WO2018144334A1

WO2018144334A1 - Dosing regimen for anti-csf-1r antibody

Info

Publication number: WO2018144334A1
Application number: PCT/US2018/015412
Authority: WO
Inventors: Sae Wook KAUH
Original assignee: ImClone LLC
Current assignee: ImClone LLC
Priority date: 2017-02-02
Filing date: 2018-01-26
Publication date: 2018-08-09
Anticipated expiration: 2019-08-02

Abstract

The invention provides for a dosing regimen for human antibodies that bind to human anti-Colony Stimulating Factor-1 Receptor (CSF-1R), preferably Antibody 1.

Description

DOSING REGIMEN FOR ANTI-CSF-1R ANTIBODY

This invention is directed to the fields of immunology and cancer treatment. More specifically, the present invention is directed to the dosing of the anti-Colony Stimulating Factor-1 Receptor (CSF-IR) antibody, Antibody 1, as a medicament for the treatment of cancer. More specifically the present invention is directed to the dosing Antibody 1 at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks. More specifically, the present invention is directed to the treatment of cancer where the cancer includes but are not limited to breast (including but not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression), ovarian (including but not limited to fallopian tube, primary peritoneal, and epithelia), melanoma, and lung (including but not limited to non- small cell).

Macrophages are among the immune cells that infiltrate solid tumors. In many cancers, higher levels of macrophage infiltration have been associated with poorer prognosis. Ruffell & Coussens, Cancer Cell (2015) 27 (4):462. Tumor-associated macrophages (TAM) are abundant in tumors, and promote growth, angiogenesis, and metastasis through secretion of proangiogenic factors and remodeling of the tumor stroma. In addition, TAMs are known to cause suppression of anticancer immune responses through direct inhibition of anti-tumor T cells by production of reactive oxygen species and suppressive cytokines. Id.

CSF-IR, also known as M-CSFR or CD-I 15, is a tyrosine kinase receptor expressed selectively on monocytes/macrophage and granulocyte cell lineages in normal individuals and on tumor cells in cancer. Upon ligand binding, CSF-IR dimerizes, leading to trans-phosphorylation of the receptor and phosphorylation and activation of downstream signaling molecules such as MAPK and Akt. Phosphorylation of CSF-IR results in: (1) the proliferation and differentiation of macrophages from hematopoietic progenitor stem cells, (2) survival and migration of macrophages to various organs and tissues in the body, particularly the tumor stroma, and (3) maintenance of the immune suppressive phenotype of TAM and other CSF-IR expressing cells of the myeloid lineage. Given the critical role of CSF-IR in the regulation and survival of TAMs and other myeloid cells, CSF-IR inhibition has been identified as a potential cancer target. The present invention seeks to provide a method of administering Antibody 1, a CSF-IR antibody, in response to a clinically unmet need for patients who fail to respond to typical therapeutic antibody dosing regimens and/or experience adverse events or toxicity issues with the typical therapeutic antibody dosing regimens. In this regard, the Antibody 1 dosing regimen of the present invention provides a solution to an unmet need for patients who fail to respond the standard dosing regimens of Antibody 1.

A novel and inventive dosing strategy of Antibody 1 for the treatment of cancer is herein presented. Antibody 1 is a recombinant human monoclonal antibody that specifically targets the human CSF-IR. The amino acid sequences of the light chains and heavy chains of Antibody 1 are disclosed in WO2011/123381 Al and in US Patent No. 8,263,079. WO2011/123381 and US Patent No. 8,263,079 also disclose the treatment of a variety of neoplastic diseases, including leukemia, breast cancer, endometrial cancer, prostate cancer, ovarian cancer, colorectal cancer, hepatocellular cancer, renal cancer, multiple myeloma, and Hodgkin's lymphoma with Antibody 1.

Antibody 1, also known as JJVIC-CS4 and LY3022855, is being studied in three ongoing clinical studies which are described on clinicaltrials.gov: NCT01346358 (hereinafter "JSCA"), first received on April 29, 2011; NCT02265536 (hereinafter "JSCB"), first received on September 24, 2014; and NCT02718911 (hereinafter "JSCC"), first received on March 21, 2016.

