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Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (KOS-1022, 17-DMAG) Administered Intravenously Twice Weekly to Patients with Acute Myeloid Leukemia

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Phase I Study of the Heat Shock Protein 90 Inhibitor Alvespimycin (KOS-1022, 17-DMAG) Administered Intravenously Twice Weekly to Patients with Acute Myeloid Leukemia Leukemia (2010) 24, 699–705 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia JE Lancet1, I Gojo2, M Burton1, M Quinn2, SM Tighe3, K Kersey4, Z Zhong4, MX Albitar5, K Bhalla6, AL Hannah4 and MR Baer2,3 1H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2University of Maryland, Greenebaum Center, Baltimore, MD, USA; 3Roswell Park Cancer Institute, Buffalo, NY, USA; 4Kosan Biosciences, Hayward, CA, USA; 5Department of Hematopathology, Nichols Institute, San Juan Capistrano, CA, USA and 6Medical College of Georgia Cancer Center, Augusta, GA, USA Heat shock protein 90 (Hsp90) is a molecular chaperone with water-soluble analog of tanespimycin (17-allylamino- many oncogenic client proteins. The small-molecule Hsp90 17-demethoxygeldanamycin (17-AAG)). When compared with inhibitor alvespimycin, a geldanamycin derivative, is being tanespimycin, alvespimycin has higher potency against Hsp90, developed for various malignancies. This phase 1 study 7,8 examined the maximum-tolerated dose (MTD), safety and longer plasma half-life and oral bioavailability. Because of the pharmacokinetic/pharmacodynamic profiles of alvespimycin high incidence of activated Hsp90 client proteins in acute in patients with advanced acute myeloid leukemia (AML). myeloid leukemia (AML), we undertook a phase I study to Patients with advanced AML received escalating doses of delineate the safety and biologic profile of alvespimycin in 2 intravenous alvespimycin (8–32 mg/m ), twice weekly, for 2 of 3 advanced AML. weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for The primary objective of this study was to define the toxicity. Alvespimycin was well tolerated; the MTD was maximum-tolerated dose (MTD) and recommended phase II 24 mg/m2 twice weekly. Common toxicities included neutrope- dose of intravenous alvespimycin administered for 1 h on days nic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred 1, 4, 8 and 11 every 3 weeks in patients with advanced 2 at 32 mg/m (elevated troponin and myocardial infarction). AML. Safety, toxicity, responses and plasma pharmacokinetics Pharmacokinetics revealed linear increases in Cmax and area of alvespimycin were also evaluated, as well as its pharmaco- under the curve (AUC) from 8 to 32 mg/m2 and minor accumulation upon repeated doses. Pharmacodynamic ana- dynamic effect on Hsp90, Hsp70 and other client proteins and lyses on day 15 revealed increased apoptosis and Hsp70 levels on apoptosis in bone marrow and peripheral blood blasts. when compared with baseline within marrow blasts. Antileuke- mia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice- Patients and methods weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a Eligibility and treatment protocols recommended phase 2 dose of 24 mg/m2. Protocol for this open-label, multicenter, phase I dose escalation Leukemia (2010) 24, 699–705; doi:10.1038/leu.2009.292; clinical trial was approved by the institutional review boards of published online 28 January 2010 participating centers, and informed consent was obtained from Keywords: alvespimycin; phase I; acute myeloid leukemia; heat all patients in accordance with the Declaration of Helsinki. shock protein 90 Patients X18 years old with advanced or high-risk AML, including accelerated or blast-phase chronic myeloid leukemia, were eligible. Other inclusion criteria included Eastern Cooperative Oncology Group performance status p2, serum Introduction bilirubin p1.5 Â upper limit of normal, alanine transaminase and aspartate transaminase p2.5 Â upper limit of normal and Molecular chaperone proteins, including heat shock proteins, serum creatinine p2.0 mg per 100 ml. After cardiac toxicity was 1 serve to protect cells from damaging stress signals. One observed in two patients treated at 32 mg/m2, the protocol was particular chaperone, heat shock protein 90 (Hsp90), likely amended to include additional entry restrictions: patients were has a vital role in the survival and propagation of neoplastic required to have normal entry troponin levels, left ventricular cells through high-affinity binding to critical oncogenic proteins, ejection fraction X40% by multigated radionuclide angio- resulting in stereochemical stabilization of these client proteins graphy or echocardiogram, baseline corrected QT interval of 2–4 and protection from proteasomal degradation. The benzo- o450 ms for