Articles

Olaratumab and doxorubicin versus doxorubicin alone for

treatment of soft-tissue sarcoma: an open-label phase 1b
and randomised phase 2 trial
William D Tap, Robin L Jones, Brian A Van Tine, Bartosz Chmielowski, Anthony D Elias, Douglas Adkins, Mark Agulnik, Matthew M Cooney,
Michael B Livingston, Gregory Pennock, Meera R Hameed, Gaurav D Shah, Amy Qin, Ashwin Shahir, Damien M Cronier, Robert Ilaria Jr, Ilaria Conti,
Jan Cosaert, Gary K Schwartz

Summary
Background Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma Published Online
and median overall survival for those treated is 12–16 months, but few, if any, novel treatments or chemotherapy June 9, 2016
http://dx.doi.org/10.1016/
combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth S0140-6736(16)30587-6
factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess
See Online/Comment
the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. http://dx.doi.org/10.1016/
S0140-6736(16)30788-7
Methods We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in Memorial Sloan Kettering
patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and Cancer Center, New York, NY,
USA (W D Tap MD,
phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of
M R Hameed MD); Weill Cornell
locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Medical College, New York, NY,
Oncology Group (ECOG) performance status of 0–2, and available tumour tissue to determine PDGFRα expression USA (W D Tap); University
by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive Washington, Seattle, WA, USA
(R L Jones MD); The Royal
either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m²) or doxorubicin alone
Marsden Hospital, London, UK
(75 mg/m²) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation (R L Jones); Washington
randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was University in St Louis, St Louis,
progression-free survival using a two-sided α level of 0·2 and statistical power of 0·8. This study was registered with MO, USA (B A Van Tine MD,
Prof D Adkins MD); UCLA
ClinicalTrials.gov, number NCT01185964. Medical Center, Jonsson
Comprehensive Cancer Center,
Findings 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients Los Angeles, CA, USA
were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of (B Chmielowski MD); University
of Colorado Cancer Center,
whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Aurora, CO, USA
Median progression-free survival in phase 2 was 6·6 months (95% CI 4·1–8·3) with olaratumab plus doxorubicin and (Prof A D Elias MD);
4·1 months (2·8–5·4) with doxorubicin (stratified hazard ratio [HR] 0·67; 0·44–1·02, p=0·0615). Median overall Northwestern University,
survival was 26·5 months (20·9–31·7) with olaratumab plus doxorubicin and 14·7 months (9·2–17·1) with Chicago, IL, USA
(M Agulnik MD); University
doxorubicin (stratified HR 0·46, 0·30–0·71, p=0·0003). The objective response rate was 18·2% (9·8–29·6) with Hospitals Case Medical Center,
olaratumab plus doxorubicin and 11·9% (5·3–22·2) with doxorubicin (p=0·3421). Steady state olaratumab serum Seidman Cancer Center,
concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL Division of Hematology and
(geometric coefficient of variation in percentage [CV%] 26·2) to 487 μg/mL (CV% 33·0) and from 123 μg/mL Oncology, Cleveland, OH, USA
(M M Cooney MD);
(CV% 31·2) to 156 μg/mL (CV% 38·0), respectively. Adverse events that were more frequent with olaratumab plus Carolinas Healthcare System,
doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), The Charlotte-Mecklenburg
nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia Hospital Authority, Charlotte,
of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: NC, USA (M B Livingston MD);
Baptist MD Anderson Cancer
nine [14%] of 65 patients). Center, Jacksonville, FL, USA
(G Pennock MD); Novartis
Interpretation This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its Pharmaceuticals, East Hanover,
NJ, USA (G D Shah MD); Eli Lilly
predefined primary endpoint for progression-free survival and achieved a highly significant improvement of
and Company, Bridgewater, NJ,
11·8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. USA (A Qin PhD, J Cosaert MD);
Eli Lilly and Company,
Funding Eli Lilly and Company. Windlesham, Surrey, UK
(A Shahir MD, D M Cronier PhD);
Eli Lilly and Company, Lilly
Introduction survival for treated patients with metastatic disease is Corporate Center, Indianapolis,
Soft-tissue sarcoma is a rare and diverse group of solid only 12–16 months, and the 2-year survival rate is roughly IN, USA (R Ilaria Jr MD,
tumours originating from mesenchymal precursors.1,2 30%.4.5 Few, if any, novel treatments or chemotherapy I Conti MD); and Columbia
University School of Medicine,
These tumours account for approximately 1% of all new combinations have been able to improve these poor
New York, NY, USA
adult malignancies.2,3 Doxorubicin, either alone or in outcomes;3–5 consequently, soft-tissue sarcoma represents (Prof G K Schwartz MD)
combination, remains a standard of care. However, an important unmet medical need.

www.thelancet.com Published online June 9, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30587-6 1

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Correspondence to:
Dr William D Tap, Memorial
Sloan Kettering Cancer Center,
New York, NY 10065, USA
tapw@mskcc.org
Research in context
Evidence before this study
We searched PubMed for all randomised trials in English that
involved single-drug doxorubicin, published from Jan 1, 1980,
to Feb 25, 2016. We used the following search terms: “soft
tissue”, “sarcoma”, “doxorubicin”, “randomized”, and “trial”.
We identified 19 randomised phase 2 or phase 3 clinical trials,
none of which showed an overall survival advantage of
single-drug or combination treatment compared with
doxorubicin alone.
Added value of this study
To our knowledge, our study is the first randomised study to
show increased survival for patients with soft-tissue sarcoma
treated with a drug added to the standard-of-care
doxorubicin treatment over single-agent doxorubicin. In our
study, the combination of olaratumab plus doxorubicin
improved both progression-free and overall survival
compared with doxorubicin only in patients with advanced
soft-tissue sarcoma. The improvement of 11·8 months in
median overall survival is highly significant, suggesting a
potential paradigm shift in the treatment of soft-tissue
sarcoma.
Implications of all the available evidence
The magnitude of improvement observed in median overall
survival with olaratumab plus doxorubicin was 80%
(11·8 months) and in progression-free survival was 61%
(2·5 months), suggesting that the inhibitory effect of
olaratumab on tumour and stromal PDGFRα signalling might
persist beyond the immediate treatment period. These clinical
results are being confirmed in a large international randomised
phase 3 study. Further refinement of the understanding of
PDGFRα in the context of tumour and stroma is at present a
focus of ongoing investigations.

Platelet-derived growth factor (PDGF) and PDGF
receptor (PDGFR) signalling plays a significant part in
mesenchymal biology, including mesenchymal stem cell
differentiation, growth, and angiogenesis.6,7 The PDGF
and PDGFR signalling pathway is also involved in cancer
through aberrant cellular signalling and has been
implicated in modulating the tumour or stromal
microenvironment and facilitating metastases in several
malignancies.8,9
Olaratumab is a recombinant human immunoglobulin
G subclass 1 (IgG1) monoclonal antibody that specifically
binds PDGFRα, blocking PDGF-AA, PDGF-BB, and
PDGF-CC binding and receptor activation.10 Preclinical
studies of olaratumab alone10 or in combination with
doxorubicin11 have shown antitumour activity in human
sarcoma xenograft models. Based on these preclinical
data and the rationale for disrupting PDGF and PDGFR
signalling in sarcoma cells and the tumour or stromal
microenvironment, we did a phase 1b and randomised
phase 2 study assessing the safety and efficacy of adding
olaratumab to doxorubicin in patients with advanced
soft-tissue sarcoma.
Methods
Study design and participants
In this two-part open-label, phase 1b and randomised
phase 2 trial, we enrolled patients at 16 clinical sites in 16
See Online for appendix cities and 15 states in the USA. For both the phase 1b and
phase 2, 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.
Patients were excluded from the study if they had
histologically or cytologically confirmed Kaposi’s
sarcoma; untreated metastases to the CNS; received
previous treatment with doxorubicin, daunorubicin,
idarubicin, or other anthracyclines and anthracenediones
(mitoxantrone), or therapy with any drug that targets the
PDGF or PDGFR; received previous radiation therapy to
the mediastinal or pericardial area; received concurrent
treatment with other anticancer therapy including other
chemotherapy, immunotherapy, hormonal therapy,
radiotherapy, chemoembolisation, targeted therapy, an
investigational agent or the non-approved use of a drug
or device within 4 weeks before study entry; a known
allergy to any of the treatment components; unstable
angina pectoris, angioplasty, cardiac stenting, or
myocardial infarction 6 months before study entry;
infection by HIV; or were pregnant or lactating. Patients
were approached in routine clinical practice by the
investigators.
The protocol was approved by the institutional review
board at each participating centre, and the study was done
in accordance with the Declaration of Helsinki and the
International Conference on Harmonisation Guidelines
for Good Clinical Practice. All patients provided written
informed consent to participate in the study.
Randomisation and masking
In the phase 2 part of the study, patients were randomly
assigned in a 1:1 ratio to receive olaratumab plus
doxorubicin or doxorubicin alone (appendix pp 6, 7).
Randomisation was dynamic and used the minimisation
randomisation technique12 to balance patients by ECOG
performance status (0–1 vs 2), histological tumour type
(leiomyosarcoma vs synovial sarcoma vs other), immuno-
histochemical PDGFR expression (positive vs negative),
and previous lines of treatments (0 vs ≥1 line of treatment;
appendix p 7). No investigators, outcome assessors, or
patients were masked to assigned treatment. The
independent radiological reviewers were blinded.

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Procedures
In the phase 1b part of the study, patients received 167 patients were screened

olaratumab (15 mg/kg) intravenously on day 1 and day 8

plus doxorubicin (75 mg/m²) on day 1 of each 21-day 133 patients were enrolled
cycle for up to eight cycles. After eight cycles of the drug
combination, in the absence of disease progression or
unacceptable toxicities, patients were allowed to receive 133 patients were randomly assigned
and included in the efficacy analysis
olaratumab monotherapy until disease progression.
During cycles 5–8, dexrazoxane was allowed on day 1 of
each cycle to reduce the potential for doxorubicin-related
cardiotoxicity. The phase 1b portion was closed to 2 patients who were randomly assigned 2 patients who were randomly assigned
enrolment once ten patients had received study treatment to the investigational arm were not to the control arm were not treated
treated
for two cycles.
In the phase 2 part of the study, randomly assigned
patientws received either olaratumab plus doxorubicin 64 assigned to receive olaratumab plus 65 assigned to receive doxorubicin
doxorubicin
(as described in the phase 1b part) or doxorubicin alone
(75 mg/m²) on day 1 of each 21-day cycle for up to eight
cycles (appendix p 4). After completion of eight cycles of 33* discontinued study treatment 65† discontinued study treatment
doxorubicin, patients in the olaratumab plus doxorubicin within the first 8 cycles within the first 8 cycles
21 had radiologically documented 27 had radiologically documented
group could receive olaratumab monotherapy until progression of disease progression of disease
disease progression, and patients in the doxorubicin 5 had adverse events 11 hadadverse events
group were observed and could receive olaratumab 2 died 1 died
2 withdrew consent 7 had progression of disease
monotherapy after documented disease progression. 3 had other reasons (symptomatic deterioration)
Tumour response was assessed every 6 weeks according 5 withdrew consent
10 had other reasons
to the Response Evaluation Criteria in Solid Tumours 4 completed treatment
(version 1.1).13 Survival was assessed every 2 months until
study completion. Blood samples were collected for
pharmacokinetic and immunogenic analyses. Safety was 31‡ patients discontinued study
treatment in the 9th cycle or later
assessed for all patients who received at least one dose of 21 had radiologically documented
study treatment. Adverse events and clinical laboratory progression of disease
3 had progression of disease
toxicity were graded according to the National Cancer (symptomatic deterioration)
Institute Common Terminology Criteria for Adverse 3 withdrew consent
Events (version 4.0). Cardiac function was monitored by 4 had other reasons

