Cancer Therapy: Clinical Phase I Study of YM155, a Novel Survivin Suppressant, in Patients with Advanced Solid Tumors

Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m/d. The MTD was determined to be 8.0 mg/m/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/ anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens. Survivin, a member of the inhibitor of apoptosis family of proteins, is expressed during embryonic and fetal development, but is undetectable in normal adult human tissues, apart from thymus, placenta, CD34 cells, and some cells within the basal crypt layer of the gastrointestinal tract (1–5). In vitro studies suggest that survivin inhibits cell death induced via the extrinsic and intrinsic apoptotic pathways. In addition, survivin may also confer resistance to apoptosis by directly suppressing caspase activity (3). Overexpression of survivin has been shown in a variety of human cancers and is reportedly associated with a poor prognosis (6–13). It has been shown that the suppression of survivin induces tumor cell apoptosis and also enhances the sensitivity to apoptosis induced by existing anticancer drugs and other apoptotic stimuli (4, 14–16). YM155 is a novel survivin suppressant that is currently in clinical development by Astellas Pharma, Inc. A preclinical study showed that YM155 suppressed both survivin protein and mRNA expression (17). In addition, sensitivity to YM155 was high in various human tumor cell lines such as hormone-refractory prostate cancer (17) and malignant lymphoma. Furthermore, YM155 exerted greater antitumor activity compared with existing anticancer drugs, and YM155 concentrations were higher in tumor tissue than in plasma. In a toxicologic study, short-term exposure at high blood concentrations caused cardiotoxicity in the form of atrioventricular Authors' Affiliations: Department of Medical Oncology, Kinki University School of Medicine; and Japan Society for Cancer Chemotherapy, Osaka, Japan; Marumo Hospital, Aichi, Japan; Social Insurance Chuo General Hospital; Kitasato University School of Medicine; National Cancer Center Hospital; and Astellas Pharma, Inc., Tokyo, Japan Received 7/14/08; revised 2/5/09; accepted 2/23/09; publishedOnlineFirst 5/26/09. Grant support: Astellas Pharma, Inc. The costs of publication of this articleweredefrayed in part by thepayment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Taroh Satoh, Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan. Phone: 81-72-366-0221; Fax: 81-72-360-5000; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-1946 8 Unpublished data. 3872 Clin Cancer Res 2009;15(11) June 1, 2009 www.aacrjournals.org Research. on April 16, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from block and myocardial degeneration/necrosis, as well as nephrotoxicity, mainly displayed as proximal tubular necrosis and increased serum creatinine. In contrast, long-term exposure at low blood concentrations by 168-hour continuous infusion did not cause cardiotoxicity. Based on the differential expression of survivin in human malignancies and the negative prognostic role, together with preclinical antitumor activity and encouraging safety data, a phase I study of YM155 in patients with advanced solid tumors was conducted in Japan. The aim of this study was to determine the recommended dose and pharmacokinetic profile of YM155 and to evaluate its safety profile and antitumor effects. Patients and Methods Study design. This was an open-label, single-center, nonrandomized, phase I dose-escalation study. The primary objective was to assess the safety of YM155 administered to patients with advanced solid tumors. The secondary objectives included the investigation of the pharmacokinetic profile and tumor activity of YM155. After one cycle, patients could continue further treatment until either an unacceptable toxicity was experienced or disease progression occurred. Inclusion and exclusion criteria. Eligibility criteria for patients enrolled in this study included refractory advanced solid tumors for which no standard therapy existed; histologic or cytologic diagnosis of cancer; at least 20 y of age; life expectancy of at least 12 wk; Eastern Cooperative Oncology Group performance status of <3; and adequate hematopoietic, hepatic, and renal functions (absolute neutrophil count of ≥1.5 × 10/L, platelets of ≥100 × 10/L, hemoglobin of ≥9 g/dL, bilirubin within 1.5× upper limit of normal, transaminases of ≤2.5× upper limit of normal, and creatinine of <1.5 × upper limit of normal). Patients must have discontinued all cancer therapies for at least 4 wk before study entry. Exclusion criteria included primary brain tumor or known central nervous system metastases, and uncontrolled clinically significant disease unrelated to the primary malignancy. The study was approved by the ethics board of the participating center, and all patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki and the applicable guidelines on good clinical practice. Dosage and drug administration. YM155 was prepared for administration by dilution of an appropriate volume of concentrated stock solution in 5% dextrose in a lightand temperature-controlled environment. The diluted drug was administered via continuous i.v. infusion over 168 h, followed by 14-d observation (1 cycle). This method of administration was selected because toxicity studies using 168-h continuous infusion in dogs showed no cardiotoxicity and time-dependent antitumor activity. A starting dose of 1.8 mg/m/d was chosen on the basis of toxicologic studies in rodents and the data from a U.S. phase I study (18). To avoid renal toxicity with YM155, patients were instructed to take sufficient quantities of water during administration of the drug. Toxicity (tolerability and safety evaluation). The following safety assessments were done for each patient: subjective/objective symptoms, vital signs, laboratory tests, and 12-lead electrocardiogram. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0. Creatinine clearance was determined by the evaluation of fluctuations in urine creatinine and serum creatinine concentrations. A dose-limiting toxicity (DLT) was defined as an adverse drug reaction including nonhematologic toxicities ≥grade 3, except transient hyperglycemia and anorexia, and serum creatinine increased to ≥2.0 mg/dL; grade 4 hematologic toxicities, except a decreased neutrophil count of grade 4 (<500/μL) persisting for 5 d or less; nausea, vomiting, or diarrhea ≥grade 3 occurring despite prophylaxis after the first episode; and failure to satisfy the criteria for the next cycle within the specified period due to unresolved adverse drug reactions. The maximum tolerated dose (MTD) was defined as the dose that was one level lower than that at which DLT occurred in more than two of six patients. Pharmacokinetics. The pharmacokinetic parameters of YM155 were evaluated during cycles 1 and 2. Venous blood samples, from a site other than the infusion site, were collected in tubes containing heparin sodium immediately before the start of the infusion (time 0): at 0.25, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 120, and 144 h after the start of infusion; at the end of infusion (168 h); and at the following times thereafter: 168.25, 168.5, 169, 170, 171, 172, 174, 180, 192, and 216 h. Samples were centrifuged immediately, and the resulting plasma was stored at −20°C before analysis. Urine samples were collected over 216 h after the start of continuous infusion to determine the urinary concentration of YM155 and were stored at −20°C before analysis. Concentrations of YM155 were measured by Astellas Europe B.V. EDD using validated liquid chromatography tandem mass spectrometry procedures (18) and following Good Laboratory Practice. The lower limits of quantitation for YM155 were 0.05 ng/mL in plasma and 1.0 ng/mL in urine. The concentrations are expressed as those of the cationic moiety of YM155. Pharmacokinetic analysis was done in a model-independent manner using actual values of plasma concentration and actual time from the start of continuous infusion. Values below the lower limits of quantitation were treated as zero. Efficacy (tumor assessment). Evaluations of lesions were done with computed tomography, magnetic resonance imaging, and bone scintigraphy, with tumor markers also evaluated. Assessment of antitumor activity was done in accordance with the Response Evaluation Criteria in Solid Tumors guidelines (19).