Clinical dosing of Antibody 1 has proven to be challenging. WO2011/123381 discloses broad dosing ranges for Antibody 1 which is typical for therapeutic monoclonal antibodies: "An exemplary, non-limiting range for a therapeutically effective amount of Antibody 1 is 0.1-50 mg/kg, more preferably 3-35 mg/kg, and more preferably 5-20 mg/kg. Dosing amounts and frequencies will be determined by the physician treating the patient and may include doses from less than 1 mg/kg to over 100 mg/kg given daily, three times per week, weekly, once every two weeks, or less often." Page 20, lines 14-19. The clinicaltrials.gov posting for JSCB recites a dosing schedule of 1.25 mg/kg of Antibody 1 administered intravenously once every two weeks during a 6 week cycle. No dosing information had been disclosed for JSCA or JSCC at the time of the provisional patent filing; see Dowlati et al., "A phase I study of LY3022855, a colony-stimulating factor-1 receptor (CSF-IR) inhibitor, in patients (pts) with advanced solid tumors," Journal of Clinical Oncology (May 2017), Abstract 2523, 35: 15_suppl, 2523-2523. Drug development is unpredictable. It is common for new molecules to fail in preclinical and/or clinical stages and such failures are often unexplained. Dosing is an added complexity that drives further unpredictability. Not all drug dosing regimens are equally suitable for a particular therapy due to various factors, including but not limited to, body weight, performance status, number of prior systemic therapies, genetics, and histological tumor type. Toxicity issues introduce additional complexities. Efficacy and toxicity must be balanced.

Pre-clinical studies with Antibody 1 provided guidance for investigating a weight- based dosing regimen; nothing in the preclinical studies suggest a non-weight based dosing regimen, and certainly did not provide motivation to investigate a non-weight based dosing regimen of 100 mg every week or 100 mg every other week as set forth in some aspects of the present invention. There is nothing in the preclinical data that would have suggested or provided insight into the fact that the therapeutic effect could be achieved by the non-weight based dosing regimens of the present invention. Although 100 mg every week or every other week may fall within the broad range of dosing disclosed in WO2011/123381, the broad range disclosed therein is typical for therapeutic oncology biological antibodies. The progression of the clinical studies in human patients (JSCA and JSCB, discussed below), including successive reductions in dosing regimens, led to the discovery that the initially proposed dosing regimen was not optimal. The dosing regimen of the present invention is effective, from a pharmacokinetic (PK) / pharmacodynamics (PD) perspective, despite being a non-weight based therapeutic regimen. Higher doses proved to have toxicology issues, and lower doses failed to provide consistent blockade of the CSF-1R signaling pathway, as demonstrated by persistent elevation of circulating CSF-1 levels, as well as suppression of circulating non- classical/inflammatory monocytes required to enable a therapeutic effect. The claimed dosing regimens provide the required balance.

The benefits of the claimed dosing regimens are truly unexpected. In preclinical animal studies, cynomologous monkeys tolerated doses of Antibody 1 of 20 mg/kg, 60 mg/kg, and 180 mg/kg without documented adverse toxicities. The no-observed-adverse- effect level (NOAEL) was identified as 180 mg/kg. Given the similar binding affinities of Antibody 1 to human and monkey CSF-1R, it is predicted that 20 mg/kg in humans will have similar findings as in the monkey at the same dose, and that a dose equal to one- eighth of this (2.5 mg/kg), would be an acceptable and safe starting dose for the first-inhuman study. This starting dose is 72-fold lower than the NOAEL (180 mg/kg). Accordingly, the about 100 mg dose of the present invention is very surprising given the cynomologous monkey NOAEL.

The proposed starting dose and regimen of Antibody 1 in the original dose escalation study for Antibody 1, JSCA, was 2.5 mg/kg, administered weekly by intravenous infusion. JSCA was originally designed to administer to various patient cohorts doses of 2.5, 5, 10, 20, and 40 mg/kg Antibody 1 once every week (hereinafter "QW") respectively, however as discussed herein, based upon observed toxicology considerations, JSCA was modified to significantly lower the dosing in subsequent cohorts from 2.5 mg/kg (QW) and up, to 0.3 mg/kg (QW), 0.6 mg/kg (QW), 1.25 mg/kg (every two weeks, hereinafter "Q2W"), and 1.25 mg/kg (QW) such that the highest dose was half of the original proposed starting dose. Ultimately many of the cohorts were never enrolled as the predicted dosing was determined to still be too high and resulted in adverse events, such as dose limiting toxicities (DLTs). Observing from a PK/PD analysis that there is minimal correlation between drug clearance and body weight, the present inventors hypothesized that a non-weight based dosing regimen may be as effective, if not better, than a weight-based dosing regimen; non-weight based arms were added as Part B of JSCA. This hypothesis is validated by the experimental data described herein. The claimed dose regimens of about 100 mg every week or about 100 mg every other week are highly unexpected, from preclinical and PK/PD modeling.

