A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial.
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.
Division of Hematology & Oncology, University of California Davis Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA 95817, USA. tianhong.li@ucdmc.ucdavis.edu
Tianhong
T
Li
Scott D
SD
Christensen
Paul H
PH
Frankel
Kim A
KA
Margolin
Sanjiv S
SS
Agarwala
Thehang
T
Luu
Philip C
PC
Mack
Primo N
PN
Lara
David R
DR
Gandara
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002140:California; D002453:Cell Cycle / Q000187:drug effects*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine