METHODS OF TREATING CANCER

Abstract

The disclosure pertains to drug delivery conjugates for targeted therapy. The disclosure relates to methods of treating PSMA expressing cancers with a combination of compounds of the formulas I-Lu or Ia-Lu, and I-Ac or Ia-Ac. The disclosure also relates to methods of treating PSMA-expressing cancers with a combination of compounds of the formulas I-Lu or Ia-Lu, and I-Ac or Ia-Ac in N patients where stable disease results after treatment with a combination of compounds of the formulas I-Lu or Ia-Lu, and I-Ac or Ia-Ac.

Claims

1. A method for treating cancer in a host animal, the method comprising the step of administering to the host animal a therapeutically effective amount of a first compound having the Formula I ##STR00047## wherein the compound is complexed with .sup.177Lu (I-Lu); in combination with a therapeutically effective amount of a second compound having the Formula I ##STR00048## wherein the compound is complexed with .sup.225Ac (I-Ac).

2. The method of claim 1, wherein the first compound is of the Formula Ia ##STR00049## wherein the compound is complexed with .sup.177Lu (Ia-Lu).

3. The method of claim 2, wherein the second compound is of the Formula Ia ##STR00050## wherein the compound is complexed with .sup.225Ac (Ia-Ac).

4. The method of claim 3, wherein the cancer is associated with expression of prostate specific membrane antigen (PSMA).

5. The method of claim 3, wherein the cancer is selected from the group consisting of prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, renal cell carcinoma, transitional cell carcinoma of the bladder, colonic adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic duct carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and breast carcinoma.

6. The method of claim 5, wherein the cancer is prostate cancer.

7. The method of claim 5, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC).

8. The method of claim 3, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq.

9. The method of claim 3, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq.

10. The method of claim 3, wherein the therapeutically effective amount of I-Lu or Ia-Lu is from about 7.4 GBq.

11. The method of claim 3, wherein the therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq; or about 5 MBq to about 10 MBq; or about 5 MBq to about 7 MBq.

12. The method of claim 3, wherein the therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq.

13. The method of claim 3, wherein the compound of Formula I-Lu or Ia-Lu is administered at the same time as the compound of Formula I-Ac or Ia-Ac.

14. The method of claim 3, wherein the compound of Formula I-Lu or Ia-Lu is administered about 1 hour prior to the compound of Formula I-Ac or Ia-Ac; or about 12 hours prior to the compound of Formula I-Ac or Ia-Ac; or about 24 hours prior to the compound of Formula I-Ac or Ia-Ac; or about 48 hours prior to the compound of Formula I-Ac or Ia-Ac; or about 72 hours prior to the compound of Formula I-Ac or Ia-Ac.

15. The method of claim 3, wherein the compound of Formula I-Ac or Ia-Ac is administered about 1 hour prior to the compound of Formula I-Lu or Ia-Lu; or about 12 hours prior to the compound of Formula I-Lu or Ia-Lu; or about 24 hours prior to the compound of Formula I-Lu or Ia-Lu; or about 48 hours prior to the compound of Formula I-Lu or Ia-Lu; or about 72 hours prior to the compound of Formula I-Lu or Ia-Lu.

16. The method of claim 13, further comprising administering a therapeutically effective amount of the compound of Formula I-Lu or Ia-Lu on a once weekly cycle for from about 1 to about 7 cycles following the administration of I-Lu or Ia-Lu and I—Ac or Ia-Ac.

17. The method of claim 14, further comprising administering a therapeutically effective amount of the compound of Formula I-Lu or Ia-Lu on a once weekly cycle for from about 1 to about 7 cycles following the administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

18. The method of claim 15, further comprising administering a therapeutically effective amount of the compound of Formula I-Lu or Ia-Lu on a once weekly cycle for from about 1 to about 7 cycles following the administration of both I-Lu or Ia-Lu and I-Ac or Ia-Ac.

19.-90. (canceled)

Description

DETAILED DESCRIPTION

[0172] The embodiments of the numbered clauses provided in the summary above, or any combination thereof, are contemplated for combination with any of the embodiments described in the Detailed Description section of this patent application.