Additionally, when compared to other therapeutic CSF-1R antibodies in clinical studies, the dosage of Antibody 1 in the dose regimen herein is considerably lower, and its benefits are highly unexpected. For example, Amgen's investigational CSF-1R antibody, AMG820, is being dosed at 0.5 mg/kg QW, and 1.5, 3, 6, 10, and 20 and 30 mg/kg Q2W. Papadopoulos et al., "First-in-Human Study of AMG 820, a Monoclonal anti-CSF-lR (c-fms) Antibody, in Patients (pts) with Advanced Solid Tumors," AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA CT137 Published 15 July 2016. Given that the maximal pH effects were seen at doses of 6 mg/kg or higher (Id.) the recommended phase 2 dose for AMG820 is likely 6 mg/kg and accordingly, if one assumes a 80 kg patient, the dose is 480 mg every two weeks, which will result in a 240% higher exposure than the dose regimen of the present invention. These ranges are weight-based and are significantly higher than the dosing regimen of the presently claimed invention.

According to the first aspect of the invention, there is provided Antibody 1 for use in the treatment of cancer, wherein Antibody 1 is administered at a dose of about 100 mg once a week or at a dose of about 100 mg once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg once every two weeks. In another aspect of the invention, the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided use of Antibody 1 for the preparation of a medicament for the treatment of cancer wherein Antibody 1 is administered at a dose of about 100 mg once a week or at a dose of about 100 mg once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg once every two weeks. In another aspect of the invention, the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a medicament comprising Antibody 1, wherein the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the medicament is for use in the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a pharmaceutical composition comprising Antibody 1, wherein to a patient, the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the pharmaceutical composition is for use in the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a kit comprising a pharmaceutical composition comprising Antibody 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients wherein the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the kit is used for the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a method of administering an effective amount of Antibody 1 to a patient in need thereof comprising administering a dose of about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the patient has breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a therapeutic regimen for Antibody 1 in the treatment of cancer comprising about 100 mg of Antibody 1 administered once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a method of reducing the risk of disease progression of a patient having cancer comprising administering about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

According to another aspect of the invention, there is provided a method of treating cancer in a patient in need thereof comprising administering about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week. In another aspect of the invention, Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks. In another aspect of the invention, the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer. In yet another aspect of the invention, the breast cancer includes but is not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression breast cancer. In yet another aspect of the invention, the ovarian cancer includes but is not limited to fallopian tube, primary peritoneal, and epithelia ovarian cancer. In yet another aspect of the invention, the lung cancer includes but is not limited to non-small cell lung cancer.

The invention provides for Antibody 1 in various aspects disclosed herein. As used herein, the term "Antibody 1" refers to an anti-CSF-lR antibody comprising: two heavy chains, each of whose amino acid sequence is that is given in SEQ ID NO: 3, and two light chains, each of whose amino acid sequences is given in SEQ ID NO: 4.

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

As used herein, the terms "treating," "treat," or "treatment" refers to restraining, slowing, lessening, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease or ameliorating clinical symptoms of a condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or disorder, stabilization of a disease or disorder (i.e., where the disease or disorder does not worsen), delay or slowing of the progression of a disease or disorder, amelioration or palliation of the disease or disorder, and remission (whether partial or total) of the disease or disorder, whether detectable or undetectable. Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease. In one embodiment, the present invention can be used as a medicament.

As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers.

Although human antibodies of the invention are particularly suitable for administration to humans, they can be administered to other mammals as well. Accordingly, as used herein, the term "patient" refers to a mammal, preferably a human. The term mammal as used herein is intended to include, but is not limited to, humans, laboratory animals, domestic pets, and farm animals.

