Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/041—Heterocyclic compounds
  • A61K51/0472—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
  • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present disclosure relates to drug delivery conjugates for targeted therapy.
• the present 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 la- Ac, wherein 177 Lu or 225 Ac are complexed to compounds I and la.
• the present 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 la- Ac.
• Prostate specific membrane antigen is a type II cell surface membrane-bound glycoprotein with -110 kD molecular weight, including an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43), and an extensive extracellular domain (amino acids 44-750). While the functions of the intracellular segment and the transmembrane domains are currently believed to be insignificant, the extracellular domain is involved in several distinct activities. PSMA plays a role in the central nervous system, where it metabolizes N-acetyl-aspartyl glutamate (NAAG) into glutamic and N-acetyl aspartic acid.
• NAAG N-acetyl-aspartyl glutamate
• PSMA is also sometimes referred to as an N-acetyl alpha linked acidic dipeptidase (NAALADase).
• PSMA is also sometimes referred to as a folate hydrolase I (FOLH I) or glutamate carboxypeptidase (GCP II) due to its role in the proximal small intestine where it removes g-linked glutamate from poly-y-glutamated folate and a-linked glutamate from peptides and small molecules.
• FOLH I folate hydrolase I
• GCP II glutamate carboxypeptidase
• PSMA is named largely due to its higher level of expression on prostate cancer cells; however, its particular function on prostate cancer cells remains unresolved.
• PSMA expression is highly restricted in man, present in only salivary gland tissue, renal tissue small numbers of cells in the small and large intestine.
• PSMA is over-expressed in the malignant prostate tissues when compared to other organs in the human body such as kidney, proximal small intestine, and salivary glands.
• Higher PSMA expression is associated with high grade, metastatic and castration resistance disease. Tumor expression in prostate cancer is typically 100 to 1, 000-fold higher.
• PSMA undergoes rapid internalization into the cell in a similar fashion to cell surface bound receptors like vitamin receptors.
• PSMA is internalized through clathrin-coated pits and subsequently can either recycle to the cell surface or go to lysosomes. It has been suggested that the dimer and monomer form of PSMA are inter-convertible, though direct evidence of the interconversion is being debated. Even so, only the dimer of PSMA possesses enzymatic activity, and the monomer does not.
• PSMA is also expressed on the neovasculature of other tumors, such as thyroid cancer, renal clear cell carcinoma, transitional cell carcinoma of bladder, colonic adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic duct carcinoma, non-small cell lung carcinoma, and soft tissue sarcoma, breast carcinoma.
• tumors such as thyroid cancer, renal clear cell carcinoma, transitional cell carcinoma of bladder, colonic adenocarcinoma, neuroendocrine carcinoma, glioblastoma multiforme, malignant melanoma, pancreatic duct carcinoma, non-small cell lung carcinoma, and soft tissue sarcoma, breast carcinoma.
• these cancers represent a large range of different tumors with different histological subtypes, growth rates and cell cycle times.
• the cancers are imbedded within normal tissues having variable radiation tolerances.
• hypoxic areas of larger deposits may also lead to radio resistance.
• PSMA represents a viable target for the selective and/or specific delivery of biologically active agents or combinations of biologically active agents, including drug compounds to such prostate cells.
• One such drug compound is the compound of Formula I
• Compounds I-Lu and I- Ac can be prepared according to the methods described in WO2015/055318, incorporated by reference for the preparation of Compounds I- Lu and I- Ac, as described in Example 3 and Example 5.
• Another such drug compound is Compound la
• Compound I or la can be described as a small molecule that specifically binds to PSMA (prostatic specific membrane antigen) which is expressed on the surface of prostate cancer cells.
• Compound I or la can be characterized as composed of a pharmacophore ligand, glutamate- urea-lysine; a chelator, DOTA (able to complex 177 Lu and 225 Ac); and a linker connecting the ligand and the chelator.
• the urea-based pharmacophore ligand allows the agent to bind to, and be internalized by PSMA at the site of disease.
• the binding of I-Lu, I- Ac, Ia-Lu, or Ia-Ac can lead to internalization through endocytosis which can provide a sustained retention of the ligand and its bound radioactive cargo within the cancer cell.
• Previous radioligand therapy (RLT) used in the clinic includes 131 I in thyroid cancer, and elements emitting alpha radiation, such as 223 Radium or 89 Strontium, for the treatment of bone metastases.
