A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma

Morris, Don G.; Bramwell, Vivien H. C.; Turcotte, Robert; Figueredo, Alvaro T.; Blackstein, Martin E.; Verma, Shail; Matthews, Sarah; Eisenhauer, Elizabeth A.

doi:https://doi.org/10.1155/SRCM/2006/64374

Sarcoma

On this page

Abstract References Copyright Related Articles

Clinical Study | Open Access

Volume 2006 | Article ID 064374 | https://doi.org/10.1155/SRCM/2006/64374

A Phase II Study of Flavopiridol in Patients With Previously Untreated Advanced Soft Tissue Sarcoma

Don G. Morris,¹Vivien H. C. Bramwell,¹Robert Turcotte,²Alvaro T. Figueredo,³Martin E. Blackstein,⁴Shail Verma,⁵Sarah Matthews,⁶and Elizabeth A. Eisenhauer⁶

Received16 Nov 2005

Revised05 Jul 2006

Accepted25 Jul 2006

Published01 Oct 2006

Abstract

Purpose. Flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor that has preclinical activity in many tumours. This synthetic flavonoid was tested in a phase II nonrandomized, nonblinded multicentre clinical trial to determine its activity and toxicity in patients with previously untreated metastatic or locally advanced soft tissue sarcoma. Methods. A total of 18 patients with histologically confirmed nonoperable soft tissue was treated with flavopiridol administered at a dose of 50 mg/m2 IV over 1 hour daily ×3 days every 3 weeks. Results. Eighteen patients were accrued to the study over a period of 6 months. No objective responses were noted in the seventeen evaluable patients. Eight patients (47%) exhibited stable disease after 2 cycles (median duration of 4.3 months (range 1.4–6.9 months). Kaplan-Meier estimates for 3- and 6-month progression-free survivial rates were 44 percent and 22 percent, respectively. The only grade 3 toxicities were diarrhea (N=2), nausea (N=2), gastritis (N=1), and fatigue (N=1). Ninety-four percent of patients received ≥ 90% of the planned dose intensity, during 55 treatment cycles. Conclusions. Flavopiridol was well tolerated at the dose and schedule used in this study, however, no objective treatment responses were seen and thus our results do not support further exploration of flavopiridol as a monotherapy at this dose and schedule in soft tissue sarcomas.