A "therapeutically effective amount" or "effective amount" as used herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

As used herein, the terms "effective response" of a patient or a patient's "responsiveness" to treatment with the agents, or "therapeutic effect" refers to the clinical or therapeutic benefit(s) imparted to a patient upon administration. As used herein, an "unexpected therapeutic effect" of the treatment of the invention is the ability to produce marked anti-cancer effects in a patient, so that the patient benefits from the treatment overall. The efficacy, i.e., therapeutic effect(s), of the treatment of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, include any one or more including, but not limited to: extending survival (including overall survival (OS) and progression free survival (PFS)); resulting in an objective response (including a complete response (CR) or a partial response (PR)); tumor regression, tumor weight or size shrinkage; longer time to disease progression; increased duration of survival; longer PFS; improved OS rate; increased duration of response; and improved quality of life and/or improving signs or symptoms of cancer, etc. Novel approaches to determine efficacy, i.e., therapeutic effect(s), of the present invention can be optionally employed, including, for example, measurement of plasma, serum, or urinary markers and measurement of response through radiological imaging.

As used herein, the term "adverse event (AE)" means any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally or permanently associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.

As used herein, the term dose-limiting toxicities (DLTs) means any Antibody 1 related AE that occurs during Cycle 1 and does not improve to Grade <2 (unless stated otherwise), despite medical management, within 7 days of documented occurrence. In the JSCA study protocol, the following are considered DLTs (subject to exception): Grade 4 neutropenia lasting >7 days; Grade 3 or 4 neutropenia complicated by fever >38.0°C or infection; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia complicated by hemorrhage; Grade 3 or 4 anemias; Grade 3 or 4 nonhematologic toxicity. In JSCA, Grade 3 or 4 nonhematologic AEs DLT exceptions include: Grade >3 liver function test (LFT) abnormality, such as alkaline phosphatase, gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), without evidence of hepatic injury; transient Grade >2 bilirubin elevation in the presence of known liver metastases lasting <7 days; laboratory abnormalities that are reversible to Grade <2 or baseline levels within 7 days after initial documentation or that are deemed not clinically significant; and Grade 3 elevation of CK without elevation in serum and urine myoglobin.

In the present invention, any suitable method or route can be used to administer Antibody 1, and optionally, to co-administer anti -neoplastic agents and/or antagonists of other receptors.

Antibody 1, where used in a mammal for the purpose of treatment, is preferably formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g. Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22^nd Edition, Pharmaceutical Press, 2012. Antibody 1 is preferably formulated as pharmaceutical compositions administered by a route that makes the compound bioavailable. Preferably, Antibody 1 compositions are for parenteral administration, such as intravenous (i.v.) administration. Such pharmaceutical compositions and processes for preparing same are well known in the art. {See e.g., id).

As used herein, the term "creatine kinase (CK)" levels mean the concentration of CK in blood, which may indicate muscle damage and can be measured by a peripheral blood test utilizing a standardized spectrophotometric technique.

As used herein, the term "myoglobin level" means the concentration of myoglobin found in bodily fluids including urine and blood serum. In urine, myoglobins can be measured by a standardized immunochemiluminometric assay (ICMA). In serum, myoglobin's can be measured by a standardized eletrochemiluminescence immunoassay (ECLIA) or enzyme-linked immunosorbent assay (ELISA).

As used herein, the term "CSF-1" is the ligand to CSF-1R. As used herein, circulating CSF-1 means the quantity of ligand in the blood. Circulating CSF-1 can be measured by ELISA.

As used herein, the term "CD14^Dim CD16^{Bri ht} cells" mean the concentration of white blood cells in peripheral blood which express cell surface markers, including but not limited to CD45 (protein tyrosine phosphatase, receptor type c) and ULA-DR (Human leukocyte antigen, antigen D related), and which have low expression of CD 14 (Myeloid Cell-Specific Leucine-Rich Glycoprotein), and highest expression of CD 16 (Fc gamma receptor III) as measured by Fluorescence-activated cell sorting (FACS). The CD16^Bnght population is determined as the highest level of measureable expression as measured by FACS. The CD14^Dim population is determined as those cells expressing CD14, lower than the brightest CD 14 positive population, but higher in expression than negative controls. CD14^Bnght population is determined as the cells which express the highest measurable level of CD 14, but express no CD 16.

The following non-limiting examples and assays further illustrate the present invention and the unexpected benefits thereof.

The following assays, analyses, and results illustrate the unexpected improvement of the dosing regimen for Antibody 1 based on as preclinical modelling, PK, and PD analyses.

The following assays and clinical study designs further illustrate the invention, but should not be construed to limit the scope of the invention in any way. Antibody 1 can be made, for example, according to the disclosure in WO2011/123381.

JSCA ("Phase 1 Study of Antibody 1, a Monoclonal Antibody Targeted to the CSF-1 Receptor (CSF-1R), In Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No Standard Therapy is Available", NCT01346358)

Primary Objectives:

The primary objectives are to establish the safety profile and characterize the PK profile of Antibody 1 in the treatment of subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy is available.

