Pharmaceutical combination of CXCR4 and PD-1 inhibitors for treating cancer

Abstract

The present invention relates to pharmaceutical combinations comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1 and their use in a method for the prevention, delay of progression or treatment of cancer in a subject.

Description

[0001] PHARMACEUTICAL COMBINATION OF CXCR4 AND PD-1 INHIBITORS FOR TREATING CANCER

[0002] Field of the invention

[0003] The present invention relates to pharmaceutical combinations comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1 and their use in a method for the prevention, delay of progression or treatment of cancer in a subject.

[0004] Background of the invention

[0005] Despite the ever-increasing number of cancer therapies in general, and combination cancer therapies in particular, cancer is still the third most common cause of death worldwide after cardiovascular diseases and infectious / parasitic diseases; in absolute numbers, this corresponds to 7.6 million deaths (ca. 13% of all deaths) in any given year. The WHO estimates deaths due to cancer to increase to 13.1 million by 2030, while the American Cancer Society expects over 1,685,210 new cancer cases diagnosed and 595,690 cancer deaths in the US in 2016. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer often requiring a multimodal treatment approach. PDAC is projected to be the second leading cause of cancer-related death by 2030 in the United States, surpassing prostate, breast, and colorectal cancer (Rahib L, Smith BD, Aizenberg R, et al., Cancer Res 2014;74:2913-21. 10.1158 / 0008-5472.CAN-14-0155). Metastatic breast cancer (mBC) remains an incurable disease. Hormonal therapy is the initial course of treatment for those breast cancers that are estrogen receptor positive. Unfortunately, most of these patients become resistant to hormone therapy, and like those patients that are hormone receptor negative, they must then rely upon cytotoxic chemotherapy to control their disease. Despite new targeted therapies and cytotoxic agents that have recently been added to the treatment armamentarium, most patients with metastatic breast cancer develop resistance within months and overall survival remains poor. Despite the recent addition of new therapeutic options, there is a distinct need for new treatment modalities for the treatment of pancreatic cancer, in particular PDAC, and of breast cancer, in particular advanced breast cancer. Cancer immunotherapy, a novel and rapidly growing field of research, investigates the use of therapies that harness the body's own immune system in the fight against cancer. Tumors utilize a variety of mechanisms to evade host immune detection. There is mounting evidence that tumor-infiltrating immune cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor- associated macrophages, actively modulate the tumor microenvironment to suppress the effector arms of this response. The aim of the cancer immunotherapy approach is to prevent the tumor's ability to suppress its own detection and elimination by the host immune system. A number of biologic agents that target a range of immune signaling mechanisms, e.g., programmeddeath receptor 1 (PD-1) / programmed-death receptor ligand 1 (PD-L1), Lymphocyteactivation gene 3 (LAG-3), and killer-immunoglobulin-like receptor (KIR), are in clinical development for the treatment of a variety of cancers. However, a fraction of subjects does not respond to these therapies as a result of local immunosuppression mediated by stromal cells (mostly fibroblasts). It was found that activated fibroblasts in the tumor stroma mediate immune suppression in several mouse models of cancer. Thus, there is a distinct need for new treatment modalities such as useful combination therapies for the treatment of cancer, in particular for the treatment of difficult to cure cancers such as pancreatic cancer which is the type of cancer which has the lowest improvement of 10 years survival rates in the last 40 years, or breast cancer.

[0006] Summary of the invention

[0007] It has now unexpectedly been found that a combination comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1 is useful for the prevention, delay of progression or treatment of cancer, in particular pancreatic cancer like PDAC, or breast cancer like triple negative breast cancer (TNBC).

[0008] Taking these unexpected findings into account, the inventors herewith provide the present invention in its following aspects.

[0009] In a first aspect the present invention provides a pharmaceutical combination comprising: (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14-

[0010] Xaa15-Pro16-)

[0011] (I), in which

[0012] Xaa3is Ala; Tyr; or Tyr(Me);

[0013] Xaa6is Ala or Acc;

[0014] Xaa7isDPro;DTyr; orDTyr(Me);

[0015] Xaa8is Dab; or Orn(iPr);

[0016] Xaa14is Lys; or Lys(iPr);

[0017] Xaa15isDPro; orDLys(iPr); wherein

[0018] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0019] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0020] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0021] Dab is (2S)-2,4-diaminobutyric acid;

[0022] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0023] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0024] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11;

[0025] (b) an inhibitor of PD-1; and

[0026] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.

[0027] In a second aspect the present invention provides a pharmaceutical combination as described herein, for use as a medicament. In a third aspect the present invention provides a pharmaceutical combination as described herein, for use in a method for the prevention, delay of progression or treatment of cancer in a subject.

[0028] In a fourth aspect the present invention provides kit of parts comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0029] (I), in which

[0030] Xaa3is Ala; Tyr; or Tyr(Me);

[0031] Xaa6is Ala or Acc;

[0032] Xaa7isDPro;DTyr; orDTyr(Me);

[0033] Xaa8is Dab; or Orn(iPr);

[0034] Xaa14is Lys; or Lys(iPr);

[0035] Xaa15isDPro; orDLys(iPr); wherein

[0036] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0037] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0038] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0039] Dab is (2S)-2,4-diaminobutyric acid;

[0040] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0041] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0042] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11; the second container comprises at least one dose of a medicament comprising an inhibitor of PD-1, and the package insert comprises optionally instructions for treating a subject for cancer using the medicaments.

[0043] Brief description of the figures

[0044] Figure 1: Combination of cyclized peptidic CXCR4 inhibitor (Balixafortide) and an inhibitor of PD-1 (RMP1-14) enhances the anti-tumor response in the KPC orthotopic model.

[0045] Figure 2: Combination of cyclized peptidic CXCR4 inhibitor Balixafortide and an anti-PD-1 antibody significantly improves anti-PD-1 immunotherapy to reduce tumor growth in mice with TNBC.

[0046] Figure 3: Combination of cyclized peptidic CXCR4 inhibitor Balixafortide and an anti-PD-1 antibody significantly increases the probability of survival or significantly reduces hazard ratios for death of mice with TNBC.

[0047] Detailed description of the invention

[0048] For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The terms "comprising", "having", and "including" are to be construed as open-ended terms (i.e. meaning "including, but not limited to,") unless otherwise noted.

[0049] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0050] The terms "individual," "subject" or "patient" are used herein interchangeably. In certain embodiments, the subject is a mammal. Mammals include, but are not limited to primates (including human and non-human primates). In a preferred embodiment, the subject is a human.

[0051] The term "pharmaceutically acceptable diluents, excipients or carriers" as used herein refers to diluents, excipients or carriers that are suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio. "Diluents" are agents which are added to the bulk volume of the active agent making up the solid composition. As a result, the size of the solid composition increases, which makes it easierto handle. Diluents are convenient when the dose of drug per solid composition is low, and the solid composition would otherwise be too small. "Excipients" can be binders, lubricants, glidants, coating additives or combinations thereof. Thus, excipients are intended to serve multiple purposes. "Carriers" can be solvents, suspending agents or vehicles, for delivering the instant compounds to a subject.

