WO2017176565A1 - Combinations of an anti-b7-h1 antibody and a cxcr4 peptide antagonist for treating a solid tumor - Google Patents

Abstract

Provided herein are methods of treating solid tumors comprising administering to a patient an effective amount of MEDI4736 or an antigen-binding fragment thereof and an effective amount of LY2510924.

Description

COMBINATIONS OF AN ANTI-B7-H1 ANTIBODY AND A CXCR4 PEPTIDE ANTAGONIST FOR TREATING A SOLID TUMOR

The present invention relates to combinations of an anti-B7-Hl antibody, preferably, MEDI4736, with a CXCR4 peptide antagonist, preferably, LY2510924, and to methods of using the combinations to treat solid tumors, such as pancreatic cancer or ovarian cancer.

The present invention is in the field of treatment of cancer. Unfortunately, cancer continues to be a major global health burden. Despite progress in the treatment of cancer, there continues to be an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancers that are resistant and/or refractory to existing therapeutics.

The role of the immune system, in particular T cell-mediated cytotoxicity, in tumor control is well recognized. There is mounting evidence mat T cells control tumor growth and survival in cancer patients, both in early and late stages of the disease.

However, tumor-specific T-cell responses are difficult to achieve and sustain in cancer patients.

One T cell pathway receiving significant attention to date signals through programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274).

PD-L1 is also part of a complex system of receptors and ligands that are involved in controlling T-cell activation. In normal tissue, PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, as well as various nonhematopoietic cells. Its normal function is to regulate the balance between T-cell activation and tolerance through interaction with its two receptors:

programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1 or B7.1). PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. PD-L1 is expressed in a broad range of cancers with a high frequency. In some cancers, expression of PD-L1 has been associated with reduced survival and unfavorable prognosis. Antibodies mat block the interaction between B7-H1 and its receptors are able to relieve PD-L1 -dependent immunosuppressive effects and enhance the cytotoxic activity of antitumor T cells in vitro. MEDI4736 (also known as Durvalumab) is a human monoclonal antibody directed against human PD-L1 mat is capable of blocking the binding of PD-L1 to both the PD-1 and CD80 receptors.

The chemokine (CXC motif) receptor 4 (CXCR4) and its only known ligand, a- chemokine stromal-cell-derived factor 1 (SDF-1, also known as CXCL12), are believed to play important roles in the regulation of organ-specific metastasis as well as in tumor growth, invasion, survival, and angiogenesis (Furusato B, Mohamed A, Uhlen M, et al: CXCR4 and Cancer, Pathology International, Blackwell Publishing Asia, 2010, pp 497- 505). CXCR4 is overexpressed in a variety of human cancers, and this overexpression is correlated with increased risk for recurrence and poor overall survival in multiple cancer patients including breast, lung, kidney, colon, ovarian, and brain cancers, as well as lymphoma and hematological malignancies such as leukemia (Peng, S. B., et al.

Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. Mol Cancer Ther. 14, 480-490 (2015)). Recently, CXCR4 inhibition has been reported to enhance the anti- tumor effect of immune checkpoint inhibitors such as PD-1 and PD-Ll antibodies (see, for example, Scala, Stefania. Molecular Pathways: Targeting the CXCR4-CXCL12 Axis— Untapped Potential in the Tumor Microenvironment. Clin Cancer Res. October 1, 2015; Feig, C, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-Ll immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 20212-20217 (2013); Chen Y, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-PD-1 immunotherapy in sorafenib-treated HCC in mice. Hepatology. 61:1591-602 (2015)).

The peptide LY2510924 is a potent and selective antagonist of CXCR4 in vitro and in vivo and inhibits SDF-1 binding to CXCR4 in human, monkey, mouse, and rat cells in a dose-dependent manner (Peng, S. B., et al. (2015)). However, in two Phase II studies the addition of LY2510924 to a standard of care (SOC) therapy did not improve outcomes for cancer patients. More specifically, in a Phase II study of

carboplatin/etoposide plus LY2510924 (20 mg daily), versus carboplatin/etoposide in patients with extensive-stage small cell lung cancer (SCLC), no improvements were observed when LY2510924 was added to the SOC (Spigel D.R, et al., Phase II study of carboplatin/etoposide plus LY2510924, a CXCR4 peptide antagonist, versus carboplatin/etoposide in patients with extensive-stage small cell lung cancer. Ann Oncol 25:iv511-6 (2014)). Furthermore, in a Phase II study of first-line treatment of metastatic renal cell carcinoma (RCC) with LY2510924 + sunitinib compared with sunitinib alone, addition of LY2510924 (20 mg daily) did not improve efficacy (Hainsworth, J.D., et al., J Clin Oncol 33, 2015 (suppl; abstr 4547); 2015 ASCO Annual Meeting, Chicago, IL, May 29-June 2 (poster board #220)).

Despite the significant progress made over the past decade in developing strategies for combatting cancer and other diseases, many patients with advanced, refractory and metastatic disease have limited clinical options. There remains a substantial unmet need for new less-toxic methods and therapeutics that have better therapeutic efficacy, longer clinical benefit, and improved safety profiles, particularly for those patients with advanced disease or cancers that are resistant to existing therapeutics.

Although the combination of an anti-PD-Ll antibody and LY2510924 to treat various solid tumors including ovarian and pancreatic cancer has been contemplated in the art (see, for example, WO 2015/019284), the present invention provides novel methods of treating patients having solid tumors by administering a combination of MEDI4736 and LY2510924 at a specific dose and frequency that provides enhanced and/or unexpected beneficial therapeutic effects from the combined activity of these therapeutic agents as compared to the therapeutic effects provided by either MEDI4736 or LY2510924 alone.

Accordingly, the present invention provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

The invention further provides a combination comprising about 1000 mg to about

2000 mg of MEDI4736 or an antigen-binding fragment thereof and a dose of about 20 mg to about 40 mg of LY2510924, for simultaneous, separate or sequential use in the treatment of solid tumors in a patient. Preferably, the solid tumor is pancreatic cancer or ovarian cancer. The invention further provides a combination comprising 1000 mg to 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a dose of about 20 mg to about 40 mg of LY2510924, for simultaneous, separate or sequential use in the treatment of ovarian cancer. Optionally, the combinations further comprise paclitaxel, docetaxel, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin.

The invention further provides the use of a combination of MEDI4736 or an antigen-binding fragment thereof at a dose of about 1000 mg to about 1500 mg for administration intravenously once every 28-day cycle and a daily dose of 20 mg to 40 mg of LY2510924 for subcutaneous administration for the manufacture of a medicament for the treatment of solid tumors in a patient. Preferably, the solid tumor is pancreatic cancer or ovarian cancer and these combinations further comprise use of paclitaxel, docetaxel, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient.

The invention provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 25 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 25 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 25 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 25 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 30 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 30 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 30 mg to about 40 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 35 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 35 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 35 mg to about 40 mg of LY2510924 to the patient The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 35 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MED14736 or an antigen- binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of 40 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of 30 mg of LY2510924 to the patient.

The invention provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 25 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 or an antigen- binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient. The invention also provides a method of treating a solid tumor in a patient, comprising administering 1500 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 20 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 30 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 1000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 30 mg to about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 2000 mg of MED 14736 or an antigen-binding fragment thereof and a daily dose of about 40 mg of LY2510924 to the patient.

The invention also provides a method of treating a solid tumor in a patient, comprising administering 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of 40 mg of LY2510924 to the patient.

The invention also provides a method of treatment comprising administering MEDI4736 or an antigen-binding fragment thereof (e.g., at or about 1000 mg, at or about 1500 mg, or at or about 2000 mg), and LY2510924 (e.g., at or about 10 mg, at or about 20 mg, at or about 30 mg, or at or about 40 mg) to a patient identified as having a PD-L1^" or PD-L1⁴ solid tumor.

A further aspect of the present invention provides for the use of MED14736 or an antigen-binding fragment thereof and LY2510924 for the manufacture of a medicament for the treatment of solid tumors, wherein MEDI4736 or an antigen-binding fragment thereof is administered at about 1000 mg, at or about 1500 mg, or at or about 2000 mg intravenously on Day 1 of a 28-day cycle and LY2510924 is administered subcutaneously daily at or about 10 mg, at or about 20 mg, at or about 30 mg, or at or about 40 mg.

The invention also provides a method of treatment comprising administering MEDI4736 or an antigen-binding fragment thereof (e.g., at 1000 mg, at 1500 mg, or at 2000 mg), and LY2510924 (e.g., at 10 mg, at 20 mg, at 30 mg, or at 40 mg) to a patient identified as having a PD-L1^" or PD-L1⁺ solid tumor.

In particular embodiments of any of the previous methods, the MEDI4736 is administered intravenously once every 28 days. In particular embodiments of any of the previous methods, the MEDI4736 is administered intravenously once every 14 days.

In particular embodiments of any of the previous methods, the LY2510924 is administered subcutaneously daily. In particular embodiments of any of the previous methods, the LY2510924 is administered subcutaneously daily for a 28 day cycle.

The invention also provides a method of treating a solid tumor in a patient, comprising administering to the patient about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof intravenously once every 28 days and about 20 mg, about 30 mg, or about 40 mg of LY2510924 subcutaneously daily for 28 days. In particular embodiments of any of the previous methods of treating a solid tumor in a patient, the solid tumor is selected from prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer. In particular embodiments of any of the previous methods of treating a solid tumor in a patient, the solid tumor is pancreatic cancer or ovarian cancer.

The invention also provides a method of treating a solid tumor in a patient comprising administering MEDI4736 or an antigen-binding fragment thereof and LY2510924 to the patient, wherein the administrations result in an increased tumor response as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

In some embodiments, the tumor response can be detected by week 6, 8, or 10. In other embodiments, the tumor response can be detected by week 33. In other

embodiments, the tumor response can be detected by week 50. The invention also provides a method of treating a solid tumor in a patient comprising administering MEDI4736 or an antigen-binding fragment thereof and LY2510924 to the patient, wherein the administrations increase progression-free survival. In some embodiments, the administrations result in an increase in progression-free survival as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

The invention also provides a method of treating a solid tumor in a patient comprising administering MEDI4736 or an antigen-binding fragment thereof and LY2510924 to the patient, wherein the administrations increase overall survival. In some embodiments, the administrations result in an increase in overall survival as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

In some embodiments of the method of the invention, the administration reduces soluble PD-L1. In some embodiments, soluble PD-L1 is reduced by at least about 65%, 80%, 90%, 95% or 99%.

In some embodiments of the methods of the invention, the tumor is refractory to at least one chemotherapeutic agent. Such chemotherapeutic agents may include, but are not limited to paclitaxel, docetaxel, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefrtinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin.

In some embodiments, the patient has previously received treatment with at least one chemotherapeutic agent. In some embodiments, the patient has previously received treatment with at least two chemotherapeutic agents. The chemotherapeutic agent can be, for example, and without limitation, paclitaxel, docetaxel, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, cisplatin, bevacizumab, erlotinib, gefrtinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin. In some embodiments, the solid tumor is refractory or resistant to at least one chemotherapeutic agent. In some embodiments, the tumor is refractory or resistant to at least two chemotherapeutic agents. The tumor can be refractor}' or resistant to one or more of, for example, and without limitation, paclitaxel, docetaxel, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of S-fluorouracil, leucovorin, folinic acid and/or oxaliplatin. In some embodiments, the solid tumor is negative for PD-L1. In some embodiments, the solid tumor is positive for PD-L1.

In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) (Oken MM, et al. Am. J. Clin. Oncol. 5: 649-55 (1982)) performance status of 0 or 1 prior to the administration of MEDI4736 or an antigen-binding fragment thereof and LY2510924.

In some embodiments of the methods of the invention, the patient is

immunotherapy-nalve prior to the administration of MEDI4736 or antigen-binding fragment thereof and LY2510924.

In some embodiments of the methods of the invention, the patient has received immunotherapy prior to the administration of MEDI4736 or antigen-binding fragment thereof and LY2510924.

In particular embodiments of the methods of the invention, the administrations reduce tumor size by at least about 10%, 25%, 50%, 75% or 100% relative to baseline.

In another aspect the invention provides for a method of treating a solid tumor with MEDI4736 or an antigen-binding fragment of MEDI4736 in combination with LY2510924 wherein the patient has a locally advanced unresectable or metastatic solid tumor selected from prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer. In particular embodiments of the methods of the invention the solid tumor is pancreatic cancer or ovarian cancer. In other embodiments of the methods of the invention, the solid tumor comprises a KRAS -mutation or an EGFR-mutation. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the treatment schema. Abbreviations: approx. = approximately; I/E = inclusion/exclusion criteria; IV = intravenous; LY = LY2510924; Phla=Phase la; PK/PD = pharmacokinetic/pharmacodynamics; pts = patients; MTD = maximum- tolerated dose; SQ = subcutaneous.

DETAILED DESCRIPTION

It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "an antibody" is understood to represent one or more antibodies. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

The phrase "solid tumor" refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. A tumor that is not cancerous is described as "benign" while a cancerous tumor is termed "malignant." Different types of solid tumors are named for the particular cells that form them, for example, sarcomas formed from connective tissue cells (bone cartilage, fat, etc.), carcinomas formed from epithelial tissue cells (breast, colon, pancreas, etc.) and lymphomas formed from lymphatic tissue cells (lymph nodes, spleen, thymus, etc.). There are three main subtypes of a solid tumor: squamous cell carcinoma, adenocarcinoma, and large cell (undifferentiated) carcinoma. Other subtypes include adenosquamous carcinoma and sarcomatoid carcinoma.

A "refractory" solid tumor cancer, also referred to a "resistant cancer" is one that does not respond to treatment. The cancer may be resistant at the outset of treatment or it may develop resistance during treatment. While those tumors that are susceptible to treatment are of course within the scope of this invention, it is anticipated that the methods of treatment provided herein will be particularly useful in the treatment of refractory tumors.

As used herein the terms "cancer" and "cancerous" refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers. By "early stage cancer" or "early stage tumor" is meant a cancer that is not advanced or metastatic or is classified as a Stage 0, L or Π cancer. Examples of cancer include prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer.

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 sy mptom, disorder, condition, or disease.

As used herein, the term "AZD9291" refers to an orally available, irreversible EGFR inhibitor (see, for example, CAS registry numbers 1421373-65-0, 1421373-66-1 (mesylate salt)), that is under development for the treatment of patients with metastatic EGFR mutation-positive (such as L858R, exon 19 deletion and T790M) NSCLC.

As used herein, the term "ASP8273" refers to an orally available, irreversible, mutant-selective, EGFR inhibitor, with potential antineoplastic activity, that is under development for the treatment of patients with NSCLC with EGFR mutations. Upon oral administration, ASP8273 covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant (see, for example, Sakagami et al., AACR Annual Meeting April 2014, abstract 1728, or PCT Application Publication No. WO 2013108754).

As used herein, the term "HM61713" refers to an orally active, EGFR mutant selective inhibitor with anti-cancer activity in several EGFR mutant lung cancer cell lines including T790M mutation harboring cell lines and under development for the treatment of patients with NSCLC with EGFR mutations who failed prior EGFR tyrosine kinase inhibitor therapy (see, for example, Kim D et al., J Clin Oncol 2014; 32(Suppl):abstract 8011; or PCT Application Publication No. WO 2014140989).

As used herein, the term "rocelitinib" refers to an orally available, irreversible EGFR inhibitor (see, for example, CAS registry numbers 1374640-70-6 (free base), 1446700-26-0 (hydrobromide salt)), mat is under development for the treatment of patients with metastatic EGFR mutation-positive (such as T790M mutation) NSCLC (see, for example, Sequist, et al., 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 2014, Abstract #8010). Rociletinib, is also known in the art as AVL-301 and CO-1686.

As used herein, the term, "paclitaxel" refers to a natural product well-known in the art which may generally effective over a wide dosage range in the combination of the present invention. For example, dosages per week are normally in two doses of 90 mg/m² on the same day.

The combination of 5-fluorouracil, folinic acid and oxaliplatin, is known as FOLFOX and may be dosed according to any of the FOLFOX protocols as known by those skilled in the art.

As used herein, the term, "temsirolimus" refers to an inhibitor of mammalian target of rapamycin which is well-known in the art.

As used herein, the term, "everolimus" refers to an inhibitor of mammalian target of rapamycin which is well-known in the art.

For everolimus and temsirolimus, an oral 10-mg starting dose is recommended for every patient regardless of age, gender, body weight, or renal function. No premedication is required. Once-daily dose is taken at the same time every day and the drug should be taken consistently with or consistently without food. Tablets should be swallowed whole with a glass of water.

Docetaxel is generally effective over a wide dosage range in the combination of the present invention. For example, dosages per week are normally in two doses of 90 mg/m² on the same day.

As used herein, "sequential" administration means the administration of a PD-L1 antibody, preferably MEDI4736, or an antigen-binding fragment thereof, and a CXCR4 peptide antagonist, preferably LY2510924, to the patient is a separate action, but the two actions are linked. For example, administering a first aqueous solution comprising a CXCR4 peptide antagonist, preferably LY2510924, by subcutaneous injection and administering a second aqueous solution comprising MEDI4736, or an antigen-binding fragment thereof, by IV infusion is considered to be sequential administration, even if the two solutions are infused into the patient at the same time or if one of the aqueous solutions is infused into the patient immediately or shortly after the infusion of the other aqueous solution. Preferably, sequential administration is the administration of a PD-L1 antibody, preferably MEDI4736, or an antigen-binding fragment thereof, and a CXCR4 peptide antagonist, preferably LY2510924, within one, two, three, four, five, six, or seven days of each other. More preferably, sequential administration is the administration of a PD-L1 antibody, preferably MEDI4736, or an antigen-binding fragment thereof, and a CXCR4 peptide antagonist, preferably LY2510924, within one, two, three, four, five, six, seven, eight, nine, ten, twelve, fourteen, sixteen, eighteen, twenty-one, or twenty-four hours of each other.

As used herein, the phrase "in combination with" also refers to the administration of a CXCR4 peptide antagonist, preferably, LY2510924, with MEDI4736, or an antigen- binding fragment thereof, sequentially in any order. Optionally, paclitaxel, everolimus, temsirolimus, docetaxel, pemetrexed, gemcitabine, erlotinib, gefitinib, afatinib, rociletinib, AZD9291, ASP8273, HM61713, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin is also administered sequentially in any order. As used herein, the phrase "in combination with" also refers to the administration of a CXCR4 peptide antagonist, preferably, LY2510924, with MEDI4736, or an antigen-binding fragment thereof in any combination thereof. Optionally, paclitaxel, everolimus, temsirolimus, docetaxel, pemetrexed, gemcitabine or one or more EGFR inhibitors such as erlotinib, gefitinib, afatinib, rociletinib, AZD9291 , ASP8273, HM61713, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin is also administered in any combination thereof.

As used herein, the term "patient" refers to a mammal, preferably a human. The terms "patient" and "subject" are used interchangeably herein.

Each of the embodiments described herein envisions within its scope

pharmaceutically acceptable salts of the compounds referenced or described herein. Accordingly, the phrase "or a pharmaceutically acceptable salt thereof is implicit in the references to or descriptions of all compounds herein.

The term "KD", as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen or antibody fragment-antigen interaction.

The phrase "specifically binds" as used herein in reference to the affinity of an antibody, or antigen-binding fragment thereof, for PD-L1 is intended to mean, unless indicated otherwise, a KD of less than about 1 x 10^"8 M, preferably, less than about 1 x 10^"9 M as determined by common methods known in the art, including by use of a surface plasmon resonance (SPR) biosensor at 25 °C or 37 °C. In some embodiments of the present invention, the cancer patients are selected for treatment with a combination therapy disclosed herein on the basis of having a tumor in which 1) polynucleotides (e.g., mRNA or DNA) encoding PD-L1 polypeptides or fragments thereof and/or 2) PD-L1 polypeptides are expressed or overexpressed.

Preferably, the PD-L1 expression status of a cancer patient's solid tumor is determined by using an immunohistochemistry (IHC) assay, PCR assay, gene sequencing assay and/or fluorescence in-situ hybridization (FISH) assay suitable for the detection of PD-L1 encoding polynucleotides or PD-L1 polypeptides. More preferably, an IHC method for determining whether a cancer patient's tumor expresses or overexpresses PD-L1 polypeptides is performed essentially as described in PCT International Publication WO2013/173223, WO2015/036499 (see, for example, Example 4) and/or WO

2015/176033 using an anti-PD-Ll antibody, or an antigen-binding fragment thereof, disclosed therein or otherwise known in the art (see, for example, Sholl, L.M., et al., Archives of Pathology & Laboratory Medicine (2016) 140:4, pp. 341-344; and Keith M. Kerr and Fred R. Hirsch (2016) Programmed Death Ligand-1 Immunohistochemistry: Friend or Foe?. Archives of Pathology & Laboratory Medicine: April (2016), Vol. 140, No. 4, pp. 326-331) that specifically binds to PD-L1. In certain embodiments, the anti- PD-LI antibody, or antigen binding fragment thereof, used in the IHC assay is the rabbit anti-human PD-L1 mAb, 28-8, 28-8, 28-1 , 28-12, 29-8, 20-12 (or an antigen-binding fragment thereof) described in WO2013/173223. In other embodiments the anti-PD-LI antibody, or antigen-binding fragment thereof, used in the IHC assay is Dako clone 22C3, Spring Biosciences clone SP142 (MPDL3280), or Spring Biosciences clone SP262, or or an antigen-binding fragment thereof. In other preferred embodiments, the diagnostic kit comprises the murine anti-human PD-L1 mAb, 5H1 (Dong et al., 2002). Subjects having a solid tumor (e.g., ovarian cancer or pancreatic cancer) may be tested for PD-L1 polynucleotide or polypeptide expression in the course of selecting a treatment method. Patients identified as having tumors that are positive for PD-L1 or by having increased levels of PD-L1 relative to a reference level (e.g., as defined by Ct or IHC-M score) are identified as preferred patients for treatment with a combination of MEDI4736 and LY2510924. A solid tumor may also comprise a mutation in KRAS or in the Epidermal Growth Factor receptor. Such mutations are known in the art (see, for example, Riely et al., Proc Am Thorac Soc. 2009 Apr 15;6(2):201-5).

As used herein, the term "MED14736" refers to an antibody that comprises two light chains and two heavy chains, and each of the light chains comprise the amino acid sequence of SEQ ID NO: 10 and each of the heavy chains comprise the amino acid sequence of SEQ ID NO: 9. Preferably, MEDI4736 selectively binds PD-L1 polypeptide. As used herein, unless indicated otherwise (for example, by reference to an "antigen- binding fragment thereof), the term "MEDI4736" includes, but is not limited to, the antibody known in the art as "durvalumab" (see, for example, World Health Organization (2014). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 112" WHO Drug Information 28 (4), pages 496-497).

Unless indicated otherwise, the term "antibody" refers to an immunoglobulin molecule comprising two heavy chains and two light chains interconnected by disulfide bonds. The amino terminal portion of each chain includes a variable region of about 100 to about 110 amino acids primarily responsible for antigen recognition via the

complementarity determining regions (CDRs) contained therein. The carboxy-terrninal portion of each chain defines a constant region primarily responsible for effector function.

As used herein, the terms "complementarity determining region" and "CDR", refer to the non-contiguous antigen combining sites found within the variable region of LC and HC polypeptides of an antibody or an antigen-binding fragment thereof. These particular regions have been described by others including Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, et al.. Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991); Chothia, et al., J. Mol. Biol. 196:901-917 (1987); MacCallum, et al., J. Mol. Biol., 262:732-745 (1996); and North, et al., J. Mol. Biol., 406, 228-256 (2011), where the definitions include overlapping or subsets of amino acid residues when compared against each other.

The CDRs are interspersed with regions that are more conserved, termed framework regions ("FR"). Each LCVR and HCVR is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3" and the three CDRs of the HC are referred to as "HCDRl, HCDR2, and HCDR3." The CDRs contain most of the residues which form specific interactions with the antigen. The numbering and positioning of CDR amino acid residues within the LCVR and HCVR regions is in accordance with known conventions (e.g., Kabat (1991), Chothia (1987), and/or North (2011)). In different embodiments of the invention, the FRs of the antibody may be identical to the human germline sequences, or may be naturally or artificially modified.

Information regarding MEDI4736 (or antigen-binding fragments thereof) for use in the methods provided herein can be found in US Patent No. 8,779,108. The fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant domain of the IgGl heavy chain that reduces binding to the complement component Clq and the Fey receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC). MEDI4736 is selective for PD-L1 and blocks the binding of PD- Ll to the PD-1 and CD80 receptors. MEDI4736 can relieve PD-L1 -mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism.

As used herein, the term "antigen-binding fragment" refers to a portion of an intact antibody and/or refers to the antigenic determining variable regions of an intact antibody which is selective for PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors. It is known that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments. An antigen-binding fragment of an antibody will typically comprise at least one variable region. Preferably, an antigen-binding fragment comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR). In a specific aspect, "an antigen-binding fragment thereof for use in the methods provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in US Patent No. 8,779,108. Antigen-binding fragments of MEDI4736 for use in the methods provided herein comprise a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In a specific aspect, an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region and alight chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8. Those of ordinary skill in the art would easily be able to identify Chothia-defined, Abm-defined or other CDR definitions known to those of ordinary skill in the art. In a specific aspect, an antigen-binding fragment thereof for use in the methods provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2.

By "LY2510924" is meant a lactam-cyclized peptide of Formula I or II which selectively binds CXCR4.

Formula I: cyclo[Phe - Tyr - Lys(iPr) - D-Arg - 2Nal - Gly - D-Glu] - Lys(iPr) - NH₂ (SEQ ID NO: 11), wherein said lactam is formed by an amide bond between the a-amino group of Phe and the side chain carboxyl group of D-Glu, or a pharmaceutically acceptable salt thereof, including, but not limited to, an acetic acid salt.

Formula Π:

The chemical structure of LY2510924 is known in the art (e.g., see, Peng, et al., Mol. Cancer Ther. 14:480 (2015)). Additional information regarding LY2510924 and pharmaceutically acceptable salts thereof, can be found, for example, in US RE 42274 (see, for example, Example #57 and #57(a), respectively).

In certain aspects, a patient presenting with a solid tumor is administered

MEDI4736 or an antigen-binding fragment thereof and LY2510924. MEDI4736 or an antigen-binding fragment thereof and LY2510924 can be administered only once or infrequently while still providing benefit to the patient. In further aspects the patient is administered additional follow-on doses and/or additional doses. Follow-on and/or additional doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and/or other factors, including the judgment of the attending physician. Preferably, follow-on and/or additional doses are administered in a cyclic fashion (such as, but not limited to, once every four weeks). The intervals between doses of MEDI4736 or an antigen-binding fragment thereof can be every four weeks. The intervals between doses of LY2510924 can be every four weeks.

In some embodiments, MEDI4736 or an antigen-binding fragment thereof is administered once over a four-week treatment period, twice over an eight-week treatment period, four times over a sixteen-week treatment period, five times over a twenty-week treatment period, six times over a twenty-four-week treatment period, or twelve times over a one-year or more treatment period. In some embodiments, LY2510924 is administered daily over a four-week treatment period, daily over an eight-week treatment period, daily over a twelve-week treatment period, daily over a sixteen-week treatment period, daily over a twenty-week treatment period, daily over a twenty-four-week treatment period, daily over a thirty-six-week treatment period, daily over a forty-eight- week treatment period, or daily over a one-year or more treatment period.

In some embodiments, MEDI4736 or an antigen-binding fragment thereof and LY2510924 are administered on the same day. In some embodiments, MEDI4736 or an antigen-binding fragment thereof is administered at the same time as LY2510924.

In certain aspects the patient is administered intravenously one or more doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 2000 mg. In certain aspects the patient is administered intravenously one or more doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1500 mg. In certain aspects the patient is administered intravenously one or more doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1000 kg. In certain aspects the patient is administered intravenously one or more doses of MEDI4736 or an antigen- binding fragment thereof wherein the dose is 1500 mg. In certain aspects the patient is administered intravenously one or more doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is 2000 mg.

In certain aspects the patient is administered intravenously at least two doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 2000 mg. In certain aspects the patient is administered intravenously at least two doses of MED 14736 or an antigen-binding fragment thereof wherein the dose is about 1500 mg. In certain aspects the patient is administered intravenously at least two doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1000 mg. In certain aspects the patient is administered intravenously at least two doses of MED 14736 or an antigen- binding fragment thereof wherein the dose is 1500 mg. In certain aspects the patient is administered intravenously at least two doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is 1000 mg. In some embodiments, the at least two doses are administered about four weeks apart.

In certain aspects the patient is administered intravenously at least three doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 2000 mg. In certain aspects the patient is administered intravenously at least three doses of

MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1500 mg. In certain aspects the patient is administered intravenously at least three doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1000 mg. In certain aspects the patient is administered intravenously at least three doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is 2000 mg. In certain aspects the patient is administered intravenously at least three doses of MEDI4736 or an antigen- binding fragment thereof wherein the dose is about 1500 mg. In certain aspects the patient is administered intravenously at least three doses of MEDI4736 or an antigen-binding fragment thereof wherein the dose is about 1000 mg. In some embodiments, the at least three doses are administered about four weeks apart. In certain aspects the patient is administered one or more doses of LY2510924 wherein the total dose is about 20 mg daily. In certain aspects the patient is administered one or more doses of LY2510924 wherein the dose is about 30 mg daily. In certain aspects the patient is administered one or more doses of LY2510924 wherein the total dose is about 40 mg daily.

In certain aspects the patient is administered one or more doses of LY2510924 wherein the total dose is 20 mg daily. In certain aspects the patient is administered one or more doses of LY2510924 wherein the dose is 30 mg daily. In certain aspects the patient is administered one or more doses of LY2510924 wherein the total dose is 40 mg daily.

In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof and/or LY2510924 according to the methods provided herein is through parenteral administration. For example, MEDI4736 or an antigen-binding fragment thereof or LY2510924 can be administered by intravenous infusion or by subcutaneous injection, respectively.

The methods provided herein can decrease, retard or stabilize tumor growth. In some aspects the reduction or retardation can be statistically significant. A reduction in tumor growth can be measured by comparison to the growth of patient's tumor at baseline, against an expected tumor growth, against an expected tumor growth based on a large patient population, or against the tumor growth of a control population. In certain aspects, a tumor response is measured using the Response Evaluation Criteria in Solid Tumors (RECIST).

In certain aspects, a tumor response is detectable at week 8. In certain aspects, a tumor response is detectable at week 33. In certain aspects, a tumor response is detectable at week 50.

In certain aspects, a patient achieves disease control (DC). Disease control can be a complete response (CR), partial response (PR), or stable disease (SD).

A "complete response" (CR), a "partial response" (PR), and "stable disease" (SD) can be determined as defined in Table 1 below.

In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof in combination with LY2510924 according to the present invention can increase progression-free survival (PFS). In certain aspects, administration of MEDI4736 or an antigen-binding fragment thereof in combination with LY2510924 according to the present invention can increase overall survival (OS).

An unexpected therapeutic effect of the combination treatments of the invention is the ability to produce marked anti-cancer effects in a patient without causing significant toxicities or adverse effects, so that the patient benefits from the combination treatment method overall. The efficacy, i.e., therapeutic effect(s), 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 disease progression, overall survival, progression free survival, overall response rate, duration of response, and/or quality of life. The therapeutic agents used in the invention may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Because the invention relates to the use of a combination of unique anti-tumor agents, novel approaches to determining efficacy, i.e., therapeutic effect(s), of any particular combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and measurement of response through radiological imaging.

As used herein, the term "Complete Response" (CR) refers to the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

As used herein, the term "Partial Response" (PR) refers to at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

As used herein, the term "Progressive Disease" (PD) refers to at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For the avoidance of doubt, the appearance of one or more new lesions is also considered progression. As used herein, the term "Stable Disease" (SD) refers to 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 "Objective Response" (OR) refers to the sum of CR plus PR

The skilled artisan will appreciate the terms CR, PR, PD, SD and OR correspond to definitions according to RECIST vl.1, Eisenhauer et al., European Journal of Cancer, 2009, 45, 228-247.

As used herein, the term "time to disease progression" or 'TI P" refers to the time, generally measured in weeks or months, from the time of initial treatment, until the cancer progresses or worsens. Such progression can be evaluated by the skilled clinician.