echocardiography or multigated acquisition scanning

before treatment start and before treatment at cycles 5
and 7. PDGFR expression was assessed by immuno-
histochemistry at a central academic laboratory before
enrolment (phase 1b) or randomisation (phase 2; appendix
p 5). After the study was completed, the randomisation
assay was found to recognise both PDGFRα and PDGFRβ,
so an additional PDGFRα-specific assay was developed
and used for all post-hoc efficacy analyses.
Outcomes
The phase 1b primary endpoint was safety. The phase 2
primary endpoint was progression-free survival;
secondary endpoints included overall survival, objective
response rate, safety, and pharmacokinetics (appendix
pp 3, 5, 8).
Statistical analysis
The phase 1b part of the trial was intended to provide an
initial look at safety outcomes relative to dose and
exposure in a small number of patients. For this purpose,
a pragmatic decision to enrol 10–15 patients was made
without formal statistical considerations. The phase 2
planned sample size was 130 patients, which assumed a
Figure 1: Trial profile in phase 2
*Four of the 33 patients received eight cycles of doxorubicin and three of the 33 patients received at least one dose
of olaratumab monotherapy. †17 of the 65 patients received eight cycles of doxorubicin and 30 of the 65 patients
received at least one dose of olaratumab monotherapy (following discontinuation of single-drug doxorubicin).
‡27 of the 31 patients received eight cycles of doxorubicin and all 31 patients received at least one dose of
olaratumab monotherapy.
50% improvement in median progression-free survival
(hazard ratio [HR] 0·67) for the olaratumab plus
doxorubicin group, a statistical power of 80%, and a two-
sided significance level of 0·20. A planned interim
analysis of the primary endpoint was done with a
nominal α spend of 0·0001, resulting in a final nominal
adjusted α level of 0·1999 (two-sided).
The primary analysis of progression-free survival and
the secondary analysis of overall survival were based on
Mantel’s log rank test and the descriptive statistics of
Kaplan-Meier. The overall survival analysis included all
randomly assigned patients. Additional analyses were
done with Cox proportional hazards models to estimate
HRs.
The efficacy analyses were done in the randomisation
patient population (intention-to-treat population). The
safety analyses were done in the population of patients

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starting any new anticancer treatment, and the other was

Olaratumab plus Doxorubicin
doxorubicin (n=67) done based on censoring at the date of starting post-
(n=66) study anticancer treatments of interest (post-study
Age (years) treatments with some degree of imbalance between the
Median (range) 58·5 (22–85) 58·0 (29–86) two study arms; appendix p 21). These included
Sex pazopanib, eribulin, gemcitabine plus docetaxel,
Men 26 (39%) 33 (49%)
doxorubicin, and trabectedin. Two additional post-hoc
Women 40 (61%) 34 (51%)
overall survival sensitivity analyses (appendix p 23) were
Race
done censoring patients who either discontinued study
treatment within the eight-cycle combination treatment
White 55 (83%) 60 (90%)
period due to adverse events or symptomatic progression
Black 6 (9%) 5 (8%)
of disease, or patients who completed fewer than four
Asian 2 (3%) 2 (3%)
cycles of doxorubicin.
Native Hawaiian or other Pacific Islander 1 (2%) 0
Other 2 (3%) 0
Role of the funding source
Ethnic origin
The study was designed by the funder, Eli Lilly and
Hispanic or Latino 6 (9%) 2 (3%)
Company, with input from sarcoma experts. The data
Not Hispanic or Latino 60 (91%) 64 (96%)
were analysed and interpreted by Eli Lilly and Company
Missing 0 1 (2%)
in collaboration with the academic authors. All authors
ECOG performance status
had access to all of the data and vouch for the accuracy
0–1 62 (94%) 63 (94%)
and completeness of the data and analyses reported and
2 4 (6%) 4 (6%) for the fidelity of the study to the study protocol. All
PDGFRα status* authors had final responsibility for the decision to submit
Stratification assay for publication. The corresponding author prepared the
Positive 58 (88%) 59 (88%) initial draft of the manuscript with editorial assistance,
Negative 8 (12%) 8 (12%) and all authors contributed to the subsequent drafts.
Exploratory assay (post hoc)† This study was registered with ClinicalTrials.gov, number
Positive 18 (33%) 19 (34%) NCT01185964.
Negative 37 (67%) 37 (66%)
Histological type Results
Leiomyosarcoma 24 (36%) 27 (40%) From Oct 6, 2010, to Jan 14, 2013, 15 patients were
Non-leiomyosarcoma‡ 42 (64%) 40 (60%) enrolled and treated in the phase 1b part of the study
Previous treatments (appendix p 10), and in the phase 2 part 133 patients were
0 27 (41%) 31 (46%) randomly assigned (66 to receive olaratumab plus
≥1 39 (59%) 36 (54%) doxorubicin and 67 to receive doxorubicin only), 129
Histological type (97%) of whom received at least one dose of study
Leiomyosarcoma 24 (36%) 27 (40%) treatment (64 in the olaratumab plus doxorubicin group
Undifferentiated pleomorphic sarcoma 10 (15%) 14 (21%) and 65 in the doxorubicin group; figure 1). Baseline
Liposarcoma 8 (12%) 15 (22%) characteristics (table 1, appendix p 16) were balanced
Angiosarcoma 4 (6%) 3 (5%) except for there being slightly more women in the
Synovial sarcoma 1 (2%) 2 (3%) olaratumab plus doxorubicin arm.
Neurofibrosarcoma 1 (2%) 0 Final analysis of the phase 2 primary endpoint of
Fibrosarcoma 1 (2%) 0 progression-free survival based on investigator
Other‡ 17 (26%) 6 (9%) assessment was done after 103 events. The median
progression-free survival was 6·6 months (95% CI
Data are n (%) unless otherwise stated. ECOG=Eastern Cooperative Oncology Group. PDGFRα=platelet-derived growth 4·1–8·3, IQR 2·7–10·2) for patients treated with
factor receptor. *PDGFRα-positive status was defined as a staining result of 2+ or greater. The results from stratification
assay results were used to stratify randomisation. †A positive status corresponds to weak intensity membranous
olaratumab plus doxorubicin and 4·1 months (2·8–5·4,
staining comprising more than 30% of the tumour or moderate-to-strong intensity membranous staining comprising 1·6–7·4) for those treated with doxorubicin (figure 2A,
more than 5% of the tumour, or both. A negative status corresponds to staining that does not meet these requirements. appendix p 18). This improvement in favour of
‡See appendix (p 16) for a complete summary of disease by histological type, including other subcategories.
olaratumab plus doxorubicin met the protocol-defined
Table 1: Baseline characteristics of patients in phase 2 (intention-to-treat population) significance level of 0·1999 for final progression-free
survival (stratified HR 0·672, 95% CI 0·442–1·021,
who received at least one dose of study treatment (safety p=0·0615). A blinded independent retrospective review
population). of the radiological scans (appendix p 11) showed a similar
Two post-hoc overall sensitivity analyses were done to HR (0·67, 0·04–1·12, p=0·1208) and a median
explore the effect of post-study anticancer treatment. progression-free survival of 8·2 months (95% CI
One analysis was done based on censoring at the date of 5·5–9·8, IQR 3·0–11·6) with olaratumab plus

