A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Doxorubicin plus Olaratumab versus Doxorubicin plus Placebo in Patients with Advanced or Metastatic Soft Tissue Sarcoma

Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] The patient signed an ICF and authorization for release of health information for
research prior to any study-specific procedures being performed.
[2] The patient is aged >= 18 years at study entry.
[3] The patient has histologically confirmed diagnosis of locally advanced unresectable or
metastatic STS not amenable to curative treatment with surgery or radiotherapy.
Patients with a diagnosis of Grade 1 liposarcoma are eligible if there is histological or
radiographic evidence of evolution to more aggressive disease. Patients with Kaposi*s
sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. Note: Evidence of disease progression is required for patients that are not newly diagnosed.
[4] The patient has measurable or nonmeasurable but evaluable disease as defined by the
Response Evaluation Criteria in Solid Tumors (RECIST 1.1, Eisenhauer et al. 2009;
refer to Attachment 6 of the Protocol). Tumors within a previously irradiated field will be designated
as *nontarget* lesions unless progression is documented or a biopsy is obtained to
confirm persistence at least 90 days following completion of radiotherapy.
[5] The patient has a performance status 0-1 on the Eastern Cooperative Oncology Group
(ECOG) scale (refer to Attachment 4 of the Protocol).
[6] The patient has not received any previous treatment with anthracyclines.
[7] The patient may have had any number of prior systemic cytotoxic therapies for
advanced/metastatic disease and are considered appropriate candidates for
anthracycline therapy. All previous anticancer treatments must be completed >= 3 weeks
(21 days) prior to first dose of study drug.
[8] The patient has resolution of adverse events and of all clinically significant toxic effects
of prior locoregional therapy, surgery, radiotherapy, or systemic anticancer therapy to
<= Grade 1, by National Cancer Institute - Common Terminology Criteria for Adverse
Events (NCI-CTCAE) Version 4.0.
[9] Availability of tumor tissue is mandatory for study eligibility. The patient must have
consented to provide archived formalin-fixed paraffin embedded (FFPE) tumor tissue
or be subject to a pre-treatment re-biopsy of primary or metastatic tumor tissue for
future central pathology review and translational research (if archived tissue is
unavailable) (refer to Section 10.4.2.3 of the Protocol regarding tissue collection parameters).
[10] The patient has adequate hematologic, organ, and coagulation function within 2 weeks
(14 days) prior to randomization:
• Absolute neutrophil count (ANC) >=1.5 x 109/L. Granulocyte colony-stimulating
factor (G-CSF) cannot be administered within 2 weeks (14 days) prior to
randomization.
• Platelet count >=100 x 109/L
• Hemoglobin >=9.0 g/dL. No transfusions are allowed within 2 weeks (14 days) prior to randomization.
• The creatinine clearance is >=45 mL/min (refer to Attachment 5 for the Cockcroft-Gault formula)
Proteinuria <=1000 mg in 24 hours (if routine urinalysis indicates >=2+ proteinuria)
• Total bilirubin below upper limit of normal (ULN) (except for patients with Gilbert*s Syndrome, who must have a total bilirubin <3 mg/dL)
• Alanine aminotransferase/aspartate aminotransferase (AST/ALT) <= 3.0 × ULN; if the liver has tumor involvement, AST and ALT <=5.0 × ULN are acceptable.
• The patient has an adequate coagulation function as defined by International Normalized Ratio (INR) or prothrombin time (PT) <=1.5 x ULN, and partial thromboplastin time (PTT or aPTT) <=1.5 x ULN if not receiving anticoagulation therapy. For patients receiving anticoagulants, exceptions to these coagulation parameters are allowed if they are within the intended or expected range for their
therapeutic use. Patients must have no history of active bleeding (defined as within 14 days of first dose of study drug) or pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known esophageal varices).
[11] The patient has left ventricular ejection fraction (LVEF) >=50% assessed within 28 days
prior to randomization.
