WO2019070497A1

WO2019070497A1 - Combination therapy for cancer

Info

Publication number: WO2019070497A1
Application number: PCT/US2018/053066
Authority: WO
Inventors: Richard Brian GAYNOR; Robert Leslie ILARIA
Original assignee: Imclone Llc
Priority date: 2017-10-04
Filing date: 2018-09-27
Publication date: 2019-04-11

Abstract

The present invention provides preparation of medicaments for use in treating and methods of treating soft tissue sarcoma, comprising administering olaratumab and pembrolizumab to a subject in need thereof.

Description

COMBINATION THERAPY FOR CANCER

The present invention relates to the field of medicine. The present invention relates to a combination of an antibody against human platelet-derived growth factor receptor alpha (PDGFRa) and an antibody against human programmed cell death 1 (PD-1) receptor, and to methods of using the combinations for treating soft-tissue sarcoma (STS). More

specifically, the present invention relates to the combination of olaratumab with

pembrolizumab for treating unresected locally advanced or metastatic soft tissue sarcoma.

Platelet-derived growth factor, a cell surface receptor tyrosine kinase, is a dimeric glycoprotein of mesenchymal origin. PDGFRa / platelet-derived growth factor (PDGF) signaling has been shown to be an important signaling regulator in epithelial mesenchymal transition in several types of cancers, including STS. The overexpression of PDGFRa and presence of PDGF ligands suggests necessary components for PDGF signaling within the tumor microenvironment. Thus, the use of a neutralizing monoclonal antibody specific to human PDGFRa could provide a therapeutic target in STS.

Olaratumab (LARTRUVO^®, FMC-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. This antibody possesses high affinity binding for

PDGFRa and blocks PDGF-AA, -BB, and -CC from binding to the receptor. Olaratumab has been conditionally approved by the US FDA, in combination with doxorubicin, for the treatment of adult patients with STS with a histologic subtype for which an anthracycline- containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. The randomized Phase 2 portion of Study I5B-IE-JGDG ([JGDG]; [FMCL CP15-0806]; olaratumab plus doxorubicin, versus doxorubicin alone in patients with advanced STS) met its primary progression-free survival (PFS) endpoint. Olaratumab plus doxorubicin also achieved a significant improvement in overall survival (OS) relative to the control arm (doxorubicin alone; Tap et al. 2016). 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. The immune system is regulated by many inhibitory pathways, collectively referred to as immune checkpoints, which maintain the tolerance to self-antigens. One of the mechanisms of cancer resistance is the ability of tumor cells to co-opt immune checkpoint pathways. The adaptive upregulation of PD-L1, a ligand of PD-1, reflects the natural physiologic process of normal cell protection from immune-mediated tissue damage. This process, which is the most common in solid tumors, including STS, is used by the cancer cells to avoid killing by the immune system.

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor expressed on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occur in some tumors, and signaling through this pathway contributes to inhibition of active T-cell immune surveillance of tumors.

Pembrolizumab (KEYTRUDA^®, MK3475) is a monoclonal antibody that binds to the human PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including the anti -turn or immune response. Pembrolizumab, sequences thereof, and methods of making and using this antibody, including for increasing the activity of an immune response through the PD-1 pathway, are disclosed WO 2008/156712.

Pembrolizumab has been approved by the US FDA for the treatment of unresectable or metastatic melanoma, non-small cell lung cancer (NSCLC) in a PD-L1 positive patient population or in combination with pemetrexed and carboplatin, and recurrent or metastatic squamous cell carcinoma of the head and neck. Pembrolizumab is also FDA-approved for certain patients with classical Hodgkin lymphoma, urothelial carcinona, or recurrent locally advanced or metastatic gastic or gastroesophageal junction adenocarcinoma. Pembrolizumab is further approved for the treatment of certain patients with microsatellite instability-high or mismatch repair deficient solid tumors. More specifically with regard to the use for treating NSCLC in PD-L1 positive patients, pembrolizumab is approved in the US for "for the first- line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS)>50%)] as determined by an FDA-approved test" and for the "treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS>1%) as determined by an FDA-approved test, with disease progression on or after platinum- containing chemotherapy" (KEYTRUDA® (pembrolizumab) "Indications of Usage").