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doxorubicin and 4·4 months (3·1–7·4; 1·5–8·6) with A

doxorubicin. The 3-month and 6-month progression-free Olaratumab Doxorubicin
plus doxorubicin
survival rates are provided in the appendix (p 18). 1·0
Patients/deaths 66/55 67/48
The objective response rate was 18·2% (95% CI 0·9 Median, months 6·6 4·1
(95% CI) (4·1–8·3) (2·8–5·4)
9·8–29·6) with olaratumab plus doxorubicin and 11·9% 0·8 HR (95% CI) 0·67 (0·44–1·02)

Progression-free survival
(5·3–22·2) with doxorubicin (p=0·3421) (appendix p 20). 0·7 Stratified p value 0·0615

The objective response rate for the independent 0·6

Independent Olaratumab Doxorubicin
assessment was 18·2% (9·8–29·6) with olaratumab plus 0·5 assessment* plus doxorubicin
doxorubicin and 7·5% (2·5–16·6) with doxorubicin 0·4
Patients/deaths 66/37 67/34
Median, months 8·2 4·4
(p=0·0740; appendix p 20). The disease control rate and 0·3 (95% CI) (5·5–9·8) (3·1–7·4)
HR (95% CI) 0·67 (0·40–1·12)
median duration of response are provided in the 0·2 Stratified p value 0·1208
appendix (p 20). Olaratumab plus doxorubicin
0·1
Final analysis of overall survival was done as planned Doxorubicin
0
after 91 (71%) patients died in the intention-to-treat 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
population. The median overall survival was 26·5 months Number at risk
Time (months)
(95% CI 20·9–31·7, IQR 13·8–not assessable) with Olaratumab 66 50 39 29 21 15 11 6 3 3 2 2 1 1 1 0
plus doxorubicin
olaratumab plus doxorubicin and 14·7 months (9·2–17·1, Doxorubicin 67 38 28 13 7 7 7 4 2 1 1 1 0 0 0 0
5·5–26·0) with doxorubicin (figure 2B). This difference
of 11·8 months represented an improvement in median B
1·0 Olaratumab Doxorubicin
overall survival (stratified HR, 0·46, 95% CI 0·30–0·71, plus doxorubicin
p=0·0003) and was consistent across the subgroup 0·9 Patients/deaths 66/39 67/52
Median, months 26·5 14·7
stratification factors including histological tumour type 0·8 (95% CI) (20·9–31·7) (9·2–17·1)
HR (95% CI) 0·46 (0·30–0·71)
(leiomyosarcoma vs non-leiomyosarcoma), number of 0·7
Stratified p value 0·0003
Overall survival

lines of previous treatment (0 vs ≥1), and PDGFRα status 0·6

(figure 3). More than 65% of patients in each of the two
treatment groups received subsequent therapy after
disease progression (table 2 and appendix). Sensitivity
analysis censoring at the time of starting any new
anticancer treatment, or select anticancer treatments
(appendix p 22), showed an HR of 0·425 (p=0·0284) and
an HR of (0·353; p=0·0005), consistent with the primary
overall survival analysis. Additional post-hoc sensitivity
analyses for overall survival are shown in the appendix
(p 23) and also showed HRs consistent with the primary
overall survival analysis.
Olaratumab serum concentrations suitable for pharma-
cokinetics analysis were available from 92 patients.
Olaratumab mean maximum serum concentration (Cmax)
reached 284 μg/mL (geometric coefficient of variation in
percentage [CV%] 23·3) and 293 μg/mL (CV% 30·5)
after the first and second doses and returned to a mean
trough serum concentration (Cmin) of 66·5 μg/mL
(CV% 40·4) at the end of the cycle (appendix p 24). Steady
state was reached during cycle 3; mean steady state Cmax
and Cmin ranged from 419 μg/mL (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) across cycles 4–9. Individual
apparent terminal elimination half-life estimates of
6·67 days and 14·4 days were obtained during cycle 3
(appendix p 25). Olaratumab serum levels recorded in
patients randomised to the doxorubicin group, who
received olaratumab monotherapy after disease
progression, were similar to those observed in patients in
the olaratumab plus doxorubicin group (appendix p 24).
Exposure-response analyses suggested that patients in
the upper quartiles of olaratumab serum exposure
showed a greater improvement in progression-free
0·5
0·4
0·3
0·2
0·1
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Time (months)
Number at risk
Olaratumab 66 62 60 57 52 51 50 47 43 41 41 39 33 32 29 26 16 16 15 8 3 3 1 1 0
plus doxorubicin
Doxorubicin 67 61 51 46 43 37 34 32 28 23 21 19 19 15 13 13 10 7 6 6 5 3 2 1 0
Figure 2: Kaplan-Meier curves for the investigator assessment of progression-free survival (A) and overall
survival (B) for the olaratumab plus doxorubicin versus doxorubicin groups in the intention-to-treat population
HR=hazard ratio.*The independent assessment of progression-free survival is included as an insert for comparison.
survival and overall survival, regardless of the
pharmacokinetic endpoint considered (Cmin at the end of
cycle 1, or average serum concentration throughout the
treatment duration; appendix pp 26, 27).
The median number of doxorubicin infusions was
seven (range 1–8, IQR 3–8) with a median cumulative
dose concentration of 487·6 mg/m² (IQR 221·7–598·8)
in the olaratumab plus doxorubicin group (appendix
p 28) and four infusions (1–8, 2–8) with a median
cumulative dose concentration of 299·6 mg/m²
(IQR 150·1–494·7) in the doxorubicin group. The median
number of olaratumab infusions in the olaratumab plus
doxorubicin group was 16·5 (range 1·0–83·0,
IQR 6–25·5; appendix p 28). 31 of 64 patients in the
olaratumab plus doxorubicin group completed the eight
cycles of doxorubicin plus olaratumab compared with
17 of 64 patients who completed the eight cycles of
doxorubicin only in the control group. The most common

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Subgroup Investigational arm Control arm HR (95% CI)

Number of Number of
events n events n
PDGFRα (exploratory assay)
Positive 14 18 17 19 0·64 (0·31–1·33)
Negative 19 37 26 37 0·40 (0·21–0·73)
Number of lines of previous treatment
0 21 40 36 47 0·47 (0·27–0·81)
1 or more 18 26 16 20 0·55 (0·28–1·10)
Histological tumour type
Leiomyosarcoma 16 24 24 27 0·47 (0·25–0·90)
Other 23 42 28 40 0·56 (0·32–0·97)
ECOG PS
0 20 36 30 38 0·51 (0·29–0·91)
1 16 26 19 26 0·46 (0·24–0·91)
Sex
Men 16 26 28 33 0·55 (0·30–1·02)
Women 23 40 24 34 0·53 (0·30–0·94)
Age (years)
18–<65 30 48 33 43 0·54 (0·33–0·89)
≤65 9 18 19 24 0·48 (0·22–1·07)
Weight (kg)
<81·4 19 29 31 37 0·53 (0·30–0·94)
≥81·4 20 37 21 30 0·56 (0·30–1·04)
Duration of disease (months)
<14·95 20 33 29 34 0·38 (0·21–0·68)
≥14·95 19 33 23 33 0·68 (0·37–1·25)
Duration of most recent previous
systemic treatment (months)
<4·12 8 11 10 12 0·48 (0·18–1·26)
≥4·12 10 15 6 8 0·69 (0·25–1·91)
Grade
Grade 1–2 5 12 10 15 0·46 (0·16–1·35)
Grade 3 21 29 25 29 0·58 (0·32–1·04)
Unknown/not assessed 13 25 17 23 0·42 (0·20–0·87)
Albumin at baseline (g/L)
<38·0 22 29 30 37 0·60 (0·34–1·05)
≥38·0 17 37 22 30 0·46 (0·24–0·87)
Liver metastases
Yes 17 26 19 22 0·45 (0·22–0·89)
No 22 40 33 45 0·51 (0·30–0·88)
Platelets at baseline (×109/L)
≤300 26 49 29 41 0·50 (0·29–0·86)
>300 13 17 23 26 0·73 (0·37–1·44)
White blood cell count at baseline (×109/L)
≤10 34 59 38 52 0·55 (0·34–0·87)
>10 5 7 14 15 0·74 (0·26–2·06)

0·1 0·5 1 2·1

Favours investigational arm Favours control arm

Figure 3: Forest plot of overall survival hazard ratios for potentially prognostic factors
Forest plot of overall survival for several subgroups that could potentially influence the overall survival treatment effect (phase 2, intention-to-treat population).
Duration of disease is the time from date of histology or pathology confirmation of soft-tissue sarcoma to date of informed consent. ECOG=Eastern Cooperative
Oncology Group. PDGFRα=platelet-derived growth factor receptor α. PS=performance status.

