Methods for treating SSTR positive cancer

Abstract

Provided herein are methods of treating somatostatin receptor-positive, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer using 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

Description

[0001] METHODS FOR TREATING SSTR POSITIVE CANCER

[0002] RELATED APPLICATION

[0003]

[0001] This application claims the benefit of US Provisional Application No. 63 / 667,313, filed July 3, 2024, which is incorporated herein by reference in its entirety for any purpose.

[0004] FIELD

[0005]

[0002] The present disclosure relates generally to use of radiopharmaceutical conjugates and compositions for treating somatostatin receptor (SSTR) expressing breast cancer.

[0006] BACKGROUND

[0007]

[0003] Recent data from 185 countries estimated over 2 million new breast cancer cases and over 0.6 million breast cancer deaths annually, representing more than 11% of all new cancer cases and 6% of all cancer deaths (Bray et al. CA Cancer J Clin. 2018; 68(6):394-424). In the United States (US), it is estimated that more than 3.8 million women have a history of breast cancer, including 150,000 living with metastatic disease, out of which three quarters were diagnosed in initial stages. One in every 8 women will be diagnosed with cancer, most between 50 to 69 years of age (DeSantis et al. CA Cancer J Clin. 2019; 69(6):438-451).

[0008]

[0004] Approximately 80% of newly diagnosed breast cancers express ERs, and 70% express progesterone receptors (Iqbal et al. Jama. 2015; 313(2): 165-73). Most of these patients benefit from sequential hormone-based treatments, with median OS rates ranging between 35 and 47 months (Schettini et al. J Natl Cancer Inst. 2020; 112(11): 1089-1097). Nevertheless, some of these patients eventually become hormone refractory and only have cytotoxic treatment options such as chemotherapy or antibody-drug conjugates (ADCs). Among these hormone-refractory patients, median OS is approximately 19 months with single-agent chemotherapy but may be as low as 12 months for patients who progressed after multiple lines of treatment (Litton et al. N Engl J Med. 2018; 379(8):753-763; Rugo et al. Lancet. 2023; 402(10411): 1423-1433).

[0009]

[0005] For treatment planning, the most important classification is based on immunophenotypic characteristics, such as ER and progesterone receptor expression, and human epidermal growth factor receptor 2 (HER2) overexpression. Estrogen and progesterone receptors are overexpressed in approximately 70% of breast cancer patients and are associated with response to hormone-based therapies. In addition to being a marker of poor prognosis, HER2 overexpression, present in approximately 20% of breast cancers, enables HER2 -targeted treatment options. (Tsang et al. Adv Anat Pathol. 2020; 27(l):27-35).

[0010]

[0006] While most cases of early breast cancer may be cured with surgery with or without adjuvant / neoadjuvant therapies, there are currently no curative treatment options for unresectable and / or locally advanced or metastatic disease (advanced breast cancer [ABC]). Historically, chemotherapy has been the most widely recommended and indicated treatment for all types of breast cancer, but recent advances have provided targeted options for most patients, utilizing anti -endocrine therapy, HER2-directed therapy, and ADCs.

[0011]

[0007] Although cytotoxic treatments are efficacious, the durability of response becomes shorter with each subsequent line of chemotherapy. Recent studies in this setting show a median PFS of less than 6 months with relatively high toxicity rates (Modi et al. J Clin Oncol. 2022 40(17)_suppl (June 10, 2022); Rugo et al. J Clin Oncol.40, 2022; (40):S17(LBA1001); Rugo et al. 2023; Bardia et al. Annals of Oncology. 2023; 34S(2);S1264). With the introduction of ADCs, especially in earlier lines of therapy, the efficacy of subsequent chemotherapy may become even lower after these novel, more potent cytotoxic options, highlighting the need for novel targeted therapies beyond endocrine and ADCs. Thus, patients with ER+, HER2-negative ABC who have exhausted hormonal therapy have a high unmet need, especially after progression following multiple chemotherapy and / or ADC regimens. Thus, there is a need to provide new treatments for patients with breast cancer.

[0012] SUMMARY

[0013]

[0008] Provided herein are methods of treating somatostatin receptor-positive (SSTR+), estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer in a patient, comprising administering to the patient225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

[0014]

[0009] Also provided herein is225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof or a composition (e.g., pharmaceutical composition) comprising225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof for treating somatostatin receptor-positive (SSTR+), estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer in a patient.

[0015]

[0010] Also provided herein are uses of a225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating somatostatin receptorpositive (SSTR+), estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer in a patient.

[0016] BRIEF DESCRIPTION OF DRAWINGS

[0017] [OH] FIG. 1 provides the study design of Example 1.

[0018] DETAILED DESCRIPTION

[0019]

[0012] The following description and examples illustrate embodiments of the present disclosure in detail. It is to be understood that this present disclosure is not limited to the particular embodiments described herein and as such can vary. Those of skill in the art will recognize that there are numerous variations and modifications of this present disclosure, which are encompassed within its scope.

[0020]

[0013] Although various features of the present disclosure may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present disclosure may be described herein in the context of separate embodiments for clarity, the present disclosure may also be implemented in a single embodiment.

[0021]

[0014] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0022]

[0015] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0023]

[0016] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0024]

[0017] DEFINITIONS

[0025]

[0018] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0026]

[0019] As used herein, “225Ac-DOTA-TATE,” “225Ac-DOTATATE,” “Actinium Ac 225 dotatate,” “Actinium (225Ac) oxodotreotide,” and “actinium-225 [225Ac]-DOTATATE,” refer to (2,2',2"-(10-(2-(((R)-l-(((4R,7S,10S,13R,16S,19R)-13-((lH-indol-3-yl)methyl)-10-(4- aminobutyl)-4-(((l S,2R)- 1 -carboxy-2-hydroxypropyl)carbamoyl)- 16-(4-hydroxybenzyl)-7-((R)- l-hydroxyethyl)-6,9,12,15,18-pentaoxo-l,2-dithia-5,8,l l,14,17-pentaazacycloicosan-19- yljamino)- 1 -oxo-3 -phenylpropan-2-yl)amino)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- l,4,7-triyl)triacetate;actinium-225(3+)).225Ac-DOT A-T ATE can be represented, e.g., by the

[0027] between225Ac and the metal chelator is not shown in structural formulas lb and Ic. In some embodiments, for example in acidic aqueous conditions, the radionuclide actinium-225 exists in a salt form with DOTA-TATE, e.g., as225Ac3+. In some embodiments,225Ac-DOT A-T ATE is in salt form. A person of ordinary skill would appreciate that the dissociation of an acid can depend on the pH value of the environment and its pK value. Accordingly, in some embodiments, a conjugate described herein can exist in a completely ionized, partially ionized or non-ionized form.225Ac-DOT A-T ATE may be supplied (e.g., to a patient) in the form of a pharmaceutical composition, e.g., a pharmaceutical composition comprising225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.225Ac-DOTA-TATE and pharmaceutical compositions thereof can be prepared according to the methods described in, e.g., U.S. Patent No. 11,497,822 Bl and WO 2023 / 191839 A2, each of which is incorporated herein by reference.

[0028]

[0020] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, reference to “a stabilizer” includes a plurality of such stabilizers, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0029]

[0021] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5 -fold, or within 2-fold, of a value.

[0030]

[0022] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0031]

[0023] “Radiolysis” refers to the decay of radionuclides accompanied by emission of energy in the form of alpha, beta and / or gamma radiations. The energy that goes into the drug-containing formulation can break chemical bonds and can generate reactive chemical species from solvent molecules, which may further decompose the radiopharmaceutical drug directly and / or indirectly.

[0032]

[0024] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0033]

[0025] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof. As used herein, “treating” includes the concepts of “alleviating”, which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and / or the associated side effects. The term “treating” also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.

[0034]

[0026] The term "therapeutically effective amount" as used herein to refer to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of a composition may vary depending on factors such as the individual's condition (e.g., age, sex, and weight), the radiopharmaceutical conjugate, and the method of administration (e.g., oral or parenteral). A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0035]

[0027] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0036]

[0028] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0037]

[0029] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In certain embodiments, the mammal is a human.

[0038]

[0030] As used herein, "cancer" refers to a condition characterized by abnormal, unregulated, malignant cell growth.

[0039]

[0031] As used herein, "tumor" and "lesion" are used interchangeably.

[0040]

[0032] As used herein, "resistant" and "refractory" refer to tumor cells that survive treatment with a therapeutic agent. Such cells may have responded to a therapeutic agent initially, but subsequently exhibited a reduction of responsiveness during treatment, or did not exhibit an adequate response to the therapeutic agent in that the cells continued to proliferate in the course of treatment with the agent. Examples of a resistant or refractory tumor is one where the treatment-free interval following completion of a course of therapy for a patient having the tumor is less than 6 months (e.g., owing to recurrence of the cancer) or where there is tumor progression during the course of therapy. As used herein, the term “somatostatin receptor typepositive” or “SSTR+” refers to breast cancer that comprises at least one RECIST-measurable lesion that is SSTR-PET positive. A lesion is SSTR-PET positive, in accordance with this disclosure, when maximum standard uptake value (SUVmax) is higher than liver mean standard uptake value (SUVmean) on SSTR-PET imaging. RECIST-measurable lesions can be identified, for example, by computed tomography (CT) or magnetic resonance imaging (MRI).

[0041]

[0033] As used herein, the term “somatostatin receptor type 2-positive” or “SSTR2+” refers to breast cancer that comprises at least one RECIST-measurable lesion that is SSTR2-PET positive. A lesion is SSTR2-PET positive, in accordance with this disclosure, when maximum standard uptake value (SUVmax) is higher than liver mean standard uptake value (SUVmean) on SSTR2-PET imaging.

[0042]

[0034] THERAPEUTIC METHODS

[0043]

[0035] Provided herein are methods of treating somatostatin receptor-positive (SSTR+), estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in a patient. The methods comprise administering to the patient 225Ac-DOTA- TATE, or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of 225Ac-DOTA-TATE, or a pharmaceutically acceptable salt thereof). In some embodiments, the breast cancer is recurrent or refractory. In some embodiments, the breast cancer is somatostatin receptor type 2-positive (SSTR2+).

[0044]

[0036] In some embodiments, the breast cancer comprises at least one RECIST-measurable lesion and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of RECIST-measurable lesions are SSTR-PET positive. In some embodiments, at least 50% of RECIST-measurable lesions are SSTR-PET positive. In some embodiments, at least 60% of RECIST-measurable lesions are SSTR-PET positive. In some embodiments, at least 70% of RECIST-measurable lesions are SSTR-PET positive. In some embodiments, at least 80% of RECIST-measurable lesions are SSTR-PET positive.

[0045]

[0037] In some embodiments, the breast cancer comprises at least one RECIST-measurable lesion and at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of RECIST-measurable lesions are SSTR2-PET positive. In some embodiments, at least 50% of RECIST-measurable lesions are SSTR2-PET positive. In some embodiments, at least 60% of RECIST-measurable lesions are SSTR2-PET positive. In some embodiments, at least 70% of RECIST-measurable lesions are SSTR2-PET positive. In some embodiments, at least 80% of RECIST-measurable lesions are SSTR2-PET positive.

[0046]

[0038] In some embodiments, a RECIST-measurable lesion is identified on a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan. In some embodiments, a RECIST-measurable lesion is identified on a CT scan. In some embodiments, a RECIST- measurable lesion is identified on a MRI scan.

[0047]

[0039] Breast cancer is “estrogen receptor-positive” or “ER+” in accordance with this disclosure if >1% of tumor cells stain positive for estrogen receptor (ER) on immunohistochemistry (IHC), or the breast cancer has an Allred IHC score of >3 / 8. In some embodiments, >1% of breast cancer cells stain positive for ER onIHC. In some embodiments, the breast cancer has an Allred IHC score of >3 / 8.

[0048]

[0040] Breast cancer is “human epidermal growth factor receptor 2-negative” or “HER2-” in accordance with this disclosure if it has an IHC score of 0 or 1, or IHC score of 2 with negative in situ hybridization (ISH). It will be appreciated that HER2-, as used herein, includes HER2- low and -ultra low breast cancers. In some embodiments, the breast cancer has an IHC score of 0 or 1. In some embodiments, the breast cancer has an IHC score of 2 with negative ISH.

[0049]

[0041] In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is progesterone receptor-negative (PR-).

[0050]

[0042] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) score of 2 prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) score of 1 prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) score of 0 prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. See Table 17 for The Eastern Cooperative Oncology Group (ECOG) Performance Status Scale.

[0051]

[0043] In some embodiments, the patient has creatinine clearance (CrCl) >60 mL / min prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

[0052]

[0044] In some embodiments, prior to administration of 225 Ac-DOT A-TATE or a pharmaceutically acceptable salt thereof, the patient has at least one of the following laboratory results: a) hemoglobin concentration >5.0 mmol / L (>8.0 g / dL); b) absolute neutrophil count (ANC) >1000 cells / pL (>1000 cells / mm3); and / or c) platelets >100 x 109 / L (100 x 103 / mm3). In some embodiments, the patient has one of the laboratory results. In some embodiments, the patient has two of the laboratory results. In some embodiments, the patient has three of the laboratory results.

[0053]

[0045] In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is locally advanced, for example, has progressed locally, but has not yet spread outside of the breast and lymph nodes. In some embodiments, the breast cancer is unresectable, for example, it cannot be entirely removed through surgery. In some embodiments, the breast cancer is locally advanced and unresectable. In some embodiments, the breast cancer is metastatic. In some embodiments, the metastatic breast cancer has spread to the bones, liver, lungs, or brain. In some embodiments, the breast cancer is metastatic and the patient has bone metastases.

[0054]

[0046] In some embodiments, the breast cancer is refractory to hormone therapy, for example, as defined by the European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) guidelines (Cardoso et al. Ann Oncol. 2023; 34:S1260-S1261).

[0055]

[0047] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 125 pCi to about 275 pCi. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 125 pCi, 175 pCi, 225 pCi, or 275 pCi. In some embodiments,225AC-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of from about 125 pCi to about 175 pCi. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of from about 175 pCi to about 225 pCi. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of from about 225 pCi to about 275 .Ci. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 125 pCi. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 175 pCi. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 225 pCi. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 275 pCi.

[0056]

[0048] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 4.6 MBq, 6.5 MBq, 8.3 MBq, or 10.2 MBq. In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of from about 4.6 MBq to about 10.2 MBq. In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of from about 4.6 MBq to about 6.5 MBq. In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of from about 6.5 MBq to about 8.3 MBq. In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of from about 8.3 MBq to about 10.2 MBq. In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of 4.6 MBq. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of 6.5MBq. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of 8.3 MBq. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a radioactivity dose of 10.2 MBq.

[0057]

[0049] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once about every 4 weeks to about every 8 weeks (e.g., once every four to eight weeks). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once about every 4 weeks to about every 6 weeks (e.g., once every four to six weeks). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once about every 6 weeks to about every 8 weeks (e.g., once every six to eight weeks). In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once about every 6 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once every 6 weeks.

[0050] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once every 28 days ± 3 days. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once every 42 days ± 3 days. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient once every 56 days ± 3 days.

[0058]

[0051] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 125 pCi once about every 6 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 175 pCi once about every 6 weeks. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 225 pCi once about every 6 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 275 pCi once about every 6 weeks.

[0059]

[0052] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 125 pCi once about every 4 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 175 pCi once about every 4 weeks. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 225 pCi once about every 4 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 275 pCi once about every 4 weeks.

[0060]

[0053] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 4.6 MBq once about every 6 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 6.5MBq once about every 6 weeks. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 8.3 MBq once about every 6 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 10.2 MBq once about every 6 weeks.

[0061]

[0054] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 4.6 MBq once about every 4 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 6.5MBq once about every 4 weeks. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 8.3 MBq once about every 4 weeks. In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of 10.2 MBq once about every 4 weeks.

[0062]

[0055] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered for 1-6 cycles, e.g., 1, 2, 3, 4, 5, or 6 cycles. In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered for 6 cycles.

[0063]

[0056] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered intravenously, e.g., by intravenous infusion.

[0064]

[0057] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a second-line therapy (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOT AT ATE or a pharmaceutically acceptable salt thereof is administered to the patient as a third-line therapy (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fourth-line therapy (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fifth-line therapy (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fifth or greater-line therapy (e.g., as a monotherapy or part of a combination therapy).

[0065]

[0058] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a first-line therapy for unresectable or metastatic breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac- DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a second-line therapy for unresectable or metastatic breast cancer (e.g. , as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a third-line therapy for unresectable or metastatic breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fourth-line therapy for unresectable or metastatic breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a first-line therapy for unresectable breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a second-line therapy for unresectable breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a third-line therapy for unresectable breast cancer (e.g., as a monotherapy or part of a combination therapy). In some embodiments,225AC-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fourth-line therapy for unresectable breast cancer e.g., as a monotherapy or part of a combination therapy).

[0066]

[0059] In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a first-line therapy for metastatic breast cancer e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a second-line therapy for metastatic breast cancer e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a third-line therapy for metastatic breast cancer e.g., as a monotherapy or part of a combination therapy). In some embodiments,225Ac-DOTATATE or a pharmaceutically acceptable salt thereof is administered to the patient as a fourth-line therapy for metastatic breast cancer e.g., as a monotherapy or part of a combination therapy).

[0067]

[0060] In some embodiments, the patient has documented radiologic progression (e.g., by RECIST vl.l) after at least two and no more than four prior lines of chemotherapy or ADC for metastatic breast cancer, with at least one line of therapy comprising, consisting essentially of, or consisting of an ADC. In some embodiments, the patient has radiologic progression (e.g., by RECIST vl.l) after one line of chemotherapy and one line of ADC for metastatic breast cancer. In some embodiments, the patient has radiologic progression (e.g., by RECIST vl.l) after two lines of chemotherapy and one line of ADC for metastatic breast cancer. In some embodiments, the patient has documented radiologic progression (e.g., by RECIST vl.l) after three lines of chemotherapy and one line of ADC for metastatic breast cancer.

[0068]

[0061] In some embodiments, e.g., when the breast cancer is metastatic and the patient has bone metastases, the 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, is admininstered in combination with a bisphosphonate. Thus, some embodiments further comprise administering to thepatient a bisphosphonate. Examples of bisphosphonates include, but are not limited to, zoledronic acid, pamidronate, ibandronate, alendronate, risedronate, alendronate and cholecalciferol, calcium carbonate and risedronate, tiludronate, and etidronate.

[0069] Also provided herein are methods of treating SSTR+, ER+, HER2- breast cancer in a patient, comprising administering to the patient 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof), in combination with an immune checkpoint inhibitor. Thus, some embodiments further comprise administering to the patient an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a programmed death receptor-1 (PD l)-blocking antibody. Examples of PD-1 blocking antibodies include, but are not limited to, pembrolizumab and nivolumab. In some embodiments, the PD-1 blocking antibody is pembrolizumab.

[0070]

[0062] Also provided herein are methods of treating SSTR+, ER+, HER2- breast cancer in a patient, comprising administering to the patient 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof e.g., a therapeutically effective amount of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof), in combination with pembrolizumab. Thus, some embodiments further comprise administering pembrolizumab to the patient. In some embodiments, pembrolizumab is administered to the patient at a dose of 400 mg once every 6 weeks.

[0071]

[0063] Some embodiments further comprise administering an anti -emetic to the patient. In some embodiments, the anti-emetic is administered prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. Suitable anti-emetics are known in the art.

[0072]

[0064] Some embodiments further comprise administering arginine and lysine (e.g., a cocktail of amino acids including arginine and lysine) to the patient. In some embodiments, the arginine and lysine are administered intravenously. In some embodiments, the arginine and lysine are administered prior to administration of 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the arginine and lysine are administered concurrently with 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof. In some embodiments, the arginine and lysine are co-infused with 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

[0073]

[0065] In some embodiments, the patient received one or more prior lines of therapy to treat the breast cancer. In some embodiments, the patient received two or more prior lines of therapy to treat the breast cancer, e.g., 2, 3, 4, 5, 6, or 2-4 prior lines of therapy.

[0074]

[0066] In some embodiments, the prior lines of therapy comprise hormone therapy, a targeted agent, an antibody drug conjugate (ADC), chemotherapy, or a combination thereof.

[0075]

[0067] In some embodiments, the patient received one or more prior lines of hormone therapy. In some embodiments, the patient received one or more prior lines of hormone therapy in combination with a CDK4 / 6 inhibitor. Examples of cyclin-dependent kinase (CDK) 4 / 6 inhibitors include, but are not limited to, palbociclib, riboci clib and abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, or a combination thereof.

[0076]

[0068] In some embodiments, prior therapy (e.g., prior first-line therapy) for the breast cancer includes a combination of an aromatase inhibitor (Al) and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor.

[0077]

[0069] In some embodiments, prior therapy (e.g., prior first-line therapy) for the breast cancer includes monotherapy with fulvestrant. In some embodiments, prior therapy (e.g., prior first- line therapy) for the breast cancer includes fulvestrant in combination with a CDK4 / 6 inhibitor. In some embodiments, prior therapy (e.g., prior first-line therapy) for the breast cancer includes fulvestrant in combination with Al. In some embodiments, prior therapy (e.g., prior first-line therapy) for breast cancer includes a selective estrogen receptor modulator (SERM) monotherapy. Examples of SERM include, but are not limited to, tamoxifen and toremifene.

[0070] In some embodiments, after progression following first-line therapy (e.g., with Al, fulvestrant and / or CDK 4 / 6 inhibitor therapy), a patient is treated with further line(s) of hormone therapy. In some embodiments, patients treated with further line(s) of hormone therapy demonstrated prolonged disease control during first-line therapy. In some embodiments, the further line(s) of hormone therapy includes monotherapy with fulvestrant or Al (or SERM for pre-menopausal women), or a steroidal Al, such as exemestane, with or without everolimus.

[0078]

[0071] In some embodiments, after progression following first-line Al and / or fulvestrant therapy, a patient is treated with a CDK 4 / 6 inhibitor.

[0079]

[0072] In some embodiments, specific tumor mutations enable alternative treatment options for patients after failing first-line treatment. For example, in some embodiments, a patient bearing tumor(s) harboring a PIK3CA mutation is treated with a phosphatidylinositol 3-kinase (PI3K) inhibitor, such as alpelisib, added to hormone therapy. For example, in some embodiments, a patient bearing tumor(s) harboring an estrogen receptor 1 (ESRI) gene mutation is treated with a selective ER degrader, such as elacestrant.

[0080]

[0073] In some embodiments, a patient whose breast cancer has progressed following hormone therapies is treated with therapeutic regimens comprising a cytotoxic agent, for example, conventional (e.g., chemotherapy) or targeted (e.g., ADC) cytotoxic agents. In some embodiments, a patients is treated with a cytotoxic agent as a monotherapy. In some embodiments, a patient is treated with a combination therapy comprising a cytotoxic agent. In some embodiments, a patient with unresectable or metastatic breast cancer is treated with singleagent chemotherapy until progressive disease (PD) or unacceptable toxicity.

[0074] In some embodiments, the patient received one or more prior lines of therapy to treat unresectable or metastatic breast cancer. In some embodiments, the patient received at least two prior lines of therapy to treat the unresectable or metatstatic breast cancer, e.g., 2, 3, 4, 5, 6, or 2- 4 prior lines of therapy. In some embodiments, the patient received two to four prior lines of therapy to treat the unresectable or metatstatic breast cancer. In some embodiments, at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises an ADC. In some embodiments, at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises a chemotherapy. In some embodiments, at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises an ADC, and another of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises a chemotherapy.

[0081]

[0075] In some embodiments, the breast cancer (e.g., unresectable or metastatic breast cancer) progressed after treatment with the prior lines of therapy.

[0082]

[0076] In some embodiments, hormone therapy comprises an aromatase inhibitor (Al), a selective estrogen receptor modulator (SERM), fulvestrant, or a combination thereof. In some embodiments, the hormone therapy is fulvestrant, exemestane, anastrozole, letrozole, tamoxifen, toremifene, or a combination thereof.

[0083]

[0077] In some embodiments, chemotherapy comprises a taxane, anthracycline, antimetabolite, or microtubule inhibitor, or a combination thereof. In some embodiments, the chemotherapy comprises paclitaxel, capecitabine, taxol, doxorubicin, eribulin, gemcitabine, vinorelbine, carboplatin, or a combination thereof. In some embodiments, chemotherapy is single-agent chemotherapy. For example, in some embodiments, the chemotherapy is a taxane, anthracycline, anti-metabolite, or microtubule inhibitor. In some embodiments, the chemotherapy is paclitaxel, capecitabine, taxol, doxorubicin, eribulin, gemcitabine, vinorelbine, or carboplatin.

[0084]

[0078] In some embodiments, the antibody-drug conjugate (ADC) is sacituzumab govitecan- hziy (TRODELVY) or fam-trastuzumab deruxtecan-nxki (e.g. ENHERTU, or trastuzumab deruxtecan).

[0085]

[0079] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. EXAMPLES

[0086]

[0080] The following examples are provided to illustrate certain disclosed embodiments and are not to be construed as limiting the scope of this disclosure in any way. In the Examples discussed below,225Ac-DOTATATE, as defined above, may be referred to as “the radiopharmaceutical conjugate,” “the investigational medicinal product (IMP)” or “the study drug,” interchangeably.

[0087]

[0081] Example 1. Treatment of Breast Cancer

[0088]

[0082] The present study is a phase lb / 2 open-label trial of225Ac-DOT AT ATE alone or in combination with pembrolizumab in subjects with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative, locally advanced and unresectable or metastatic breast cancer expressing somatostatin receptors (SSTRs) and progressed after antibody-drug conjugates and / or chemotherapy (TRACY-1).

[0089]

[0083] Introduction and Study Rationale

[0090]

[0084] The present study evaluates preliminary efficacy of225Ac-DOT AT ATE alone or in combination with pembrolizumab in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative, unresectable, locally advanced and unresectable or metastatic breast cancer (advanced breast cancer [ABC]). The study will enroll late-line patients who have exhausted available hormone therapy and have already failed multiple chemotherapy or antibody-drug conjugate (ADC) regimens.

[0091]

[0085] Table 1 describes the objectives and endpoints of the study.

[0092]

[0086] Table 1. Objectives and Endpoints:

[0093] Abbreviations: ABC=advanced breast cancer; AE=adverse event; BICR=blinded independent central review; BOR=best overall response; CBR=clinical benefit rate; CR=complete response; CTCAE v5.0=Common Terminology Criteria for Adverse Events, version 5.0; DCR=disease control rate; DLT=dose-limiting toxicity; DNA=deoxyribonucleic acid; DOR=duration of response; DRR=durable response rate; ER+=estrogen receptor-positive; ECG- electrocardiogram; HER2= human epidermal growth factor receptor 2; NCI=National Cancer Institute; ORR=objective response rate; OS=overall survival; PD=progressive disease; PET=positron emission tomography; PFS=progression-free survival; PR=partial response;

[0094] RECIST vl.l= response evaluation criteria in solid tumors version 1.1; RNA=ribonucleic acid; RP2D=recommended phase 2 dose; SAE=serious adverse event; SSTR=somatostatin receptor; SSTR+= somatostatin receptor-positive; SUV=standard uptake value; SUVmax=maximum standard uptake value; SUVmean=mean standard uptake value; SUVpeak=peak standard uptake value.

[0087] Study Design: This is a multicenter, open-label, three-part (Dose Escalation followed by Randomization and Expansion) study to determine the RP2D and the treatment regimen for Expansion, and to evaluate preliminary efficacy of 225Ac-DOTATATE alone or in combination with pembrolizumab in locally advanced and unresectable or metastatic ER+, HER2 -negative, breast cancer. Subjects must be considered hormone refractory with limited or no benefit expected from further endocrine therapy and must have progressive disease (PD) following at least two, and no more than four, prior lines of chemotherapy or ADCs; at least one prior line of therapy must have been an ADC. Subjects must also demonstrate adequate hematologic, renal, and hepatic function and documented SSTR-positivity on PET imaging.

[0095]

[0088] After meeting all eligibility criteria, subjects will be sequentially enrolled into one of the Dose Escalation cohorts as defined in Table 4. The 225Ac-DOTATATE starting dose will be 6.5 MBq (Dose Level 1) and escalation to dose levels 2 (8.3 MBq) and 3 (10.2 MBq) will be decided by the Data Review Committee (DRC) based on the dose-limiting toxicity (DLT) rate observed during the DLT-review period (defined as first 6 weeks following the first treatment of 225Ac-DOTATATE) guided by the Bayesian optimal interval (BOIN) design (Yuan et al. Clin Cancer Res. 2016; 22(17):4291 -301 ). If Dose Level 1 is not tolerated, the dose will be deescalated to 4.6 MBq (Dose Level -1). Intermediate doses may be explored based on evaluation of all available data and recommendations from the DRC. After at least three subjects have been treated and observed for the DLT-review period, the DRC will convene to review the safety data and decide on the dose for the next subjects, study termination or declare the RP2D. For a dose to be declared the RP2D, at least six subjects must have been treated with at least one infusion at that dose level and observed through the DLT-review period. A target DLT rate of 33.3% with the corresponding boundaries (26.0%, 39.5%) will be used to guide the actions at the DRC review.

[0096]

[0089] At Randomization, subjects will be randomized in a 1 : 1 ratio to receive 225 Ac- DOTATATE monotherapy or 225Ac-DOTATATE in combination with pembrolizumab. Approximately 30 subjects are planned for each randomization cohort (approximately 60 subjects in total). In both monotherapy and combination therapy cohorts, 225Ac-DOTATATE will be administered at the RP2D on Day 1 of each 6-week treatment cycle, for a total of 6 cycles in each cohort. In the combination therapy cohort, pembrolizumab will be administered at 400 mg once every 6 weeks starting on Day 1 of the first 225Ac-DOTATATE treatment cycle. After completion of the last 225Ac-DOTATATE treatment, subjects will continue to receive pembrolizumab infusions as maintenance therapy every 6 weeks, up to a maximum of 2 years after the first dose of study treatment.

[0090] Initial safety data for subjects randomized to 225Ac-DOTATATE plus pembrolizumab will be reviewed by the DRC after 6 subjects have initiated study treatment and been observed for at least 6 weeks in the combination therapy cohort. Based on the BOIN design (Yuan et al. 2016), a target DLT rate of 33.3% with the corresponding boundaries (26.3%, 39.8%) will be used to guide the actions at the DRC review.

[0097]

[0091] After all subjects in Randomization have received at least three doses of 225 Ac- DOTATATE or have discontinued study treatment, the DRC will select the treatment regimen to be utilized for cohort expansion. The treatment regimen for Expansion will be chosen based on review of all safety and efficacy data from the Dose Escalation and Randomization. Once the treatment regimen is defined, a single-arm expansion cohort will be opened, and approximately 100 additional subjects will be enrolled to receive 225Ac-DOTATATE at that treatment regimen.

[0098]

[0092] An overall schema of the study design is provided in Fig. 1. The study will consist of an optional SSTR-prescreening with S STR-PET imaging, a screening period of up to 28 days, treatment and follow-up periods for all subjects in all three parts of the study. For optional SSTR-prescreening, subjects who are expected to be eligible for the study may provide specific written informed consent to undergo SSTR-prescreening, which will consist of collection of baseline data and an SSTR-PET scan to verify eligibility for the main study.

[0099]

[0093] Interim analyses will be performed during Randomization when the number of efficacy- evaluable subjects (defined below) reaches 15, 20, and 25.

[0100]

[0094] Study Duration: Individual subject follow-up will continue until approximately 5 years after the last subject has completed 225Ac-DOTATATE treatment.

[0101]

[0095] Number of Subjects:

[0102]

[0096] Dose Escalation: 6 to 18 subjects will be enrolled in Dose Escalation, at approximately five clinical sites .

[0103]

[0097] Randomization: Approximately 60 subjects, 30 subjects in each randomization cohort, at up to approximately 55 clinical sites.

[0104]

[0098] Expansion: Up to approximately 100 subjects are planned at up to approximately 55 clinical sites.

[0105]

[0099] Diagnosis and Criteria for Inclusion and Exclusion:

[0106]

[0100] Optional SSTR-Prescreening Eligibility Criteria:

[0107]

[0101] To be eligible to undergo optional SSTR-prescreening to test for SSTR positivity by SSTR-PET imaging, subjects must meet all of the following criteria:

[0108]

[0102] SSTR-Prescreening Inclusion Criteria: 1. Age of at least 18 years at the time of signing the SSTR-prescreening informed consent form (ICF).

[0109] 2. Histologically confirmed, ER+ (defined as >1% of tumor cells stain positive for ER on immunohistochemistry (IHC) or, if no percentage is available, then an Allred IHC score of >3 / 8), HER2-negative (defined as IHC score of 0 or 1, or IHC score of 2 with negative in situ hybridization [ISH]) breast cancer.

[0110] 3. At least one RECIST v 1.1 -measurable lesion identified on computed tomography (CT) / magnetic resonance imaging (MRI) scan.

[0111] 4. Expected to be eligible for the study of the present example within approximately 3 months.

[0112] 5. Capable of undergoing a S STR-PET scan.

[0113]

[0103] SSTR-Prescreening Exclusion Criteria:

[0114] 1. Known hypersensitivity to225Ac, Gallium-68 (68Ga), Copper-64 (64Cu), octreotate, or any of the excipients of DOTATATE imaging agents.

[0115] 2. Unable or unwilling to comply with the requirements of the study protocol.

[0116]

[0104] Study Inclusion Criteria:

[0117]

[0105] Subjects must meet all the following criteria for enrollment in the study:

[0118] 1. At least 18 years old at the time of signing the main study ICF.

[0119] 2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) <2.

[0120] 3. Life expectancy of at least 12 weeks.

[0121] 4. Histologically confirmed, ER+ (defined as >1% of tumor cells staining positive for ER on IHC, or if no percentage is available, then an Allred IHC score of >3 / 8), HER2-negative (defined as IHC score of 0 or 1, or IHC score of 2 with negative ISH) locally advanced and unresectable or metastatic breast cancer not amenable to treatment with curative intent.

[0122] 5. Availability of archival or fresh tumor tissue for central biomarker analysis. Subjects with no archival tissue available and for whom a biopsy procedure is considered a significant risk by the Investigator may be eligible if approved by the Sponsor.

[0123] 6. Endocrine refractory, as defined by the European School of Oncology (ESO)- European Society for Medical Oncology (ESMO) guidelines (Cardoso et al. Ann Oncol. 2020; 31(12): 1623-1649), and no further clinical benefit expected from hormonal therapy. Documented radiologic progression (by RECIST vl .1) after at least 2 and no more than 4 prior chemotherapy or ADC regimens in the metastatic setting, with at least 1 being an ADC. At least one RECIST vl .1 -measurable tumor lesion that is SSTR-PET positive (defined as maximum standard uptake value (SUVmax) higher than liver mean standard uptake value (SUVmean) on SSTR-PET imaging) and at least 80% of RECIST v 1.1 -measurable tumor lesions are SSTR-PET positive within 90 days of enrollment. Sufficient renal function, as evidenced by creatinine clearance (CrCl) >60 mL / min calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation (Levey et al. Ann Intern Med. 2009; 150(9):604-612).

[0124] CKD-EPI Equation: The CKD-EPI equation, expressed as a single equation, is glomerular filtration rate (GFR) = 141 x min(Scr / K, 1)“ x max(Scr / K, 1) ■L209x 0.993Agex 1.018 [if female] > 1.159 [if black], where Scr is serum creatinine, K is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, min indicates the minimum of Scr / K or 1, and max indicates the maximum of Scr / K or 1. In this equation, the multiplication factors for race and sex are incorporated into the intercept, which results in different intercepts for age and sex combinations. Adequate hematologic function, defined by the following laboratory results: a. Hemoglobin concentration >5.0 mmol / L (>8.0 g / dL) b. Absolute neutrophil count (ANC) >1000 cells / pL (>1000 cells / mm3) c. Platelets >100 x 109 / L (100 x 103 / mm3)

[0125] Note: Colony-stimulating factors, platelet-production stimulators and / or transfusions within 4 weeks prior to screening and first dose of study treatment are not permitted to meet these criteria. Adequate hepatic function, defined by the following laboratory results: a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x upper limit of normal (ULN) (or <5 x ULN if presence of liver metastases) b. Total bilirubin <3 x ULN c. Serum albumin >3.0 g / dL Adequate coagulation function, defined by international normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) <1.5 x ULN, unless subject is receiving anticoagulant therapy and PT or aPTT is within therapeutic range of intended use of anticoagulants. 13. For women of childbearing potential (WOCBP): a. Negative serum pregnancy test within 48 hours prior to the first dose of study treatment b. Agreement to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group [CTFG] 2020. Available at: 2020_09_HMA_CTFG_Contraception_guidance_Version_l.l_updated.pdf) while receiving study treatment and for 7 months following their last dose of study treatment. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.

[0126] A woman is considered to be of childbearing potential if she is postmenarche, has not reached a postmenopausal state (>12 continuous months of amenorrhea [no menstrual bleeding of any kind, including menstrual period, irregular bleeding, spotting, etc.] with no identified cause other than menopause), and has not undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before first dose of study treatment).

[0127] 14. Sexually active male subjects must use a condom during intercourse while receiving 225Ac-DOTATATE and for at least 120 days after the last dose of the study treatment and should not father a child during this period. a. Male study subjects whose sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2020) while receiving 225Ac-DOTATATE and for at least 4 months following their last dose. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject. b. Vasectomized men are also required to use a condom during intercourse, including with a male partner, to prevent delivery of the drug via seminal fluid.

[0128] 15. Able to read and / or understand the details of the study and provide written informed consent prior to any study-specific assessments and procedures commence.

[0129]

[0106] Study Exclusion Criteria:

[0130]

[0107] Subjects who meet any of the following criteria will be excluded from the study:

[0131] 1. History of severe hypersensitivity (Grade >3) to any of the components or excipients used in the study treatments or imaging agents.

[0132] 2. Prior RPT, including radioembolization. Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti -programmed cell death -ligand 1 (anti-PD-Ll), or anti-programmed cell deathligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or co- inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA- 4], OX 40, CD137). Prior solid organ or bone marrow transplantation. Anticancer treatments within the following intervals prior to the first dose of study treatment (if not used as anticancer treatment, may be permitted if approved by the medical monitor): a. Cytotoxic chemotherapy, targeted agents, immunotherapy, antibody, retinoid, or anticancer hormonal treatment: 4 weeks. b. External -beam radiotherapy (EBRT), major surgery, and other invasive procedures: 6 weeks. (EBRT including more than 25% of the bone marrow is always exclusionary). Has received a live vaccine within 28 days prior to the first dose of study treatment. Any toxicities from prior treatments that have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade <1, except for alopecia. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study treatment. Inhaled or topical steroids and single dose of steroids as premedication for imaging scans with contrast are permitted. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).

[0133] Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Significant cardiovascular disease, defined as: a. New York Heart Association (NYHA) Class >11 heart failure. b. Known left ventricular ejection fraction (LVEF) <50%. c. History of myocardial infarction, acute coronary syndrome, or coronary angioplasty / stenting / bypass within the last 6 months. d. QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 ms, demonstrated by the average value of 3 consecutive electrocardiograms (ECGs).

[0134] 11. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB Ale) >8%.

[0135] 12. Liver cirrhosis.

[0136] 13. Known history of active tuberculosis (Mycobacterium tuberculosis).

[0137] 14. Active infection requiring systemic therapy.

[0138] 15. History of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.

[0139] 16. Hi story of interstitial lung di sease .

[0140] 17. History of human immunodeficiency virus (HIV) or hepatitis B infection or known active hepatitis C virus infection.

[0141] 18. Known brain, meningeal, or spinal cord metastases. Subjects with brain metastases may be eligible if asymptomatic, previously treated, and all brain lesions must have been controlled for at least 6 months prior to enrollment. Subjects with untreated brain lesions that are SSTR-positive may be eligible after approval by the medical monitor.

[0142] 19. History of hypersensitivity or allergy to pembrolizumab or any of its components, or to225Ac,68Ga,64Cu, octreotate, or any of the excipients of DOTATATE imaging agents.

[0143] 20. Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the study safety or efficacy assessments.

[0144] 21. Pregnancy or 1 actati on .

[0145] 22. Participation in another clinical study with an investigational medicinal product (IMP) administered within 4 weeks prior to the first dose of study treatment.

[0146] 23. Current somatic or psychiatric disease / condition that may interfere with the objectives and assessments of the study.

[0147] 24. Candidate for other treatment that in the opinion of the Investigator would be more appropriate than 225Ac-DOTATATE.

[0148] 25. Unable or unwilling to comply with the requirements of the study protocol.

[0149]

[0108] Screening / Baseline Imaging

[0150]

[0109] Imaging assessments during screening and SSTR-prescreening will be evaluated locally. In addition, all imaging performed during the study will be submitted to a central vendor for retrospective imaging analysis during Dose Escalation and Randomization and for blinded independent central review (BICR) during Expansion; however, no central confirmation is required before enrollment / randomization. Screening / baseline imaging assessments include the following: SSTR-PET imaging; FDG-PET, sodium fluoride (NaF)-PET, or a technetium-99m [99mTc] bone scan; and CT / MRI.

[0151] [HO] SSTR-PET imaging will be completed using any regulatory agency-approved SSTR-PET imaging agent. The SSTR-PET scan may be completed within 90 days (inclusive) prior to enrollment / randomization and can be completed during SSTR-prescreening or screening. The SSTR-PET imaging acquisition protocol should be consistent with the prescribing information. SSTR-PET performed in SSTR-prescreening may be used for screening in the main study if performed within 90 days prior to enrollment / randomization. The SSTR- PET imaging results will be confirmed locally prior to enrollment / randomization. Additional details are provided in the Imaging Manual. Note: an additional SSTR-PET scan may be completed upon documented PD (optional).

[0152]

[0111] FDG-PET, sodium fluoride (NaF)-PET, or a technetium-99m [99mTc] bone scan will be completed using any regulatory agency-approved FDG-PET imaging agent. The FDG-PET or NaF-PET or 99mTc bone scan may be completed within 28 days (inclusive) prior to subject enrollment / randomization and within 42 days before first dose of study treatment. The FDG- PET imaging acquisition protocol should be consistent with the prescribing information. The FDG-PET results will be used only for exploratory analyses and will not be considered for eligibility assessment.

[0153]

[0112] CT / MRI of chest, abdomen, and pelvis (as well as any other known site of disease) is required at screening unless available within 28 days of enrollment / randomization and no more than 42 days from the first dose of study treatment. If treatment cannot be started within 42 days of the screening CT / MRI, subjects must repeat the CT / MRI scan before treatment initiation.

[0154]

[0113] If central nervous system (CNS) metastases are confirmed or suspected, brain imaging (MRI or CT scan with contrast) is to be performed within 28 days of enrollment / randomization and no more than 42 days from the first dose of study treatment.

[0155]

[0114] Optional SSTR-Prescreening

[0156]

[0115] Subjects who are expected to be eligible for participation in the study may undergo optional SSTR-prescreening to test for SSTR positivity; SSTR-prescreening should be completed within approximately 3 months of enrollment / randomization in the study. After providing written informed consent for SSTR-prescreening, subjects who meet the eligibility criteria outlined herein will undergo SSTR-PET imaging, using any regulatory agency-approved SSTR-PET imaging agent, and other SSTR-prescreening assessments as detailed in Table 2. In addition, demography, relevant medical history, cancer history and histology data, as well as results from the last CT / MRI scan (if available) will be collected (if an SSTR-PET-CT / MRI is performed during SSTR-prescreening, data from the CT / MRI portion should be recorded as the last CT / MRI scan). Results from the SSTR-prescreening SSTR-PET imaging assessment and other data collected during SSTR-prescreening may be used for screening purposes in the main study if the subject provides written informed consent to participate in the main study.

[0157]

[0116] Table 2 Schedule of Activities: Optional SSTR-Prescreening AE=adverse event; AJCC=American Joint Committee on Cancer; BICR=blinded independent central review; CT= computed tomography; ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; MRI=magnetic resonance imaging; PD-Ll=programmed cell deathligand 1; PET= positron emission tomography; SAE=serious adverse event;

[0158] SSTR=somatostatin receptor.

[0159]

[0117] Table 3 Schedule of Activities: Screening

[0160] "mTc=Technetium-99m; AE=adverse event; AJCC=American Joint Committee on Cancer; BICR=blinded independent central review; C=Cycle; CHF=chronic heart failure; COVID- 19=coronavirus disease 2019; CT=computed tomography; D=day(s); EBRT=external-beam radiotherapy; ECG=electrocardiogram; ECOG PS =Eastem Cooperative Oncology Group performance status; ER=estrogen receptor; FDG=fluorodeoxyglucose; HER2=human epidermal growth factor receptor 2; ICF=informed consent form; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; NaF=sodium fluoride; PD- Ll=programmed cell death-ligand 1; PET=positron emission tomography; MUGA=multiple- gated acquisition; SSTR=somatostatin receptor; WOCBP=women of child-bearing potential.

[0161]

[0118] Investigational Medicinal Products (IMPs), Dosage, and Mode of Administration:

[0162]

[0119] Investigational Drug:

[0163]

[0120] 225Ac-DOTATATE will be supplied as a clear and colorless to slightly yellow solution in a single-dose vial for intravenous (i.v.) infusion.

[0164]

[0121] 225Ac-DOTATATE Administration

[0165]

[0122] Prior to 225Ac-DOTATATE Administration

[0166]

[0123] Use radiation shielding and aseptic technique during administration of IMP. To minimize radiation exposure and contamination risk, gloves and tongs should be used to handle the IMP vial. When the vial is not in use, it should be contained in the provided lead container enclosed with the lead cap.

[0167]

[0124] Inspect the product visually for discoloration and particulate matter under a light source and shielded screen. Discard vial if a coloration other than slightly yellow or particulate matter is present and notify the Sponsor. Disposal of any unused product and / or waste should be completed in accordance with local / national guidelines as well as the site’s radiation safety protocols.

[0168]

[0125] Prior to infusion, verify the correct radioactivity of the vial by measuring in the dose calibrator on the predetermined calibration number. Record the starting activity. The actual dose assay may not vary more than ± 10% of the activity on the label.

[0169]

[0126] 225Ac-DOTATATE Preparation and Pre-medications

[0170]

[0127] (1) It is recommended that subjects wear a hospital gown to avoid radioactive contamination of their clothing. (2) Administer anti emetics approximately 15-30 minutes prior to the start of the amino acid infusion. (3) Concomitant amino acids (containing arginine and lysine) will be co-infused with each 225Ac-DOTATATE administration for renal protection in accordance with local practice and consistent with labeling, (a) Spike the amino acid bag using the first sterile tubing set and prime with the amino acid solution, (b) It is recommended that amino acids and IMP are administered using separate peripheral venous access sites. During the IMP infusion, both IMP and amino acids must run concurrently. IMP may be administered through the same venous access as the amino acid (e.g. double lumen PICC line), if necessary, in subjects with poor venous access. Central lines may be used for amino acids and anti emetics, but peripheral venous access is recommended for administration of IMP. (c) The amino acid infusion should be administered at a constant rate (no more than 250 ml / hr) to allow infusion of the total volume per institutional / local practice and consistent with labelling. 4) Prime the other sterile tubing set with 0.9% sterile sodium chloride. 5) Ensure that the subject has emptied his / her bladder immediately prior to IMP administration.

[0171]

[0128] 225Ac-DOTATATE Setup and Administration Procedures

[0172]

[0129] IMP may be infused using gravity, an infusion pump or a syringe pump. Detailed instructions for all methods are described below.

[0173]

[0130] In the event of a dose modification below 125 pCi for an adverse reaction the infusion pump method or syringe pump method should be used, as use of the gravity method may result in delivery of the incorrect volume of IMP if the dose is not adjusted prior to administration.

[0174]

[0131] Gravity Method

[0175]

[0132] (1) Confirm that the amino acids infusion has begun at a constant rate and per local practice and consistent with labeling before beginning the IMP infusion. (2) A mark can be made on the plastic container that holds the IMP vial to act as a visual aid for monitoring solution level to ensure constant volume during infusion (see step 7). (3) Connect the short sterile non-vented needle to 500mL 0.9% sterile sodium chloride solution via a catheter prefilled with 0.9% sterile sodium chloride. Prime the needle with sterile sodium chloride and clamp the line. Insert the short needle into the IMP vial at an angle in a swift clean motion avoiding further damage to the septum. Sodium chloride should not be allowed to flow into the 225Ac- DOTATATE vial prior to the initiation of the IMP infusion. Additionally, IMP must not be injected directly into the sodium chloride. The short sterile needle must not touch the IMP solution in the vial. This needle must also not be connected directly to the subject. Always wear gloves and PPE when handling materials. (4) Attach the long needle to one end of the m / m tubing and the luer lock to luer lock connector to the other end of the m / m tubing. Prime the m / m tubing with 0.9% sterile sodium chloride. Clamp the m / m tubing. Insert the long needle into the IMP vial at an angle using a swift clean motion avoiding further damage to the septum and confirm it touches the bottom of the vial. Ensure that the needle bevel stays at the bottom of the vial for the duration of the IMP infusion. Ensure intravenous line patency. Remove the Luer lock to Luer lock connector and connect the m / m tubing to the subject. Unclamp the m / m tubing. (5) Use an infusion pump or clamp to regulate the flow of the sodium chloride from the short needle into the IMP vial at a rate of 25-50mL / hr for 5-10 minutes. If not using an infusion pump, mL / hr can be converted to drops per minute using the following formula: mL / hr / 60 minutes x drop factor= gtt / min. Consult the IV tubing packaging to determine the drop factor (the number of drops it takes to make up ImL of fluid). Using the GM survey meter or alpha / beta scintillation meter, confirm flow of 225Ac-DOTATATE into the subject’s catheter. The infusion site should be directly observed during administration for signs of infiltration (slowing of the infusion, pain or swelling). In the event of infiltration, clearance of IMP from the site can be facilitated with warm packs, compression, and elevation. (6) Administration of IMP should continue at a rate of 100-200 mL / hr for an additional 25-30 minutes. IMP should not be administered as a bolus infusion. (7) The level of solution in the IMP vial must remain constant throughout the infusion. (8) After 10-20 minutes of infusion, survey the top of the vial or survey underneath the m / m line. Survey every 5 minutes until a stable reading (within background levels) is achieved. (9) Stop the flow from the saline bag and close the saline line when the survey reading is stable for at least 5 minutes. (10) Flush the subject’s intravenous line with 25mL of 0.9% sterile sodium chloride to ensure no IMP is left in the line.

[0176]

[0133] Infusion Pump Method

[0177]

[0134] (1) Confirm that the amino acids infusion has begun at a constant rate and per local practice and consistent with labeling before beginning the IMP infusion. (2) It is recommended to place a wedge safely under the IMP lead shielded container for a tilted vial positioning to allow proper needle placement to ensure infusion of the total dose volume. (3) Insert the short sterile vented needle at an angle using a swift clean motion avoiding further damage to the septum into the vial. Make sure the needle does not touch the solution in the vial, and do not connect this short needle to the subject or the infusion pump. (4) Attach the m / m tubing to the long needle and the 3-way stopcock and prime the tubing and needle with 0.9% sterile sodium chloride. Close the clamp. Insert the long needle into the vial and secure the needle bevel to the bottom of the vial. Ensure that the needle bevel stays at the lowest point on the bottom of the tilted vial for the duration of the infusion. Attach the tubing with 0.9% sterile sodium chloride solution to the 3 -way stopcock valve. (5) Attach the half-set infusion pump tubing that will carry IMP to the subject to the 3 -way stopcock. Adjust the stopcock valve to allow the normal saline to prime the half-set infusion pump tubing. Insert the half-set infusion pump tubing into the infusion pump. (6) Connect the primed IV catheter to the subject and set the 3 -way stopcock valve so that the IMP solution is in line with the infusion pump. (7) Infuse the full volume of IMP at a constant rate over a 25-30-minute period (for example, 25mL / hr). If administering a reduced dose of IMP, infuse half of the volume listed on the vial at a constant rate over a 30- minute period (for example, 12mL / hr). (8) When the correct volume of IMP is delivered, stop the infusion pump and change the position of the 3 -way stopcock valve so that the infusion pump is in line with the 0.9% sterile sodium chloride solution. The status of the infusion must be monitored, as this step must be completed before air is introduced into the line connected to the subject. Using the infusion pump, administer a 25mL flush of the 0.9% sterile sodium chloride solution through the IV catheter to the subject at approximately 2.5mL / min to ensure any remaining IMP is cleared from the IV line.

[0178]

[0135] Syringe Pump Method

[0179]

[0136] (1) Confirm that the amino acids infusion has begun at a constant rate and per local practice and consistent with labeling before beginning the IMP infusion. (2) Wearing waterproof gloves, pierce the septum of the IMP vial with the short, vented needle, ensuring that the needle bevel does not touch the liquid. (3) Withdraw the required volume of IMP solution using an appropriately shielded sterile syringe. Remove the needle used to withdraw the IMP and cap syringe. (4) Assay the IMP syringe for radioactivity in the dose calibrator and record the findings in the IMP Accountability Log. Ensure the IMP syringe remains shielded during transport. (5) Connect the appropriate primed tubing to the syringe pump and the patient. Place the IMP syringe into the shielded syringe pump. (6) Use sterile 0.9% normal saline to prime all the appropriate tubing. (7) Connect the primed tubing to the IMP syringe and the subject. (8) Infuse the required volume of IMP over 25-30 minutes at a constant rate. Visually confirm that there is no volume of IMP remaining in the syringe. (9) Flush the line and syringe with 0.9% sterile sodium chloride solution to clear remaining IMP from the IV line.

[0180]

[0137] Dose Escalation

[0181]

[0138] During Dose Escalation, subjects will receive 225Ac-DOTATATE as a monotherapy by i.v. infusion every 6 weeks for up to 6 cycles. The starting dose of 225Ac-DOTATATE will be 6.5 MBq (Dose Level 1) and escalation to dose levels 2 (8.3 MBq) and 3 (10.2 MBq) will be decided by the DRC based on the DLT rate observed during the DLT-review period. If Dose Level 1 is not tolerated, the dose will be de-escalated to 4.6 MBq (Dose Level -1). See Fig. 1 and Table 4. Intermediate doses may be explored based on evaluation of all available data and recommendations from the DRC.

[0139] After at least three subjects have been treated and observed for the DLT-review period, the DRC will convene to review the safety data and decide between: dose escalation, dose de- escalation, additional recruitment at the current dose level, exploration of intermediate dose levels, termination of dose escalation, and RP2D identification (may only be declared after at least 6 DLT-evaluable subjects).

[0182]

[0140] Table 4. Dose Escalation Cohorts recommendations from Data Review Committee. Dose Level 3 (10.2 MBq) is the maximum dose to be used in the study.

[0183]

[0142] For a dose to be declared the RP2D, at least 6 subjects must have been treated with at least one infusion at that dose level and observed through the DLT-review period. A target DLT rate of 33.3% with the corresponding boundaries (26.0%, 39.5%) will be used to guide the actions at the DRC review (Table 5).

[0184]

[0143] Table 5. Dose Escalation and De-escalation Boundaries for the Dose Escalation Cohorts

[0185] Abbreviations: DLT=dose-limiting toxicity.

[0186]

[0145] DLT definition:

[0187]

[0146] Non-hematologic: o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) with concurrent increase in total bilirubin >2 times the ULN without evidence of cholestasis or alternative explanations such as viral hepatitis, disease progression in the liver, etc. (Hy’s Law) o Any AST or ALT elevation >8xULN regardless of duration or AST or ALT evaluation 5-8xULN that persists for greater than 2 weeks - all regardless of the presence or absence of liver metastasis. o Any Grade 3 or higher non-hematologic toxicity, except:

[0188] ■ Grade 3 nausea / vomiting or diarrhea for less than 72 hours with adequate antiemetic and other supportive care

[0189] ■ Grade 3 fatigue for less than 1 week

[0190] ■ Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions.

[0191] ■ Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis

[0192]

[0147] Hematologic: o Febrile neutropenia o Grade 4 neutropenia or thrombocytopenia for more than 7 days o Grade 3 or higher thrombocytopenia with clinically significant bleeding o Any Grade 3 or higher hematologic toxicity (except lymphocytopenia) that does not recover within 6 weeks from the time of its onset

[0193] • Any death not clearly due to the underlying disease or extraneous causes

[0194]

[0148] Table 6 Schedule of Activities: Dose Escalation and 225Ac-DOTATATE Monotherapy Arm in Randomization

[0195]

[0196]

[0197] "mTc=Technetium-99m; AE=adverse event; AESI=adverse event of special interest; BICR=blinded independent central review; C=Cycle;

[0198] CHF=chronic heart failure; CT=computed tomography; D=day(s); ECG=electrocardiogram; ECOG PS =Eastern Cooperative Oncology Group performance status; eCRF=electronic case report form; EFU=efficacy follow-up; EOS=End-of-Study visit; ET=Early Termination;

[0199] FDG=fluorodeoxyglucose; i.v. intravenously; LTFU=long-term follow-up; LVEF=left ventricular ejection fraction; Mo=month(s); MRI=magnetic resonance imaging; MUGA=multiple-gated acquisition; NaF=sodium fluoride; PD=disease progression; PET=positron emission tomography;

[0200] RECIST vl.l= Response Evaluation Criteria in Solid Tumors version 1.1; SSTR=somatostatin receptor; Wk=week(s); WOCBP=women of childbearing potential.

[0201]

[0149] Table 7 Schedule of Activities: 225Ac-DOTATATE + Pembrolizumab Combination Therapy

[0202]

[0203]

[0204] "mTc=Technetium-99m; AE=adverse event; AESI=adverse event of special interest; BICR=blinded independent central review; C=Cycle; CHF=chronic heart failure; CT=computed tomography; D=day(s); ECG=electrocardiogram; ECOG PS =Eastern Cooperative Oncology Group performance status; eCRF=electronic case report form; EFU=efficacy follow-up; EOS=End-of-Study visit; ET=Early Termination;

[0205] FDG=fluorodeoxyglucose; FT3=free triiodothyronine; FT4=free thyroxine; i.v.=intravenously; LTFU=long-term follow-up; LVEF=left ventricular ejection fraction; Mo=month(s); MUGA=multiple-gated acquisition; MRI=magnetic resonance imaging; NaF=sodium fluoride; PD=progressive disease; PET=positron emission tomography; PM=pembrolizumab maintenance; RECIST vl. l=Response Evaluation Criteria in Solid Tumors version 1.1; SSTR=somatostatin receptor; T3=triiodothyronine; TSH= thyroid-stimulating hormone; Wk=week(s); WOCBP=women of childbearing potential.

[0206]

[0150] Randomization

[0207]

[0151] In Randomization cohorts, 225Ac-DOTATATE will be administered at the RP2D by i.v. infusion every 6 weeks for a total of 6 infusions. There must be at least 6 and no more than 12 weeks between doses of 225Ac-DOTATATE to allow for recovery of toxicities.

[0208]

[0152] Once the RP2D is declared by the DRC, subjects will be randomized in a 1 : 1 ratio to receive 225Ac-DOTATATE monotherapy or 225Ac-DOTATATE in combination with pembrolizumab as shown in FIG. 1. Approximately 30 subjects are planned for each randomization cohort (approximately 60 subjects in total).

[0209]

[0153] In both monotherapy and combination therapy cohorts, 225 Ac-DOT AT ATE will be administered at the RP2D by i.v. infusion on Day 1 of each 6-week treatment cycle, for a total of 6 cycles.

[0210]

[0154] In the combination therapy cohort, pembrolizumab will be administered at 400 mg once every 6 weeks starting on Day 1 of the first 225Ac-DOTATATE treatment cycle. Study procedures will be performed during treatment and follow-up as outlined in Table . After completion of the last 225Ac-DOTATATE treatment, subjects will continue to receive pembrolizumab infusions as maintenance therapy every 6 weeks, up to a maximum of 2 years after the first dose of study treatment. Further details on pembrolizumab administration are provided herein.

[0211]

[0155] Initial safety data from Randomization will be reviewed by the DRC after six subjects have initiated study treatment and been observed for the DLT-review period, defined as the first 6 weeks following the subject’s first treatment with 225Ac-DOTATATE plus pembrolizumab in the combination therapy cohort. Based on the BOIN design (Yuan et al. 2016), a target DLT rate of 33.3% with the corresponding boundaries (26.3%, 39.8%) will be used to guide the actions at the DRC review (Table 8; DLT definitions described herein).

[0212]

[0156] Table 8. Decision Rules for the Combination Therapy Cohort

[0213] Abbreviations: DLT=dose-limiting toxicity.

[0214]

[0158] The primary efficacy endpoint will be monitored using the Bayesian optimal phase 2 (BOP2) design (Zhou et al. Stat Med. 2017; 36(21):3302-3314). Interim analyses will be performed during Randomization when the number of efficacy-evaluable subjects reaches 15, 20, and 25. The stopping criteria for each cohort to support decision making for the treatment regimen for Expansion are provided in Table 9, but are non-binding and the sponsor may decide to continue the study if stopping criteria are met.

[0215]

[0159] Table 9. Optimized Stopping Boundaries for Durable Response Rate at each Interim Analysis

[0216]

[0160] DLT-Evaluable Populations are defined separately for Dose Escalation and Randomization.

[0217]

[0161] DLT-Evaluable Population in Dose Escalation: includes any subject who received at least one dose of 225Ac-DOTATATE and completed the DLT review period or experienced a DLT.

[0218]

[0162] DLT-Evaluable Population in Randomization: includes any subject in the combination therapy cohort who received at least one dose of 225Ac-DOTATATE and completed the DLT review period or experienced a DLT.

[0219]

[0163] The following analysis populations are defined for each portion of the study (Dose Escalation, Randomization, and Expansion) and for the overall study:

[0220]

[0164] Safety Population: includes any subject who received at least one dose of 225 Ac- DOTATATE.

[0221]

[0165] Efficacy-Evaluable Population: includes any subject who received at least one dose of 225Ac-DOTATATE, met the eligibility criteria, had one or more measurable lesions at baseline, and had at least one post-baseline disease assessment or died prior to the first scheduled efficacy assessment.

[0222]

[0166] After all subjects in Randomization have received at least three doses of 225 Ac- DOTATATE or have discontinued study treatment and data are available to compare monotherapy and combination therapy cohorts, the cohort considered most promising (monotherapy or combination therapy) and the dosing regimen (number of 225Ac-DOTATATE treatment cycles and 225 Ac-DOTATATE treatment cycle length) will be selected to continue to cohort expansion. During Expansion, additional subjects (up to approximately 100) will be enrolled to further evaluate efficacy. With 100 subjects, the study is adequately powered to detect the difference in the efficacy of selected treatment against a predefined clinically meaningful effect based on current SoC. In the meantime, it allows for a comprehensive evaluation of the study drug safety profile which is crucial for making an informed risk-benefit assessment.

[0223]

[0167] Expansion

[0224]

[0168] In Expansion, subjects will be administered 225Ac-DOTATATE at the treatment regimen for Expansion determined in Randomization. Once the treatment regimen for Expansion is defined, a single-arm expansion cohort will be opened, and approximately 100 additional subjects will be enrolled to receive 225Ac-DOTATATE at that treatment regimen.

[0225]

[0169] There must be at least 6 and no more than 12 weeks between doses of 225 Ac- DOTATATE to allow for recovery of toxicities.

[0226]

[0170] Concomitant amino acid i.v. infusions (containing L-arginine and L-lysine) will be coinfused with each 225Ac-DOTATATE administration for renal protection in accordance with local practice and consistent with labeling. Subjects should also receive antiemetics, if clinically indicated, before the start of each amino acid infusion.

[0227]

[0171] A drug order form must be submitted in advance prior to each 225Ac-DOTATATE infusion.

[0228]

[0172] Storage and Handling of 225Ac-DOTATATE

[0229]

[0173] 225Ac-DOTATATE is stored in a glass vial that is sealed with a septum and crimp, and the vial must be stored in a leaded container used to attenuate radiation exposure. The leaded container is then enclosed in an approved Type A package that has met all Nuclear Regulatory Commission (NRC) and Department of Transportation (DOT) regulations for transport of radioactive materials.

[0230]

[0174] When not in use, the glass vial containing 225Ac-DOTATATE must be kept inside the leaded container at all times, and the entire container (with the vial) must be kept at room temperature, between 20 to 25°C.

[0231]

[0175] As soon as the Type A package arrives, the package should be wipe tested for contamination per appropriate regulatory guidelines. The lead container should be carefully removed from the package and inspected for any evidence of liquid spill. The vial should then be removed from the leaded container with tongs and behind leaded glass, inspected for any evidence of liquid spills. If no liquid is present on the exterior of the glass vial, the vial is placed in the dose calibrator well. The dose calibrator should be appropriately calibrated for 225 Ac (calibration factor defined by the site nuclear medicine department), and the vial should be assayed to ensure the appropriate radioactivity amount was dispensed.

[0232]

[0176] Combination Therapy Agent: Keytruda® (pembrolizumab):

[0177] Keytruda® (pembrolizumab) will be obtained commercially from a marketed source and provided centrally by the Sponsor. Pembrolizumab will be provided as a clear to lightly opalescent, colorless to slightly yellow solution in a single-dose vial and will be stored according to the regional product label.

[0233]

[0178] Subjects receiving combination therapy will be administered pembrolizumab 400 mg by i.v. infusion over 30 minutes on Day 1 (±3 days) of Cycle 1. Thereafter, pembrolizumab will be administered once every 6 weeks. When 225Ac-DOTATATE and pembrolizumab are administered on the same day, 225Ac-DOTATATE should be administered first, and pembrolizumab should be administered at least 30 minutes after completion of the 225 Ac- DOTATATE infusion. After the completion of the last 225Ac-DOTATATE infusion, pembrolizumab infusions will continue as maintenance therapy every 6 weeks until PD or unacceptable toxicity for a maximum of 2 years after the first dose of study treatment.

[0234]

[0179] Refer to the regional pembrolizumab prescribing information for detailed information regarding administration of pembrolizumab.

[0235]

[0180] Treatment Duration:

[0236]

[0181] In all parts of the study, subjects will receive 225Ac-DOTATATE every 6 weeks for a total of 6 cycles, for a total duration of 225Ac-DOTATATE therapy of 36 weeks (or longer if treatment delays are needed).

[0237]

[0182] In Randomization, subjects in the combination therapy cohorts will also receive pembrolizumab every 6 weeks up to a maximum of 2 years after first dose.

[0238]

[0183] Statistical Methods:

[0239]

[0184] Sample Size:

[0240]

[0185] Dose Escalation: 6 to 18 subjects will be enrolled in Dose Escalation. After at least 3 subjects in a dose level have been treated and observed for the DLT-review period, the DRC will convene to review the safety data. For a dose to be declared the RP2D, at least 6 subjects must have been treated with at least one infusion at that dose level and observed through the DLT- review period.

[0241]

[0186] Randomization: Randomization will enroll up to approximately 60 subjects randomized in a 1 : 1 ratio to 225 Ac-DOTATATE monotherapy or 225 Ac-DOTATATE in combination with pembrolizumab. The primary efficacy endpoint will be monitored using the Bayesian optimal phase 2 (BOP2) design. Interim analyses will be performed during Randomization when the number of efficacy-evaluable subjects (defined below) reaches 15, 20, and 25. The design parameters in the BOP2 design are optimized to maximize power under the alternative hypothesis of Hi: Durable response rate (DRR) for either arm >50%, while controlling the type I error rate (i.e., the probability of incorrectly claiming that the treatment is promising under Ho) at 0.102. The sample size and the decision rules lead to the stopping boundaries for each interim analysis and yield a statistical power of 0.976 under Hi.

[0242]

[0187] Expansion: Approximately 100 subjects will be enrolled in one expansion cohort. Expansion will test the null hypothesis that the objective response rate (ORR) is <21% against the alternative hypothesis that is >50%. The sample size is estimated at 100 subjects, with at least 90% power and 1-sided alpha=0.025. In addition, assuming 20% of the subjects experience a certain type of safety event, a total sample size of N=100 can exclude an incidence rate of greater than 30% with 95% confidence.

[0243]

[0188] Analysis Populations:

[0244] • Safety Population: includes any subject who received at least one dose of 225 Ac- DOTATATE.

[0245] • DLT-Evaluable Population: includes any subject who received at least one dose of 225Ac-DOTATATE and completed the DLT review period or experienced a DLT.

[0246] • Efficacy-Evaluable Population: includes any subject who received at least one dose of 225Ac-DOTATATE, met the eligibility criteria, had one or more measurable lesions at baseline, and had at least one post-baseline disease assessment or died prior to the first scheduled efficacy assessment.

[0247] • DLT-Evaluable Population in Dose Escalation: includes any subject who received at least one dose of 225Ac-DOTATATE and completed the DLT review period or experienced a DLT.

[0248] • DLT-Evaluable Population in Randomization: includes any subject in the combination therapy cohort who received at least 1 dose of 225 Ac-DOTATATE and completed the DLT review period or experienced a DLT.

[0249]

[0189] Statistical Analysis

[0250]

[0190] Primary Efficacy Analyses:

[0251]

[0191] Efficacy analysis will be based on the Efficacy-Evaluable Population and Investigator tumor assessments. During Expansion, efficacy endpoints will also be evaluated by blinded independent central review (BICR).

[0252]

[0192] DRR is defined as the proportion of subjects with measurable disease at baseline who achieve a confirmed response (either a complete response [CR] or a PR) per RECIST vl.l lasting at least 6 months.

[0193] ORR is defined as the proportion of subjects with a measurable disease at baseline who achieve confirmed response (either a CR or a PR) per RECIST vl .1. For DRR and ORR, the Clopper-Pearson 80% and 95% confidence intervals [Cis] will be provided.

[0253]

[0194] Duration of response (DOR) is defined as the time from the first occurrence of a response (CR or PR) until the date of PD per RECIST vl .1 or death, whichever is earlier. It will be calculated among responders (confirmed CR or PR). The Kaplan-Meier methodology will be used to estimate median DOR and the Cis. Subjects who continue to respond at the time of the analysis will be censored at the last assessment of response.

[0254]

[0195] Disease control rate (DCR) is defined as the proportion of subjects who achieve a best response of CR, PR, or stable disease. DCR will be analyzed similarly to the ORR.

[0255]

[0196] Clinical benefit rate (CBR) is defined as the proportion of subjects who achieve a CR or PR or maintain stable disease for at least 6 months.

[0256]

[0197] Progression Free Survival (PFS) is measured from the date of first dose of study treatment (225Ac-DOTATATE or pembrolizumab), whichever is first, until the first date when PD is objectively documented or death from any cause, whichever is earlier. Subjects without PD or death will be censored at the last available tumor assessment. Alternative censoring methods will also be considered and will be described in detail in the statistical analysis plan (SAP). PFS will be summarized using the Kaplan-Meier methodology.

[0257]

[0198] Overall survival (OS) is measured from the date of study drug (225Ac-DOTATATE or pembrolizumab), whichever is first, until death due to any cause. Subjects who are alive will be censored at the last known alive date. OS will be summarized using the Kaplan-Meier methodology.

[0258]

[0199] Safety Analysis:

[0259]

[0200] Safety analyses will be performed on the Safety Population in Dose Escalation, Randomization by treatment arm, the Safety Population for Expansion, and the Safety Population for the overall study. In particular, the initial safety data reviewed by the DRC will be based on the DLT Evaluable Population.

[0260]

[0201] Verbatim adverse event (AE) terms will be coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA) and graded by the Investigator according to the National Cancer Institute (NCI) CTCAE, version 5.0. Subject incidence of all treatment-emergent adverse events (TEAEs) will be tabulated by MedDRA system organ class and preferred term. Summary tables of TEAEs that are fatal, serious, treatment-related, Grade 3 or 4, adverse events of special interest (AESIs), AEs leading to dose reduction or interruption, and AEs leading to permanent discontinuation of study treatment and / or withdrawal from the study will be provided.

[0261]

[0202] Treatment exposure will be summarized to include treatment duration, cycle length, and number of doses received.

[0262]

[0203] Clinical chemistry, hematology, and urinalysis data will be summarized. Laboratory values outside the normal reference ranges will be identified and summarized. Summary tables of change from baseline over time and maximum shift in toxicity grade from baseline for select laboratory parameters may be provided. Changes in vital signs and ECG parameters over time will be summarized.

[0263]

[0204] Imaging Analysis:

[0264]

[0205] The association between screening / SSTR-prescreening imaging results and the primary efficacy endpoints will be analyzed to support S STR-PET (and corresponding imaging agents permitted by the protocol) as an appropriate patient selection method for treatment with 225 Ac- DOTATATE. Subjects will be grouped by imaging agent used for the screening SSTR-PET, cutpoints defined based on SUVmax and SUVmean (e.g., above or below the group median SUVmax and group median SUVmean). Inter- and intra-reader agreement for assessment of the reliability of SSTR-PET will also be performed. Refer to the SAP for details.

[0265]

[0206] Interim Analysis:

[0266]

[0207] Interim analyses for efficacy will be conducted at three key junctures: when the number of efficacy-evaluable subjects reaches 15, 20, and 25. These points were strategically chosen to balance timely decision-making with the accumulation of sufficient data to inform those decisions. At each interim analysis, the number of responders will be evaluated against predetermined thresholds as outlined in Error! Reference source not found.. These thresholds (which will inform efficacy) were established based on the BOP2 design (Zhou et al. 2017).

[0267]

[0208] Committees:

[0268]

[0209] A DRC and Safety Review Committee (SRC) will be established to oversee the safety of subjects enrolled in the study.

[0269]

[0210] The DRC will comprise Sponsor representatives and site Investigators. The DRC will review initial safety data in Dose Escalation after 3 subjects have been treated and observed for the DLT-review period at each dose level. During Randomization, the DRC will review initial safety data after 6 subjects have initiated study treatment and have been observed for at least 6 weeks in the combination therapy cohort. At the end of Randomization, after all subjects in Randomization have received at least 3 doses of 225Ac-DOTATATE or have discontinued study treatment, the DRC will define the treatment regimen to be utilized for Expansion. The DRC may convene later for the primary efficacy analysis to allow time for subjects with ongoing CR or PR to achieve a durable response (defined as a RECIST vl .1 CR or PR sustained for at least 6 months).

[0270]

[0211] The SRC, comprising the Sponsor and the contract research organization (CRO), will perform ongoing review of serious adverse events (SAEs) and other safety trends throughout the conduct of the study.

[0271]

[0212] 225Ac-DOTATATE, as well as 177Lu-DOTATATE, is excreted to the kidneys and renal toxicity may result from radiation exposure. Proximal tubular reabsorption may increase the residence time of 225 Ac-DOTATATE in the kidneys, potentially resulting in higher radiation doses and risk of kidney toxicity. Biodistribution studies with 177Lu-DOTATATE have shown that an amino acid co-infusion may block tubular reabsorption and accelerate passage through the kidneys, which can reduce radiation doses by approximately 47%. Therefore, a concomitant amino acid infusion (containing L-arginine hydrochloride [HC1] 2.5% and L-lysine HC1 2.5%) should be administered with each 225 Ac-DOTATATE dose for renal protection.

[0272]

[0213] There is a strong rationale for combining RPT, especially alpha-emitters, with immune check-point inhibitors (ICIs). There is substantial pre-clinical evidence that alpha-particle emitter RPT (alpha-RPT) has immunostimulatory effects, releasing cytosolic DNA, which activates guanosine monophosphate-adenosine monophosphate(GMP-AMP) synthase (cGAS)- stimulator of interferon genes (STING) signaling, resulting in interferon 1 (IFNl)-induced inflammatory remodeling (Kleinendorst et al. Clin Cancer Res. 2022 ;28(17):3652-3657). Efficacy studies with 177Lu-DOTATATE and 225Ac-PSMA-617 in murine models have shown strong synergism between RPT and ICIs (Czernin et al. J Nucl Med. 2021; 62(2):228-231; Esfahani et al. J Nucl Med. 2023; 64(7): 1056-1061).

[0273]

[0214] Although ICIs are not approved specifically for unresectable or metastatic ER+ breast cancer, evidence suggests their anti-tumor activity in other settings. The addition of pembrolizumab or nivolumab to neoadjuvant chemotherapy increased the pathologic complete response (CR) rate in patients with high-risk, ER+, early-stage breast cancer (Loi et al. Ann Oncol. 2023; 34, S1259-S1260; Cardoso et al. 2023). Pembrolizumab is also approved for programmed cell death -ligand 1 (PD-Ll)-positive, triple-negative breast cancer (TNBC) in combination with first-line chemotherapy, and emerging data from recent studies suggest that the combination of ICIs and TROP-2-targeted ADCs may also enable efficacy in PD-L1- negative patients (Schmid et al. Annals of Oncology. 2023; 34 : S337). This is consistent with the hypothesis that effective DNA damage can create a favorable environment for ICIs, which may also occur with alpha radiation.

[0274]

[0215] The available data support the conduct of a Phase 2 study to investigate the efficacy of 225Ac-DOTATATE in ER+ ABC. Given the high unmet need, the study will enroll late-line patients who have exhausted available hormone therapy and have already failed multiple chemotherapy or ADC regimens. Considering the body of evidence suggesting immunostimulatory effects from alpha radiation damage to tumor cell DNA, the combination of 225Ac-DOTATATE with an ICI will also be investigated.

[0275]

[0216] Several measures have been included in the study protocol to minimize the risks associated with 225Ac-DOTATATE exposure. Subjects with poor hematologic, renal, and hepatic function will be excluded, and frequent monitoring of laboratory parameters throughout treatment and follow-up will allow for timely identification of acute and late toxicities. Dose modifications must be implemented in case of severe toxicities, requiring delaying subsequent treatment until recovery, dose reductions if resuming treatment, and permanent discontinuation of 225Ac-DOTATATE in cases of recurrence.

[0276]

[0217] Pembrolizumab is approved for advanced TNBC and has a known positive benefit / risk ratio. Although efficacy results in ER+ metastatic breast cancer are not promising, evidence suggests possible synergism with alpha-RPT. The known risks associated with pembrolizumab, as well as recommended measures to mitigate these risks, are outlined in the protocol, and frequent safety monitoring will also ensure the recommendations are being observed (Keytruda USPI 2023; Keytruda SmPC 2023).

[0277]

[0218] Hormone-refractory breast cancer patients who have progressed after initial lines of chemotherapy or ADCs have few effective options, and available options are associated with relatively high toxicity. There is an urgent need for new therapies exploring new targets and mechanisms. Therefore, there is a potential for significant benefit for study subjects. 225 Ac- DOTATATE has been well tolerated in the Phase lb portion of the ACTION-1 study and the measures implemented in the protocol will mitigate the potential risks.

[0278]

[0219] Dose

[0279]

[0220] In this study, 225Ac-DOTATATE will be administered once every 6 weeks for up to 6 cycles.

[0280]

[0221] End of Study Definition

[0281]

[0222] The end of the study (EOS) is defined as the date of the last visit of the last subject (LSLV) in the study. The EOS visit is defined as the visit performed when an individual subject completes the study or withdraws from the study and is unwilling to complete additional follow-up.

[0282]

[0223] Treatment Period

[0283]

[0224] The Treatment Period is defined as the time between the first dose of study treatment (225Ac-DOTATATE or pembrolizumab) and the end of the last treatment cycle (6 weeks after the last 225Ac-DOTATATE dose or 6 weeks after the last pembrolizumab dose, whichever is later).

[0284]

[0225] Non-investigational medicinal products (NIMPs) used in the study include pembrolizumab, anti emetics used as premedication, amino acids used for renal protection, medications that may be administered to manage adverse events (AEs), and other permitted concomitant medications.

[0285]

[0226] The term “study treatment” refers to 225Ac-DOTATATE alone or combination with pembrolizumab.

[0286]

[0227] The products that will be used in this study are outlined in Error! Reference source not found..

[0287]

[0228] Table 10 Study Intervention(s) Administered

[0288] Abbreviations: IMP=investigational medicinal product; i.v.=intravenous; NA=not applicable;

[0289] NIMP=non-investigational medicinal product; PD=progressive disease; Q6W=every 6 weeks;

[0290] RP2D=recommended phase 2 dose.

[0291]

[0229] Study Population

[0292]

[0230] The study population will consist of adult subjects with ER+, HER2-negative, SSTR+, ABC that has progressed after endocrine therapy and initial lines of chemotherapy or ADC. Each subject must meet all the inclusion criteria described herein and none of the exclusion criteria described herein for enrollment in the study. Waivers to the inclusion criteria will not be allowed.

[0293]

[0231] Subjects who are expected to be eligible for participation in the study within 3 months may undergo optional SSTR-prescreening to test for SSTR positivity. Subjects who choose to undergo optional SSTR-prescreening must sign the SSTR-prescreening informed consent form (ICF) and must meet the eligibility criteria outlined herein. Results and data collected during SSTR-prescreening may be used for screening in the main study if the subject provides written informed consent for participation in the main study.

[0294]

[0232] Dose Modification

[0295]

[0233] 225Ac-DOTATATE will be administered at increasing dose levels every 6 weeks for a total of 6 infusions in Dose Escalation. During Randomization, 225Ac-DOTATATE will be administered at the RP2D alone or in combination with pembrolizumab administered at 400 mg every 6 weeks for a maximum of 2 years. Recommendation for dose modifications for 225 Ac- DOTATATE and pembrolizumab due to adverse reactions are detailed herein.

[0296]

[0234] When several toxicities with different grades of severity occur at the same time, the dose interruptions or modifications should be implemented according to the highest grade observed. The treating physician may use discretion in accelerating the dose modification guidelines described in the sections below depending on the severity of toxicity and an assessment of the risk versus benefit for the subject.

[0297]

[0235] Dose Modifications for 225Ac-DOTATATE due to Adverse Reactions

[0298]

[0236] Recommendations for 225Ac-DOTATATE dose modification due to adverse reactions considered at least possibly related to 225Ac-DOTATATE are provided in Table 7.

[0299]

[0237] The first dose of 225Ac-DOTATATE may be delayed for no more than 6 weeks from enrollment / randomization. After treatment initiation, if subsequent 225Ac-DOTATATE treatments are delayed, the delay may not exceed 12 weeks since the last 225Ac-DOTATATE administration. Subjects with AEs that require a dose delay of more than 12 weeks since the last 225Ac-DOTATATE administration must permanently discontinue 225Ac-DOTATATE.

[0300]

[0238] If 225Ac-DOTATATE is being administered in combination with pembrolizumab and the subject meets criteria for a dose modification or discontinuation of 225Ac-DOTATATE, subjects may continue treatment with pembrolizumab at the same dose and schedule if determined to be safe by the Investigator (Table 7). In the event of an 225Ac-DOTATATE dose delay, subsequent cycles and respective study visits will be delayed until 225Ac-DOTATATE is resumed. Efficacy imaging assessments and pembrolizumab administrations (if applicable and as clinically indicated) will continue every 6 weeks regardless of the visit or 225Ac- DOTATATE or pembrolizumab dosing schedule.

[0301] Table 11 Recommendations for 225Ac-DOTATATE Dose Modifications for Adverse Reactions

[0302] Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; CrCl=creatinine clearance; CTCAE v5.0=Common Toxicity Criteria for Adverse Events, version 5.0; NCI=National Cancer Institute; ULN=upper limit of normal. a After subsequent dose of 225 Ac-DOTATATE.

[0303]

[0239] Criteria for Restarting Treatment with 225Ac-DOTATATE

[0304]

[0240] All subjects must meet the following criteria before each subsequent 225 Ac- DOTATATE infusion:

[0305] • Hemoglobin concentration >5.0 mmol / L (>8.0 g / dL); ANC >1000 cells / pL (>1000 cells / mm3); platelets >75 * 109 / L (75 * 103 / mm3)

[0306] • CrCl >50 mL / min (calculated using the CKD-EPI equation; Levey et al. 2009)

[0307] • Serum albumin >3.0 g / dL unless PT is within the normal range

[0308] • Total bilirubin <3 x ULN

[0309] • ECOG PS <2

[0310]

[0241] Dose Modifications for Pembrolizumab

[0311]

[0242] Management of AEs, including supportive therapy and dose modifications for subjects in receiving pembrolizumab will be as per the Investigator’s judgement and in accordance with local prescribing information. No dose reduction for pembrolizumab is recommended. Subjects should be monitored for signs and symptoms that may be indicative of immune-mediated adverse reactions. In general, the following guidelines should be followed: (1) Withhold pembrolizumab for severe (Grade 3) immune-mediated adverse reactions. (2) Permanently discontinue pembrolizumab for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for pembrolizumab for adverse reactions that require management different from these general guidelines are summarized in Table 12.

[0312]

[0243] If 225Ac-DOTATATE and pembrolizumab are being administered in combination and the subject meets criteria for a dose modification or discontinuation of pembrolizumab, subjects may continue treatment with 225 Ac-DOTATATE at the same dose and schedule if determined to be safe by the Investigator (Table 7).

[0313]

[0244] Table 12 Recommendations for Pembrolizumab Dose Modifications for Adverse

[0314] Reactions

[0315] Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=drug rash with eosinophilia and systemic symptoms, NCI=National Cancer Institute; SJS=Stevens Johnson syndrome, TEN=toxic epidermal necrolysis, ULN=upper limit of normal.aResume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.bIf AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue pembrolizumab based on recommendations for hepatitis with no liver involvement.

[0316]

[0246] Premedication

[0317]

[0247] Concomitant amino acid i.v. infusions (L-arginine and L-lysine) will be co-infused with each 225Ac-DOTATATE administration for renal protection in accordance with local practice and consistent with labeling. The amino acid solution should have lysine HC1 and arginine HC1 content between 18 and 25 g (each) in a volume of 1 to 2 liters. It is recommended that amino acids and 225Ac-DOTATATE are administered using separate venous access. 225Ac- DOTATATE may be administered through the same venous access as the amino acid if necessary (e.g., poor venous access). The dose of the amino acid solution should not be reduced if the 225Ac-DOTATATE dose is reduced (e.g., due to toxicity). Compounded amino acids will be provided by the Sponsor in some countries.

[0318]

[0248] Subjects may also receive anti emetics, if clinically indicated, before the start of each amino acid i.v. infusion. Recommended options include granisetron 3 mg, ondansetron 8 mg, or tropisetron 5 mg. Other antiemetics may be used. However, prednisone and other glucocorticoids must be avoided as antiemetic premedication due to their potential propensity to downregulate SSTRs (Table 13).

[0319]

[0249] Premedication may also be indicated for subjects receiving pembrolizumab if infusion- related reactions are observed or expected.

[0320]

[0250] Prohibited and Cautionary Therapy

[0251] Concomitant treatments that are prohibited while the subject is receiving study treatment, and their respective washout periods prior to first dose of study treatment, are listed in Table 13.

[0321] Table 13 Prohibited Medications and Treatments

[0322] Abbreviations: AE=adverse event; CT=computed tomography; EBRT=external-beam radiotherapy; N / A=not applicable. a These treatments may be permitted during study treatment if not being used as an anti cancer therapy and approved by the medical monitor. b Subjects with prior EBRT to more than 25% of the bone marrow will be excluded from the study. Palliative EBRT during study treatment is permitted if radiation field does not encompass a target lesion or more than 25% of the bone marrow. c Use of colony-stimulating factors, platelet-production stimulators, and / or transfusions during the study for treatment of toxicities is allowed; prophylactic use is not permitted and may not be used to meet study eligibility criteria. d Does not apply to inhaled or topical steroids and single dose of steroids as pre-medication for CT scans with contrast. Short-course systemic steroids for treatment of acute AEs are permitted during study treatment.

[0323]

[0252] It may be necessary for a subject to permanently discontinue study treatment. Reasons for permanent discontinuation of study treatment include: intolerable toxicity related to the study treatment or a toxicity that requires a delay in treatment of more than 12 weeks since the last 225Ac-DOTATATE dose, disease progression (radiographic PD per Investigator assessment), subject has started anticancer therapy not allowed by the protocol, pregnancy, withdrawal of consent to study treatment, investigator decision, or other.

[0324]

[0253] Efficacy Assessments

[0325]

[0254] Tumor and Response Evaluations

[0255] A contrast-enhanced CT scan should be the preferred imaging modality for most subjects. A contrast-enhanced MRI (if possible) of the abdomen, and pelvis, with a noncontrasted CT scan of the chest, should be performed if a subject is known to have a contraindication to i.v. contrast at screening / baseline or if a subject develops a contraindication during the study.

[0326]

[0256] A CT / MRI of the brain should also be performed within 28 days before enrollment / randomization and within 42 days before first dose of study treatment for all subjects with known or suspected brain metastases at screening and if clinically indicated during the study.

[0327]

[0257] If skeletal lesions are identified at screening which are not visible on the chest, abdomen or pelvis CT / MRI scan, additional CT / MRI scans of the specific sites of metastases will also be required at all postbaseline imaging timepoints (every 6 weeks). The CT / MRI portion of a whole-body PET-CT / MRI or bone scan may also be used for assessments of bone lesions, provided all lesions are visible.

[0328]

[0258] During Dose Escalation, Randomization and Expansion, tumor assessments will be performed locally. During Expansion, on-study tumor assessments will also be performed by BICR. In all parts, all imaging performed during study will be provided for central imaging analysis.

[0329]

[0259] Tumor assessments should be performed according to the protocol-specified schedule regardless of study treatment dose delays, interruptions, or discontinuations as detailed in the Schedule of Activities. Disease progression and tumor response will be evaluated using RECIST vl. l (Eisenhauer et al. Eur J Cancer. 2009; 45(2):228-247). Summaries of the time point responses for target lesions, non-target lesions, and overall response are provided in Tables 14, 15, and 16 for reference. Subjects should remain on their assigned treatment until documented PD. Management of the subject will be based on the Investigator’s assessment of the disease.

[0330]

[0260] Subjects who discontinue study treatment for documented radiographic PD will enter the LTFU After entering LTFU, subjects will be followed approximately every 6 months, until the end of the study for survival status, AEs considered to be related to study treatment, AESIs, laboratory evaluations (may be completed locally), and subsequent anticancer therapy information.

[0331]

[0261] For each subject, the same radiographic procedures and technique used to assess tumor sites at screening must be used throughout the study (e.g., the same contrast protocol for CT scans). All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation. To the extent feasible, assessments should be performed by the same evaluator to ensure internal consistency across visits.

[0332]

[0262] Tumor scans may be repeated at the Investigator’s discretion at any time if PD is suspected. All radiologic imaging will be assessed locally.

[0333]

[0263] Table 14 Response Criteria for Target Lesions

[0334] Abbreviations: CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease.aThe appearance of one or more new lesions is also considered progression.

[0335]

[0264] Table 15 Response Criteria for Non-target Lesions

[0336] Abbreviations: CR=complete response; PD=progressive disease.

[0337] Note: Unequivocal progression in non-target lesions must be substantial and generally sufficient to require change in therapy. The increase in overall disease burden should be comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e., an increase in tumor burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion).

[0265] Table 16 Overall Lesion Response at each Assessment

[0338] Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable disease.

[0339]

[0267] Table 17 Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

[0340]

[0268] Table 18 Clinical Laboratory Tests

[0341] Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated thromboplastin; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CA15-3=carcinoma antigenl5-3; CA27.29=cancer antigen 27.29; CEA=carcinoembryonic antigen (CEA); CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration;

[0342] CrCl=creatinine clearance; ER=estrogen receptor; GGT=gamma-glutamyltransferase; hCG=human chorionic gonadotropin; HER2=human epidermal growth factor receptor 2; HgB AlC=hemoglobin A1C; IEC=Independent Ethics Committee; INR=intemational normalized ratio; IRB=Institutional Review Board; PD-Ll=programmed cell death-ligand 1; PT=prothrombin time; RBC=red blood cells; T3= triiodothyronine; FT3=free triiodothyronine; FT4=free thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell. a T3 or FT3 to be done based on local practice. b Local urine pregnancy testing will be standard for the protocol unless serum testing is required by local regulation or IRB / IEC.

[0343]

[0269] Abbreviations

[0344] Actinium-225, 225Actinium

[0345] Copper-64

[0346] 68Ga Gallium-68 177LU Lutetium- 177 225Ra Radium-225 99my^ Technetium-99m 90y Yttrium-90 ABC advanced breast cancer ADC antibody-drug conjugate ADL activities of daily living AE adverse event AESI adverse event of special interest Al aromatase inhibitor alpha-RPT alpha-particle emitter radiopharmaceutical therapy ALT alanine aminotransferase ANC absolute neutrophil count aPTT activated partial thromboplastin time AST aspartate aminotransferase BICR blinded independent central review BOIN Bayesian optimal interval BOP2 Bayesian optimal phase 2 BOR best overall response CBR clinical benefit rate cyclin-dependent kinase

[0347] Code of Federal Regulations confidence interval cytokeratin

[0348] Chronic Kidney Disease Epidemiology Collaboration coronavirus disease 2019 combined positive score complete response creatinine clearance contract research organization computed tomography clinical trial agreement

[0349] Common Terminology Criteria for Adverse Events (version 5.0) Clinical Trials Facilitation Group disease control rate diabetic ketoacidosis dose-limiting toxicity deoxyribonucleic acid duration of response

[0350] Data Review Committee durable response rate el ectrocardi ogram

[0351] Eastern Cooperative Oncology Group electronic case report form external-beam radiotherapy electronic data capture efficacy follow-up

[0352] End-of- Study (visit) estrogen receptor estrogen receptor-positive early termination fluorodeoxy glucose Good Clinical Practice gastroenteropancreatic neuroendocrine tumor hydrochloride human epidermal growth factor receptor 2 hormone receptor informed consent form

[0353] International Conference for Harmonisation immune check-point inhibitor

[0354] Independent Ethics Committee immunohi stochemi stry investigational medicinal product Institutional Review Board in situ hybridization intravenous(ly) long-term follow-up

[0355] Lutetium 177-labelled DOTATATE (DOTA-octreotate) left ventricular ejection fraction MedDRA Medical Dictionary for Regulatory Activities MRI magnetic resonance imaging NaF sodium fluoride NCI National Cancer Institute NET neuroendocrine tumor ORR objective response rate OS overall survival PD progressive disease PD-L1 programmed cell death-ligand 1 PET positron emission tomography PFS progression-free survival PI3K phosphatidylinositol 3 -kinase PR partial response PS performance status PSMA prostate-specific membrane antigen PT prothrombin time

[0356] RECIST (v 1.1) Response Evaluation Criteria in Solid Tumors (version 1.1) RNA ribonucleic acid RP2D recommended phase 2 dose RP3D recommended Phase 3 dose RPT radiopharmaceutical therapy SAE serious adverse event SAP statistical analysis plan SD standard deviation SERM selective estrogen receptor modulator SoA schedule of activities SoC standard of care SRC Safety Review Committee SRE skeletal -related event SSA somatostatin analogue SSTR somatostatin receptor SSTR2 somatostatin receptor-type 2 SUV standard uptake value SUVmax maximum standard uptake value SU mean mean standard uptake value T1DM type 1 diabetes mellitus TEAE treatment-emergent adverse event TNBC triple-negative breast cancer TROP2 trophoblast cell surface antigen 2 ULN upper of limit normal US United States

[0357] WOCBP woman of childbearing potential

Claims

CLAIMSWe Claim:

1. A method of treating somatostatin receptor-positive (SSTR+), estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer in a patient, comprising administering to the patient225Ac-DOTA- TATE or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is administered at a dose of about 125 to about 275 pCi.

3. The method of claim 1 or 2, wherein the dose is administered once every 4-8 weeks.

4. The method of claim 3, wherein the dose is administered once every 6 weeks.

5. The method of claim 3, wherein the dose is administered once every 42 days ± 3 days.

6. The method of claim 3, wherein the dose is administered once every 4 weeks.

7. The method of claim 3, wherein the dose is administered once every 28 days ± 3 days.

8. The method of any one of claims 1-7, wherein the225Ac-DOTA- TATE is administered for 1-6 cycles.

9. The method of claim 8, wherein the225Ac-DOTA-TATE is administered for 6 cycles.

10. The method of any of claims 1-9, wherein the breast cancer is progesterone receptorpositive (PR+).

11. The method of any one of claims 1 -9, wherein the breast cancer is progesterone receptornegative (PR-).

12. The method of any one of claims 1-11, wherein the breast cancer is somatostatin receptor type 2-positive (SSTR2+).

13. The method of any of claims 1-12, wherein the breast cancer is unresectable or metastatic.

14. The method of claim 13, wherein the breast cancer is unresectable.

15. The method of claim 14, wherein the breast cancer is locally advanced and unresectable.

16. The method of claim 13, wherein the breast cancer is metastatic.

17. The method of any of claims 1-16, wherein the breast cancer is refractory to hormone therapy.

18. The method of any of claims 1-17, wherein the patient received at least two prior lines of therapy to treat the breast cancer.

19. The method of claim 18, wherein the prior lines of therapy comprise hormone therapy, a targeted agent, an antibody drug conjugate (ADC), chemotherapy, or a combination thereof.

20. The method of any one of claims 1-19, wherein the patient received one or more prior lines of hormone therapy.

21. The method of any one of claims 1-20, wherein the patient received one or more prior lines of hormone therapy in combination with a CDK4 / 6 inhibitor.

22. The method of any one of claims 1-21, wherein the patient received at least two prior lines of therapy to treat unresectable or metastatic breast cancer.

23. The method of claim 22, wherein the patient received 2 to 4 prior lines of therapy to treat the unresectable or metastatic breast cancer.

24. The method of claim 22 or 23, wherein at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises an ADC.

25. The method of claim 22, 23, or 24, wherein at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises a chemotherapy.

26. The method of any one of claims 22-25, wherein at least one of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises an ADC, and another of the at least two prior lines of therapy to treat the unresectable or metastatic breast cancer comprises a chemotherapy.

27. The method of claim 25 or 26, wherein the chemotherapy is single-agent chemotherapy.

28. The method of any one of claims 18-27, wherein the breast cancer progressed after treatment with the prior lines of therapy.

29. The method of any one of claims 19-28, wherein the ADC is sacituzumab govitecan-hziy or fam -trastuzumab deruxtecan-nxki.

30. The method of any one of claims 17-29, wherein the hormone therapy comprises an aromatase inhibitor (Al), a selective estrogen receptor modulator (SERM), fulvestrant, or a combination thereof.

31. The method of claim 30, wherein the hormone therapy comprises fulvestrant, exemestane, anastrozole, letrozole, tamoxifen, toremifene, or a combination thereof.

32. The method of any one of claims 19-31, wherein the chemotherapy comprises a taxane, anthracycline, anti-metabolite, or microtubule inhibitor.

33. The method of claim 32, wherein the chemotherapy comprises paclitaxel, capecitabine, taxol, doxorubicin, eribulin, gemcitabine, vinorelbine, carboplatin, or a combination thereof.

34. The method of any one of claims 21-33, wherein the CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, or a combination thereof.

35. The method of any of claims 1-34, wherein the breast cancer comprises at least one RECIST-measurable lesion and at least 60% of RECIST-measurable lesions are S STRPET positive prior to administration of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

36. The method of any of claims 1-35, wherein the breast cancer comprises at least one RECIST-measurable lesion and at least 80% of RECIST-measurable lesions are S STRPET positive prior to administration of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the RECIST-measurable lesion is identified on a computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan.

38. The method of claim 36, wherein the RECIST-measurable lesion is identified on a computed tomography (CT) scan.

39. The method of claim 36, wherein the RECIST-measurable lesion is identified on a magnetic resonance imaging (MRI) scan.

40. The method of any of claims 1-39, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 prior to the administration of225Ac-DOTA- TATE or a pharmaceutically acceptable salt thereof.

41. The method of any of claims 1-40, wherein the patient has creatinine clearance (CrCl) >60 mL / min prior to administration of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

42. The method of any of claims 1-41, wherein prior to administration of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof, the patient has at least one of the following laboratory results:(i) Hemoglobin concentration >5.0 mmol / L (>8.0 g / dL);(ii) Absolute neutrophil count (ANC) >1000 cells / pL (>1000 cells / mm3); and / or(iii) Platelets >100 x 109 / L (100 x 103 / mm3).

43. The method of claim 42, wherein the patient has one of the laboratory results.

44. The method of claim 42, wherein the patient has two of the laboratory results.

45. The method of claim 42, wherein the patient has three of the laboratory results.

46. The method of any of claims 1-45, further comprising administering to the patient a PD- 1 blocking antibody.

47. The method of claim 46, wherein the PD-1 blocking antibody is pembrolizumab.

48. The method of claim 47, wherein the pembrolizumab is administered to the patient at a dose of 400 mg once every 6 weeks.

49. The method of any of claims 1-48, wherein the dose of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is about 125 pCi.

50. The method of any of claims 1-48, wherein the dose of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is about 175 pCi.

51. The method of any of claims 1-48, wherein the dose of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is about 225 pCi.

52. The method of any of claims 1-48, wherein the dose of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is about 275 pCi.

53. The method of any of claims 1-52, further comprising administering an anti -emetic to the patient.

54. The method of claim 53, wherein the anti-emetic is administered prior to administration of225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

55. The method of any of claims 1-54, further comprising administering arginine and lysine to the patient.

56. The method of claim 55, wherein the arginine and lysine are administered intravenously.

57. The method of claim 55 or 56, wherein the arginine and lysine are administered prior to administration of the225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

58. The method of claim 55 or 56, wherein the arginine and lysine are co-infused with the 225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof.

59. The method of any of claims 1-58, wherein225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is administered intravenously.

60. The method of any of claims 1-58, wherein225Ac-DOTA-TATE or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

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