A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial

Tianhong Li, Scott D Christensen, Paul H Frankel, Kim A Margolin, Sanjiv S Agarwala, Thehang Luu, Philip C Mack, Primo N Lara Jr, David R Gandara, Tianhong Li, Scott D Christensen, Paul H Frankel, Kim A Margolin, Sanjiv S Agarwala, Thehang Luu, Philip C Mack, Primo N Lara Jr, David R Gandara

Abstract

Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m(2) over 3 h on cycle 1, reduced to 45 mg/m(2) over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥ 20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.

Trial registration: ClinicalTrials.gov NCT00072189.

Figures

Fig. 1
Fig. 1
Schema of the study
Fig. 2
Fig. 2
Kaplan-Meier curves of progression-free survival (A) and overall survival (B) in all 17 patients

References

    1. Jemal A et al (2010) Cancer Statistics, 2010. CA Cancer J Clin
    1. Barth A, Wanek LA, Morton DL. Prognostic factors in 1, 521 melanoma patients with distant metastases. J Am Coll Surg. 1995;181(3):193–201.
    1. Tawbi HA, Buch SC. Chemotherapy resistance abrogation in metastatic melanoma. Clin Adv Hematol Oncol. 2010;8(4):259–266.
    1. Mouawad R, et al. Treatment for metastatic malignant melanoma: old drugs and new strategies. Crit Rev Oncol Hematol. 2010;74(1):27–39. doi: 10.1016/j.critrevonc.2009.08.005.
    1. Yang AS, Chapman PB. The history and future of chemotherapy for melanoma. Hematol Oncol Clin North Am. 2009;23(3):583–597. doi: 10.1016/j.hoc.2009.03.006.
    1. Middleton MR, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–166.
    1. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–723. doi: 10.1056/NEJMoa1003466.
    1. Sauroja I, et al. Analysis of G(1)/S checkpoint regulators in metastatic melanoma. Genes Chromosom Cancer. 2000;28(4):404–414. doi: 10.1002/1098-2264(200008)28:4<404::AID-GCC6>;2-P.
    1. High WA, Robinson WA. Genetic mutations involved in melanoma: a summary of our current understanding. Adv Dermatol. 2007;23:61–79. doi: 10.1016/j.yadr.2007.07.009.
    1. Palmieri G, et al. Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases. The Melanoma Cooperative Group. Br J Cancer. 2000;83(12):1707–1714. doi: 10.1054/bjoc.2000.1513.
    1. Vuhahula E, Straume O, Akslen LA. Frequent loss of p16 protein expression and high proliferative activity (Ki-67) in malignant melanoma from black Africans. Anticancer Res. 2000;20(6C):4857–4862.
    1. Takahashi I, et al. UCN-01, a selective inhibitor of protein kinase C from Streptomyces. J Antibiot (Tokyo) 1987;40(12):1782–1784.
    1. Takahashi I, et al. Potent selective inhibition of 7-O-methyl UCN-01 against protein kinase C. J Pharmacol Exp Ther. 1990;255(3):1218–1221.
    1. Akiyama T, et al. G1-checkpoint function including a cyclin-dependent kinase 2 regulatory pathway as potential determinant of 7-hydroxystaurosporine (UCN-01)-induced apoptosis and G1-phase accumulation. Jpn J Cancer Res. 1999;90(12):1364–1372. doi: 10.1111/j.1349-7006.1999.tb00721.x.
    1. Akiyama T, et al. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res. 1997;57(8):1495–1501.
    1. Abe S, et al. UCN-01 (7-hydoxystaurosporine) inhibits in vivo growth of human cancer cells through selective perturbation of G1 phase checkpoint machinery. Jpn J Cancer Res. 2001;92(5):537–545. doi: 10.1111/j.1349-7006.2001.tb01127.x.
    1. Fuse E, et al. Review of UCN-01 development: a lesson in the importance of clinical pharmacology. J Clin Pharmacol. 2005;45(4):394–403. doi: 10.1177/0091270005274549.
    1. Kurata N, et al. Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor, UCN-01. Cancer Chemother Pharmacol. 1999;44(1):12–18. doi: 10.1007/s002800050939.
    1. Dees EC, et al. A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res. 2005;11(2 Pt 1):664–671.
    1. Sausville EA, et al. Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol. 2001;19(8):2319–2333.
    1. Lara PN, Jr, et al. The cyclin-dependent kinase inhibitor UCN-01 plus cisplatin in advanced solid tumors: a California cancer consortium phase I pharmacokinetic and molecular correlative trial. Clin Cancer Res. 2005;11(12):4444–4450. doi: 10.1158/1078-0432.CCR-04-2602.
    1. Hotte SJ, et al. Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study. Ann Oncol. 2006;17(2):334–340. doi: 10.1093/annonc/mdj076.
    1. Jimeno A, et al. Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors. Cancer Chemother Pharmacol. 2008;61(3):423–433. doi: 10.1007/s00280-007-0485-9.
    1. Welch S, et al. UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol Oncol. 2007;106(2):305–310. doi: 10.1016/j.ygyno.2007.02.018.
    1. Fracasso PM et al (2010) A phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies. Cancer Chemother Pharmacol
    1. Kummar S, et al. A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas. Cancer Chemother Pharmacol. 2010;65(2):383–389. doi: 10.1007/s00280-009-1154-y.
    1. Therasse P, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. doi: 10.1093/jnci/92.3.205.
    1. Rodolfo M, Pierotti MA, Parmiani G. A merging duo in melanoma formation. J Invest Dermatol. 2005;125(6):xii–xiii. doi: 10.1111/j.0022-202X.2005.23965.x.
    1. Lazar-Molnar E, et al. Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine. 2000;12(6):547–554. doi: 10.1006/cyto.1999.0614.
    1. Porter GA, et al. Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes. Ann Surg Oncol. 2001;8(2):116–122. doi: 10.1007/s10434-001-0116-3.
    1. Sausville EA. Cyclin-dependent kinase modulators studied at the NCI: pre-clinical and clinical studies. Curr Med Chem Anticancer Agents. 2003;3(1):47–56. doi: 10.2174/1568011033353560.
    1. Senderowicz AM. Inhibitors of cyclin-dependent kinase modulators for cancer therapy. Prog Drug Res. 2005;63:183–206. doi: 10.1007/3-7643-7414-4_8.
    1. Flaherty KT, McArthur G (2010) BRAF, a target in melanoma: implications for solid tumor drug development. Cancer

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere