, Ettinghausen SE, et al: In vivo administration of purified human interleukin 2: II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2. J Immunol 135:2865-2875, 1985[Abstract] 16. van Gameren MM, Willemse PH, Mulder NH, et al: Effects of recombinant human interleukin-6 in cancer patients: A phase I-II study. Blood 84:1434-1441, 1994 17. Atkins MB, Robertson MJ, Gordon M, et al: Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3:409-417, 1997[Abstract] 18. Gollob JA, Mier JW, Veenstra K, et al: Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: Ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 6:1678-1692, 2000 19. Chiron Corporation: Proleukin: Package insert. Emeryville, CA, Chiron Corporation, 2000 20. Robertson MJ, Mier JW, Logan T, et al: Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res 12:4265-4273, 2006 21. Schering Corporation: Intron A: Package insert. Kenilworth, NJ, Schering Corporation, 2006 22. Davis ID, Skrumsager BK, Cebon J, et al: An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 13:3630-3636, 2007 Submitted September 15, 2007; accepted December 17, 2007.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
z) of rIL-21 was 3.09 hours (38.8% coefficient of variation [CV]), the peak concentration (Cmax) was 141 ng/mL (74.2% CV), and the area under the concentration versus time curve extrapolated to time infinity (AUC0-
) was 219 ng x h/mL (37.3% CV). No statistically significant effects of cycle and day were observed in these parameters, as assessed by linear mixed-effects testing. 