As used herein, the term "extending TTP" refers to increasing the time to disease progression in a treated patient relative to i) an untreated patient or relative, or ii) a patient treated with less than all of the anti-tumor agents in a particular combination therapy.

As used herein, the term "survival" refers to the patient remaining alive, and includes overall survival as well as progression free survival.

As used herein, the term, "overall survival" refers to the patient remaining alive for a defined period of time, such as 1 year, S years, etc., from the time of diagnosis or treatment.

As used herein, the term, "progression free survival" refers to the patient remaining alive, without the cancer progressing or getting worse.

As used herein, the term "extending survival" is meant increasing overall or progression free survival in a treated patient relative to i) an untreated patient, ii) a patient treated with less than all of the anti-tumor agents in a particular combination therapy, or iii) a control treatment protocol. Survival is monitored for at least about one month, at least about one month, at least about two months, at least about four months, at least about six months, at least about nine months, or at least about 1 year, or at least about 2 years, or at least about 3 years, or at least about 4 years, or at least about 5 years, or at least about 10 years, etc., following the initiation of treatment or following the initial diagnosis of cancer. As used herein, the term "primary tumor" or "primary cancer" is meant the original cancer and not a metastatic lesion located in another tissue, organ, or location in the patient's body.

As used herein, the term "effective amount" refers to the amount or dose of a PD- LI antibody or antigen-binding fragment thereof and to the amount or dose of CXCR4 peptide antagonist which, upon single or multiple dose administration to the patient, provides an effective response in the patient under treatment. As used herein, the term "effective amount" also refers to the amount or dose of MEDI4736 or an antigen-binding fragment thereof, and to the amount or dose of LY2510924, which, upon single or multiple dose administration to the patient, provides an effective response in the patient under treatment. It is understood that a combination therapy of the present invention is carried out by administering a PD-LI antibody or antigen-binding fragment thereof together with an anti-CXCR4 peptide antagonist in any manner which provides effective levels of the PD-LI antibody or antigen-binding fragment thereof and the anti-CXCR4 peptide antagonist in the body. It is also understood that a combination therapy of the present invention is carried out by administering MEDI4736 or an antigen-binding fragment thereof, together with LY2510924 in any manner which provides effective levels of MED 14736 or an antigen-binding fragment thereof, and LY2510924 in the body.

As used herein, the terms "effective response" of a patient or a patient's

"responsiveness" to treatment with a combination of agents, or "therapeutic effect" refers to the clinical or therapeutic benefit(s) imparted to a patient upon administration of i) a combination of a PD-LI antibody or an antigen-binding fragment thereof and an CXCR4 peptide antagonist, ii) MEDI4736 or an antigen-binding fragment thereof and

LY2510924, or iii) MED14736 and LY2510924. Such benefit(s) include any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); tumor regression, tumor weight or size shrinkage, longer time to disease progression, increased duration of survival, longer progression free survival, improved overall response rate, increased duration of response, and improved quality of life and/or improving signs or symptoms of cancer, etc. According to the methods provided herein, administration of MEDI4736 or an antigen-binding fragment thereof and LY2510924 can result in desirable pharmacokinetic parameters as shown in some early data Total drug exposure can be estimated using the "area under the curve" (AUC). " AUC (tau)" refers to AUC from time 0 to time x, the dosing interval, whereas "AUC (inf)" refers to the AUC until infinite time. The administration can produce AUC (tau) of about 600 to about 3,000 pg/mL*day of MEDI4736 or antigen-binding fragment thereof and about 3000 to about 5000 ng/mL of LY2510924 at the 20 mg daily dose. The administration can produce a maximum observed concentration (Cmax) of about 60 to about 300 pg/niL of MEDI4736 and of about 400 to about 1000 ng/mL LY2510924 at the 20 mg daily dose. The administration can produce a C trough (minimum plasma drug concentration) of about 5 to about 40 pg/mL MEDI4736.

As provided herein, MEDI4736 or an antigen-binding fragment thereof can also decrease free (soluble) PD-L1 levels. Free (soluble) PD-L1 refers to PD-L1 that is not bound (e.g., by MEDI4736). In some embodiments, PD-L1 levels are reduced by at least 65%. In some embodiments, PD-L1 levels are reduced by at least 80%. In some embodiments, PD-L1 levels are reduced by at least 90%. In some embodiments, PD-L1 levels are reduced by at least 95%. In some embodiments, PD-L1 levels are reduced by at least 99%. In some embodiments, PD-L1 levels are not detectable following

administration of MEDI4736 or an antigen-binding fragment thereof and LY2510924.

In some embodiments, PD-L1 levels are reduced by at least 65% after a single administration of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 80% after a single administration of MED14736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 90% after a single administration of MEDI4736 or an antigen- binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 95% after a single administration of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 99% after a single administration of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are not detectable following a single administration of MED14736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 65% after administration of two doses of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 80% after administration of two doses of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD- LI levels are reduced by at least 90% after administration of two doses of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 95% after administration of two doses of MED14736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are reduced by at least 99% after administration of two doses of MEDI4736 or an antigen-binding fragment thereof. In some embodiments, PD-L1 levels are not detectable following administration of two doses of MEDI4736 or an antigen-binding fragment thereof.

Treatment of a patient with a solid tumor using both MEDI4736 or an antigen- binding fragment thereof and LY2510924 (i.e., co-therapy) as provided herein can result in a synergistic effect. As used herein, the term "synergistic" refers to a combination of therapies (e.g. , a combination of MEDI4736 or an antigen-binding fragment thereof and LY2510924) which is more effective than the additive effects of the single therapies.

A synergistic effect of a combination of therapies (e.g., a combination of a MEDI4736 or an antigen-binding fragment thereof and LY2510924) permits the use of lower dosages of one or more of the therapeutic agents and/or less frequent administration of said therapeutic agents to a patient with a solid tumor. The ability to utilize lower dosages of therapeutic agents and/or to administer said therapies less frequently reduces the toxicity associated with the administration of said therapies to a subject without reducing the efficacy of said therapies in the treatment of a solid tumor. In addition, a synergistic effect can result in improved efficacy of therapeutic agents in the

management, treatment, or amelioration of a solid tumor. The synergistic effect of a combination of therapeutic agents can avoid or reduce adverse or unwanted side effects associated with the use of either single therapy.

In co-therapy, MEDI4736 or an antigen-binding fragment thereof can be optionally included in the same pharmaceutical composition as the LY2510924, or may be included in a separate pharmaceutical composition. In this latter case, the

pharmaceutical composition comprising MEDI4736 or an antigen-binding fragment thereof is suitable for administration prior to or following administration of the pharmaceutical composition comprising LY2510924. In certain instances, the

MEDI4736 or an antigen-binding fragment thereof is administered at overlapping times as LY2510924 in a separate composition.

Subjects having a solid tumor (e.g. , ovarian cancer or pancreatic cancer) may be tested for PD-L1 polynucleotide or polypeptide expression in the course of selecting a treatment method. Patients identified as having tumors that are negative for PD-L1 (e.g., as defined by Ct or MC-M score) or by having reduced or undetectable levels of PD-L1 relative to a reference level are identified as responsive to treatment with a combination of an anti-PD-Ll antibody and LY2510924. Such patients are administered MED14736, or an antigen-binding fragment thereof, in combination with LY2510924.

The present invention also provides MEDI4736 or an antigen-binding fragment thereof for use in simultaneous, separate or sequential combination with LY2510924 in the treatment of a solid tumor, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient. Preferably, the MEDI4736 or an antigen- binding fragment thereof is administered in a dose of 1000 mg, 1500 mg or 2000 mg intravenously on the first day of a 28 day cycle. Also preferably the LY2510924 is administered subcutaneously in a daily dose of 20-25 mg, 20-30 mg, 20-35 mg, 25-40 mg, 30-40 mg, 35-40 mg, 20 mg, 30 mg or 40 mg. More preferably, the LY2510924 is administered subcutaneously in a daily dose of 20-25 mg, 20-30 mg, 20-35 mg, 25-40 mg, 30-40 mg, 35-40 mg, 20 mg, 30 mg or 40 mg for at least one 28 day cy cle.

EXAMPLE 1: A Study of Durvalumab in Combination with LY2510924 for

Patients with Advanced Solid Tumors

(a) SUBJECTS

Subjects are 18 years of age or older, have a minimum body weight of >30 kg, have histologic or cytologic confirmation of an advanced solid tumor (see American Joint Committee on Cancer Staging Criteria; Edge et al. 2009), and have at least 1 measurable lesion assessable using standard techniques by Response Evaluation Criteria in Solid Tumours (RECIST) vl.l (Eisenhauer et al. 2009). Preferably, the advanced solid tumor is 1) pancreatic cancer, more preferably pancreatic adenocarcinoma and not acinar cell carcinoma, adenosquamous carcinoma, nor neuroendocrine islet cell neoplasms or 2) ovarian cancer including, but not limited to, fallopian tube cancer or primary peritoneal cancer. Subjects may include those that have failed to respond to standard treatment, relapsed following standard treatment, declined standard treatment, or have not been eligible for standard treatment. Furthermore, subjects have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Preferably, the subjects have adequate organ (hepatic and renal) and marrow function. Adequate organ and marrow function are defined as: hemoglobin > 9 g/dL; absolute neutrophil count > 1,500/mm³; platelet count > 100,000/mm³; total bilirubin < 1.5 x upper limit of normal (ULN), unless associated with Gilbert's syndrome or liver metastasis (for these subjects, baseline total bilirubin must be < 3.0 mg/dL); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 2.5 ^χ ULN unless associated with hepatic metastases (for these subjects, ALT and AST must be < 5 ^χ ULN); and serum creatinine < 2.0 mg/dL.

Subjects are not able to participate if they are on any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Subjects are not able to participate if they have taken any investigational anticancer therapy within 28 days prior to me first dose of durvalumab and/or LY2510924. Subjects are not able to participate if they have any prior Grade > 3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CXCR4 treatment, or any unresolved irAE > Grade 1. Preferably, subjects are excluded if they have undergone a major surgical procedure within 28 days prior to the first dose of durvalumab or LY2510924 or if they are still recovering from prior surgery or if they have unresolved toxicities from prior anticancer therapy, defined as having not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC AE) v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab and LY2510924 may be included while subjects using, or having used immunosuppressive medication within 14 days before the first dose of durvalumab or LY2510924. If subjects have active or prior autoimmune disease, including inflammatory bowel disease, diverticulitis, irritable bowel disease, celiac disease, Wegener syndrome, and Hashimoto syndrome, within the past 3 years, except for vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years), they are excluded, as are subjects with a history of primary immunodeficiency or tuberculosis, if they have known active or chronic viral hepatitis A, B, or C; if they have human immunodeficiency virus (HTV); other active serious illnesses or uncontrolled inter-current illnesses; have received live, attenuated vaccine within 28 days prior to the first dose of durvalumab and LY2510924; have other invasive malignancy within 5 years; or known allergy or hypersensitivity to study drug formulations.

(b) STUDY DESIGN

An open-label Phase la/lb study may be conducted in 2 parts. The first part (Phase la) of the study may consist of a dose-escalation assessment of the safety and tolerability of LY2510924 administered with durvalumab (MEDI4736) with advanced refractory solid tumors (Figure 1 ), with starting dose level at 20 mg LY2510924.

Subsequent dose levels of LY2510924 will reflect a maximum increment of 10 mg from the prior dose level, with the highest dose level going up to 40 mg. The second part (Phase lb) of the study may be disease restricted to include two expansion arms in advanced pancreatic cancer (N=approximately 15 patients) and ovarian cancer

(N=approximately 15 patients). The maximum tolerated dose (MTD) of LY2510924 determined during Phase la may be used for the dose of LY2510924 for Phase lb. The MTD may be defined as the highest dose of LY2510924 within a cohort where no more than 1 of 6 patients experiences aDLT. (c) TREATMENT REGIMEN

In the dose-escalation phase of the study (Phase 1 a), all patients may receive LY2510924 (a daily dose starting at a dose level of 20 mg administered subcutaneously for a 28-day cycle) in combination with durvalumab (1500 mg administered

intravenously on Day 1 of each 28-day cycle) for a treatment duration of one up to thirteen or more 28-day cycles. Subsequent dose levels will reflect a maximum increment of 10 mg from the prior dose level. If the MTD has not yet been reached at the highest dose level of 40 mg, then additional dose levels may be investigated based on both safety and the available PK data, durvalumab will be administered Q4W for between one to up to 13 doses or more. (d) STUDY DRUGS

LY2510924 for Injection (20 mg/mL) may be supplied as a single use sterile clear solution formulation in 2 mL glass vials. Each vial may contain 1.15 mL of a 20 mg/mL LY2510924 solution to facilitate the withdrawal of a 20-mg unit dose. One mL will be drawn from each vial to deliver 20 mg of LY2510924. The LY2510924 drug product contains no antimicrobial preservative. The drug product is composed of LY2510924 and the inactive ingredients sodium citrate dihydrate, citric acid monohydrate, sodium chloride, sterile water for injection with sodium hydroxide and/or hydrochloric acid used if necessary for pH adjustment. Vials of LY2510924 for Injection, 20 mg/mL, are stored refrigerated (2°C to 8°C).

Durvalumab will be supplied as a 500-mg vial solution for infusion. The solution may contain 50 mg/mL durvalumab, 26 mM Wstidine/histidine -hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it may have a pH of 6.0. The nominal fill volume may be 10 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen.

Total time from needle puncture of the durvalumab vial to the start of

administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature

Infusion solutions must be allowed to equilibrate to room temperature prior to commencement of administration. Durvalumab does not contain preservatives.

LY2510924 may be self-administered subcutaneously prior to the start of durvalumab intravenous infusion on the days both drugs are given together.

Each patient may receive IV administration of durvalumab (1500 mg) on Day 1 of each 28-day cycle at least 30 minutes after LY2510924. Standard infusion time is approximately 1 hour and the total allowed time should not exceed 8 hours at room temperature. (e) RESULTS

Tumor assessments may be performed during screening (day -28 to day -1), and at reasonable frequency such as at week 8 (day 50 + 3 days), and at week 33 (day 225 + 3 days) in the dose-escalation phase, for example. Tumor assessments may be based on RECIST guidelines vl.1 with modifications and may include the following evaluations: physical examination (with photograph and measurement of skin lesions as applicable), CT, or MRI scan of the chest, abdomen, and pelvis, and CT or MRI scan of the brain. Computed tomography or MRI scan of the brain may be performed only at screening.

Assessments of anti-tumor activity may be based on the measurement of tumor lesions, the evaluation of target lesions, the evaluation of non-target lesions, and the appearance of new lesions.

Target Lesion Evaluation

For the evaluation of target lesions, complete response 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 (the sum may not be "0" if there are target nodes).

For the evaluation of target lesions, partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

For the evaluation of target lesions, progressive disease may be defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions may also considered

progression.

For the evaluation of target lesions, stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.

Non-target Lesion Evaluation

For the evaluation of non-target lesions, complete response (CR) is defined as the disappearance of all non-target lesions. All lymph nodes must be < 10 mm in short axis. For the evaluation of non-target lesions, non-compete response/non-progressive disease may be defined as the persistence of one more non-target lesions and/or maintenance of tumor marker level above the normal limits.

For the evaluation of non-target lesions, progressive disease may be defined as the overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. In the absence of measurable disease, change in non- measurable disease comparable in magnitude to the increase that would be required to declare PD for measurable disease.

New Lesion

The appearance of new lesions may be considered PD according to RECIST guidelines v l. l. Considering the unique response kinetics that have been observed with immunotherapy, new lesions may not represent true disease progression. In the absence of rapid clinical deterioration, subjects may continue to receive treatment with durvalumab and LY2510924.

Overall Response

Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The evaluation of overall response based on target lesion, non-target lesion, and new lesion evaluation may be determined as in Table 1 below.

Table 1: Evaluation of Overall Response

made at an assessment.

