WO2019231803A1

WO2019231803A1 - Combination therapy for soft tissue sarcoma

Info

Publication number: WO2019231803A1
Application number: PCT/US2019/033668
Authority: WO
Inventors: Robert Leslie ILARIA; Volker Wacheck
Original assignee: Imclone Llc
Priority date: 2018-05-31
Filing date: 2019-05-23
Publication date: 2019-12-05

Abstract

The present invention provides for use in treating and methods of treating soft tissue sarcoma with olaratumab, in combination with gemcitabine and docetaxel.

Description

COMBINATION THERAPY FOR SOFT TISSUE SARCOMA

The present invention relates to the field of medicine. More specifically, the present invention relates to combinations of olaratumab, an antibody against platelet-derived growth factor receptor alpha (PDGFRa), with gemcitabine and docetaxel, and to methods of use of the combination to treat soft tissue sarcoma (STS).

Olaratumab (LARTRUVO^®, EVIC-3G3) is a recombinant human immunoglobulin G subclass 1 (IgGl)-type monoclonal antibody that binds to PDGFRa and blocks interaction between PDGFRa and its ligands. In addition to blocking ligand-induced cell mitogenesis and receptor autophosphorylation, olaratumab inhibits phosphorylation of downstream signaling molecules including Akt and mitogen-activated proteinkinase also by PDGFRa internalization and degredation (Loizos et al., Mol Cancer Ther. 2005; 4(3): 369-379; Dolloff et al. Cancer Res 2007; 67: (2). January 15, 2007). Olaratumab, sequences thereof, and methods of making and using this antibody, including for the treatment of neoplastic diseases such as solid and non-solid tumors, are disclosed in WO 2006/138729.

Gemcitabine (CAS Registry' No. 95058-81-4), a nucleoside metabolic inhibitor, is the active pharmaceutical ingredient in GEMZAR^®, which has been approved: in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum- based therapy ; in combination with paclitaxel, for first- line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated; in combination with cisplatin for the treatment of non-small cell lung cancer; and as a single agent for the treatment of pancreatic cancer. See the US and European labels of GEMZAR^® (gemcitabine).

Docetaxel (TAXOTERE^®, CAS Registry No. 114977-28-5) is a chemotherapy drug belonging to a class of medications known as taxanes that work by stopping or slowing the growth of cancer cells in the body through microtubule inhibition. Docetaxel is used in the treatment of certain types of breast, lung, prostate, stomach, and head and neck cancers. See the US and European labels of TAXOTERE^® (docetaxel). STS is a heterogeneous group of malignant tumors that arise from tissue of mesenchymal origin. STS arises primarily from the embryonic mesoderm, with some neuroectodermal contribution and differentiation to non-epithelial extraskeletal tissue, including striated skeletal and smooth muscle, adipose, and fibrous tissue (Sharma S, et al, BMC Cancer. 2013; 13: 385; D’Angelo SP, et a , Sarcoma. 2014; 2014: 39196; Linch M, et al., Nat Rev Clin Oncol. 2014; 11(4): 187-202). There are at least approximately 50 different subtypes of STS that can be found in almost any anatomic location (American Cancer Society, 2014; cancer.org/acs/groups/cid/documents/webcontent/003 l38-pdf.pdf; Linch et al. 2014). STS is rare, comprising approximately 1% of adult cancers. The annual incidence of STS in the United Kingdom (UK) and United States (US) is 3300 and 10,000, respectively (Jemal A, et al., Methods Mol Biol. 2009; 471: 3-29; National Cancer Intelligence Network, 2013; ncin.org.uk/view ?rid=2353). Management of localized disease is usually with curative intent, using surgical resection with or without radiotherapy and chemotherapy. In spite of initial aggressive management, there is for localized, high-risk STS a frequent recurrence of local inoperable or metastatic disease, and at this point systemic therapy plays a prominent role in the multidisciplinary management of STS (Linch et al. 2014).

The mainstay therapy for treating advanced-stage STS has been chemotherapy, which in the first-line setting has provided overall response rates of up to approximately 25% (Linch et al. 2014). Even with the use of chemotherapy, advanced-stage STS is usually fatal and there remains an unmet medical in need for novel and more effective therapies. Doxorubicin either administered as monotherapy or in combination with other anti-neoplastic agents has been the standard of care for the initial treatment for metastatic sarcoma for many years. Various drug combinations have been explored (Linch et al. 2014). In 2016, Olaratumab (trade name“LARTRUVO™”), in combination with doxorubicin, was granted accelerated approval by the U.S. Food and Drug Administration (“FDA”) for the treatment of adult patients with soft tissue sarcoma with a histologic subtype for which an anthracycline- containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery (see the US labels of LARTRUVO™ (olaratumab)); on April 25, 2019, it was announced that Lilly“has been working to facilitate the withdrawal of LARTRUVO® (olaratumab) from the market for the treatement of advanced soft tissue sarcoma (STS). Lilly’s actions to withdraw LARTRUVO from the market follow the failure of the Phase 2 ANNOUNCE clinical trial...” (Eli Lilly and Company, April 25, 2019; investor.lilly.com/news-releases/news-release-details/lilly-establish-access-program-patients- it-prepares-withdraw) .

The novel and inventive treatment for STS w ith olaratumab, in combination with gemcitabine and docetaxel, is being studied in a Phase lb (open label) / Phase 2 (randomized, double blinded) clinical trial. (Study Number NCT02659020, available on clinicaltrials.gov)(hereinafter“Study”).

The combination of gemcitabine and docetaxel as a first line treatment in previously untreated advanced or metastatic STS w'as studied in a Phase 3 trial (Seddon et al. Lancet Oncology 2017; 18: 1397-410 (hereinafter“GeDDis”). The GeDDis study reported a 24- weeks progression-free survival (PFS) rate as primary endpoint of 46.4% (95% confidence interval [Cl] : 37.5, 54.8) of those receiving gemcitabine/docetaxel relative to 46.3% (95% CL 37.5, 54.6) in those receiving doxorubicin. The proportion of patients achieving disease control (complete or partial response or stabilized disease at any tumor assessment) was similar in the two groups: 66% of patients in the doxorubicin group and 59% in the gemcitabine and docetaxel group and a best response of stable disease (SD) in 47% of patients relative to 39%, for those who received doxorubicin versus those who received gemcitabine and docetaxel. (Id. at 1402-1403.)

Other relevant clinical trials evaluating the combination of gemcitabine and docetaxel include a study of previously treated patients with metastatic STS in a Phase 2 trial with various fixed dose rate infusions (Maki et al. Journal of Clinical Oncology 2007; 25: 2755- 276) (hereinafter“Maki”) and a second-line therapy for metastatic uterine leiomyosarcoma a Phase 2 trial (Hensley et al., Gynecologic Oncology 2008; 109: 324-328) (hereinafter “Hensley”). Due to study design differences, the Maki study and the Hensley study are not directly comparable to the Study.

Novel methods for use of the combination of olaratumab, gemcitabine, and docetaxel to treat locally advanced or metastatic STS are presented herein. Accordingly, the present invention provides for olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the administration of olaratumab, and wherein the docetaxel is administered following the gemcitabine. More particularly, the olaratumab is administered at a first dose of: (i) about 15 mg/kg, or (ii) about 20 mg/kg, followed by one or more subsequent dose(s) of olaratumab to the patient of: (iii) about 15 mg/kg, or (iv) about 20 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first two doses of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, wherein the cycle is 21 days. More particularly, the olaratumab is administered at two doses of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by two doses of about 15 mg/kg in subsequent cycles of olaratumab. More particularly, the olaratumab is administered at a first dose of about 20 mg/kg in a first cycle of olaratumab to the patient, a second dose of about 15 mg/kg in a first cycle of olaratumab to the patient, followed by two doses of about 15 mg/kg in subsequent cycles of olaratumab. More particularly, the olaratumab is administered in each cycle, at a dose of about 20 mg/kg in the first dose of olaratumab to the patient in the cycle, followed by about 15 mg/kg in a second dose olaratumab to the patient in the cycle. In a futher aspect, the olaratumab is administered at two doses of about 15 mg/kg in a first cycle of olaratumab to the patient, followed by two doses of about 20 mg/kg in subsequent cycles of olaratumab. More particularly, the olaratumab is administered at a dose of about 20 mgkg in the first dose of olaratumab to the patient, followed by 15 mg/kg in the second dose of olaratumab to the patient, followed by about 20 mg_'kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at a dose of about 15 mg/kg in the first dose of olaratumab to the patient, followed by 20 mg/kg in the second dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at a dose of about 15 mg/kg in the first dose of olaratumab to the patient, followed by about 20 mg/kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at a first dose of about 15 mg/kg in a first cycle of olaratumab to the patient, a second dose of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by two doses of about 15 mg/kg in subsequent cycles of olaratumab. More particularly, the olaratumab is administered by intravenous infusion over about 60 minutes. In further aspects, the olaratumab is administered on days 1 and 8 of the 21 day cycle. More particularly, the gemcitabine is administered at a dose of about 900 mg/m². More particularly, the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute. hi further apsects, the gemcitabine is administered at a reduced dose of less than about 900 mg/m², more particularly the gemcitabine is administered at the reduced dose of about 675 mg/m² or about 500 mg/m². More particularly, the gemcitabine is administered on days 1 and 8 of the 21 day cycle. In further aspects, the docetaxel is administered at a dose of about 75 mg/m², even more particularly, the docetaxel is administered at a reduced dose of less than about 75 mg/m² or about 60 mg/m² hi a further aspect, the gemcitabine is administered by intravenous infusion over about 30 minutes. More particularly, the docetaxel is administered at the reduced dose of about 45 mg/m². More particularly, the docetaxel is administered by intravenous infusion over about 60 minutes. More particularly, the docetaxel is administered on day 8 of a 21 day cycle. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. In another aspect, the soft tissue sarcoma is leiomyosarcoma. In a further aspect, a premedication for the olaratumab is administered to the patient about 30 to about 90 minutes prior to the olaratumab dose. More particularly, the premedication comprises a histamine Hl antagonist and or a corticosteroid. More particularly, the histamine Hl antagonist is diphenhydramine, and the corticosteroid is dexamethasone. In a further aspect, a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics. In a further aspect, a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid. More particularly, the corticosteroid is dexamethasone, and even more particularly, the dexamethasone is administered orally at about 8 mg twice a day. More particularly, the dexamethasone is administered the day prior to the docetaxel administration, the day of the docetaxel administration, and the day after the docetaxel administration. In another aspect, a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte-colony stimulating factors or peg-granulocyte-colony stimulating factors. More particularly, the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s). More particularly, the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s). In a further aspect, the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use. In an alternative aspect, the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use. In a futher aspect, the present invention provides for olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the administration of olaratumab, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m². More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In a preferred aspect, olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the administration of olaratumab, and wherein the docetaxel is administered following the gemcitabine; wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, and wherein a premedication of histamine Hl antagonist, including but not limited to diphenhydramine, and a premedication of a corticosteroid, including but not limited to dexamethasone is administered to the patient prior to the olaratumab dose; and wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein a premedication of prophylactic antiemetics is administered to the patient prior to the gemcitabine dose; and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m², and wherein a premedication of a corticosteroid, including but not limited to dexamethasone, is administed, including but not limited to orally at about 8 mg twice a day, on the day prior to the docetaxel administration, the day of the docetaxel administration, and the day after the docetaxel administration. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma. More particularly, soft tissue sarcoma patients with a history of pelvic radiation are administered granulocyte-colony stimulating factors, at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s), or peg-granulocyte-colony stimulating factors in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

hi a preferred aspect, olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, is administered to the patient in the following sequence: on day 1 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, including but not limited to diphenhydramine, and corticosteroid, including but not limited to dexamethasone, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, including but not limited to dexamethasone twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, including but not limited to diphenhydramine, and corticosteroid, including but not limited to dexamethasone, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, followed by docetaxel, followed by the second daily dose of the dexamethasone; on day 9 of the 21 day cycle, a corticosteroid, including but not limited to dexamethasone, twice a day.

In a preferred aspect, olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, is administered to the patient in the following sequence in cycle 1 : on day 1 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, including but not limited to diphenhydramine, and corticosteroid, including but not limited to dexamethasone, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, including but not limited to dexamethasone twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, including but not limited to diphenhydramine, and corticosteroid, including but not limited to dexamethasone, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, followed by docetaxel, followed by the second daily dose of the dexamethasone; on day 9 of the 21 day cycle, a corticosteroid, including but not limited to dexamethasone, twice a day. Further, the following sequence is used in one or more subsequent cycle(s): on day 1 of the 21 day cycle, the following are administered to the patient: histamine HI antagonist, including but not limited to diphenhydramine, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, including but not limited to dexamethasone twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, including but not limited to diphenhydramine, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, followed by corticosteroid, including but not limited to dexamethasone, followed by docetaxel, followed by the second daily dose of the dexamethasone; on day 9 of the 21 day cycle, a corticosteroid, including but not limited to dexamethasone, twice a day.

In a preferred aspect, olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, is administered to the patient in the following sequence: on day 1 of the 21 day cycle, the following are administered to the patient: histamine HI antagonist and corticosteroid, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine HI antagonist, and corticosteroid, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, followed by docetaxel, followed by the corticosteroid; on day 9 of the 21 day cycle, a corticosteroid, twice a day. More specifically, the histamine Hl antagonist, includes but not limited to diphenhydramine, and the corticosteroid includes but not limited to dexamethasone.

In a preferred aspect, olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, is administered to the patient in the following sequence in cycle 1 : on day 1 of the 21 day cycle, the following are administered to the patient: histamine HI antagonist and corticosteroid, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, and corticosteroid, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, followed by docetaxel, followed by corticosteroid: on day 9 of the 21 day cycle, a corticosteroid, twice a day. Further, the following sequence is used in one or more subsequent cycle(s): on day 1 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine; on day 7 of the 21 day cycle, the following are administered to the patient: a corticosteroid, twice a day; on day 8 of the 21 day cycle, the following are administered to the patient: histamine Hl antagonist, followed by olaratumab, followed by prophylactic antiemetics, followed by gemcitabine, and corticosteroid, followed by docetaxel, followed by corticosteroid; on day 9 of the 21 day cycle, a corticosteroid, twice a day. More specifically, the histamine HI antagonist, includes but not limited to diphenhydramine, and the corticosteroid includes but not limited to dexamethasone.

In another aspect, the invention provides for the method of treating soft tissue sarcoma, comprising administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering gemcitabine to the patient, wherein the gemcitabine is administered following the olaratumab administration; and administering docetaxel to the patient following the gemcitabine administration. More particularly, the olaratumab is administered at a first dose of: (i) about 15 mg/kg, or (ii) about 20 mg/kg, followed by one or more subsequent dose(s) of olaratumab to the patient of: (iii) about 15 mg/kg, or (iv) about 20 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one of more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one of more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days. More particularly, the olaratumab is administered by intravenous infusion over about 60 minutes. Even more particularly, the olaratumab is administered on days 1 and 8 of the 21 day cycle. In a futher aspect, the gemcitabine is administered at a dose of about 900 mg/m². More particularly, the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute. More particularly, the gemcitabine is administered at a reduced dose of less than about 900 mg/m² wherein the reduced dose is about 675 mg/m² or about 500 mg/m². More particularly, the gemcitabine is administered on days 1 and 8 of the 21 day cycle. In a further aspect, the docetaxel is administered at a dose of about 75 mg/m². More particularly, the docetaxel is administered at a reduced dose of less than about 75 mg/m² wherein the reduced dose is about 60 mg/m² or about 45 mg/m². More particularly, the docetaxel is administered by intravenous infusion over about 60 minutes. More particularly, the docetaxel is administered on day 8 of a 21 day cycle. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/nr/minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In a further aspect, a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose. More particularly, the premedication a histamine HI antagonist and or a corticosteroid. More particularly, the histamine HI antagonist is diphenhydramine, and the corticosteroid is dexamethasone. In a further aspect, a premedication for gemcitabine is administered to the patient, and the premedication is prophylactic antimetics. hi a further aspect, a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid. More particularly, the corticosteroid is dexamethasone. More particularly, the dexamethasone is administered orally at about 8 mg orally twice a day. More particularly, the dexamethasone is administered the day prior to the docetaxel administration, the day of the docetaxel administration, and the day after the docetaxel administration. In further aspect, a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte-colony stimulating factors or peg-granulocyte-colony stimulating factors. More particularly, the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s). More particularly, the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

In another aspect, the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said method. In a still further aspect, the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said method.

In another aspect, the invention provides for the method of treating soft tissue sarcoma, comprising administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering gemcitabine to the patient, wherein the gemcitabine is administered following the olaratumab administration, and administering docetaxel to the patient following the gemcitabine administration, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m². More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In another aspect, the invention provides for a kit comprising a container comprising a pharmaceutical composition comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, a container comprising a pharmaceutical composition comprising gemcitabine with one or more pharmaceutically acceptable carriers, diluents, or excipients, and a container comprising a pharmaceutical composition comprising docetaxel with one or more pharmaceutically acceptable carriers, diluents, or excipients, for use in the treatment soft tissue sarcoma. More particularly, the kit further comprising either (i) written instructions for administering olaratumab, gemcitabine and docetaxel, or (ii) an internet address from which instructions for administering olaratumab, gemcitabine and docetaxel can be obtained.

hi another aspect, the invention provides for a use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, where in the medicament is to be administered in combination with gemcitabine and docetaxel, wherein the gemcitabine is administered to a patient after the olaratumab is administered and before the docetaxel is administered. More particularly, the olaratumab is administered at a first dose of: (i) about 15 mg/kg, or (ii) about 20 mg/kg, followed by one or more subsequent dose(s) of olaratumab to the patient of: (iii) about 15 mg/kg, or (iv) about 20 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg. More particularly, the olaratumab is administered at a dose of about 20 mgkg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab. More particularly, the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days. More particularly, the olaratumab is administered by intravenous infusion over about 60 minutes. More particularly, the olaratumab is administered on days 1 and 8 of the 21 day cycle hi another aspect, the gemcitabine is administered at a dose of about 900 mg/m². More particularly, the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute. More particularly, the gemcitabine is administered at a reduced dose of less than about 900 mg/m² including but not limited to about 675 mg/m² or about 500 mg/m². More particularly, the gemcitabine is administered on days 1 and 8 of the 21 day cycle. In a further aspect, the docetaxel is administered at a dose of about 75 mg/m². More particularly, the docetaxel is administered at a reduced dose of less than about 75 mg/m² including but not limited to about 60 mg/m² or about 45 mg/m². More particularly, the docetaxel is administered by intravenous infusion over about 60 minutes. More particularly, the docetaxel is administered on day 8 of the 21 day cycle. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In a further aspect, a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose. More particularly, the premedication comprises a histamine Hl antagonist and or a corticosteroid. More particularly, the histamine HI antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone. In another aspect, a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics. In a futher aspect, a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid. More particularly, the corticosteroid is dexamethasone. More particularly, the dexamethasone is administered orally at about 8 mg twice a day. More particularly, the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration. In a further aspect, a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte- colony stimulating factors or peg-granulocyte-colony stimulating factors. More particularly, the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s). More particularly, the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

hi another aspect, the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use. hi an alternative aspect, the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use.

In another aspect, the invention provides for the use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, where in the medicament is to be administered in combination with gemcitabine and docetaxel, wherein the wherein the gemcitabine is administered to the patient following tire olaratumab, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/nr/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein tire docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m². More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In another aspect, the invention provides for a pharmaceutical composition comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, for use in combination with gemcitabine and docetaxel, wherein the gemcitabine is administered to a patient after the olaratumab is administered and before the docetaxel is administered. More particularly, the olaratumab is administered at a first dose of: (i) about 15 mg/kg, or (ii) about 20 mg/kg, followed by one or more subsequent dose(s) of olaratumab to the patient of: (iii) about 15 mg/kg, or (iv) about 20 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab to the patient. More particularly, the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient, and wherein the cycle is 21 days. More particularly, the olaratumab is administered by intravenous infusion over about 60 minutes. More particularly, the olaratumab is administered on days 1 and 8 of the 21 day cycle. In another aspect, the gemcitabine is administered at a dose of about 900 mg/m². More particularly, the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute. More particularly, the gemcitabine is administered at a reduced dose of less than about 900 mg/m² including but not limited to about 675 mg/m² or about 500 mg/m². More particularly, the gemcitabine is administered on days 1 and 8 of the 21 day cycle. In another aspect, the docetaxel is administered at a dose of about 75 mg/m². More particularly, the docetaxel is administered at a reduced dose of less than about 75 mg/m² including but not limited to about 60 mg/m² or about 45 mg/m². More particularly, the docetaxel is administered by intravenous infusion over about 60 minutes. More particularly, the docetaxel is administered on day 8 of a 21 day cycle. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m² /minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

In a further aspect, a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose. More particularly, the premedication comprises a histamine Hl antagonist and or a corticosteroid. More particularly, the histamine Hl antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone. In another aspect, a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics. In another aspect, a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid. More particularly, the corticosteroid is dexamethasone. More particularly, the dexamethasone is administered orally at about 8 mg twice a day. More particularly, the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration. In another aspect, a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte- colony stimulating factors or peg- ranulocyte-colony stimulating factors. More particularly, the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s). More particularly, the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

In a another aspect, the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said pharmaceutical composition. In a further aspect, the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said phamiaceutical composition.

In another aspect, the invention provides for the pharmaceutical composition in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the olaratumab administration, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/nr/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg_/in². More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

hi another aspect, the invention provides for the medicament for the treatment of soft tissue sarcoma comprising olaratumab, wherein the treatment comprises: administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering a gemcitabine to the patient, wherein the gemcitabine is administered following said step of administering olaratumab; and administering docetaxel to the patient, wherein docetaxel is administered following said step of administering the gemcitabine. More particularly, the olaratumab is administered at a first dose of: (i) about 15 mg/kg, or (ii) about 20 mg/kg, followed by one or more subsequent dose(s) of olaratumab to the patient of: (iii) about 15 mg/kg, or (iv) about 20 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg. More particularly, the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg. More particularly, the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent doses of olaratumab. More particularly, the olaratumab is administered at one or more dose(s) of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days. More particularly, the olaratumab is administered by intravenous infusion over about 60 minutes. More particularly, the olaratumab is administered on days 1 and 8 of the 21 day cycle. In a further aspect, the gemcitabine is administered at a dose of about 900 mg/m². More particularly, the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute. More particularly, the gemcitabine is administered at a reduced dose of less than about 900 mg/m² including but not limited to, about 675 mg/m² or about 500 mg/m². More particularly, the gemcitabine is administered on days 1 and 8 of the 21 day cycle. In a further aspect, the docetaxel is administered at a dose of about 75 mg/m². More particularly, the docetaxel is administered at a reduced dose of less than about 75 mg/m² including but not limited to about 60 mg/m² or 45 mg/m². More particularly, the docetaxel is administered by intravenous infusion over about 60 minutes. More particularly, the docetaxel is administered on day 8 of a 21 day cycle. In another aspect, the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days I and 8 of the 21 day cycle; and wherein the docetaxel is administered to the patient at a dose of about 75 mg_/in² by intravenou infusion over about 60 minutes on day 8 of the 21 day cycle. More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly, the soft tissue sarcoma is leiomyosarcoma.

hi another aspect, a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose. More particularly, the premedication comprises a histamine Hl antagonist and or a corticosteroid. More particularly, the histamine HI antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone. In aother aspect, a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics. In another aspect, a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid. More particularly, the corticosteroid is dexamethasone. More particularly, the dexamethasone is administered orally at about 8 mg twice a day. More particularly, the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration. In another aspect, a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte-colony stimulating factors or peg-granulocyte-colony stimulating factors. More particularly, the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s). More particularly, the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

In one aspect, the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said medicament hr yet another aspect, the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said medicament.

In another aspect, the invention provides for the medicament for the treatment of soft tissue sarcoma comprising olaratumab, wherein the treatment comprises: administering olaratumab to a patient, wherein the patient has soft tissue sarcoma wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient; administering gemcitabine to the patient, wherein the gemcitabine is administered following said step of administering olaratumab, and wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/ni²; and administering docetaxel to tire patient, wherein docetaxel is administered following said step of administering the gemcitabine, and wiierein the docetaxel is administered by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m². More particularly, the soft tissue sarcoma is locally advanced soft tissue sarcoma or metastatic soft tissue sarcoma. More particularly,the soft tissue sarcoma is leiomyosarcoma.

In another aspect, the invention provides for a fixed dose combination kit of olaratumab for sequencal use with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, comprising 20 mg/kg of olaratumab, 900 mg/ni² of gemcitabine, and 75 mg/m² docetaxel administered in a first cycle to the patient, followed by 15 mg/kg of olaratumab, 900 mg/m² of gemcitabine, and 75 mg/m² docetaxel administered in one or more subsequent cycle(s) to the patient wherein the gemcitabine is administered following the olaratumab, and wherein the docetaxel is administered following the gemcitabine.

Description of the Figures: FIGURE 1 depicts the Study design.

hi one aspect of the invention,“olaratumab” refers to any antibody that is olaratumab as defined by the International Nonproprietary Name (INN) found in WHO Drug Information Vol. 25, No. 1, 2011, pp. 76-77. It has also been identified as IMC-3G3, and CAS registry number 1024603-93-7.

As used herein,“about” means ± 5% (e.g., 95 - 105 mg per week or 95 - 105 mg every other week). As used herein,“about” also means ± 5 minutes.

As used herein, the terms“treating,”“to treat,” or“treatment” refers to restraining, slowing, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, disease, or cancer.

As used herein,“course of treatment” means a prescribed regimen to be followed for a specific period of time.

As used herein, the term“patient” refers to a mammal, preferably a human.

As used herein, the term“kit” refers to a package comprising containers, e.g., vials. A“kit” may also include instructions to administer all or a portion of the contents of the containers to a cancer patient.

A potential advantage of the combination treatments of the invention is the possibility of producing marked and/or prolonged anti-cancer effects in a patient with an acceptable safety profile, including acceptable tolerability, toxicities and/or adverse events, so that the patient benefits from the combination treatment method overall. The efficacy of the combination treatment of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, objective response rate, disease control rate, clinical benefit rate, time to treatment failure, patient reported outcomes (including but not limited to pain, health-related quality of life and health status), safety, tolerability, pharmacokinetic, and immunogenicity. Without being bound by theory, the therapeutic agents used in the invention may function by a variety of mechanisms, including an anti tumor effect. Because the invention relates to the use of a unique combination of anti-tumor agents, various approaches to determining efficacy of any particular combination therapy of the present invention can be optionally employed, including, for example, cell-cycle dependent biomarkers measurement/visualization, and measurement of response through radiological imaging.

