iRGD Analogs and Related Therapeutic Methods

Abstract

Provided herein are methods and compositions for treating solid tumor cancers.

Description

[Technical field]

[0001] The present invention relates to compounds, methods and agents useful in the treatment of diseases, such as solid tumors. [Background technology]

[0002] According to estimates by the National Cancer Institute, approximately 1,735,350 new cases of cancer will be diagnosed in the United States in 2018, and 609,640 people will die from the disease. Despite advances in the treatment of certain forms of cancer with surgery, radiation therapy, chemotherapy, and more recently immunotherapy, most types of solid tumors are essentially incurable. Even when effective treatments are available for certain cancers, side effects from the treatments can have a significant negative impact on patients' quality of life.

[0003] Pancreatic cancer is a particularly severe cancer and a life-threatening condition. In most cases, the early stages of the disease are asymptomatic, and less than 20% of pancreatic cancers are operable. Furthermore, invasive and metastatic pancreatic cancers are poorly responsive to existing treatments in chemotherapy and radiation therapy, with response rates typically less than 30%. The National Cancer Institute (NCI) estimates that the survival rate for exocrine pancreatic cancer is less than 5%, with a median survival time of less than one year after diagnosis. The continued poor prognosis and lack of effective treatments for pancreatic cancer highlights an unmet medical need to develop less toxic and more efficient treatment strategies that will improve the clinical management and prognosis of patients with pancreatic cancer.

[0004] An important reason why most anticancer drugs are toxic and have limited efficacy in solid tumors is the fact that they penetrate blood vessels to a depth of only 3-5 cell diameters, leaving some areas of the tumor exposed to ineffective concentrations of the drug or no drug at all. As an example, studies have shown that less than 1% of administered nab-paclitaxel can penetrate / enter pancreatic ductal adenocarcinoma tissue. Summary of the Invention

[0005] Improved penetration of chemotherapy drugs by CEND-1 Results from both in vivo and in vitro pharmacological and mechanistic studies indicate that combining the iRGD analog CEND-1 of the present invention (FIG. 2) with chemotherapeutic agents significantly increases the tumor penetration of these agents and improves their efficacy. Although the method of the present invention is applicable to a wide variety of cancers and / or solid tumors, the first indication for this test agent is pancreatic ductal adenocarcinoma (PDAC), which, in addition to its poor prognosis, is characterized by a dense extracellular matrix stroma that acts as a physical barrier to drug entry. CEND-1 appears to be particularly well suited to target PDAC, since the tumor homing and trafficking process initiated by CEND-1 has been shown to be active in the PDAC stroma, and preclinical studies have shown increased drug penetration and efficacy in different types of PDAC models.

[0006] Thus, provided herein is a pharmaceutical composition comprising an iRGD analog and a pharma- ceutically acceptable excipient. In certain embodiments, the compositions of the present invention correspond to the iRGD analog (i.e., CEND-1) shown structurally in Figure 2. CEND-1 of the present invention differs from prior art iRGD peptides in the specific moieties used to block the amino and carboxy termini, which provides significant advantages over prior art cyclic iRGD peptides. For example, the iRGD analog of the present invention (shown as CEND-1 in Figure 2) has the following molecular formula: C37H60N14O14S2, MW989.1, and recent CAS Registry Number: 2580154-02-3. On the other hand, one prior art iRGD with at least one inferior therapeutic property has the molecular formula: C37H60N14O14S2, MW989.1, and recent CAS Registry Number: 2580154-02-3. 35 H 57 N 13 O 14 S 2 , which corresponds to iRGD having a molecular weight of 948.04, and CAS registry number 1392278-76-0.

[0007] The advantages of the CEND-1 iRGD analog of the present invention (FIG. 2, C37 H60 N14 O14 S2, MW 989.1) compared to the prior art CAS Registry Number 1392278-76-0 cyclic peptide and other known iRGD molecules are the following, while maintaining good in vitro / in vivo potency and efficacy: favorable pharmacokinetic properties, Improved stability in plasma / serum (e.g., pooled human plasma as described in the Examples herein); Improved stability in formulated solutions; Improved stability upon storage (e.g., in phosphate buffered saline as described in the Examples herein); and / or These include one or more of improved protection from proteases such as aminopeptidases and carboxypeptidases.

[0008] In certain embodiments, the favorable and / or improved pharmacokinetic properties are selected from one or more of absorption, distribution, metabolism, and / or excretion. In certain embodiments, CEND-1 has a degradation rate that is 3-fold lower than that of iRGD in phosphate buffered saline at 37° C. and pH=7.4 (e.g., improved stability) and / or a degradation rate that is 1.6-fold lower than that of iRGD in pooled human plasma. In another embodiment, CEND-1 has been found to have a 46% increased half-life in vivo compared to iRGD.

[0009] Provided herein is a method of treating, inhibiting or reducing tumor volume in a subject or patient in need thereof, comprising administering CEND-1 or a pharma- ceutically acceptable salt thereof in combination with at least one anti-cancer agent or anti-cancer treatment, either simultaneously, separately or sequentially. In certain embodiments, the tumor is a malignant solid tumor characterized by a dense tumor stroma. In other embodiments, the tumor is a solid tumor of a cancer selected from the group consisting of breast cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrioma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatoma, and head and neck cancer. In another embodiment, the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anticancer drug resistant pancreatic cancer, and adenocarcinoma. In a particular embodiment, the cancer is a ductal adenocarcinoma, such as stage 0 to IV.

[0010] In certain embodiments, the anti-cancer agent or treatment is selected from the group consisting of chemotherapeutic agents, small molecules, antibodies, antibody drug conjugates, nanoparticles, cell therapies, polypeptides, peptides, peptidomimetics, nucleic acid molecules, ribozymes, antisense oligonucleotides, as well as transgenes, viruses, cytokines, nucleic acid molecules encoding cytotoxic polypeptides; pro-apoptotic polypeptides, anti-angiogenic polypeptides, cytotoxic cells such as cytotoxic T cells, and / or vaccines (mRNA or DNA).

[0011] In other embodiments, the chemotherapeutic agent is a taxane, docetaxel, paclitaxel, nab-paclitaxel, a nucleoside, gemcitabine, an anthracycline, doxorubicin, an alkylating agent, a vinca alkaloid, an antimetabolite, a platinum agent, cisplatin, carboplatin, a steroid, methotrexate, an antibiotic, adriamycin, isoflurane, a selective estrogen receptor modulator, a maytansinoid, mertansine, emtansine; an antibody such as trastuzumab, an anti-epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, a caspase, caspase-8; diphtheria toxin A chain, Pseudomonas excreta. Toxin A, cholera toxin, ligand fusion toxin, DAB389EGF, castor bean toxin (ricin); chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor macrophages (CAR-M), chimeric antigen receptor natural killer cells (CAR-K), and tumor infiltrating lymphocytes (TIL), anti-PD-1 antibodies, nivolumab, panitumumab, pembrolizumab, atezolizumab, avelumab, durvalumab; anti-CTLA-4 antibodies, ipilimumab; bispecific antibodies, catumaxomab, Moderna's mRNA-4157, and / or BioNTech's BNT122.

[0012] In certain embodiments, CEND-1 (iRGD analog as described in FIG. 2) is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of cancer therapy, about 0.3-17 mg / kg body weight per dose of cancer therapy, about 0.4-14 mg / kg body weight per dose of cancer therapy, about 0.5-11 mg / kg body weight per dose of cancer therapy, about 0.6-8 mg / kg body weight per dose of cancer therapy, about 0.7-5 mg / kg body weight per dose of cancer therapy, and about 0.8-3.2 mg / kg body weight per dose of cancer therapy. In certain embodiments, CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of cancer therapy.

[0013] In certain embodiments, CEND-1 is administered prior to or during administration of an anti-cancer therapy, the cancer therapy being administered at a dosage regimen selected from the group consisting of 4 times per day, 3 times per day, twice daily, once daily, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and / or once monthly. In one embodiment, the CEND-1 is in a dry formulation or suspended in a biocompatible medium.

[0014] In certain embodiments, the biocompatible medium is selected from the group consisting of water, a buffered aqueous medium, saline, buffered saline, optionally a buffered solution of amino acids, optionally a buffered solution of proteins, optionally a buffered solution of sugars, optionally a buffered solution of vitamins, optionally a buffered solution of synthetic polymers, and a lipid-containing emulsion. In certain embodiments, CEND-1 is administered intravenously.