Adverse events may be monitored following administration of durvalumab. Other assessments include physical examination, vital sign monitoring, and laboratory measurements. Subjects who achieve and maintain disease control (DC) (i.e., complete response (CR), partial response (PR), or stable disease (SD)) through to the end of the 12-month durvalumab and LY2510924 treatment period will enter follow-up. Upon evidence of progressive disease (PD) during follow-up, subjects may be re-administered durvalumab and LY2510924 for up to another 12 months with the same treatment guidelines followed during the initial 12-month period if the subject has not received other treatments for their disease and still meet inclusion and exclusion criteria for the study protocol. Only one round of retreatment with durvalumab and LY2510924 will be allowed.

durvalumab and LY2510924 administration can be modified or discontinued as a result of toxicities. Dose modifications may not be required for adverse events (AEs) that are clearly not attributed to durvalumab or LY2510924 (such as an accident) or for laboratory abnormalities that are not deemed to be clinically significant.

(f) PHAMACOKINETIC, ANTI-TUMOR, BIOMARKER,

SOLUBLE FACTOR, AND SAFETY ASSESSMENTS

Measurement of durvalumab and LY2510924 concentrations in serum may be performed using a validated immunoassay.

Blood samples may be drawn from all patients for the assessment of LY2510924 in plasma and durvalumab concentrations in serum (also known as bioanalytical samples). Blood samples for pharmacokinetic assessment may be collected on the following days during the dose-escalation phase: day 1 (pre-dose and end of infusion), day 8 ( + 1 day), day 15 ( + 1 day), day 28 (pre-dose of LY2510924, at the end of treatment, 60 days after end of treatment, and 90 days after end of treatment.

Blood samples for pharmacokinetic assessment may be collected on the following days during the dose-expansion phase: day 1 (pre-dose and end of infusion, at the end of treatment, 60 days after end of treatment, and 90 days after end of treatment.

The presence of anti-drug antibodies (ADA) will be assessed on Day 1, at the end of treatment, 60 days after the end of treatment, and 90 days after the end of treatment. Validated electrochemiluminescence assays using a Meso Scale Discovery platform will be used for the determination of anti-MEDI4736 antibodies in human serum and for determination of anti-LY2510924 antibodies in human serum. Blood samples may be collected for analysis of circulating soluble factors including soluble PD-L1 (sPD-Ll). During the dose-escalation phase, levels of sPD-Ll may be assessed on day 1, day 8 (+ 1 day), day 15 (+ 1 day), at the end of treatment, 60 days after end of treatment, and 90 days after end of treatment. During the dose- expansion phase, levels of sPD-Ll may be assessed on day 1, at the end of treatment, 60 days after end of treatment, and 90 days after end of treatment.

This Phase 1 study assesses the safety/tolerability, antitumor activity, pharmacokinetics (PK) and immunogenicity of combination therapy with durvalumab LY2510924 in a specific dose and frequency treatment regimen in patients with advanced solid tumor(s). The study has dose-escalation and -expansion phases. This study may demonstrate that durvalumab and LY2510924 have favorable pharmacokinetic properties and the combination of agents in a specific dose and frequency treatment regimen described herein suppresses sPD-Ll. Furthermore, because durvalumab and LY2510924 block distinct interactions contributing to immunosuppression and/or tumorigenicity, the combination of durvalumab and LY2510924 therapy in the specific dose and frequency treatment regimen described herein may provide greater antitumor activity compared with either agent alone in patients with advanced solid tumors including, but not limited to, pancreatic cancer and ovarian cancer.

LISTING OF SEQUENCES

SEQ ID NO:l MEDI4736 VL (human)

EIVLTQSPGTTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRA TGIPDRFSGSGSGTDFTLΉSRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK SEQ ID NO:2 MEDI4736 VH (human)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRWMSWVRQAPGKGLEWVANIKQ DGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGEL AFDYWGQGTLVTVSS

SEQ ID NO:3 - MEDI4736 VH CDR1 (human)

GFTFSRYWMS

SEQ ID NO:4 - MEDI4736 VH CDR2 (human)

NIKQDGSEKYYVDSVKG SEQ ID NO:5 - MEDI4736 VH CDR3 (human)

EGGWFGELAFDY

SEQ ID NO:6 - MEDI4736 VL CDR1 (human)

RASQRVSSSYLA

SEQ ID NO:7 - MEDI4736 VL CDR2 (human)

DASSRAT

SEQ ID NO:8 - MEDI4736 VL CDR3 (human)

QQYGSLPWT

SEQ ID NO: 9 - MEDI4736 Heavy Chain (artificial)

EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYWMSWVRQA P GKGLEW V AN IKQDGSEKYY VDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAREG GWFGELAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEFEG GPSVFLFPPK PKDTLMISRT PEVTCVWDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRWSVL TVLHQDWLNG KEYKCKVSNK ALPASIEIOl SKAKGQPREP QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD 1AVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K

SEQ ID NO: 10 - MEDI4736 Light Chain (human)

EIVLTQSPGT LSLSPGERAT LSCRASQRVS SSYLAWYQQK PGQAPRLLIY DASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSLPWTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASWCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC SEQ ID NO:ll: - LY2510924 (artificial)

Phe TyrXaa Arg Xaa Gly GluXaa

<221> MOD RES

<222> (1)..(7)

<223> Lactam bridge

<220>

<221> MISC_FEATURE

<222> (3)..(3)

<223> Xaa = Lys(iPr)

<220>

<221> MOD_RES

<222> (4)..(4)

<223> d isomer

<220>

<221> M1SC_FEATURE

<222> (5)..(5)

<223> Xaa = 2Nal

<220>

Claims

WE CLAIM: 1. A method of treating a solid tumor in a patient, comprising administering MEDI4736 and LY2510924 to the patient.

2. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

3. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of 20 mg of LY2510924 to the patient.

4. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of about

25 mg to about 40 mg of LY2510924 to the patient.

5. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of about

30 mg to about 40 mg of LY2510924 to the patient.

6. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of about

35 mg to about 40 mg of LY2510924 to the patient.

7. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 and a daily dose of about

35 mg to about 40 mg of LY2510924 to the patient.

8. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 1500 mg of MEDI4736 and a daily dose of about

40 mg of LY2510924 to the patient.

9. A method of treating a solid tumor in a patient, comprising administering about 1000 mg to about 2000 mg of MEDI4736 and a daily dose of 40 mg of LY2510924 to the patient.

10. A method of treating a solid tumor in a patient, comprising administering 1000 mg of MEDI4736 and a daily dose of 40 mg of LY2510924 to the patient.

11. A method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

12. A method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 and a daily dose of 30 mg of LY2510924 to the patient.

13. A method of treating a solid tumor in a patient, comprising administering about 1500 mg of MEDI4736 and a daily dose of 40 mg of LY2510924 to the patient.

14. A method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 and a daily dose of 20 mg of LY2510924 to the patient.

15. A method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 and a daily dose of 30 mg of LY2510924 to the patient.

16. A method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

17. A method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 and a daily dose of about 20 mg to about 35 mg of LY2510924 to the patient.

18. A method of treating a solid tumor in a patient, comprising administering about 1500 mg to about 2000 mg of MEDI4736 and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

19. A method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDI4736 and a daily dose of about 20 mg to about 30 mg of LY2510924 to the patient.

20. A method of treating a solid tumor in a patient, comprising administering 1500 mg of MEDT4736 and a daily dose of about 20 mg of LY2510924 to the patient.

21. A method of treating a solid tumor in a patient, comprising administering about 2000 mg of MED 14736 and a daily dose of about 30 mg of LY2510924 to the patient.

22. A method of treating a solid tumor in a patient, comprising administering about 2000 mg of MEDI4736 and a daily dose of 30 mg of LY2510924 to the patient.

23. A method of treating a solid tumor in a patient, comprising administering about 2000 mg of MEDI4736 and a daily dose of 40 mg of LY2510924 to the patient.

24. A method of treating a solid tumor in a patient, comprising administering 2000 mg of MEDI4736 and a daily dose of 40 mg of LY2510924 to the patient.

25. The method of any one of claims 1-24, wherein the MEDI4736 is

administered intravenously once every 28 days.

26. The method of any one of claims 1-25, wherein the LY2510924 is

administered subcutaneously daily for 28 days.

27. The method of any one of claims 1-26, wherein the administrations result in an increased tumor response as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

28. The method of any one of claims 1-26, wherein the administrations result in an increase in progression-free survival as compared to the

administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

29. The method of any one of claims 1-26, wherein the administrations result in an increase in overall survival as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

30. The method of any one of claims 1-29, wherein the administration reduces soluble PD-L1.

31. The method of claim 30, wherein soluble PD-L1 is reduced by at least 65%.

32. The method of claim 30, wherein soluble PD-L1 is reduced by at least

90%.