As used herein, the term“Complete Response” (CR) is defined as the 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. CR is also defined as disappearance of all nontarget lesions and normalization of tumor marker level. All lymph nodes must be non-pathological or normal in size (<10 nun short axis).

As used herein, the term“Partial Response” (PR) is defined as at least a 30% decrease in the sum of diameter of target lesions ( longest for non-nodal lesions, short axis for nodal lesions), taking as reference the baseline sum diameters.

As used herein the term“Progressive Disease” (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions), taking as reference the smallest sum on study (including the baseline sum if that is the smallest) hi addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. For equivocal findings of progression (for example, very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected. PD is also defined as, unequivocal progression of existing nontarget lesions; the appearance of one or more new lesions is also considered progression.

As used herein, for the evaluation of nontarget lesions, “non-CR”/“non-PD” is defined as persistence of one or more nontarget lesions and/or maintenance of tumor marker level above the normal limits. As used herein, the term“Stable Disease” (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the diameters of target lesions while on study.

As used herein, the term“Not Evaluable” (NE) is define as when an incomplete radiologic assessment of target lesions is performed or there is a change in the method of measurement from baseline that impacts the ability to make a reliable evaluation of response. NE is also defined for the evaluation of nontarget lesions as when a change in method of measurement from baseline occurs and impacts the ability to make a reliable evaluation of response.

As used herein, the term“Progression-Free Survival” (PFS) is defined for each patient as the time from the date of first study dose (Phase lb part) or randomization (Phase 2 part) to the first date of radiologic disease progression (as defined by Response Evaluation Criteria In Solid Tumors, Version 1.1 [RECIST v.l.l]) or death due to any cause whichever is earlier. Censoring for PFS may differ based on phase.

As used herein, the term“Overall Survival” (OS) is defined for each patient as the time from the date of first study dose (Phase lb) or randomization (Phase 2) to the date of death from any cause. If the patient is alive at the cutoff date for the analysis (or was lost to follow-up without a confirmed date of death), OS will be censored for analysis on the last date the patient was known to be alive.

As used herein, the term“Duration of Response” (DoR) is defined for each patient with a best response of CR or PR as the duration from the first date of CR or PR to the first date of radiologic disease progression or death due to any cause. The censoring rules for DoR will be the same as the censoring rules of PFS.

As used herein, the term“Disease Control Rate” (DCR) is defined for each patient with a best response of CR, PR, or SD as the time from the date of first study dose (Phase lb) or randomization (Phase 2) to the first date of radiologic disease progression or death due to any cause. The censoring rules for the DCR will be the same as the censoring rules of PFS.

As used herein, the term“Objective Response Rate” is defined as the proportion of safety population (Phase lb) or randomized population (Phase 2) achieving a best overall response of PR or CR per RECIST v.l.l. Patients who do not have any post baseline tumor response assessments are considered non-responders and are included in the denominator when calculating the response rate. Tumor assessments performed after initiation of new' anticancer treatment (systemic therapy) will be excluded from evaluating the best overall response.

As used herein, the term“Overall Response Rate” is based on each patient’s best objective response and will be determined for all patients evaluable via the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 criteria. The Overall Response Rate (%) will be calculated as the number of patients with best objective response of CR or PR divided by the number of patients with measurable disease at baseline. The best objective response for a given patient will be based on objective responses determined from data obtained up to progression or the last evaluable assessment in the absence of progression. Patients for whom an objective response cannot be determined, or for who the best objective response is NE, will be considered non-responders. The Overall Response Rate will be summarized along with the 95% Clopper Pearson confidence interval.

As used herein, the term“clinical benefit” or“effective response” of a patient or a patient's“responsiveness” to treatment with a combination of agents and similar wording refers to the clinical or therapeutic benefit imparted to a patient upon co-administration of gemcitabine, docetaxel, and olaratumab. Such benefit includes any one or more of: extending survival (including OS and PFS); resulting in an objective response (including a CR or a PR): or improving signs or symptoms of cancer, etc.

As used herein, intravenous (hereinafter“IV”) infusion and intravenous injection can be used interchangeably.

As used herein, the terms“administer,”“administered,”“administration” refers to providing, giving, and/or applying a substance, including but not limited to by injection, inhalation, application, or ingestion, to the body of a patient. As used herein, these terms can be used interchangeably. As used herein, administration my occur by anyone or anything, including but not limited to a health care provider and/or his/her authorized agent, self administration by the patient, or a patient carergiver. Patient caregiver may be any such person or persons who provide assistance to the patient when the patient may or maynot be able to fully provide care for thesmselves, including but not limited to a family member, friend, hired professional, or other party.

As used herein, the phrase “in combination with” refers to the sequential administration of olaratumab with gemcitabine and docetaxel. As used herein, the phrase“in combination with” also refers to the administration of olaratumab with gemcitabine and docetaxel sequentially wherein gemcitabine is administered following olaratumab administration, docetaxel is administered following gemcitabine administration.

Where olaratumab is administered at repeated intervals (e.g., during a standard course of treatment), gemcitabine and docetaxel can be administered subsequent to each administration of olaratumab. Where olaratumab is administered at repeated intervals ( e.g ., during a standard course of treatment), gemcitabine and docetaxel can be administered at different intervals in relation to therapy with olaratumab. Where olaratumab is administered at repeated intervals (e.g. , during a standard course of treatment), gemcitabine and docetaxel can be administered in a single or series of dose(s) subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals {e.g. , during a standard course of treatment), gemcitabine and docetaxel can be administered in single or sequential doses subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g., during a standard course of treatment), gemcitabine and docetaxel can be administered in a series of doses subsequent to the course of treatment with olaratumab.

The following examples and clinical study results further illustrate the present invention.

The following clinical study designs further illustrate the invention, but should not be construed to limit the scope of the invention in any wuy.

A Study of Olaratumab in Combination with Gemcitabine and Docetaxel

in the Treatment of STS

Clinical Study Design The Study is an open label Phase lb/randomized, double-blind, placebo-controlled Phase 2 study to investigate the efficacy, safety, and tolerability of olaratumab combined with gemcitabine and docetaxel in approximately 301 patients with locally advanced or metastatic STS not amenable to treatment with surgical resection or radiotherapy with curative intent. The Study consists of several phases (see Figure 1) including:

Phase lb: dose escalation of olaratumab (about 15 mg/kg or about 20 mg/kg IV) administered on Day 1 and Day 8, followed by gemcitabine (about 900 mg/m² IV [fixed dose rate: about 10 mg/m²/minute]) on Day 1 and Day 8, followed by docetaxel (about 75 mg/m² IV/) on Day 8, every 21 days in patients with STS.

Phase 2: expansion cohort of olaratumab (a loading dose of about 20 mg/kg of olaratumab for the first cycle followed by about 15 mg/kg of olaratumab for subsequent cycles) administered on Day 1 and Day 8, followed by a fixed regimen of gemcitabine (about 900 mg/m² IV [fixed dose rate: about 10 mg/m²/minute] ) on Day 1 and Day 8, followed by docetaxel (about 75 mg/m² IV) on Day 8 of every 21 days in patients with STS.

Approximately 54 patients are enrolled in Phase lb, with between 15 to 30 patients enrolled at each dose level of olaratumab, to determine the recommended dose that may be safely administered in combination with gemcitabine (about 900 mg/m² IV [fixed dose rate: about 10 mg/m²/minute]) and docetaxel (about 75 mgin² IV). The determination of the recommended Phase 2 dose is based on a review of safety data, including the number and type of dose-limiting toxicities (DLTs), other safety information, and relevant PK.

Approximately 256 patients (166 patients - olaratumab naive; 90 patients - olaratumab pretreated) are to be enrolled in Phase 2 in a randomized, double-blinded 2-arm study. Patients will be randomized 1: 1 for treatment with olaratumab (Arm A) or placebo (Arm B). For Arm A and Arm B, the respective olaratumab and/or placebo treatments will be administered on Day 1 and Day 8 of a 21 -day cycle over about 60 minutes (± 5 minutes), followed by' a fixed regimen, for both Arm A and Arm B, of gemcitabine (about 900 mg/m² IV [fixed dose rate: about 10 mg/m²/minute])(alternatively gemcitabine may be given over 30 minutes) on Day 1 and Day 8 of a 21 -day cycle over about 90 minutes (± 5 minutes), followed by docetaxel (about 75 mg/m² IV) on Day 8 every 21 -day cycle over about 60 minutes (± 5 minutes). Patients in Arm A will receive a loading dose of about 20 mg/kg of olaratumab for the first cycle followed by about 15 mg/kg of olaratumab for subsequent cycles. Patients will continue treatment until there is documented disease progression, unacceptable toxicity, death, or other discontinuation criteria are met. Tire primary per- patient measure for efficacy is OS; secondary end points are progression-free survival (PFS), objective response rate (ORR), disease control rate (OCR), time to first worsening of the mBPI-sf (Brief Pain Inventory Short Form Modified) “worst pain” score, time to any progression (censoring for death without progression), time to any new metastases (censoring for death and for other type of PD), new-metastases-free survival (nMFS), time to any progression based solely on increased sum of target lesions, time to sustained worsening of The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30) scale scores (for example, Global Health Status / Quality of Life score, Physical Functioning score, and Role Functioning score), time to first worsening of ECOG PS, and second PFS (PFS2) after end of study treatment while on subsequent anticancer therapy.

Patients are assessed for tumor response every 6 weeks. Patients receiving olaratumab and experiencing ongoing clinical benefit and no undue risks may continue to receive olaratumab in the continued access period. The continued access period begins after Study completion and will continue until the end of trial. The end of trial occurs after Study completion, and after the last patient has discontinued study treatment and completed any applicable continued access follow-up. From first patient visit in the Phase lb part to last patient visit in the Phase 2 part, the estimated Study duration is 47 months.

Major eligibility criteria include: 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 (Atypical Lipomatous Neoplasms) are eligible if there is histological or radiographic evidence of evolution to more aggressive disease. Further, eligibility criteria include measurable or nonmeasurable, but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1, Eisenhauer et al., 2009); a performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al., 1982); and no more than two prior lines of systemic therapies for locally advanced or metastatic disease and is suitable to receive gemcitabine and docetaxel therapy. Major eligibility criteria for“pre-treated” patients include: prior olaratumab therapy must have been received with doxorubicin as indicated on the olaratumab label; prior olaratumab therapy must have included at least 2 full cycles of olaratumab/doxorubicin (i.e. a minimum of 4 doses of olaratumab); the most recent dose of olaratumab must have been received within 180 days of randomization in this study.

Patients in the Study are to receive the following premedications: Premedicate all patients receiving o 1 aratum ab/p 1 ac ebo with the following medications (or equivalent) intravenously: a histamine HI antagonist (for example, diphenhydramine) and dexamethasone may be administered 30 to 60 minutes prior to the olaratumab/placebo doses on Days 1 and 8 of Cycle 1. For subsequent cycles, premedication of patients with a histamine HI antagonist (for example, diphenhydramine) intravenously 30 to 60 minutes prior to each dose of olaratumab/placebo is recommended. Alternatively, an oral histamine Hi antagonist and oral dexamethasone (or other corticosteroid) given at least 60 minutes prior to olaratumab/placebo may be administered. Premedication with additional agents may be provided at investigator discretion. Premedications must be documented. Prophylactic antiemetics will be routinely administered as a premedication for gemcitabine; premedication for gemcitabine may be administered according to institutional guidelines and/or clinical practice with consultation to manufacturer’s instructions for gemcitabine for complete prescribing information. Premedication for docetaxel may be administered according to institutional guidelines and/or clinical practice. Recommended premedication for the docetaxel is corticosteroids such as dexamethasone at a dose of about 8 mg orally twice a day for three days starting the day prior to docetaxel administration (e.g. the day prior to docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration) or at the discretion of the investigator. Patients who develop peripheral edema as a side effect of docetaxel may be treated with diuretics at the discretion of the investigator. Additional antiemetic premedication may be employed at the discretion of the investigator. Sites should consult the manufacturer’s instructions for docetaxel for complete prescribing information and follow institutional procedures for the administration of docetaxel. Further, granulocyte-colony stimulating factors (G-CSF) use is recommended in all cycles for patients with a prior history of pelvic radiation. For all other patients, G-CSF use is recommended if ANC falls below' 1000 (that is, < 1.0 x l0⁹/L). Patients with a prior history of pelvic radiation who require chemotherapy dose reduction despite prophylactic G- CSF are not required to have prophylactic G-CSF in subsequent cycles if per investigator assessment such chemotherapy dose reductions adequately address the risk of further myelosuppression. Prophylactic use of G-CSF should consist of at least 5 days of G-CSF (about 5 micrograms/kg/day subcutaneously) beginning on Day 9, or a single dose of peg-G- CSF (about 6 mg, subcutaneously) on Day 9 or 10.

In the case of toxicity related to myelosuppression and its complications, the relative roles of gemcitabine and docetaxel are often impossible to separate, and thus it is expected such toxicity would result in dose reductions of both agents. In cases where adverse events (AE), in the opinion of the investigator, are more likely due to one drug than another, adjustment of one of the chemotherapy agents and not the other is permissible. Dose level reductions are as follows: Starting dose - gemcitabine 900 mg/m² and docetaxel 75 mg/m²; dose reduction 1 - gemcitabine 675 mg/m² and docetaxel 60 mg/m²; dose reduction 2 - gemcitabine 500 mg/m² and docetaxel 45 mg/m². The infusion time of gemcitabine after its dose reduction may be maintained at 90 minutes (+/- 5 min) or may be shortened to keep a rate of approximately 10 mg/m²/minute according to the discretion of the investigator. The infusion start and stop times must be recorded.

In the event of permanent discontinuation of olaratumab/placebo therapy due to an olaratumab/placebo-related toxicity, patients may continue on gemcitabine and docetaxel treatment per protocol. If either gemcitabine or docetaxel are permanently discontinued due to toxicity, the patient should discontinue active treatment with the gemcitabine/docetaxel combination if it is unclear which individual agent is the cause of the toxicity. If toxicity is clearly related, as determined by the investigator, to one agent or the other, for example neuropathy due to docetaxel, only that agent should be discontinued. The patient may continue treatment with olaratumab/placebo alone, at the discretion of the investigator, if gemcitabine and/or docetaxel are permanently discontinued.

In the Study Phase lb, patients in any cohort who do not complete Cycle 1 treatment for reasons other than a DLT will be replaced. In Part 2, investigators are blinded to treatment assignment (olaratumab versus placebo) and should adjust dosing of olaratumab/placebo as if all patients are receiving olaratumab.

Study Objectives

The primary' objective of Phase lb is to determine a recommended Phase 2 dose of olaratumab that may be safely administered in combination with gemcitabine and docetaxel to patients with locally advanced or metastatic STS.

The primary objective of Phase 2 is to compare the OS in olaratumab-naive patients with locally advanced or metastatic STS treated with olaratumab plus gemcitabine and docetaxel versus placebo plus gemcitabine and docetaxel.

The secondary objectives of the Study for Phase lb include: (i) to characterize the safety and toxicity profile of olaratumab in combination with gemcitabine and docetaxel; (ii) to evaluate the PK and immunogenicity of olaratumab in combination with gemcitabine and docetaxel; (iii) to evaluate the PK of gemcitabine and docetaxel in combination with olaratumab; and (iv) to document any antitumor activity observed with gemcitabine and docetaxel in combination with olaratumab.

The secondary objectives for Phase 2 include comparisons of PFS, ORR, DCR, patient reported outcomes (PROs), and safety and tolerability between the olaratumab plus gemcitabine and docetaxel versus placebo plus gemcitabine and docetaxel in both olaratumab-naive and olaratumab pre-treated groups as well as the evaluation of the PK and immunogenicity of olaratumab.

The exploratory' objectives for Phase lb and Phase 2 include exploration of biomarkers associated with clinical outcome and/or pathogenesis of STS and exploration of the exposure-response relationship of olaratumab for efficacy and/or safety. Exploratory objectives for Phase 2 only include evaluating change in tumor size from baseline to best overall response and assessment of the association between clinical variables, such as histological subtypes, and clinical outcomes.

Preliminary Study Findings

The Study is ongoing as of the time of filing.

In Phase lb Study patients treated with olaratumab 15 mg/kg in combination with gemcitabine and docetaxel, there was no obvious increase in grade 3 or higher toxicity in comparison to the Maid or GeDDis studies. In Phase lb Study patients treated with olaratumab 20 mg/kg in combination with gemcitabine and docetaxel, the grade 3 or higher toxicity that occurred more frequently in comparison to the Maki or GeDDis studies was anemia.

As of November 13, 2017, preliminary anti-tumor activity in the Phase lb intent-to- treat population showed an overall response rate (ORR) of 9.3% (95% Cl: 3.1, 20.3), and a 6 month progression-free-survival (PFS) rate of 43% (95% Cl: 29.0, 56.2). The Phase lb intent-to-treat population also showed a disease control rate (DCR) (CR/PR/SD) of 72.2% (95% Cl: 58.4, 83.5); a complete response (CR) rate of 1.9% (95% Cl: 0.0, 9.9), a partial response (PR) rate of 7.4% (95% Cl: 2.1, 17.9), and a stable disease (SD) rate of 63.0% (95% Cl: 48.7, 75.7). These results likely underestimate the true PFS rate due to the relatively short follow up of those patients enrolled in the latter time frame of the study. It is too early to determine overall survival.

These results are unexpected given previous publications on the combination of gemcitabine and docetaxel.

The GeDDis Study, which enrolled untreated advanced unresectable or metastatic STS population, reported a DCR of 59% (GeDDis, at 1403) relative to 72% observed in the Phase lb part of the Study. Further GeDDis reported a 24-w'eeks PFS rate of 46.4% (GeDDis, at 1402) relative to 6 month PFS of 43.0% (95% Cl: 29.0, 56.2) observed in the Phase lb part of the Study. While the GeDDis study enrolled only patients who 'ere previously untreated, the Phase lb part of the Study allowed both untreated and previously treated patients. As previously treated patients are expected to have a shorter PFS than newly diagnosed patients, previously treated patients are expected to lower the median PFS of the entire group; despite this negative prognostic impact, the Study showed a similar 24-week PFS rate, which may be a signal for improved activity in the Study. Accordingly, despite similar reported six month PFS rates in the combination of gemcitabine/docetaxel as reported in GeDDis and the Study combination of olaratumab/gemcitabine/docetaxel, the Study combination of olaratumab/gemcitabine/docetaxel reported an improved DCR as compared to the DCR of gemcitabine/docetaxel as reported in GeDDis.

In sum, the preliminary Study findings report an acceptable, monitorable, and manageable safety profile; the nature and frequency of adverse events observed to date were similar to historical data for combinations of gemcitabine plus docetaxel in STS patients (see GeDDis and Maki). With respect to the preliminary efficacy findings, despite similar PFS rates, the Study combination of olaratumab/gemcitabine/docetaxel reported an improved DCR as compared to gemcitabine/docetaxel alone (GeDDis). Accordingly, the preliminary efficacy findings of the Study are unexpected given previous publications on the combination of gemcitabine and docetaxel.

Claims

WE CLAIM:

1. Olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the administration of olaratumab, and wherein the docetaxel is administered following the gemcitabine.

2. Olaratumab for use according to Claim 1, wherein the olaratumab is administered at a first dose of:

(i) about 15 mg/kg, or (ii) about 20 mg/kg,

followed by one or more subsequent dose(s) of olaratumab to the patient of:

(iii) about 15 mg/kg, or (iv) about 20 mg/kg.

3. Olaratumab for use according to Claim 2, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg_''kg.

4. Olaratumab for use according to Claim 2, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg.

5. Olaratumab for use according to Claim 2, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab.

6. Olaratumab for use according to Claim 2 or Claim 5, wherein the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, wherein the cycle is 21 days.

7. Olaratumab for use according to any one of Claims 1 to 6, wherein the olaratumab is administered by intravenous infusion over about 60 minutes.

8. Olaratumab for use according to Claim 6 or Claim 7, wherein the olaratumab is administered on days 1 and 8 of the 21 day cycle.

9. Olaratumab for use according to any one of Claims 1 to 8, wherein the gemcitabine is administered at a dose of about 900 mg/m².

10. Olaratumab for use according to any one of Claims 1 to 9, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/nr /minute.

11. Olaratumab for use according to Claim 9, wherein the gemcitabine is administered at a reduced dose of less than about 900 mg/m².

12. Olaratumab for use according to Claim 11, wherein the gemcitabine is administered at the reduced dose of about 675 mg/m².

13. Olaratumab for use according to Claim 11, wherein the gemcitabine is administered at the reduced dose of about 500 mg/m².

14. Olaratumab for use according to any one of Claims 6 to 13, wherein the gemcitabine is administered on days 1 and 8 of the 21 day cycle.

15. Olaratumab for use according to any one of Claims 1 to 14, wherein the docetaxel is administered at a dose of about 75 mg/m².

16. Olaratumab for use according to Claim 15, wherein the docetaxel is administered at a reduced dose of less than about 75 mg/m².

17. Olaratumab for use according to Claim 16, wherein the docetaxel is administered at the reduced dose of about 60 mg/m².

18. Olaratumab for use according to Claim 16, wherein the docetaxel is administered at the reduced dose of about 45 mg/m².

19. Olaratumab for use according to any one of Claims 1 to 18, wherein the docetaxel is administered by intravenous infusion over about 60 minutes.

20. Olaratumab for use according to any one of Claims 6 to 19, wherein the docetaxel is administered on day 8 of a 21 day cycle.

21. Olaratumab for use according to any one of Claims 1 to 20, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed- dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle.

22. Olaratumab for use according to any one of Claims 1 to 21, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

23. Olaratumab for use according to any one of Claims 1 to 21, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

24. Olaratumab for use according to any one of Claims 1 to 23, wherein the soft tissue sarcoma is leiomyosarcoma.

25. Olaratumab for use according to any one of Claims 1 to 24, wherein a premedication for the olaratumab is administered to the patient about 30 to about 90 minutes prior to the olaratumab dose.

26. Olaratumab for use according to Claim 25, wherein the premedication comprises a histamine Hl antagonist and or a corticosteroid.

27. Olaratumab for use according to Claim 26, wherein the histamine HI antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone.

28. Olaratumab for use according to any one of Claims 1 to 27, wherein a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics.

29. Olaratumab for use according to any one of Claims 1 to 28, wherein a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid.

30. Olaratumab for use according to Claim 29, wherein the corticosteroid is dexamethasone.

31. Olaratumab for use according to Claim 30, wherein the dexamethasone is administered orally at about 8 mg twice a day.

32. Olaratumab for use according to Claim 30 and Claim 31 , wherein the dexamethasone is administered the day prior to the docetaxel administration, the day of the docetaxel administration, and the day after the docetaxel administration.

33. Olaratumab for use according to any one of Claims 1 to 32, wherein a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte- colony stimulating factors or peg-granulocyte-colony stimulating factors.

34. Olaratumab for use according to Claim 33, wherein the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s).

35. Olaratumab for use according to Claim 33, wherein the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

36. Olaratumab for use according to any one of Claims 1 to 35, wherein the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use.

37. Olaratumab for use according to any one of Claims 1 to 35, wherein the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use.

38. Olaratumab for use in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the administration of olaratumab, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed - dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m².

39. Olaratumab for use according to Claim 38, wherein the soft tissue sarcoma is locally- advanced soft tissue sarcoma. /-

40. Olaratumab for use according Claim 38, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

41. Olaratumab for use according to any one of Claims 38 to 40, wherein the soft tissue sarcoma is leiomyosarcoma.

42. The method of treating soft tissue sarcoma, comprising administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering gemcitabine to the patient, wherein the gemcitabine is administered following the olaratumab administration; and administering docetaxel to the patient following the gemcitabine administration.

43. The method according to Claim 42, wherein the olaratumab is administered at a first dose of:

(i) about 15 mg/kg, or (ii) about 20 mg/kg,

followed by one or more subsequent dose(s) of olaratumab to the patient of:

(iii) about 15 mg/kg, or (iv) about 20 mg/kg.

44. The method according to Claim 43, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg.

45. The method according to Claim 43, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg.

46. The method according to Claim 43, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one of more subsequent dose(s) of olaratumab.

47. The method according to Claim 43 or Claim 46, wherein the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one of more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days.

48. The method according to any one of Claims 42 to 47, wherein the olaratumab is administered by intravenous infusion over about 60 minutes.

49. The method according to Claim 47 or Claim 48, wherein the olaratumab is administered on days 1 and 8 of the 21 day cycle.

50. The method according to any one of Claims 42 to 49, wherein the gemcitabine is administered at a dose of about 900 mg/m².

51. The method according to any one of Claims 42 to 50, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute.

52. The method according to Claim 50, wherein the gemcitabine is administered at a reduced dose of less than about 900 mg/m².

53. The method according to Claim 52, wherein the gemcitabine is administered at the reduced dose of about 675 mg/m².

54. The method according to Claim 52, wherein the gemcitabine is administered at the reduced dose of about 500 mg/m².

55. The method according to any one of Claims 47 to 54, wherein the gemcitabine is administered on days 1 and 8 of the 21 day cycle.

56. The method according to any one of Claims 42 to 55, wherein the docetaxel is administered at a dose of about 75 mg/m².

57. The method according to Claim 56, wherein the docetaxel is administered at a reduced dose of less than about 75 mg/m².

58. The method according to Claim 57, wherein the docetaxel is administered at the reduced dose of about 60 mg/m².

59. The method according to Claim 57, wherein the docetaxel is administered at the reduced dose of about 45 mg/m².

60. The method according to any one of Claims 42 to 59, wherein the docetaxel is administered by intravenous infusion over about 60 minutes.

61. The method according to any one of Claims 47 to 60, wherein the docetaxel is administered on day 8 of a 21 day cycle.

62. The method according to any one of Claims 42 to 61, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle;

wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and

wherein the docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle.

63. The method according to any one of Claims 42 to 62, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

64. The method according to any one of Claims 42 to 62, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

65. The method according to any one of Claims 42 to 64, wherein the soft tissue sarcoma is leiomyosarcoma.

66. The method according to any one of Claims 42 to 65, wherein a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose.

67. The method according to Claim 66, wherein the premedication a histamine Hi antagonist and or a corticosteroid.

68. The method according to Claim 67, wherein the histamine HI antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone.

69. The method according to any one of Claims 42 to 68, wherein a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics.

70. The method according to any one of Claims 42 to 69, wherein a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid.

71. The method according to Claim 70, wherein the corticosteroid is dexamethasone.

72. The method according to Claim 71, wherein the dexamethasone is administered orally at about 8 mg orally twice a day.

73. The method according to Claim 71 and Claim 72, wherein the dexamethasone is administered the day prior to the docetaxel administration, the day of the docetaxel administration, and the day after the docetaxel administration.

74. The method according to any one of Claims 42 to 73, wherein a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte-colony stimulating factors or peg-granulocyte-colony stimulating factors .