[0173] Referring to FIG. 1, the method design can be described according to the schematic shown. In some embodiments, stratification factors for the design include, but are not limited to serum lactate dehydrogenase (LDH) (</=260 IU/L v. >260 IU/L), presence of liver metastases, ECOG score (0-1 v. 2), inclusion of NAAD in best supportive/best standard of care, and the like. In some embodiments, the primary endpoint can be overall survival. In some embodiments, secondary endpoints include, but are not limited to, radiographic progression-free survival (rPFS), RECIST response, time to first symptomatic skeletal event (SSE), and the like. In some embodiments, additional secondary endpoints include, but are not limited to, safety and tolerability, heather-related quality of life (HRQoL; EQ-5D-5L, FACT-P and Brief Pain Inventory—Short FORM [BPI-SF]), health economics, progression-free survival (PFS) (radiological, clinical or PSA progression), biochemical response, such as PSA levels, alkaline phosphatase level, and/or lactate dehydrogenase level. In some embodiments, an endpoint for the treatment methods described herein can be a patient who has achieved a >1=50% decrease from baseline that is confirmed by a second PSA measurement >/=4 weeks. In some embodiments, an endpoint for the treatment methods described herein can be a patient who has achieved a >/=40% decrease from baseline that is confirmed by a second PSA measurement >/=4 weeks. In some embodiments, an endpoint for the treatment methods described herein can be a patient who has achieved a >/=30% decrease from baseline that is confirmed by a second PSA measurement >/=4 weeks.

[0174] In one embodiment, the methods described herein can be used for both human clinical medicine and veterinary applications. Thus, a “patient” can be administered a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and/or PSMA ligand-imaging conjugates described herein, and can be human or, in the case of veterinary applications, can be a laboratory, agricultural, domestic, or wild animal. In one aspect, the patient can be a human, a laboratory animal such as a rodent (e.g., mice, rats, hamsters, etc.), a rabbit, a monkey, a chimpanzee, domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, and wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.

[0175] In some embodiments, patients with PSMA positive scans can be randomized in a 2:1 ratio to receive either a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac plus best supportive/best standard of care or to receive best supportive/best standard of care only. In some embodiments, best supportive/best standard of care can be determined by the treating physician/investigator. In some embodiments, best supportive/best standard of care can be determined by the treating physician/investigator, but will exclude investigational agents, cytotoxic chemotherapy, other systemic radioisotopes, and hemi-body radiotherapy. In some embodiments, novel androgen axis drugs [NAADs], such as abiraterone or enzalutamide, are allowed.

[0176] In some embodiments, patients will be monitored throughout the 6 to 10-month treatment period for survival, disease progression, and adverse events. In some embodiments, a long-term follow-up period can include the collection of survival and treatment updates, adverse events assessment, as well as blood for hematology and chemistry testing.

[0177] In some embodiments, the patient is 18 Years of age or older. In some embodiments, the patient is a male. In some embodiments, the patient has previously been diagnosed with prostate cancer. In some embodiments, the patient has been previously diagnosed with metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the patient meets one or more criteria, selected from the group consisting of Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; a life expectancy at least 6 months; histological, pathological, and/or cytological confirmation of prostate cancer; a positive .sup.68Ga-PSMA-11 PET/CT scan; prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L); previously received at least one NAAD, such as enzalutamide and/or abiraterone; previously treated with at least 1 or 2 previous taxane regimens, wherein a taxane regimen comprises a minimum exposure of 2 cycles of a taxane, or previously received only one taxane regimen, and a. the patient is not willing to receive a second taxane regimen, or b. The patient's physician deems him unsuitable to receive a second taxane regimen, such as due to frailty assessed by geriatric or health status evaluation or intolerance; progressive mCRPC, such as documented progressive mCRPC based on at least one criteria, such as a. serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior, where the minimal start value is 2.0 ng/mL, b. soft-tissue progression defined as an increase >20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions, and c. progression of bone disease, such as evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria); at least one metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained <28 days prior to beginning therapy with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac; recovered to ≤Grade 2 from all clinically significant toxicities related to prior therapies, such as prior chemotherapy, radiation, immunotherapy, and the like; adequate organ function, such as a. bone marrow reserve including white blood cell (WBC) count ≥2.5×109/L (2.5×10{circumflex over ( )}9/L is equivalent to 2.5×10.sup.3/μL and 2.5×K/μL and 2.5×10.sup.3/cumm and 2500/μL) or absolute neutrophil count (ANC) ≥1.5×10.sup.9/L (1.5×10.sup.9/L is equivalent to 1.5×10.sup.3/μL and 1.5×K/μL and 1.5×10.sup.3/cumm and 1500/μL), platelets≥100×10{circumflex over ( )}9/L (100×10{circumflex over ( )}9/L is equivalent to 100×10{circumflex over ( )}3/μL and 100×K/μL and 100×10{circumflex over ( )}3/cumm and 100,000/μL), and/or hemoglobin≥9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L); b. hepatic, such as total bilirubin ≤1.5×the institutional upper limit of normal (ULN) (for patients with known Gilbert's Syndrome ≤3×ULN is permitted), alanine aminotransferase (ALT) or aspartate aminotransferase (AST)≤3.0×ULN OR ≤5.0×ULN for patients with liver metastases, and c. renal, such as serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min; albumin ≥3.0 g/dL (3.0 g/dL is equivalent to 30 g/L); and a stable bisphosphonate or denosumab regimen for ≥30 days prior to treatment.

[0178] In some embodiments, a patient may not receive treatment if the patient has one of more of previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation within about 6 months prior treatment; previous PSMA-targeted radioligand therapy; previous systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within about 28 days prior to treatment; previous administration of investigational agents within about 28 days prior to treatment; a known hypersensitivity to the components of the therapy or its analogs; any other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy; a transfusion within about 30 days of treatment; a history of CNS metastases that have received therapy (surgery, radiotherapy, gamma knife) and are neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity; a superscan as seen in the baseline bone scan; a symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression; concurrent serious (as determined by a physician) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair treatment or cooperation; or been diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment.

[0179] In various embodiments, the cancers described herein can be a cancer cell population that is tumorigenic, including benign tumors and malignant tumors, or the cancer can be non-tumorigenic. The cancer can arise spontaneously or by such processes as mutations present in the germline of the patient or somatic mutations, or the cancer can be chemically-, virally-, or radiation-induced. Cancers applicable to the present disclosure described herein include, but are not limited to, a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.

[0180] In some aspects the cancers can be lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancer of the neck, cutaneous melanoma, intraocular melanoma uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple negative breast cancer, metastatic breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, non-small cell lung cancer, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphomas, pleural mesothelioma, cancer of the bladder, Burkitt's lymphoma, cancer of the ureter, cancer of the kidney, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioma, brain stem glioma, pituitary adenoma, and adenocarcinoma of the gastroesophageal junction.

[0181] Compound Ia has the formula

##STR00046##

wherein .sup.177Lu is complexed to the compound in Ia-Lu, and .sup.225Ac is complexed to the compound in Ia-Ac.

[0182] In other embodiments, any of a variety of PSMA ligand-imaging conjugates detectable by PET imaging, SPECT imaging, and the like can be used. The exact manner of imaging is not limited to the imaging agents described herein. Collectively, the PSMA ligand-imaging conjugates useful for imaging described herein, including those described by formulas and the agents useful for PET imaging, SPECT imaging, etc. are referred to as “PSMA ligand-imaging conjugates.”

[0183] In one embodiment, the Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and/or PSMA ligand-imaging conjugates described herein bind to expressed PSMA on cancer cells. In one illustrative aspect, the Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and/or PSMA ligand-imaging conjugates are capable of differentially binding to PSMA on cancer cells compared to normal cells due to preferential expression (or over-expression) of PSMA on the cancer cells. In some embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and PSMA ligand-imaging conjugates described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers. In some aspects of these embodiments, the combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac will be co-formulated. In some aspects of these embodiments, the combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac will be administered as individually formulated agents. The carriers can be excipients. The choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of a combination of Compounds or Ia-Lu, and I-Ac or Ia-Ac and PSMA ligand-imaging conjugates described herein and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington: The Science & Practice of Pharmacy, 21th Edition (Lippincott Williams & Wilkins, 2005), incorporated herein by reference.

[0184] In one illustrative aspect, a pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, and combinations thereof, that are physiologically compatible. In some embodiments, the carrier is suitable for parenteral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Supplementary active compounds can also be incorporated into compositions of the present disclosure.

[0185] In various embodiments, liquid formulations may include suspensions and solutions. Such formulations may comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid.

[0186] In one embodiment, an aqueous suspension may contain the active materials in admixture with appropriate excipients. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally-occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol; a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate; or one or more coloring agents.

[0187] In one illustrative embodiment, dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, for example, coloring agents, may also be present.

[0188] Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

[0189] In other embodiments, isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can be included in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.

[0190] Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like.

[0191] Depending upon the cancer type as described herein, the route of administration and/or whether a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and/or PSMA ligand-imaging conjugates are administered locally or systemically, a wide range of permissible dosages are contemplated herein, including doses falling in the range from about 1 MBq to about 4 MBq of I-Ac or Ia-Ac. In some embodiments, permissible dosages for I-Lu or Ia-Lu are contemplated herein in the units GBq, including doses falling in the range from about 2 GBq to about 13 GBq. The dosages may be single or divided, and may administered according to a wide variety of protocols, including q.d., b.i.d., t.i.d., or even every other day, biweekly (b.i.w.), once a week, once a month, once a quarter, and the like. In each of these cases it is understood that the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, monthly, or quarterly dose, as determined by the dosing protocol. In some embodiments, a combination of compounds of the formula I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be administered on independent schedules of once, or once per week, or once every two weeks, or once every three weeks, or once every four weeks, or once every five weeks, or once every six weeks, or once every seven weeks, or once every eight weeks, and the like

[0192] In one aspect, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or a PSMA ligand-imaging conjugate as described herein may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0193] In one illustrative aspect, parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. In other embodiments, any of the liquid formulations described herein may be adapted for parenteral administration of the I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates described herein. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization under sterile conditions, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. In one embodiment, the solubility of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or a PSMA ligand-imaging conjugate used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[0194] In various embodiments, formulations for parenteral administration may be formulated for immediate and/or modified release. In one illustrative aspect, a combination of the active agents of the present disclosure (i.e., Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates) may be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates can be prepared with carriers that will protect Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugate against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PGLA). Methods for the preparation of such formulations are generally known to those skilled in the art. In another embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates described herein or compositions comprising the Compounds I-Lu or Ia-Lu, and I—Ac or Ia-Ac or PSMA ligand-imaging conjugates may be continuously administered, where appropriate.

[0195] In one embodiment, a kit is provided. If a combination of active Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac and PSMA ligand-imaging conjugates is to be administered, two or more pharmaceutical compositions may be combined in the form of a kit suitable for sequential administration or co-administration of the compositions. Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugate described herein, and means for separately retaining the compositions, such as a container, divided bottle, or divided foil packet. In another embodiment, compositions comprising one or more of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates described herein, in containers having labels that provide instructions for use of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugates for patient selection and/or treatment are provided.

[0196] In one embodiment, sterile injectable solutions can be prepared by incorporating the active agent in the required amount in an appropriate solvent with one or a combination of ingredients described above, as required, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac or PSMA ligand-imaging conjugate into a sterile vehicle which contains a dispersion medium and any additional ingredients of those described above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof, or the ingredients may be sterile-filtered together.

[0197] The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In one embodiment, the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0198] Any effective regimen for administering a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be used. For example, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be administered as single doses, or the doses can be divided and administered as a multiple-dose daily regimen. Further, a staggered regimen, for example, one to five days per week can be used as an alternative to daily treatment, and for the purpose of the methods described herein, such intermittent or staggered daily regimen is considered to be equivalent to every day treatment and is contemplated. In one illustrative embodiment the patient is treated with multiple injections of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac to treat the cancer. In one embodiment, the patient is injected multiple times (preferably about 2 up to about 50 times) with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac, for example, at 12-72 hour intervals or at 48-72 hour intervals. Additional injections of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be administered to the patient at an interval of days or months after the initial injections(s) and the additional injections can prevent recurrence of the cancer. In another illustrative embodiment the patient is treated with single injections of Compound I-Lu or Ia-Lu and Compound I-Ac or Ia-Ac on the same day, in any order of injection, followed by multiple injections of I-Lu or Ia-Lu to treat the cancer. In some embodiments, the patient is injected multiple times (preferably about 2 up to about 50 times) with Compound I-Lu or Ia-Lu, after receiving an initial injection of each of Compound I-Lu or Ia-Lu and Compound I-Ac or Ia-Ac on the same day, in any order, or at the same time, for example, at 12-72 hour intervals, or at 48-72 hour intervals, or once weekly, or once every two weeks.

[0199] Any suitable course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I—Ac or Ia-Ac can be used. In one illustrative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is administered in a single daily dose administered five days a week, in weeks 1, 2, and 3 of each 4 week cycle, with no dose administered in week 4. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is administered in a single daily dose administered three days a week, of weeks 1, and 3 of each 4 week cycle, with no dose administered in weeks 2 and 4. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is administered biweekly on weeks 1 and 2, i.e. on days 1, 4, 8, 11, of a 3-week cycle. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is administered once weekly on weeks 1 and 2, i.e. days 1 and 8 of a 3-week cycle. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are administered on a single day, in any order, or at the same time, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are administered on a single day, in any order, or at the same time, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles, followed by administration of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac on a single day, in any order, or at the same time, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles.

[0200] In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are administered within about 2 to 72 hours of each other, in any order, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles. In an alternative embodiment, a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are administered within about 2 to 72 hours of each other, in any order, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles, followed by administration of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac on a single day, in any order, or at the same time, followed by administration of Compound I-Lu or Ia-Lu once weekly cycle for from about 2 to about 6-cycles.

[0201] Dose levels of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be measured in GBq and MBq, respectively. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 20 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 13 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 4 GBq to about 11 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 5 GBq to about 10 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 9 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 6.5 GBq to about 8.5 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from about 7 GBq to about 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 15 GBq to about 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 25 GBq to about 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 35 GBq to about 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from about 40 GBq to about 100 GBq. In some embodiments, the total dose of I-Lu, or Ia-Lu is about 44 GBq. In some embodiments, the maximum duration of treatment of a subject is about 19 to 23 months.

[0202] In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 2 GBq to 20 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 2 GBq to 13 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 4 GBq to 11 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 5 GBq to 10 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6 GBq to 9 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6 GBq to 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 6.5 GBq to 8.5 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is from 7 GBq to 8 GBq. In some embodiments, a therapeutically effective amount of I-Lu or Ia-Lu is 7.4 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 15 GBq to 200 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 25 GBq to 185 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 35 GBq to 150 GBq. In some embodiments, the total dose of I-Lu or Ia-Lu ranges from 40 GBq to 100 GBq. In some embodiments, the total dose of I-Lu, or Ia-Lu is 44 GBq. In some embodiments, the maximum duration of treatment of a subject is 19 to 23 months.

[0203] In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 20 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 4 MBq to about 14 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 5 MBq to about 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 6 MBq to about 8 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 5 MBq to about 7 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 1 MBq to about 4 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from about 2 MBq to about 3 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is about 5 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is about 2.5 MBq.

[0204] In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 20 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 4 MBq to 14 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 5 MBq to 10 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 6 MBq to 8 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 5 MBq to 7 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 1 MBq to 4 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is from 2 MBq to 3 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is 5 MBq. In some embodiments, a therapeutically effective amount of I-Ac or Ia-Ac is 2.5 MBq.

[0205] The PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. Accordingly, it is to be understood that the present disclosure includes pure stereoisomers as well as mixtures of stereoisomers, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. The PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may be capable of existing as geometric isomers. Accordingly, it is to be understood that the present disclosure includes pure geometric isomers or mixtures of geometric isomers.

[0206] It is appreciated that the PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, and Ia-Lu, Ia-Ac described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. The PSMA ligand-imaging conjugates and Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0207] In another embodiment, compositions and/or dosage forms for administration of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are prepared from Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are prepared from Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0208] In another embodiment, compositions and/or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least 90%, or at least 95%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0209] In another embodiment, compositions and/or dosage forms for administration of radiolabeled PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a radiochemical purity of at least about 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%, or about 99.5%. In another embodiment, compositions and or dosage forms for administration of the PSMA ligand-imaging conjugate are prepared from the PSMA ligand-imaging conjugate with a purity of at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%.

[0210] The purity of Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or the PSMA ligand-imaging conjugates described herein may be measured using any conventional technique, including various chromatography or spectroscopic techniques, such as high pressure or high performance liquid chromatography (HPLC), nuclear magnetic resonance spectroscopy, TLC, UV absorbance spectroscopy, fluorescence spectroscopy, and the like.

[0211] In another embodiment, Compounds I-Lu, I-Ac, Ia-Lu, and Ia-Ac or PSMA ligand-imaging conjugate described herein is provided in a sterile container or package.

[0212] In one aspect, a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized as overall survival (OS). As used herein, the term “overall survival (OS)” means the time from the date of randomization to the date of death from any cause.

[0213] In one aspect, a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized utilizing Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Illustratively, the criteria have been adapted from the original WHO Handbook (3), taking into account the measurement of the longest diameter for all target lesions: complete response, (CR)—the disappearance of all target lesions; partial response (PR)—at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; stable disease (SD)—neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started; progressive disease (PD)—at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. In another aspect overall disease response rate (ORR) is a clinical benefit and is calculated as the percent of patients who achieve a best response of CR or PR. Overall disease control rate (DCR) can be another clinical benefit and is calculated as the percent of patients who achieve a best response of CR, PR, or SD. In some embodiments, the response can be disease control rate (DCR) as measured by RECIST v1.1 criteria.

[0214] In another aspect, a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized as radiographic progression-free survival (rPFS). As used herein, “radiographic progression-free survival (rPFS)” means the time from the date of randomization to the date of radiographic disease progression as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines or death from any cause. See, for example, Scher H I, Morris M J, Stadler W M, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Work Group 3. J Clin Oncol 2016; 34(12):1402-18. In another aspect, a clinical benefit of the patient to treatment with I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized as time to a first symptomatic skeletal event (SSE). It will be appreciated that symptomatic skeletal event means a clinically significant pathological fracture, surgery or radiation to bone, or spinal cord compression. As used herein, “time to a first symptomatic skeletal event” means date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, or requirement for radiation therapy to relieve bone pain, whichever occurs first.

[0215] In one illustrative example overall survival is the time to death for a given patient defined as the number of days from the first day the patient received protocol treatment (CIDI) to the date of the patient's death. All events of death can be included, regardless of whether the event occurred while the patient was still taking the study drug or after the patient discontinued the study drug. If a patient has not died, then the data can be censored at the last study visit, or the last contact date, or the date the patient was last known to be alive, whichever is last.

[0216] Alternatively, a clinical benefit of the patient as a result of treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac can be characterized as inhibition of tumor growth which can be identified in a patient through, for example, follow-up imaging of the patient's cancer after treatment with I-Lu or Ia-Lu, and I-Ac or Ia-Ac. For example, inhibition of tumor growth can be characterized by measuring the size of tumors in a patient after administration of I-Lu or Ia-Lu, and I-Ac or Ia-Ac according to any of the imaging techniques described herein, where the inhibition of tumor growth is indicated by a stable tumor size, or by a reduction in tumor size. It will be appreciated that the identification of inhibition of tumor growth can be accomplished using a variety of techniques, and is not limited to the imaging methods described herein (e.g CT, MRI, PET imaging, SPECT imaging or chest x-ray).

[0217] In one embodiment, a method is provided of determining whether a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is indicated for the treatment of a patient with cancer, the method comprising the step of determining the PSMA status in a patient with cancer wherein a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is indicated for the treatment of the patient if the PSMA status of the patient is positive.

[0218] In one embodiment, a method is provided of assessing whether a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are indicated for the treatment of a patient with one of the cancers described herein. The method comprises the steps of visually determining PSMA status in the patient wherein PSMA status is based on a imaging tumors that are PSMA positive in the patient, and wherein the a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac are indicated for the treatment of the patient when the PSMA status of the patient is positive.

[0219] In the above-described embodiments, if a patient is in the group with positive PSMA status, a clinical benefit of treatment with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac is indicated. In one embodiment, the clinical benefit to the patient can be overall survival of the patient, ability to receive four or more cycles of therapy with a combination of Compounds I-Lu or Ia-Lu, and I-Ac or Ia-Ac, inhibition of tumor growth, stable disease, a partial response of the patient to therapy, a complete response of the patient to therapy, disease control (i.e., the best result obtained is a complete response, a partial response, or stable disease), and/or overall disease response (i.e., the best result obtained is a complete response or a partial response). In one illustrative example, the clinical benefit for a patient being treated for pleural mesothelioma or adenocarcinoma (e.g. adenocarcinoma of the gastroesophageal junction) is stable disease.

[0220] In another embodiment, the methods described herein include the following examples. The examples further illustrate additional features of the various embodiments of the present disclosure. However, it is to be understood that the examples are illustrative and are not to be construed as limiting other embodiments of the present disclosure. In addition, it is appreciated that other variations of the examples are included in the various embodiments of the present disclosure. In addition, it will be appreciated that all ranges described herein, such as those described in connection with the various embodiments, are exemplary and not intended to be limiting. One of skill in the art will appreciate that all ranges described by an lower and upper bound, such as about 1 to about 20, includes all possible values contained in the lower and upper bound, and includes all possible ranges of values available by the set of possible values contained in the lower and upper bound.

EXAMPLES

Example 1

[0221] Patients with PSMA positive scans will be administered a single dose of Compound Ia-Ac on day 1, cycle 1 of the clinical regimen of 7.4 GBq Compound Ia-Lu, administered 6 weekly for a maximum of 5 cycles. Subjects will be reviewed weekly for assessment of adverse events (onset, duration, grade and relatedness to treatment) during cycle 1 only. DLT will be determined by AE on cycle 1 only.

[0222] Subjects will be restaged at the end of every 2 cycles. At the time of each restaging, patients will be assessed by PSMA PET and Fluorinated PET/CT bone scan. Assesment of bone disease consistent with PCWG23 criteria. PSA evaluation will be measured according to institutional practice at a minimum of 2 weekly.