[0052] The term "dose" as used herein refers to the total amount of an active ingredient (e.g., the backbone cyclized peptidic CXCR4 inhibitor or inhibitor of PD-1 to be taken each time by a subject (e.g. a human), except indicated otherwise, e.g., amount of an active ingredient per kg of body weight of a subject (e.g. human).

[0053] The term "objective response rate" (ORR) as used herein refers to the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression. Generally, the FDA has defined ORR as the sum of partial responses plus complete responses. When defined in this manner, ORR is a direct measure of drug antitumor activity, which can be evaluated in a single-arm study. The ORR refers to the sum of complete response (CR) and partial response (PR).

[0054] The term "clinical benefit rate" (CBR) as used herein refers to the sum of complete response (CR), partial response (PR) and stable disease (SD) >6 months.

[0055] The term "complete response" (CR) as used herein in relation to target lesions refers to disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. The term complete response (CR) as used herein in relation to non-target lesions refers to disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non- pathological in size (<10 mm short axis).

[0056] The term "partial response" (PR) as used herein in relation to target lesions refers to at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

[0057] The term "progressive disease" (PD) as used herein in relation to target lesions refers to at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions. The term progressive disease (PD) as used herein in relation to non-target lesions refers to appearance of one or more new lesions and / or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

[0058] The term "stable disease" (SD) as used herein in relation to target lesions refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The term "progression-free survival" (PFS) as used herein relates to the duration of time from start of treatment to time of progression or death, whichever occurs first.

[0059] The terms "cancer" and "cancerous" as used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, kaposi sarcoma, endometrial cancer, head and neck cancer, oesophageol cancer, breast cancers, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, and gastric cancer.

[0060] The term "pancreatic cancer" as used herein refers to or describes a malignant neoplasm of the pancreas which has normally a low early- diagnosis rate and poor prognosis. Its incidence rate has risen in recent years, and it now comprises l%-2% of common tumors. Each year about 185,000 individuals globally are diagnosed with this condition. The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma. Pancreatic cancer is a type of cancer that begins as a growth of cells in the pancreas. The pancreas lies behind the lower part of the stomach. As its symptoms are usually non-specific, pancreatic cancer is often not diagnosed until it reaches an advanced stage. The anatomical structure of the pancreas is very complicated. The high interstitial tension and inadequate blood perfusion of the pancreatic tumors give them extreme resistance to most chemotherapy drugs. Consequently, conventional systemic IV chemotherapy often fails to reach effective concentrations. High dosages may cause severe adverse reactions, thus impairing the immune system and reducing the potential therapeutic effect. In some embodiments, the pancreatic cancer is recurrent pancreatic cancer. In some embodiments, the pancreatic cancer has reoccurred after remission. In some embodiments, the individual has measurable disease (for example, according to RECIST criteria). In some embodiments, the individual has one or more metastatic tumors measurable, for example, by CT scan (or MRI). In some embodiments, the pancreatic cancer is unresectable pancreatic cancer. In some embodiments, the pancreatic cancer is a resectable pancreatic cancer. In some embodiments, the pancreatic cancer is borderline resectable. In some embodiments, the primary location of the pancreatic cancer is the head of the pancreas. In some embodiments, the primary location of the pancreatic cancer is the body of the pancreas. In some embodiments, the primary location of the pancreatic cancer is the tail of the pancreas.

[0061] The term "pancreatic ductal adenocarcinoma (PDAC)" as used herein refers to or describes a type of exocrine pancreatic cancer. It develops from cells lining small tubes in the pancreas called ducts. These carry the digestive juices, which contain enzymes, into the main pancreatic duct and then on into the duodenum (first part of the small intestine). PD AC can grow anywhere in the pancreas, although it is most often found in the head of the pancreas. According to a specific embodiment, the PDAC comprises intraductal papillary mucinous neoplasm.

[0062] The terms "metastatic cancer", "metastatic pancreatic cancer" or "metastatic pancreatic ductal adenocarcinoma (PDAC)" as used herein means the state of cancer, e.g. the state of pancreatic cancer or PDAC where the cancer cells are transmitted from the original site to one or more sites elsewhere in the body, by the blood vessels or lymphatics, to form one or more secondary tumors at one or more sites or organs besides the original site or organ.

[0063] The term "refractory metastatic pancreatic ductal adenocarcinoma (PDAC)" as used herein refers to or describes metastatic pancreatic ductal adenocarcinoma which does not respond to treatment, either being resistant at the beginning of treatment or becoming resistant during treatment.

[0064] The term "breast cancer" as used herein means cancer that forms in tissues of the breast. The most common type of breast cancer is ductal carcinoma, which begins in the lining of the milk ducts. Another type of breast cancer is lobular carcinoma, which begins in the lobules (milk glands) of the breast. Invasive breast cancer is breast cancer that has spread from where it began in the breast ducts or lobules to surrounding normal tissue.

[0065] The term "metastatic breast cancer" as used herein means the state of breast cancer where the cancer cells are transmitted from the original site to one or more sites elsewhere in the body, by the blood vessels or lymphatics, to form one or more secondary tumors at one or more sites or organs besides the original site or organ. According to the criteria of the American Joint Committee on Cancer (AJCC, 8th edition) metastatic breast cancer is staged as stage IV breast cancer.

[0066] The term "relapsed metastatic breast cancer" and "recurrent metastatic breast cancer" are used synonymously herein and therefore have the same meaning. They refer to breast cancer that has returned after initial treatment and has spread to other parts of the body, such as the bones, liver, lungs, or brain. This type of cancer is also referred to as Stage IV breast cancer.

[0067] The terms "locally advanced breast cancer" and "locally recurrent breast cancer" are used synonymously herein and therefore have the same meaning, "locally advanced breast cancer" and "locally recurrent breast cancer" mean the most advanced stage breast cancer that is still potentially curable with surgery, radiation, and systemic therapy. In general, cancers of the breast are considered to be locally advanced if they are large and / or have infiltrated into adjacent tissues (the overlying skin or underlying muscles) and / or are found to have extensive locoregional lymph node involvement. Locally advanced breast cancer does not represent a single clinical entity but rather a heterogeneous group of breast tumors that share a common theme of extensive locoregional spread without overt evidence of distant metastatic disease According to the criteria of the American Joint Committee on Cancer (AJCC, 8th edition) locally advanced breast cancer is staged as stage III breast cancer.

[0068] The term "advanced breast cancer" as used herein includes metastatic breast cancer and locally advanced breast cancer, as used herein.

