A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma.
Melanoma continues to be a major health problem with no effective therapy. Melanocytes, both benign and malignant, express many anti-apoptotic factors. Survivin is a member of the family of inhibitors of apoptosis proteins (IAP) and is preferentially expressed in tumor cells, including melanoma. YM155 is a small molecule suppressant of survivin that has been shown in preclinical cell lines, xenograft models and phase I studies to have anti-tumor activity.


METHODS
This was an open-label, multi-center, study of YM155 monotherapy in subjects with unresectable stage III or IV melanoma. Thirty-four chemotherapy naïve subjects were treated with YM155 at a dose of 4.8 mg/m(2)/day administered by continuous infusion for 168-hours (7 days) followed by a 14-day rest period, for up to 6 cycles or until disease progression.


RESULTS
One subject had a partial response to treatment seen at cycle two and lasting through cycle eight. Median progression-free survival was 1.3 months (95% CI; 1.3-2.7). Median overall survival was 9.9 months (95% CI; 7.0-14.5). Overall, YM155 was well tolerated with the most common (>20%) adverse events reported as fatigue, nausea, pyrexia, headache, arthralgia and back pain. Only four subjects required dose reductions.


CONCLUSIONS
YM155 was well tolerated in subjects with advanced melanoma; however, the pre-specified primary end-point for efficacy which required two responders in 29 evaluable subjects was not achieved.
Lewis
Karl D
KD
University of Colorado Health Sciences Center, Aurora, CO, USA. karl.lewis@ucdenver.edu
Samlowski
Wolfram
W
Ward
John
J
Catlett
Joseph
J
Cranmer
Lee
L
Kirkwood
John
J
Lawson
David
D
Whitman
Eric
E
Gonzalez
Rene
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D000077022:Survivin; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium