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Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4804-4809 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.185 Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)From the Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX; Children's Oncology Group Operations Center, Arcadia, CA; Rainbow Babies and Children's Hospital, Cleveland, OH; Hospital Ste-Justine, Montréal, Canada; and Children's Hospital of Philadelphia, Philadelphia, PA. Address reprint requests to Susan M. Blaney, MD, Texas Children's Cancer Center, 6621 Fannin, CC 1410.00, Houston, TX 77030; e-mail: sblaney{at}txccc.org
PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors. PATIENTS AND METHODS: An intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Fifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2 dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% ± 7.6% at the 1.2 mg/m2/dose and 76.5% ± 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses. CONCLUSION: Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.
Bortezomib (formerly PS-341, Velcade; Millennium Pharmaceuticals Inc, Cambridge, MA), a dipeptidyl boronic acid, is a novel agent that exerts an antitumor effect through specific and selective inhibition of the 26S proteasome. The 26S proteasome is an adenosine triphosphate–dependent multicatalytic protease that is central to the ubiquitin-proteasome pathway. This pathway plays a pivotal role in the regulated degradation of proteins involved in cell cycle control and tumor growth.1 There are many important regulatory proteins that are affected by inhibition of the ubiquitin proteasome pathway, including nuclear factor kappa ß, p53, and the cyclin-dependent kinase inhibitor p21. Aberrant regulation or dysfunction of cell cycle proteins can result in accelerated and uncontrolled cell division, leading to tumorigenesis, cancer growth, and metastasis. In preclinical studies, bortezomib has been shown to have antitumor activity at nanomolar concentrations in a variety of cell lines. Activity has been observed against a broad range of tumor types, including CNS malignancies, melanoma, non–small-cell lung cancer, and colon, ovarian, renal, and prostate carcinomas.2 Preclinical antitumor activity of proteasome inhibitors has also been observed in leukemias and lymphomas and childhood tumors such as neuroblastoma,3,4 rhabdomyosarcoma,5 and Ewing's sarcoma.6 The pattern of growth inhibition and cytotoxic activity of bortezomib is unique compared with other anticancer agents, suggesting a novel mechanism of cytotoxicity.7 Two bortezomib dosing schedules have been evaluated in adult phase I clinical trials: a twice weekly for 4 weeks schedule followed by a 2-week rest, and a twice weekly for 2 weeks schedule followed by a 2-week rest. The maximum-tolerated dose (MTD) for the twice weekly for 4 weeks schedule was 1.04 mg/m2. Dose-limiting toxicities at higher dose levels (1.20 or 1.38 mg/m2) included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise.8 Other serious adverse events included one episode of postural hypotension and one hypersensitivity reaction.8 Antitumor activity was observed in patients with refractory multiple myeloma and non-Hodgkin's lymphoma.8 The MTD for the twice weekly for 2 weeks schedule was 1.56 mg/m2.9 The dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. There was no dose-limiting hematologic toxicity.9 There was one objective response in a patient with non–small-cell lung carcinoma.9 The antitumor activity of bortezomib was confirmed in two recently completed phase II clinical trials in adults with multiple myeloma.10 The overall objective response rate after bortezomib administration was 33% in a heavily pretreated population. This high level of antitumor activity resulted in recent US Food and Drug Administration approval of bortezomib for third-line treatment in adults with multiple myeloma. A randomized phase III trial of bortezomib versus high-dose dexamethasone in patients with multiple myeloma is in progress. This report presents the results of a phase I trial and pharmacodynamic study of bortezomib, given twice weekly for 2 consecutive weeks every 21 days, in pediatric patients with refractory solid tumors. The objectives of this study were to identify the optimal bortezomib dose for phase II pediatric trials, to determine the incidence and severity of toxicities associated with bortezomib administration, and to evaluate inhibition of the 20S proteasome after bortezomib administration.
Patient Eligibility Patients younger than 22 years of age with a histologically confirmed solid tumor refractory to standard therapy were eligible for this trial. Patients with intrinsic brainstem gliomas or optic pathway tumors were excluded from the requirement for histologic verification. Other eligibility criteria included: a Karnofsky or Lansky performance score of  50; a life expectancy of greater than 8 weeks; adequate bone marrow function [absolute neutrophil count 1,500/µL, platelet count 75,000 µL (transfusion independent), and hemoglobin 8 gm/dL]; adequate liver function (serum bilirubin < 1.5 mg/dL, ALT < 5 x the upper limit of normal for age, and albumin 2 g/dL); adequate renal function (serum creatinine below the upper limits or normal for age or a radioisotope glomerular filtration rate 70/mL/min/1.73 m2); recovery from the toxic effects of prior chemotherapy, radiotherapy, and immunotherapy with a minimum elapsed period of at least 3 months for prior allogeneic stem-cell transplant and of at least 6 months for prior craniospinal or hemipelvic radiation. Study exclusion criteria included pregnancy or lactation in women of childbearing age, uncontrolled infection, receipt of concomitant anticonvulsants, or prior receipt of study drug. Informed consent was obtained from the patient or his or her parent in accordance with the US National Cancer Institute (NCI), Children's Oncology Group, and individual institutional policies before entry onto this study.