[0015] Also provided herein is a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient an effective amount of CEND-1 in combination with gemcitabine and / or nab-paclitaxel, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anticancer drug resistant pancreatic cancer, and adenocarcinoma. In certain embodiments, the cancer is ductal adenocarcinoma (stages 0-IV).

[0016] In certain embodiments, CEND-1 is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of cancer therapy, about 0.3-17 mg / kg body weight per dose of cancer therapy, about 0.4-14 mg / kg body weight per dose of cancer therapy, about 0.5-11 mg / kg body weight per dose of cancer therapy, about 0.6-8 mg / kg body weight per dose of cancer therapy, about 0.7-5 mg / kg body weight per dose of cancer therapy, and about 0.8-3.2 mg / kg body weight per dose of cancer therapy. In one embodiment, CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of cancer therapy.

[0017] In certain embodiments, CEND-1 is administered prior to or during administration of an anti-cancer therapy, the cancer therapy being administered at a dosing regimen selected from the group consisting of 4 times per day, 3 times per day, twice daily, once daily, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and / or once monthly. In certain embodiments of the anti-cancer therapy, CEND-1 is administered in an amount ranging from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy; nab-paclitaxel is administered in an amount ranging from 1-500, 10-450, 20-400, 30-350, 40-300, 50-250, 60-200, 70-175, 80-160, 90-150, 100-140, 110-140, 115-135, or 120-130 mg / m2; and Gemcitabine is administered in an amount in a range selected from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, or 900-1100 mg / m2.

[0018] In yet another embodiment of the anti-cancer treatment method, CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy, nab-paclitaxel is administered at 125 mg / m2, and / or gemcitabine is administered at 1000 mg / m2. In yet another embodiment of the anti-cancer treatment method, CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy, nab-paclitaxel is administered at 125 mg / m2, and gemcitabine is administered at 1000 mg / m2.

[0019] In yet another embodiment of the anti-cancer treatment for thyroid cancer, melanoma, liver cancer, e.g., hepatocellular carcinoma, renal cell carcinoma, etc., The iRGD analog CEND-1 of the present invention is administered in an amount ranging from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy in combination with: sorafenib is administered in an amount selected from 1-500, 10-450, 20-400, 30-350, 40-300, 50-250, 60-200, 70-175, 80-160, 90-150, 100-140, 110-140, 115-135, or 120-130 mg / m2, or 100-1000 mg orally every 12 hours, 200-800 mg orally every 12 hours, 300-7000 mg orally every 12 hours, or 400 mg orally every 12 hours, and / or Doxorubicin is administered in an amount in a range selected from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, or 900-1100 mg / m2.

[0020] In certain embodiments of the methods of the invention provided herein, the efficacy or clinical activity of the methods is measured by determining objective response rate (ORR), progression free survival (PFS) and / or overall survival (OS). In yet another embodiment, the efficacy or clinical activity of the method is measured by determining one or more of: objective response rate (ORR) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; progression free survival (PFS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; and / or overall survival (OS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%.

[0021] Also provided herein is a kit or composition comprising an iRGD analog (CEND-1) and an anti-cancer agent. In certain embodiments, the iRGD analog is depicted as the structure in FIG. [Brief description of the drawings]

[0022] [Figure 1] 1 shows the waterfall plot described in Example 2. [Diagram 2] 1 shows the chemical structure of a CEND-1 iRGD analog cyclic peptide of the present invention, having the molecular formula C37H60N14O14S2, MW 989.1, and CAS Registry Number 2580154-02-3, which has all natural amino acids and can also be represented as: Ac-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-NH2 (Cys&Cys Bridge), or as: L-Cysteinyl-L-Arginylglycyl-L-α-aspartyl-L-lysylglycyl-L-prolyl-L-α-aspartyl-cyclic(1.fwdarw.9)-disulfide, in which the N-terminal amino group is blocked with an acetyl group and the C-terminal carbonyl group is blocked with a carboxamide group. [Diagram 3] 1 shows the stability of CEND-1 and iRGD in phosphate buffered saline (pH=7.4). [Figure 4] 1 shows the stability of CEND-1 and iRGD in pooled human plasma depending on concentration. [Diagram 5] 1 shows the stability of CEND-1 and iRGD in the presence of carboxypeptides Y and B. [Figure 6] 1 shows the stability of CEND-1 and iRGD in the presence of aminopeptidases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Provided herein is a method for treating, inhibiting or reducing tumor volume in a subject or patient in need thereof, comprising administering CEND-1 or a pharma- ceutically acceptable salt thereof in combination with at least one anti-cancer drug or anti-cancer treatment, either simultaneously, separately or sequentially. The present invention provides improved methods and drugs for more effectively treating solid tumors with anti-cancer treatments. CEND-1 is a tumor-penetrating peptide that is an analog of iRGD (internalizing arginyl glycylaspartic acid cyclic peptide). iRGD molecules in general, and CEND-1 as an iRGD analog in particular, have a cyclized (SS bond via cysteine ​​side chain) structure containing nine amino acids. In a particular embodiment, the iRGD analog of the present invention corresponds to the iRGD analog peptide sequence of the present invention, i.e., CEND-1, which corresponds to the particular cyclic peptide chemical structure depicted in FIG. 2, described as Ac-Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys-NH2 and having CAS Registry Number 2580154-02-3. The pharmacological action of CEND-1 is restricted to tumors via a primary RGD tumor homing motif interaction with αv-integrin (highly expressed in tumor growth but not in healthy tissues). The secondary "CendR" motif regulates the tumor microenvironment via NRP-1. Based on experimental models, interaction with Neuropilin-1 transforms the solid tumor microenvironment into a temporary drug conduit, allowing efficient tumor access of anti-cancer therapeutics administered in combination with CEND-1. Studies have demonstrated that CEND-1 increases the accumulation and penetration of anti-cancer drugs in tumors, but not in normal tissues, via the tumor microenvironment regulation mechanisms described above. As a result, anti-tumor activity is enhanced while potentially improving therapeutic margins / safety profiles. In addition to the iRGD analogs of the invention (CEND-1, FIG. 2), given the data, dosages and results provided herein, other iRGD peptides and analogs known in the art, such as those described above, can be used in the methods of the invention.

[0024] In certain embodiments, the tumor is a malignant solid tumor characterized by a dense tumor stroma. In other embodiments, the tumor is a solid tumor of a cancer selected from the group consisting of breast cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrioma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, and head and neck cancer. In another embodiment, the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anticancer drug resistant pancreatic cancer, and adenocarcinoma. In certain embodiments, the cancer is a ductal adenocarcinoma (e.g., stage 0 to IV).

[0025] As used herein, the phrase "solid tumor" refers to an essentially solid neoplastic growth having a low liquid content other than a cyst or tumor metastasis (ie, in the metastatic stage of the disease).

[0026] As used herein, the term "in combination" refers to the administration of multiple therapeutic agents to each patient in need thereof. In certain embodiments, CEND-1 is administered together with at least one other anti-cancer therapeutic agent.

[0027] As used herein, the phrase "concurrent, separate, or sequential administration" refers to administration of CEND-1 simultaneously with one or more other cancer therapeutic agents, or either before or after administration of the co-administered anti-cancer agents, whereby the concurrent administration can be from separate pharmaceutical compositions administered in the same or different dosing regimens. In certain embodiments, CEND-1 is administered prior to the subsequent sequential administration of one or more anti-cancer agents.

[0028] As used herein, the term "malignant" refers to a tumor or cancer in which abnormal cells divide uncontrollably and can invade nearby tissues. Malignant cancer cells can also spread to other parts of the body via the blood and lymphatic systems.

[0029] Based on the novel drug delivery mechanism discovered by the present inventors, the method and drug of the present invention are suitable for using CEND-1 (iRGD analog) to enhance the therapeutic effect of any anticancer drug used to treat solid tumors. Thus, the method and drug of the present invention contain a combination of iRGD analog (CEND-1) and any anticancer drug used to treat solid tumors, such as at least one of taxanes such as docetaxel or paclitaxel (including nab-paclitaxel), nucleosides such as gemcitabine, anthracyclines such as doxorubicin, alkylating agents, vinca alkaloids, antimetabolites, platinum agents such as cisplatin or carboplatin, steroids such as methotrexate, antibiotics such as adriamycin, isofluranes, selective estrogen receptor modulators, or antibodies such as trastuzumab.

[0030] Anticancer drugs whose effects can be enhanced by CEND-1 can be antibodies, such as humanized monoclonal antibodies. As an example, the anti-epidermal growth factor receptor 2 (HER2) antibody trastuzumab (Herceptin: Genentech, South San Francisco, Calif.) is a useful therapeutic agent in combination to treat breast cancers that overexpress HER2 / neu (White et al., Annu. Rev. Med. 52:125-141 (2001)).

[0031] The anticancer drug whose effect can be enhanced by CEND-1 may also be a cytotoxic drug, which as used herein may be any molecule that directly or indirectly promotes cell death. Useful cytotoxic drugs include, but are not limited to, small molecules, polypeptides, peptides, peptidomimetics, nucleic acid molecules, cells and viruses. As non-limiting examples, useful cytotoxic drugs include cytotoxic small molecules such as doxorubicin, docetaxel or trastuzumab; antimicrobial peptides as further described below; pro-apoptotic polypeptides such as caspases and toxins, e.g., caspase-8; diphtheria toxin A chain, pseudomonas exotoxin A, cholera toxin, ligand fusion toxins such as DAB389EGF, castor toxin (ricin); and cytotoxic cells such as cytotoxic T cells. See, e.g., Martin et al., Cancer Res. 60:3218-3224 (2000); Kreitman and Pastan, Blood 90:252-259 (1997); Allam et al., Cancer Res. 57:2615-2618 (1997); and Osborne and Coronado-Heinsohn, Cancer J. Sci. Am. 2:175 (1996). Those skilled in the art will understand that these and additional cytotoxic drugs described herein or known in the art can be combined with CEND-1 in the disclosed methods and drugs.

[0032] In one embodiment, the anti-cancer agent whose effect can be enhanced by CEND-1 can be a therapeutic polypeptide. As used herein, a therapeutic polypeptide can be any polypeptide having a biologically useful function. Useful therapeutic polypeptides include, but are not limited to, cytokines, antibodies, cytotoxic polypeptides; pro-apoptotic polypeptides; and anti-angiogenic polypeptides. The anti-cancer agent whose effect can be enhanced by CEND-1 can be an anti-angiogenic agent. As used herein, the term "anti-angiogenic agent" refers to a molecule that inhibits or blocks angiogenesis, the growth and development of blood vessels. A combination of CEND-1 and an anti-angiogenic agent can be used to treat cancers associated with angiogenesis. Various anti-angiogenic agents can be prepared by conventional methods. Such anti-angiogenic agents include, but are not limited to, small molecules; proteins such as dominant negative forms of angiogenic factors, transcription factors, and antibodies; peptides; and nucleic acid molecules including ribozymes, antisense oligonucleotides; and nucleic acid molecules encoding, for example, dominant negative forms of angiogenic factors and receptors, transcription factors, and antibodies and antigen-binding fragments thereof. See, e.g., Hagedorn and Bikfalvi, Crit. Rev. Oncol. Hematol. 34:89-110 (2000), and Kirsch et al., J. Neurooncol. 50:149-163 (2000).

[0033] In certain embodiments, the anti-cancer agent or treatment is selected from the group consisting of chemotherapeutic agents, small molecules, antibodies, antibody drug conjugates, nanoparticles, cell therapies, polypeptides, peptides, peptidomimetics, nucleic acid molecules, ribozymes, antisense oligonucleotides, as well as transgenes, viruses, cytokines, nucleic acid molecules encoding cytotoxic polypeptides; pro-apoptotic polypeptides, anti-angiogenic polypeptides, cytotoxic cells such as cytotoxic T cells, and / or vaccines (mRNA or DNA).

[0034] In other embodiments, the chemotherapeutic agent is a taxane, docetaxel, paclitaxel, nab-paclitaxel, a nucleoside, gemcitabine, an anthracycline, doxorubicin, an alkylating agent, a vinca alkaloid, an antimetabolite, a platinum agent, cisplatin, carboplatin, a steroid, methotrexate, an antibiotic, adriamycin, isoflamide, a selective estrogen receptor modulator, a maytansinoid, mertansine, emtansine, an auristatin, monomethyl auristatin E (MMAE) and F (MMAF), a natural antimitotic inhibitor, an antibody, trastuzumab, an anti-epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, a caspase, caspase-8; diphtheria toxin A chain, and / or selected from the group consisting of Pseudomonas exotoxin A, cholera toxin, ligand fusion toxin, DAB389EGF, castor toxin (ricin); chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor macrophages (CAR-M), chimeric antigen receptor natural killer cells (CAR-K), and tumor infiltrating lymphocytes (TIL), anti-PD-1 antibodies, nivolumab, panitumumab, pembrolizumab, atezolizumab, avelumab, durvalumab; anti-CTLA-4 antibodies, ipilimumab; bispecific antibodies, catumaxomab, anti-CD47 antibodies, enfortumab, sacituzumab, antibody drug conjugates, mRNA-4157 from Moderna, and / or BNT122 from BioNTech.

[0035] In certain embodiments, CEND-1 (iRGD analog as described in FIG. 2) is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of cancer therapy, about 0.3-17 mg / kg body weight per dose of cancer therapy, about 0.4-14 mg / kg body weight per dose of cancer therapy, about 0.5-11 mg / kg body weight per dose of cancer therapy, about 0.6-8 mg / kg body weight per dose of cancer therapy, about 0.7-5 mg / kg body weight per dose of cancer therapy, and about 0.8-3.2 mg / kg body weight per dose of cancer therapy. In certain embodiments, CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of cancer therapy.

[0036] As used herein, the phrase "per dose of cancer therapy" refers to the administration of CEND-1 simultaneously with one or more anti-cancer agents, such that each time an anti-cancer therapeutic agent is administered, CEND-1 is likewise administered simultaneously to facilitate penetration of the therapeutic agent into the tumor. The concurrent administration of CEND-1 per dose does not have to be completely simultaneous with the therapeutic agent(s), and CEND-1 can be administered either before or after administration of the therapeutic agent.

[0037] In certain embodiments, CEND-1 is administered prior to or during administration of an anti-cancer therapy, the cancer therapy being administered at a dosage regimen selected from the group consisting of 4 times per day, 3 times per day, twice daily, once daily, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and / or once monthly. In one embodiment, the CEND-1 is in a dry formulation or suspended in a biocompatible medium.

[0038] In certain embodiments, the biocompatible medium is selected from the group consisting of water, a buffered aqueous medium, saline, buffered saline, optionally a buffered solution of amino acids, optionally a buffered solution of proteins, optionally a buffered solution of sugars, optionally a buffered solution of vitamins, optionally a buffered solution of synthetic polymers, and a lipid-containing emulsion. In certain embodiments, CEND-1 is administered intravenously.

[0039] The method of the present invention is particularly suitable for the treatment of pancreatic cancer, which is characterized by a significantly dense tumor stroma that acts as a physical barrier to drug entry. Thus, advanced pancreatic cancer was selected as the first clinical indication for CEND-1. As an example of clinical utility, we present safety and efficacy results, including the ability to enhance tumor response when CEND-1 is administered alone or in combination with nab-paclitaxel and gemcitabine.

[0040] Also provided herein is a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient an effective amount of CEND-1 in combination with gemcitabine and / or nab-paclitaxel, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anticancer drug resistant pancreatic cancer, and adenocarcinoma. In certain embodiments, the cancer is ductal adenocarcinoma (stages 0-IV).

[0041] In another embodiment, the above-mentioned CEND-1 for use in the treatment of pancreatic cancer can be administered in combination with at least one additional anticancer drug, preferably known to be effective against pancreatic cancer, such as gemcitabine.In the context of the present invention, it has been found that the use of CEND-1 enhances the clinical activity of other pancreatic cancer drugs, such as gemcitabine and nab-paclitaxel, administered by intravenous route.

[0042] Also provided herein is a method of treating pancreatic, colon or appendiceal cancer in a patient in need thereof, comprising administering to the patient an effective amount of CEND-1 in combination with Folfirinox and / or panitumumab or a pharma- ceutically acceptable salt thereof. In certain embodiments, the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anticancer drug resistant pancreatic cancer, and adenocarcinoma. In certain embodiments, the cancer is ductal adenocarcinoma (stages 0-IV).

[0043] As used herein, the term "FOLFIRINOX", FOLFIRINOX regimen or its grammatical variants refer to the well-known combination of oxaliplatin, leucovorin calcium (folinic acid), irinotecan hydrochloride and fluorouracil, respectively, in the context of cancer treatment.In other embodiments, FOLFIRINOX-based combinations can be used, such as Folfox, which corresponds to oxaliplatin, leucovorin calcium (folinic acid) and fluorouracil, and Folfiri, which corresponds to leucovorin calcium (folinic acid), fluorouracil and irinotecan hydrochloride.

[0044] In another embodiment, the above-mentioned CEND-1 for use in the treatment of pancreatic cancer can be administered in combination with at least one additional anticancer drug, preferably known to be effective against pancreatic cancer, such as gemcitabine.In the context of the present invention, it has been found that the use of CEND-1 enhances the clinical activity of other pancreatic cancer drugs, such as gemcitabine and nab-paclitaxel, administered by intravenous route.

[0045] In certain embodiments, CEND-1 is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of cancer therapy, about 0.3-17 mg / kg body weight per dose of cancer therapy, about 0.4-14 mg / kg body weight per dose of cancer therapy, about 0.5-11 mg / kg body weight per dose of cancer therapy, about 0.6-8 mg / kg body weight per dose of cancer therapy, about 0.7-5 mg / kg body weight per dose of cancer therapy, and about 0.8-3.2 mg / kg body weight per dose of cancer therapy. In one embodiment, CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of cancer therapy.

[0046] In certain embodiments, CEND-1 is administered prior to or during administration of an anti-cancer therapy, the cancer therapy being administered at a dosing regimen selected from the group consisting of 4 times per day, 3 times per day, twice daily, once daily, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once weekly, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and / or once monthly. In certain embodiments for treating pancreatic cancer, CEND-1 is administered in an amount ranging from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy; nab-paclitaxel is administered in an amount ranging from 1-500, 10-450, 20-400, 30-350, 40-300, 50-250, 60-200, 70-175, 80-160, 90-150, 100-140, 110-140, 115-135, or 120-130 mg / m2; and Gemcitabine is administered in an amount in a range selected from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, or 900-1100 mg / m2.

[0047] In yet another embodiment for treating pancreatic cancer, CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per chemotherapy dose, nab-paclitaxel is administered at 125 mg / m2, and gemcitabine is administered at 1000 mg / m2.

[0048] In another embodiment for treating any of pancreatic, colon, and appendix cancer, CEND-1 is administered in an amount in a range selected from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy; Each of the forms of oxaliplatin, leucovorin, and irinotecan, FOLFIRINOX, is administered in an amount ranging from 1 to 500, 10 to 450, 20 to 400, 30 to 350, 40 to 300, 50 to 250, 60 to 200, 70 to 175, 80 to 160, 90 to 150, 100 to 140, 110 to 140, 115 to 135, and 120 to 130 mg / m2; and Fluorouracil is administered in an amount ranging from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, or 900-1100 mg / m2; and / or panitumumab is administered at a dose of 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-18, 0.18-20, 0.19-30, 0.20-30, 0.21-30, 0.22-30, 0.23-40, 0.24-50, 0.25-60, 0.30-70, 0.31-80, 0.32-90, 0.33-100, 0.34-100, 0.35-100, 0.36-100, 0.37-100, 0.38-100, 0.39-200, 0.40-200, 0.41-200, 0.42-200, 0.43-200, 0.44-200, 0.45-300, 0.46-300, 0.47-300, 0.48-300, 0.49-400, 0.50-500, 0.51-500, 0.52-500, 0.53-500, 0.54-500, 0.55-500, 0.56-500, 0.57-500, 0.58- 0.17-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg of body weight, or in an amount selected from 1-20 mg / kg per 14 days, 2-15 mg / kg per 14 days, 3-12 mg / kg per 14 days, 4-10 mg / kg per 14 days, 5-8 mg / kg per 14 days, or 6 mg / kg per 14 days.

[0049] In yet another embodiment for treating any of pancreatic, colon, and appendiceal cancer, CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy, oxaliplatin is administered at 85 mg / m2, leucovorin is administered at 400 mg / m2, irinotecan is administered at 180 mg / m2, fluorouracil is administered at 2400 mg / m2, and / or panitumumab is administered at 6 mg / kg every 14 days.

[0050] In certain embodiments of the methods of the invention provided herein, the efficacy or clinical activity of the methods is measured by determining objective response rate (ORR), progression free survival (PFS) and / or overall survival (OS). In yet another embodiment, the efficacy or clinical activity of the method is measured by determining one or more of: objective response rate (ORR) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; progression free survival (PFS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; and / or overall survival (OS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%.

[0051] Also provided herein is a pharmaceutical composition comprising an iRGD analog and a pharma- ceutically acceptable excipient. In one embodiment, the iRGD analog is CEND-1. Pharmaceutically acceptable excipients are well known in the art. The CEND-1 composition can be administered to an individual (such as a human) by a variety of routes, including, for example, intravenous, intraarterial, intraperitoneal, intrapulmonary, oral, and inhalation, subcutaneous, and the like, by bolus injection or infusion. In some embodiments, the composition is administered intravenously.

[0052] The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials and can be stored in a freeze-dried (lyophilized) condition for injection requiring only the addition of a sterile liquid vehicle, for example, physiological saline, immediately prior to use.

[0053] In certain embodiments, CEND-1 for injection is a sterile, white, lyophilized powder supplied as a 100 mg per vial of active ingredient dosage strength for intravenous administration. CEND-1 injection consists of CEND-1 drug substance, which includes sodium acetate trihydrate and mannitol as excipients.

[0054] In certain embodiments, the compositions of the invention correspond to the iRGD analog (CEND-1) structurally depicted in FIG. 2. The iRGD analogs of the invention differ from prior art iRGD peptides in the specific moieties used to block the amino and carboxy termini, which provide significant advantages over prior art cyclic iRGD peptides. In some embodiments, the moieties are acetyl and carboxyamide groups. In some embodiments, the N-terminal amine is acetylated and the C-terminal carboxyl is amidated. In some embodiments, the N-terminal amino group is blocked with an acetyl group and the C-terminal carboxy group, i.e., the C-terminal carbonyl group, is blocked with a carboxyamide group. For example, the iRGD analog of the invention (depicted as CEND-1 in FIG. 2) has the following molecular formula C37H60N14O14S2, MW989.1, and the most recent CAS Registry Number: 2580154-02-3. On the other hand, one prior art iRGD with at least one inferior therapeutic property has the molecular formula: C 35 H 57 N 13 O 14 S 2, which corresponds to "scientific" or "conventional" iRGD, having a molecular weight of 948.04, and CAS Registry Number 1392278-76-0. In some embodiments, D-amino acids are used in the peptides rather than L-amino acids. In some embodiments, modified amino acids known in the art are used rather than unmodified amino acids, and such modifications may include those described by Wang (Current Biotechnology, Volume 1, Number 1, 2012, pp. 72-79(8)), which is incorporated herein by reference in its entirety.

[0055] The advantages of the CEND-1 iRGD analog of the present invention (FIG. 2, C37 H60 N14 O14 S2, MW989.1) compared to the prior art CAS Registry Number 1392278-76-0 cyclic peptide and other known iRGD molecules are that it has the following advantages while maintaining good in vitro / in vivo potency and / or efficacy: favorable pharmacokinetic properties, Improved stability in plasma / serum, Improved stability in formulated solutions; Improved stability on storage, and / or These include one or more of improved protection from proteases such as aminopeptidases and carboxypeptidases.

[0056] In certain embodiments, the favorable and / or improved pharmacokinetic properties are selected from one or more of absorption, distribution, metabolism, and / or excretion. In certain embodiments, CEND-1 has a degradation rate that is 3-fold lower (e.g., improved stability) than the degradation rate of iRGD in phosphate buffered saline at 37° C. and pH=7.4. In further embodiments, CEND-1 has a degradation rate that is 1.6-fold lower (i.e., improved stability) than the degradation rate of iRGD in pooled human plasma.

[0057] As used herein, the phrase "while maintaining good in vitro / in vivo efficacy and / or effectiveness" refers to the continued effect of CEND-1 on the respective therapeutic agent such that efficacy and / or effectiveness is not diminished by CEND-1.

[0058] Also provided herein is a kit or composition comprising an iRGD analog (CEND-1) and an anti-cancer drug. The kit of claim 26, wherein the iRGD analog is shown in the structure of Figure 2.

[0059] Also provided herein are methods for producing iRGD analogs, including CEND-1. In embodiments, iRGD analogs, including CEND-1, are chemically synthesized using currently available laboratory equipment using either Fmoc (9-fluorenylmethyloxycarbonyl) or Boc (tert-butyloxycarbonyl) chemistry. Alternatively, iRGD analogs, including CEND-1, are synthesized by cell-free expression systems or using mammalian, microbial, insect or avian cells according to biomanufacturing methods known to those skilled in the art. Boc / Bzl protection, when used with in situ neutralization, can provide excellent results for long or difficult peptide sequences. A strong acid, such as TFMSA or HF, is required to cleave the peptide product from the resin. Fmoc / tBu protection usually does not require stronger reagents than 50% TFA to remove the side chain protecting groups and cleave the peptide from the resin support, and therefore can be easily scaled up in the laboratory. The side chains can be deprotected while keeping the N-terminal Fmoc in place, allowing for side chain modification. Additionally, a variety of other side chain protecting groups are available that allow selective deprotection at specific sites.

[0060] The acetylation and amidation modifications described herein are also applied according to methods known to those skilled in the art. In embodiments, the C-terminal amide is prepared with an amide-forming resin, such as MBHA, Rink or Sieber resin. In other embodiments, the C-terminal amide is formed by cleaving the peptide from the resin by aminolysis. Aminolysis can be performed with many standard resins, such as Merrifield and Wang resins, but oxime and HMBA resins are preferred. In embodiments, N-terminal acetylation is achieved by adding a final capping step to the peptide synthesis protocol. In embodiments, capping is performed with 6% Ac2O and 3% DIPEA by volume in DMF for 2 x 10 minutes. EXAMPLES

[0061] Example 1: Stability of CEND-1 Compared to Non-acetylated, Non-amidated iRGD The effect of N-terminal acetylation of CEND-1 (Figure 2) and C-terminal amidation of CEND-1 on its stability in phosphate buffered saline, pooled human plasma, and in the presence of carboxypeptidases and aminopeptidases was evaluated. CEND-1 (CAS Registry Number 2580154-02-3) was compared to non-acetylated, non-amidated "conventional" cyclic iRGD (CAS Number 1392278-76-0).

[0062] method: For stability testing in phosphate buffered saline (PBS) (pH=7.4), 10x PBS stocks were diluted to normal 1x PBS concentration, and CEND-1 or iRGD was dissolved to a final concentration of approximately 1 mg / mL. For stability testing in pooled human plasma, frozen pooled human plasma was first thawed, mixed, and then clarified by centrifugation. CEND-1 or iRGD was dissolved in clarified pooled human plasma to a final concentration of approximately 2.5 mg / mL. For stability testing with carboxypeptidase Y (CY), a 50 mM sodium phosphate buffer solution at pH=6.5 was prepared containing 0.15 M sodium chloride, 6 units / mL carboxypeptidase, and approximately 0.1 mg / mL CEND-1 or iRGD. For stability testing with carboxypeptidase B (CB), 25 mM Tris·HCl buffer at pH = 7.7 was prepared containing 0.10 M sodium chloride, 14 units / mL carboxypeptidase B, and approximately 0.1 mg / mL CEND-1 or iRGD. For stability testing with aminopeptidase (AP), 20 mM Tris·HCl buffer at pH = 8 was prepared containing 10 units / mL carboxypeptidase B, and approximately 0.1 mg / mL CEND-1 or iRGD.

[0063] Solutions were incubated at 25°C and 37°C and samples were taken at appropriate time intervals for analysis. Samples in PBS, samples with carboxypeptidases Y and B and aminopeptidase were used directly for HPLC analysis without prior dilution. Samples containing pooled human plasma (0.1 mL) were diluted with 0.15 mL of 0.1% trifluoroacetic acid in methanol, mixed and centrifuged to remove insoluble plasma proteins.

[0064] result: At 37° C., CEND-1 degraded at a rate of 1.1% per day in phosphate buffered saline (pH=7.4) (FIG. 3). At 37° C., iRGD degraded at a rate of 3.3% per day in phosphate buffered saline (pH=7.4) (FIG. 3). The ratio of the degradation rates of iRGD and CEND-1 was three-fold, indicating that CEND-1 is more stable in phosphate buffered saline (pH=7.4) compared to iRGD (Table 1). [Table 1]

[0065] At 37° C., CEND-1 degraded at a rate of 2.5% per day in pooled human plasma (FIG. 2). At 37° C., iRGD degraded at a rate of 4% per day in pooled human plasma (FIG. 4). The ratio of the degradation rates of iRGD to CEND-1 in human plasma was 1.6, indicating that CEND-1 is more stable in pooled human plasma than iRGD (Table 1).

[0066] Carboxypeptides Y and B did not degrade CEND-1 or iRGD at 25° C. in the respective buffers as recommended by the enzyme supplier (FIG. 5). The purity of CEND-1 and iRGD was not affected by the enzymes. Aminopeptidase did not degrade CEND-1 or iRGD at 25° C. in the buffers as recommended by the enzyme supplier (FIG. 6). The purity of CEND-1 and iRGD was not affected by the enzymes.

[0067] Conclusion: In phosphate buffered saline (PBS) (pH = 7.4), CEND-1 was 3-fold (300%) more stable than iRGD when incubated at 37°C. In pooled human plasma, CEND-1 was 1.6-fold (60%) more stable than iRGD when incubated at 37°C. Carboxypeptidases Y and B did not significantly degrade CEND-1 or iRGD at 25°C in the buffers recommended by the enzyme manufacturers. Aminopeptidases did not significantly degrade CEND-1 or iRGD at 25°C in the buffers recommended by the enzyme manufacturers.

[0068] Therefore, iRGD is less stable in PBS and pooled human plasma compared to CEND-1. The stability of both CEND-1 and iRGD is not affected by the carboxypeptidases and aminopeptidases used. Cyclization of the peptides may confer resistance to carboxypeptidases and aminopeptidases. The linear forms of CEND-1 and iRGD may be less resistant to carboxypeptidases and aminopeptidases.

[0069] Example 2: Pharmacokinetic studies in mice This example demonstrates the advantageous pharmacokinetic properties of CEND-1 compared to iRGD, including increased half-life in vivo. CEND-1 or iRGD was administered as an intravenous bolus to fed CD-1 ICR mice at a nominal dose of 4.5 mg / kg in both groups, with four mice per group, and the actual administered doses were 3.87 mg / kg for CEND-1 and 4.33 mg for iRGD. CEND-1 and iRGD were formulated in saline at a concentration of 0.9 mg / ml. Plasma levels of CEND-1 and iRGD were measured at different time points in mice using liquid chromatography-mass spectrometry (LC-MS). Pharmacokinetic parameters were then calculated. At 1 hour after administration, the mean plasma concentration of iRGD was 209 ng / ml, while the mean plasma concentration of CEND-1 was 535 ng / ml, a 2.56-fold increase. The half-lives were calculated to be 0.243 hours for CEND-1 and 0.167 hours for iRGD, which corresponds to a 46% increased half-life for CEND-1 compared to conventional iRGD in vivo. This unexpected increase in half-life is expected to significantly improve the therapeutic efficacy of CEND-1. [Table 2] [Table 3]

[0070] Example 3: Phase I Study of CEND-1 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer (referred to as the CEND-001 Study) This example demonstrates that CEND-1 is well tolerated in combination with gemcitabine and nab-paclitaxel and provides clinical benefit to patients with advanced pancreatic cancer. The response rate is more than 2-fold higher when compared to benchmark studies. CEND-1 is also referred to herein as an iRGD analogue corresponding to the chemical structure depicted in FIG. 2 and CAS Registry Number 2580154-02-3.

[0071] material: CEND-1 formulations are synthetic peptides produced using solid-phase peptide synthesis techniques with high chemical purity. CEND-1 for injection is a sterile, white, lyophilized powder supplied as 100 mg per vial of active ingredient dosage strength for intravenous administration. CEND-1 injection consists of CEND-1 drug substance, with sodium acetate trihydrate and mannitol as excipients.

[0072] method: The open-label, dose-escalation, multicentre (three active centres in Australia) trial consisted of a run-in phase (days 1–7) of escalating CEND-1 monotherapy, followed by CEND-1 plus nab-paclitaxel (125 mg / m 2 ) and gemcitabine (1000 mg / m 2 Patients first received intravenous infusion of nab-paclitaxel (125 mg / m over 30 minutes (± 3 minutes)). 2 ). CEND-1 will be administered intravenously at an applicable dose level as a slow intravenous push over 1 min (± 30 s) immediately after completion of the post-nab-paclitaxel saline washout. An intravenous infusion of gemcitabine (1000 mg / m2 over 30 min (± 3 min)) will be started as soon as possible, but no later than 10 min after CEND-1 administration. [Table 4]

[0073] Patients (n=31) with measurable metastatic pancreatic cancer who had not received conventional treatment for metastatic disease and an ECOG PS of 0 to 1 were included. Primary endpoints were safety and optimal biologic dose, and secondary and exploratory endpoints included response rate, pharmacokinetics, and biomarkers.

[0074] Results: Twenty-nine patients completed the first treatment cycle and were evaluated for response (data cutoff, April 27, 2020). No dose-limiting toxicities were observed. Adverse events were generally consistent with those of nab-paclitaxel and gemcitabine. The only drug-related grade (gr) 3-4 adverse events (AEs) present in ≥3 patients were neutropenia in 18 (62%) patients and anemia in 5 (17%) patients. By investigator-assessed RECIST 1.1 criteria, 1 patient had a complete response (3.4%), 16 patients had a partial response (55%), 10 patients had stable disease (34%), and 2 patients had progressive disease (6.9%). Among patients with elevated CA19-9 and available postbaseline evaluation, a total of 96% of patients had at least a 20% decline from baseline and 74% had at least a 90% decline and / or normalized CA19-9 levels to baseline.

[0075] Conclusions: CEND-1 in combination with nab-paclitaxel and gemcitabine is safe and without dose-limiting toxicity. The incidence of grade 3 and 4 adverse events was lower than in similar published studies. The median treatment duration was longer than in benchmark studies and the response rate was more than double. [Table 5]

[0076] The following frequencies are compared to the iMPACT3 study, data in brackets (Von Hoff et al., 2013).

[0077] Efficacy Outcomes – Response Rate The overall response rate (ORR) for all evaluable patients (N=29) was 59% (vs. 23%). The overall disease control rate over 16 weeks was 79% (vs. 48%).

[0078] Figure 1 corresponds to a waterfall plot of the maximum percentage change from baseline in the size of target lesions according to the Guidelines for Response Evaluation in Solid Tumors, version 1.1. A total of 16 patients showed a partial response (55%) and 10 patients had stable disease (34%).

[0079] CA19-9 A total of 24 patients had elevated baseline CA19-9 (≥37 U / L). Of these, 23 patients had at least one on-treatment CA19-9 measurement. A total of 96% of patients had at least a 20% decrease from baseline (vs. 61%), and 74% had at least a 90% decrease and / or normalized CA19-9 levels to baseline.

[0080] At the end of the study, median (IQR) PFS was 9.7 months [6.2-11.6] and median OS was 13.2 months [9.7-22.5].

[0081] therapeutic exposure safety Table 2 below shows the frequency of bone marrow toxicity observed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5. The frequency of grade 3-4 bone marrow toxicity with this agent was 55% for neutropenia, 14% for leukopenia, 3% for thrombocytopenia, and 24% for anemia.

[0082] CEND1-001 Study In the CEND1-001 study, as described above, CEND-1 was initially administered at escalating doses of 0.2 mg / kg to 3.2 mg / kg over a 1- to 7-day run-in period during which the pharmacokinetics and safety of the single agent were evaluated.

[0083] There were eight patients in cohort 1a: one patient at dose level 1 (CEND-1 0.2 mg / kg), one patient at dose level 2 (0.8 mg / kg), three patients at dose level 3 (1.6 mg / kg), and three patients at dose level 4 (3.2 mg / kg). There were 23 patients in cohort 1b: 11 patients at dose level 3 (1.6 mg / kg), 11 patients at dose level 4 (3.2 mg / kg), and one patient who was assigned to dose level 4 (3.2 mg / kg) but discontinued the study after the run-in period and only received the run-in dose of CEND-1 0.2 mg / kg.

[0084] Of the 31 patients enrolled, 29 were evaluated for efficacy, 31 for pharmacokinetics, and 30 for pharmacodynamics (N=14 at the 1.6 mg / kg CEND-1 dose and N=14 at the 3.2 mg / kg CEND-1 dose level, excluding 2 patients in the low-dose CEND-1 group). There were 10 patient deaths reported during the study, 9 caused by progression of underlying disease (metastatic pancreatic cancer), and 1 caused by left middle cerebral artery stroke (approximately 3 months after the last CEND-1 dose).

[0085] Confirmed objective responses (OR) occurred in 17 / 29 (58.6%) patients (95% CI = 38.9, 76.5). Overall, the number of patients with progression was 16 / 29 (55.2%), and the median time to progression was approximately 9.7 months.

[0086] These response rates (ORs) clearly exceed and represent a significant improvement over those achieved in historically comparable trials (Table 3). In a phase 3 registrational trial of nab-paclitaxel, the response rate in patients with stage 1 metastatic pancreatic cancer treated with the gemcitabine / nab-paclitaxel combination was 23%, with a progression-free survival of 5.5 months (Von Hoff et al., 2013). [Table 6] TIFF2024517221000008.tif114162

[0087] Because there was a trend toward improved outcome at the 3.2 mg / kg dose level, this was selected as the dose to be further explored in future studies.

[0088] Tumor Biomarkers On cycle day 5, the number of patients with a ≥50% decrease in CA19-9 from baseline increased to a high of 20 / 22 patients (90.9%).

[0089] Tumor biomarker results for CEND-1 at dose levels of 1.6 mg / kg and 3.2 mg / kg show a trend towards decreased CA values ​​with successive dosing cycles, supporting further development of CEND-1 in combination with agents such as Nab-paclitaxel and gemcitabine in patients with metastatic cancer.

[0090] Pharmacokinetics of CEND-1 Overall, the median Tmax of CEND-1 was 0.067 hours across all days of pharmacokinetic sampling (minimum 0.03, maximum 0.55). There was a dose-proportional increase in Cmax without increase with repeated dosing.

[0091] Evaluation of plasma CEND-1 parameters showed that exposure (AUC0-t, AUC0-6h, and AUC0-inf) tended to increase with increasing dose, following the same pattern as described for Cmax. Dose-normalized pharmacokinetic parameters (AUC0-t / D, AUC0-6h / D, and AUC0-inf / D) were comparable between visits and treatments.

[0092] CEND-1 was cleared with a median T1 / 2 between 1.6 and 1.8 hours across all days of pharmacokinetic sampling. Mean CL values ​​ranged between 106.8 mL / h / kg and 266.5 mL / h / kg. Mean terminal volume of distribution (Vz) values ​​ranged between 220.9 mL / kg and 277.4 mL / kg across all days of pharmacokinetic sampling.

[0093] CEND-1 safety During the run-in period of CEND-1 during dose escalation, the following definitions of dose-limiting toxicity were used:

[0094] CEND-1 Monotherapy: Dose-limiting toxicities during the run-in period were defined as follows: Grade 4 neutropenia lasting ≥5 days or grade 3 or 4 neutropenia accompanied by fever and / or infection - Grade 4 thrombocytopenia (or grade 3 with bleeding) - Grade 3 or 4 treatment-related non-hematologic toxicity (grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite maximal treatment is a dose-limiting toxicity; inadequate treatment would be inappropriate for study conduct and is not an exception to the dose-limiting toxicity criteria) - Dose delay of >2 weeks due to treatment-emergent adverse events or related severe laboratory abnormalities.

[0095] No dose-limiting toxicities or grade 3 or 4 adverse events were present at any CEND-1 dose level during the single-agent run-in portion of the study, and no clinically significant adverse events attributable to CEND-1 were reported.

[0096] During the combination portion of the study, the following definitions of dose-limiting toxicities were used. Any side effects that are more severe, last longer, or occur more frequently than expected based on the package insert for nab-paclitaxel and gemcitabine. -Any adverse event not included in the nab-paclitaxel and gemcitabine package insert that meets the definition of a dose-limiting toxicity for monotherapy above.

[0097] No dose-limiting toxicities were reported during the study. Most treatment-emergent adverse events were CTCAE grade 1 or 2. The number of treatment-emergent adverse events reported at each grade was similar across CEND-1 dose levels. Overall, the severity of treatment-emergent adverse events did not increase with CEND-1 dose. The most common CTCAE grade 3-4 treatment-emergent adverse events with standard therapy were blood and lymphatic system disorders.

[0098] Example 4: Trial of CEND-1 in combination with neoadjuvant FOLFIRINOX-based therapy (CENDIFOX) in pancreatic, colon and appendix cancer Cohort 1 Pancreatic cancer Biopsy for tissue immune profile if archived tissue is not available. Repeat biopsy for second tissue immune profile after 3 cycles of Folfirinox infusion. 3 cycles of Folfirinox+CEND1 infusion. Participants undergo surgery 72 hours after the last infusion.

[0099] Treatment with CEND-1 is administered in the clinic as an intravenous (IV) infusion (via a needle in a vein) once every 14 days (or on day 1 of each 14-day cycle starting with the fourth cycle). FOLFIRINOX is the name of a chemotherapy treatment regimen that includes several different drugs given in a specific order as follows:

[0100] All of these drugs are administered in the clinic as an intravenous (IV) infusion (through a needle in a vein) once every 14 days (or on the first day of each 14-day cycle). Oxaliplatin - the dose is 85 mg / m2 and the infusion takes about 2 hours. Leucovorin - the dose is 400 mg / m2 - is given at the same time as irinotecan (below) and the infusion takes about 1.5 hours. Irinotecan - the dose is 180 mg / m2 - is given simultaneously with leucovorin (see above) and the infusion takes approximately 1.5 hours. after that Fluorouracil - the dose is 2400 mg / m2 - this infusion takes 46-48 hours (2 days) using an intravenous pump done at home.

[0101] Cohort 2 Peritoneal metastasis Biopsy for tissue immune profile if archived tissue is not available. After 3 cycles of Folfirinox + panitumumab (if RAS / BRAF) infusion, repeat biopsy for second tissue immune profile. 3 cycles of Folfirinox + panitumumab (if RAS / BRAF positive) and CEND1 infusion. Participants undergo surgery 72 hours after the last infusion.

[0102] Treatment with CEND-1 is administered in the clinic as an intravenous (IV) infusion (via a needle in a vein) once every 14 days (or on the first day of each 14-day cycle starting with cycle 4). Patients in need of treatment who have cancer that has spread to certain areas of the body and have certain genes in their tumors called "RAS / BRAF wild-type" receive a therapeutically effective amount of panitumumab (as described above) in addition to CEND-1 and FOLFIRINOX.

[0103] FOLFIRINOX is the name of a chemotherapy treatment regimen that includes several different drugs given in a specific order, all of which are given in the clinic as an intravenous (IV) infusion (through a needle in a vein) once every 14 days (or on the first day of each 14-day cycle) as follows: Oxaliplatin - the dose is 85 mg / m2 and the infusion takes about 2 hours. Leucovorin - the dose is 400 mg / m2 - is given at the same time as irinotecan (below) and the infusion takes about 1.5 hours. Irinotecan - the dose is 180 mg / m2 - is given simultaneously with leucovorin (see above) and the infusion takes approximately 1.5 hours. after that Fluorouracil - the dose is 2400 mg / m2 - this infusion takes 46-48 hours (2 days) using an intravenous pump done at home.

[0104] Cohort 3 Oligometastatic colon cancer Biopsy for tissue immune profile if archived tissue is not available. After 3 cycles of Folfirinox + panitumumab (if RAS / BRAF) infusion, repeat biopsy for second tissue immune profile. 3 cycles of Folfirinox + panitumumab (if RAS / BRAF positive) and CEND1 infusion. Participants undergo surgery 72 hours after the last infusion.

[0105] Treatment with CEND-1 is administered in the clinic as an intravenous (IV) infusion (via a needle in a vein) once every 14 days (or on day 1 of each 14-day cycle starting with the 4th cycle). Patients in need of treatment who have cancer that has spread to certain areas of the body and have certain genes in their tumors called "RAS / BRAF wild-type" receive a therapeutically effective amount of panitumumab (as described above) in addition to CEND-1 and FOLFIRINOX.

[0106] FOLFIRINOX is the name of a chemotherapy treatment regimen that includes several different drugs given in a specific order, all of which are given in the clinic as an intravenous (IV) infusion (through a needle in a vein) once every 14 days (or on the first day of each 14-day cycle) as follows: Oxaliplatin - the dose is 85 mg / m2 and the infusion takes about 2 hours. Leucovorin - the dose is 400 mg / m2 - is given at the same time as irinotecan (below) and the infusion takes about 1.5 hours. Irinotecan - the dose is 180 mg / m2 - is given simultaneously with leucovorin (see above) and the infusion takes approximately 1.5 hours. after that Fluorouracil - the dose is 2400 mg / m2 - this infusion takes 46-48 hours (2 days) using an intravenous pump done at home.

[0107] Results show favorable results with 90% confidence intervals for one or more of the following: overall survival (OS) reported using median survival, disease-free survival (DFS) reported using median survival, overall response rate (ORR), RO resection rate (RORR) and / or pathological response rate (PCR).

Claims

1. A pharmaceutical composition comprising an iRGD analog and a pharma- ceutically acceptable excipient.

2. The iRGD analogs have one or more improved properties compared to prior art iRGD molecules; The improved properties include Improved pharmacokinetic properties, Improved stability in plasma / serum; Improved stability in formulated solutions; Improved stability on storage, and / or Improved protection from proteases such as aminopeptidases and carboxypeptidases; Selected from the group consisting of: The composition of claim 1.

3. The composition of claim 2 , wherein the improved pharmacokinetic properties are selected from one or more of absorption, distribution, metabolism and / or excretion.

4. The composition of claim 1 , wherein the iRGD analog maintains good in vitro or in vivo potency and / or efficacy.

5. 2. The composition of claim 1, wherein the iRGD analog is CEND-1 (CAS Registry No. 2580154-02-3), the structure of which is shown in FIG.

6. 6. The composition of claim 5, wherein CEND-1 has a degradation rate that is 3-fold lower than the degradation rate of iRGD in phosphate buffered saline at 37° C. and pH=7.4, and / or 1.6-fold lower than the degradation rate of iRGD in pooled human plasma.

7. The composition of claim 5, wherein CEND-1 has a 46% increased half-life in vivo compared to iRGD.

8. 1. A method for treating, inhibiting or reducing the volume of a tumor of a cancer in a subject or patient in need thereof, the method comprising administering CEND-1 or a pharmaceutically acceptable salt thereof in combination with simultaneous, separate or sequential administration of at least one anti-cancer agent or anti-cancer treatment.

9. 9. The method of claim 8, wherein the tumor is a malignant solid tumor characterized by a dense tumor stroma.

10. 9. The method of claim 8, wherein the tumor is a solid tumor of a cancer selected from the group consisting of breast cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrioma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatoma, and head and neck cancer.

11. The method of claim 10, wherein the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anti-cancer drug resistant pancreatic cancer, and adenocarcinoma.

12. The method of claim 8, wherein the cancer is ductal adenocarcinoma (stages 0-IV).

13. 9. The method of claim 8, wherein the anti-cancer agent or anti-cancer treatment is selected from the group consisting of chemotherapeutic agents, small molecules, antibodies, antibody drug conjugates, nanoparticles, cell therapy, polypeptides, peptides, peptidomimetics, nucleic acid molecules, ribozymes, antisense oligonucleotides; transgenes, viruses, cytokines, nucleic acid molecules encoding cytotoxic polypeptides; pro-apoptotic polypeptides, anti-angiogenic polypeptides, cytotoxic cells such as cytotoxic T cells, and vaccines (mRNA or DNA).

14. The chemotherapeutic agents include taxanes, docetaxel, paclitaxel, nab-paclitaxel, nucleosides, gemcitabine, anthracyclines, doxorubicin, alkylating agents, vinca alkaloids, antimetabolites, platinum agents, cisplatin, carboplatin, steroids, methotrexate, antibiotics, adriamycin, isofluranes, selective estrogen receptor modulators, maytansinoids, mertansine, emtansine; antibodies such as trastuzumab, anti-epidermal growth factor receptor 2 (HER2) antibodies, trastuzumab, caspases, caspase-8; diphtheria toxin A chain, pseudomonas exotoxin A, cholera toxin , ligand fusion toxins, DAB389EGF, castor bean toxin (ricin); chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor macrophages (CAR-M), chimeric antigen receptor natural killer cells (CAR-K), and tumor infiltrating lymphocytes (TIL), anti-PD-1 antibodies, nivolumab, panitumumab, pembrolizumab, atezolizumab, avelumab, durvalumab; anti-CTLA-4 antibodies, ipilimumab; bispecific antibodies, catumaxomab, mRNA-4157 from Moderna, and / or BNT122 from BioNTech.

15. The method of claim 8, wherein CEND-1 is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of anti-cancer agent or cancer therapy, about 0.3-17 mg / kg body weight per dose of anti-cancer agent or cancer therapy, about 0.4-14 mg / kg body weight per dose of anti-cancer agent or cancer therapy, about 0.5-11 mg / kg body weight per dose of anti-cancer agent or cancer therapy, about 0.6-8 mg / kg body weight per dose of anti-cancer agent or cancer therapy, about 0.7-5 mg / kg body weight per dose of anti-cancer agent or cancer therapy, or about 0.8-3.2 mg / kg body weight per dose of anti-cancer agent or cancer therapy.

16. 9. The method of claim 8, wherein CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of cancer therapy.

17. 9. The method of claim 8, wherein CEND-1 is administered prior to or during administration of an anti-cancer agent or cancer therapy, and the anti-cancer agent or cancer therapy is administered at a dosing regimen selected from the group consisting of 4 times / day, 3 times / day, twice a day, once a day, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and once a month.

18. The method of claim 8, wherein the CEND-1 is in a dry formulation or suspended in a biocompatible medium.

19. 20. The method of claim 18, wherein the biocompatible medium is selected from the group consisting of water, a buffered aqueous medium, saline, buffered saline, optionally a buffered solution of amino acids, optionally a buffered solution of proteins, optionally a buffered solution of sugars, optionally a buffered solution of vitamins, optionally a buffered solution of synthetic polymers, and a lipid-containing emulsion.

20. The method of claim 8, wherein CEND-1 is administered intravenously.

21. 1. A method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient an effective amount of CEND-1 in combination with an anti-cancer therapy, wherein the anti-cancer therapy is gemcitabine and / or nab-paclitaxel, or a pharmaceutically acceptable salt thereof.

22. 22. The method of claim 21, wherein the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anti-cancer drug resistant pancreatic cancer, and adenocarcinoma.

23. The method of claim 21, wherein the cancer is ductal adenocarcinoma (stages 0-IV).

24. 22. The method of claim 21, wherein CEND-1 is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of anti-cancer therapy, about 0.3-17 mg / kg body weight per dose of anti-cancer therapy, about 0.4-14 mg / kg body weight per dose of anti-cancer therapy, about 0.5-11 mg / kg body weight per dose of anti-cancer therapy, about 0.6-8 mg / kg body weight per dose of anti-cancer therapy, about 0.7-5 mg / kg body weight per dose of anti-cancer therapy, or about 0.8-3.2 mg / kg body weight per dose of anti-cancer therapy.

25. 22. The method of claim 21, wherein CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of anti-cancer therapy.

26. 22. The method of claim 21, wherein CEND-1 is administered prior to or during administration of an anti-cancer therapy, said anti-cancer therapy being administered at a dosing regimen selected from the group consisting of 4 times per day, 3 times per day, twice per day, once per day, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once per week, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and once per month.

27. CEND-1 is administered in an amount in a range selected from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, and 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy; nab-paclitaxel is administered in an amount in a range selected from 1-500, 10-450, 20-400, 30-350, 40-300, 50-250, 60-200, 70-175, 80-160, 90-150, 100-140, 110-140, 115-135, and 120-130 mg / m2; and 22. The method of claim 21, wherein gemcitabine is administered in an amount in a range selected from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, and 900-1100 mg / m2.

28. 22. The method of claim 21, wherein CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy, nab-paclitaxel is administered at 125 mg / m2, and gemcitabine is administered at 1000 mg / m2.

29. 1. A method of treating pancreatic, colon or appendiceal cancer in a patient in need thereof, comprising administering to the patient an effective amount of CEND-1 in combination with an anti-cancer therapy, wherein the anti-cancer therapy is any of FOLFIRINOX, Folfox or Folfiri, and / or panitumumab or a pharmaceutically acceptable salt thereof.

30. 30. The method of claim 29, wherein the pancreatic cancer is selected from the group consisting of primary pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, anti-cancer drug resistant pancreatic cancer, and adenocarcinoma.

31. 30. The method of claim 29, wherein the cancer is ductal adenocarcinoma (stages 0-IV).

32. 30. The method of claim 29, wherein CEND-1 is administered in an amount selected from the group consisting of about 0.2-20 mg / kg body weight per dose of anti-cancer therapy, about 0.3-17 mg / kg body weight per dose of anti-cancer therapy, about 0.4-14 mg / kg body weight per dose of anti-cancer therapy, about 0.5-11 mg / kg body weight per dose of anti-cancer therapy, about 0.6-8 mg / kg body weight per dose of anti-cancer therapy, about 0.7-5 mg / kg body weight per dose of anti-cancer therapy, or about 0.8-3.2 mg / kg body weight per dose of anti-cancer therapy.

33. 30. The method of claim 29, wherein CEND-1 is administered in an amount equivalent to 3.2 mg / kg body weight per dose of anti-cancer therapy.

34. 30. The method of claim 29, wherein CEND-1 is administered prior to or during administration of an anti-cancer therapy, said anti-cancer therapy being administered at a dosing regimen selected from the group consisting of 4 times per day, 3 times per day, twice per day, once per day, once every other day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once per week, once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, once every 2 weeks, once every 3 weeks, and once per month.

35. CEND-1 is administered in an amount in a range selected from 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.17-6, 0.18-5, 0.19-4, and 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy; each of the forms of oxaliplatin, leucovorin, and irinotecan is administered in an amount ranging from 1-500, 10-450, 20-400, 30-350, 40-300, 50-250, 60-200, 70-175, 80-160, 90-150, 100-140, 110-140, 115-135, or 120-130 mg / m2; and Fluorouracil is administered in an amount in a range selected from 1-5000, 100-4500, 200-4000, 300-3500, 400-3000, 500-2500, 550-2000, 600-1750, 650-1500, 700-1400, 750-1300, 800-1200, or 900-1100 mg / m2; and / or panitumumab is administered at 0.01-100, 0.02-90, 0.03-80, 0.04-70, 0.05-60, 0.06-50, 0.07-40, 0.08-30, 0.09-30, 0.1-25, 0.11-20, 0.12-15, 0.13-10, 0.14-9, 0.15-8, 0.16-7, 0.1 30. The method of claim 29, wherein the compound is administered in an amount ranging from 7-6, 0.18-5, 0.19-4, or 0.2-3.2 mg / kg of body weight, or from 1-20 mg / kg per 14 days, from 2-15 mg / kg per 14 days, from 3-12 mg / kg per 14 days, from 4-10 mg / kg per 14 days, from 5-8 mg / kg per 14 days, or from 6 mg / kg per 14 days.

36. 30. The method of claim 29, wherein CEND-1 is administered in the range of 0.2-3.2 mg / kg body weight per day or per dose of chemotherapy, oxaliplatin is administered at 85 mg / m2, leucovorin is administered at 400 mg / m2, irinotecan is administered at 180 mg / m2, fluorouracil is administered at 2400 mg / m2, and / or panitumumab is administered at 6 mg / kg every 14 days.

37. The method according to any one of claims 8 to 36, wherein the efficacy or clinical activity of said method is measured by determining objective response rate (ORR), progression free survival (PFS) and / or overall survival (OS).

38. 37. The method of any one of claims 8 to 36, wherein the efficacy or clinical activity of the method is measured by determining one or more of: an objective response rate (ORR) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; a progression free survival (PFS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%; and / or an overall survival (OS) selected from greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or greater than 95%.

39. A kit or composition comprising the iRGD analog of any one of claims 1 to 7 and an anti-cancer agent.

40. 40. The kit of claim 39, wherein the iRGD analog is CEND-1, the structure of which is shown in FIG.

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