Although there is limited clinical data with PD-L1 inhibitors in sarcoma, sarcomas have been linked to the immune system as early as the 1800s, when William Coley noted a relationship between infection and regression of sarcoma (McCarthy 2006).

Without being bound by theory, combining olaratumab, shown to work in

combination with doxorubicin in STS, with pembrolizumab in STS, may enhance anti-tumor activity observed through modulation of the tumor microenvironment.

Unfortunately, a cure for unresectable or metastatic STS remains elusive and therapeutic options remain limited with poor prognosis for such patients. Thus, there remains a need for more and different therapies that may prove to be effective in treating STS.

Novel methods for use of the combination of olaratumab and pembrolizumab to treat STS and metastatic STS are presented herein. Accordingly, some aspects of the present invention provide for olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of STS. Some aspects of the present invention provide for olaratumab for use in simultaneous, separate, or sequential combination with

pembrolizumab in the treatment of sarcoma. Some aspects of the present invention provide for olaratumab for use in simultaneous, separate, or sequential combination with

pembrolizumab in the treatment of unresectable locally advanced or metastatic STS.

Additionally, some aspects of the present invention provide for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab in the treatment of unresectable locally advanced or metastatic STS. Some aspects of the present invention provide for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab in the treatment of sarcoma. In some aspects of the present invention provide for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab in the treatment of STS. In a preferred aspect, olaratumab is administered at a dose of 15-20 mg. In another preferred aspect, pembrolizumab is administered at a dose of 200 mg. Accordingly, some aspects of the present invention provide for olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of STS. In a preferred aspect, olaratumab is administered at a dose of 15-20 mg. In another preferred aspect, pembrolizumab is administered at a dose of 200 mg.

More particularly, olaratumab is administered at a dose of 15 mg. More particularly, olaratumab is administered at a dose of 20 mg.

In a preferred aspect, olaratumab is administered by intravenous infusion. In another preferred aspect, olaratumab is administered over a period of about 60 minutes.

In a preferred aspect, pembrolizumab is administered by intravenous infusion. In another preferred aspect, pembrolizumab is administered over a period of about 30 minutes.

More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

More particularly, olaratumab is administered at a dose of 15 mg - 20 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle. More particularly, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3 -week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle. More particularly, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle.

In another preferred aspect, an HI antagonist is administered prior to olaratumab administration. More particularly, the HI antagonist is diphenhydramine. In another preferred aspect, the HI antagonist (e.g., diphenhydramine) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, HI antagonist (e.g., diphenhydramine) is administered intravenously. In another preferred aspect, a corticosteroid is administered prior to olaratumab administration. In another preferred aspect, the corticosteroid is administered prior to olaratumab. In another preferred aspect, the corticosteroid is administered prior to olaratumab during only the first cyle of olaratumab administration. In another preferred aspect, the corticosteroid is selected from the group consisting of hydrocortisone,

methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betametasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate and tixocortol pivalate. In another preferred aspect, the corticosteroid is dexamethasone. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered intravenously.

The present invention also provides for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab for the treatment of sarcoma. In a preferred aspect, pembrolizumab is administered at a dose of 200 mg, and olaratumab is administered at a dose of a dose of 15-20 mg. More particularly, pembrolizumab is administered at a dose of 200 mg. More particularly, olaratumab is administered at a dose of 15 mg. More particularly, pembrolizumab is administered at a dose of 200 mg. More particularly, olaratumab is administered at a dose of 20 mg. More particularly, the sarcoma is STS.

More particularly, pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle and olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle. More particularly, pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle, and olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3 -week cycle. In a preferred aspect, olaratumab is administered by intravenous infusion. In another preferred aspect, olaratumab is administered over a period of about 60 minutes.

