Dosing regimens for peptide conjugates of topoisomerase I inhibitors

Abstract

The present invention relates to dosing regimens for peptide conjugates of topoisomerase I inhibitors (eg, peptide conjugates of the topoisomerase I inhibitor exatecan) that are useful in the treatment of diseases such as cancer.

Description

[Technical field]

[0001] The present invention relates to dosing regimens for peptide conjugates of topoisomerase I inhibitors (eg, peptide conjugates of the topoisomerase I inhibitor exatecan) that are useful in the treatment of diseases such as cancer.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an ASCII text file named 43236-0019WO1_ST25.txt. The ASCII text file, created on April 26, 2022, is 2.20 kilobytes in size. The material in this ASCII text file is incorporated herein by reference in its entirety. [Background technology]

[0003] Cancer is a group of diseases characterized by abnormal control of cell growth. The annual incidence of cancer is estimated to be over 1.6 million in the United States alone. Although surgery, radiation, chemotherapy, and hormones are used to treat cancer, cancer remains the second leading cause of death in the United States. It is estimated that approximately 600,000 Americans die from cancer each year.

[0004] Treatment of human cancers with systemic administration of pharmaceuticals often works by slowing or terminating the uncontrolled replication that is a hallmark of cancer cells. One class of such drugs is topoisomerase I inhibitors. The topoisomerase 1 enzyme relaxes supercoiled DNA, relaxes the helical structure of DNA, and is involved in transcriptional regulation. See Li, M., Genomics Proteomics Bioinformatics 14(2016), 166-171. Topoisomerase I is essential for the development of mammalian systems due to its dynamic function in DNA replication and transcription. However, due to its direct role in transcriptional regulation, dysfunction of topoisomerase I can lead to abnormal cellular function. See Li, M., Genomics Proteomics Bioinformatics 14(2016), 166-171. Thus, several human diseases, such as cancer, neurodegenerative diseases, and autoimmune diseases, are linked to the regulation and activity of topoisomerase I.

[0005] Inhibitors of topoisomerase I have been developed and continue to be developed as anti-cancer drugs. In particular, topoisomerase I inhibitors are widely used in the treatment of colorectal cancer, gastric cancer, and other cancers. See Ogitani, Bioorg. Med. Chem. Lett. 26 (2016), 5069-5072. Although topoisomerase I inhibitors are useful in the treatment of cancer, these compounds also exhibit side effects such as neutropenia and severe diarrhea. Preferential delivery of topoisomerase inhibitors to these diseased tissues may avoid these serious side effects. Peptide conjugates of topoisomerase I inhibitors are described in U.S. Patent Application Publication No. 2021 / 009719. Further development of peptide conjugates of topoisomerase inhibitors and their administration regimens is needed. Summary of the Invention

[0006] The present disclosure relates, inter alia, to a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 wherein the linker is covalently attached to The compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg, as measured by the amount of the free form of the compound.

[0007] The present disclosure relates, inter alia, to a method of treating cancer in a patient, comprising administering to the patient a compound 1 having the following structure: [ka] or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1); The method is provided, wherein Compound 1, or a pharma- ceutically acceptable salt thereof, is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg, as measured by the amount of free form of Compound 1.

[0008] The present disclosure further provides a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 wherein the linker is covalently attached to The compound or a pharma- ceutical acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0009] The present disclosure further provides a method of treating cancer in a patient, comprising administering to the patient a compound 1 having the structure: [ka] or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1); Compound 1 or a pharma- ceutical acceptable salt thereof is administered at a concentration of about 5 mg / m2 as measured by the amount of the free form of Compound 1. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0010] The present disclosure further provides a method of administering Compound 1, or a pharma- ceutically acceptable salt thereof, to a patient in need of treatment, comprising administering to the patient Compound 1, having the structure: [ka] or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1); The method is provided, wherein Compound 1, or a pharma- ceutically acceptable salt thereof, is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg, as measured by the amount of free form of Compound 1.

[0011] The present disclosure further provides a method of administering Compound 1, or a pharma- ceutically acceptable salt thereof, to a patient in need of treatment, comprising administering to the patient Compound 1, having the structure: [ka] or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1); Compound 1 or a pharma- ceutical acceptable salt thereof is administered at a concentration of about 5 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0012] The disclosure further provides the use of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer.

[0013] The disclosure further provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in any of the methods described herein.

[0014] The present disclosure further provides the use of Compound 1, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

[0015] The disclosure further provides Compound 1, or a pharma- ceutically acceptable salt thereof, for use in any of the methods described herein. [Brief description of the drawings]

[0016] [Figure 1A] Mean plasma levels on day 1 of Compound 1 and exatecan (Cohort A) are shown. [Figure 1B] Mean plasma levels of Compound 1 and Exatecan (Cohort A) on day 4 are shown. [Figure 2A] Mean plasma levels on day 1 of Compound 1 and exatecan (Cohort B) are shown. [Figure 2B] Mean plasma levels of Compound 1 and Exatecan (Cohort B) on day 3 are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Administration of Compounds of Formula (I) The present disclosure relates, inter alia, to a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 wherein the linker is covalently attached to The compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg, as measured by the amount of the free form of the compound.

[0018] The present disclosure further provides a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 wherein the linker is covalently attached to The compound or a pharma- ceutical acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0019] The present disclosure further relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, comprising parenterally delivering the compound to the patient. [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 is a linker covalently attached to The compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg, as measured by the amount of the free form of the compound.

[0020] The present disclosure further relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, comprising parenterally delivering the compound to the patient. [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 is a linker covalently attached to The compound or a pharma- ceutical acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0021] The present disclosure further relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, comprising parenterally delivering the compound or a pharma- ceutically acceptable salt thereof to the patient. [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 is a linker covalently attached to The compound or a pharma- ceutical acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0022] The present disclosure further relates to a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof to a patient in need of treatment, comprising parenterally delivering the compound or a pharma- ceutically acceptable salt thereof to the patient. [In the formula, R 1 is a peptide, R 2 is a small molecule topoisomerase I targeting moiety that binds topoisomerase I, Q is the part R 1 and R 2 is a linker covalently attached to The compound or a pharma- ceutical acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 The method further comprises administering a daily dose of

[0023] In some embodiments, R 1 The peptide has 10 to 50 amino acids, 20 to 40 amino acids, 10 to 20 amino acids, 20 to 30 amino acids, or 30 to 40 amino acids.

[0024] In some embodiments, R 1The peptides of are conformationally restricted peptides. Conformationally restricted peptides can include, for example, macrocyclic peptides and stapled peptides. Stapled peptides are peptides that are constrained by a covalent bond between two amino acid side chains to form a peptide macrocycle. Conformationally restricted peptides are described, for example, in Guerlavais et al., Annual Reports in Medicinal Chemistry 2014, 49, 331-345; Chang et al., Proceedings of the National Academy of Sciences of the United States of America (2013), 110(36), E3445-E3454; Tesauro et al., Molecules 2019, 24, 351-377; Dougherty et al., Journal of Medicinal Chemistry (2019), 62(22), 10098-10107; and Dougherty et al., Chemical Reviews (2019), 119(17), 10241-10287, each of which is incorporated herein by reference in its entirety.

[0025] In some embodiments, R 1The peptides of are environmentally sensitive peptides and are described, for example, in U.S. Patent Nos. 8,076,451 and 9,289,508, and U.S. Patent Publication No. 2019 / 209580, each of which is incorporated herein by reference in its entirety, although other peptides that allow for such selective insertion may be used. Other suitable peptides are described, for example, in Weerakkody, et al., PNAS 110(15), 5834-5839 (April 9, 2013), also incorporated herein by reference in its entirety. Without wishing to be bound by theory, it is believed that environmentally sensitive peptides change conformation in response to physiological changes (e.g., pH) and insert across cell membranes. The peptides target acidic tissues and can selectively translocate polar cell-impermeable molecules across cell membranes in response to a decrease in extracellular pH. In some embodiments, the peptides can selectively deliver molecules across cell membranes that have an acidic or hypoxic mantle with a pH less than about 6.0. In some embodiments, the peptides are capable of selectively delivering molecules across cell membranes that have an acidic or hypoxic mantle having a pH of less than about 6.5. In some embodiments, the peptides are capable of selectively delivering molecules across cell membranes that have an acidic or hypoxic mantle having a pH of less than about 5.5. In some embodiments, the peptides are capable of selectively delivering molecules across cell membranes that have an acidic or hypoxic mantle having a pH of about 5.0 to about 6.0.

[0026] The term "acidic and / or hypoxic mantle" refers to the environment of cells in the diseased tissue in question, where the pH is lower than 7.0, preferably lower than 6.5. The acidic or hypoxic mantle more preferably has a pH of about 5.5, most preferably about 5.0. Compounds of formula (I) insert across cell membranes having an acidic and / or hypoxic mantle in a pH-dependent manner to induce R 2 - into cells, after which the disulfide linker is cleaved to release the free R 2H. Because the compounds of formula (I) are pH dependent, they preferentially insert across cell membranes only in the presence of an acidic or hypoxic mantle surrounding the cell, and do not insert across the cell membrane of "normal" cells that do not have an acidic or hypoxic mantle. An example of a cell that has an acidic or hypoxic mantle is a cancer cell.