33. The method of claim 30, wherein soluble PD-L1 is reduced by at least 95%.

34. The method of any one of claims 1-34, wherein the solid tumor is

refractory to at least one chemotherapeutic agent.

35. The method of claim 34, wherein the chemotherapeutic agent is paclitaxel, docetaxel, capecitabine, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin.

36. The method of any one of claims 1-35, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

37. The method of any one of claims 1-36, wherein the patient is

irnmunotherapy-narve prior to the administration of MEDI4736 or antigen- binding fragment thereof and LY2510924.

38. The method of any one of claims 1-37, wherein the patient has received immunotherapy prior to the administration of MEDI4736 or antigen- binding fragment thereof and LY2510924.

39. The method of any one of claims 1-38, wherein the administrations reduce tumor size by at least about 25% or 50% relative to baseline.

40. The method of any one of claims 1-39, wherein the patient has locally advanced unresectable or metastatic solid tumor.

41. The method of any one of claims 1-40, wherein the solid tumor comprises a KRAS-mutation or an EGFR-mutation.

42. The method of any one of claims 1-41, wherein the solid tumor is PD-L1 positive.

43. The method of any one of claims 1-42, wherein the solid tumor is PD-L1 negative.

44. The method of any one of claims 1-43, wherein solid tumor is selected from prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer.

45. The method of any one of claims 1-43, wherein solid tumor is selected from pancreatic cancer and ovarian cancer.

46. A method of treatment comprising administering MEDI4736, or an

antigen-binding fragment thereof, and LY2510924 to a patient identified as having a PD-L1- or PD-L1+ solid tumor.

47. A combination comprising MEDI4736, or an antigen-binding fragment thereof, and LY2510924, for simultaneous, separate or sequential use in therapy.

48. A combination comprising MEDI4736, or an antigen-binding fragment thereof, and LY2510924, for simultaneous, separate or sequential use in the treatment of a solid tumor.

49. A combination for use according to claim 47 or 48 wherein the solid tumor is pancreatic or ovarian cancer.

50. A combination for use according to any one of claims 47-49, further

comprising paclitaxel, docetaxel, capecitabine, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof.

51. A combination for use according to any one of claims 47-49, further

comprising everolimus, temsirolimus, or a pharmaceutically acceptable salt thereof.

52. A combination for use according to any one of claims 47-51, further comprising any combination of 5-fluorouracil, leucovorin, folinic acid and oxaliplatin, or a pharmaceutically acceptable salt thereof.

53. A combination comprising MEDI4736, or an antigen-binding fragment thereof, and LY2510924, for simultaneous, separate or sequential use in the treatment of a solid tumor wherein solid tumor is selected from prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer.

54. LY2510924 for use in simultaneous, separate or sequential combination with MEDI4736 or an antigen-binding fragment thereof in the treatment of a solid tumor, comprising administering about 1000 mg to about 2000 mg of MEDI4736 or an antigen-binding fragment thereof and a daily dose of about 20 mg to about 40 mg of LY2510924 to the patient.

55. LY2510924 for use according to claim 54, wherein the daily dose of

LY2510924 is of about 20 mg to about 35 mg.

56. LY2510924 for use according to claim 54 or claim 55, wherein the daily dose of LY2510924 is of about 20 mg to about 30 mg.

57. LY2510924 for use according to any one of claims 54-56, wherein the daily dose of LY2510924 is of about 30 mg.

58. LY2510924 for use according to any one of claims 54-56, wherein the daily dose of LY2510924 is of about 20 mg to about 25 mg.

59. LY2510924 for use according to any one of claims 54-56 and 57, wherein the daily dose of LY2510924 is of about 20 mg.

60. LY2510924 for use according to claim 54, wherein the daily dose of

LY2510924 is of about 25 mg to about 40 mg.

61. LY2510924 for use according to claim 54 or claim 60, wherein the daily dose of LY2510924 is of about 30 mg to about 40 mg.

62. LY2510924 for use according to claim any one of claims 54 and 60-61, wherein the daily dose of LY2510924 is of about 35 mg to about 40 mg.

63. LY2510924 for use according to any one of claims 54 and 60-62, wherein the daily dose of LY2510924 is of about 40 mg.

64. LY2510924 for use according to any one of claims 54-63, wherein

LY2510924 is administered subcutaneously daily for 28 days.

65. LY2510924 for use according to any one of claims 54-64, wherein about

1000 mg to about 1500 mg of MEDI4736 or an antigen-binding fragment thereof are administered.

66. LY2510924 for use according to any one of claims 54-65, wherein about 1000 mg of MEDI4736 or an antigen-binding fragment thereof are administered.

67. LY2510924 for use according to any one of claims 54-64, wherein about 1500 mg to about 2000 mg of MED 14736 or an antigen-binding fragment thereof are administered.

68. LY2510924 for use according to any one of claims 54-65 and 67, wherein about 1500 mg of MEDI4736 or an antigen-binding fragment thereof are administered.

69. LY2510924 for use according to any one of claims 54-68, wherein the MEDI4736 or an antigen-binding fragment thereof is administered intravenously once every 28 days.

70. LY2510924 for use according to any one of claims 54-69, wherein the administrations result in an increased tumor response as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

71. LY2510924 for use according to any one of claims 54-69, wherein the administrations result in an increase in progression-free survival as compared to the administration of either the MEDI4736 or an antigen- binding fragment thereof or the LY2510924 alone.

72. LY2510924 for use according to any one of claims 54-69, wherein the administrations result in an increase in overall survival as compared to the administration of either the MEDI4736 or an antigen-binding fragment thereof or the LY2510924 alone.

73. LY2510924 for use according to any one of claims 54-69, wherein the administration reduces soluble PD-L1.

74. LY2510924 for use according to claim 73, wherein soluble PD-L1 is

reduced by at least 65%.

75. LY2510924 for use according to claim 73, wherein soluble PD-L1 is

reduced by at least 90%.

76. LY2510924 for use according to claim 73, wherein soluble PD-L1 is

reduced by at least 95%.

77. LY2510924 for use of any one of claims 54-76, wherein the solid tumor is refractory to at least one chemotherapeutic agent.

78. LY2510924 for use of claim 77, wherein the chemotherapeutic agent is paclitaxel, docetaxel, capecitabine, capecitabine, gemcitabine, everolimus, temsirolimus, vemurafenib, erlotinib, afatinib, rociletinib, AZD9291, ASP8273, and HM61713, cetuximab, carboplatin, cisplatin, bevacizumab, erlotinib, gefitinib, pemetrexed, or a pharmaceutically acceptable salt thereof, and/or any combination of 5-fluorouracil, leucovorin, folinic acid and/or oxaliplatin.

79. LY2510924 for use of any one of claims 54-78, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

80. LY2510924 for use of any one of claims 54-79, wherein the patient is immunotherapy-narve prior to the administration of MEDI4736 or antigen- binding fragment thereof and LY2510924.

81. LY2510924 for use of any one of claims 54-79, wherein the patient has received immunotherapy prior to the administration of MEDI4736 or antigen-binding fragment thereof and LY2510924.

82. LY2510924 for use of any one of claims 54-81, wherein the

administrations reduce tumor size by at least about 25% or 50% relative to baseline.

83. LY2510924 for use of any one of claims 54-82, wherein the patient has locally advanced unresectable or metastatic solid tumor.

84. LY2510924 for use of any one of claims 54-83, wherein the solid tumor comprises a KRAS-mutation or an EGFR-mutation.

85. LY2510924 for use of any one of claims 54-84, wherein the solid tumor is PD-L1 positive.

86. LY2510924 for use of any one of claims 54-84, wherein the solid tumor is PD-L1 negative.

87. LY2510924 for use of any one of claims 54-86, wherein solid tumor is selected from prostate cancer, breast cancer, triple negative breast cancer, colon cancer, lung cancer, bladder cancer, a solid tumor, head and neck cancer, melanoma, gastric cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma, and hepatic cancer.

88. LY2510924 for use of any one of claims 54-87, wherein solid tumor is selected from pancreatic cancer and ovarian cancer.

89. LY2510924 for use of any one of claims 54-88, wherein MEDI4736 is administered.