[0069] The term "triple negative breast cancer" (TNBC) used herein refers to a type of breast cancer characterized by the absence of three specific receptors commonly found in other breast cancers: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). This means that the cancer cells test negative for these three receptors, hence the name "triple negative". TNBC tends to be more aggressive and has fewer treatment options compared to other types of breast cancer. It also tends to grow and spread more quickly. This subtype accounts for about 10-15% of all breast cancers and is more common in younger women, particularly those who are Black or have a BRCA1 gene mutation.

[0070] The term "solid tumor" or "solid tumor indication" used herein refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Preferably malignant solid tumors are treated with the methods of the present invention. Different types of malignant solid tumors are usually named for the type of cells that form them. Examples of malignant solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form malignant solid tumors (definition according to the national cancer institute of the NIH). Malignant solid tumors include, but are not limited to, abnormal mass of cells which may stem from different tissue types.

[0071] The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxy-benzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-enel-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e. g. an alkaline metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0072] The term "about" as used herein refers to + / - 10% of a given measurement.

[0073] Thus, in a first aspect the present invention provides a pharmaceutical combination comprising:

[0074] (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14-

[0075] Xaa15-Pro16-)

[0076] (I), in which

[0077] Xaa3is Ala; Tyr; or Tyr(Me);

[0078] Xaa6is Ala or Acc;

[0079] Xaa7isDPro;DTyr; orDTyr(Me);

[0080] Xaa8is Dab; or Orn(iPr);

[0081] Xaa14is Lys; or Lys(iPr);

[0082] Xaa15isDPro; orDLys(iPr); wherein

[0083] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0084] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0085] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0086] Dab is (2S)-2,4-diaminobutyric acid;

[0087] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0088] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0089] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11; b) an inhibitor of PD-1; and (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.

[0090] Backbone cyclized peptidic CXCR4 inhibitors

[0091] The term "CXCR4 inhibitor" as used herein refers to a compound that binds to the CXCR4 receptor and generally antagonizes ligand (CXCL12)-induced signaling and can also act as an inverse agonist or a partial agonist of the CXCR4 receptor (W. Zhang et al. 2002, 27, 24515-24521).

[0092] In a preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0093] (la), in which

[0094] Xaa3is Ala; Tyr; or Tyr(Me);

[0095] Xaa7isDPro;DTyr; orDTyr(Me);

[0096] Xaa8is Dab; or Orn(iPr);

[0097] Xaa14is Lys; or Lys(iPr);

[0098] Xaa15isDPro; orDLys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0099] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0100] Dab is (2S)-2,4-diaminobutyric acid;

[0101] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0102] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0103] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and wherein the compound of formula la has a disulfide bond between Cys4and Cys11. In a more preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(l\ / le)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof.

[0104] In an even more preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(l\ / le)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), or pharmaceutically acceptable salts thereof.

[0105] In a particular preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable salts thereof.

[0106] In a more particular preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable sals thereof. Cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), is also referred as POL6326 herein or Balixafortide. POL6326 is a cyclic synthetic peptide consisting of 16 amino acids and an antagonist of the highly conserved chemokine receptor CXCR4. In vitro receptor binding studies demonstrated a significant affinity of POL6326 for the human CXCR4 receptor, as well as a general lack of significant binding to other potential target receptors.

[0107] Particularly suitable pharmaceutically acceptable salts of the backbone cyclized peptidic CXCR4 inhibitor to be useful in the context of the present invention include the acetates, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonate, 2-hydroxyethanesulfonic acid, ethane-1,2- disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene- disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl- sulfamic acid, or other organic protonic acids, such as ascorbic acid. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.

[0108] Inhibitors of PD-1

[0109] The terms "inhibitor of PD-1", "PD-1 antagonist", or "PD-1 inhibitor" are used herein interchangeably and refer to a molecule e.g. an antibody which totally or partially reduces, inhibits, interferes with, or negatively modulates the function of PD1, PDL1 (PD-L1) and / or PDL2 (PD-L2).

[0110] The term "Programmed Death- 1", "Programmed cell death protein 1" or "PD-1" is used herein interchangeably and refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. And likewise, the term "PD-L1" as used herein includes human PD-L1 (hPD-Ll), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll and, the term "PD-L2" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at least one common epitope with hPD-L2. The complete hPD-1 sequence can be found under GenBank Accession No. U64863 or Uniprot No. Q15116. The complete human PD-L1 protein sequence can be found under Uniprot No. Q9NZQ7 and the complete human PD-L2 sequence can be found under Uniprot No. Q9BQ51.

[0111] In one embodiment the inhibitor of PD-1 is an antagonistic PD-1 antibody, antagonistic PDL-1 antibody (antagonistic PD-L1 antibody) or an antagonistic PDL-2 antibody (antagonistic PD-L2 antibody), more preferably an antagonistic PD-1 antibody or an antagonistic PDL-1 antibody (antagonistic PD-L1 antibody).

[0112] In a preferred embodiment, the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab and Sugemalimab.

[0113] In a more preferred embodiment, the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab and Retifanlimab.

[0114] In an even more preferred embodiment, the inhibitor of PD-1 is Pembrolizumab or RMP1-

[0115] 14.

[0116] Most preferably, the inhibitor of PD-1 is Pembrolizumab. In another preferred embodiment, the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, Cosibelimab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB- 2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR).

[0117] In still another preferred embodiment , the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR- 1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR).

[0118] In another more preferred embodiment, the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, Sugemalimab and Cosibelimab.

[0119] In still another more preferred embodiment, the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab.

[0120] In another even more preferred embodiment, the inhibitor of PD-1 is Cosibelimab. Pharmaceutical combinations

[0121] As outlined above, in a first aspect, the present invention provides a pharmaceutical combination comprising: a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14-

[0122] Xaa15-Pro16-)

[0123] (I), in which

[0124] Xaa3is Ala; Tyr; or Tyr(Me);

[0125] Xaa6is Ala or Acc;

[0126] Xaa7isDPro;DTyr; orDTyr(Me);

[0127] Xaa8is Dab; or Orn(iPr);

[0128] Xaa14is Lys; or Lys(iPr);

[0129] Xaa15isDPro; orDLys(iPr); wherein

[0130] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0131] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0132] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0133] Dab is (2S)-2,4-diaminobutyric acid;

[0134] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0135] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0136] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11;

[0137] (b) an inhibitor of PD-1; and

[0138] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers. A pharmaceutical combination according to the invention is for example a combined preparation or a pharmaceutical composition, for simultaneous, separate or sequential use.

[0139] The term "combined preparation" as used herein defines especially a "kit of parts" in the sense that said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 can be dosed independently, either in separate form e.g. as separate tablets or by use of different fixed combinations with distinguished amounts of the active ingredients. The ratio of the amount of backbone cyclized peptidic CXCR4 inhibitor to the amount of inhibitor of PD-1 to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of a single patient, which needs can be different due to age, sex, body weight, etc. of a patient. The individual parts of the combined preparation (kit of parts) can be administered simultaneously or sequentially, i.e. chronologically staggered, e.g. at different time points and with equal or different time intervals for any part of the kit of parts.