men and 470 ms for women and no left bundle quinone ansamycin geldanamycin derivatives are small- branch block. Patients with previous allogeneic hematopoietic molecule inhibitors of Hsp90, being developed in a variety of stem cell transplantation were excluded, but patients with 5,6 malignancies. Alvespimycin (17-dimethylaminoethylamino- previous autologous transplant at least 4 weeks before study 17-demethoxygeldanamycin (17-DMAG) KOS-1022) is a entry were eligible. Correspondence: Dr JE Lancet, Moffitt Cancer Center, 12902 Magnolia Drive, SRB4, Tampa, FL 33612, USA. Pretreatment evaluation E-mail: jeffrey.lancet@moffitt.org Complete history and physical examination, collection of base- Presented in abstract form at the 48th annual meeting of the American Society of Hematology, Orlando, FL, 10 December 2006. line hematologic and blood chemistry laboratory parameters Received 13 July 2009; revised 11 December 2009; accepted 16 and urinalysis were performed within 14 days of study entry. December 2009; published online 28 January 2010 After protocol amendment in September 2005 as detailed Alvespimycin i.v. for acute myeloid leukemia JE Lancet et al 700 above, screening echocardiograms or multigated radionuclide leukemia were based on previous recommendations.11 angiographies were obtained. Bone marrow aspirate and Responding patients were permitted to continue protocol biopsy were obtained within 28 days of entry, and cytogenetics therapy for up to 6 months, subject to safety and tolerability. and FLT3 (Fms-like tyrosine kinase 3) status were determined Patients with progressive disease were removed from the study. whenever possible. Additional studies (for example, computed tomography scans for extramedullary disease) were performed when clinically indicated. Pharmacokinetics To determine plasma alvespimycin levels, we obtained blood samples at the following time points on day 1: (1) before Study design infusion, (2) at 30 and 55 min after the start of infusion, (3) at Groups of three patients were sequentially assigned to alvespi- 5, 15, 30 and 60 min after the start of infusion, (4) at 2, 3, 4, 5, 6, mycin cohorts, beginning at 8 mg/m2, given on days 1, 4, 8 and 24, 48 and 72 h after the start of infusion and (5) at the same time 11 every 3 weeks. The initial dose (8 mg/m2) was based on points but only up to 24 h on day 11. We analyzed these levels safety data in a different phase I clinical trial of intravenous using a liquid chromatography/tandem mass spectrometry alvespimycin administered twice weekly.9 method. In brief, 50 ml of plasma was mixed with 200 mlof Toxicities were classified according to the National Cancer acetonitrile containing 4 ng/ml KOS-1761 (an alvespimycin Institute Common Toxicity Criteria version 3.0. Dose-limiting analog) as an internal standard. Samples were filtered through toxicity (DLT; assessed during or after cycle 1 only) was defined a 0.22-mm filter, and 10 ml of each filtrate was injected onto as: (1) any non-hematologic toxicity of grade X3 considered an liquid chromatography/tandem mass spectrometry system unrelated to underlying disease or tumor lysis syndrome consisting of a Shimadzu HPLC (Shimadzu Scientific Instrument, persisting for X14 days (the occurrence of any clinically Columbia, MD, USA) and a Waters Quattro Premiere triple significant grade X3 toxicity, however, was labeled a DLT quadrapole mass spectrometer (Waters Corporation, Milford, regardless of duration); (2) grade 3 nausea and/or vomiting that MA, USA). A 2.1 Â 50 mM RP-Max column (Phenomenex, persisted for at least 48 h despite the use of adequate/maximal Torrance, CA, USA) separated alvespimycin from other inter- medical intervention and/or prophylaxis; and (3) grade fering analytes in plasma. The bioanalytical method was 4 neutropenia or thrombocytopenia persisting beyond day 42, validated to quantify alvespimycin from 0.2 to 500 ng/ml, with in the absence of detectable leukemia. After the occurrence of a lowest limit of quantification of 0.2 ng/ml. two events of cardiac ischemia in the final cohort, the protocol Noncompartmental pharmacokinetic analyses were per- was amended to define as DLT any (new) occurrence of atrial formed on individual plasma concentration versus time data dysrhythmia, grade 3–4 QTc prolongation, or any troponin-I after doses 1 and 4. WinNonlin version 5.2 (Pharsight, Mountain elevation. If DLT occurred in 1 of 3 patients, the group was View, CA, USA) was used for all computations. Dose propor- expanded to 6 patients. If no further toxicity was observed, tionality was assessed by a power model: area under the curve 3 patients were enrolled at the next dose level. Doses were (AUC) ¼ adose b in which a is the intercept and b is
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