75. The method according to Claim 74, wherein the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s).

76. The method according to Claim 74, wherein the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

77. The method according to any one of Claims 42 to 76, wherein the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said method.

78. The method according to any one of Claims 42 to 76, wherein the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said method.

79. The method of treating soft tissue sarcoma, comprising administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering gemcitabine to the patient, wherein the gemcitabine is administered following the olaratumab administration, and administering docetaxel to the patient following the gemcitabine administration, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m².

80. The method according to Claim 79, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

81. The method according to Claim 79, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

82. The method according to any one of Claims 79 to 81, wherein the soft tissue sarcoma is leiomyosarcoma.

83. A kit comprising a container comprising a pharmaceutical composition comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, a container comprising a pharmaceutical composition comprising gemcitabine with one or more pharmaceutically acceptable carriers, diluents, or excipients, and a container comprising a pharmaceutical composition comprising docetaxel with one or more pharmaceutically acceptable carriers, diluents, or excipients, for use in the treatment soft tissue sarcoma.

84. The kit of Claim 83, further comprising either (i) written instructions for administering olaratumab, gemcitabine and docetaxel, or (ii) an internet address from which instructions for administering olaratumab, gemcitabine and docetaxel can be obtained.

85. Use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, w'here in the medicament is to be administered in combination with gemcitabine and docetaxel, wherein the gemcitabine is administered to a patient after the olaratumab is administered and before the docetaxel is administered.

86. Use of olaratumab according to Claim 85, wherein the olaratumab is administered at a first dose of:

(i) about 15 mg/kg, or (ii) about 20 mg/kg,

followed by one or more subsequent dose(s) of olaratumab to the patient of:

(iii) about 15 mg/kg, or (iv) about 20 mg/kg.

87. Use of olaratumab according to Claim 86, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg.

88. Use of olaratumab according to Claim 86, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg.

89. Use of olaratumab according to Claim 86, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab.

90. Use of olaratumab according to Claim 86 or Claim 89, wherein the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days.

91. Use of olaratumab according to any one of Claims 85 to 90, wherein the olaratumab is administered by intravenous infusion over about 60 minutes.

92. Use of olaratumab according Claim 90 or Claim 91, wherein the olaratumab is administered on days 1 and 8 of the 21 day cycle.

93. Use of olaratumab according to any one of Claims 85 to 92, wherein the gemcitabine is administered at a dose of about 900 mg/m².

94. Use of olaratumab according to any one of Claims 85 to 93, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute.

95. Use of olaratumab according to Claim 93, wherein the gemcitabine is administered at a reduced dose of less than about 900 mg/m².

96. Use of olaratumab according to Claim 95, wherein the gemcitabine is administered at the reduced dose of about 675 mg/m².

97. Use of olaratumab according to Claim 95, wherein the gemcitabine is administered at the reduced dose of about 500 mg/m².

98. Use of olaratumab according to any one of Claims 85 to 97, wherein the gemcitabine is administered on days 1 and 8 of the 21 day cycle.

99. Use of olaratumab according to any one of Claims 85 to 98, wherein the docetaxel is administered at a dose of about 75 mg/m².

100. Use of olaratumab according to Claim 99, wherein the docetaxel is administered at a reduced dose of less than about 75 mg/m².

101. Use of olaratumab according to Claim 100, wherein the docetaxel is administered at the reduced dose of about 60 mg/m².

102. Use of olaratumab according to Claim 100, wherein the docetaxel is administered at the reduced dose of about 45 mg/m².

103. Use of olaratumab according to any one of Claims 85 to 102, wherein the docetaxel is administered by intravenous infusion over about 60 minutes.

104. Use of olaratumab according to any one of Claims 90 to 103, wherein the docetaxel is administered on day 8 of the 21 day cycle.

105. Use of olaratumab according to any one of Claims 85 to 104, wherein the olaratumab is administered at a dose of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle.

106. Use of olaratumab according to any one of Claims 85 to 105, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

107. Use of olaratumab according to any one of Claims 85 to 105, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

108. Use of olaratumab according to any one of Claims 85 to 107, wherein the soft tissue sarcoma is leiomyosarcoma.

109. Use of olaratumab according to any one of Claims 85 to 108, wherein a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose.

110. Use of olaratumab according to Claim 109, w'herein the premedication comprises a histamine Hl antagonist and or a corticosteroid.

111. Use of olaratumab according to Claim 110, wherein the histamine Hl antagonist is diphenhydramine, and w'herein the corticosteroid is dexamethasone.

112. Use of olaratumab according to any one of Claims 85 to 111, wherein a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics.

113. Use of olaratumab according to any one of Claims 85 to 112, wherein a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid.

114. Use of olaratumab according to Claim 113, wherein the corticosteroid is dexamethasone.

115. Use of olaratumab according to Claim 114, wherein the dexamethasone is administered orally at about 8 mg twice a day.

116. Use of olaratumab according to Claim 114 and Claim 115, wherein the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration.

117. Use of olaratumab according to any one of Claims 85 to 116, wherein a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte- colony stimulating factors or peg-granulocyte-colony stimulating factors.

118. Use of olaratumab according to Claim 117, wherein the granulocyte-colony stimulating factors are administered at a dose of about 5 m i c ro gram s/k g/d ay subcutaneously for at least 5 days, beginning on day 9 of the cycle(s).

119. Use of olaratumab according to Claim 117, wiierein the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

120. Use of olaratumab according to any one of Claims 85 to 119, wherein the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use.

121. Use of olaratumab according to any one of Claims 85 to 119, wherein the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said use.

122. Use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, where in the medicament is to be administered in combination with gemcitabine and docetaxel, wherein the wherein the gemcitabine is administered to the patient following the olaratumab, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m².

123. Use of olaratumab according to Claim 122, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

124. Use of olaratumab according Claim 122, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

125. Use of olaratumab according to any one of Claims 122 to 124, wherein the soft tissue sarcoma is leiomyosarcoma.

126. A pharmaceutical composition comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, for use in combination with gemcitabine and docetaxel, wherein the gemcitabine is administered to a patient after the olaratumab is administered and before the docetaxel is administered.

127. The pharmaceutical composition according to Claim 126, wherein the olaratumab is administered at a first dose of:

(i) about 15 mg/kg, or (ii) about 20 mg/kg,

followed by one or more subsequent dose(s) of olaratumab to the patient of:

(iii) about 15 mg/kg, or (iv) about 20 mg/kg.

128. The pharmaceutical composition according to Claim 127, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg.

129. The pharmaceutical composition according to Claim 127, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg.

130. The pharmaceutical composition according to Claim 127, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent dose(s) of olaratumab to the patient.

131. The pharmaceutical composition according to Claim 127 or Claim 130, wherein the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient, and wherein the cycle is 21 days.

132. The pharmaceutical composition according to Claim 130 and Claim 131, wherein the olaratumab is administered by intravenous infusion over about 60 minutes.

133. The pharmaceutical composition according to any one of Claims 126 to 132, witerein the olaratumab is administered on days 1 and 8 of the 21 day cycle.

134. The pharmaceutical composition according to any one of Claims 126 to 133, wherein the gemcitabine is administered at a dose of about 900 mg/m².

135. The pharmaceutical composition according to any one of Claims 126 to 134, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute.

136. The pharmaceutical composition according to Claim 134, wherein the gemcitabine is administered at a reduced dose of less than about 900 mg/m².

137. The pharmaceutical composition according to Claim 136, wherein the gemcitabine is administered at the reduced dose of about 675 mg/m².

138. The pharmaceutical composition according to Claim 136, wherein the gemcitabine is administered at the reduced dose of about 500 mg/m².

139. The pharmaceutical composition according to any one of Claims 131 to 138, wherein the gemcitabine is administered on days 1 and 8 of the 21 day cycle.

140. The pharmaceutical composition according to any one of Claims 126 to 139, wherein the docetaxel is administered at a dose of about 75 mg/m².

141. The pharmaceutical composition according to Claim 140, wherein the docetaxel is administered at a reduced dose of less than about 75 mg/m².

142. The pharmaceutical composition according to Claim 141, wherein the docetaxel is administered at the reduced dose of about 60 mg/m².

143. The pharmaceutical composition according to Claim 141, wherein the docetaxel is administered at the reduced dose of about 45 mg/m².

144. The pharmaceutical composition according to any one of Claims 126 to 143, wherein the docetaxel is administered by intravenous infusion over about 60 minutes.

145. The phannaceutical composition according to any one of Claims 131 to 144, wherein the docetaxel is administered on day 8 of a 21 day cycle.

146. The pharmaceutical composition according to any one of Claims 126 to 145, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered to the patient at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenous infusion over about 60 minutes on day 8 of the 21 day cycle.

147. The pharmaceutical composition according to any one of Claims 126 to 146, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

148. The pharmaceutical composition according to any one of Claims 126 to 146, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

149. The pharmaceutical composition according to any one of Claims 126 to 148, wherein the soft tissue sarcoma is leiomyosarcoma.

150. The pharmaceutical composition according to any one of Claims 126 to 149, wherein a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose.

