Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma.
OBJECTIVE
Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients.


METHODS
Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety.


RESULTS
Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies.


CONCLUSIONS
ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.
Baker
Laurence H
LH
University of Michigan Medical School, Ann Arbor, MI 48106, USA. bakerl@umich.edu
Rowinsky
Eric K
EK
Mendelson
David
D
Humerickhouse
Rod A
RA
Knight
Raymond A
RA
Qian
Jiang
J
Carr
Robert A
RA
Gordon
Gary B
GB
Demetri
George D
GD
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D016017:Odds Ratio; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012189:Retrospective Studies; D012509:Sarcoma / Q000188:drug therapy*; D019700:Thrombospondin 1 / Q000378:metabolism*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1