• 177 Lu has a half-life or 6.7 days. It emits a combination of 0.5MeV energy consisting of negatively charged Beta particles (electrons) that travel chaotically through tissues for approximately 20-80 cells or 0.5-2mm and cause predominantly base damage and single strand breaks. At high dose these lesions can interact to convert sublethal damage (SLD) or potentially lethal damage (PLD) to irreparable, lethal damage. 177 Lu also emits H3Kv and 208kV radiation which can be used for imaging.
• SLD sublethal damage
• PLD lethal damage
• H3Kv and 208kV radiation which can be used for imaging.
• 225 Ac has a half-life of 9.9 days, and in contrast emits 8.38MV energy alpha particles. Only 0.5% of energy is emitted as l42Kv photon emissions. The majority of radiation particles are therefore positively charged, and about 8,000 times larger than b particles. Furthermore, the energy from these particles is deposited over relatively short distances (2-3 cells). As a result, there is dense and severe tissue damage in the form of double strand breaks with multiply damaged sites that represent irreparable lethal damage. This is called High Linear Energy Transfer (LET) or densely ionizing ionization and it delivers 3-7 x more absorbed dose than b.
• LET High Linear Energy Transfer
• 177 Lu is believed to provide a longer path length of radiation and therefore can be effective in delivering radiation to adjacent cells.
• SLD sub lethal damage
• PLD lethal damage
• 225 Ac delivers extremely powerful, high LET radiation, and the potential for repair of normal tissue is much more limited.
• the radiological biological effectiveness of alpha radiation is at least 5 times that of beta irradiation and administered doses the relative biological effectiveness (RBE) has to be taken into account.
• RBE relative biological effectiveness
• 225 Ac therapy the type of DNA damage inflicted does not require the presence of oxygen so it will also be more effective in hypoxic tumor regions.
• a possible disadvantage of 225 Ac therapy is that the short path length can lead to large amounts of damaging radiation deposited only within a short distance of 2-4 cells.
• Another such compound is the PSMA-imaging conjugate 4
• PSMA imaging conjugate 4 can be prepared according to the methods described in (Eder, 2012), and (Eder, 2012) is incorporated by reference for the preparation of PSMA imaging conjugate 4, as described in the examples.
• the present disclosure provides a method for treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective amount of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• the present disclosure provides use of Compound I-Lu or Ia-Lu, in combination with Compound I- Ac or la- Ac for treating a cancer in a patient.
• the use comprises administering to the patient a therapeutically effective amount of the
• the present disclosure provides use of a combination of
• the medicament comprises a therapeutically effective combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• the present disclosure provides use of Compound I-Lu or Ia-Lu, in the preparation of a medicament useful for the treatment of a cancer in a patient in combination with Compound I- Ac or la- Ac.
• the medicament comprises a therapeutically effective amount of Compound I-Lu or I-Lu.
• the present disclosure provides use of Compound I- Ac or la- Ac, in the preparation of a medicament useful for the treatment of a cancer in a patient in combination with Compound I-Lu or Ia-Lu.
• the medicament comprises a therapeutically effective amount of Compound I- Ac or I- Ac.
• the present disclosure provides use of Compound I-Lu or Ia-Lu, in the preparation of a first medicament useful for the treatment of a cancer in a patient in combination with a second medicament comprising Compound I- Ac or la- Ac.
• the first medicament comprises a therapeutically effective amount of Compound I-Lu or I-Lu
• the second medicament comprises a therapeutically effective amount of Compound I- Ac or I- Ac.
• the cancer is a PSMA expressing cancer. In some aspects of these embodiments, the compound is at least about 98 percent pure. In some embodiments, the cancer is selected from the group consisting of a glioma, a carcinoma, a sarcoma, a lymphoma, a melanoma, a mesothelioma, a nasopharyngeal carcinoma, a leukemia, an adenocarcinoma, and a myeloma.
• the cancer is selected from the group consisting of 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 carcinoma, 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 carcinoma, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), thyroid cancer, transitional cell carcinoma of the bladder, colonic adenocarcinom
• the cancer is a primary or secondary brain cancer.
• the cancer is prostate cancer.
• the cancer is metastatic prostate cancer.