reason for discontinuation from study treatment in both

Olaratumab plus doxorubicin (n=66)
Any additional treatment 44 (67%)
1 18 (27%)
2 12 (18%)
3 9 (14%)
4 1 (2%)
>4 4 (6%)
*Olaratumab monotherapy was not counted as a regimen for patients in the doxorubicin arm who elected to receive
olaratumab monotherapy upon disease progression during doxorubicin treatment.
Table 2: Total number of post-study anticancer treatments received (phase 2)
Doxorubicin* (n=67)
groups was progression of disease (figure 1). The most
33 (49%) common adverse event leading to patient discontinuation
16 (24%) of doxorubicin was ejection-fraction decrease in three
10 (15%) (5%) of 64 patients with olaratumab plus doxorubicin
2 (3%) and four (6%) of 64 patients with doxorubicin. The most
1 (2%) common adverse event leading to discontinuation of
4 (6%) olaratumab was infusion-related reaction in two (3%) of
64 patients. In the olaratumab plus doxorubicin group,
34 (53%) of 64 patients ended the olaratumab plus
doxorubicin combination treatment and received one or
more cycles of olaratumab monotherapy (median nine
infusions, range 2–68, IQR 4–24; median 4·5 cycles,
IQR 2–12; appendix p 29). In the doxorubicin group, 30
(46%) of 65 patients opted to receive olaratumab

6 www.thelancet.com Published online June 9, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30587-6

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Olaratumab plus doxorubicin (n=64) Doxorubicin (n=65)

Any Grade Grade 3 Grade ≥4 Any Grade Grade 3 Grade ≥4
Patients with any adverse event† 63 (98%) 24 (38%) 27 (42%) 64 (98%) 25 (38%) 20 (31%)
Nausea 47 (73%) 1 (2%) 0 34 (52%) 2 (3%) 0
Fatigue‡ 44 (69%) 6 (9%) 0 45 (69%) 2 (3%) 0
Neutropenia§¶ 37 (58%) 12 (19%) 22 (34%) 23 (35%) 5 (8%) 16 (25%)
Mucositis|| 34 (53%) 2 (3%) 0 23 (35%) 3 (5%) 0
Alopecia 33 (52%) 0 0 26 (40%) 0 0
Vomiting 29 (45%) 0 0 12 (18%) 0 0
Anaemia** 26 (41%) 8 (13%) 0 24 (37%) 6 (9%) 0
Leucopenia††¶ 26 (41%) 14 (22%) 9 (14%) 12 (18%) 5 (8%) 6 (9%)
Constipation 22 (34%) 0 0 21 (32%) 1 (2%) 0
Diarrhoea 22 (34%) 2 (3%) 0 15 (23%) 0 0
Decreased appetite 20 (31%) 1 (2%) 0 13 (20%) 0 0
Abdominal pain‡‡ 15 (23%) 2 (3%) 0 9 (14%) 0 0
Pyrexia 15 (23%) 0 0 12 (18%) 0 0
Musculoskeletal pain§§ 41 (64%) ¶¶ ¶¶ 16 (25%) |||| ||||
Febrile neutropenia*** 8 (13%) 7 (11%) 1 (1·6%) 9 (14%) 9 (14%) 0
Infections and infestations***††† 27 (42%) 5 (8%) 0 27 (42%) 4 (6%) 3 (5%)
Infusion-related reaction***‡‡‡ 8 (13%) 0 2 (3%) 0 0 0
Treatment-related adverse event 63 (98%) 18 (28%) 25 (39%) 63 (97%) 19 (29%) 17 (26%)
Adverse event leading to discontinuation of treatment 8 (13%) 1 (2%) 3 (5%) 12 (18%) 3 (5%) 5 (8%)
Serious adverse event
Any event 27 (42%) 20 (31%) 7 (11%) 25 (38%) 14 (22%) 8 (12%)
Treatment-related event 14 (22%) 8 (13%) 6 (9%) 17 (26%) 11 (17%) 5 (8%)
Cardiac dysfunction§§§¶¶¶ 15 (23%) 1 (2%) 0 11 (17%) 0 0
Oedema peripheral 10 (16%) 0 0 7 (11%) 0 0
Ejection fraction decreased 5 (8%) 1 (2%) 0 4 (6%) 0 0
Congestive cardiac failure 1 (2%) 1 (2%) 0 0 0 0
Hepatojugular reflux 1 (2%) 0 0 0 0 0
Jugular vein distension 1 (2%) 0 0 0 0 0
Left ventricular dysfunction 1 (2%) 0 0 0 0 0
Cardiac dysfunction 5 (8%) 1 (2%) 0 4 (6%) 0 0
(excluding peripheral oedema) ||||||
LVEF (lowest post-baseline)
n**** 51 ·· ·· 32 ·· ··
LVEF <50% 6 (12%) ·· ·· 3 (9%) ·· ··