[0140] The term "pharmaceutical composition" refers to a fixed-dose combination (FDC) that includes the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1 combined in a single dosage form, having a predetermined combination of respective dosages. In one embodiment, the pharmaceutical combination of the invention is a pharmaceutical composition and includes other medicinal or pharmaceutical agents, e.g., one or more pharmaceutically acceptable diluents, excipients or carriers.

[0141] The pharmaceutical combination further may be used as add-on therapy. As used herein, "add-on" or "add-on therapy" means an assemblage of reagents for use in therapy, the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time. For example, adding inhibitor of PD-1 therapy to a patient already receiving backbone cyclized peptidic CXCR4 inhibitor therapy and vice versa. In a preferred embodiment, the pharmaceutical combination according to the invention is a combined preparation.

[0142] The amount of the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1 to be administered will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific backbone cyclized peptidic CXCR4 inhibitor being administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated.

[0143] In one embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, wherein said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 are present in a therapeutically effective amount.

[0144] The expression "effective amount" or "therapeutically effective amount" as used herein refers to an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention: (i) increase of objective response rate (ORR); (ii) inhibition or arrest of tumor growth, including, reducing the rate of tumor growth or causing complete growth arrest; (iii) reduction in the number of tumor cells; (iv) reduction in tumor size; (v) reduction in tumor number; (vi) inhibition of metastasis (i.e. reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs; (vii) enhancement of antitumor immune response, which may, but does not have to, result in the regression or elimination of the tumor; (viii) relief, to some extent, of one or more symptoms associated with cancer; (ix) increase in progression-free survival (PFS) and / or; overall survival (OS) of the subject receiving the combination.

[0145] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. In some embodiments, a therapeutically effective amount of the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1 may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow down to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) delay occurrence and / or recurrence of a tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and / or delay one or more of symptoms of cancer.

[0146] The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one ordinary skilled in the art.

[0147] In a preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, wherein said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 produce an additive therapeutic effect i.e. wherein said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 are present in an amount producing an additive therapeutic effect.

[0148] As used herein, the term "additive" means that the effect achieved with the pharmaceutical combinations of this invention is approximately the sum of the effects that result from using the agents, namely the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1, as a monotherapy.

[0149] In a further preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, wherein said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 produce a synergistic therapeutic effect, i.e. wherein said backbone cyclized peptidic CXCR4 inhibitor and said inhibitor of PD-1 are present in an amount producing a synergistic therapeutic effect. As used herein, the term "synergistic" means that the effect achieved with the pharmaceutical combinations of this invention is greater than the sum of the effects that result from using the agents, namely the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1, as a monotherapy.

[0150] In one embodiment, the invention provides a pharmaceutical combination comprising an inhibitor of PD-1 and a backbone cyclized peptidic CXCR4 inhibitor, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is is from about 0.3 to about 3500 mg, or from about 0.3 to about 2500 mg, or from about 0.3 to about 1600 mg, or from about 0.3 to about 1200 mg, or from about 0.3 to about 800 mg, or from about 1 to about 500 mg, preferably from about 0.3 to about 1200 mg, from about 0.3 to about 800 mg, from about 1 to about 500 mg, or from about 1 to about 400 mg. Where said backbone cyclized peptidic CXCR4 inhibitor is in the form of a pharmaceutically acceptable salt, the amounts of backbone cyclized peptidic CXCR4 inhibitor provided herein are calculated on the basis of the respective free base.

[0151] In one embodiment, the invention provides a pharmaceutical combination comprising an inhibitor of PD-1 and a backbone cyclized peptidic CXCR4 inhibitor, wherein the amount of said inhibitor of PD-1 in the combination is from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 10 to about 300 mg, or from about 100 to about 250 mg, or preferably about 800 mg, or about 200 mg.

[0152] In one embodiment, the invention provides a pharmaceutical combination comprising an inhibitor of PD-1 and a backbone cyclized peptidic CXCR4 inhibitor, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is from about 0.3 to about 3500 mg, or from about 0.3 to about 2500 mg, or from about 0.3 to about 1600 mg, or from about 0.3 to about 1200 mg, or from about 0.3 to about 800 mg, or from about 1 to about 500 mg, preferably from about 0.3 to about 1200 mg, from about 0.3 to about 800 mg, from about 1 to about 500 mg, or from about 1 to about 400 mg, and wherein the amount of said inhibitor of PD-1 in the combination is from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 10 to about 300 mg, or from about 100 to about 250 mg, or preferably 800 mg, or about 200 mg.

[0153] In one embodiment, there is provided a pharmaceutical combination comprising:

[0154] (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14-

[0155] Xaa15-Pro16-)

[0156] (I), in which

[0157] Xaa3is Ala; Tyr; or Tyr(Me);

[0158] Xaa6is Ala or Acc;

[0159] Xaa7isDPro;DTyr; orDTyr(Me);

[0160] Xaa8is Dab; or Orn(iPr);

[0161] Xaa14is Lys; or Lys(iPr);

[0162] Xaa15isDPro; orDLys(iPr); wherein

[0163] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0164] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0165] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0166] Dab is (2S)-2,4-diaminobutyric acid;

[0167] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0168] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0169] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11;

[0170] (b) an inhibitor of PD-1; and

[0171] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab and Retifanlimab, and more preferably wherein the inhibitor of PD-1 is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD-1 is Pembrolizumab.

[0172] In another embodiment, there is provided a pharmaceutical combination comprising: (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0173] (I), in which

[0174] Xaa3is Ala; Tyr; or Tyr(Me);

[0175] Xaa6is Ala or Acc;

[0176] Xaa7isDPro;DTyr; orDTyr(Me);

[0177] Xaa8is Dab; or Orn(iPr);

[0178] Xaa14is Lys; or Lys(iPr);

[0179] Xaa15isDPro; orDLys(iPr); wherein

[0180] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0181] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0182] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0183] Dab is (2S)-2,4-diaminobutyric acid;

[0184] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0185] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0186] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11;

[0187] (b) an inhibitor of PD-1; and

[0188] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab, and more preferably wherein the inhibitor of PD-1 is Atezolizumab.

[0189] In one embodiment, there is provided a pharmaceutical combination comprising:

[0190] (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0191] (la), in which

[0192] Xaa3is Ala; Tyr; or Tyr(Me);

[0193] Xaa7isDPro;DTyr; orDTyr(Me);

[0194] Xaa8is Dab; or Orn(iPr);

[0195] Xaa14is Lys; or Lys(iPr);

[0196] Xaa15isDPro; orDLys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0197] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid; Dab is (2S)-2,4-diaminobutyric acid;

[0198] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0199] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0200] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and wherein the compound of formula la has a disulfide bond between Cys4and Cys11;

[0201] (b) an inhibitor of PD-1; and

[0202] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab and Retifanlimab, and more preferably wherein the inhibitor of PD-1 is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD-1 is Pembrolizumab.