• a combination of Compounds I-Lu or Ia-Lu and I- Ac or la- Ac is administered in a parenteral dosage form. In some aspects of these embodiments, a combination of Compounds I-Lu or Ia-Lu and I- Ac or la- Ac is administered in a parenteral dosage form. In some aspects of these embodiments, a combination of Compounds I-Lu or Ia-Lu and I- Ac or la- Ac is administered in a parenteral dosage form. In some aspects of these
• the parenteral dosage form is selected from the group consisting of intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, and intrathecal.
• the therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 13 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is from about 4 GBq to about 11 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is from about 5 GBq to about 10 GBq.
• the therapeutically effective amount of I-Lu or Ia-Lu is from about 6 GBq to about 9 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is from about 6.5 GBq to about 8.5 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is from about 7 GBq to about 8 GBq. In some aspects of these embodiments, the therapeutically effective amount of I-Lu or Ia-Lu is about 7.4 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 15 GBq to about 200 GBq.
• the total dose of I-Lu or Ia-Lu ranges from about 25 GBq to about 185 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 35 GBq to about 150 GBq. In some aspects of these embodiments, the total dose of I-Lu or Ia-Lu ranges from about 40 GBq to about 100 GBq. In some aspects of these embodiments, the total dose of I-Lu, or Ia- Lu is about 44 GBq. In some aspects of these embodiments, the maximum duration of treatment of a subject is about 19 to 23 months.
• the therapeutically effective amount of I- Ac or la- Ac is from about 1 MBq to about 20 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is from about 4 MBq to about 14 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is from about 5 MBq to about 10 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is from about 6 MBq to about 8 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is from about 1 MBq to about 4 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is from about 2 MBq to about 3 MBq. In some aspects of these embodiments, the therapeutically effective amount of I- Ac or la- Ac is about 2.5 MBq.
• the methods and uses described herein further comprise imaging PSMA expression by the cancer.
• the step of imaging occurs before the step of administering.
• the step of imaging occurs after the step of administering.
• the imaging is performed by imaging wherein the imaging is selected from the group consisting of SPECT imaging, PET imaging, IHC, and FISH.
• the imaging is performed by SPECT imaging.
• the step of imaging comprises administering to the patient a PSMA ligand-imaging conjugate of the formula 2
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein a radionuclide is bound to the conjugate.
• the step of imaging comprises administering a PSMA ligand-imaging conjugate of the formula 3
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium.
• the PSMA ligand-imaging conjugate is of the formula 2a
• the PSMA ligand-imaging conjugate is of the formula 3a
• the step of imaging comprises administering to the patient a PSMA ligand-imaging conjugate of the formula 4
• the radionuclide is 68 Ga.
• the step of imaging comprises detecting the compound of the formula I-Lu or Ia-Lu administered for the purpose of treating.
• the methods and uses described herein further comprise determining the PSMA status of the patient by imaging.
• the step of determining occurs before the step of administering.
• the step of determining occurs after the step of administering.
• the imaging is SPECT imaging.
• the PSMA status of the patient correlates with a clinical benefit to the patient.
• the clinical benefit is selected from the group consisting of inhibition of tumor growth, stable disease, a partial response, and a complete response.
• the clinical benefit is stable disease.
• the PSMA positive lesions indicate functionally active PSMA.
• the step of determining comprises administering to the patient a PSMA ligand- imaging conjugate of the formula 2
• R' is hydrogen, or R' is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein the conjugate is bound to a radionuclide.
• the step of determining comprises administering a PSMA ligand- imaging conjugate of the formula 3
• R’ is hydrogen, or R’ is selected from the group consisting of alkyl, aminoalkyl, carboxyalkyl, hydroxyalkyl, heteroalkyl, aryl, arylalkyl and heteroarylalkyl, each of which is optionally substituted, and wherein M is a cation of a radionuclide.
• M in the conjugate, or a pharmaceutically acceptable salt thereof is selected from the group consisting of an isotope of gallium, an isotope of indium, an isotope of copper, an isotope of technetium, and an isotope of rhenium. In some aspects of these embodiments, M in the conjugate, or a pharmaceutically acceptable salt thereof, is an isotope of technetium. In some aspects of these embodiments, the PSMA ligand imaging conjugate is of the formula 2a
• the PSMA ligand-imaging conjugate is of the formula 3 a
• the step of determining comprises administering to the patient a PSMA ligand- imaging conjugate of the formula 4
• the radionuclide is 68 Ga.
• the step of determining comprises detecting the compound of the formula I-Lu or Ia-Lu administered for the purpose of treating.