Dosage and Drug Administration
Trial Design A minimum of three patients were entered at each dose level and the dose level was expanded to up to six patients if one patient experienced dose-limiting toxicity during the first course of therapy. When dose-limiting toxicity was observed in two patients of a cohort of three to six patients receiving the same dose of drug, the MTD was exceeded and an additional three to six patients were added at the dose level immediately below the dose level at which the unacceptable level of toxicity was observed. The MTD of bortezomib was defined as the dose level immediately below the level at which at least two patients experience dose-limiting toxicity.
Toxicities were graded according to the NCI Common Toxicity Criteria (version 2.0). Dose-limiting nonhematologic toxicity was defined as any grade 3 or 4 adverse event attributable to the study drug with the specific exclusion of grade 3 nausea or vomiting, grade 3 hepatic transaminase (AST and/or ALT) elevation returning to Patient history, physical examination, and laboratory studies were obtained before treatment and then weekly throughout the first course of therapy and before subsequent courses thereafter. CBCs were obtained at least twice weekly throughout the first course of study and then weekly. Patients with measurable disease had appropriate radiographic or bone marrow evaluations at baseline, after the first and second course of therapy, and then every other course thereafter.
Criteria for Assessment of Response
Pharmacodynamic Studies Inhibition of 20S proteasome activity was measured using a previously described assay developed by investigators at Millennium Pharmaceuticals Inc.11 Briefly, blood cells were lysed with 5 mmol/L EDTA (pH 8.0) for 1 hour and then centrifuged at 600 x g for 10 minutes at 40°C. The resultant whole blood lysate samples were added to substrate buffer (20 mmol/L HEPES, 0.5 mmol/L EDTA, 0.05% sodium dodecyl sulfate, and 60 mmol/L chymostrypsin substrate–Suc-Leu-Leu-Val-Tyr–amido-4-methylcoumarin [AMC]; Bachem, King of Prussia, PA). The reaction was carried out for 37°C for 5 minutes, and the in vitro chymotryptic activity of the 20S proteasome was measured by monitoring the release of the fluorophore AMC from the synthetic peptide substrate LLVY-AMC. The protein content of the samples was determined using a Coomassie protein assay (Pierce Corp, Rockford, IL).
Fifteen patients were enrolled onto this study, of whom 11 were fully assessable for toxicity and response. Two patients were not fully assessable for toxicity because they did not complete the first course of bortezomib secondary to rapid disease progression; two additional patients were not fully assessable because twice-weekly CBCs were not obtained during course 1. These inassessable patients did not experience any unusual or severe bortezomib-related toxicity. Patient characteristics for the assessable patients are listed in Table 1.
Nine patients assessable for response—five at dose level 1 (1.2 mg/m2/dose) and four at dose level 2 (1.6 mg/m2/dose)—received one course of therapy. One patient enrolled at the 1.6 mg/m2/dose level received two courses of therapy. One patient enrolled at the 1.2 mg/m2/dose level received six courses of therapy. There were no objective antitumor responses.
Adverse Events
Thrombocytopenia, which prevented administration of the complete first course of therapy, was dose-limiting in two of five assessable patients at the 1.6 mg/m2/dose level. Both of these patients had baseline platelet counts that exceeded 100,000/µL. Grade 1 peripheral neuropathy was reported in one patient; however, there was no dose-limiting peripheral neuropathy. There were no other severe or unusual adverse events.