Data are n (%). LVEF=left ventricular ejection fraction. *Adverse events and clinical laboratory toxicity were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events
(version 4.0). †The adverse events listed here were reported in at least 15% of patients in the olaratumab plus doxorubicin group, except as noted in footnote ¶¶. These included individual preferred terms from the
Medical Dictionary for Regulatory Activities (MedDRA) and specific consolidated terms combining clinically synonymous MedDRA preferred terms. ‡Consolidated term comprising the following preferred terms:
fatigue and asthenia. §Consolidated term comprising the following preferred terms: neutropenia and neutrophil count decreased. ¶Some patients reported both neutropenia and leucopenia. ||Consolidated term
comprising the following preferred terms: mucosal inflammation, oropharyngeal pain, and stomatitis.**Consolidated term comprising the following preferred terms: anaemia and haemoglobin decreased.
††Consolidated term comprising the following preferred terms: leucopenia and white blood cell count decreased. ‡‡Consolidated term comprising the following preferred terms: abdominal pain upper, abdominal
pain, and abdominal pain lower. §§Preferred terms reported were: arthralgia, back pain, spasms, musculoskeletal chest pain, myalgia, and pain in extremity. ¶¶5 (7·8%) patients (%) had musculoskeletal pain of grade
≥3 in the olaratumab plus doxorubicin group. |||| 1 (1·5%) patient had musculoskeletal pain of grade ≥3 in the doxorubicin group. ***These events are included here because they were considered clinically
important.†††Includes all preferred terms within the MedDRA system organ class of infections and infestations. ‡‡‡Consolidated term comprising the following preferred terms (from AESI): hypersensitivity,
infusion-related reaction, and face oedema. §§§Includes individual preferred terms from MedDRA. ¶¶¶Some patients reported more than one cardiac dysfunction event term. ||||||No patients with reported adverse
events of peripheral oedema had any reported adverse events to suggest cardiac dysfunction.****Number of patients assessed at baseline and at least one post-baseline timepoint.

Table 3: Adverse events (phase 2)*

monotherapy after disease progression and received a
median (range) of four infusions (1–81, IQR 4–8; median
two cycles, IQR 2–4; appendix p 29).
Treatment-emergent adverse events are summarised in
the appendix (p 30) for phase 1b and phase 2 (table 3).
The most common treatment-emergent adverse events
with olaratumab plus doxorubicin in the phase 2 portion
were nausea, fatigue, neutropenia, and mucositis, and
with doxorubicin there were fatigue, nausea, alopecia,
and neutropenia (table 3). Adverse events often associated
with doxorubicin treatment that were more frequent
with olaratumab plus doxorubicin versus doxorubicin

www.thelancet.com Published online June 9, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30587-6 7

 Articles
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%]). The number of infusion-related
reactions in the olaratumab plus doxorubicin arm was
(eight [13%] vs 0 for doxorubicin).
Treatment-related adverse events of grade 3 or higher
and serious adverse events of grade 3 or higher were
more frequent in patients treated with olaratumab plus
doxorubicin than in those treated with doxorubicin
(table 3). Fatigue and neutropenia of grade 3 or higher
were more frequent with olaratumab plus doxorubicin
(six [9%] and 34 [53%]) than with doxorubicin (two [3%]
and 21 [32%]). However, the incidence of febrile
neutropenia was similar in both groups: olaratumab plus
doxorubicin (eight [13%] of 64) versus doxorubicin
(nine [14%] of 65). The percentage of patients who
discontinued treatment because of an adverse event was
lower in the olaratumab plus doxorubicin group
(eight [13%] of 64) than in the doxorubicin group (12 [18%]
of 65).
Of the 129 treated patients in the phase 2 part of the
study, 39 (61%) in the olaratumab plus doxorubicin group
and 51 (79%) in the doxorubicin group had died at the
time of data cutoff. In the olaratumab plus doxorubicin
group, death was attributed to disease progression in
38 patients and an unknown cause in one patient. In the
doxorubicin group, death was attributed to disease
progression in 44 patients, adverse events in six patients
(aspirational pneumonia, respiratory failure, sepsis,
septic shock, and small bowel obstruction), and an
unknown cause in one patient. Doxorubicin-related
toxicities (neutropenia, mucositis, nausea, vomiting, and
diarrhoea) were more frequent in patients treated with
olaratumab plus doxorubicin, but did not result in an
increased number of febrile neutropenia events, hospital
admissions (appendix p 32), treatment discontinuations,
or deaths.
The prevalence of cardiac dysfunction (a consolidated
term comprised of peripheral oedema, decreased ejection
fraction, congestive cardiac failure, hepatojugular reflux,
jugular vein distention, and left ventricular dysfunction
at any grade) was 23% (15 patients) with olaratumab plus
doxorubicin and 17% (11 patients) with doxorubicin
(table 3). Excluding the patients with peripheral oedema
(none reported other adverse events to suggest cardiac
dysfunction), the total prevalence of cardiac dysfunction
was 8% (five patients) with olaratumab plus doxorubicin
and 6% (four patients) with doxorubicin. Changes in left
ventricular ejection fraction from baseline are
summarised in table 3.
85 patients were assessable for the presence or absence
of antidrug antibodies. The overall prevalence of
treatment-emergent antidrug antibodies was 6% (five of
85; appendix p 33). No effect of immunogenicity on
safety was recorded, and in those patients who developed
treatment-emergent antidrug antibodies, olaratumab
8 www.thelancet.com Published online June 9, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30587-6
serum concentrations remained unaffected until
cessation of treatment at the time of disease progression.
Analysis of PDGFRα expression showed that 88% of
tumours in patients treated with olaratumab plus
doxorubicin and 88% of tumours in patients treated with
doxorubicin were PDGFRα positive (table 1). However,
this assay was subsequently found to have poor
specificity for PDGFRα by also detecting PDGFRβ,
precluding meaningful data analysis. Reanalysis of study
tumour samples with an assay that had better specificity
for PDGFRα showed that 33% of tumours in patients
treated with olaratumab plus doxorubicin and 34% of
tumours in patients treated with doxorubicin were
positive for PDGFRα, consistent with a 2015 study.14 The
interaction effect between PDGFRα expression (positive
or negative) and treatment was not significant for
either overall (p=0·3209) or progression-free survival
(p=0·5924).
Discussion
The combination of olaratumab plus doxorubicin
improved both progression-free and overall survival
compared with the standard of care treatment of
doxorubicin only in patients with advanced soft-tissue
sarcoma. Ad-hoc analyses of pretreatment, concomitant,
and post-treatment factors revealed no consistent
imbalances that could have meaningfully affected the
robustness of the study results. Treatment arms were well
balanced for line of treatment, performance status, and
prognostic factors implicated in soft-tissue sarcoma.15
Although the proportion of treatment discontinuation
because of adverse events was higher in the control arm,
most of these were considered to be serious adverse
events, and single-drug doxorubicin worked as expected
from historical data.4,16–18 An ad-hoc sensitivity analysis
(appendix p 23) of patients discontinuing study treatment
because of adverse events or symptomatic progressive
disease within the first eight cycles, or patients completing
fewer than four cycles of doxorubicin showed HRs similar
to the overall study results, making these factors an
unlikely source of bias for the observed overall survival
results. The number of poststudy lines of treatment were
well balanced between both arms with modest imbalances
in some chemotherapeutic drugs. An ad-hoc sensitivity
analysis censoring patients (appendix p 22) at the start of
any new anticancer treatment or upon starting specific
chemotherapeutic drugs showed HRs similar to the
overall study results. None of these drugs have improved
median overall survival in the broad soft-tissue sarcoma
population. Lastly, the early separation of the overall
survival curves is consistent with an effect of the
combination of olaratumab plus doxorubicin rather than
confounding post-treatment factors.
The magnitude of improvement reported in median
overall survival with olaratumab plus doxorubicin (80%,
11·8 months) was greater than that observed in
progression-free survival (61%, 2·5 months). This