• the present disclosure provides a method of treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective combination of Compounds I-Lu and I- Ac
• the present disclosure provides a method of treating a cancer in a patient in need of such treatment comprising, administering to the patient a therapeutically effective combination of Compounds Ia-Lu and la- Ac
• the use comprises administering to the patient a therapeutically effective combination of Compounds I-Lu and I- Ac
• the present disclosure provides use of Compounds Ia-Lu and Ia-
• the use comprises administering to the patient a therapeutically effective combination of Compounds Ia-Lu and la- Ac.
• the present disclosure provides use of Compounds I-Lu and I- Ac
• the medicament comprises a therapeutically effective combination of the Compounds I-Lu and I- Ac.
• the present disclosure provides use of Compounds I-Lu and I- Ac
• the medicament comprises a therapeutically effective combination of the Compounds I-Lu and I- Ac.
• the present disclosure provides use of Compounds Ia-Lu and Ia- Ac
• the medicament comprises a therapeutically effective combination of the Compounds Ia-Lu and la- Ac.
• the present disclosure provides use of Compounds Ia-Lu and Ia-
• the medicament comprises a therapeutically effective combination of the Compounds Ia-Lu and la- Ac.
• the patient has been treated with at least one prior treatment.
• the at least one prior treatment is selected from the group consisting of an androgen axis systemic treatment, a chemotherapeutic agent, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, and hyperthermia.
• the at least one prior treatment is a systemic treatment.
• the systemic treatment is selected from the group consisting of palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• the cancer is a PSMA expressing cancer.
• the compound is at least about 98 percent pure.
• I-Lu or Ia-Lu is administered prior to I- Ac or Ia- Ac. In some aspects of these embodiments, I-Lu or Ia-Lu is administered prior to I-Ac or Ia-Ac on the same day. In some aspects of these embodiments, I-Lu or Ia-Lu is administered at the same time as I- Ac or Ia-Ac. In some aspects of these embodiments, I- Ac or Ia-Ac is administered prior to I-Lu or Ia-Lu. In some aspects of these embodiments, I- Ac or Ia-Ac is administered prior to I-Lu or Ia-Lu on the same day.
• a method for treating cancer in a host animal comprising the step of administering to the host animal a therapeutically effective amount of a first compound having the Formula I
• 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.
• mCRPC metastatic castration-resistant prostate cancer
• 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 7MBq. 12. The method of any one of the preceding clauses, wherein the therapeutically effective amount of I- Ac or la- Ac is about 5 MBq.
• PSMA prostate specific membrane antigen
• cancer 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.
• mCRPC metastatic castration-resistant prostate cancer
• the compound is complexed with 177 Lu, in the preparation of a medicament comprising a therapeutically effective amount of the compound of the Formula I-Lu, for treating cancer in a patient in combination with a therapeutically effective amount of a compound of the Formula I- Ac
• any one of clauses 37 to 40 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.
• mCRPC metastatic castration-resistant prostate cancer
• clause 50 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 la- Ac.
• composition comprising a compound of the Formula I-Lu,
• the compound is complexed with 177 Lu, in a therapeutically effective amount, for use in the treatment of cancer in a patient, in combination with a therapeutically effective amount of a compound of the Formula I- Ac
• PSMA prostate specific membrane antigen
• mCRPC metastatic castration-resistant prostate cancer
• composition of clause 67 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 la- Ac.
• composition of clause 68 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 la- Ac.
• composition of clause 69 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 la- Ac.
• a medicament comprising a compound of the Formula I-Lu
• 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.
• mCRPC metastatic castration-resistant prostate cancer
• the medicament of clause 89 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.
• a synergistic composition comprising a compound of the Formula I-Lu,
• the compound is complexed with 177 Lu, in a therapeutically effective amount, for use in the treatment of cancer in a patient, in combination with a therapeutically effective amount of a compound of the Formula I- Ac
• any one of clauses 91 to 94 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.
• 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.
• mCRPC metastatic castration-resistant prostate cancer
• synergistic composition of clause 103 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 la- Ac.
• PSMA functionally active PSMA
• PSMA ligands are well known to those skilled in the art such as those described in US patent publication no. US 2010/0324008 Al, incorporated herein by reference.
