A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma.
OBJECTIVE
Thrombospondins are natural inhibitors of angiogenesis, tumor metastases, and tumor growth (melanoma). ABT-510 is a synthetic analog of thrombospondin-1, well tolerated in phase I studies. We conducted a phase II trial evaluating the clinical efficacy of ABT-510 and its effects on biomarkers of angiogenesis and immunity in patients with metastatic melanoma (MM).


METHODS
A 2-stage phase II clinical trial was conducted to assess the clinical efficacy, safety, and pharmacodynamic effects (angiogenesis and immunity) of ABT-510 in patients with stage IV melanoma. The primary endpoint was 18-week treatment failure rate. Patients self-administered 100 mg of ABT-510 subcutaneously twice daily. Blood samples were collected at baseline and every 3 weeks while on therapy. Eligible patients demonstrated measurable disease, good performance status and no evidence of intracranial metastases. Correlative laboratory studies evaluated biomarkers of angiogenesis and immunity.


RESULTS
Twenty-one patients were enrolled. Most patients were stage M1c (71%) and all had prior therapy for MM. Only 3 of the first 20 patients enrolled were progression free and on treatment at 18 weeks resulting in early termination of the study. Decreases in peripheral blood VEGF-A levels and VEGF-C levels, and CD146 and CD34/133 counts relative to pretreatment were detected. Limited changes in antitumor T cell immunity were observed.


CONCLUSIONS
ABT-510 therapy administered at 100 mg twice/day in patients with MM did not demonstrate definite clinical efficacy. Further dose escalation or combination with cytotoxic therapy may be more effective therapeutically.
Markovic
Svetomir N
SN
Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. markovic.svetomir@mayo.edu
Suman
Vera J
VJ
Rao
Ravi A
RA
Ingle
James N
JN
Kaur
Judith S
JS
Erickson
Lori A
LA
Pitot
Henry C
HC
Croghan
Gary A
GA
McWilliams
Robert R
RR
Merchan
Jaime
J
Kottschade
Lisa A
LA
Nevala
Wendy K
WK
Uhl
Cindy B
CB
Allred
Jacob
J
Creagan
Edward T
ET
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy*; D019700:Thrombospondin 1; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1