References

A Jemal, T Murray, E Ward et al., “Cancer statistics, 2005,” CA-A Cancer Journal for Clinicians, vol. 55, no. 1, pp. 10–30, 2005.
View at: Google Scholar
J Verweij and H M Pinedo, “Systemic treatment of advanced or metastatic soft tissue sarcoma,” in Soft Tissue Sarcomas: New Developments in the Multidisciplinary Approach to Treatment, H M Pinedo, J Verweij, and H D Suti, Eds., pp. 75–91, Kluwer Academic, Boston, Mass, 1991.
View at: Google Scholar
J H Edmonson, L M Ryan, R H Blum et al., “Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas,” Journal of Clinical Oncology, vol. 11, no. 7, pp. 1269–1275, 1993.
View at: Google Scholar
R H Blum and J H Edmonson, “Investigations of ifosfamide for adult soft tissue sarcoma in ECOG,” European Journal of Cancer, vol. 27, no. suppl, p. S350, 1995.
View at: Google Scholar
A Le Cesne, I Judson, D Crowther et al., “Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus infosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a trial of the european organization for research and treatment of cancer/soft tissue and bone sarcoma group,” Journal of Clinical Oncology, vol. 18, no. 14, pp. 2676–2684, 2000.
View at: Google Scholar
N B Bui, M C DeMaille, and C Chevreau, “ $_{9}$ MAID vs MAID + 25% with G-CSF in adults with advanced soft tissue sarcoma (STS). First results of a randomized study of the FNCLCC Sarcoma Group,” Proceedings of the American Society for Clinical Oncology, vol. 17, p. 517a, 1998.
View at: Google Scholar
S H Kim, J J Lewis, M F Brennan, J M Woodruff, M Dudas, and C Cordon-Cardo, “Overexpression of cyclin D1 is associated with poor prognosis in extremity soft-tissue sarcomas,” Clinical Cancer Research, vol. 4, no. 10, pp. 2377–2382, 1998.
View at: Google Scholar
R L Huuhtanen, C P Blomqvist, T O Böhling et al., “Expression of cyclin A in soft tissue sarcomas correlates with tumor aggressiveness,” Cancer Research, vol. 59, no. 12, pp. 2885–2890, 1999.
View at: Google Scholar
J A Pindzola, J P Palazzo, A J Kovatich, B Tuma, and M Nobel, “Expression of p21(WAF1/CIP1) in soft tissue sarcomas: a comparative immunohistochemical study with p53 and Ki-67,” Pathology Research and Practice, vol. 194, no. 10, pp. 685–691, 1998.
View at: Google Scholar
S Kawauchi, Y Goto, X P Liu et al., “Low expression of p $27^{kip 1}$ , a cyclin-dependent kinase inhibitor, is a marker of poor prognosis in synovial sarcoma,” Cancer, vol. 91, no. 5, pp. 1005–1012, 2001.
View at: Publisher Site | Google Scholar
B Carlson, T Lahusen, S Singh et al., “Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol,” Cancer Research, vol. 59, no. 18, pp. 4634–4641, 1999.
View at: Google Scholar
G Melillo, E A Sausville, K Cloud, T Lahusen, L Varesio, and A M Senderowicz, “Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes,” Cancer Research, vol. 59, no. 21, pp. 5433–5437, 1999.
View at: Google Scholar
G I Shapiro, D A Koestner, C B Matranga, and B J Rollins, “Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines,” Clinical Cancer Research, vol. 5, no. 10, pp. 2925–2938, 1999.
View at: Google Scholar
Investigator's Brochure, HMR 1275, Hoechst Marion Roussel, Bridgewater, NJ, 1st edition, 1998.
W M Stadler, N J Vogelzang, R Amato et al., “Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago phase II consortium study,” Journal of Clinical Oncology, vol. 18, no. 2, pp. 371–375, 2000.
View at: Google Scholar
G K Schwartz, D Ilson, L Saltz et al., “Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma,” Journal of Clinical Oncology, vol. 19, no. 7, pp. 1985–1992, 2001.
View at: Google Scholar
G I Shapiro, J G Supko, A Patterson et al., “A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer,” Clinical Cancer Research, vol. 7, no. 6, pp. 1590–1599, 2001.
View at: Google Scholar
V Patel, A M Senderowicz, D Jr Pinto et al., “Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis,” Journal of Clinical Investigation, vol. 102, no. 9, pp. 1674–1681, 1998.
View at: Google Scholar
F Arguello, M Alexander, J A Sterry et al., “Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts,” Blood, vol. 91, no. 7, pp. 2482–2490, 1998.
View at: Google Scholar
A R Tan, D Headlee, R Messmann et al., “Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms,” Journal of Clinical Oncology, vol. 20, no. 19, pp. 4074–4082, 2002.
View at: Publisher Site | Google Scholar
P J Van Veldhuizen, J R Faulkner, P N Jr Lara et al., “A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109,” Cancer Chemotherapy and Pharmacology, vol. 56, no. 1, pp. 39–45, 2005, Epub 2005 March 25.
View at: Publisher Site | Google Scholar
P Therasse, S G Arbuck, E A Eisenhauer et al., “New guidelines to evaluate the response to treatment in solid tumors (RECIST guidelines),” Journal of the National Cancer Institute, vol. 92, no. 3, pp. 205–216, 2000.
View at: Google Scholar
National Cancer Institute Clinical Trials Evaluation Program Common Toxicity Criteria Version 2.0, 6/99 update. http://ctep.cancer.gov/forms/.
A M Senderowicz, “Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials,” Investigational New Drugs, vol. 17, no. 3, pp. 313–320, 1999.
View at: Publisher Site | Google Scholar
M Motwani, T M Delohery, and G K Schwartz, “Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells,” Clinical Cancer Research, vol. 5, no. 7, pp. 1876–1883, 1999.
View at: Google Scholar
D S Schrump, W Matthews, G A Chen, A Mixon, and N K Altorki, “Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells,” Clinical Cancer Research, vol. 4, no. 11, pp. 2885–2890, 1998.
View at: Google Scholar
S Wittmann, P Bali, S Donapaty et al., “Flavopiridol down-regulates antiapoptotic proteins and sensitizes human breast cancer cells to epothilone B-induced apoptosis,” Cancer Research, vol. 63, no. 1, pp. 93–99, 2003.
View at: Google Scholar
K C Bible and S H Kaufmann, “Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration,” Cancer Research, vol. 57, no. 16, pp. 3375–3380, 1997.
View at: Google Scholar
G K Schwartz, E O'Reilly, D Ilson et al., “Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 20, no. 8, pp. 2157–2170, 2002.
View at: Publisher Site | Google Scholar
S Ali, B F El-Rayes, O Aranha, F H Sarkar, and P A Philip, “Sequence dependent potentiation of gemcitabine by flavopiridol in human breast cancer cells,” Breast Cancer Research and Treatment, vol. 90, no. 1, pp. 25–31, 2005.
View at: Publisher Site | Google Scholar
R W Robey, W Y Medina-Pérez, K Nishiyama et al., “Overexpression of the ATP-binding cassette half-transporter, ABCG2 (MXR/BCRP/ABCP1), in flavopiridol-resistant human breast cancer cells,” Clinical Cancer Research, vol. 7, no. 1, pp. 145–152, 2001.
View at: Google Scholar
V Smith, F Raynaud, P Workman, and L R Kelland, “Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol,” Molecular Pharmacology, vol. 60, no. 5, pp. 885–893, 2001.
View at: Google Scholar
J H Hooijberg, H J Broxterman, G L Scheffer et al., “Potent interaction of flavopiridol with MRP1,” British Journal of Cancer, vol. 81, no. 2, pp. 269–276, 1999.
View at: Google Scholar
O Merimsky, I Meller, G Flusser et al., “Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study,” Cancer Chemotherapy and Pharmacology, vol. 45, no. 2, pp. 177–181, 2000.
View at: Google Scholar
M Van Glabbeke, J Verweij, I Judson, and O S, on behalf of the EORTC Soft Tissue and Bone Sarcoma Group Nielsen, “Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas,” European Journal of Cancer, vol. 38, no. 4, pp. 543–549, 2002.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2006 Don G. Morris et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation Order printed copies

Views

280

Downloads

969

Citations