[0027] Peptide R 1 , or peptide R 1 The term "pH-sensitive" or "pH-dependent" as used herein to refer to the mode of insertion of the compounds of the invention across a cell membrane means that the peptide has a higher affinity for cell membrane lipid bilayers having an acidic or hypoxic mantle than for membrane lipid bilayers at neutral pH. Thus, the compounds of the invention preferentially insert through cell membranes and promote R expression when the cell membrane lipid bilayer has an acidic or hypoxic mantle ("diseased" cells). 2 - into the interior of the cell (hence, R 2 H), but does not insert through the cell membrane unless the mantle (environment of the cell membrane lipid bilayer) is acidic or hypoxic ("normal" cells). This preferential insertion is due to the peptide R 1 is believed to be achieved as a result of the formation of a helical structure that facilitates membrane insertion.

[0028] In some embodiments, R 1 The peptide has the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2); ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3); Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4); and AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5) Includes at least one of the following:

[0029] In some embodiments, R 1 The peptide has the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1), AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2), and ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3) Includes at least one of the following:

[0030] In some embodiments, R 1 The peptide comprises the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1; Pv1).

[0031] In some embodiments, R 1 The peptide comprises the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2).

[0032] In some embodiments, R 1 The peptide comprises the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3).

[0033] In some embodiments, R 1 The peptide comprises the sequence Ac-AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4).

[0034] In some embodiments, R 1 The peptide comprises the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5).

[0035] In some embodiments, R 1The peptide consists essentially of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1; Pv1).

[0036] In some embodiments, R 1 The peptide consists essentially of the sequence AEQNPIYWARYADWLFTTPLLLLDLALLVDADECG (SEQ ID NO:2; Pv2).

[0037] In some embodiments, R 1 This peptide consists essentially of the sequence ADDQNPWRAYLDLLFPTDTLLLDLLWDADECG (SEQ ID NO:3; Pv3).

[0038] In some embodiments, R 1 The peptide consists essentially of the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTKCG (SEQ ID NO: 4; Pv4).

[0039] In some embodiments, R 1 The peptide consists essentially of the sequence AAEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTC (SEQ ID NO:5; Pv5).

[0040] Additional peptides are disclosed in U.S. Patent Application Publication No. 2019 / 209580, U.S. Patent Application No. 16 / 925,094, and U.S. Patent Application No. 16 / 924,445, each of which is incorporated herein in its entirety.

[0041] The term "small molecule topoisomerase I targeting moiety" or "topoisomerase I inhibitor" refers to a chemical group that binds to topoisomerase I. Small molecule topoisomerase I targeting moieties can be groups derived from compounds that inhibit the activity of topoisomerase I. Topoisomerase inhibitors include camptothecin and its derivatives and analogs, such as opotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, and exatecan. Topoisomerase inhibitors are described, for example, in Ogitani, Bioorg. Med. Chem. Lett. 26(2016), 5069-5072; Kumazawa, E., Cancer Chemother Pharmacol 1998, 42:210-220; Tahara, M, Mol Cancer Ther 2014, 13(5):1170-1180; Nakada, T., Bioorganic & Medicinal Chemistry Letters 2016, 26:1542-1545.

[0042] Compounds of formula (I) having a topoisomerase I targeting moiety are described in U.S. Patent Application Publication No. 2021 / 0009719. In some embodiments of the compounds of formula (I), R 2 is camptothecin, opotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, or exatecan. 2 is exatecan.

[0043] The moiety Q serves as a tether between the peptide and the topoisomerase I inhibitor that can be cleaved when the conjugate, or a portion thereof, is inside a cell. 1 and R 2In some embodiments, Q is a chain of 1 to 40, 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, or 1 to 5 chain atoms and 1 to 10 R q may be substituted with substituents, one or more chain carbon atoms of Q may be oxidized to form a carbonyl (C=O), and one or more N and S chain atoms may each be optionally oxidized to form an amine oxide, sulfoxide or sulfonyl group; Each R q are independently OH, CN, -COOH, NH 2 , Haro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, NH(C 1-6 alkyl), and N(C 1-6 Alkyl) 2 Selected from R q C 1-6 Alkyl, Phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each selected from halo, OH, CN, -COOH, NH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, Phenyl, C 3-10 optionally substituted with cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl; The Two R's q The groups, together with the chain atoms to which they are attached, are selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl, or C 3-6 A cycloalkyl ring can be formed.

[0044] In some embodiments, R q are independently OH, CN, -COOH, NH2 , Haro, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NH(C 1-6 alkyl) and N(C 1-6 Alkyl) 2 is selected from.

[0045] In some embodiments, the compound is a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, R 1 is a peptide, R 2 is a topoisomerase I inhibitor, Ring Z is a monocyclic C 5-7 a cycloalkyl ring or a monocyclic 5- to 7-membered heterocycloalkyl ring; Each R Z is independent, C 1-4 Alkyl, halo, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 is selected from or two adjacent R Z together with the atoms to which they are attached form a fused monocyclic C 5-7 Cycloalkyl ring, fused monocyclic 5- to 7-membered heterocycloalkyl ring, fused C 6 - 10Form an aryl ring or a fused 6- to 10-membered heteroaryl ring, each of which is C 1-4 Alkyl, halo, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from R a1 , R b1 , R c1 , and R d1 are independently H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, halo, OH, CN, and NO 2 and n is 0, 1, 2, or 3.

[0046] In some embodiments of the compound of Formula (II), R 1 is a peptide comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.

[0047] In some embodiments of the compound of Formula (II), R 1 is Pv1, PV2, PV3, PV4, or PV5.

[0048] In some embodiments of the compound of Formula (II), R 1 is R 1and one of the sulfur atoms of the disulfide moiety of formula II is derived from a cysteine ​​residue.

[0049] In some embodiments of the compound of Formula (II), R 2 are camptothecin, opotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, or exatecan.

[0050] In some embodiments of the compound of Formula (II), R 2 is exatecan.

[0051] In some embodiments of the compound of Formula (II), R 2 is attached to the core via an N atom.

[0052] In some embodiments of the compound of Formula (II), ring Z is a monocyclic C 5-7 It is a cycloalkyl ring.

[0053] In some embodiments of the compounds of Formula (II), ring Z is a cyclopentyl ring.

[0054] In some embodiments of the compounds of Formula (II), ring Z is a cyclohexyl ring.

[0055] In some embodiments of the compound of Formula (II), ring Z is a cycloheptyl ring.

[0056] In some embodiments of the compound of Formula (II), ring Z is a monocyclic 5-7 membered heterocycloalkyl ring.

[0057] In some embodiments of the compounds of Formula (II), ring Z is a 5-membered heterocycloalkyl ring.

[0058] In some embodiments of the compounds of Formula (II), ring Z is a 6-membered heterocycloalkyl ring.

[0059] In some embodiments of the compounds of Formula (II), ring Z is a 7-membered heterocycloalkyl ring.

[0060] In some embodiments of the compound of Formula (II), two adjacent R Z together with the atoms to which they are attached form a fused monocyclic C 5-7 Cycloalkyl ring, fused monocyclic 5- to 7-membered heterocycloalkyl ring, fused C 6-10 aryl ring, or a fused 6- to 10-membered heteroaryl ring, each of which is 1-4 Alkyl, halo, CN, NO 2 , OR a1 , S.R. a1 , C(O)R b1 , C(O)NRc1R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , and N.R. c1 C(O)NR c1 R d1 and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0061] In some embodiments of the compound of Formula (II), n is 0.

[0062] In some embodiments of the compound of Formula (II), n is 1.

[0063] In some embodiments of the compound of Formula (II), n is 2.

[0064] In some embodiments of the compound of Formula (II), n is 3.

[0065] In some embodiments, the compound of the present invention is a compound of formula (III), formula (IV), or formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 , R 2 , R Z and n is defined as in any of the above embodiments for formula (II).

[0066] In some embodiments, the compound is Compound 1, having the structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1).

[0067] In some embodiments, the method includes administering to a patient a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.50 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound.

[0068] Provided herein is a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I), wherein the compound is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.1 mg / kg to about 1.25 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg to about 0.50 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.5 mg / kg to about 0.75 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.5 mg / kg to about 1.25 mg / kg.

[0069] In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.75 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 1.0 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 1.25 mg / kg as measured by the amount of the free form of the compound.

[0070] In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.5 mg / kg. In some embodiments, the compound is administered at a daily dose of about 0.75 mg / kg. In some embodiments, the compound is administered at a daily dose of about 1.0 mg / kg. In some embodiments, the compound is administered at a daily dose of about 1.25 mg / kg.

[0071] In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 1.5 mg / kg or less as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 1.25 mg / kg or less as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 1.0 mg / kg or less as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.75 mg / kg or less as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.5 mg / kg or less as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered at a daily dose of about 0.25 mg / kg or less as measured by the amount of the free form of the compound.

[0072] In some embodiments, the compound is administered at a daily dose of about 1.5 mg / kg or less. In some embodiments, the compound is administered at a daily dose of about 1.25 mg / kg or less. In some embodiments, the compound is administered at a daily dose of about 1.0 mg / kg or less. In some embodiments, the compound is administered at a daily dose of about 0.75 mg / kg or less. In some embodiments, the compound is administered at a daily dose of about 0.5 mg / kg or less. In some embodiments, the compound is administered at a daily dose of about 0.25 mg / kg or less.

[0073] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered intravenously. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg, as measured by the amount of the free form of the compound.In some embodiments, the compound or its pharmaceutically acceptable salt is administered as an intravenous infusion at a dose of about 0.5 mg / kg, as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered as an intravenous infusion at a dose of about 0.75 mg / kg, as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered as an intravenous infusion at a dose of about 1.0 mg / kg, as measured by the amount of the free form of the compound. In some embodiments, the compound or its pharmaceutically acceptable salt is administered as an intravenous infusion at a dose of about 1.25 mg / kg, as measured by the amount of the free form of the compound.

[0074] In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.5 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.5 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.25 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.25 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.75 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.5 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 0.75 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.25 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.5 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.25 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.5 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 0.75 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 1.0 mg / kg. In some embodiments, the compound is administered as an intravenous infusion at a dose of about 1.25 mg / kg.

[0075] Provided herein is a method of treating cancer in a patient, comprising administering to the patient a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound or a pharma- ceutically acceptable salt thereof is administered at a concentration of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 5 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 30mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 is administered at a daily dose of

[0076] Provided herein is a method of treating cancer in a patient, comprising administering to the patient a compound, the compound being administered at a concentration of about 5 mg / m 2 ~about 100mg / m 2 In some embodiments, the compound is administered at a daily dose of about 10 mg / m 2 ~about 100mg / m 2 In some embodiments, the compound is administered at a daily dose of about 5 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered at a daily dose of about 10 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered at a daily dose of about 20 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered at a daily dose of about 20 mg / m 2 ~about 100mg / m 2 In some embodiments, the compound is administered at a daily dose of about 20 mg / m 2 ~about 45mg / m 2 In some embodiments, the compound is administered at a daily dose of about 20 mg / m 2 ~about 30mg / m 2 In some embodiments, the compound is administered at a daily dose of about 10 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered at a daily dose of about 10 mg / m 2 ~about 45mg / m2 In some embodiments, the compound is administered at a daily dose of about 30 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered at a daily dose of about 30 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered at a daily dose of about 30 mg / m 2 ~about 45mg / m 2 is administered at a daily dose of

[0077] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a dose of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 45 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 60 mg / m2, as measured by the amount of the free form of the compound. 2 is administered at a daily dose of

[0078] In some embodiments, the compound is administered at about 5 mg / m 2 In some embodiments, the compound is administered at a daily dose of about 10 mg / m 2 In some embodiments, the compound is administered at a daily dose of about 20 mg / m 2 In some embodiments, the compound is administered at a daily dose of about 30 mg / m 2In some embodiments, the compound is administered at a daily dose of about 45 mg / m 2 In some embodiments, the compound is administered at a daily dose of about 60 mg / m 2 is administered at a daily dose of

[0079] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a dose of about 10 mg / m2 as measured by the amount of the free form of the compound. 2 The following daily doses are administered: In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 45 mg / m2, as measured by the amount of the free form of the compound. 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 60 mg / m2, as measured by the amount of the free form of the compound. 2 The following daily doses are administered:

[0080] In some embodiments, the compound is administered at about 5 mg / m 2 The following daily doses are administered: In some embodiments, the compound is administered at a dose of about 10 mg / m 2 The following daily doses are administered: In some embodiments, the compound is administered at a dose of about 20 mg / m 2 The following daily doses are administered: In some embodiments, the compound is administered at a dose of about 30 mg / m 2 The following daily doses are administered: In some embodiments, the compound is administered at a dose of about 45 mg / m 2 The following daily doses are administered: In some embodiments, the compound is administered at a dose of about 60 mg / m 2 The following daily doses are administered:

[0081] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered at a dose of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 5 mg / m2 as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 100mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 30mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 80mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 60mg / m 2 In some embodiments, the compound or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2, as measured by the amount of the free form of the compound. 2 ~about 45mg / m 2 It is administered as an intravenous infusion at a dose of

[0082] Provided herein is a method of treating cancer in a patient, comprising administering to the patient a compound, the compound being administered at a concentration of about 5 mg / m 2 ~about 100mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 100mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 5 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 100mg / m 2In some embodiments, the compound is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 45mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 30mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 45mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 80mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 60mg / m 2 In some embodiments, the compound is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 45mg / m 2 It is administered as an intravenous infusion at a dose of

[0083] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered on a continuous dosing schedule, hi some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once a week.

[0084] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which the compound or a pharma- ceutically acceptable salt thereof is administered and a second period of consecutive days during which the compound or a pharma- ceutically acceptable salt thereof is not administered.

[0085] In some embodiments, the total length of each cycle is between 7 days and 60 days. In some embodiments, the total length of each cycle is between 14 days and 30 days. In some embodiments, the total length of each cycle is 21 days. In some embodiments, the total length of each cycle is 14 days. In some embodiments, the total length of each cycle is 28 days.

[0086] In some embodiments, the first period is 6 days and the second period is the remainder of the cycle. In some embodiments, the first period is 5 days and the second period is the remainder of the cycle. In some embodiments, the first period is 4 days and the second period is the remainder of the cycle. In some embodiments, the first period is 3 days and the second period is the remainder of the cycle. In some embodiments, the first period is 2 days and the second period is the remainder of the cycle. In some embodiments, the first period is 1 day and the second period is the remainder of the cycle.

[0087] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on day 1 of a 21 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on days 1 and 8 of a 21 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, and 15 of a 21 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on day 1 of a 28 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on days 1 and 8 of a 28 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, and 15 of a 28 day cycle. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, 15, and 22 of a 28 day cycle.

[0088] Administration of Compound 1 The present application relates, inter alia, to a method of treating cancer in a patient, comprising administering to a patient a compound having the following structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein Pv1 is a peptide.

[0089] The present application further relates to a method of administering Compound 1, or a pharma- ceutically acceptable salt thereof, to a patient in need of treatment, comprising administering to the patient Compound 1, having the structure: [ka] or a pharma- ceutically acceptable salt thereof, wherein Pv1 is a peptide.

[0090] Compound 1 is described in U.S. Patent Application Publication No. 2021 / 009719, the entire contents of which are incorporated herein by reference. Compound 1 is a peptide conjugate of the topoisomerase I inhibitor exatecan. As a peptide conjugate of a topoisomerase I inhibitor, compound 1 is useful for the treatment of various diseases, such as cancer.

[0091] In some embodiments, Pv1 is a peptide comprising a 10-50 amino acid sequence composed of naturally occurring amino acid residues and optionally one or more non-naturally occurring amino acids. In some embodiments, Pv1 is a peptide of 20-40, 20-30 amino acids, or 30-40 residues. In some embodiments, Pv1 is an environmentally sensitive peptide. As used herein, an "environmentally sensitive peptide" is one that can insert across a cell membrane via a conformational change or secondary structure change in response to a change in environment (e.g., pH). In some embodiments, the peptide is capable of selectively delivering the exatecan moiety across a cell membrane having an acidic or hypoxic mantle having a pH less than about 6.0.

[0092] In some embodiments, Pv1 is a peptide that includes the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1).

[0093] In some embodiments, Pv1 is a peptide comprising the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1), which sequence contains 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions.

[0094] In some embodiments, Pv1 is an environmentally sensitive peptide comprising the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1), which sequence contains 1, 2, 3, 4, or 5 amino acid substitutions, additions, or deletions, so long as the peptide retains its environmental sensitivity.

[0095] In some embodiments, Pv1 is a peptide consisting essentially of the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1).

[0096] In some embodiments, Pv1 is a peptide consisting of the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO:1).

[0097] Provided herein is a method of treating cancer in a patient, comprising administering to the patient Compound 1 or a pharma- ceutically acceptable salt thereof, wherein Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.1 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of Compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.50 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of compound 1.

[0098] Provided herein is a method of treating cancer in a patient, comprising administering Compound 1 to the patient, wherein Compound 1 is administered at a daily dose of about 0.1 mg / kg to about 1.5 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.1 mg / kg to 1.25 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg to about 0.50 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.5 mg / kg to about 0.75 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.5 mg / kg to about 1.25 mg / kg.

[0099] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.75 mg / kg, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.0 mg / kg, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.25 mg / kg, as measured by the amount of the free form of compound 1.

[0100] In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.5 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 0.75 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 1.0 mg / kg. In some embodiments, Compound 1 is administered at a daily dose of about 1.25 mg / kg.

[0101] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.5 mg / kg or less, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.25 mg / kg or less, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.0 mg / kg or less, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.75 mg / kg or less, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.5 mg / kg or less, as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg or less, as measured by the amount of the free form of compound 1.

[0102] In some embodiments, Compound 1 is administered at a daily dose of about 1.5 mg / kg or less. In some embodiments, Compound 1 is administered at a daily dose of about 1.25 mg / kg or less. In some embodiments, Compound 1 is administered at a daily dose of about 1.0 mg / kg or less. In some embodiments, Compound 1 is administered at a daily dose of about 0.75 mg / kg or less. In some embodiments, Compound 1 is administered at a daily dose of about 0.5 mg / kg or less. In some embodiments, Compound 1 is administered at a daily dose of about 0.25 mg / kg or less.

[0103] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.5 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of compound 1. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered as an intravenous infusion at a dose of about 0.25 mg / kg, as measured by the amount of Compound 1 in free form.In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.5 mg / kg, as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 0.75 mg / kg, as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 1.0 mg / kg, as measured by the amount of the free form of Compound 1. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion at a dose of about 1.25 mg / kg, as measured by the amount of the free form of Compound 1.

[0104] In some embodiments, compound 1 is administered intravenously. In some embodiments, compound 1 is administered as an intravenous infusion. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.5 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.5 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.1 mg / kg to about 1.25 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 1.25 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.75 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.25 mg / kg to about 0.5 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 0.75 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.25 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.5 mg / kg to about 1.5 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.25 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.5 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 0.75 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 1.0 mg / kg. In some embodiments, compound 1 is administered as an intravenous infusion at a dose of about 1.25 mg / kg.

[0105] Provided herein is a method of treating cancer in a patient, comprising administering to the patient Compound 1, or a pharma- ceutical acceptable salt thereof, wherein Compound 1, or a pharma- ceutical acceptable salt thereof, is administered at a concentration of about 5 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 5 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 60mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 30mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 60mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 60mg / m 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2 is administered at a daily dose of

[0106] Provided herein is a method of treating cancer in a patient, comprising administering to the patient Compound 1, wherein Compound 1 is administered at a concentration of about 5 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 10 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 5 mg / m 2 ~about 80mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 10 mg / m2 as measured by the amount of free Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 20 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 20 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 20 mg / m 2 ~about 45mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 20 mg / m 2 ~about 30mg / m 2In some embodiments, Compound 1 is administered at a daily dose of about 10 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 10 mg / m 2 ~about 45mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 30 mg / m 2 ~about 80mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 30 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 30 mg / m 2 ~about 45mg / m 2 is administered at a daily dose of

[0107] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 5 mg / m2 as measured by the amount of the free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 45 mg / m2 as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 60 mg / m2 as measured by the amount of free form of Compound 1. 2 is administered at a daily dose of

[0108] In some embodiments, Compound 1 is administered at a dose of about 5 mg / m 2In some embodiments, Compound 1 is administered at a daily dose of about 10 mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 20 mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 30 mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 45 mg / m 2 In some embodiments, Compound 1 is administered at a daily dose of about 60 mg / m 2 is administered at a daily dose of

[0109] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 10 mg / m2 as measured by the amount of the free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 20 mg / m2, as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered at a daily dose of about 30 mg / m2, as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 45 mg / m2 as measured by the amount of free form of Compound 1. 2 In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 60 mg / m2, as measured by the amount of free form of Compound 1. 2 The following daily doses are administered:

[0110] In some embodiments, Compound 1 is administered at a dose of about 5 mg / m 2 The following daily doses are administered: In some embodiments, Compound 1 is administered at about 10 mg / m 2 The following daily doses are administered: In some embodiments, Compound 1 is administered at about 20 mg / m 2 The following daily doses are administered: In some embodiments, Compound 1 is administered at about 30 mg / m 2 The following daily doses are administered: In some embodiments, Compound 1 is administered at about 45 mg / m2 The following daily doses are administered: In some embodiments, Compound 1 is administered at about 60 mg / m 2 The following daily doses are administered:

[0111] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as an intravenous infusion. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 5 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 In some embodiments, Compound 1, or a pharma- ceutical acceptable salt thereof, is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 5 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1, or a pharma- ceutical acceptable salt thereof, is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 60mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 100mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 20 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 30mg / m 2 In some embodiments, Compound 1, or a pharma- ceutical acceptable salt thereof, is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 60mg 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 10 mg / m2, as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 60mg / m 2 In some embodiments, Compound 1 or a pharma- ceutical acceptable salt thereof is administered as an intravenous infusion at a dose of about 30 mg / m2 as measured by the amount of free form of Compound 1. 2 ~about 45mg / m 2 It is administered as an intravenous infusion at a dose of

[0112] Provided herein is a method of treating cancer in a patient, comprising administering to the patient Compound 1, wherein Compound 1 is administered at a concentration of about 5 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 5 mg / m 2 ~about 80mg / m 2In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 10 mg / m as measured by the amount of free Compound 1. 2 ~about 80mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 100mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 45mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 20 mg / m 2 ~about 30mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 10 mg / m 2 ~about 45mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 80mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 60mg / m 2 In some embodiments, Compound 1 is administered as an intravenous infusion at a dose of about 30 mg / m 2 ~about 45mg / m 2 It is administered as an intravenous infusion at a dose of

[0113] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered on a continuous dosing schedule. In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered once a week.

[0114] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt thereof, is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which Compound 1, or a pharma- ceutically acceptable salt thereof, is administered and a second period of consecutive days during which Compound 1, or a pharma- ceutically acceptable salt thereof, is not administered.

[0115] In some embodiments, the total length of each cycle is between 7 days and 60 days. In some embodiments, the total length of each cycle is between 14 days and 30 days. In some embodiments, the total length of each cycle is 21 days. In some embodiments, the total length of each cycle is 14 days. In some embodiments, the total length of each cycle is 28 days.

[0116] In some embodiments, the first period is 6 days and the second period is the remainder of the cycle. In some embodiments, the first period is 5 days and the second period is the remainder of the cycle. In some embodiments, the first period is 4 days and the second period is the remainder of the cycle. In some embodiments, the first period is 3 days and the second period is the remainder of the cycle. In some embodiments, the first period is 2 days and the second period is the remainder of the cycle. In some embodiments, the first period is 1 day and the second period is the remainder of the cycle.

[0117] In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on day 1 of a 21-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on days 1 and 8 of a 21-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, and 15 of a 21-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on day 1 of a 28-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on days 1 and 8 of a 28-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, and 15 of a 28-day cycle. In some embodiments, compound 1 or a pharma- ceutically acceptable salt thereof is administered only on days 1, 8, 15, and 22 of a 28-day cycle.

[0118] In some embodiments, the recited dosages are expressed in terms of the patient's body weight and are provided in units of mg / kg (e.g., the amount of compound to be administered divided by the patient's body weight). In some embodiments, the recited dosages are expressed in terms of the patient's body surface area and are provided in mg / m 2 The amount of the compound to be administered is provided in units of (e.g., the amount of the compound to be administered divided by the square of the patient's body surface area). The patient's body surface area can be calculated using methods and formulas known to those skilled in the art. For example, the patient's body surface area can be calculated using the formula published by Mosteller in 1987 (Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987; 317(17): 1098).

[0119] Examples of cancers treatable using the disclosed methods include ovarian cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, urothelial carcinoma, and sarcoma. Further examples of cancers treatable using the disclosed methods include appendiceal cancer and osteosarcoma.

[0120] Further examples of cancers treatable using the methods of the present disclosure include colorectal cancer, gastric cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic ... These include, but are not limited to, chronic or acute leukemias, including lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including those induced by asbestos, and combinations of these cancers.

[0121] In some embodiments, cancers treatable with the methods of the present disclosure include bladder cancer, bone cancer, glioma, breast cancer (e.g., triple negative breast cancer), cervical cancer, colon cancer, colorectal cancer, uterine cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer), intestinal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0122] In some embodiments, cancers treatable with the methods of the present disclosure include melanoma (e.g., metastatic melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using Compound 1 or another compound of the present disclosure.

[0123] In some embodiments, cancers treatable using the methods of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., leukemias such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma or multiple myeloma), and combinations of these cancers.

[0124] The compounds of the present disclosure may exhibit certain therapeutic advantages over topoisomerase I inhibitors themselves. For example, administration of the compounds of the present disclosure may exhibit reduced toxicity (e.g., bone marrow or stomach toxicity) compared to administration of the corresponding topoisomerase I inhibitor (e.g., exatecan). In some embodiments, bone marrow toxicity is measured by total bone marrow counts from a subject's sample (e.g., total bone marrow counts in the femur of a mouse). In some embodiments, bone marrow toxicity is measured by PARylation in bone marrow tissue. In some embodiments, bone marrow toxicity is measured according to total nucleated bone marrow cells. In some embodiments, gastric toxicity is evaluated using photographs of the stomach of a subject (e.g., a mouse) taken both in situ and ex vivo.

