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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3678-3685 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.4964 Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report
From the Departments of Hematology-Oncology, Molecular Pharmacology and Pharmaceutical Sciences, St Jude Children's Research Hospital; Keck School of Medicine, University of Southern California, Los Angeles; Children's Oncology Group Operations Center, Arcadia, CA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; Children's Hospital of Philadelphia, Philadelphia, PA; Texas Children's Cancer Center/Baylor College of Medicine, Houston, TX Address reprint requests to Maryam Fouladi, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org, CC: pubs{at}childrensoncologygroup.org
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. RESULTS: There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m2 with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. CONCLUSION: Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.
Deregulated acetylation of histones plays an important role in the pathogenesis of many malignancies by altering chromatin structure and gene transcription.1-5 The removal of acetyl groups from histones by histone deacetylases (HDACs) leads to compaction of chromatin and silencing of gene transcription.2 HDAC inhibitors are associated with open chromatin structure, activating the transcription of previously silenced genes that lead to cellular differentiation, inhibition of cell cycle progression, and induction of apoptosis.6 Depsipeptide is a novel HDAC inhibitor with potent in vitro activity against many human tumor cell lines at concentrations of less than 10 nmol/L7 and in a variety of xenograft models.8-17 Depsipeptide leads to cell cycle arrest at G1/G2M,18 downregulation of cyclin D1, upregulation of p21,19 and inhibition of angiogenesis.20 In adults with recurrent solid tumors, depsipeptide given on day 1 and 5 of a 21-day course was well tolerated with a maximum-tolerated dose (MTD) of 17.8 mg/m2. Dose-limiting toxicities (DLTs) included nausea, vomiting, fatigue, and myelosuppression. Nonspecific ECG changes, including ST-T wave abnormalities and atrial fibrillation, were also reported.21 Accumulation of acetylated histones was observed in patients' peripheral blood mononuclear cells (PBMCs) for up to 24 hours after the infusion. A weekly for 3 consecutive weeks every 28 days schedule of depsipeptide was better tolerated with DLTs of fatigue and thrombocytopenia and an MTD of 13.3 mg/m2. Asymptomatic, nonspecific ST-T wave changes22 and QTc prolongation23 have been reported with this schedule. In phase II trials, depsipeptide has shown activity in patients with peripheral and cutaneous T-cell lymphoma.24 We report the results of a phase I trial of depsipeptide in children with recurrent or refractory solid tumors. The primary objectives of this trial were to estimate the MTD and DLTs of depsipeptide given as a 4-hour intravenous infusion weekly for 3 consecutive weeks every 28 days. The secondary objectives were to assess the biologic activity of depsipeptide by measuring histone acetylation status in PBMCs, to characterize the pharmacokinetics of depsipeptide in children, and to preliminarily evaluate its antitumor activity.
Patient Eligibility To be eligible patients had to be younger than 22 years of age with a histologically verified solid tumor refractory to conventional therapy, a Lansky or Karnofsky performance score of 60 or higher, and a life expectancy 8 weeks or longer. Patients must have recovered from the acute toxic effects of prior therapy, and must not have received any of the following: growth factors within 1 week of study entry, myelosuppressive chemotherapy within 3 weeks, craniospinal or hemipelvic radiotherapy for 6 months or longer, local palliative radiotherapy for 2 weeks or longer, or allogeneic stem-cell transplant 6 months or longer. Patients on enzyme inducing anticonvulsants, hydrochlorothiazide, medications associated with QTc prolongation or those with uncontrolled infection, congestive heart failure, uncontrolled cardiac arrhythmias, QTc higher than 450 milliseconds, and pregnant or lactating women were excluded. Other requirements included adequate bone marrow function (peripheral absolute neutrophil count, 1,000/µL or higher; platelet counts 100,000/µL or higher [transfusion independent]; hemoglobin, 8.0 g/dL or higher), adequate renal function (age-adjusted normal serum creatinine or a glomular filtration rate, 70 mL/min/1.73m2 or higher), adequate liver function (total bilirubin 1.5x institutional upper limit of normal for age or higher); ALT (5x institutional upper limit of normal for age or lower and albumin 2 g/dL or higher); adequate cardiac function (shortening fraction of 27% or higher by echocardiogram or an left ventricular ejection fraction of 50% or higher by gated radionuclide study); adequate pulmonary functions, and normal serum calcium, magnesium, and potassium. Informed consent was obtained from patients, parents, or guardians, and assent was obtained as appropriate, at the time of protocol enrollment. The protocol was approved by the institutional review boards of participating institutions.
Drug Administration and Study Design The starting dose of depsipeptide was 10 mg/m2 (80% of the adult MTD). Dose levels for subsequent groups of patients were escalated in 30% increments. Requirements for subsequent courses of therapy included hemoglobin 8 g/dL or higher, absolute neutrophil count 1,000/µL or higher, platelets 75,000/µL or higher, and serum calcium, magnesium, and potassium within institutional normal limits. A minimum of three assessable patients were treated at each dose level. If one of three patients at a given dose level experienced a DLT, three more patients were accrued at the same dose level. If two or more patients experienced DLT, then the MTD was exceeded and three more patients were treated at the next lower dose level. The MTD was defined as the dose level at which at most one patient experienced DLT with at least two of three to six patients experiencing a DLT at the next higher level. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). Hematological DLT was defined as grade 4 neutropenia of longer than 7 days duration, grade 4 thrombocytopenia requiring more than two transfusions in the first 28 days, or any hematological toxicity that resulted in a longer than 7-day delay beyond the planned interval between treatment courses. Nonhematologic DLT was defined as grade 3 or 4 nonhematologic toxicity with the specific exclusion of grade 3 nausea and vomiting controlled with adequate antiemetic prophylaxis, grade 3 transaminase elevations that return to grade 1 or lower before the next treatment course, or grade 3 transaminase elevation that occurred before completion of the first course and resolved to lower than grade 2 before the start of the next course. Dose limiting cardiac toxicity was defined as course 1 related QTc prolongation longer than 500 milliseconds in patients with normal serum electrolytes, atrial or ventricular arrhythmias, T-wave inversions in all inferior or lateral ECG leads, ST segment deflection below the J point 2 mm or more below baseline in inferior or lateral leads, troponin I higher than 5 ng/mL, left ventricular ejection fraction decrease to 40% or less or decreased by 25% or more, but not below 40% verified by multiple-gated acquisition (MUGA). Pretreatment evaluations included a history, physical examination, CBC, electrolytes, renal and liver function tests, serum protein, and albumin. Serum total creatine phophokinase and troponin I were required prestudy, 24 hours after the first dose, twice-weekly in the first course, and as clinically indicated thereafter. MUGA scans were required pretherapy, before course 3, and every third course, thereafter. CBCs were obtained twice-weekly during the first course and weekly thereafter. History, physical examinations, and laboratory studies were obtained weekly in course 1 and before each subsequent course. ECGs were obtained within 24 hours before start of the drug on day 1 of each course. During course 1, ECGs were obtained within 2 hours after completion of the day 1 infusion and within 24 hours before the infusions on days 8 and 15 and then before each subsequent course. All ECGs were reviewed by local cardiologists and by the study cardiologist. Disease evaluations were obtained at baseline, at the end of course 1, and after every other course. Tumor response was reported using the Response Evaluation Criteria in Solid Tumors (RECIST).25
Pharmacokinetics Studies
Pharmacokinetic analyses were performed using compartmental techniques and maximum likelihood estimation as implemented in ADAPT II (Biomedical Simulations Resources, University of Southern California, Los Angelos, CA).27 Appropriateness of model fit was determined from visual examination of the goodness of fit and the regression coefficient. Estimated model parameters included the volume of the central compartment (Vc), elimination rate constant (ke), and the intercompartment rate constants (kcp and kpc). Systemic clearance (CL), terminal half-life (T1/2ß), and area under the plasma depsipeptide concentration-time curve from 0 to infinity (AUC0-
Biologic Assays Sample preparation. Three mL phosphate-buffered saline (PBS) was added to 2 mL whole blood collected in heparin; samples were mixed. Diluted blood was layered onto 5 mL Histopaque 1077 (Sigma-Aldrich, Zwijndrecht, the Netherlands) in 15 mL conical tubes, centrifuged at 400 xg for 30 minutes at room temperature. The upper layer, to within 0.5 cm of the opaque interface containing PBMC, was aspirated and discarded. The opaque interface with PBMC cells was transferred to clean conical centrifuge tubes, mixed with 10 mL PBS, and centrifuged at 250 xg for 10 minutes. The lymphocyte pellet was resuspended and washed twice with 5 mL PBS, centrifuged (250 xg, 10 minutes), resuspended in PBS, and retained on ice. Cells were resuspended at 6 x105/mL. Fifty µl of cell suspension was transferred into a cytospin funnel, and centrifuged for 8 minutes at 400 rpm. Slides were air dried at room temperature. Immunohistochemistry. Polyclonal rabbit antibodies against H3-histone (Upstate, Chicago, IL) and acetyl-H3-histone (Upstate) were used for immunocytochemical detection. Cells on cytoslides were fixed 1 minute in the mixture of 95% ethanol and 5% acetic acid, washed twice in PBS for 15 minutes, and incubated 1 hour in 1% bovine serum albumin in PBS (PBSA; blocking reagent). Cells were washed twice with PBS for 15 minutes and incubated overnight at 4°C with corresponding antibodies diluted with PBSA. Cells were washed twice for 5 minutes with PBS, and incubated in the dark for 1 hour with goat antirabbit IgG fluorescent-conjugated secondary antibody diluted with PBSA. Control cells were treated with nonspecific rabbit IgG or PBS followed by incubation with a secondary antirabbit antibody. After washing three times with PBS for 5 minutes, slides were mounted in Vectashield medium: 50% Vectashield (Vector Laboratories Inc, Burlingame, CA), 45% glycerol, 5% 1M Tris-Hcl pH 7.5, 2 µL/mLDAPI (Roche, Nutley, NJ). Cells were examined using a confocal microscope (Leica, model TCS SP, Wetzlar, Germany), and images captured were taken.
Of 24 patients enrolled onto the study, one was ineligible (taking contraindicated medication). Among the remaining 23 patients, 18 were assessable for toxicity. Table 1 summarizes the characteristics of eligible patients. Among the five toxicity-unassessable patients, one patient withdrew after one dose, two patients withdrew before therapy, one patient withdrew because of nondose limiting nausea and vomiting, and one patient experienced progressive disease during course 1. The median number of courses of depsipeptide was one (range, 1 to 7).
Toxicity Table 2 summarizes the DLTs reported on this trial. DLTs in three patients included asymptomatic, reversible T-wave inversions in the inferior leads at 22 mg/m2 (n = 2) and in the lateral leads at 13 mg/m2 (n = 1), without associated change in troponin levels or ejection/shortening fraction. The changes resolved within 24 hours in two patients, but were noted on the day 8 predepsipeptide ECG in one patient. One patient at 17 mg/m2 developed asymptomatic, reversible (within 48 hours) sick sinus syndrome and grade 4 hypocalcemia.
Among the 18 assessable patients, 129 ECGs were performed and centrally reviewed. Grade 1 (QTc, > 450 to 470 msec) and 2 (QTc, > 470 to 500 msec) QTc prolongation was documented in 17 ECGs in seven patients and was detectible up to the day 15 preinfusion ECG. No changes were noted on serial MUGA scans in these patients. One patient, on coumadin for a pre-existing deep vein thrombosis, experienced increases in fibrinogen, prothrombin time, partial thromboplastin time, D-dimer, and factor VIII. Depsipeptide potentiation of the effects of coumadin could not be ruled out. Overall, depsipeptide was well tolerated. Table 3summarizes all grade 2 or higher adverse events that were possibly, probably, or definitely attributable to depsipeptide.