• “clinical benefit” means a response of a patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac, where the response includes overall survival of the patient, ability to receive four or more cycles of therapy (e.g., four weeks of therapy) with Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac, inhibition of tumor growth, stable disease, a partial response, and/or a complete response, among other clinical benefits defined by the Food and Drug Administration in the United States of America.
• “inhibition of tumor growth” means reduction in tumor size, complete disappearance of a tumor, or growth of a patient tumor of less than 30% over the course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• stable disease means no material progression of disease in a patient over the course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• a partial response means a decrease in tumor size of 30% or greater in a patient treated with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• a complete response means the disappearance of detectable disease in a patient treated with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac.
• prior treatment means the patient has been treated with at least one prior treatment known in the art. It will be appreciated that a prior treatment can be any treatment known to those of skill in the art, including, but not limited, chemotherapeutic agent, surgery, radiation therapy, immunotherapy, photodynamic therapy, stem cell therapy, hyperthermia, and the like.
• Prior treatments can include systemic treatments including, but not limited to treatment with abiraterone, orteronel, galeterone, seviteronel, apalutamide, enzalutamide, palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclophosphamide, doxorubicin, regorafinib, and combinations thereof.
• systemic treatments including, but not limited to treatment with abiraterone, orteronel, galeterone, seviteronel, apalutamide, enzalutamide, palifosfamide, 5-fluorouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribulin, docetaxel, cyclopho
• alkyl includes a chain of carbon atoms, which is optionally branched. It will be further understood that in certain embodiments, alkyl is advantageously of limited length, including C 1 -C 24 , C 1 -C 12 , Ci-C 8 , Ci-Ce, and C 1 -C 4 . Illustratively, such particularly limited length alkyl groups, including Ci-C 8 , Ci-Ce, and C 1 -C 4 may be referred to as lower alkyl. It is appreciated herein that shorter alkyl, alkenyl, and/or alkynyl groups may add less lipophilicity to the compound and accordingly will have different pharmacokinetic behavior.
• alkyl refers to alkyl as defined herein, and optionally lower alkyl.
• Illustrative alkyl groups include, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3 -pentyl, neopentyl, hexyl, heptyl, octyl, and the like.
• a “carboxyalkyl” group includes a combination of an“alkyl” group as described herein with a “carboxy” group.
• a“hydroxyalkyl” group includes a combination of an“alkyl” group as described herein with a“hydroxy” group.
• a“aminoalkyl” group includes a combination of an“alkyl” group as described herein with a“amino” group.
• heteroalkyl includes a chain of atoms that includes both carbon and at least one heteroatom, and is optionally branched.
• Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also include phosphorus, and selenium.
• aryl includes monocyclic and polycyclic aromatic carbocyclic groups having from 6 to 14 ring carbon atoms, each of which may be optionally substituted.
• Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like.
• heteroaryl includes aromatic heterocyclic groups, having from 5 to 10 ring atoms, each of which may be optionally substituted.
• Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.
• heteroarylalkyl includes a combination of an“alkyl” group as described herein with a“heteroaryl” group described herein.
• arylalkyl includes a combination of an“alkyl” group as described herein with a“aryl” group described herein, for example a benzyl group.
• optionally substituted includes the replacement of hydrogen atoms with other functional groups on the radical that is optionally substituted.
• Such other functional groups illustratively include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof, carboxylic acids and derivatives thereof, and the like.
• any of amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
• administering includes all means of introducing a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac and/or a PSMA ligand-imaging conjugate as described herein to the patient, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac and/or a PSMA ligand- imaging conjugate as described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles.
• becquerel means a SI derived unit of radioactivity as it is commonly understood by one of skill in the art.
• One becquerel is defined as the activity of a quantity of radioactive material in which one nucleus decays per second. A becquerel is therefore equivalent to an inverse second, s-l.
• the becquerel is known to one of skill in the art as the successor of the curie (Ci), an older, non-SI unit of radioactivity based on the activity of 1 gram of radium-226.
• the curie is defined as 3.7. 1010 s-l, or 37 GBq..
• “curie” or“Ci” means a unit of radioactivity named after the French physicist and chemist Marie Curie as commonly understood by one of skill in the art.
• the prefixes milli and micro are from the metric system and represent .001 and .000001, respectively. So, a millicurie (mCi) is .001 curie.
• a microcurie (pCi) is .000001 curie.
• LDH serum lactate dehydrogenase
• ECOG score (0-1 v. 2)
• NAAD NAAD in best supportive/best standard of care
• the primary endpoint can be overall survival.
• 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.
• 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.
• a“patient” can be administered a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• 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.
• a rodent e.g., mice, rats, hamsters, etc.
• a rabbit e.g., a monkey, a chimpanzee
• domestic animals such as dogs, cats, and rabbits
• agricultural animals such as cows, horses, pigs, sheep, goats
• wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas
• 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 la- Ac plus best supportive/best standard of care or to receive best supportive/best standard of care only.
• best supportive/best standard of care can be determined by the treating physician/investigator.
• 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.
• novel androgen axis drugs [NAADs] such as abiraterone or enzalutamide, are allowed.
• patients will be monitored throughout the 6 to lO-month treatment period for survival, disease progression, and adverse events.
• 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.
• 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).
• mCRPC metastatic castration-resistant prostate cancer
• 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 68 Ga-PSMA-ll 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.
• EOG Eastern Cooperative Oncology Group
• 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.
• SOD diameter
• 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 la- 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.
• WBC white blood cell
• hepatic such as total bilirubin ⁇ 1.5 x the institutional upper limit of normal (ULN) (for patients with known Gilbert’s Syndrome ⁇ 3 x ULN is permitted), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ⁇ 3.0 x ULN OR ⁇ 5.0 x ULN for patients with liver metastases, and c. renal, such as serum creatinine ⁇ 1.5 x 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.
• UPN institutional upper limit of normal
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• renal such as serum creatinine ⁇ 1.5 x ULN or creatinine clearance >50 mL/min
• albumin >3.0
• 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,
• 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
• 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.
• 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 lymph
• 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.”
• the Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac and/or PSMA ligand-imaging conjugates described herein bind to expressed PSMA on cancer cells.
• the Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac and PSMA ligand-imaging conjugates described herein may be administered as a formulation in association with one or more pharmaceutically acceptable carriers.
• the combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac will be co formulated.
• the combination of Compounds I-Lu or Ia- Lu, and I- Ac or la- 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.
• compositions suitable for the delivery of a combination of Compounds or Ia-Lu, and I- Ac or la- 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, 2lth Edition (Lippincott Williams &
• 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.
• 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.
• 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.
• an aqueous suspension may contain the active materials in admixture with appropriate excipients.
• 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,
• 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.
• 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.
• 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.
• 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.
• Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like.
• 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 la- Ac.
• 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.
• biweekly b.i.w.
• 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.
• a combination of compounds of the formula I-Lu or Ia-Lu, and I- Ac or la- 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
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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, intrastemal, intracranial, intratumoral, intramuscular and subcutaneous delivery.
• Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
• 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.
• a suitable vehicle such as sterile, pyrogen- free water.
• any of the liquid formulations described herein may be adapted for parenteral administration of the I-Lu or Ia-Lu, and I- Ac or la- Ac or PSMA ligand-imaging conjugates described herein.
• parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
• solubility of a combination of Compounds I-Lu or Ia- Lu, and I- Ac or la- 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.
• formulations for parenteral administration may be formulated for immediate and/or modified release.
• a combination of the active agents of the present disclosure i.e., Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- Ac or PSMA ligand-imaging conjugates can be prepared with carriers that will protect Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac or PSMA ligand-imaging conjugate against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac or PSMA ligand-imaging conjugates described herein or compositions comprising the Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac or PSMA ligand-imaging conjugates may be continuously administered, where appropriate.
• kits are provided. If a combination of active Compounds I-Lu or Ia- Lu, and I- Ac or la- 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
• compositions comprising one or more of a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- Ac or PSMA ligand-imaging conjugates for patient selection and/or treatment are provided.
• 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.
• dispersions are prepared by incorporating the active combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac or PSMA ligand-imaging conjugate into a sterile vehicle which contains a dispersion medium and any additional ingredients of those described above.
• 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.
• 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.
• 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.
• any effective regimen for administering a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be used.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be administered as single doses, or the doses can be divided and administered as a multiple-dose daily regimen.
• 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.
• the patient is treated with multiple injections of a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac to treat the cancer.
• 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 la- 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 la- 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.
• the patient is treated with single injections of Compound I-Lu or Ia-Lu and Compound I- Ac or la- Ac on the same day, in any order of injection, followed by multiple injections of I-Lu or Ia-Lu to treat the cancer.
• 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 la- 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.
• any suitable course of therapy with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be used.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac is administered biweekly on weeks 1 and 2, i.e. on days 1, 4, 8, 11, of a 3-week cycle.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac is administered once weekly on weeks 1 and 2, i.e. days 1 and 8 of a 3-week cycle.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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.
• a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- 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.
• Dose levels of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be measured in GBq and MBq, respectively.
• a therapeutically effective amount of I-Lu or Ia- Lu is from about 2 GBq to about 20 GBq.
• a therapeutically effective amount of I-Lu or Ia-Lu is from about 2 GBq to about 13 GBq.
• a therapeutically effective amount of I-Lu or Ia-Lu is from about 4 GBq to about 11 GBq.
• a therapeutically effective amount of I-Lu or Ia-Lu is from about 5 GBq to about 10 GBq.
• 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.
• 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.
• 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.
• 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
• a therapeutically effective amount of I-Lu or Ia-Lu is 7.4 GBq.
• the total dose of I-Lu or Ia-Lu ranges from 15 GBq to 200 GBq.
• the total dose of I-Lu or Ia-Lu ranges from 25 GBq to 185 GBq.
• the total dose of I-Lu or Ia-Lu ranges from 35 GBq to 150 GBq.
• the total dose of I-Lu or Ia-Lu ranges from 40 GBq to 100 GBq.
• the total dose of I-Lu, or Ia-Lu is 44 GBq.
• the maximum duration of treatment of a subject is 19 to 23 months.
• a therapeutically effective amount of I- Ac or la- 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.
• 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 la- Ac is from about 2 MBq to about 3 MBq. In some embodiments, a therapeutically effective amount of I- Ac or la- Ac is about 5 MBq. In some embodiments, a therapeutically effective amount of I- Ac or la- Ac is about 2.5 MBq.
• a therapeutically effective amount of I- Ac or la- Ac is from 1 MBq to 20 MBq. In some embodiments, a therapeutically effective amount of I- Ac or la- Ac is from 1 MBq to 10 MBq. In some embodiments, a therapeutically effective amount of I- Ac or la- 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.
• 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.
• 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.
• PSMA ligand-imaging conjugates and Compounds I-Lu, I- Ac, Ia-Lu, and 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.
• 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%.
• compositions and or dosage forms for administration of a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac are prepared from Compounds I-Lu or Ia-Lu, and I- Ac or la- 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%.
• 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%.
• 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%.
• 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%.
• 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%.
• 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%.
• the purity of Compounds I-Lu, I- Ac, Ia-Lu, and la- 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.
• HPLC high pressure or high performance liquid chromatography
• TLC nuclear magnetic resonance spectroscopy
• UV absorbance spectroscopy fluorescence spectroscopy
• Compounds I-Lu, I- Ac, Ia-Lu, and la- Ac or PSMA ligand imaging conjugate described herein is provided in a sterile container or package.
• a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be characterized as overall survival (OS).
• OS overall survival
• the term“overall survival (OS)” means the time from the date of randomization to the date of death from any cause.
• a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be characterized utilizing Response
• Evaluation Criteria in Solid Tumors include 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.
• overall disease response rate 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.
• the response can be disease control rate (DCR) as measured by RECIST vl.l criteria.
• a clinical benefit of the patient to treatment with a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- Ac can be characterized as radiographic progression- free survival (rPFS).
• rPFS radiographic progression- free survival
• PCWG3 Prostate Cancer Working Group 3
• a clinical benefit of the patient to treatment with I-Fu or Ia-Fu, and I- Ac or la- Ac can be characterized as time to a first symptomatic skeletal event (SSE).
• SSE first symptomatic skeletal event
• symptomatic skeletal event means a clinically significant pathological fracture, surgery or radiation to bone, or spinal cord compression.
• 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.
• 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 (C1D1) 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.
• C1D1 patient received protocol treatment
• 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 la- 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 la- Ac.
• 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 la- 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).
• a method is provided of determining whether a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- Ac is indicated for the treatment of the patient if the PSMA status of the patient is positive.
• a method is provided of assessing whether a combination of Compounds I-Lu or Ia-Lu, and I- Ac or la- 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 la- Ac are indicated for the treatment of the patient when the PSMA status of the patient is positive.
• 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 la- 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).
• the clinical benefit for a patient being treated for pleural mesothelioma or adenocarcinoma is stable disease.
• 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.
• cycle 1 of the clinical regimen of 7.4GBq 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.
• 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.

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