[0125] Compound 1 may exhibit certain therapeutic advantages over topoisomerase I inhibitors themselves. For example, administration of compound 1 may exhibit reduced toxicity (e.g., bone marrow or gastric toxicity) compared to administration of the corresponding topoisomerase I inhibitor (e.g., exatecan). In some embodiments, bone marrow toxicity is measured by total bone marrow counts from a subject's sample (e.g., total bone marrow counts in the femur of a mouse). In some embodiments, bone marrow toxicity is measured by PARylation in bone marrow tissue. In some embodiments, bone marrow toxicity is measured according to total nucleated bone marrow cells. In some embodiments, gastric toxicity is evaluated using photographs of the stomach of a subject (e.g., a mouse) taken both in situ and ex vivo.

[0126] In some embodiments, the cancer is refractory. In some embodiments, the patient has failed at least one previous treatment for cancer. Previous treatment for cancer can include, for example, chemotherapy, targeted cancer therapy, immunotherapy or radiation therapy. Previous treatment chemotherapy can include any exemplary chemotherapy listed herein.

[0127] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an additional therapy, which may include, for example, a chemotherapeutic agent, a targeted cancer therapy, an immunotherapy, or a radiation therapy.

[0128] In some embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in combination with an additional therapy, which may include, for example, a chemotherapeutic agent, a targeted cancer therapy, an immunotherapy, or a radiation therapy.

[0129] Exemplary chemotherapeutic agents include alkylating agents (including, but not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas, and triazenes), such as, for example, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0130] Additional chemotherapy agents include dacarbazine (DTIC), optionally in combination with other chemotherapy agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide.

[0131] Additional chemotherapeutic agents include immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0132] Additional chemotherapeutic agents include, for example, antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0133] Additional chemotherapeutic agents include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide.

[0134] Additional chemotherapeutic agents include, for example, navelbene, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0135] Additional chemotherapeutic agents include, for example, epidophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutics; leucovorin; tegafur; and hematopoietic growth factors.

[0136] Further chemotherapeutic agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies against cytokines (IL-10, TGF-α, etc.).

[0137] Additional chemotherapeutic agents include those that block immune cell migration, such as antagonists to chemokine receptors, including CCR2 and CCR4.

[0138] Additional chemotherapeutic agents include chemotherapy combinations, such as platinum-based doublets (cisplatin or carboplatin + gemcitabine; cisplatin or carboplatin + docetaxel; cisplatin or carboplatin + paclitaxel; cisplatin or carboplatin + pemetrexed) or gemcitabine + paclitaxel conjugated particles (Abraxane®) used in lung cancer and other solid tumors.

[0139] The term "treatment" as used herein includes administration of a compound or composition that reduces the frequency, delays the onset, or reduces the progression of diseases involving acidic or hypoxic diseased tissues, such as cancer, stroke, myocardial infarction, or long-term neurodegenerative diseases, in a subject compared to subjects not administered the compound or composition. This includes reversing, reducing, or arresting the symptoms, clinical signs, or underlying pathology of a condition in a manner that improves or stabilizes the subject's condition (e.g., regression of tumor growth in the case of cancer, or reduction or amelioration of myocardial ischemia-reperfusion injury in myocardial infarction, stroke, or similar cardiovascular disease). The terms "inhibit" or "reduce" are used in cancer in reference to methods of inhibiting or reducing tumor growth (e.g., reducing tumor size) in a population compared to an untreated control population.

[0140] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0141] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. The term "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0142] All publications mentioned herein, including patents, are incorporated herein by reference for the purpose of describing and disclosing, for example, the structures and procedures described in the publications that may be used in connection with the disclosure set forth herein. The publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application.

[0143] Several types of ranges are disclosed herein. When any type of range is disclosed or claimed, the intention is to disclose or claim each possible number that such range can reasonably encompass, including the end points of the range, and any subranges and combinations of subranges encompassed therein. For example, when a therapeutically effective amount range of an active ingredient is disclosed or claimed, the intention is to disclose or claim each possible number that such range can encompass, consistent with the disclosure of this specification. For example, it is disclosed or claimed by disclosure that the therapeutically effective amount of a compound can be in the range of about 1 mg / kg (of control body weight) to about 50 mg / kg. EXAMPLES

[0144] Example 1. Phase 1 / 2 Study of Compound 1 This is a first-in-human, Phase 1 / 2, open-label, multicenter, dose-escalation, safety, pharmacokinetic (PK), and biomarker study of compound 1 in subjects with advanced or metastatic refractory solid tumors.

[0145] Phase 1 is the dose escalation part of the study in which the safety and tolerability of two dosing schedules of Compound 1 will be evaluated.

[0146] Main purpose: To determine the safety and tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of Compound 1 in subjects with advanced or metastatic refractory solid tumors when administered on the following schedule: 1 daily dose every 3 weeks x 5 (Part A) 1 daily dose every 3 weeks x 3 (Part B) Establish the recommended phase 2 dose (RP2D) of Compound 1 for each schedule

[0147] Secondary Objectives: To determine the pharmacokinetics (PK) of compound 1 To evaluate the preliminary antitumor activity of Compound 1 based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1: Objective response rate (ORR) Duration of response (DoR) Progression-free survival (PFS)

[0148] exploratory purpose To evaluate the occurrence and impact of anti-drug antibodies (ADA) To evaluate the PK of unbound exatecan To evaluate potential biomarkers of compound 1 (e.g., intratumoral concentrations of exatecan)

[0149] Part A Phase 1 Part A will begin enrollment prior to Part B. Part A subjects will be treated with Compound 1 at a daily dose 5 times per week every 3 weeks (Schedule A, i.e., 5 days on, 16 days off; cycle length 3 weeks). A 3+3 design will be utilized. However, to minimize the number of subjects treated at potentially subtherapeutic doses, the first cohort of Phase 1 will enroll a single subject. Single subject cohorts will be enrolled until a subject has a grade 2 adverse event (AE) deemed potentially related to Compound 1 during the dose-limiting toxicity (DLT) period (i.e., the subject's first 3-week cycle), at which time two additional subjects will be enrolled in that cohort, and a 3+3 design will then be utilized. Dose escalation to 100% of the previous dose will be permitted until a grade 2 AE deemed potentially related to Compound 1 occurs during the DLT period.

[0150] Subsequent dose escalations may be up to 50% of the previous dose.

[0151] In the 3+3 design, a cohort of three subjects is enrolled at one dose level. If none of the three subjects experience a DLT, the dose is increased to the next higher level. If one of the first three subjects in the cohort experiences a DLT, up to three additional subjects are enrolled and treated at the same dose. If none of the three additional subjects experience a DLT (i.e., only one of the six subjects in the cohort has a DLT), the dose is increased to the next higher level. If two or more of the maximum six subjects at a dose level have a DLT, enrollment in that cohort is stopped and the dose is considered to be above the maximum tolerated dose (MTD). The dose is then reduced to the previous dose level or to a level intermediate to the dose level previously evaluated. If only three subjects are enrolled at this dose level, three additional subjects are enrolled and treated to confirm that this dose level is a tolerated dose level. The MTD will be the highest dose evaluated at which 1 in 6 (or <1 / 3 of subjects if more than 6 subjects are enrolled in a cohort) has a DLT. A minimum of 5 DLT-evaluable subjects will be enrolled at any dose level evaluated as the potential MTD.

[0152] The starting dose for Part A will be 0.25 mg / kg / day.

[0153] Part B Phase 1 Part B subjects will be treated with Compound 1 on a daily dose 3 times per week schedule every 3 weeks (Schedule B, i.e., 3 days on, 18 days off; cycle length 3 weeks). The first cohort of Part B may begin enrolling once at least two cohorts of Part A have been evaluated for safety through the DLT period. The initial dose of Part B will be determined based on the safety and tolerability of Part A subjects to that point. If the maximum grade of Compound 1-related AE in Part A is Grade 2, then Dose Level 1 of Part B will be selected such that the total dose in the new cohort of Part A and the first cohort of Part B will reach the same total weekly dose of Compound 1 as shown in Table 1. As an example, if the maximum AE grade in Part A Cohort 2 (e.g., 0.50 mg / kg) on ​​a daily dose x 5 schedule is Grade 2 and the SRC recommends dose escalation in Part A Cohort 3 (e.g., to 0.75 mg / kg: 5-day total dose = 3.75 mg / kg), the SRC may recommend initiating Part B Cohort 1 at a dose of up to 1.25 mg / kg / day for a 3-day total = 3.75 mg / kg. However, if the maximum AE grade in Part A Cohort 2 is greater than Grade 2, the daily doses in Part A Cohort 3 and Part B Cohort 1 will be the same (e.g., 0.75 mg / kg / day) (see Table 2).