[0203] In another embodiment, there is provided a pharmaceutical combination comprising:

[0204] (a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0205] (la), in which

[0206] Xaa3is Ala; Tyr; or Tyr(Me);

[0207] Xaa7isDPro;DTyr; orDTyr(Me);

[0208] Xaa8is Dab; or Orn(iPr);

[0209] Xaa14is Lys; or Lys(iPr);

[0210] Xaa15isDPro; orDLys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0211] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0212] Dab is (2S)-2,4-diaminobutyric acid;

[0213] Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0214] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0215] DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and wherein the compound of formula la has a disulfide bond between Cys4and Cys11;

[0216] (b) an inhibitor of PD-1; and

[0217] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab, and more preferably wherein the inhibitor of PD-1 is Atezolizumab .

[0218] In one embodiment, there is provided a pharmaceutical combination comprising:

[0219] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0220] (b) an inhibitor of PD-1; and

[0221] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab and Retifanlimab, and more preferably wherein the inhibitor of PD-1 is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD-1 is

[0222] Pembrolizumab.

[0223] In another embodiment there is provided a pharmaceutical combination comprising:

[0224] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0225] (b) an inhibitor of PD-1; and

[0226] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(l\ / le)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab, and more preferably wherein the inhibitor of PD-1 is Atezolizumab.

[0227] In one embodiment, there is provided a pharmaceutical combination comprising:

[0228] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0229] (b) an inhibitor of PD-1; and

[0230] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab and Retifanlimab, more preferably wherein the inhibitor of PD-1 is Pembrolizumab or RMP1-14 and even more preferably wherein the inhibitor of PD-1 is Pembrolizumab.

[0231] In still another embodiment there is provided a pharmaceutical combination comprising:

[0232] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0233] (b) an inhibitor of PD-1; and

[0234] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein the backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, Cosibelimab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR- 1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-L1 / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, Sugemalimab, and Cosibelimab, and more preferably wherein the inhibitor of PD-1 is Cosibelimab. In one embodiment, there is provided a pharmaceutical combination comprising:

[0235] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0236] (b) an inhibitor of PD-1; and

[0237] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP- 224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab and Retifanlimab, and more preferably wherein the inhibitor of PD-1 is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD-1 is Pembrolizumab.

[0238] In another embodiment, there is provided a pharmaceutical combination comprising:

[0239] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0240] (b) an inhibitor of PD-1; and

[0241] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable salts thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824;

[0242] PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab, and more preferably wherein the inhibitor of PD-1 is Atezolizumab.

[0243] In one embodiment, there is provided a pharmaceutical combination comprising:

[0244] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0245] (b) an inhibitor of PD-1; and

[0246] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable sals thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP- 224, AMP-514, Acrixolimab and Sugemalimab, preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab and Retifanlimab, and more preferably wherein the inhibitor of PD-1 is is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD-1 is Pembrolizumab.

[0247] In another embodiment, there is provided a pharmaceutical combination comprising: (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0248] (b) an inhibitor of PD-1; and

[0249] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable sals thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824;

[0250] PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, and Sugemalimab, and more preferably wherein the inhibitor of PD-1 is Atezolizumab.

[0251] In still anther embodiment, there is provided a pharmaceutical combination comprising:

[0252] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0253] (b) an inhibitor of PD-1; and

[0254] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable sals thereof, and wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, Cosibelimab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR- 1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824;

[0255] PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR), preferably selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, Sugemalimab, and Cosibelimab, and more preferably wherein the inhibitor of PD-1 is Cosibelimab.

[0256] In a particular preferred embodiment there is provided a pharmaceutical combination comprising:

[0257] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0258] (b) an inhibitor of PD-1; and

[0259] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable sals thereof, and said inhibitor of PD- 1 is is RMP1-14 or Pembrolizumab, and even more preferably wherein the inhibitor of PD- 1 is Pembrolizumab.

[0260] In another particular preferred embodiment there is provided a pharmaceutical combination comprising:

[0261] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0262] (b) an inhibitor of PD-1; and

[0263] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable sals thereof, and said inhibitor of PD-1 is Atezolizumab. In still another particular preferred embodiment there is provided a pharmaceutical combination comprising:

[0264] (a) a backbone cyclized peptidic CXCR4 inhibitor;

[0265] (b) an inhibitor of PD-1; and

[0266] (c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers, wherein said backbone cyclized peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable sals thereof, and said inhibitor of PD-1 is Cosibelimab.

[0267] Formulations and modes of administration

[0268] The formulation and route of administration chosen may be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.

[0269] The pharmaceutical compositions or combined preparations of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal, transmucosal, transdermal, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as e.g. an inhalant via pulmonary adminstration, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0270] One mode for administration is administration by injection, preferably intravenous administration by injection. The forms in which the backbone cyclized peptidic CXCR4 inhibitor and / or the inhibitor of PD-1, may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, peanut oil, or castor oil, or chemical modified derivatives of the aforesaid oils thereof, as for example Cremophor EL, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline may also conventionally be used for injection, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer are used as aqueous solutions. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0271] Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously ste rile-fi Itered solution thereof. In certain embodiments, for parenteral administration, sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.3 to 3500 mg of the backbone cyclized peptidic CXCR4 inhibitor and / or e.g., 1 to 500 mg of the inhibitor of PD-1. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0272] A pharmaceutical combination according to the invention is, preferably, suitable for injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, more preferably suitable for intravenous injection, and usually comprises a therapeutically effective amount of the active ingredients and one or more suitable pharmaceutically acceptable diluent, excipient or carrier. Thus in a preferred embodiment the pharmaceutical combination is administered to the subject intravenously, i.e. the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1, respectively, are administered to the subject intravenously.

[0273] Pharmaceutical compositions or combined preparations in separate form comprising a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1 may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions or combined preparations in separate form may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active ingredient into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

[0274] For topical administration the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

[0275] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

[0276] For oral administration, the compounds can be readily formulated by combining the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 with pharmaceutically acceptable carriers well known in the art. Such carriers enable the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, e. g. lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose; granulating agents; and binding agents. If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques. For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

[0277] For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.

[0278] For administration by inhalation, the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compounds of the invention and a suitable powder base such as lactose or starch.

[0279] The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.

[0280] In addition to the formulations described previously, the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. For the manufacture of such depot preparations the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts. In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the backbone cyclized peptidic CXCR4 inhibitor and / or inhibitor of PD-1 may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

[0281] Using the combinations of the invention to treat cancer

[0282] According to a second aspect the present invention provides a pharmaceutical combination as described herein, for use as a medicament.

