Methods for treating cancer with PDGFRα inhibitors

Abstract

A method of treating a cancer patient with a human platelet-derived growth factor receptor alpha inhibitor compound, wherein the patient is identified as having a human platelet-derived growth factor receptor beta negative cancer.

Description

[Technical Field]

[0001] The present invention relates to the field of cancer. More specifically, the present invention relates to the treatment of cancer patients with platelet-derived growth factor receptor alpha ("PDGFRα") inhibitory compounds. Even more particularly, the present invention relates to the treatment of cancer patients with PDGFRα inhibitory compounds, where the cancer patients are identified as PDGFR beta ("PDGFRβ") negative. [Background technology]

[0002] Cancer is a disease with extensive histo-clinical heterogeneity, including large variations in tumor morphology and physiology. Although some conventional histological and clinical features correlate with prognosis, extensive heterogeneity in cancer morphology, from the cellular to the tissue level, affects response to treatment and subsequent patient benefit. Therefore, selectively treating cancer patients who will benefit from specific treatments remains a continuing challenge. Summary of the Invention

[0003] PDGFRα inhibitory compounds have shown promise as cancer therapeutics in preclinical and clinical studies. Despite this promise, PDGFRα inhibitory compounds have failed to achieve therapeutic endpoints in clinical trials in several cancer areas. For example, in clinical trials for the treatment of soft tissue sarcoma, LARTRUVO®, an antibody that specifically binds to human PDGFRα, failed to achieve certain therapeutic endpoints. Therefore, improved methods for treating patients with PDGFRα inhibitory compounds are needed. In particular, such methods should provide prognostic, diagnostic, or predictive value for cancer patients treated with PDGFRα inhibitory compounds. The present disclosure addresses this need by providing methods for treating cancer patients with PDGFRα inhibitory compounds.

[0004] While in some instances, methods for treating certain types of cancer or for treating patients with particular therapeutic agents have shown promise, there are currently no reliable methods for treating cancer patients with PDGFRα inhibitory compounds. Surprisingly, the present disclosure provides methods for treating cancer patients with PDGFRα inhibitory compounds that provide prognostic, diagnostic, or predictive value for cancer patients treated with PDGFRα inhibitory compounds. More specifically, embodiments of the present disclosure provide methods for treating cancer patients with human PDGFRβ-negative cancers by administering a PDGFRα inhibitory compound.

[0005]

[0010] Embodiments of the present disclosure further provide a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a PDGFRα inhibitory compound. Specifically, embodiments of the present disclosure provide a method of treating cancer in a patient in need thereof, wherein the patient is identified as having a human PDGFRβ-negative cancer, comprising administering to the patient an effective amount of a PDGFRα inhibitory compound. In yet another embodiment, the present disclosure provides a method of treating a patient with a human PDGFRβ-negative cancer, comprising administering to the patient an effective amount of a PDGFRα inhibitory compound.

[0006] Accordingly, embodiments of the present disclosure provide methods of treating cancer in a patient, comprising identifying the patient as having a human PDGFRβ-negative cancer. In certain embodiments, the present disclosure provides such methods in a patient in need of cancer treatment, comprising identifying the patient as having a human PDGFRβ-negative cancer and administering to the patient an effective amount of a PDGFRα inhibitory compound. In further embodiments, the present disclosure provides such methods in a patient in need of cancer treatment by administering to the patient an effective amount of a PDGFRα inhibitory compound, wherein the patient has been identified as having a human PDGFRβ-negative and human PDGFRα-positive cancer.

[0007] In some embodiments of the present disclosure, a method for identifying a patient as having a human PDGFRβ-negative cancer includes contacting a biological sample from the patient with an antibody that specifically binds to human PDGFRβ, and detecting binding of the antibody to human PDGFRβ in the biological sample.

[0008] According to embodiments of the present disclosure, there are provided methods for detecting PDGFRβ in a biological sample. Such methods include performing an assay on a biological sample from a patient. Embodiments of the present disclosure further provide methods including contacting the biological sample with an antibody that specifically binds human PDGFRβ and detecting binding of the antibody to human PDGFRβ in the biological sample.

[0009] According to embodiments of the present disclosure, there is provided a method for diagnosing a cancer patient as needing treatment with a PDGFRα inhibitor compound. Such a method comprises identifying the patient as having a human PDGFRβ-negative cancer. Such a method further comprises performing an assay on a biological sample from the patient. Embodiments of the present disclosure further provide a method comprising contacting the biological sample with an antibody that specifically binds human PDGFRβ and detecting binding of the antibody to human PDGFRβ in the biological sample.

[0010] According to embodiments of the present disclosure, there is provided a method for quantifying human PDGFRβ in a biological sample, comprising contacting a biological sample from a patient with an antibody that specifically binds to human PDGFRβ, and detecting binding of the antibody to human PDGFRβ in the biological sample.

[0011] In certain embodiments of the present disclosure, a biological sample is determined to be PDGFRβ negative if PDGFRβ in the biological sample is determined to be present in less than about 10% of tumor cells in the biological sample. In yet other embodiments, a biological sample is determined to be PDGFRβ positive if PDGFRβ in the biological sample is determined to be present in about 10% or more of tumor cells in the biological sample. In a further embodiment of the present disclosure, if a biological sample from a patient is determined to be PDGFRβ negative, the patient is administered a PDGFRα inhibitory compound.

[0012] In certain embodiments, the present disclosure provides a method for diagnosing a cancer patient as needing treatment with a PDGFRα inhibitory compound, the method comprising: obtaining a biological sample from the patient; contacting the biological sample with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, wherein a complex between the antibody or antigen-binding fragment thereof and the human PDGFRβ is formed; contacting the complex between the human PDGFRβ antibody or antigen-binding fragment thereof and the human PDGFRβ with a second antibody or antigen-binding fragment thereof, wherein the second antibody comprises a detectable label; and detecting a signal provided by the detectable label; wherein the cancer patient is diagnosed as needing treatment with a PDGFRα inhibitory compound if the biological sample from the cancer patient is determined to be PDGFRβ negative. In a further embodiment, the disclosure comprises administering an effective amount of a PDGFRα inhibitory compound to the cancer patient if the biological sample is determined to be PDGFRβ negative.

[0013]

[0010] One embodiment of the present disclosure provides an in vitro method for diagnosing a cancer patient as needing treatment with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα, the method comprising the steps of: obtaining a biological sample from the patient; contacting the biological sample with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, wherein a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ is formed; removing any non-specifically bound PDGFRβ antibody or antigen-binding fragment thereof; and detecting and quantifying the PDGFRβ antibody or antigen-binding fragment thereof in the biological sample, wherein the cancer patient is diagnosed as needing treatment with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα. In yet a further embodiment, the step of detecting human PDGFRβ in the biological sample comprises detecting a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ in the biological sample using a second antibody or antigen-binding fragment thereof. In still further embodiments of the present disclosure, at least one of the PDGFRβ antibody or antigen-binding fragment thereof, or the second antibody or antigen-binding fragment thereof, comprises a detectable label. In still further embodiments, such a step of detecting human PDGFRβ in a biological sample comprises detecting a signal provided by the detectable label upon formation of a complex comprising the PDGFRβ antibody and human PDGFRβ or the second antibody and human PDGFRβ. In still further embodiments, such a step of detecting human PDGFRβ in a biological sample comprises detecting a signal provided by the detectable label upon formation of a complex comprising the antibody, human PDGFRβ, and the second antibody.

[0014] Further embodiments of the present disclosure include administering to the cancer patient an effective amount of an antibody that specifically binds to PDGFRα if the biological sample is determined to be PDGFRβ negative.

[0015] In embodiments of the present disclosure, the PDGFRα inhibitory compound is an antibody or antigen-binding fragment thereof. In other embodiments of the present disclosure, the PDGFRα inhibitory compound is a small molecule inhibitor. In particular embodiments, the PDGFRα inhibitory compound is an antibody that specifically binds to PDGFRα. In even more particular embodiments, the antibody that specifically binds to PDGFRα is olaratumab. In some embodiments, the PDGFRα inhibitory compound is an antibody-drug conjugate. In some embodiments, the PDGFRα inhibitory compound is an antibody, and the antibody is labeled with a radiopharmaceutical targeting agent.

[0016] According to some embodiments, an antibody that specifically binds to PDGFRα is provided. In more specific embodiments, the antibody that specifically binds to PDGFRα comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises SEQ ID NO: 5, HCDR2 comprises SEQ ID NO: 6, HCDR3 comprises SEQ ID NO: 7, LCDR1 comprises SEQ ID NO: 8, LCDR2 comprises SEQ ID NO: 9, and LCDR3 comprises SEQ ID NO: 10. In a further embodiment, the VH of the antibody that specifically binds to PDGFRα comprises SEQ ID NO: 3, and the VL comprises SEQ ID NO: 4. In yet a further embodiment, the antibody that specifically binds to PDGFRα comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 1 and the LC comprises SEQ ID NO: 2. In a more particular embodiment, the antibody that specifically binds to PDGFRα is olaratumab.

[0017] In still further embodiments of the present disclosure, an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PDGFRα is administered to a patient identified as having a human PDGFRβ-negative cancer. In such embodiments, an effective amount of the antibody or antigen-binding fragment thereof is administered to a patient identified as having a human PDGFRβ-negative cancer at a loading dose of about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of an initial 21-day cycle, or on each of days 1 and 8 of an initial 28-day cycle, after which a standard dose of the antibody or antigen-binding fragment thereof is administered to the patient at about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of a subsequent 21-day cycle, or on each of days 1 and 8 of a subsequent 28-day cycle. In still further embodiments, the antibody or antigen-binding fragment thereof is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent comprises at least one of nab-paclitaxel, doxorubicin, gemcitabine, or docetaxel.

[0018] In yet further embodiments of the present disclosure, an effective amount of olaratumab is administered to a patient identified as having a human PDGFRβ-negative cancer. In such embodiments, an effective amount of olaratumab is administered to a patient identified as having a human PDGFRβ-negative cancer at a loading dose of about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on days 1 and 8 of an initial 21-day cycle, or on days 1 and 8 of an initial 28-day cycle, after which a standard dose of olaratumab is administered to the patient at about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on days 1 and 8 of a subsequent 21-day cycle, or on days 1 and 8 of a subsequent 28-day cycle. In still further embodiments, olaratumab is administered in simultaneous, separate, or sequential combination with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent comprises at least one of nab-paclitaxel, doxorubicin, gemcitabine, or docetaxel.

[0019] In some embodiments of the present disclosure, the cancer determined to be PDGFRβ negative is soft tissue sarcoma, pancreatic cancer, endometrial cancer, ovarian cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, breast cancer, bone cancer, or prostate cancer. In some embodiments, the cancer is leiomyosarcoma. In some embodiments, the cancer is liposarcoma. In certain embodiments of the present disclosure, the cancer is a primary tumor. In certain embodiments, the cancer is a metastatic cancer. In yet other embodiments, the cancer has metastasized. In certain embodiments of the present disclosure, the patient is a female, and the female is determined to have a PDGFRβ negative cancer.

[0020] Platelet-derived growth factor receptor alpha (PDGFRα) and platelet-derived growth factor receptor beta (PDGFRβ) belong to the type III tyrosine kinase receptor (RTK) family and are involved in various cancer types. PDGFRα is thought to be a factor involved in tumor growth, angiogenesis, and metastatic dissemination in various cancer types.

[0021] The terms "PDGFRα inhibitory compound" or "PDGFRα inhibitor," used interchangeably herein, refer to a compound that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PDGFRα with one or more of its ligands or binding partners. The PDGFRα inhibitory compound may be an extracellular inhibitor or an intracellular inhibitor, and two or more inhibitors may be used. Extracellular inhibitors include, but are not limited to, compounds that bind to PDGFRα or one or more of its ligands (e.g., PDGF-AA, -AB, -BB, -CC). Intracellular inhibitors include, but are not limited to, small molecule receptor tyrosine kinase inhibitors. Non-limiting examples of PDGFRα inhibitory compounds include antibodies, antigen-binding fragments thereof, small molecule inhibitors, antibody-drug conjugates, fusion proteins, immunoadhesin molecules, and oligopeptides.

[0022] As used herein, the terms "antibody" and "antigen-binding fragment thereof" refer to an immunoglobulin molecule that specifically binds to an antigen. In certain embodiments, the antibody or antigen-binding fragment thereof specifically binds to PDGFRα. An exemplary antibody of the present disclosure is an immunoglobulin G type 1 (IgG1) antibody or antigen-binding fragment thereof. According to certain embodiments, such an antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the CDRs HCDR1, HCDR2, and HCDR3, and the VL comprises the complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, wherein HCDR1 has the amino acid sequence of SEQ ID NO: 3, HCDR2 has the amino acid sequence of SEQ ID NO: 4, HCDR3 has the amino acid sequence of SEQ ID NO: 5, LCDR1 has the amino acid sequence of SEQ ID NO: 6, LCDR2 has the amino acid sequence of SEQ ID NO: 7, and LCDR3 has the amino acid sequence of SEQ ID NO: 8. According to some embodiments of the antibody or antigen-binding fragment thereof provided by the present disclosure, the VH has the amino acid sequence of SEQ ID NO: 3, and the VL has the amino acid sequence of SEQ ID NO: 4. According to some embodiments, the antibody or antigen-binding fragment thereof provided by the present disclosure comprises a light chain (LC) and a heavy chain (HC), wherein the HC has the amino acid sequence of SEQ ID NO: 1, and the LC has the amino acid sequence of SEQ ID NO: 2. In an embodiment of the present disclosure, the antibody is olaratumab.

[0023] According to some embodiments, the antibodies of the present disclosure may be humanized. In some embodiments, the antibodies of the present disclosure comprise an IgG1 heavy chain. In some embodiments, the antibodies of the present disclosure comprise a kappa light chain. According to still further embodiments, the present disclosure provides pharmaceutical compositions comprising an antibody of the present disclosure and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0024] Antibody embodiments include monoclonal, polyclonal, human, humanized, chimeric, bispecific or multispecific, or conjugated antibodies. The antibody may be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4).

[0025] The assignment of amino acid residues to CDRs can be performed using the methods of Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987), Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics This can be done by well-known schemes, including those described in the Imgt database, available at www.imgt.org (see Lefranc et al., Nucleic Acids Res. 1999;27:209-212).

[0026] As used herein, the term "specifically binds to PDGFRα" or "binds to PDGFRα" refers to the interaction of an antibody with an epitope region of human PDGFRα, for example, as provided in NCBI Reference Sequence P16234.1 (SEQ ID NO: 11). As used herein, the term "specifically binds to PDGFRβ" or "binds to PDGFRβ" refers to the interaction of an antibody with an epitope region of human PDGFRβ, for example, as provided in NCBI Reference Sequence P09619.1 (SEQ ID NO: 12).

[0027] As used herein, the term "PDGFRβ-negative" or "PDGFRβ-positive" refers to whether a patient's cancer is a PDGFRβ-negative or a PDGFRβ-positive form of cancer. As detailed herein, whether a patient's cancer is a PDGFRβ-negative or a PDGFRβ-positive form of cancer can be determined based on a qualitative or quantitative assessment. According to embodiments herein, whether a patient's cancer is a PDGFRβ-negative or a PDGFRβ-positive form of cancer can be determined based on an evaluation of the approximate level of PDGFRβ present in a biological sample from a cancer patient compared to a reference value. According to more specific embodiments, a patient is determined to have a PDGFRβ-negative form of cancer if the approximate level of PDGFRβ present in the biological sample is less than about 10% of tumor cells in the patient-derived biological sample, as determined by an IHC assay. In another embodiment, a patient is determined to have a PDGFRβ-negative form of cancer based on the level of PDGFRβ determined by a grading system using a reference value.

[0028] The level of PDGFRβ provided by the assays of the present invention or assays known in the art can be an absolute value (e.g., level in a biological sample) or a relative value (e.g., level compared to a reference). The level of PDGFRβ in tumor cells can be assessed by assays including, but not limited to, immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative, qualitative, or semi-quantitative reverse transcription PCR (RT-PCR), application of automated or semi-automated image analysis of IHC, or other quantitative / semi-quantitative / qualitative assessment of protein expression or mRNA expression, artificial intelligence analysis of scanned slides or other laboratory-acquired data for protein expression, bright-field in situ hybridization (BRISH), fluorescent in situ hybridization (RNA FISH), protein immunofluorescence, quantitative / semi-quantitative / qualitative proteomics methods, cytological assays, and RNA sequencing.

[0029] As used herein, a "reference value" refers to a known or approximate level of a reference value, which may be an absolute or relative level, a range, a minimum level, an average level, a threshold level, and / or a median level. In addition, a reference value may serve as a baseline or threshold. According to certain embodiments as used herein, a "reference value" of PDGFRβ indicates whether a patient's form of cancer is a PDGFRβ-negative or -positive form of cancer.

[0030] The terms "biological sample" or "patient sample," used interchangeably herein, refer to a human sample. Non-limiting sources of biological samples for use in the present invention include cancers, tumors, tumor biopsies, biopsy aspirates, solid tissues, tumor cells, and metastatic, migratory, circulating tumor cells. In addition, a biological sample can also refer to blood, plasma, serum, lymph, ascites, fluid extracts, external skin, respiratory, nasal, intestinal, and genitourinary tracts, tears, saliva, milk, organs, cell cultures, and / or cell culture components.

[0031] As used herein, the term "about" means within 5%.

[0032] The term "cancer," as used herein, refers to a disease pathologically characterized by a physiological condition in mammals that is typically characterized by uncontrolled cell proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain characteristic morphological features. Often, cancer cells are in the form of a tumor, but such cells may exist alone or circulate in the bloodstream as independent cells, e.g., leukemia cells, or metastatic, migratory, or circulating tumor cells. Cancer may be a solid tumor or a leukemia. Tumors may be benign, malignant, or dormant, and may be characterized as primary or metastatic tumors. In some embodiments, non-limiting examples of cancer include soft tissue sarcoma, pancreatic cancer, endometrial cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, breast cancer, osteosarcoma, prostate cancer, gastrointestinal cancer, colon cancer, squamous cell carcinoma, head and neck cancer, small cell lung cancer, non-small cell lung cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, liver cancer, and / or laryngeal cancer.

[0033] As used herein, the term "soft tissue sarcoma" or "STS" refers to a type of cancer that develops in tissues that connect, support, and surround other body structures. This includes fat, muscle, fibrous tissue, blood vessels, nerves, tendons, inside joints, or deep skin tissue, and / or inside joints. They can be found in any part of the body. There are over 50 subtypes of soft tissue sarcoma. Types of STS include, but are not limited to, angiodermatofibrosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, liposarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0034] Chemotherapeutic agents are chemicals or drugs that selectively destroy cancer cells and tissues. Chemotherapeutic agents may include, but are not limited to, compounds such as taxane compounds, compounds that act via a taxane mechanism, platinum compounds, anthracycline compounds, antimetabolites, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof. Chemotherapeutic agents can be administered alone or in combination with other therapeutic agents. In some embodiments, the chemotherapeutic agent comprises nab-paclitaxel, doxorubicin, docetaxel, or gemcitabine.

[0035] As used herein, the term "diagnosis" is used to refer to the identification or classification of a molecular or pathological state, disease, or condition (e.g., cancer). For example, "diagnosis" can refer to the identification of a particular type of cancer. "Diagnosis" can also refer to the classification of a particular subtype of cancer, for example, by histopathological criteria or by molecular features (e.g., a subtype characterized by the expression of one or a combination of biomarkers (e.g., specific genes or proteins encoded by such genes, or expression levels of specific genes or proteins encoded by such genes)).

[0036] Embodiments of the present disclosure also relate to methods of clinical diagnosis or prognosis of a subject performed by a medical professional using the methods disclosed herein. The methods described herein can be performed, for example, by an individual, a medical professional, or a third party, such as a service provider, who interprets information from the subject. As described herein, the medical professional can initiate or modify treatment after receiving information related to the diagnostic methods of the present disclosure. For example, the medical professional can recommend a therapy, a change in therapy, or additional diagnostic evaluation.

[0037] As used herein, the terms "treat" or "treating" or "treatment" refer to a process that involves slowing, interrupting, suppressing, controlling, halting, reducing, regressing, and / or reversing the progression or severity of an existing disease, such as cancer, but does not necessarily involve complete elimination of the disease or disease state.

[0038] As used herein, the term "effective amount" refers to an amount of a protein or nucleic acid or vector or composition or inhibitory compound that induces a biological or medical response in a subject, e.g., a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease, etc. In non-limiting embodiments, the term "effective amount" refers to the necessary quantity (dosage and duration and means of administration) of a protein or nucleic acid or vector or composition or inhibitory compound that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disorder, or disease to achieve a desired therapeutic result. The effective amount of a protein or antibody or vector or composition or inhibitory compound may vary depending on factors such as the disease type and condition, age, sex, and weight of the individual, and the ability of the protein or nucleic acid or vector or composition or therapeutic agent, e.g., an antibody, to induce a desired response in the individual. An effective amount is also an amount in which any toxic or detrimental effects of a protein or antibody or vector or composition or inhibitory compound of the invention are outweighed by the therapeutically beneficial effects.

[0039] The terms "patient," "subject," and "individual," used interchangeably herein, refer to a human. In certain embodiments, the patient is further characterized as having a disease, disorder, or condition (e.g., cancer). In other embodiments, the patient is further characterized as being at risk for developing a disorder, disease, or condition (e.g., cancer or tumor metastasis, growth, spread) and would benefit from a reduced risk of cancer or tumor metastasis, growth, spread.

[0040] The antibodies of the present invention can be prepared by methods well known in the art and incorporated into pharmaceutical compositions comprising the antibodies of the present invention and one or more pharmaceutically acceptable carriers and / or diluents (e.g., Remington, The Science and Practice of Pharmacy, 22nd Edition, Loyd V., Ed., Pharmaceutical Press, 2012, which provides an overview of formulation techniques generally known to practitioners). Carriers suitable for pharmaceutical compositions include any material that, when combined with the antibodies of the present invention, retains the activity of the molecule and is non-reactive with the patient's immune system. Pharmaceutical compositions comprising the antibodies of the present invention can be administered via parenteral routes (e.g., intravenously, subcutaneously, intraperitoneally, intramuscularly, or transdermally) to patients at risk for or exhibiting the diseases or disorders described herein. [Example]

[0041] Example 1: Evaluation of overall survival in patients with PDGFRβ-negative advanced or metastatic soft tissue sarcoma Study Design: Patients with advanced or metastatic soft tissue sarcoma were randomly assigned to receive olaratumab (loading dose of 20 mg / kg on days 1 and 8 of cycle 1 of a 21-day cycle, followed by 15 mg / kg on days 1 and 8 of subsequent 21-day cycles) and doxorubicin (75 mg / m on day 1). 2 ) (the "active cohort") and placebo (days 1 and 8) plus doxorubicin (75 mg / m on day 1). 2 ) (the "control cohort"). Patients are treated for 8 cycles and continue on olaratumab monotherapy or placebo until progression, signs of unacceptable toxicity, or death. The patient's PDGFRβ tumor expression status is determined substantially as described herein.

[0042] Patients will be assessed for median overall survival (OS).

[0043] Methods for determining PDGFRβ expression: PDGFRβ expression in tumor cells can be assessed by methods including, but not limited to, immunohistochemistry, quantitative, qualitative, or semi-quantitative reverse transcription PCR (RT-PCR), application of automated or semi-automated image analysis of IHC or other quantitative / semi-quantitative / qualitative assessment of protein expression, artificial intelligence analysis of scanned slides or other laboratory-acquired data for protein expression, bright field in situ hybridization (BRISH), fluorescent in situ hybridization (RNA FISH), protein immunofluorescence, quantitative / semi-quantitative / qualitative proteomics methods, and RNA sequencing.