finding suggests that the inhibitory effect of olaratumab
on tumour and stromal PDGFRα signalling might
persist beyond the immediate treatment period.
Although tumour PDGFRα expression alone did not
correlate with outcome, tumour samples available for
study were a heterogeneous mixture of archival primary
and metastatic tumours. Ongoing and future work will
explore both tumour and stromal expression of PDGFRα
and related ligands and more fully characterise
immunohistochemical criteria for PDGFRα positivity.
Our findings are particularly notable given the little
progress in improvement of median overall survival in
patients with advanced soft-tissue sarcoma. Most
patients are treated with traditional regimens of
doxorubicin or doxorubicin in combination with
ifosfamide; however, the prognosis for patients with
metastatic disease is poor because the efficacy of these
and other treatment options is limited. In a phase 3
study by the European Organisation for Treatment of
Cancer Soft Tissue and Bone Sarcoma Group, use of
doxorubicin plus high-dose ifosfamide improved
progression-free survival and response proportions
compared with doxorubicin treatment alone.4 These
important palliative outcomes were achieved at the
expense of increased drug toxicity and without an
improvement in median overall survival compared with
doxorubicin alone (14·3 vs 12·8 months, respectively
[HR 0·83, p=0·076]). Other combination and novel-drug
studies also did not show improvement in overall
survival compared with doxorubicin alone,5,17,19–22
reinforcing the challenging nature of improving
outcomes in advanced soft-tissue sarcoma.
In conclusion, this study of olaratumab in combination
with doxorubicin met its predefined, statistical, primary
endpoint for progression-free survival and achieved
a highly statistically significant improvement of
11·8 months in median overall survival compared with
doxorubicin alone. Importantly, the improvement in
median overall survival was achieved without an increase
in serious toxicity, despite a higher cumulative exposure
to doxorubicin. Although the proportion of some
doxorubicin-associated toxicities such as neutropenia
and mucositis were higher in the olaratumab plus
doxorubicin group than in the control group, this did not
lead to a higher rate of febrile neutropenia, infection,
hospital admission, or treatment-related mortality.
Altogether, the pronounced survival benefit, along with
an acceptable safety profile including cardiac safety,
represents a positive benefit-risk profile for olaratumab
plus doxorubicin in the treatment of patients with soft-
tissue sarcoma.
Contributors
AQ was involved in the study design and led the statistical analyses.
WDT, RLJ, BAVT, BC, ADE, DA, MA, MMC, MBL, GP, MRH, GDS, and
GKS were involved in the data collection. DMC led the pharmacokinetic
analyses. All authors were involved in the interpretation of the data.
WDT wrote the first draft of the manuscript, and all authors contributed
to subsequent drafts.
www.thelancet.com Published online June 9, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30587-6
Articles
Declaration of interests
AQ, AS, DMC, RI, and IC are employees of Eli Lilly and Company.
JC and GDS were employees of ImClone Systems (now Eli Lilly and
Company) during study design, and conduct, and JC was an employee
during the analysis. WDT reports personal fees from Eli Lilly and
Company, Advaxis, Ariad, Boehringer Ingelheim, EMD Serono,
Daiichi Sankyo, Morphotek, and Plexxikon. RLJ has received a grant
from ImClone. BAVT served on an advisory board for Eli Lilly and
Company. BC reports personal fees from Eli Lilly and Company, Amgen,
Astella, Genentech, and BMS. DA has received grants from Eli Lilly and
Company. MA reports personal fees from EMD Serono, Janssen, and
Novartis. GP reports personal fees from Bristol-Myers Squibb. GDS was
an employee of Novartis during the conduct of the study. AQ, AS, DMC,
RI, and IC are employees of and stockholders in Eli Lilly and Company.
JC was an employee of Eli Lilly and Company during the conduct of the
study. ADE, MMC, MBL, MRH, and GKS declare no competing
interests.
Acknowledgments
This study was funded by Eli Lilly and Company. We thank
Patrick Peterson, Eli Lilly and Company, for statistical assistance and
Joseph Giaconia, INC Research, for writing assistance.
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