[12] Females of child-bearing potential must have a negative serum pregnancy test within
7 days prior to randomization.
(a) Exceptions: Females not of child-bearing potential due to surgical
sterilization (at least 6 weeks following surgical bilateral oophorectomy
with or without hysterectomy or tubal ligation) confirmed by medical
history or menopause.
A *postmenopausal woman* is a woman meeting either of the following criteria:
• spontaneous amenorrhea for at least 12 months, not induced by a medical
condition such as anorexia nervosa and not taking medications during the
amenorrhea that induced the amenorrhea (for example, oral contraceptives,
hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen
receptor modulators (SERMs), or chemotherapy
• spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone
(FSH) level >40 mIU/mL
[13] Females of child-bearing potential and males and must agree to use highly effective
contraceptive precautions during the trial and up to 6 months following the last dose of
study drug. A highly effective method of birth control is defined as one that results in a
low failure rate (that is, <1% per year) when used consistently and correctly, such as
implants, injectables, combined oral contraceptives, some intrauterine contraceptive
devices (IUDs), sexual abstinence, or a vasectomized partner.
[14] The patient has, in the opinion of the investigator, a life expectancy of at least
3 months.

Patients will be excluded from the study if they meet any of the following criteria:
[15] The patient is diagnosed with GIST or Kaposi sarcoma.
[16] The patient has active central nervous system (CNS) or leptomeningeal metastasis
(brain metastasis) at the time of randomization. Patients with a history of a CNS
metastasis previously treated with curative intent (for example, stereotactic radiation or
surgery) that have not progressed on follow-up imaging, have been asymptomatic for at
least 60 days and are not receiving systemic corticosteroids and or/anticonvulsants, are
eligible. Patients with signs or symptoms of neurological compromise should have
appropriate radiographic imaging performed before randomization to rule out brain
metastasis.
[17] The patient has received prior treatment with doxorubicin, epirubicin, idarubicin, and/or
other anthracyclines or anthracenediones; the patient has received prior treatment with olaratumab or has participated in a prior olaratumab trial.
[18] The patient had prior radiotherapy of the mediastinal/pericardial area or whole pelvis
radiation.
[19] The patient has history of another primary cancer, with the exception of a) curatively
treated non-melanomatous skin cancer, b) curatively treated cervical carcinoma in situ,
c) other primary non-hematologic malignancies or solid tumor treated with curative
intent, no known active disease and no treatment administered during the last 3 years
prior to randomization.
[20] The patient has electively planned or will require major surgery during the course of the
study.
[21] The patient has uncontrolled intercurrent illness including, but not limited to, an
ongoing/active infection requiring parenteral antibiotics, symptomatic congestive heart
failure (CHF), left ventricular dysfunction (LVEF < 50%), severe myocardial
insufficiency, cardiac arrhythmia, cardiomyopathy, or a psychiatric illness/social
situation that would limit compliance with study requirements.
[22] The patient has unstable angina pectoris, angioplasty, cardiac stenting, or myocardial
infarction within 6 months of randomization.
[23] DELETED
[24] The patient has a QTcB interval of >450 msec for males and >470 msec for females on
screening electrocardiogram (ECG) utilizing Bazett*s correction (refer to formula in
Table JGDJ.8 of the Protocol).
[25] Females who are pregnant or breastfeeding
[26] The patient has a known allergy to any of the treatment components including a history
of allergic reactions attributed to compounds of chemical or biological composition
similar to olaratumab.
[27] The patient is enrolled in, or discontinued study treatment from another trial involving
an investigational agent or use of non-approved drug or device within 28 days of being
randomized in this trial, or concurrent enrollment in any other type of medical research
judged scientifically or medically incompatible with this trial. Patients participating in
surveys or observational studies are eligible to participate in this study.
[28] DELETED.
[29] The patient has a known investigator-assessed active fungal, bacterial, or viral infection including
human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not
required).