[0154] [Table 1] [Table 2]

[0155] Part B follows a 3+3 design and follows the same dose level escalation / tapering rules as described in Part A. The DLT period for each subject in Phase 1 is 3 weeks (i.e., 1 cycle). Subjects receive at least 4 of the 5 planned daily doses in cycle 1 in Part A and 2 of the 3 planned daily doses in cycle 1 in Part B and are considered evaluable for DLT if they are evaluable for safety or have a DLT over the 3-week DLT period. Subjects who are not evaluable for safety throughout the entire DLT period for reasons other than Compound 1-related toxicity will be shuffled in the same dose cohort.

[0156] In Parts A and B, after all subjects in a cohort have completed treatment for the DLT period or discontinued treatment due to a DLT, all available safety data, including DLTs and all available PK data, for that cohort will be considered and a dose-level recommendation will be made. The primary basis for the dose-level recommendation will be the occurrence of DLTs in the cohort, but will take into account all available safety and PK data, including long-term safety data from subjects treated in lower-dose cohorts.

[0157] The recommended Phase II dose (RP2D) is determined for each schedule as the MTD or as the biologically active dose below the MTD. If a clearly biologically active (i.e., confirmed response) and tolerated dose is reached before the MTD is reached, further dose escalation may be stopped before defining the MTD. A minimum of 6 subjects will be evaluated at the RP2D in each of Part A and Part B.

[0158] Once RP2D is established in both Part A and Part B, phase 2 expansion cohorts can be initiated. Either or both schedules (3 daily doses every 3 weeks; 5 daily doses every 3 weeks) can proceed to phase 2. One expansion cohort will enroll subjects with platinum-refractory epithelial ovarian cancer (including primary peritoneal and fallopian tube cancer) and one expansion cohort will enroll subjects with platinum-resistant SCLC. The protocol can be amended to include additional expansion cohorts based on new activity signals from phase 1 or in tumor types with demonstrated efficacy of topoisomerase 1 inhibitors.

[0159] Subjects will receive treatment with Compound 1 and will be monitored for safety and disease status by AE assessment, physical examination, clinical laboratory tests, radiological evaluation, and ECG. PK and biomarker samples will be collected. All AEs and serious adverse events (SAEs) will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) will be performed at protocol-specified intervals. Subjects may continue treatment as long as they tolerate it without disease progression based on RECIST 1.1.

[0160] All subjects will return to the study site approximately 30 days after the last dose of Compound 1 for an end-of-treatment (EOT) evaluation. Subjects without disease progression will continue to be followed until progression or initiation of new systemic anti-cancer therapy. Ongoing Compound 1-related SAEs and clinically significant AEs will undergo additional follow-up until resolution or stability.

[0161] The trial is planned to include approximately 112 subjects, with approximately 30 subjects in Phase 1 and approximately 41 subjects in each of the Phase 2 expansion cohorts.

[0162] Dose-limiting toxicity DLTs will be assessed throughout the first 3-week treatment cycle (Cycle 1, DLT period) for all subjects enrolled in Phase 1. Any AE occurring during the DLT period that is judged to be at least possibly related to Compound 1 and meets the following criteria will be designated as a DLT. If intra-subject dose escalation is recommended for a subject and toxicity is observed during escalation, this will not be considered a DLT since it did not occur during the subject's first 3-week cycle. However, this will be taken into account in subsequent dose level recommendations in the SRC.

[0163] Non-hematological DLTs: Any grade 5 AE Any grade 4 AE other than electrolyte abnormalities that is asymptomatic and resolves to grade 2 within 2 days without clinical sequelae with or without medical management Grade 3 or higher aspartate aminotransferase (AST) and bilirubin >2x the upper limit of normal (ULN) (and direct bilirubin >35%) without evidence of bile duct obstruction Any other grade 3 non-hematologic AE with the following exceptions: - Grade 3 AST or ALT with improvement to Grade 2 within 3 days - Grade 3 nausea, vomiting, diarrhea, or mucositis occurring without optimal precautions or improving to grade 2 within 3 days with or without medical management - Grade 3 rash improving to grade 2 within 3 days with or without medical management - Grade 3 fever, uncomplicated, without clinical sequelae, improving to grade 2 within 3 days - Grade 3 electrolyte abnormalities that are asymptomatic, have no clinical sequelae, and improve to Grade 2 within 3 days with or without medical management - Grade 3 fatigue or asthenia improving to grade 2 within 7 days hematology DLT Any grade 5 AE Grade 3 or Grade 4 febrile neutropenia Grade 4 neutropenia without fever or clinically significant infection Persistent for 7 days or symptomatic Grade 4 thrombocytopenia Grade 3 thrombocytopenia with clinically significant bleeding

[0164] Subject Selection Criteria 1. Subjects have a histologically or cytologically diagnosed solid tumor that is progressive or metastatic and has progressed during or after at least one systemic therapy regimen administered for progressive or metastatic disease, or for which no approved therapy exists. Subjects' prior treatment should include all approved regimens that have demonstrated improved survival for the subject's disease, stage, and line of treatment. In Phase 1, priority will be given to subjects with the following tumor types: Ovarian cancer ·SCLC ·Non-small cell lung cancer (NSCLC) Hormone receptor positive (HR+) / HER2 negative (HER2-) breast cancer ·stomach cancer ·Esophageal cancer ·Colorectal cancer Pancreatic cancer ·Urothelial cancer ·sarcoma Tumors with BRCA1 or BRCA2 mutations However, subjects with other solid tumors who meet the eligibility criteria will not be excluded. In the phase 2 expansion cohort, subjects with epithelial ovarian cancer or SCLC must have had disease progression or recurrence within 6 months of their last dose of platinum chemotherapy. 2. The participant must be 18 years of age at the time of signing the Informed Consent Form (ICF). 3. Have measurable disease by RECIST 1.1 4. Adequate tumor samples must be obtained from core needle biopsies or incisional or excision biopsies taken during the screening period and after the subject's most recent systemic therapy. Previously obtained archival samples may be approved for this inclusion criterion by the Medical Monitor, provided the sample was taken after the most recent systemic therapy. Biopsies should not be from previously irradiated lesions, unless that lesion has shown disease progression after radiation therapy. A minimal adequate tumor sample is defined as an equivalent amount of tumor from approximately 3 core needle biopsies, with tissue from 4-5 cores being optimal. 5. Agree to an on-treatment biopsy, preferably an on-treatment biopsy of the same lesion from which a pre-Compound 1 treatment sample was obtained, so long as the Investigator judges that such a biopsy can be performed with acceptable safety. Lesions from which 3-5 core biopsies can be obtained should be identified during the screening period. 6.Written informed consent has been provided 7.ECOG performance status of 0 or 1. 8. Adequate hepatic, renal, hematological, pulmonary, and coagulation function as follows: Bilirubin ≦ 1.5 × ULN b.AST(SGOT), ALT(SGPT)≦3.0×ULN c. Serum creatinine ≤ 1.5 x ULN and / or estimated creatinine clearance ≥ 60 ml / min based on the Cockcroft-Gault equation Absolute neutrophil count ≥ 1500 / mm 3 e. Platelet count ≧100,000 / mm 3 f. Hemoglobin ≥ 9 g / dL. Transfusions are permitted to meet eligibility criteria. g. International normalized ratio (INR) ≦ 1.5 x ULN, and activated partial thromboplastin time (aPTT) ≦ 1.5 x ULN. Subjects receiving therapeutic doses of anticoagulants should have an INR and / or aPTT below the upper therapeutic limit for intended use. h. Room air O 2 Saturation>90% i. Serum potassium, magnesium, and calcium or ionized calcium >= LLN within 3 days of the first dose of Compound 1. Subjects may receive supplementation that meets this eligibility criterion. 9. A negative serum pregnancy test during screening (for women of childbearing potential) and a negative serum or urine pregnancy test on Day 1 of Cycle 1 prior to the first dose of Compound 1 10. Females of childbearing potential must agree to use highly effective contraception and to refrain from donating or storing eggs during study treatment and for 4 months after the final dose of Compound 1. Females are considered of childbearing potential unless: a.Has had a hysterectomy, bilateral tubal occlusion, or bilateral oophorectomy; b. Age 60 years or older and amenorrhea; or c. Age < 60 years, amenorrhea (including absence of irregular menses or spotting) for 12 months or more in the absence of medications inducing the menopausal state, and confirmed ovarian failure by serum estradiol and follicle-stimulating hormone concentrations within the institutional postmenopausal laboratory ranges. 11. Males of fertile potential agree to use highly effective contraception and to refrain from donating or storing sperm during study treatment and for 4 months after the last dose of Compound 1. Men are considered fertile unless they have had a bilateral vasectomy with confirmed azoospermia, or a bilateral orchiectomy.

[0165] Exclusion criteria 1. Cytotoxic chemotherapy, biologics, investigational agents, or radiation therapy within 3 weeks prior to the first dose of Compound 1. This interval may be shortened to 2 weeks with approval of the medical monitor if bone-only radiation therapy or investigational agents are not expected to be related to AEs after 2 weeks from the last dose. 2. Small molecule kinase inhibitors or hormones within 14 days prior to the first dose of Compound 1 3. Clinically significant AEs that have not resolved to Grade ≤1 based on baseline or NCI CTCAE v5.0 4.Subjects currently receiving other anticancer drugs or investigational drugs (multiple options possible) 5. Major surgery within 4 weeks or minor surgery within 14 days prior to the first dose of Compound 1. Requires adequate wound healing. 6. Clinically significant intercurrent illness, including but not limited to: New York Heart Association class III or IV heart failure b. Myocardial infarction or stroke within 26 weeks prior to the first administration of Compound 1 c. Unstable angina within 13 weeks prior to the first dose of Compound 1, unless the underlying disease was ameliorated by procedural intervention (e.g., stent, bypass) and the subject was angina-free for 4 weeks prior to the first dose of Compound 1. D. Severe aortic stenosis e. Uncontrolled Cardiac Arrhythmia: Requires approval of the medical monitor for subjects with confirmed arrhythmias. f. QTc>450 ms by Fredericia criteria (QTcF) during screening (based on the average of three QTcF values ​​from three ECGs obtained within 10 minutes at 1-2 minute intervals) g. Clinically significant active infection requiring systemic antibiotics, antivirals, or antifungals. Subjects must be medically stable, afebrile, and not receiving antimicrobial therapy for at least 3 days prior to the first dose of Compound 1 (except for subjects with uncomplicated urinary tract or upper respiratory tract infections). h. Ongoing inflammatory disease or process that may result in a low pH tissue environment other than the tumor microenvironment (unless approved by medical monitor). 7. Subject with primary CNS tumor or clinically active CNS metastases or carcinomatous meningitis brain metastases are considered stable if there is no progression when a brain MRI or CT scan obtained within 2 weeks prior to the first planned dose of Compound 1 is compared with one obtained at least 4 weeks prior and the subject has not required a dose of steroids equivalent to prednisone >10 mg / day, an increase in steroids, or other treatment to control the brain metastases between scans. 8. Subjects taking medications known to prolong the QT interval or medications associated with torsade de pointes, unless the subject can safely discontinue these or change to an equivalent medication that does not significantly prolong the QT interval at least 5 half-lives or 7 days (whichever is longer) prior to the first dose of Compound 1. 9. Subjects taking strong CYP3A4 or CYP1A2 inhibitors or inducers, unless the subject can safely discontinue these or change to an equivalent medication that is not a strong inducer or inhibitor of CYP3A4 or CYP1A2 at least 5 half-lives prior to the first dose of Compound 1. 10. Subjects taking sensitive substrates of CYP3A and CYP2B6 with narrow therapeutic ranges, unless the subject can safely discontinue these or switch to equivalent medications that are not sensitive substrates of CYP3A and CYP2B6 with narrow therapeutic ranges. 11. Known HIV infection 12. Active hepatitis B or C infection 13. History of another malignancy (unless potentially curative treatment has been administered). 14. Pregnant or lactating women. 15. Unwillingness or inability to comply with the procedures required by this Protocol.

[0166] Discontinuation criteria for subjects Subjects must discontinue treatment with Compound 1 for any of the following reasons: The subject wishes to discontinue study treatment. An unacceptable AE is observed that suggests, in the investigator's opinion, that continued study treatment is not in the subject's best interest. There is a concomitant medical condition where continuing study treatment may expose the subject to unacceptable risk or affect the subject's ability to continue to comply with study requirements or to freely provide informed consent. Non-compliance with study medication or protocol requirements (e.g., missed study visits) Use of unacceptable concomitant medications, such as off-protocol anticancer drugs. · Pregnant or breastfeeding women. · Protocol-specified reasons for treatment discontinuation. Cancellation of the trial by the sponsor.

[0167] Description of study medication and administration Compound 1 is manufactured aseptically as a lyophilized powder cake (target dose 20 mg / vial, each vial containing 21.5 mg of active substance to allow for overage) generated from a sterile filtered solution. The product is intended to be reconstituted with water for injection (WFI) (5.0 mL per vial used) and then transferred to an infusion bag for dilution.

[0168] Preliminary results Compound 1 was administered as a 1-hour intravenous infusion. As above, the first patient in the study was treated with a starting dose of 0.25 mg / kg, administered as a daily dose 5 times per week for every 3 weeks (Schedule A). Accelerated dose escalation was utilized initially, where single patient cohorts were enrolled and the dose was increased by 100% in each new cohort until a treatment-related adverse event (TRAE) of grade 2 or higher occurred. A single patient was enrolled in Cohort A1 (0.25 mg / kg). Cohort A2 doubled the dose to 0.5 mg / kg and enrolled 3 patients in this cohort due to the occurrence of an adverse event above the grade 2 level. Findings from the first 4 patients in Schedule A were as follows: The half-life of compound 1 was approximately 20 hours, which was longer than the predicted half-life (approximately 8 hours), and significant accumulation occurred after 5 consecutive days of administration. Dosing on a mg / kg basis resulted in large variability in dosing within a cohort (e.g., in one instance, one patient received more than twice the dose as another patient in the same cohort).

[0169] Of note, one patient with ovarian cancer had a partial response (PR) after cycle 1. The patient was dose reduced and restaging in cycle 2 showed a complete response (CR) and normalization of CA-125 biomarker levels.

[0170] As a result of the findings on Schedule A, patients were enrolled on the following dosing schedule: Schedule B: Once daily 3 times a week for 3 weeks, mg / m 2 Based (i.e., dose calculated based on patient's body surface area) Schedule C: Once weekly, mg / m 2 Patients treated on this schedule received a sentinel dose on day -14 followed by 2 weeks off treatment to evaluate the full PK profile of compound 1 and exatecan. Weekly dosing began on day 1 of cycle 1.

[0171] FIG. 1A shows the mean plasma levels on day 1 of Compound 1 and exatecan (Cohort A).

[0172] FIG. 1B shows the mean plasma levels of Compound 1 and exatecan (Cohort A) on day 4.

[0173] FIG. 2A shows the mean plasma levels of Compound 1 and exatecan (Cohort B) on Day 1.

[0174] FIG. 2B shows the mean plasma levels of Compound 1 and exatecan (Cohort B) on day 3.

[0175] The table below summarises the status of patients enrolled in Schedule B and Schedule C. [Table 3-1] [Table 3-2] [Table 3-3]

[0176] As shown in the table above, some patients enrolled in this study achieved clinical benefit. For example: Patients 2-5 (cohort B2) had heavily pretreated breast cancer with the topoisomerase inhibitor trastuzumab deruxtecan 28 months prior to disease progression on this treatment. After four cycles of compound 1, the patients had stable disease. Patients 2-6 (Cohort B2) were breast cancer patients with large chest wall lesions causing pain. Two cycles of Compound 1 demonstrated a 20% reduction in chest wall lesions (from pretreatment), elimination of pain, and a reduction in numerous non-target lesions. Four cycles of Compound 1 demonstrated a further reduction in both target lesions (29.1% reduction from pretreatment) and a further reduction in non-target lesions. Patients 1-9 (Cohort B3) were colorectal cancer patients who had received prior treatment with an irinotecan-containing regimen of FOLFIRI + bevacizumab. Investigators reported a 16% reduction in target lesions and resolution of bowel symptoms after two cycles of Compound 1 treatment. Patient 3-1 (cohort B3) was a patient with colorectal cancer who had received prior treatment with two lines of irinotecan-containing regimens (FOLFURI + bevacizumab; FOLFIRINOX + bevacizumab). Two cycles of compound 1 demonstrated stable disease with a decrease in carcinoembryonic antigen (CEA). Patient 2-11 (Cohort B3) was a heavily pretreated ovarian cancer patient. Two cycles of compound 1 demonstrated stable disease with a decline in CA-125 biomarker levels. Patient 2-9 (cohort C1) was a heavily pretreated breast cancer patient who had received two cycles of compound 1 and showed a partial response.

[0177] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including but not limited to all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

1. 2. A compound of formula (I) for treating cancer in a patient: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof [In the formula, R １ is a peptide, R ２ is a small molecule topoisomerase I targeting moiety that binds topoisomerase I; Q is the part R １ and R ２ is a linker covalently attached to The medicament, wherein said compound or said pharma- ceutically acceptable salt thereof is administered in a daily dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of said compound.

2. R １ The pharmaceutical of claim 1 , wherein said peptide is a conformationally restricted peptide.

3. R １ across cell membranes with acidic or hypoxic mantles having a pH below about 6.0 -QR ２ The pharmaceutical according to claim 1, which is a peptide capable of selectively delivering

4. R ２ The pharmaceutical composition according to claim 1, wherein is a radical of camptothecin, opotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, or exatecan.

5. 1. A compound having the following structure: 【Chemistry 2】 or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1), A medicament, wherein said compound 1 or said pharma- ceutically acceptable salt thereof is administered in a daily dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of said compound 1 in free form.

6. The method of claim 5 , wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously to the patient.

7. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound 1.

8. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound 1.

9. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound 1.

10. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg as measured by the amount of the free form of the compound 1.

11. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.50 mg / kg as measured by the amount of the free form of the compound 1.

12. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.75 mg / kg as measured by the amount of the free form of the compound 1.

13. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.25 mg / kg as measured by the amount of the free form of the compound 1.

14. The method of claim 5 or 6, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered in a continuous dosing schedule.

15. 7. The pharmaceutical composition of claim 5 or 6, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is administered and a second period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is not administered.

16. The method of claim 15, wherein the total length of each cycle is between 7 and 60 days.

17. The method of claim 15, wherein the total length of each cycle is between 14 and 30 days.

18. The method of claim 15, wherein the total length of each cycle is 21 days.

19. 16. The method of claim 15, wherein the first period is 5 days and the second period is the remainder of the cycle.

20. 16. The method of claim 15, wherein the first period is 3 days and the second period is the remainder of the cycle.

21. 16. The method of claim 15, wherein the first period is 2 days and the second period is the remainder of the cycle.

22. 16. The method of claim 15, wherein the first period is one day and the second period is the remainder of the cycle.

23. 2. A compound of formula (I) for treating cancer in a patient: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof [In the formula, R １ is a peptide, R ２ is a small molecule topoisomerase I targeting moiety that binds topoisomerase I; Q is the part R １ and R ２ is a linker covalently attached to The compound or a pharma- ceutically acceptable salt thereof is administered in an amount of about 5 mg / m2 as measured by the amount of the free form of the compound. ２ ~Approx. 100mg / m ２ The medicament is administered in a daily dose of

24. R １ The method of claim 23, wherein said peptide is a conformationally restricted peptide.

25. R １ across cell membranes with acidic or hypoxic mantles having a pH below about 6.0 -QR ２ The pharmaceutical composition of claim 23, which is a peptide capable of selectively delivering

26. R ２ The pharmaceutical agent according to claim 23, wherein is a radical of camptothecin, opotecan, irinotecan (CPT-11), ciratecan (DB-67, AR-67), cositecan (BNP-1350), lurtotecan, gimatecan (ST1481), belotecan (CKD-602), rubitecan, topotecan, deruxtecan, or exatecan.

27. 1. A compound having the following structure: 【Chemistry 4】 or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the following sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1), The compound 1 or the pharma- ceutical acceptable salt thereof is about 5 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~Approx. 100mg / m ２ The medicament is administered in a daily dose of

28. The method of claim 27, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously to the patient.

29. The compound 1 or a pharma- ceutical acceptable salt thereof is about 10 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~about 80mg / m ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

30. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~about 60mg / m ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

31. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~Approx. 45mg / m ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

32. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

33. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 30 mg / m2 as measured by the amount of the free form of the compound 1. ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

34. The compound 1 or a pharma- ceutical acceptable salt thereof is about 45 mg / m2 as measured by the amount of the free form of the compound 1. ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

35. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 60 mg / m2 as measured by the amount of the free form of the compound 1. ２ 29. The method of claim 27 or 28, wherein the medicament is administered in a daily dose of

36. 29. The method of claim 27 or 28, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in a continuous dosing schedule.

37. The method of claim 27 or 28, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered once a week.

38. 29. The pharmaceutical composition of claim 27 or 28, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is administered and a second period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is not administered.

39. The method of claim 38, wherein the total length of each cycle is between 7 and 60 days.

40. The method of claim 38, wherein the total length of each cycle is between 14 and 30 days.

41. 39. The pharmaceutical composition of claim 38, wherein the total length of each cycle is 21 days.

42. 39. The method of claim 38, wherein the first period is 5 days and the second period is the remainder of the cycle.

43. 39. The method of claim 38, wherein the first period is 3 days and the second period is the remainder of the cycle.

44. 39. The method of claim 38, wherein the first period is 2 days and the second period is the remainder of the cycle.

45. 39. The method of claim 38, wherein the first period is one day and the second period is the remainder of the cycle.

46. 30. The pharmaceutical of claim 1, 5, 23 or 27, wherein the cancer is selected from ovarian cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, urothelial cancer, and sarcoma.

47. 30. The method of claim 1, 5, 23 or 27, wherein the patient has failed at least one previous treatment for cancer.

48. 30. The method of claim 1, 5, 23 or 27, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in combination with an additional therapy.

49. Compound 1, or a pharma- ceutical acceptable salt thereof, for administering to a patient in need of treatment, has the structure: 【Chemistry 5】 or a pharma- ceutical agent comprising: Compound 1, or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1); wherein said Compound 1, or a pharma- ceutical acceptable salt thereof, is delivered parenterally to said patient; A medicament, wherein said compound 1 or said pharma- ceutically acceptable salt thereof is administered in a daily dose of about 0.1 mg / kg to about 1.5 mg / kg as measured by the amount of said compound 1 in free form.

50. The method of claim 49, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously to the patient.

51. The method of claim 49 or 50, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.5 mg / kg as measured by the amount of the free form of the compound 1.

52. The method of claim 49 or 50, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 1.25 mg / kg as measured by the amount of the free form of the compound 1.

53. The method of claim 49 or 50, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg to about 0.75 mg / kg as measured by the amount of the free form of the compound 1.

54. 51. The method of claim 49 or 50, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.25 mg / kg as measured by the amount of the free form of compound 1.

55. 51. The method of claim 49 or 50, wherein the compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.50 mg / kg as measured by the amount of the free form of the compound 1.

56. 51. The method of claim 49 or 50, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 0.75 mg / kg as measured by the amount of the free form of compound 1.

57. 51. The method of claim 49 or 50, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered at a daily dose of about 1.25 mg / kg as measured by the amount of free form of compound 1.

58. 51. The method of claim 49 or 50, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in a continuous dosing schedule.

59. 51. The pharmaceutical composition of claim 49 or 50, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is administered and a second period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is not administered.

60. 60. The method of claim 59, wherein the total length of each cycle is between 7 and 60 days.

61. 60. The method of claim 59, wherein the total length of each cycle is between 14 and 30 days.

62. 60. The pharmaceutical agent of claim 59, wherein the total length of each cycle is 21 days.

63. 60. The method of claim 59, wherein the first period is 5 days and the second period is the remainder of the cycle.

64. 60. The method of claim 59, wherein the first period is 3 days and the second period is the remainder of the cycle.

65. 60. The method of claim 59, wherein the first period is 2 days and the second period is the remainder of the cycle.

66. 60. The method of claim 59, wherein the first period is one day and the second period is the remainder of the cycle.

67. 50. The method of claim 49, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in combination with an additional therapy.

68. Compound 1, or a pharma- ceutical acceptable salt thereof, for administering to a patient in need of treatment, has the structure: 【Chemistry 6】 or a pharma- ceutical agent comprising: Compound 1, or a pharma- ceutical acceptable salt thereof, wherein Pv1 is a peptide comprising the sequence: ADDQNPWRAYLDLLFPTDTLLLDLLWCG (SEQ ID NO: 1); wherein said Compound 1, or a pharma- ceutical acceptable salt thereof, is delivered parenterally to said patient; The compound 1 or the pharma- ceutical acceptable salt thereof is about 5 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~Approx. 100mg / m ２ The medicament is administered in a daily dose of

69. The method of claim 68, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered intravenously to the patient.

70. The compound 1 or a pharma- ceutical acceptable salt thereof is about 10 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~about 80mg / m ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

71. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~about 60mg / m ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

72. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ ~Approx. 45mg / m ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

73. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 20 mg / m2 as measured by the amount of the free form of the compound 1. ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

74. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 30 mg / m2 as measured by the amount of the free form of the compound 1. ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

75. The compound 1 or a pharma- ceutical acceptable salt thereof is about 45 mg / m2 as measured by the amount of the free form of the compound 1. ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

76. The compound 1 or a pharma- ceutical acceptable salt thereof is administered in an amount of about 60 mg / m2 as measured by the amount of the free form of the compound 1. ２ 70. The pharmaceutical composition of claim 68 or 69, wherein the pharmaceutical composition is administered in a daily dose of

77. 70. The method of claim 68 or 69, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in a continuous dosing schedule.

78. 70. The method of claim 68 or 69, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered once a week.

79. 70. The pharmaceutical composition of claim 68 or 69, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered on an intermittent dosing schedule comprising one or more cycles, each cycle comprising a first period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is administered and a second period of consecutive days during which compound 1 or a pharma- ceutically acceptable salt thereof is not administered.

80. 80. The method of claim 79, wherein the total length of each cycle is between 7 and 60 days.

81. 80. The method of claim 79, wherein the total length of each cycle is between 14 and 30 days.

82. 80. The pharmaceutical agent of claim 79, wherein the total length of each cycle is 21 days.

83. 80. The method of claim 79, wherein the first period is 5 days and the second period is the remainder of the cycle.

84. 80. The method of claim 79, wherein the first period is 3 days and the second period is the remainder of the cycle.

85. 80. The method of claim 79, wherein the first period is 2 days and the second period is the remainder of the cycle.

86. 80. The method of claim 79, wherein the first period is one day and the second period is the remainder of the cycle.

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