Secondary Objectives:

The secondary objectives are: (1) Part A only: To define the recommended Phase 2 dose using weight-based dosing; (2) Part B only: To define the recommended Phase 2 dose using non-weight-based dosing; (3) To characterize the PD profile of Antibody 1 on circulating levels of CSF-1; and (4) To assess the development of antibodies against Antibody 1 (immunogenicity).

Study Design:

An open-label, dose-escalation, Phase 1 study of approximately 72 subjects in 2 parts: Part A consists of dose escalation of Antibody 1 using weight-based dosing; Part B consists of dose escalation of Antibody 1 using non-weight-based dosing. Actual enrollment is dependent on the number of DLTs observed and the resultant size of each cohort.

This open-label study is open to subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy is available. Solid tumors include but are not limited to breast (including but not limited to triple negative, hormone receptor positive, HER2 over expressing, and hormone receptor expressing but without HER2 over expression), ovarian (including but not limited to fallopian tube cancer, primary peritoneal, and epithelia), melanoma, lung (including but not limited to non-small cell). Dose cohorts, including revised dose and revised dosing schedule, are summarized in Table 1. For each cohort, one cycle is 6 weeks. In each cohort, subjects receive Antibody 1 by intravenous (IV.) infusion (with an observation period for weekly [QW] and every-2-week [Q2W] cohorts in Cycle 1 only, as described in Table 1).

Table 1 Revised Dose Cohort Assi nment

Perform and memorialize numerous physiological measurements of the patients including but not limited to creatine kinase (CK) levels, elevated urine and serum myoglobin, measurements of circulating CSF-1, and FACS of CD14^Dim CD16^{Bri ht} cells in circulation.

Results:

As of the 6 September 2016 data cut-off date, 6 patients have been treated in Cohort 1 (2.5 mg/kg QW), 4 patients in Cohort 2 (0.3 mg/kg QW), 3 patients in Cohort 3 (0.6 mg/kg QW), 6 patients in Cohort 4 (1.25 mg/kg Q2W), 5 patients in Cohort 5 (1.25 mg/kg QW), 5 patients in a maximum tolerated dose (MTD) expansion cohort at the same dose as Cohort 4 (1.25 mg/kg Q2W), 3 patients in Cohort 6a (lOOmg QW), and 3 patients in Cohort 7a (150mg QW). This study is ongoing.

As background, 2 of the first 3 patients in Cohort 1 experienced AE thus did not complete Cycle 1. Per the protocol, 3 additional patients were treated in Cohort 1. These additional patients also exhibited adverse advents. However, those events were not classified as a DLT upon comprehensive clinical evaluation of the patient due to the lack of clinical signs and symptoms of organ toxicity.

Based on enzyme levels and pre-clinical dose-response correlations and serum enzyme levels of the preliminary data, continued dose escalation in Study JSCA was considered likely to result in a DLT. Therefore, it was considered medically prudent not to dose escalate beyond Cohort 1 with the originally planned dosage schedule, which was 5, 10, 20, and 30 mg/kg QW.

Thus, in order to better characterize the Antibody 1 dose-response effect on the monocyte/macrophage system and on various serologic and hematologic parameters, the dosing scheme and schedule for Study JSCA were revised to reflect dose reductions and prolonged administration intervals. Under the revised dose-escalation plan, the dosages for subsequent dose explorations were as follows: Cohort 2 (0.3 mg/kg QW), Cohort 3 (0.6 mg/kg QW), Cohort 4 (1.25 mg/kg Q2W), Cohort 5 (1.25 mg/kg QW), and Cohort 6 (2.5 mg/kg Q2W) as shown in Table 1.

Under this revised dose-escalation plan, patients were treated at dosages up to 1.25 mg/kg QW (Cohort 5). Two of the Cohort 5 patients experienced DLTs, so the recommended Phase 2 dose was identified as 1.25 mg/kg Q2W (Cohort 4). However, subsequent analysis of clinical data suggested sub-maximal target engagement on a Q2W schedule as opposed to QW dosing. Additionally, exploratory graphical analysis of the PK of Antibody 1 in weight- based dosing Cohorts 1 to 5 indicated no clear relationship between body weight and drug clearance. Therefore, additional cohorts were added (Part B of the study) in a protocol amendment, to evaluate safety, PK, and PD of non-weight-based dosing of Antibody 1 administered on a weekly schedule.

Consistent blockade of the CSF-1R signaling pathway is demonstrated by persistent elevation of circulating CSF-1 levels as well as reduction of the number of circulating non-classical/inflammatory monocytes, (CD14^dim CD 16 ^nght cells in peripheral circulation as determined by fluorescent antibody cell sorting (FACS)). Thus, increases in CSF-1 serum and decreases in CD14^dim CD16 ^nght cells in peripheral circulation are measures of the PD effect of Antibody 1. The recommended phase 2 dose initially determined in Part A of Study JSCA was 1.25mg/kg Q2W. However, subsequent PD and PK analyses of the preliminary data revealed intermittent target engagement with every 2 week dosing (dose level 4) compared to weekly dosing (dose level 5); as well as minimal correlation for drug clearance and body weight. Tables 2, 3, 6 and 7 provide preliminary patient specific results.

Based upon the PD and PK results from Part A of Study JSCA, the study was amended to explore additional non-weight based dosages on weekly administration schedules. In Part B of Study JSCA three patients were treated at 100 mg QW; none of these patients experienced a dose limiting toxicity (DLT). Therefore three additional patients were treated at the next higher dose level of 150 mg QW. One of the three patients experienced a DLT event of elevated creatine kinase in conjunction with elevated urine and serum myoglobin. At this point PD data suggested little difference in terms of target engagement (as indicated by circulating CSF-1 and CD14^Dim CD16^Bnght cells in circulation) between the dose of lOOmg QW and 150mg QW but given clinical evidence of increased toxicity noted at the 150mg QW dose, the dose of lOOmg QW (dose level 6a) was determined to be the new recommended phase 2 dose. Tables 4, 5, 8 and 9 illustrate the minimal difference in maximum CSF-1 levels as well as changes in the observed number of CD14^Dim CD16^Bnght cells in circulation between the patients treated at lOOmg QW versus 150mg QW as based on the preliminary data. Table 2: Dose Level 4 (1.25mg/kg Q2W) Mean Circulating CSF-1

Table 3 : Dose Level 5 (1.25mg/kg QW) Mean Circulating CSF-1

Table 4: Dose Level 6a (lOOmg QW) Mean Circulating CSF-1

Table 5: Dose Level 7a 150m QW Mean Circulatin CSF-1

Table 6: FACS Results CD14^Dim CD16^Bnght) at Dose Level 4 (1.25mg/kg Q2W)

Table 7: FACS Results CD14^Dim CD16^Bnght) at Dose Level 5 (1.25mg/kg QW)

Table 8: FACS Results (CD14^Dim CD16^Bnght) at Dose Level 6a (lOOmg QW)

Table 9: FACS Results CD14^Dim CD16^Bnght) at Dose Level 7a (150mg QW)

Conclusion:

Based on the consistent increase in CSF-1 levels, and decrease of CD14^dim and CD16^bnght cell in circulation, a dose regimen of about 100 mg every week was determined to be safe and thus has become the recommended phase 2 dose.

JSCB ("Phase 1 Study to Identify the Immunomodulatory Activity of Antibody 1 in

Patients With Advanced, Refractory Breast or Prostate Cancer", NCT02265536) Primary Objectives:

The primary objectives are to document the immunomodulatory activity of Antibody 1 treatment in patients with advanced, refractory breast or prostate cancers, according to the following measures: (1) changes from baseline over time in peripheral blood immune cell subsets, as determined by flow cytometric analysis using an antibody panel; and (2) changes from baseline over time in serum cytokines, as determined by Meso Scale Discovery (MSD) multiplex cytokine immunoassay technology or ELISA.

Secondary Objectives:

The secondary objectives include but are not limited to are: (1) to evaluate the safety and toxicity profile of Antibody 1, as assessed by the Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0); (2) to assess the PK serum concentrations of Antibody 1; (3) to document antitumor activity, per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and immune-related RECIST (irRECIST); and (4) to assess the development of antibodies against Antibody 1 (immunogenicity), as assessed by a validated immunogenicity assay.

Study Design:

A single-center, open-label, nonrandomized, noncontrolled Phase 1 study of IV. Antibody 1 in patients with advanced, refractory breast or prostate cancer. Eligible patients receive Antibody 1 as an infusion, suggested to be administered over approximately 90 minutes for the first infusion, decreasing by 30 minutes for subsequent infusions, until administered over 30 minutes.