151. The pharmaceutical composition according to Claim 150, wherein the premedication comprises a histamine H I antagonist and or a corticosteroid.

152. The pharmaceutical composition according to Claim 151, wherein the histamine Hl antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone.

153. The pharmaceutical composition according to any one of Claims 126 to 152, wherein a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics.

154. The pharmaceutical composition according to any one of Claims 126 to 153, wherein a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid.

155. The pharmaceutical composition according to Claim 154, wherein the corticosteroid is dexamethasone.

156. The pharmaceutical composition according to Claim 155, wherein the dexamethasone is administered orally at about 8 mg twice a day.

157. The pharmaceutical composition according to Claim 154 and Claim 155, wherein the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration.

158. The pharmaceutical composition according to any one of Claims 126 to 157, wherein a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte-colony stimulating factors or peg-granulocyte-colony stimulating factors.

159. The pharmaceutical composition according to Claim 158, wherein the granulocyte- colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s).

160. The pharmaceutical composition according to Claim 158, wherein the peg- granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

161. The pharmaceutical composition according to any one of Claims 126 to 160, wherein the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said pharmaceutical composition.

162. The pharmaceutical composition according to any one of Claims 126 to 160, wherein the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said pharmaceutical composition.

163. The pharmaceutical composition in combination with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, wherein the gemcitabine is administered following the olaratumab administration, and wherein the docetaxel is administered following the gemcitabine, wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient, wherein the gemcitabine is administered to the patient by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m², and wherein the docetaxel is administered to the patient by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m².

164. The pharmaceutical composition according to Claim 163, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

165. The pharmaceutical composition according Claim 163, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

166. The pharmaceutical composition according to any one of Claims 163 to 166, wherein the soft tissue sarcoma is leiomyosarcoma.

167. A medicament for the treatment of soft tissue sarcoma comprising olaratumab, wherein the treatment comprises:

administering olaratumab to a patient, wherein the patient has soft tissue sarcoma; administering a gemcitabine to the patient, wherein the gemcitabine is administered following said step of administering olaratumab; and

administering docetaxel to the patient, wherein docetaxel is administered following said step of administering the gemcitabine.

168. The medicament according to Claim 167, wherein the olaratumab is administered at a first dose of:

(i) about 15 mg/kg, or (ii) about 20 mg/kg,

followed by one or more subsequent dose(s) of olaratumab to the patient of:

(iii) about 15 mg/kg, or (iv) about 20 mg/kg.

169. The medicament according to Claim 168, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 15 mg/kg.

170. The medicament according to Claim 168, wherein the first and subsequent dose(s) of olaratumab are administered at a dose of about 20 mg/kg.

171. The medicament according to Claim 168, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first dose of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent doses of olaratumab.

172. The medicament according to Claim 168 or Claim 171, wherein the olaratumab is administered at one or more dose(s) of about 20 mg/kg in a first cycle of olaratumab to the patient, followed by one or more dose(s) of about 15 mg/kg in one or more subsequent cycle(s) of olaratumab, and wherein the cycle is 21 days.

173. The medicament according to any one of Claims 167 to 172, wherein the olaratumab is administered by intravenous infusion over about 60 minutes.

174. The medicament according to Claim 172 or Claim 173, wherein the olaratumab is administered on days 1 and 8 of the 21 day cycle.

175. The medicament according to any one of Claims 167 to 174, wherein the gemcitabine is administered at a dose of about 900 mg/m².

176. The medicament according to any one of Claims 167 to 175, wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute.

177. The medicament according to Claim 175, wherein the gemcitabine is administered at a reduced dose of less than about 900 mg/m².

178. The medicament according to Claim 177, wherein the gemcitabine is administered at the reduced dose of about 675 mg/m².

179. The medicament according to Claim 177, wherein the gemcitabine is administered at the reduced dose of about 500 mg/m².

180. The medicament according to any one of Claims 172 to 179, wherein the gemcitabine is administered on days 1 and 8 of the 21 day cycle.

181. The medicament according to any one of Claims 167 to 180, wherein the docetaxel is administered at a dose of about 75 mg/m².

182. The medicament according to Claim 181, wherein the docetaxel is administered at a reduced dose of less than about 75 mg/m².

183. The medicament according to Claim 182, wherein the docetaxel is administered at the reduced dose of about 60 mg/m².

184. The medicament according to Claim 182, wherein the docetaxel is administered at the reduced dose of about 45 mg/m².

185. The medicament according to any one of Claims 167 to 184, wherein the docetaxel is administered by intravenous infusion over about 60 minutes.

186. The medicament according to any one of Claims 172 to 185, wherein the docetaxel is administered on day 8 of a 21 day cycle.

187. The medicament according to any one of Claims 167 to 186, wherein the olaratumab is administered at a dose of about 20 mg/kg in the first cycle of olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of olaratumab to the patient by intravenous infusion over about 60 minutes on days 1 and 8 of the 21 day cycle; wherein the gemcitabine is administered at a dose of about 900 mg/m² by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of the 21 day cycle; and wherein the docetaxel is administered to the patient at a dose of about 75 mg/m² by intravenou infusion over about 60 minutes on day 8 of the 21 day cycle.

188. The medicament according to any one of Claims 167 to 187, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

189. The medicament according to any one of Claims 167 to 187, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

190. The medicament according to any one of Claims 167 to 189, wherein the soft tissue sarcoma is leiomyosarcoma.

191. The medicament according to any one of Claims 167 to 190, wherein a premedication for the olaratumab is administered to the patient about 30 to 60 minutes prior to the olaratumab dose.

192. The medicament according to Claim 191, wherein the premedication comprises a histamine Hl antagonist and or a corticosteroid.

193. The medicament according to Claim 192, wherein the histamine Hl antagonist is diphenhydramine, and wherein the corticosteroid is dexamethasone.

194. The medicament according to any one of Claims 167 to 193, wherein a premedication for gemcitabine is administered to the patient, and wherein the premedication is prophylactic antimetics.

195. The medicament according to any one of Claims 167 to 194, wherein a premedication for docetaxel is administered to the patient, and wherein the premedication is a corticosteroid.

196. The medicament according to Claim 195, wherein the corticosteroid is dexamethasone.

197. The medicament according to Claim 196, wherein the dexamethasone is administered orally at about 8 mg twice a day.

198. The medicament according to Claim 196 and Claim 197, wherein the dexamethasone is administered the day prior to the docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration.

199. The medicament according to any one of Claims 167 to 198, wherein a patient with soft tissue sarcoma and a history of pelvic radiation is administered granulocyte- colony stimulating factors or peg-granulocyte-colony stimulating factors.

200. The medicament according to Claim 199, wherein the granulocyte-colony stimulating factors are administered at a dose of about 5 micrograms/kg/day subcutaneously for at least 5 days, beginning on day 9 of the cycle(s).

201. The medicament according to Claim 199, wherein the peg-granulocyte-colony stimulating factors is administered in a single dose of about 6 mg, subcutaneously on day 9 or 10 of the cycle(s).

202. The medicament according to any one of Claims 167 to 201, wherein the patient has not previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said medicament.

203. The medicament according to any one of Claims 167 to 201, wherein the patient has previously received olaratumab in a course of treatment for soft tissue sarcoma prior to said medicament.

204. A medicament for the treatment of soft tissue sarcoma comprising olaratumab, wherein the treatment comprises:

administering olaratumab to a patient, wherein the patient has soft tissue sarcoma wherein the olaratumab is administered by intravenous infusion over about 60 minutes on days 1 and 8 of a 21 day cycle at a dose of about 20 mg/kg in a first cycle of the olaratumab to the patient, followed by about 15 mg/kg in one or more subsequent cycle(s) of the olaratumab to the patient;

administering gemcitabine to the patient, wherein the gemcitabine is administered following said step of administering olaratumab, and wherein the gemcitabine is administered by intravenous infusion over about 90 minutes at a fixed-dose rate of about 10 mg/m²/minute on days 1 and 8 of a 21 day cycle at a dose of about 900 mg/m²; and

administering docetaxel to the patient, wherein docetaxel is administered following said step of administering the gemcitabine, and wherein the docetaxel is administered by intravenous infusion over about 60 minutes on day 8 of a 21 day cycle at a dose of about 75 mg/m².

205. The medicament according to Claim 204, wherein the soft tissue sarcoma is locally advanced soft tissue sarcoma.

206. The medicament according Claim 204, wherein the soft tissue sarcoma is metastatic soft tissue sarcoma.

207. The medicament according to any one of Claims 204 to 206, wherein the soft tissue sarcoma is leiomyosarcoma.

208. A fixed dose combination kit of olaratumab for sequencal use with gemcitabine and docetaxel in the treatment of soft tissue sarcoma, comprising 20 mg/kg of olaratumab, 900 mg/m² of gemcitabine, and 75 mg/m² docetaxel administered in a first cycle to the patient, followed by 15 mg/kg of olaratumab, 900 mg/m² of gemcitabine, and 75 mg/m² docetaxel administered in one or more subsequent cycle(s) to the patient wherein the gemcitabine is administered following the olaratumab, and wherein the docetaxel is administered following the gemcitabine.