title: A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma.
abstract: Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m(2) ) in combination with YM155 (5 mg/m(2) per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m(2) and 56 patients received 75 mg/m(2) of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3-48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5-43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Ragini
authors.initials: R
authors.lastname: Kudchadkar
authors.affiliation: London Regional Cancer Centre, London, Ontario, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Ernst
authors.affiliation: University of California-Los Angeles, Ronald Reagan UCLA Medical Center, Los Angeles, California.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Redman
authors.affiliation: Astellas Pharmaceuticals Global Development, Northbrook, Illinois.
authors.forename: Joyce
authors.initials: J
authors.lastname: Steinberg
authors.affiliation: Astellas Pharmaceuticals Global Development, Northbrook, Illinois.
authors.forename: Anne
authors.initials: A
authors.lastname: Keating
authors.affiliation: Astellas Pharmaceuticals Global Development, Northbrook, Illinois.
authors.forename: Fei
authors.initials: F
authors.lastname: Jie
authors.affiliation: Astellas Pharmaceuticals Global Development, Northbrook, Illinois.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chen
authors.affiliation: University of Colorado Denver, Comprehensive Cancer Center, Denver, Colorado.
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, Florida.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D015415:Biomarkers; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007093:Imidazoles; D009285:Naphthoquinones; D043823:Taxoids; D000077143:Docetaxel; C523798:sepantronium
keywords: Docetaxel; YM155; melanoma; survivin protein