Table 10: Summary of Dosing Regimens in JSCB

Enrollment sequentially, starting with the assignment of patients to Dosage A (Antibody 1, 1.25 mg/kg every 2 weeks [Q2W] of a 6-week cycle), then assignment patients to Dosage B (Antibody 1, 1.0 mg/kg on Weeks 1, 2, 4, and 5 of a 6-week cycle) once the Dosage A cohort is fully enrolled. Once the Dosage B breast cancer cohort is fully enrolled, assign patients with breast cancer to Dosage C (Antibody 1, 100 mg QW of a 6-week cycle) or D (Antibody 1, 100 mg Q2W of a 6-week cycle) on an alternating basis until 5 patients are enrolled to each of Dosages C and D. Once 5 patients are enrolled to each of Dosages C and D, review clinical data to determine if enrollment of an additional 5 patients to each of Dosages C and D is warranted.

Patients receive Dosage A, B, C, or D for one 6-week cycle or until the patient meets one or more criteria for study discontinuation. After 1 cycle, patients who are benefitting from study treatment (that is, no disease progression or unacceptable toxicity) may continue to receive study treatment at the same dose and schedule until there is clear (confirmed) evidence of disease progression or other withdrawal criteria are met. At the time of study completion, if a patient continues to benefit from study treatment, that patient may enter the continued access period.

In addition, for all patients, perform blood work and tumor biopsy procedures. For patients with measurable disease per RECIST, clinical endpoints for response will be standard tumor response as determined by RECIST 1.1 and irRECIST criteria. For the prostate cancer cohort only, progression in bone will be determined by using the PCWG2 criteria.

Results:

As of the data cut-off date, 28 January 2016, 9 patients have been treated with 1.25 mg/kg LY3022855 Q2W of every 6-week cycle (Dosage A) and 5 patients have been treated with 1.0 mg/kg LY3022855 on Weeks 1, 2, 4, and 5 of every 6-week cycle (Dosage B). This study is ongoing. Two of five patients with breast cancer treated at a dose of 1.25 mg/kg Q2W were documented to have tumor regression on radiological imaging. None of the five patients with breast cancer treated at a dose of 1 mg/kg on Weeks 1, 2, 4, 5 were documented to experience tumor regression. Although the PD data suggests weekly dosing (QW) will lead to a more consistent inhibition of CSF-1R, the clinical data suggest that the every other week dosing (Q2W) (intermittent inhibition of CSF-1R) may be clinically efficacious and warrants further investigation. Based upon these results, further exploration in a breast cancer population utilizing the recommended phase 2 dose of 100 mg QW as well as a dose of 100 mg Q2W will be performed. A Q2W schedule was decided to be studied given that the two patients with tumor reduction were treated on a Q2W schedule.

As of the data cut-off date, 13 November 2017, 6 patients have been treated with 100 mg LY3022855 QW of every 6-week cycle (Dosage C) and 5 patients have been treated with 100 mg LY3022855 Q2W of every 6-week cycle (Dosage D). Efficay was not an endpoint of the JSCB study; however none of the patients with breast cancer were documented to have tumor regression on radiological imaging. Many factors including but not limited to low number of patients studied, tumor type (i.e. breast cancer), patient histology including but not limited to disease stage and previous treatments, distribution of metastatic sites, and biomarkers (including but not limited to HER2 status and hormone receptor status), are believed to impact any potential preliminary efficacy study findings. Further study is needed to determine efficacy.

Conclusions

In conclusion, based on the totality of work to date, including preliminary data and analysis (as the studies are on-going) and trends seen in the aforementioned PK/PD, exposure-response analysis, and modelling, the Antibody 1 dosing regimen of the present invention offers a safe and efficacious dose regime. The present invention, currently being explored in the Phase 1 Studies (JSCA, JSCB, JSCC), are expected to maximize the number of patients exposed to potentially therapeutic Antibody 1 serum levels, with minimal risk of increased toxicity, which can further optimize the benefit-risk ratio, and provide benefit for a patient population with a current unmet need.

Accordingly, the present invention provides an opportunity for improved patient outcomes, while minimizing risk of increased toxicity. Amino Acid Sequences

SEQ ID NO: 1 (HCVR Antibody 1)

QDQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGEGLEWVAVIWY DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDYEVDYG MDVWGQGTTVTVAS

SEQ ID NO: 2 (LCVR Antibody 1)

AIQLTQSPSSLSASVGDRVTITCRASQGISNALAWYQQKPGKAPKLLIYDASSLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPWTFGQGTKVEIK

SEQ ID NO: 3 (HC Antibody 1)

QDQLVESGGGVVQPGRSLRLSC AASGFTF S S YGMHWVRQ APGEGLEWVAVIW Y

DGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGDYEVDYG

MDVWGQGTTVTVASASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS

WNSGALT SGVHTFP A VLQ S SGLYSLS S V VT VP S S SLGTQT YICNVNHKP SNTKVD

KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH

EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH

EALHNHYTQKSLSLSPGK

SEQ ID NO: 4 (LC Antibody 1)

AIQLTQSPSSLSASVGDRVTITCRASQGISNALAWYQQKPGKAPKLLIYDASSLES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPWTFGQGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKD STYSLSSTLTL SK AD YEKHK V Y ACE VTHQGL S SP VTK SFNRGEC

SEQ ID NO: 5 (HCDR1 Antibody 1)

SYGMH

SEQ ID NO: 6 (HCDR2 Antibody 1) VIWYDGSNKYYADSVKG

SEQ ID NO: 7 (HCDR3 Antibody 1)

GDYEVDYGMDV

SEQ ID NO: 8 (LCDR1 Antibody 1)

RASQGISNALA

SEQ ID NO: 9 (LCDR2 Antibody 1)

DASSLES

SEQ ID NO: 10 (LCDR3 Antibody 1) QQFNSYPWT

Claims

WE CLAIM:

1. Antibody 1 for use in the treatment of cancer, wherein Antibody 1 is administered at a dose of about 100 mg once a week or at a dose of about 100 mg once every two weeks.

2. Antibody 1 for use according to Claim 1, wherein Antibody 1 is administered at a dose of about 100 mg once a week.

3. Antibody 1 for use according to Claim 1, wherein Antibody 1 is administered at a dose of about 100 mg once every two weeks.

4. Antibody 1 for use according to any one of Claims 1-3, wherein the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer.

5. Use of Antibody 1 for the preparation of a medicament for the treatment of cancer wherein Antibody 1 is administered at a dose of about 100 mg once a week or at a dose of about 100 mg once every two weeks.

6. Use of Antibody 1 according to Claim 5, wherein Antibody 1 is administered at a dose of about 100 mg once a week.

7. Use of Antibody 1 according to Claim 5, wherein Antibody 1 is administered at a dose of about 100 mg once every two weeks.

8. Use of Antibody 1 according to any one of Claims 5-7, wherein the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer.

9. A medicament comprising Antibody 1, wherein the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks.

10. The medicament according to Claim 9, for use in the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer.

11. A pharmaceutical composition comprising Antibody 1, wherein to a patient, the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks.

12. The pharmaceutical composition according to Claim 11, for use in the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer.

13. A kit comprising a pharmaceutical composition comprising Antibody 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients wherein the Antibody 1 is administered at a dose of about 100 mg once a week or about 100 mg of Antibody 1 once every two weeks.

14. The kit according to Claim 13, wherein the kit is used for the treatment of breast cancer, ovarian cancer, melanoma, or lung cancer.

15. A method of administering an effective amount of Antibody 1 to a patient in need thereof comprising administering a dose of about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks.

16. The method of Claim 15, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week.

17. The method of Claim 15, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks.

18. The method of Claim 15, wherein the patient has breast cancer, ovarian cancer, melanoma, or lung cancer.

19. A therapeutic regimen for Antibody 1 in the treatment of cancer comprising about 100 mg of Antibody 1 administered once a week or about 100 mg of Antibody 1 once every two weeks.

20. The therapeutic regimen of Claim 19, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week.

21. The therapeutic regimen of Claim 19, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks.

22. The therapeutic regimen of Claim 19, wherein the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer.

23. A method of reducing the risk of disease progression of a patient having cancer comprising administering about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks.

24. The method of Claim 23, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week.

25. The method of Claim 23, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks.

26. The method of Claim 23, wherein the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer.

27. A method of treating cancer in a patient in need there of comprising administering about 100 mg of Antibody 1 once a week or about 100 mg of Antibody 1 once every two weeks.

28. The method of Claim 27, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once a week.

29. The method of Claim 27, wherein Antibody 1 is administered at a dose of about 100 mg of Antibody 1 once every two weeks.

30. The method of Claim 27, wherein the cancer is breast cancer, ovarian cancer, melanoma, or lung cancer.