[0283] According to a third aspect the present invention provides a pharmaceutical combination as described herein, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject.

[0284] Also provided is the use of a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer in a subject.

[0285] Also provided is the use of a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of cancer in a subject, more preferably for the treatment of cancer in a subject. Also provided is a method for the prevention, delay of progression or treatment of cancer in a subject, preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein.

[0286] As used herein, the term "prevention" / "preventing" e.g. preventive treatments comprise prophylactic treatments. In preventive applications, the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer.

[0287] As used herein, the term "delay of progression" / "delaying of progression" means increasing the time to appearance of a symptom of a cancer or a mark associated with a cancer or slowing the increase in severity of a symptom of a cancer. Further, "delay of progression" as used herein includes reversing or inhibition of disease progression. "Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[0288] The terms "treatment" / "treating" as used herein includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof; and / or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. In therapeutic applications, the pharmaceutical combination is usually administered to a subject such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0289] In the case wherein the subject's condition does not improve, the pharmaceutical combination of the invention may be administered chronically, which is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.

[0290] In the case wherein the subject's status does improve, the pharmaceutical combination may be administered continuously; alternatively, the dose of drugs being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").

[0291] Once improvement of the patient's condition has occurred, a maintenance dose of the pharmaceutical combination of the invention is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease is retained.

[0292] In one embodiment of the invention, there is provided a pharmaceutical combination according to the invention, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a solid tumor in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, breast cancer and colon cancer, even more preferably wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer, in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC) , in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, even more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC), wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) comprises liver metastasis or is more particular refractory metastatic pancreatic ductal adenocarcinoma (PDAC).

[0293] In another embodiment of the invention, there is provided a pharmaceutical combination according to the invention, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, preferably for use in a method for the delay of progression or treatment of a solid tumor in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, breast cancer and colon cancer, even more preferably wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer, in particular wherein the solid tumor is breast cancer, preferably advanced breast cancer, locally advanced breast cancer , metastatic breast cancer, relapsed metastatic breast cancer and / or triple negative breast cancer, even more preferably, triple negative breast cancer.

[0294] Also provided is the use of a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of a solid tumor in a subject, more preferably for the manufacture of a medicament for the treatment of cancer, wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, breast cancer and colon cancer, even more preferably wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer, in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC) , in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, even more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC), wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) comprises liver metastasis or is more particular refractory metastatic pancreatic ductal adenocarcinoma (PDAC), or wherein the solid tumor is breast cancer, preferably advanced breast cancer, locally advanced breast cancer, metastatic breast cancer, relapsed metastatic breast cancer and / or triple negative breast cancer, even more preferably, triple negative breast cancer.

[0295] Also provided is the use of a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of a solid tumor in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, breast cancer and colon cancer, even more preferably wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer, in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC) , in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, even more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC), wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) comprises liver metastasis or is more particular refractory metastatic pancreatic ductal adenocarcinoma (PDAC), or wherein the solid tumor is breast cancer, preferably advanced breast cancer, locally advanced breast cancer, metastatic breast cancer, relapsed metastatic breast cancer and / or triple negative breast cancer, even more preferably, triple negative breast cancer.

[0296] Also provided is a method for the prevention, delay of progression or treatment of cancer in a subject, preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of a solid tumor in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is a solid tumor selected from the group consisting of pancreatic cancer, breast cancer and colon cancer, even more preferably wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer, in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC) , in particular wherein the solid tumor is pancreatic cancer, preferably metastatic pancreatic cancer, even more preferably pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC), wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) comprises liver metastasis or is more particular refractory metastatic pancreatic ductal adenocarcinoma (PDAC), or wherein the solid tumor is breast cancer, preferably advanced breast cancer, locally advanced breast cancer, metastatic breast cancer, relapsed metastatic breast cancer and / or triple negative breast cancer, even more preferably, triple negative breast cancer.

[0297] In one embodiment the subject who has cancer is (i) refractory to at least one chemotherapy treatment e.g. to Standard of Care (SOC), or (ii) is in relapse after treatment with chemotherapy e.g. after Standard of Care (SOC), or a combination thereof.

[0298] In some embodiments, the subject is refractory to at least two, at least three, or at least four anti-cancer therapy (including, for example, standard or experimental chemotherapies such as Standard of Care (SOC)).

[0299] A subject who is refractory to at least one anti-cancer therapy and / or is in relapse after treatment with at least one anti-cancer therapy, as described above, may have undergone one or more prior therapies. In some embodiments, such subjects have undergone one, two, three, or four, or five, or at least one, at least two, at least three, at least four, or at least five, or between one and ten, between one and nine, between one and eight, between one and seven, between one and six, between one and five, or between one and four, or between one and three, between four and six or between seven and ten anticancer therapies prior to treatment using the methods described herein (e.g., prior to the administration of a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1).

[0300] Dosing regimen

[0301] The dosing regimen of the backbone cyclized peptidic CXCR4 inhibitor in combination with an inhibitor of PD-1, in the methods provided herein may vary depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosing regimen can be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy. Further refinement of the doses appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosing information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate doses can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.

[0302] The amount, e.g. the therapeutically effective amount of the backbone cyclized peptidic CXCR4 inhibitor may be provided in a single dose or multiple doses to achieve the desired treatment endpoint.

[0303] The frequency of dosing will depend on the pharmacokinetic parameters of the compound administered, the route of administration, and the particular disease treated. The dose and frequency of dosing may also depend on pharmacokinetic and pharmacodynamic, as well as toxicity and therapeutic efficiency data. For example, pharmacokinetic and pharmacodynamic information about a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1, used in the methods provided herein, a therapeutically effective dose can be estimated initially from biochemical and / or cellbased assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.

[0304] Toxicity and therapeutic efficacy of a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the "therapeutic index", which typically is expressed as the ratio LD50 / ED50. Compounds that exhibit large therapeutic indices, i.e. the toxic doses are substantially higher than the effective doses, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The doses of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.

[0305] A backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, may be administered to the subject (e.g. a human) within minutes or hours. In some embodiments, a backbone cyclized peptidic CXCR4 inhibitor may be administered to the subject (e.g. a human) over about 1 to about 240 minutes, over about 1 to about 180 minutes, or over about 5 to about 150 minutes, or over about 5 to about 120 minutes, or over about 1 to 60 minutes, or over about 1 to 10 minutes, or over about 5 minutes, preferably over about 120 minutes, and / or an inhibitor of PD-1 may be administered to the subject (e.g. a human), over 1 to about 120 minutes, or over about 1 to 90 minutes, or over about 10 to 60 minutes, preferably over about 30 minutes.