Responses No objective responses were reported. Three patients (one each with ependymoma, peripheral primitive neuroectodermal tumor, and rhabdomyosarcoma) experienced prolonged disease stabilization for four, five, and seven courses, respectively.
Pharmacokinetics
Pharmacodynamic Data Biology studies were received in 12 patients: three were delayed in or damaged during shipment, one was sent frozen and could not be processed, and in another no pretreatment sample was provided. Samples from dose levels 13 mg/m2 (n = 5), 17 mg/m2 (n = 2), and 22 mg/m2 (n = 2) were analyzed. The level of H3 histone and acetyl-H3 histone were evaluated visually on scale from 1 to 4 according to intensity of specific immunofluorescence detected in nuclei of PBMCs. The level of H3 histone remained constant during and postinfusion of depsipeptide in all samples. In contrast, the intensity of acetyl-H3 immunofluorescence increased gradually, from the base level of 1+ intensity to 2+ (two patients), 3+ (for three patients), or 4+ (four patients). Despite the short median t1/2 reported for depsipeptide (range, 1.5 hours to 2.4 hours), the maximal intensity of acetyl-H3 immunofluorescence in PBMCs was variable and was detected at a median of 4 hours (range, 0 hour to 20 hours) after the end of infusion. Figure 3 demonstrates accumulation of acetyl H3 histones in a patient before therapy and 2 hours after the end of the depsipeptide infusion.
This pediatric phase I trial establishes the MTD of depsipeptide as 17 mg/m2 given weekly for 3 consecutive weeks every 28 days. The DLTs included asymptomatic T-wave inversions, transient and asymptomatic sick sinus syndrome, and hypocalcemia. Similar ST-T wave changes and mild reversible dysrhythmias, unassociated with alterations in ejection fraction, have been described in adult trials.21,22,28 Other frequent adverse events were myelosuppression, fatigue, nausea, and vomiting, also well documented in adult trials.21,22,29 Although no objective responses were reported, three patients (one each with peripheral primitive neuroectodermal tumor, rhabdomyosarcoma, and ependymoma) experienced prolonged disease stabilization disease.
Our pharmacokinetics results were similar to those previously reported in adults.21 Sandor et al observed a mean (± standard deviation) depsipeptide clearance and AUC0- Accumulation of acetyl H3 histones in PBMCs was detected consistently in all patients with available samples8 at various dose levels, with maximal accumulation occurring at 4 hours after the end of infusion. There was no correlation between intensity and duration of acetylated histone accumulation and disease stabilization. Other studies have also reported similar dose-independent increases in acetylated histones in patients' PBMCs, as well as acute myeloid leukemia and CLL blasts29 lasting up to 24 hours after the depsipeptide infusion. Depsipeptide has demonstrated some activity in preclinical adult and pediatric tumor models as a single agent7-11,13-16,28 and in combination with other therapies.30,31 Depsipeptide has led to tumor regressions or stabilization in pediatric xenograft models of primitive neuroectodermal tumor, atypical teratoid rhabdoid tumor and Wilms tumors, anaplastic astrocytoma, and rhabdomyosarcoma.28 Cameron et al32 reported that DNA demethylation and histone deacetylase inhibition act synergistically in the re-expression of genes silenced in cancer. A combination of depsipeptide and 5 aza-2-deoxycitidine resulted in enhanced histone acetylation, and cytotoxicity.33 Histone deacetylase inhibitors have demonstrated additive or synergistic activity in combination with topoisomerase I and II inhibitors,34 imatinib mesylate,35 all-trans retinoic acid,36-38 bortezomib,39 trastuzumab,40 and other tyrosine kinase inhibitors in transformed cell lines.41,42 Future trials under consideration include combination trials with DNA methyltransferase inhibitors or tyrosine kinase inhibitors in children with recurrent neuroblastoma or CNS malignancies.
The authors indicated no potential conflicts of interest.