[0044] Immunohistochemical assay to determine PDGFRβ expression: For immunohistochemical analysis, tumor tissue from patients was collected, formalin-fixed in 10% neutral-buffered formalin, and paraffin-embedded (FFPE). PDGFRβ protein expression on tumor cells was assessed immunohistochemically. Briefly, 4-6 micrometer sections were obtained from FFPE tissue blocks containing patient tumor tissue and placed on positively charged glass slides. Anti-PDGFRβ mouse monoclonal antibody 2B3 was used to detect the expression of PDGFRβ (clone 2B3, Cell Signaling Technology® catalog number 3175S) diluted at 0.25 μg / mL in Dako Primary Antibody Diluent with Background Reducing Components (Dako / Agilent catalog number S3022). Immunohistochemistry was performed in a Dako Autostainer Link 48 / PT Link Incubator. Deparaffinization was completed in the Link 48 / PT Link Incubator at 97°C for 20 minutes. Target retrieval is then achieved by immersion of unstained slides in EnVision™ FLEX Target Retrieval Solution High pH (Dako) on a Dako Link48 / PT Link Incubator. After rinsing in RT EnVision™ FLEX Wash Buffer (1x), specific immunohistochemical staining with the 2B3 antibody is achieved by applying FLEX Peroxidase Block for 5 minutes, applying the anti-human PDGFRβ antibody 2B3 at a concentration of 0.25 μg / mL and incubating for 60 minutes, followed by FLEX / HRP application and incubation for 20 minutes, then applying FLEX DAB+Substrate Chromogen for 10 minutes, and finally FLEX Hematoxylin for 5 minutes. A pre-prepared FLEX Mouse Negative Control (Dako / Agilent catalog number IR750) is run in parallel with the PDGFRβ staining and serves as a quality control (negative control) for the assay. Stained slides are then evaluated by trained personnel using brightfield microscopy.PDGFRβ tumor expression status was provided dichotomously as "positive" or "negative," with a "positive" result defined as a sample in which at least 10% (rounded to the nearest decile) of the tumor cells present exhibited at least weak but specific membrane staining (1+ on a 0, 1+, 2+, 3+ scale of staining intensity, with 1+ being the weakest but still specific membrane staining and 3+ being strong and diffuse membrane staining). "Negative" corresponded to staining that did not meet these criteria.

[0045] result: STS patients: As shown in Table 1, STS patients identified as having PDGFRβ-negative tumor status had a significantly improved median OS of 28.32 months in the active cohort compared with 20.57 months for patients in the control cohort (HR = 0.85 [95% CI: 0.54-1.33] p = 0.4861). Furthermore, active cohort patients identified as having both PDGFRβ-negative and PDGFRα-positive tumor status also showed a significantly improved median OS of 28.5 months (N = 66) compared with 20.6 months (N = 75) for patients in the control cohort. However, no significant differences in median OS were observed between the active and control cohorts in patients whose tumor status was identified as PDGFRβ-positive (18.8 vs. 19.9 months for the active and control cohorts, respectively), PDGFRα-positive (17.2 vs. 19.1 months for the active and control cohorts, respectively), and PDGFRα-negative (23.6 vs. 21.9 months for the active and control cohorts, respectively).

[0046] [Table 1] N = patients treated in the active or control cohort, OS = overall survival, HR = hazard ratio, CI = confidence interval, p-value = stratified log-rank p-value.

[0047] LMS patients: As shown in Table 2, LMS patients in the active cohort identified as having PDGFRβ-negative tumor status had a significantly improved median OS of 29.11 months (N = 29) compared with 21.88 months (N = 37) in the control cohort (HR = 0.65 [95% CI: 0.33-1.25, p = 0.1970]). However, median OS in LMS patients identified as having PDGFRβ-positive tumor status did not differ between the active cohort (20.14 months, N = 77) and the control cohort (21.39 months, N = 73) (HR = 1.05 [95% CI: 0.71-1.55, p = 0.7951]).

[0048] Female LMS Patients: Analysis of PDGFRβ status in female LMS patients revealed a significant improvement in OS HR (0.55, N=53, p=0.14) in the subpopulation of female LMS patients identified with PDGFRβ-negative tumor status when compared with the OS HR (1.34, N=115, p=0.20) in female LMS patients identified with PDGFRβ-positive tumor status. Furthermore, after adjusting for ECOG PS, the OS HR for PDGFRβ-positive LMS women was 1.34 (N=115, p=0.20), while the OS HR for PDGFRβ-negative LMS women was 0.55 (N=53, p=0.14). This difference in OS HR between PDGFRβ-positive and -negative women with LMS resulted in a statistically significant "treatment with PDGFRβ" interaction (N=168, p=0.040).

[0049] LMS patients (excluding female LMS patients with PDGFRβ-positive tumor status): As shown in Table 2, female LMS patients identified with PDGFRβ-positive tumor status are excluded from the LMS median OS analysis. In LMS patients, a significant overall survival benefit of 28.5 months (N=58) in the active cohort is observed compared to 20.9 months (N=61) in the control cohort (HR=0.60, N=119, p=0.035). This interaction by PDGFRβ expression status is not observed in men with LMS.

[0050] [Table 2] N = patients treated in the active or control cohort, OS = overall survival, HR = hazard ratio, CI = confidence interval, p-value = stratified log-rank p-value.

[0051] Example 2: Evaluation of overall survival in patients with PDGFRβ-negative unresectable metastatic pancreatic cancer Study Design: Median overall survival in patients with PDGFRβ-negative, unresectable metastatic pancreatic cancer will be assessed using olaratumab on an escalating dose schedule (15 mg / kg, 20 mg / kg, or 25 mg / kg on days 1, 8, and 15 of a 28-day cycle) in combination with nab-paclitaxel and gemcitabine (administered on days 1, 8, and 15 of a 28-day cycle according to the US package insert). Patients with unresectable metastatic pancreatic cancer will be treated with olaratumab on days 1, 8, and 15 of a 28-day cycle, followed by nab-paclitaxel (125 mg / m²) and gemcitabine (1000 mg / m²) on days 1, 8, and 15 of each 28-day cycle. Patients will be evaluated for overall survival.

[0052] Example 3: Evaluation of overall survival in patients with PDGFRβ-negative advanced soft tissue sarcoma Study Design: Median overall survival in patients with PDGFRβ-negative advanced or metastatic soft tissue sarcoma treated with olaratumab in a dose-escalation study of 15 mg / kg olaratumab (administered on days 1 and 8) or 20 mg / kg olaratumab (administered on days 1 and 8) in combination with gemcitabine administered at 900 mg / m2 on days 1 and 8 of a 21-day cycle and docetaxel administered at 75 mg / m2 on day 8. Patients will be evaluated for overall survival.

[0053] array SEQ ID NO: 1 (HC of human PDGFR alpha antibody) MGWSCIILFLVATATGVHSQLQLQESGPGLVKPSETLSL TCTVSGGSINSSSYYWGWLRQSPGKGLEWIGSFFYTGSTY YNPSLRSRLTISVDTSKNQFSLMLSSVTAADTAVYYCARQ STYYYGSGNYYGWFDRWDQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 2 (LC of human PDGFR alpha antibody) MGWSCIILFLVATATGVHSEIVLTQSPATLSLSPGERAT LSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPAFGQ GTKVEIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 3 (VH of human PDGFR alpha antibody) QLQLQESGPGLVKPSETLSLTTCTVSGGSINSSSYYWGWL RQSPGKGLEWIGSFFYTGSTYYNPSLRSRLTISVDTSKNQ FSLMLSSVTAADTAVYYCARQSTYYYGSGNYYGWFDRWDQ GTLVTVSS SEQ ID NO: 4 (VL of human PDGFR alpha antibody) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPAFGQGTKVEIK SEQ ID NO: 5 (HCDR1 of human PDGFR alpha antibody) SSSYY SEQ ID NO: 6 (HCDR2 of human PDGFR alpha antibody) SFFYTGSTYYNPSLRS SEQ ID NO: 7 (HCDR3 of human PDGFR alpha antibody) QSTYYYGSGNYYGWFDR SEQ ID NO: 8 (LCDR1 of human PDGFR alpha antibody) RASQSVSSYLA SEQ ID NO: 9 (LCDR2 of anti-human PDGFR alpha antibody) DASNRAT SEQ ID NO: 10 (LCDR3 of human PDGFR alpha antibody) QQRSNWPPA SEQ ID NO: 11 (human PDGFR alpha) MGTSHPAFLVLGCLLTGLSLILCQLSLPSILPNENEKVV QLNSSFSLRCFGESEVSWQYPMSEEESSDVEIRNEENNSG LFVTVLEVSSASAAHTGLYTCYYNHTQTEENELEGRHIYI YVPDPDVAFVPLGMTDYLVIVEDDDSAIIPCRTTDPETPV TLHNSEGVVPASYDSRQGFNGTFTVGPYICEATVKGKKFQ TIPFNVYALKATSELDLEMEALKTVYKSGETIVTCAVFN NEVVDLQWTYPGEVKGKGITMLEEIKVPSIKLVYTLTVPE ATVKDSGDYECAARQATREVKEMKKVTISVHEKGFIEIKP TFSQLEAVNLHEVKHFVVEVRAYPPPRISWLKNNLTLIEN LTEITTDVEKIQEIRYRSKLKLIRAKEEDSGHYTIVAQNE DAVKSYTFELLTQVPSSILDLVDDHHGSTGGQTVRCTAEG TPLPDIEWMICKDIKKCNNETSWTILANNVSNIITEIHSR DRSTVEGRVTFAKVEETIAVRCLAKNLLGAENRELKLVAP TLRSELTVAAAVLVLLVIVIISLIVLVVIWKQKPRYEIRW RVIESISPDGHEYIYVDPMQLPYDSRWEFPRDGLVLGRVL GSGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQ ALMSELKIMTHLGPHLNIVNLLGACTKSGPIYIITEYCFY GDLVNYLHKNRDSFLSHHPEKPKKELDIFGLNPADESTRS YVILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQR SLYDRPASYKKKSMLDSEVKNLLSDDNSEGLTLLLDLLSFT YQVARGMEFLASKNCVHRDLAARNVLLAQGKIVKICDFGL ARDIMHDSNYVSKGSTFLPVKWMAPESIFDNLYTTLSDVW SYGILLWEIFSLGGTPYPGMMVDSTFYNKIKSGYRMAKPD HATSEVYEIMVKCWNSEPEKRPSFYHLSEIVENLLPGQYK KSYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEEDK LKDWEGGLDEQRLSADSGYIIPLPDIDPVPEEEDLGKRNR HSSQTSEESAIETGSSSSTFIKREDETIEDIDMMDDIGID SSDLVEDSFL SEQ ID NO: 12 (human PDGFR beta) MRLPGAMPALALKGELLLLSLLLLLEPQISQGLVVTPPG PELVLNVSSTFVLTCSGSAPVVWERMSQEPPQEMAKAQDG TFSSVLTLTNLTGLDTGEYFCTHNDSRGLETDERKRLYIF VPDPTVGFLPNDAEELFIFLTEITEITI PCRVTDPQLVVT LHEKKGDVALPVPYDHQRGFSGIFEDRSYICKTTIGDREV DSDAYYVYRLQVSSINVSVNAVQTVVRQGENITLMCIVIG NEVVNFEWTYPRKESGRLVEPVTDFLLDMPYHIRSILHIP SAELEDSGTYTCNVTESVNDHQDEKAINITVVESGYVRLL GEVGTLQFAELHRSRTLQVVFEAYPPPTVLWFKDNRTLGD SSAGEIALSTRNVSETRYVSELTLVRVKVAEAGHYTMRAF HEDAEVQLSFQLQINVPVRVLELSESHPDSGEQTVRCRGR GMPQPNIIWSACRDLKRCPRELPPTLLGNSSEEESQLETN VTYWEEEQEFEVVSTLRLQHVDRPLSVRCTLRNAVGQDTQ EVIVVPHSLPFKVVVISAILALVVLTIISLIILIMLWQKK PRYEIRWKVIESVSSDGHEYIYVDPMQLPYDSTWELPRDQ LVLGRTLGSGAFGQVVEATAHGLSHSQATMKVAVKMLKST ARSSEKQALMSELKIMSHLGPHLNVVNLLGACTKGGPIYI ITEYCRYGDLVDYLHRNKHTFLQHHSDKRRPPSAELYSNA LPVGLPLPSHVSLTGESDGGYMDMSKDESVDYVPMLDMKG DVKYADIESSNYMAPYDNYVPSAPERTCRATLINESPVLS YMDLVGFSYQVANGMEFLASKNCVHRDLAARNVLICEGKL VKICDFGLARDIMRDSNYISKGSTFLPLKWMAPESIFNSL YTTLSDVWSFGILLWEIFTLGGTPYPELPMNEQFYNAIKR GYRMAQPAHASDEIYEIMQKCWEEKFEIRPPFSQLVLLLE RLLGEGYKKKYQQVDEEFLRSDHPAILRSQARLPGFHGLR SPLDTSSVLYTAVQPNEGDNDYIIPLPDPKPEVADEGPLE GSPSLASSTLNEVNTSSTISCDSPLEPQDEPEPEPQLELQ VEPEPELEQLPDSGCPAPRAEAEDSFL The inventions described in the original claims of this application are set forth below. [1] The method in a patient in need of cancer treatment, comprising administering to said patient an effective amount of a PDGFRα inhibitory compound, wherein said patient is identified as having a human PDGFRβ-negative cancer. [2] A method of treating a patient having a human PDGFRβ-negative cancer, comprising administering to the patient an effective amount of a PDGFRα inhibitory compound. [3] 1. A method for treating cancer in a patient in need thereof, comprising: identifying the patient as having a human PDGFRβ-negative cancer; administering to said patient an effective amount of a PDGFRα inhibitory compound. [4] 1. A method for diagnosing a cancer patient as in need of treatment with a PDGFRα inhibitor compound, comprising identifying the patient as having a human PDGFRβ-negative cancer. [5] The method according to [4], wherein if the patient is identified as having a human PDGFRβ-negative cancer, an effective amount of a PDGFRα inhibitor compound is administered to the patient. [6] The method of any one of [1], [3] and [4], wherein identifying the patient as having a human PDGFRβ-negative cancer comprises performing an assay on a biological sample derived from the patient. [7] The method according to [6], wherein the biological sample comprises tissue or body fluid. [8] The method according to [7], wherein the tissue comprises tumor tissue. [9] The method according to [7], wherein the body fluid comprises blood, plasma, or serum.

[10] The assay comprises performing an in vitro assay on the biological sample. The method according to any one of [6] to [9].

[11] The in vitro assay includes a histological assay or a cytological assay. [0] The method described above.

[12] The method according to

[10] , wherein the in vitro assay comprises an immunoassay or a polymerase chain reaction assay.

[13] The method according to any one of [6] to

[11] , wherein the assay comprises contacting the biological sample with an antibody that specifically binds to human PDGFRβ, and detecting binding of the antibody to human PDGFRβ in the biological sample.

[14] The method of

[13] , wherein the assay further comprises quantifying human PDGFRβ in the biological sample and determining whether the biological sample is PDGFRβ negative.

[15] The method according to

[14] , wherein the biological sample is determined to be PDGFRβ negative if PDGFRβ in the biological sample is determined to be present in less than approximately 10% of tumor cells in the biological sample.

[16] The method according to any one of [1] to

[15] , wherein the PDGFRα inhibitory compound is an antibody, an antigen-binding fragment thereof, or a small molecule inhibitor.

[17] The method according to

[16] , wherein the PDGFRα inhibitor compound is an antibody, and the antibody specifically binds to PDGFRα.

[18] the antibody that specifically binds to PDGFRα comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3; said HCDR1 comprising SEQ ID NO: 5; said HCDR2 comprising SEQ ID NO: 6; said HCDR3 comprises SEQ ID NO: 7; said LCDR1 comprising SEQ ID NO: 8; said LCDR2 comprising SEQ ID NO: 9; The method according to

[17] , wherein the LCDR3 comprises SEQ ID NO: 10.

[19] The method according to

[18] , wherein the VH comprises SEQ ID NO: 3 and the VL comprises SEQ ID NO: 4.

[20] The method according to

[17] , wherein the antibody that specifically binds to PDGFRα comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 1 and the LC comprises SEQ ID NO: 2. The method according to any one of

[17] to

[20] , wherein the antibody that specifically binds to PDGFRα is olaratumab.

[22]

[21] The method of claim 21, wherein an effective amount of olaratumab is administered to the patient at a loading dose of about 15 mg / kg, or about 20 mg / kg, or about 25 mg / kg on days 1 and 8 of an initial 21-day cycle, or on days 1 and 8 of an initial 28-day cycle, followed by a standard dose of olaratumab at about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on days 1 and 8 of a subsequent 21-day cycle, or on days 1 and 8 of a subsequent 28-day cycle.

[23]

[22] The method according to

[22] , wherein olaratumab is administered in simultaneous, separate or sequential combination with one or more chemotherapeutic agents.

[24]

[23] The method according to

[23] , wherein the chemotherapeutic agent comprises at least one of nab-paclitaxel, doxorubicin, gemcitabine, or docetaxel.

[25] The method according to any one of [1] to

[24] , wherein the cancer is soft tissue sarcoma, pancreatic cancer, endometrial cancer, ovarian cancer, bone cancer, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, or prostate cancer.

[26] The method according to

[25] , wherein the soft tissue sarcoma is leiomyosarcoma.

[27] The method according to

[25] , wherein the soft tissue sarcoma is liposarcoma.

[28] The method according to any one of [1] to

[27] , wherein the cancer is metastatic cancer.

[29] The method according to any one of [1] to

[28] , wherein the patient is a female and the female is determined to have PDGFRβ-negative cancer.

[30] 1. A method for identifying a cancer patient having PDGFRβ in a biological sample derived from the cancer patient, comprising: contacting the sample with an antibody that specifically binds human PDGFRβ; detecting binding of said antibody to said human PDGFRβ in said sample.

[31] 1. A method for diagnosing a cancer patient as in need of treatment with a PDGFRα inhibitor compound, comprising: obtaining a biological sample from the patient; contacting the biological sample with a first antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, thereby forming a complex between the first antibody or antigen-binding fragment thereof and human PDGFRβ; contacting the complex of the human PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ with a second antibody or antigen-binding fragment thereof, wherein the second antibody comprises a detectable label; detecting the signal provided by the detectable label; wherein when the biological sample from the cancer patient is determined to be PDGFRβ negative, the cancer patient is diagnosed as needing treatment with a PDGFRα inhibitory compound.

[32] 1. An in vitro method for diagnosing a cancer patient as in need of treatment with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα, comprising: a. obtaining a biological sample from said patient; b. contacting the biological sample with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, thereby forming a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ; c. removing any non-specifically bound first antibody or antigen-binding fragment thereof; d. detecting and quantifying the human PDGFRβ in the biological sample; When the biological sample from the cancer patient is determined to be PDGFRβ negative, the cancer patient is diagnosed as needing treatment with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα.

[33] The method according to

[32] , wherein the detecting step comprises detecting a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ in the biological sample with a second antibody.

[34] The method of any one of

[32] or

[33] , wherein at least one of the antibody or the second antibody comprises a detectable label, and the detecting step comprises detecting a signal provided by the detectable label upon formation of the complex comprising the antibody and human PDGFRβ or the second antibody and human PDGFRβ.

[35] The method of any one of

[32] or

[33] , wherein the second antibody comprises a detectable label, and the detecting step comprises detecting a signal provided by the detectable label upon formation of the complex comprising the antibody, human PDGFRβ, and the second antibody.

[36] The method according to any one of

[30] to

[35] , further comprising the step of administering to the cancer patient an effective amount of an antibody that specifically binds to PDGFRα if the biological sample is determined to be PDGFRβ-negative.

[37] The method according to

[36] , wherein the antibody is olaratumab.

[38]

[37] The method of claim 37, wherein an effective amount of olaratumab is administered to a patient in need thereof at a loading dose of about 15 mg / kg, or about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of an initial 21-day cycle, or on each of days 1 and 8 of an initial 28-day cycle, followed by a standard dose of olaratumab at about 15 mg / kg, or about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of a subsequent 21-day cycle, or on each of days 1 and 8 of a subsequent 28-day cycle.

[39] The method according to

[38] , wherein olaratumab is administered in simultaneous, separate or sequential combination with one or more chemotherapeutic agents.

[40]

[39] The method according to

[39] , wherein the chemotherapeutic agent comprises at least one of nab-paclitaxel, doxorubicin, gemcitabine, or docetaxel.

Claims

1. 1. A pharmaceutical composition for treating a human PDGFRβ-negative cancer in a patient, comprising an effective amount of a PDGFRα inhibitory compound, the PDGFRα inhibitor compound is an antibody, and the antibody specifically binds to PDGFRα; the antibody that specifically binds to PDGFRα comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 1 and the LC comprises SEQ ID NO: 2; the antibody that specifically binds to PDGFRα is administered in simultaneous, separate, or sequential combination with doxorubicin; the cancer is a soft tissue sarcoma; the soft tissue sarcoma is a leiomyosarcoma, and The pharmaceutical composition, wherein the patient is a female and the female is determined to have a PDGFRβ-negative cancer.

2. 2. The pharmaceutical composition of claim 1, wherein an effective amount of olaratumab is administered to the patient at a loading dose of about 15 mg / kg, or about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of an initial 21-day cycle, or on each of days 1 and 8 of an initial 28-day cycle, followed by a standard dose of olaratumab at about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg on each of days 1 and 8 of a subsequent 21-day cycle, or on each of days 1 and 8 of a subsequent 28-day cycle.

3. A method for determining whether a cancer is effectively treated with a PDGFRα inhibitory compound, comprising: contacting a biological sample obtained from a cancer patient with a first antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, thereby forming a complex between the first antibody or antigen-binding fragment thereof and human PDGFRβ; contacting the complex of the human PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ with a second antibody or antigen-binding fragment thereof, wherein the second antibody comprises a detectable label; detecting the signal provided by the detectable label; and when the biological sample derived from the cancer patient is determined to be PDGFRβ negative, the cancer patient is determined to be in need of treatment with a PDGFRα inhibitory compound, the PDGFRα inhibitor compound is an antibody, and the antibody specifically binds to PDGFRα; the antibody that specifically binds to PDGFRα comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 1 and the LC comprises SEQ ID NO: 2; the antibody that specifically binds to PDGFRα is administered in simultaneous, separate, or sequential combination with doxorubicin; the cancer is a soft tissue sarcoma; the soft tissue sarcoma is a leiomyosarcoma, and The method, wherein the patient is female and the female is determined to have a PDGFRβ-negative cancer if PDGFRβ in the biological sample is determined to be present in less than about 10% of tumor cells in the biological sample by immunohistochemistry (IHC).

4. An in vitro method for determining which cancer will be effectively treated with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα, comprising: a. contacting a biological sample obtained from a cancer patient with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRβ, wherein a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ is formed; b. removing any non-specifically bound first antibody or antigen-binding fragment thereof; c. detecting and quantifying the human PDGFRβ in the biological sample; a method for determining that PDGFRβ is present in less than about 10% of tumor cells in a biological sample collected from a cancer patient by immunohistochemistry (IHC), the biological sample is determined to be PDGFRβ-negative; and a method for determining that the cancer patient is in need of treatment with an antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα, the method comprising: the antibody or antigen-binding fragment thereof that specifically binds to human PDGFRα comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises SEQ ID NO: 1 and the LC comprises SEQ ID NO: 2; the cancer is soft tissue sarcoma; the soft tissue sarcoma is a leiomyosarcoma, and The method, wherein the patient is female and the female is determined to have a PDGFRβ-negative cancer.

5. The method of claim 4 , wherein the detecting step comprises detecting a complex between the PDGFRβ antibody or antigen-binding fragment thereof and human PDGFRβ in the biological sample with a second antibody.

6. 6. The method of claim 4 or 5, wherein at least one of the antibody or the second antibody comprises a detectable label, and the detecting step comprises detecting a signal provided by the detectable label upon formation of the complex comprising the antibody and human PDGFRβ or the second antibody and human PDGFRβ.

7. 6. The method of claim 4 or 5, wherein the second antibody comprises a detectable label, and the detecting step comprises detecting a signal provided by the detectable label upon formation of the complex comprising the antibody, human PDGFRβ, and the second antibody.

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