[0306] An exemplary treatment regime entails administration once daily, twice daily, three times daily, every day, every second day, every third day, every fourth day, every fifth day, every sixth day, twice per week, once per week. The combination of the invention is usually administered on multiple occasions. Intervals between single dosages can be, for example, less than a day, a day, two days, three days, four days, five days, six days or a week. The combination of the invention may be given as a continous uninterrupted treatment. The combination of the invention may also be given in a regime in which the subject receives cycles of treatment (administration cycles) interrupted by a drug holiday or period of nontreatment. Thus, the combination of the invention may be administered according to the selected intervals above for a continuous period of one week or a part thereof, for two weeks, for three weeks for four weeks, for five weeks or for six weeks and then stopped for a period of one week, or a part thereof, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks or for even more weeks. The combination of the treatment interval and the non-treatment interval is called a cycle. The cycle may be repeated one or more times. Two or more different cycles may be used in combination for repeating the treatment one or more times. The administration of the pharmaceutical combination according to the invention may start with a run-in cycle.

[0307] Exemplary doses of the backbone cyclized peptidic CXCR4 inhibitor for a subject, preferably for a human subject, may be from about 0.1 to about 1200 mg / kg, or from about 0.1 to about 700 mg / kg, or from about 0.1 to about 500 mg / kg, or from about 0.1 to about 250 mg kg; or from about 0.1 to about 200 mg / kg, or from about 0.1 to about 150 mg / kg, or from about 0.1 to about 100 mg / kg, or from about 0.1 to about 75 mg / kg, or from about 0.1 to about 50 mg / kg, or from about 0.3 to about 50 mg / kg, or from about 1 to about 50 mg / kg, or preferably from about 7.5 to about 16 mg / kg, or from about 5.5 to about 11 mg / kg.

[0308] Exemplary doses of inhibitor of PD-1, for a subject, preferably for a human subject, may be from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 10 to about 300 mg, or from about 100 to about 250 mg, or preferably about 800 mg, or about 200 mg.

[0309] In one embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination from about 0.1 to about 700 mg / kg, or from about 0.1 to about 500 mg / kg, or from about 0.1 to about 250 mg kg; or from about 0.1 to about 200 mg / kg, or from about 0.1 to about 150 mg / kg, or from about 0.1 to about 100 mg / kg, or from about 0.1 to about 75 mg / kg, or from about 0.1 to about 50 mg / kg, or from about 0.3 to about 50 mg / kg, or from about 1 to about 50 mg / kg, or preferably from about 5.5 to about 11 mg / kg, and wherein the amount of said inhibitor of PD-1 in the combination is from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 10 to about 300 mg, or from about 100 to about 250 mg, or preferably about 200 mg.

[0310] In another embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination from about 0.1 to about 700 mg / kg, or from about 0.1 to about 500 mg / kg, or from about 0.1 to about 250 mg kg; or from about 0.1 to about 200 mg / kg, or from about 0.1 to about 150 mg / kg, or from about 0.1 to about 100 mg / kg, or from about 0.1 to about 75 mg / kg, or from about 0.1 to about 50 mg / kg, or from about 0.3 to about 50 mg / kg, or from about 1 to about 50 mg / kg, or preferably from about 7.5 to about 16 mg / kg, and wherein the amount of said inhibitor of PD-1 in the combination is from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 10 to about 300 mg, or from about 100 to about 250 mg, or preferably about 800 mg.

[0311] In a preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is from about 5.5 to about 11 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 200 mg.

[0312] In another preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is from about 7.5 to about 16 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 800 mg. In a more preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 5.5 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 200 mg.

[0313] In another more preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 7.5 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 800 mg.

[0314] In a further preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 8.25 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 200 mg.

[0315] In another further preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 11 mg / kg; and wherein the amount of said inhibitor of PD-1 in the combination is 800 mg.

[0316] In a further preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 11 mg / kg; and / or wherein the amount of said inhibitor of PD-1 in the combination is 200 mg.

[0317] In another further preferred embodiment, the invention provides a pharmaceutical combination comprising a backbone cyclized peptidic CXCR4 inhibitor and inhibitor of PD-1, wherein the amount of said backbone cyclized peptidic CXCR4 inhibitor in the combination is about 16 mg / kg; and / or wherein the amount of said inhibitor of PD-1 in the combination is 800 mg.

[0318] In one embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1, 8 and 15 of a 21-day cycle administration.

[0319] In another embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1 and 8 of a 14-day cycle administration.

[0320] In one embodiment the inhibitor of PD-1 is administered to the subject on day 1 of a 21- day cycle administration.

[0321] In one embodiment the inhibitor of PD-1 is administered to the subject on day 1 of a 14- day cycle administration.

[0322] In a preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1, 8 and 15 of a 21-day cycle administration and the inhibitor of PD-1 is administered to the subject on day 1 of the 21-day cycle administration.

[0323] In another preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1 and 8 of a 14-day cycle administration and the inhibitor of PD-1 is administered to the subject on day 1 of the 14-day cycle administration.

[0324] In one embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 5.5 to about 11 mg / kg for about 2 hours. In another embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 7.5 to about 16 mg / kg for about 2 hours.

[0325] In one embodiment the inhibitor of PD-1 is administered to the subject at a dose of about 200 mg for about 30 minutes.

[0326] In another embodiment the inhibitor of PD-1 is administered to the subject at a dose of about 800 mg for about 60 minutes.

[0327] In a preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 5.5 to about 11 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 200 mg for about 30 minutes.

[0328] In another preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 7.5 to about 16 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 800 mg for about 60 minutes.

[0329] In a more preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about

[0330] 5.5 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 200 mg for about 30 minutes.

[0331] In another more preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about

[0332] 7.5 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 800 mg for about 60 minutes. In a further preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 8.25 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 200 mg for about 30 minutes.

[0333] In another further preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 11 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 800 mg for about 60 minutes.

[0334] In a further preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 11 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 200 mg for about 30 minutes.

[0335] In another further preferred embodiment the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 16 mg / kg for about 2 hours and the inhibitor of PD-1 is administered to the subject at a dose of 800 mg for about 60 minutes.

[0336] Additional combination therapies

[0337] Provided herein are also methods of treatment in which the backbone cyclized peptidic CXCR4 inhibitor in combination with an inhibitor of PD-1, is administered to a subject (e.g. a human) in additional combination with one or more additional therapies. Thus, in some embodiments, the method for treating cancer in a subject (e.g. a human), comprises administering to the subject a therapeutically effective amount of a backbone cyclized peptidic CXCR4 inhibitor and an inhibitor of PD-1, together with one or more additional therapies, which can be useful for treating the cancer. The one or more additional therapies may involve the administration of one or more therapeutic agents, preferably therapeutic anti-cancer agents. Kit of parts

[0338] A pharmaceutical combination e.g. a combined preparation (including, for example, formulations and unit dosages) comprising the backbone cyclized peptidic CXCR4 inhibitor and the inhibitor of PD-1, can be prepared and placed in an appropriate container, and labeled for treatment of an indicated condition. Kits of parts also are contemplated. For example, a kit can comprise unit dosage forms of the backbone cyclized peptidic CXCR4 inhibitor and of the inhibitor of PD-1, and a package insert containing instructions for use of the composition in treatment of a medical condition. In some embodiments, the kit comprises a unit dosage form of a backbone cyclized peptidic CXCR4 inhibitor and / or an inhibitor of PD-1. The instructions for use in the kit may be for treating a cancer.