In another preferred aspect, an HI antagonist is administered prior to olaratumab administration. More particularly, the HI antagonist is diphenhydramine. In another preferred aspect, the HI antagonist (e.g., diphenhydramine) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, HI antagonist (e.g., diphenhydramine) is administered intravenously.

In another preferred aspect, a corticosteroid is administered prior to olaratumab administration. In another preferred aspect, the corticosteroid is administered prior to olaratumab. In another preferred aspect, the corticosteroid is administered prior to olaratumab during only the first cyle of olaratumab administration. In another preferred aspect, the corticosteroid is selected from the group consisting of hydrocortisone,

methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betametasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate and tixocortol pivalate. In another preferred aspect, the corticosteroid is dexamethasone. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered intravenously. The present invention also provides for use of olaratumab in the manufacture of a medicament for the treatment of sarcoma. In a preferred aspect, olaratumab is administered at a dose of 15 mg to 20 mg in simultaneous, separate, or sequential combination with pembrolizumab, and pembrolizumab is administered at a dose of 200 mg. More particularly, olaratumab is administered at a dose of 15 mg. More particularly, olaratumab is

administered at a dose of 20 mg. More particularly, the sarcoma is STS.

More particularly, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle. More particularly, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle.

In another preferred aspect, a corticosteroid is administered prior to olaratumab administration. In another preferred aspect, the corticosteroid is administered prior to olaratumab. In another preferred aspect, the corticosteroid is administered prior to olaratumab during only the first cyle of olaratumab administration. In another preferred aspect, the corticosteroid is selected from the group consisting of hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betametasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortisone acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate and tixocortol pivalate. In another preferred aspect, the corticosteroid is dexamethasone. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered intravenously.

The present invention also provides for the use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, wherein olaratumab is administered at a dose of 15 mg to 20 mg in simultaneous, separate, or sequential combination with

pembrolizumab, wherein pembrolizumab is administered at a dose of 200 mg.

More particularly, the soft tissue sarcoma is unresected locally advanced or metastatic soft tissue sarcoma. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

More particularly, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle. More particularly, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3 -week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle. In a preferred aspect, olaratumab is administered by intravenous infusion. In another preferred aspect, olaratumab is administered over a period of about 60 minutes.

The present invention also provides for use of pembrolizumab in the manufacture of a medicament for the treatment of sarcoma. In a preferred aspect, pembrolizumab is administered at a dose of 200 mg in simultaneous, separate, or sequential combination with olaratumab, and olaratumab is administered at a dose of 15 mg to 20 mg. More particularly, olaratumab is administered at a dose of 15 mg. More particularly, olaratumab is

administered at a dose of 20 mg. More particularly, the sarcoma is STS.

More particularly, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle. More particularly, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3 -week cycle and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle.

In another preferred aspect, a corticosteroid is administered prior to olaratumab administration. In another preferred aspect, the corticosteroid is administered prior to olaratumab. In another preferred aspect, the corticosteroid is administered prior to olaratumab during only the first cyle of olaratumab administration. In another preferred aspect, the corticosteroid is selected from the group consisting of hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclometasone, betametasone, dexamethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, mometasone furoate, ciclesonide, cortison acetate, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, prednicarbate and tixocortol pivalate. In another preferred aspect, the corticosteroid is dexamethasone. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, the corticosteroid (e.g., dexamethasone) is administered intravenously.

The present invention also provides for the use of pembrolizumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, wherein pembrolizumab is administered at a dose of 200 mg in simultaneous, separate, or sequential combination with olaratumab.

In a preferred aspect, pembrolizumab is administered by intravenous infusion. In another preferred aspect, pembrolizumab is administered over a period of about 30 minutes. In another preferred aspect, an HI antagonist is administered prior to olaratumab administration. More particularly, the HI antagonist is diphenhydramine. In another preferred aspect, the HI antagonist (e.g., diphenhydramine) is administered 30-60 minutes prior to olaratumab administration. In another preferred aspect, HI antagonist (e.g., diphenhydramine) is administered intravenously.

The present invention provides for a kit comprising olaratumab and pembrolizumab for use in the treatment of sarcoma. In a preferred aspect, the amount of olaratumab is 15 mg to 20 mg, and the amount of pembrolizumab is 200 mg. More particularly, the sarcoma is STS.

More particularly, the amount of olaratumab is 15 mg. More particularly, the amount of olaratumab is 20 mg.

In a preferred aspect, olaratumab is administered by intravenous infusion. In another preferred aspect, olaratumab is administered over a period of about 60 minutes. In a preferred aspect, pembrolizumab is administered by intravenous infusion. In another preferred aspect, pembrolizumab is administered over a period of about 30 minutes.

The present invention provides for a kit comprising a first container containing a pharmaceutical composition comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, and a second container containing a

pharmaceutical composition comprising pembrolizumab with one or more pharmaceutically acceptable carriers, diluents, or excipients for use in the treatment of sarcoma, wherein the amount of olaratumab is 15 mg to 20 mg, and the amount of pembrolizumab is 200 mg. More particularly, the sarcoma is STS.

The present invention also provides for a kit comprising a first container containing a pharmaceutical composition comprising olaratumab, wherein olaratumab is formulated for infusion at a final concentration of 10 mg/mL in 10-mM histidine, 100-mM glycine, 50-mM sodium chloride, 75-mM mannitol, and 0.02% polysorbate- 20, pH 5.5, and a second container containing a pharmaceutical composition comprising pembrolizumab, wherein pembrolizumab is reconstituted with 2.3-mL sterile water for injection (SWFI; injected along the walls of the vial and not directly on the powder) to yield a 2.4-mL solution containing 25 mg/mL of pembrolizumab, then formulated for infusion at a final concentration between 1-10 mg/mL in 0.9% Sodium Chloride Injection, USP (normal saline). If normal saline is unavailable, the reconstituted pembrolizumab may be formulated for infusion at a final concentration between 1-10 mg/mL in 5% Dextrose Injection, USP. More particularly, the amount of olaratumab is 15 mg to 20 mg, and the amount of pembrolizumab is 200 mg. More particularly, the amount of olaratumab is 15 mg. More particularly, the amount of olaratumab is 20 mg.

More particularly, the cancer is sarcoma. More particularly, the cancer is STS. More particularly, the cancer is unresectable locally advanced or metastatic STS.

Accordingly, in some aspects, the present invention provides a method of treating sarcoma in a patient, comprising administering to the patient in need of such a treatment an effective amount of olaratumab in combination with an effective amount of pembrolizumab, wherein olaratumab is administered at a dose of 15 mg to 20 mg, and wherein

pembrolizumab is administered at a dose of 200 mg. More particularly, the sarcoma is STS.

More particularly, the amount of olaratumab is 15 mg. More particularly, the amount of olaratumab is 20 mg. More particularly, the amount of pembrolizumab is 200 mg.

More particularly, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle. More particularly, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle. Yet, more particularly, pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle.

More particularly, the combination of olaratumab and pembrolizumab is administered simultaneously, separately, or sequentially.

More particularly, the sarcoms is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments. Preferably, the combination of olaratumab and pembrolizumab is administered simultaneously, separately, or sequentially.

The present invention also provides for olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of sarcoma in a patient. In a preferred aspect, olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3- week cycle, and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle. More particularly, the sarcoma is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

The present invention also provides for olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of sarcoma in a patient. The present invention also provides for olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of soft-tissue sarcoma in a patient. In another preferred aspect, olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3 -week cycle, and pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

The present invention also provides for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab for the treatment of sarcoma. In a preferred aspect, pembrolizumab is administered at a dose of 200 mg on day 1 of each 3- week cycle, and olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3- week cycle. More particularly, the sarcoma is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

The present invention also provides for pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab for the treatment of sarcoma in a patient, wherein pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle, and wherein olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle. More particularly, the sarcoma is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

The present invention also provides for use of pembrolizumab in the manufacture of a medicament for the treatment of sarcoma, wherein pembrolizumab is administered at a dose of 200 mg in simultaneous, separate, or sequential combination with olaratumab

administered at a dose of 15 mg. More particularly, the sarcoma is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

administered at a dose of 20 mg. More particularly, the sarcoma is STS. More particularly, the STS is unresectable locally advanced or metastatic STS. More particularly, the STS is unresectable locally advanced or metastatic STS in patients who have failed in standard treatments.

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, the term "patient" refers to a mammal, preferably a human.

As used herein, the terms "cancer" and "cancerous" refers to or describes the physiological condition in patients that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers. Examples of cancer include STS, among others.

As used herein, the term "kit" refers to a package comprising at least two separate containers, wherein a first container contains a pharmaceutical composition comprising olaratumab and a second container contains a pharmaceutical composition comprising pembrolizumab. A "kit" may also include instructions to administer all or a portion of the contents of these first and second 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, and quality of life. The therapeutic agents used in the invention may cause inhibition of metastatic spread without shrinkage of the primary tumor, or may simply exert a tumoristatic 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.

As used herein, the term Partial Response (PR) is defined as at least a 30% decrease in the sum of diameter of target 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, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%), the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 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.

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 diameters while on study.

As used herein, the term Not Evaluable (NE) is defined 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. As used herein, the term Progression-Free Survival (PFS) is defined as the time from the date of first dose of any study drug until the date of radiographically documented PD or death due to any cause, whichever is earlier.

As used herein, the term Overall Survival (OS) is defined as the time from the date of study first dose of any study drug to the date of death from any cause.

As used herein, the term Objective Response Rate is defined as the proportion of patients achieving a best overall response of PR or CR.

As used herein, the term Disease Control Rate (DCR) is defined as the proportion of patients achieving a best overall response of SD, PR, or CR.

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 E, 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 "effective amount" refers to the amount or dose of olaratumab, and/or to the amount or dose of pembrolizumab, which, upon single or multiple dose administration to the patient, provides an effective response in the patient under diagnosis or treatment. It is also understood that a combination therapy of the present invention is carried out by administering olaratumab, together with pembrolizumab, in any manner which provides effective levels of olaratumab and pembrolizumab in the body.

An effective amount can be readily determined by one skilled in the art, by the use of known techniques, and by observing results obtained under analogous circumstances. In determining the effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the degree of, or involvement, or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

As used herein, the term "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

pembrolizumab, 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.

Olaratumab is generally effective over a dosage range in the combination of the present invention. For example, dosages per 21 -day cycle normally fall within the range of about 10 to 20 mg as an intravenous infusion over about 60 min, with dosages on 2 days of that cycle, preferably about 15 to 20 mg on Day 1 and Day 8 of each 21 -day cycle, and most preferably about 15 mg on Day 1 and Day 8 of each 21 -day cycle, and most preferable about 20 mg on Day 1 and Day 8 of each 21 -day cycle. Pembrolizumab is generally effective over a dosage range in the combination of the present invention. For example, dosages per 21 -day cycle normally fall within the range of about 100 mg to about 300 mg as an intravenous infusion over about 30 minutes, more preferably about 200 mg as an intravenous infusion over 30 minutes, and most preferably about 200 mg as an intravenous infusion over about 30 min on Day 1 of a 21 -day cycle.

Dosage regimens may be adjusted for patient safety or to provide the optimum desired response (e.g., a therapeutic response). Dosing schedules, for intravenous (IV) or non-intravenous administration, localized or systemic, or combinations thereof, will typically range from a single bolus dosage or continuous infusion, to multiple administrations per day (e.g., every 4-6 hours), or as indicated by the treating physician and the patient's condition. As used herein, intravenous infusion and intravenous injection can be used interchangeably. As used herein, the phrase "in combination with" refers to the administration of olaratumab with pembrolizumab simultaneously. As used herein, the phrase "in combination with" also refers to the administration of olaratumab with pembrolizumab sequentially in any order. As used herein, the phrase "in combination with" also refers to the administration of olaratumab with pembrolizumab in any combination thereof. Olaratumab can be

administered prior to administration of pembrolizumab. Olaratumab can be administered at the same time as administration of pembrolizumab. Olaratumab can be administered subsequent to administration of pembrolizumab. Olaratumab can be administered prior to, at the same time as, or subsequent to administration of pembrolizumab, or in some combination thereof. Pembrolizumab can be administered prior to administration of olaratumab.

Pembrolizumab can be administered at the same time as administration of olaratumab.

Pembrolizumab can be administered subsequent to administration of olaratumab.

Pembrolizumab can be administered prior to, at the same time as, or subsequent to administration of olaratumab, or in some combination thereof.

Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered prior to each administration of

olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered at the same time as each administration of olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered subsequent to each administration of olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered prior to, at the same time as, or subsequent to, each administration of olaratumab or some combination thereof. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab 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), pembrolizumab can be administered in a single or series of dose(s) prior to, at any time during, or subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a single dose prior to, at any time during, or subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a single dose prior to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a single dose at any time during the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a single dose subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a series of doses prior to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a series of doses subsequent to the course of treatment with olaratumab. Where olaratumab is administered at repeated intervals (e.g. during a standard course of treatment), pembrolizumab can be administered in a series of doses subsequent to the course of treatment with olaratumab.

The present invention also contemplates a therapeutic regimen for treating STS comprising: a) selecting a patient having STS and whose protein expression level of PD-L1 is less than 50% of the viable tumor cells showing partial or complete membrane staining, and b) administering to the patient a 15 mg dose of olaratumab on days 1 and 8 of each 3-week cycle, and a 200 mg dose of pembrolizumab on day 1 of each 3 -week cycle.

The invention contemplates using a PD-1 ligand, more particularly PD-L1, as a biomarker for cancer patients who respond to treatment when the cancer has PD-1 expression. The invention further contemplates the method of predicting successful treatment of a patient with olaratumab in combination pembrolizumab by measuring the PD- Ll levels in tumor tissue of the patient. PD-L1 expression levels can be measured in a variety of methods, including qualitative immunohistochemical assay, such as the companion diagnostic approved by the FDA for KEYTRUDA® (pembrolizumab), PD-L1 fflC 22C3 pharmDx. PD-L1 protein expression can be determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining." (fflC PD-L1 fflC 22C3 pharmDx, Approval Order Letter for PMA P150013, 2 November 2015.)

Olaratumab can be made, for example, according to the disclosure in WO

2006/138729. Pembrolizumab can be made, for example, according to the disclosure in WO 2008/156712.

The following examples and clinical study results further illustrate the present invention, but should not be construed to limit the scope of the invention in any way.

A Study of Olaratumab (LY3012207) Plus Pembrolizumab (MK3475) in Participants

With Advanced or Metastatic Soft Tissue Sarcoma

Clinical Study Design

A Phase la/lb open-label, multicenter, nonrandomized, noncomparative, dose escalation study that includes a dose-expansion component to evaluate intravenous olaratumab plus pembrolizumab in about 74 patients with unresectable locally advanced or metastatic STS who have failed standard treatments. See NCT03126591, available on clinicaltrials.gov. The Study consists of several parts including:

• Part A: escalating doses of olaratumab (15 mg and 20 mg IV) are administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W in patients with unresectable locally advanced or metastatic STS.

• Part B: expansion cohort with the dose of olaratumab identified in Part A in

combination with a fixed regimen of pembrolizumab (200 mg IV) on Day 1 Q3W in patients with unresectable locally advanced or metastatic STS.

Approximately 27 patients are enrolled in Part A and 55 patients in Part B.

Maximum duration of treatment with pembrolizumab is 35 cycles (approximately 2 years); treatment duration with olaratumab is not fixed. Patients will be treated until PD, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Patients who are on study therapy at study completion may continue to receive study therapy in the continued access period until they meet discontinuation criteria.

Study Objectives

The primary objective of Part A of the Study is to investigate safety and tolerability of pembrolizumab 200 mg Q3W when combined with olaratumab administered at the doses of 15 mg and 20 mg on Days 1 and 8 of 21 -day cycles in patients with unresectable locally advanced or metastatic STS as measured by number of patients with a dose-limiting toxicity during Cycle 1; and for Part B to confirm the safety and tolerability of olaratumab at the recommended dose in combination with pembrolizumab in patients unresectable locally advanced or metastatic STS who have failed standard treatments.

The secondary objectives of the Study include: for Part A: (i) To characterize the pharmacokinetics and (PK) pharmacodynamics (PD) of olaratumab when administered in combination with pembrolizumab; (ii) To determine the immunogenicity of olaratumab when administered in combination with pembrolizumab; (iii) To document any antitumor activity of olaratumab when administered in combination with pembrolizumab as assessed by the Objective response Rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) vl . l and immune-related RECIST (irRECIST), Disease Control Rate (DCR) using RECIST vl . l and irRECIST, Duration of Response (DOR) using RECIST vl . l and irRECIST, PFS using RECIST vl .1 and irRECIST, and OS; for Part B: (i) To document any antitumor activity of olaratumab at the recommended dose when administered in

combination with pembrolizumab as assessed by: (a) ORR using RECIST vl . l and irRECIST; (b) Disease Control Rate (DCR) using RECIST vl . l and irRECIST; (c) DOR using RECIST vl . l and irRECIST, (d) PFS using RECIST vl . l and irRECIST; and (e) OS; (ii) To characterize the PK and PD of olaratumab at the recommended dose when

administered in combination with pembrolizumab; and, (iii) To determine the

immunogenicity of olaratumab at the recommended dose when administered in combination with pembrolizumab. The correlation of potential biomarkers to clinical outcome may also be assessed.

Claims

WE CLAIM:

1. Olaratumab for use in simultaneous, separate, or sequential combination with pembrolizumab in the treatment of soft tissue sarcoma in a patient, wherein olaratumab is administered at a dose of 15 mg to 20 mg, and wherein pembrolizumab is administered at a dose of 200 mg.

2. Olaratumab for the use of claim 1, wherein olaratumab is administered at a dose of 15 mg.

3. Olaratumab for the use of claim 1, wherein olaratumab is administered at a dose of 20 mg.

4. Olaratumab for the use of any one of claims 1 to 3, wherein olaratumab is

administered at a dose of 15-20 mg on days 1 and 8 of each 3-week cycle.

5. Olaratumab for the use of any one of claims 1 to 3, wherein olaratumab is

administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle.

6. Olaratumab for the use of any one of claims 1 to 3, wherein olaratumab is

administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle.

7. Olaratumab for the use of any one of claims 1 to 6, wherein pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle.

8. Olaratumab for the use of any one of claims 1 to 7, wherein the soft tissue

sarcoma is unresected locally advanced or metastatic soft tissue sarcoma.

9. Pembrolizumab for use in simultaneous, separate, or sequential combination with olaratumab for the treatment of soft tissue sarcoma of in a patient, wherein pembrolizumab is administered at a dose of 200 mg, and wherein olaratumab is administered at a dose of 15 mg to 20 mg.

10. Pembrolizumab for use of claim 9, wherein olaratumab is administered at a dose of 15 mg.

11. Pembrolizumab for use of claim 9, wherein olaratumab is administered at a dose of 20 mg.

12. Pembrolizumab for use of any one of claims 9 to 11, wherein pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle and wherein olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3-week cycle.

13. Pembrolizumab for use of any one of claims 9 to 11, wherein pembrolizumab is administered at a dose of 200 mg on day 1 of each 3-week cycle and wherein olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3-week cycle.

14. Pembrolizumab for the use of any one of claims 9 to 13, wherein the soft tissue sarcoma is unresected locally advanced or metastatic soft tissue sarcoma.

15. Use of olaratumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, wherein olaratumab is administered at a dose of 15 mg to 20 mg in simultaneous, separate, or sequential combination with pembrolizumab, wherein pembrolizumab is administered at a dose of 200 mg.

16. Use of claim 15, wherein olaratumab is administered at a dose of 15 mg.

17. Use of claim 15, wherein olaratumab is administered at a dose of 20 mg.

18. Use of any one of claims 15 to 17, wherein soft tissue sarcomais unresected locally advanced or metastatic soft tissue sarcoma.

19. Use of pembrolizumab in the manufacture of a medicament for the treatment of soft tissue sarcoma, wherein pembrolizumab is administered at a dose of 200 mg in simultaneous, separate, or sequential combination with olaratumab.

20. Use of claim 19, wherein olaratumab is administered at a dose of 15 mg.

21. Use of claim 19, wherein olaratumab is administered at a dose of 20 mg.

22. Use of any one of claims 19 to 21, wherein the soft tissue sarcoma is unresected locally advanced or metastatic soft tissue sarcoma.

23. A kit comprising olaratumab and pembrolizumab for use in the treatment of soft tissue sarcoma, wherein the amount of olaratumab is 15 mg to 20 mg, and the amount of pembrolizumab is 200 mg.

24. The kit of claim 23, wherein the amount of olaratumab is 15 mg.

25. The kit of claim 23, wherein the amount of olaratumab is 20 mg.

26. The kit of any one of claims 23 to 24, wherein the soft tissue sarcoma is

unresected locally advanced or metastatic soft tissue sarcoma.

27. A kit comprising a first container containing a pharmaceutical composition,

comprising olaratumab with one or more pharmaceutically acceptable carriers, diluents, or excipients, and a second container containing a pharmaceutical composition, comprising pembrolizumab with one or more pharmaceutically acceptable carriers, diluents, or excipients for use in the treatment of soft tissue sarcoma, wherein the amount of olaratumab is 15 mg to 20 mg, and the amount of pembrolizumab is 200 mg.

28. The kit of claim 27, wherein the amount of olaratumab is 15 mg.

29. The kit of claim 27, wherein the amount of olaratumab is 20 mg.

30. The kit of any one of claims 27 to 29, wherein the soft tissue sarcoma is

unresected locally advanced or metastatic soft tissue sarcoma.

31. A kit comprising a first container containing a pharmaceutical composition

comprising olaratumab wherein olaratumab is formulated at a final concentration of 10 mg/mL with 10-mM histidine, 100-mM glycine, 50-mM sodium chloride, 75-mM mannitol, and 0.02% poly sorb ate-20, pH 5.5, and a second container containing a pharmaceutical composition comprising pembrolizumab, wherein pembrolizumab is reconstituted at a final concentration of 25 mg/mL with sterile water for injection.

32. The kit of claim 31, wherein the amount of olaratumab is 15 mg to 20 mg, and wherein the amount of pembrolizumab is 200 mg.

33. The kit of claim 31, wherein the amount of olaratumab is 15 mg and the amount of pembrolizumab is 200 mg.

34. The kit of claim 31, wherein the amount of olaratumab is 20 mg and the amount of pembrolizumab is 200 mg.

35. A method of treating soft tissue sarcoma in a patient, comprising administering to the patient in need of such a treatment an effective amount of olaratumab in combination with an effective amount of pembrolizumab, wherein olaratumab is administered at a dose of 15 mg to 20 mg, and wherein pembrolizumab is administered at a dose of 200 mg.

36. The method of claim 35, wherein olaratumab is administered at a dose of 15 mg on days 1 and 8 of each 3 -week cycle.

37. The method of claim 35, wherein olaratumab is administered at a dose of 20 mg on days 1 and 8 of each 3 -week cycle.

38. The method of claim 36 or 37, wherein pembrolizumab is administered at a dose of 200 mg on day 1 of each 3 -week cycle.

39. The method of any one of claims 35 to 37, wherein the combination of

olaratumab and pembrolizumab is administered simultaneously, separately, or sequentially.

40. The method of any one of claims 35 to 39, wherein the soft tissue sarcoma is unresected locally advanced or metastatic soft tissue sarcoma.