We thank John Wiernikowski, PharmD, for his assistance with protocol development.
Supported by National Cancer Institute Grants No. U01 CA97452 and NCRR M01 RR00188. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Marks P, Rifkind R, Richon V, et al: Histone deacetylases and cancer: Causes and therapies. Nature Reviews 1:194-202, 2001[Medline] 2. Weidle UH, Grossmann A: Inhibition of histone deacetylases: A new strategy to target epigenetic modifications for anticancer treatment. Anticancer Res 20:1471-1485, 2000[Medline] 3. Giles RH, Peters DJ, Breuning MH: Conjunction dysfunction: CBP/p300 in human disease. Trends Genet 14:178-183, 1998[CrossRef][Medline] 4. Gayther SA, Batley SJ, Linger L, et al: Mutations truncating the EP300 acetylase in human cancers. Nat Genet 24:300-303, 2000[CrossRef][Medline] 5. Rowley JD, Reshmi S, Sobulo O, et al: All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90:535-541, 1997 6. Johnstone RW: Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287-299, 2002[CrossRef][Medline] 7. 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Okada T, Tanaka K, Nakatani F, et al: Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells. Int J Cancer 118:90-97, 2006[CrossRef][Medline] 16. Sakimura R, Tanaka K, Nakatani F, et al: Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer 116:784-792, 2005[CrossRef][Medline] 17. Ueda H, Manda T, Matsumoto S, et al: FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice J Antibiot (Tokyo) 47:315-323, 1994 18. Nakajima H, Kim YB, Terano H, et al: FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241:126-133, 1998[CrossRef][Medline] 19. 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Graham C, Tucker C, Creech J, et al: Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo. Clin Cancer Res 12:223-234, 2006 29. Byrd JC, Marcucci G, Parthun MR, et al: A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood 105:959-967, 2005 30. Zhang Y, Jung M, Dritschilo A, et al: Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat Res 161:667-674, 2004[Medline] 31. Zhang Y, Adachi M, Zhao X, et al: Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino-methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. Int J Cancer 110:301-308, 2004[CrossRef][Medline] 32. Cameron EE, Bachman KE, Myohanen S, et al: Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103-107, 1999[CrossRef][Medline] 33. Zhu WG, Lakshmanan RR, Beal MD, et al: DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res 61:1327-1333, 2001 34. Kim MS, Blake M, Baek JH, et al: Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291-7300, 2003 35. Kawano T, Horiguchi-Yamada J, Iwase S, et al: Depsipeptide enhances imatinib mesylate-induced apoptosis of Bcr-Abl-positive cells and ectopic expression of cyclin D1, c-Myc or active MEK abrogates this effect. Anticancer Res 24:2705-2712, 2004 36. Ferrara FF, Fazi F, Bianchini A, et al: Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2-7, 2001 37. Coffey DC, Kutko MC, Glick RD, et al: The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. Cancer Res 61:3591-3594, 2001 38. Coffey DC, Kutko MC, Glick RD, et al: Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro. Med Pediatr Oncol 35:577-581, 2000[CrossRef][Medline] 39. Mitsiades CS, Mitsiades NS, McMullan CJ, et al: Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications. Proc Natl Acad Sci U S A 101:540-545, 2004 40. Fuino L, Bali P, Wittmann S, et al: Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2:971-984, 2003 41. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) were calculated using the model parameters and the log-linear trapezoidal method, respectively. Finally, using the resultant maximum likelihood parameter distribution from the population satisfying the full sampling scheme, a maximum a posteriori Bayesian approach was used to describe depsipeptide pharmacokinetics in patients with limited plasma sampling (ie, one or more missing samples). Inter- and intrapatient variability for selected depsipeptide pharmacokinetic parameters was assessed using linear mixed effects modeling (S-Plus software; Insightful Corp, Redmond, WA). The Wilcoxon signed rank test was used to determine whether pharmacokinetic parameters differed significantly between doses one and three. Preliminary pharmacokinetics results from patients treated at the 17 mg/m2 dose level have previously been reported.
