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Clinical Cancer Research Vol. 8, 718-728, March 2002
© 2002 American Association for Cancer Research

Clinical Trials

Phase I Trial of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228, NSC 630176), in Patients with Refractory Neoplasms

Victor Sandor, Susan Bakke, Robert W. Robey, Min H. Kang, Mikhail V. Blagosklonny, Jonathon Bender, Rebecca Brooks, Richard L. Piekarz, Eben Tucker, William D. Figg, Kenneth K. Chan, Barry Goldspiel, Antonio Tito Fojo, Stanley P. Balcerzak and Susan E. Bates1

McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2 [V. S.]; Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute [S. B., R. W. R., M. H. K., M. V. B., R. L. P., W. D. F., A. T. F., S. E. B.], Clinical Center, Cardiology [E. T.], and Clinical Center, Pharmacy [B. G.], NIH, Bethesda, Maryland 20892; and The Ohio State University, Columbus, Ohio 43210 [J. B., R. B., K. K. C., S. P. B.]

Purpose: The primary objectives of this trial were to define the maximum tolerated dose (MTD) and to characterize the toxicities and pharmacokinetics of depsipeptide (FR901228) given on a day-1 and day-5 schedule every 21 days. A secondary objective of the trial was to seek evidence of antineoplastic activity.

Patients and Methods: Patients with advanced or refractory neoplasms received depsipeptide by a 4-h i.v. infusion on days 1 and 5 of a 21-day cycle. On the basis of preclinical data suggesting that depsipeptide may have significant cardiac toxicity, patients were treated while receiving continuous cardiac monitoring and were followed with serial cardiac enzyme determinations, electrocardiograms (ECGs), and nuclear ventriculograms (MUGA scans). The starting dose of the trial was 1 mg/m2, and dose escalations proceeded through a total of eight dose levels to a maximum of 24.9 mg/m2. Toxicities were graded using the National Cancer Institute common toxicity criteria, and pharmacokinetics were determined using a liquid chromatography/tandem mass spectrometry method.

Results: Patients (37) received a total of 88 cycles of treatment on study (range: one to eight cycles). Dose-limiting toxicity (DLT) was observed, and the MTD exceeded at a dose of 24.9 mg/m2. The DLTs included grade-3 fatigue (3 patients), grade-3 nausea and vomiting (1 patient), grade-4 thrombocytopenia (2 patients), and grade-4 cardiac arrhythmia (1 patient, atrial fibrillation). The MTD was defined at the seventh dose level (17.8 mg/m2). Reversible ST/T changes and mild reversible dysrhythmias were observed on the post-treatment ECG. There were no clinically significant changes in left ventricular ejection fraction. One patient achieved a partial response. The plasma disposition of depsipeptide was well described by a first-order, two-compartment model. The mean volume of distribution, clearance, t1/2{alpha} and t1/2ß at a dose of 17.8 mg/m2 was: 8.6 liters/m2, 11.6 liters/h/m2, 0.42 h, and 8.1 h, respectively. The mean maximum plasma concentration at the MTD was 472.6 ng/ml (range: 249–577.8 ng/ml). Biological assays showed that the serum levels achieved could cause the characteristic cell cycle effects of this agent when serum was added to PC3 cells in culture, as well as increased histone acetylation in patient-derived peripheral blood mononuclear cells.

Conclusion: The MTD of depsipeptide given on a day-1 and -5 schedule every 21 days is 17.8 mg/m2. The DLTs are fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia. Whereas cardiac toxicity was anticipated based on preclinical data, there was no evidence of myocardial damage. However, reversible ECG changes with ST/T wave flattening were regularly observed. Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m2 administered on day 1 and 5 of a 21-day cycle.


Commentary

Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment : Commentary re: V. Sandor et al., Phase I Trial of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228, NSC 630176), in Patients with Refractory Neoplasms. Clin. Cancer Res., 8: 718–728, 2002.
Victoria M. Richon and James P. O’Brien
Clin. Cancer Res. 2002 8: 662-664. [Full Text] [PDF]



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J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655.
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 Proc. Natl. Acad. Sci. USAHome page
A. V. Roschke, S. Lababidi, G. Tonon, K. S. Gehlhaus, K. Bussey, J. N. Weinstein, and I. R. Kirsch
Karyotypic "state" as a potential determinant for anticancer drug discovery
PNAS, February 22, 2005; 102(8): 2964 - 2969.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. C. Byrd, G. Marcucci, M. R. Parthun, J. J. Xiao, R. B. Klisovic, M. Moran, T. S. Lin, S. Liu, A. R. Sklenar, M. E. Davis, et al.
A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia
Blood, February 1, 2005; 105(3): 959 - 967.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
S. Doi, H. Soda, M. Oka, J. Tsurutani, T. Kitazaki, Y. Nakamura, M. Fukuda, Y. Yamada, S. Kamihira, and S. Kohno
The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells
Mol. Cancer Ther., November 1, 2004; 3(11): 1397 - 1402.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
S. Roychowdhury, R. A. Baiocchi, S. Vourganti, D. Bhatt, B. W. Blaser, A. G. Freud, J. Chou, C.-S. Chen, J. J. Xiao, M. Parthun, et al.
Selective Efficacy of Depsipeptide in a Xenograft Model of Epstein-Barr Virus-Positive Lymphoproliferative Disorder
J Natl Cancer Inst, October 6, 2004; 96(19): 1447 - 1457.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. Gilbert, S. D. Gore, J. G. Herman, and M. A. Carducci
The Clinical Application of Targeting Cancer through Histone Acetylation and Hypomethylation
Clin. Cancer Res., July 15, 2004; 10(14): 4589 - 4596.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
N. Druesne, A. Pagniez, C. Mayeur, M. Thomas, C. Cherbuy, P.-H. Duee, P. Martel, and C. Chaumontet
Diallyl disulfide (DADS) increases histone acetylation and p21waf1/cip1 expression in human colon tumor cell lines
Carcinogenesis, July 1, 2004; 25(7): 1227 - 1236.
[Abstract] [Full Text] [PDF]

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 BloodHome page
R. L. Piekarz, R. W. Robey, Z. Zhan, G. Kayastha, A. Sayah, A. H. Abdeldaim, S. Torrico, and S. E. Bates
T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance
Blood, June 15, 2004; 103(12): 4636 - 4643.
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 EndocrinologyHome page
F. Furuya, H. Shimura, H. Suzuki, K. Taki, K. Ohta, K. Haraguchi, T. Onaya, T. Endo, and T. Kobayashi
Histone Deacetylase Inhibitors Restore Radioiodide Uptake and Retention in Poorly Differentiated and Anaplastic Thyroid Cancer Cells by Expression of the Sodium/Iodide Symporter Thyroperoxidase and Thyroglobulin
Endocrinology, June 1, 2004; 145(6): 2865 - 2875.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Adachi, Y. Zhang, X. Zhao, T. Minami, R. Kawamura, Y. Hinoda, and K. Imai
Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells
Clin. Cancer Res., June 1, 2004; 10(11): 3853 - 3862.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
N. Mori, T. Matsuda, M. Tadano, T. Kinjo, Y. Yamada, K. Tsukasaki, S. Ikeda, Y. Yamasaki, Y. Tanaka, T. Ohta, et al.
Apoptosis Induced by the Histone Deacetylase Inhibitor FR901228 in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells
J. Virol., May 1, 2004; 78(9): 4582 - 4590.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
C. E. Denlinger, M. D. Keller, M. W. Mayo, R. M. Broad, and D. R. Jones
Combined proteasome and histone deacetylase inhibition in non-small cell lung cancer
J. Thorac. Cardiovasc. Surg., April 1, 2004; 127(4): 1078 - 1086.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
X. D. Zhang, S. K. Gillespie, J. M. Borrow, and P. Hersey
The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells
Mol. Cancer Ther., April 1, 2004; 3(4): 425 - 435.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
D. M. Nguyen, W. D. Schrump, G. A. Chen, W. Tsai, P. Nguyen, J. B. Trepel, and D. S. Schrump
Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells
Clin. Cancer Res., March 1, 2004; 10(5): 1813 - 1825.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
N. Gurvich, O. M. Tsygankova, J. L. Meinkoth, and P. S. Klein
Histone Deacetylase Is a Target of Valproic Acid-Mediated Cellular Differentiation
Cancer Res., February 1, 2004; 64(3): 1079 - 1086.
[Abstract] [Full Text] [PDF]

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 BloodHome page
C. Yu, M. Rahmani, D. Conrad, M. Subler, P. Dent, and S. Grant
The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571
Blood, November 15, 2003; 102(10): 3765 - 3774.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. E. Goldsmith, M. Kitazono, P. Fok, T. Aikou, S. Bates, and T. Fojo
The Histone Deacetylase Inhibitor FK228 Preferentially Enhances Adenovirus Transgene Expression in Malignant Cells
Clin. Cancer Res., November 1, 2003; 9(14): 5394 - 5401.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
Wm. K. Kelly, V. M. Richon, O. O'Connor, T. Curley, B. MacGregor-Curtelli, W. Tong, M. Klang, L. Schwartz, S. Richardson, E. Rosa, et al.
Phase I Clinical Trial of Histone Deacetylase Inhibitor: Suberoylanilide Hydroxamic Acid Administered Intravenously
Clin. Cancer Res., September 1, 2003; 9(10): 3578 - 3588.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
J. A. Plumb, P. W. Finn, R. J. Williams, M. J. Bandara, M. R. Romero, C. J. Watkins, N. B. La Thangue, and R. Brown
Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101
Mol. Cancer Ther., August 1, 2003; 2(8): 721 - 728.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
G. Graziani, L. Tentori, I. Portarena, M. Vergati, and P. Navarra
Valproic Acid Increases the Stimulatory Effect of Estrogens on Proliferation of Human Endometrial Adenocarcinoma Cells
Endocrinology, July 1, 2003; 144(7): 2822 - 2828.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
D. D. Klisovic, S. E. Katz, D. Effron, M. I. Klisovic, J. Wickham, M. R. Parthun, M. Guimond, and G. Marcucci
Depsipeptide (FR901228) Inhibits Proliferation and Induces Apoptosis in Primary and Metastatic Human Uveal Melanoma Cell Lines
Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2390 - 2398.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. W. Mayo, C. E. Denlinger, R. M. Broad, F. Yeung, E. T. Reilly, Y. Shi, and D. R. Jones
Ineffectiveness of Histone Deacetylase Inhibitors to Induce Apoptosis Involves the Transcriptional Activation of NF-{kappa}B through the Akt Pathway
J. Biol. Chem., May 23, 2003; 278(21): 18980 - 18989.
[Abstract] [Full Text] [PDF]

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 BloodHome page
N. Mitsiades, C. S. Mitsiades, P. G. Richardson, C. McMullan, V. Poulaki, G. Fanourakis, R. Schlossman, D. Chauhan, N. C. Munshi, T. Hideshima, et al.
Molecular sequelae of histone deacetylase inhibition in human malignant B cells
Blood, May 15, 2003; 101(10): 4055 - 4062.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
D. M. Nguyen, W. D. Schrump, W. S. Tsai, A. Chen, J. H. Stewart IV, F. Steiner, and D. S. Schrump
Enhancement of depsipeptide-mediated apoptosis of lung or esophageal cancer cells by flavopiridol: Activation of the mitochondria-dependent death-signaling pathway
J. Thorac. Cardiovasc. Surg., May 1, 2003; 125(5): 1132 - 1142.
[Abstract] [Full Text] [PDF]

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 JCBHome page
G. D. Kao, W. G. McKenna, M. G. Guenther, R. J. Muschel, M. A. Lazar, and T. J. Yen
Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response
J. Cell Biol., March 31, 2003; 160(7): 1017 - 1027.
[Abstract] [Full Text] [PDF]

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 BloodHome page
S. Skov, K. Rieneck, L. F. Bovin, K. Skak, S. Tomra, B. K. Michelsen, and N. Odum
Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal pathway essential for CD154 expression
Blood, February 15, 2003; 101(4): 1430 - 1438.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
S. Zochbauer-Muller, J. D. Minna, and A. F. Gazdar
Aberrant DNA Methylation in Lung Cancer: Biological and Clinical Implications
Oncologist, October 1, 2002; 7(5): 451 - 457.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
V. M. Richon and J. P. O'Brien
Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment : Commentary re: V. Sandor et al., Phase I Trial of the Histone Deacetylase Inhibitor, Depsipeptide (FR901228, NSC 630176), in Patients with Refractory Neoplasms. Clin. Cancer Res., 8: 718-728, 2002.
Clin. Cancer Res., March 1, 2002; 8(3): 662 - 664.
[Full Text] [PDF]


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