Pharmacodynamics
In this trial, we evaluated the clinical toxicities of bortezomib administered twice weekly for 2 consecutive weeks followed by a 1-week rest. Bortezomib is a novel anticancer agent that selectively inhibits the Z6S proteasome, an ATP-dependent multisubunit protein that degrades proteins involved in multiple cellular processes including cell cycle regulation, transcription factor activation, apoptosis, and cell trafficking.12 Bortezomib was well tolerated with minimal systemic toxicity. The toxicity profile of bortezomib in children was similar to that in adults. However, in contrast to the experience in adults, peripheral neuropathy was not a predominant toxicity. This may be a reflection of the fact that peripheral neuropathy associated with anticancer agents seems to be less common in children than in adults. However, it may also be a reflection of the limited exposure to bortezomib of the children treated; the median number of cycles administered was only one. Therefore, children who receive multiple cycles of bortezomib in future trials should be observed closely for the occurrence of this toxicity. Thrombocytopenia, which prevented administration of a complete course of therapy at the assigned dose level, was the dose-limiting toxicity at the 1.6 mg/m2 dose level. Thus, the recommended dose of bortezomib for additional evaluation in children with solid tumors is the 1.2 mg/m2/dose. There are numerous preclinical studies demonstrating that bortezomib potentiates the cytotoxic effect of multiple chemotherapeutic agents, including dexamethasone,13 doxorubicin, and melphalan.14 Similarly, bortezomib has been shown to increase mouse mammary tumor sensitivity to cyclophosphamide and cisplatin, pancreatic and colorectal cell line sensitivity to irinotecan,15,16 and pancreatic cell line sensitivity to gemcitabine.17 There is also evidence that bortezomib may be synergistic with other apoptotic agents such as tumor necrosis factor–related apoptosis inducing ligand,18 and with heat-shock binding proteins, such as geldanamycin or 17-allylaminogeldanamycin.19,20 Thus, on the basis of the results of these preclinical studies, the preliminary results of adult clinical trials, and the favorable toxicity profile of this agent in phase I clinical trials, it is reasonable to pursue additional pediatric development of bortezomib despite the fact that there was no objective antitumor activity observed in this phase I trial. It is not uncommon for there to be minimal or no observed antitumor activity in pediatric phase I clinical trials because they involve a limited number of heavily pretreated patients who have diverse tumor types, and are not designed to assess antitumor activity as a study end point. In summary, bortezomib was well tolerated in children with refractory solid tumors, and the recommended dose for additional study in children (1.2 mg/m2/dose) is similar to doses administered to adults. Because the dose-limiting toxicity of bortezomib in children with solid tumors was hematologic, a separate phase I study in children with recurrent or refractory leukemias will be performed in an attempt to identify the nonhematologic dose-limiting toxicity of this agent. In addition, the results of preclinical studies in pediatric tumor cell lines will be used to guide additional pediatric development of this novel agent in pediatric solid tumors.
The authors indicated no potential conflicts of interest.
Supported by National Cancer Institute grant No. U01 CA97552 and National Center for Research Resources grant No. M01 RR00188-37. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Fenteany G, Standaert R, Reichard G, et al: A beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line. Proc Natl Acad Sci U S A 91:3358-3362, 1994 4. Omura S, Matsuzaki K, Fujimoto T: Structure of lactacystin, a new microbial metabolite which induces differentiation of neuroblastoma cells. J Antibiot 44:117-118, 1991[Medline] 5. Mugita N, Honda Y, Nakamura H: The involvement of proteasome in myogenic differentiation of murine myocytes and human rhabdomyosarcoma cells. Int J Mol Med 3:127-137, 1999[Medline]
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8. Orlowski R, Stinchcombe T, Mitchell B, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002
9. Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-2511, 2002
10. Richardson P, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003
11. Lightcap ES, McCormack TA, Pien C, et al: Proteasome inhibition measurements: Clinical applications. Clin Chem 46:673-683, 2000 12. Teicher B, Ara G, Herbst R, et al: The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2368-2645, 1999
13. Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071-3076, 2001 14. Mitsiades N, Mitsiades C, Richardson P, et al: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications. Blood 101:2377-2380, 2002
15. Cusack J Jr, Liu R, Houston M, et al: Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappa B inhibition. Cancer Res 61:3535-3540, 2001 16. Shah S, Potter M, McDade T, et al: 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 82:110-122, 2001[CrossRef][Medline] 17. Bold R, Virudachalam S, McConkey D: Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11-17, 2001[CrossRef][Medline]
18. Sayers T, Brooks A, Koh C, et al: The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102:303-310, 2003 19. Mimnaugh E, Xu W, Isaacs J, et al: Geldanamycin combined with PS-341 synergistically activates a cellular stress response, causes massive accumulation of ubiquitinated proteins and shows enhanced antitumor activity. Proc Am Assoc Cancer Res 43:179, 2003 (abstr 785) 20. Mitsiades C, Mitsiades N, Poulaki V, et al: Hsp90 inhibitors prolong survival in a SCID/NOD mouse model of diffuse multiple myeloma: Therapeutic implications. Proc Am Assoc Cancer Res 43:180, 2003 (abstr 788) Submitted December 26, 2003; accepted September 22, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 1. If a patient experienced any ongoing drug-related grade 2 toxicities at the time of a scheduled bortezomib dose, then subsequent doses in that cycle were reduced to the previous dose level. Similarly, for drug-related grade 3 or greater toxicities during a course of therapy, the next dose of bortezomib was either withheld or omitted. 
