Advanced or Metastatic Soft Tissue Sarcoma

The primary objective is to compare doxorubicin plus olaratumab versus doxorubicin plus placebo with respect to overall survival (OS) in 2 populations: (1) Patients with advanced or metastatic STS not amenable to treatment with surgery or radiotherapy with curative intent (2) Patients with advanced or metastatic leiomyosarcoma (LMS) not amenable to treatment with surgery or radiotherapy with curative intent

Olaratumab (LY3012207)

LY3012207

Injection

500mg (10 mg/mL)

Primary Outcome Measures :
1. Overall Survival (OS) [ Time Frame: Randomization to Date of Death Due to Any Cause (Up to 35.8 Months) ]
Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters.

2. Overall Survival (OS) Leiomyosarcoma (LMS) [ Time Frame: Randomization to Date of Death Due to Any Cause (Up to 35.8 Months) ]
Overall survival was defined as the time from the date of randomization to the date of death due to any cause. For each participant, prior to data analysis, a reasonable effort was made to obtain the most up-to-date status (date of death or last date known to be alive). For any participant not known to have died as of the data cutoff date, OS was censored at the date the participant was last known to be alive. For any participant who withdrew consent for survival follow-up, OS was censored at the last date for which the participant provided consent for follow-up contact. The Kaplan-Meier method was used to estimate median parameters.


Secondary Outcome Measures :
1. Progression Free Survival (PFS) [ Time Frame: Randomization to Objective Progression or Death Due to Any Cause (Up to 35.8 Months) ]
PFS was defined by (Response Evaluation Criteria In Solid Tumors RECIST v.1.1) as the time from the date of randomization to the first date of radiologic disease progression or death due to any cause. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 millimeter (mm), or unequivocal progression of non-target lesions, or 1 or more new lesions. Censoring for death or PD due to increase sum of target lesions is defined for each participant as the time from the date of randomization to the first date of radiographic documentation of 1 or more lesions. Censoring for death without progression is defined as the date of death if there is no prior or concurrent radiologic disease progression.

2. Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months) ]
ORR was defined as the percentage of participants achieving a best overall response of complete response (CR) + partial response (PR). CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to RECIST v1.1.

3. Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: Randomization to Objective Disease Progression or Death Due to Any Cause (Up to 45 Months) ]
DCR was defined as the percentage of randomized participants achieving a best overall response of CR, PR, or SD per RECIST v.1.1. CR is the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. PD is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

4. Time to First Worsening on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores [ Time Frame: Randomization (Cycle 1) through Follow-up (Up to 35.8 Months) ]
Time to first worsening was calculated as the time from the first study drug dose to the first observation of worsening according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). The EORTC QLQ-C30 self-reported general cancer instrument consists of 30 total items covered by 1 of 3 dimensions (1 global health status/QoL total score, 5 functional subscales [physical, role, cognitive, emotional, and social]), and 9 symptom subscales [fatigue/nausea/vomiting/pain/dyspnea/insomnia/appetite loss/constipation/diarrhea]). There are 28 questions answered on a 4-point scale where 1=Not at all (best) to 4=Very Much (worst) and 2 questions answered on a 7-point scale where 1=Very poor (worst) to 7= Excellent (best). A linear transformation was used to obtain total score ranging from 0 to 100 where "worsening" was defined as an increase of at least 10 points for the symptom scales or a decrease of at least 10 points for the functional scales and the global health status/QoL scale.

5. Change From Baseline to Maximum Improvement in Health Status Index Score on the EuroQol 5-Dimension 5-Level (EQ-5D-5L) [ Time Frame: Randomization through Follow-up (Up to 35.8 Months) ]
The EQ-5D-5L is a standardized measure of health status used to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L consists of a descriptive system of the respondent's health which comprises the following 5 dimensions: (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Health status was calculated from a set of item weights to derive a score of 0 to 1, with 1 representing the best health status. United Kingdom (UK) weights were applied. The analysis includes all cycles for which at least 25% of participants in each arm have an assessment. For each participant a change from baseline was calculated for every post-baseline assessment by subtracting the baseline assessment result from the current assessment result. Maximum improvement (over baseline) was determined from the set of all post-baseline change scores.

6. Time to First Worsening of the Brief Pain Inventory Short Form Modified (mBPI-sf) "Worst Pain Score" [ Time Frame: Randomization through Follow-up (Up to 34.5 Months) ]
Time to first worsening of the brief pain inventory short form modified (mBPI-sf) "worst pain score" was defined as the time from the date of the first study drug dose (baseline date) to the first date of a "worst pain" score increase of greater than or equal to (≥) 2 points from baseline. The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity ranging from 0 (no pain or does not interfere) and ranged through 10 (pain as bad as you can imagine or completely interferes).

7. Duration of Overall Response (DoR) [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Up to 33.4 Months) ]
The duration of overall response was defined for each participant with a best response of CR or PR and measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that disease is recurrent or objective disease progression or death due to any cause is observed (taking as reference for PD the smallest measurements recorded on study).

8. Duration of Disease Control (DDC) [ Time Frame: Date of CR, PR, or SD to Objective Disease Progression or Death Due to Any Cause (Up to 35.8 Months) ]
Duration of disease control was defined for each participant with a best response of CR, PR, or stable disease (SD) as the time from randomization to the first date of disease progression or death due to any cause.

9. Pharmacokinetics (PK) Clearance of Olaratumab Mean Parameter Estimate [ Time Frame: Cycle 1- 9: Day 1 and 8, Predose, 5 minutes Post dose and then every other cycle and follow-up (30 Days) ]
The PK systemic clearance parameter estimates from the current analysis are listed together with the population PK model estimates.

10. PK: Volume of Distribution at Steady State (Vss) of Olaratumab: Mean Parameter Estimate [ Time Frame: Cycle 1- 9: Day 1 and 8; Predose, 5 Minutes Post dose and then every other cycle and follow-up (30 Days) ]
The PK parameter estimates from the current analysis are listed together with the population PK model estimates. The Vss is the sum of central volume of distribution (V1) + peripheral volume of distribution (V2).

Inclusion Criteria
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.
[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). 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).
[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 therapies must have been completed ≥ 4 weeks
(28 days) prior to randomization.
[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 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).
 Total bilirubin within normal limits (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.
[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 3 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.

Exclusion Criteria
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 and anthracenediones; the patient has received prior olaratumab
treatment.
[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] The patient has a resting heart rate of >100 bpm.
[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).
[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] The patient has current hematologic malignancies.
[29] The patient has an active fungal, bacterial, and/or known viral infection including
human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not
required).