BACKGROUND: Treatment with doxorubicin is a present standard of care for 
patients with metastatic soft-tissue sarcoma and median overall survival for 
those treated is 12-16 months, but few, if any, novel treatments or chemotherapy 
combinations have been able to improve these poor outcomes. Olaratumab is a 
human antiplatelet-derived growth factor receptor α monoclonal antibody that has 
antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy 
of olaratumab plus doxorubicin in patients with advanced or metastatic 
soft-tissue sarcoma.
METHODS: We did an open-label phase 1b and randomised phase 2 study of 
doxorubicin plus olaratumab treatment in patients with unresectable or 
metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the 
phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or 
older and had a histologically confirmed diagnosis of locally advanced or 
metastatic soft-tissue sarcoma not previously treated with an anthracycline, an 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and 
available tumour tissue to determine PDGFRα expression by immunohistochemistry. 
In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio 
to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus 
doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 
21-day cycle for up to eight cycles. Randomisation was dynamic and used the 
minimisation randomisation technique. The phase 1b primary endpoint was safety 
and the phase 2 primary endpoint was progression-free survival using a two-sided 
α level of 0.2 and statistical power of 0.8. This study was registered with 
ClinicalTrials.gov, number NCT01185964.
FINDINGS: 15 patients were enrolled and treated with olaratumab plus doxorubicin 
in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus 
doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom 
received at least one dose of study treatment (64 received olaratumab plus 
doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 
2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 
months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, 
p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab 
plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 
0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) 
with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin 
(p=0.3421). Steady state olaratumab serum concentrations were reached during 
cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL 
(geometric coefficient of variation in percentage [CV%] 26.2) to 487 μg/mL (CV% 
33.0) and from 123 μg/mL (CV% 31.2) to 156 μg/mL (CV% 38.0), respectively. 
Adverse events that were more frequent with olaratumab plus doxorubicin versus 
doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 
[53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 
[18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or 
higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 
64 patients vs doxorubicin: nine [14%] of 65 patients).
INTERPRETATION: This study of olaratumab with doxorubicin in patients with 
advanced soft-tissue sarcoma met its predefined primary endpoint for 
progression-free survival and achieved a highly significant improvement of 11.8 
months in median overall survival, suggesting a potential shift in the treatment 
of soft-tissue sarcoma.
FUNDING: Eli Lilly and Company.