[0339] Thus in a fourth aspect the present invention provides a kit of parts comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)

[0340] (I), in which

[0341] Xaa3is Ala; Tyr; or Tyr(Me);

[0342] Xaa6is Ala or Acc;

[0343] Xaa7isDPro;DTyr; orDTyr(Me);

[0344] Xaa8is Dab; or Orn(iPr);

[0345] Xaa14is Lys; or Lys(iPr);

[0346] Xaa15isDPro; orDLys(iPr); wherein

[0347] Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0348] DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;

[0349] Acc is 1-aminocyclopropane-l-carboxylic acid;

[0350] Dab is (2S)-2,4-diaminobutyric acid; Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;

[0351] Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;

[0352] DLys(iPr) is (2 / ?)-l\T-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11; the second container comprises at least one dose of a medicament comprising an inhibitor of PD-1, and the package insert comprises optionally instructions for treating a subject for cancer using the medicaments. The cancerthe instructions relate to are usually the cancers as described supra.

[0353] Examples

[0354] The present examples are intended to illustrate the present invention without restricting it.

[0355] Peptide Synthesis

[0356] The peptides according to formula (I) can be prepared according to W02008 / 104090, WO2012 / 168336, as well as WO2013 / 182240, or prepared analoguously.

[0357] Example 1

[0358] For the orthotopic model PDAC cells (2 x 106) of the KPC cell line were injected subcutaneously into the flanks of syngeneic female C57BI / 6 mice. After 1 to 2 weeks, the subcutaneous tumors were harvested and cut into approximately 2 mm3pieces. The orthotopic tumor inoculation was performed on female C57BI / 6 mice at ages 6-8 weeks, on day 0 as described previously (PMID: 32675194). Tumors were then treated with Balixafortide (CXCR4 inhibitor [CXCR4i BLX]) and RMP1-14 (Bio X Cell, Lebanon, NH, USA) (inhibitor of PD-1 [a-PD-1]). Tumor volume, represented as mm3, on the y axis was calculated using three dimensional (3D) US measurements within the transverse and sagittal planes.

[0359] Results

[0360] Treatment with the combination of Balixafortide and RMP1-14 resulted in strong tumor growth inhibition compared to the treatment with Balixafortide alone (Figure 1). Therefore, the combination of the CXCR4 inhibitor Balixafortide and the inhibitor of PD-1 RMP1-14, improved the therapeutic effect compared to the CXCR4 inhibitor Balixafortide alone. Example 2

[0361] LIST OF ABBREVIATIONS

[0362] AE Adverse Event

[0363] ALT Alanine Aminotransferase

[0364] ALC Absolute Lymphocyte Count

[0365] AST Aspartate Aminotransferase

[0366] BUN Blood Urea Nitrogen

[0367] CBC Complete Blood Count

[0368] CMP Comprehensive Metabolic Panel

[0369] CR Complete Response

[0370] CT Computed Tomography

[0371] CTCAE Common Terminology Criteria for Adverse Events

[0372] DILI Drug Induced Liver Injury

[0373] DLT Dose Limiting Toxicity

[0374] DSMC Data and Safety Monitoring Committee

[0375] DSMP Data and Safety Monitoring Plan

[0376] ECOG Eastern Cooperative Oncology Group

[0377] H&P History & Physical Exam

[0378] HRPP Human Research Protections Program

[0379] IV (or iv) Intravenously

[0380] MTD Maximum Tolerated Dose

[0381] NCI National Cancer Institute

[0382] ORR Overall Response Rate

[0383] OS Overall Survival

[0384] PBMCs Peripheral Blood Mononuclear Cells

[0385] PD Progressive Disease

[0386] PFS Progression Free Survival p.o. per os / by mouth / orally

[0387] PR Partial Response

[0388] SAE Serious Adverse Event

[0389] SD Stable Disease

[0390] SGOT Serum Glutamic Oxaloacetic Transaminase

[0391] SPGT Serum Glutamic Pyruvic Transaminase

[0392] WBC White Blood Cells BACKGROUND AND RATIONALE

[0393] Disease Background

[0394] Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease often requiring a multimodal treatment approach. PDAC is projected to be the second leading cause of cancer-related death by 2030 in the United States, surpassing prostate, breast, and colorectal cancerl. More than 50% of patients present with locally advanced or metastatic disease at the time of diagnosis 2-3. Surgical resection is the only curative option, yet the rate of recurrence is 80%, where systemic therapy remains the only treatment option. As a result, the 5-year survival rate is dismal at 11% and novel therapeutic approaches are desperately needed to address the treatment refractory nature of PDAC.

[0395] Rationale

[0396] This trial is testing Balixafortide (POL6326, BLX), a more potent, best in class, highly selective synthetic peptide CXCR4 inhibitor (CXCR4i) administered IV weekly with anti-PDl therapy. It has been extensively studied in phase l-lll trials in multiple tumor types, particularly breast cancer which has shown to be safe both alone and in combination with chemotherapyl2-13. Balixafortide has the highest relative exposure to all other CXCR4 candidates. Additionally, Balixafortide is more potent than small molecular inhibitors, like AMD3100 (Plerixafor), with high selectivity, without any in-vitro off target effects and has high receptor occupancy and affinity compared to AMD3100.

[0397] The starting dose of Balixafortide is 5.5 mg / kg IV weekly. This dose was found to be safe with an acceptable tolerability profile in a phase 1 dose escalation trial of Balixafortide plus Eribulin for HER2-negative, heavily pre-treated, metastatic breast cancer. Furthermore, objective response was higher compared to prior published data of eribulin alone. Trial investigators decided to explore further antitumor activity at the 5.5 mg / kg dose with the expansion cohort.

[0398] Study Hypothesis

[0399] For the current trial, study investigators hypothesize the addition of CXCR4i, Balixafortide, to anti-PDl antibody, Pembrolizumab will be a safe and well-tolerated regimen with significant potential of efficacy in future combinatorial phase II and registration clinical trials. This phase I trial is to evaluate the safety of combination Pembrolizumab and Balixafortide in patients with metastatic PDAC who progressed after standard of care (SOC) chemotherapy.

[0400] The dosing scheme is listed below in Table 1.

[0401] Table 1: Dosing scheme

[0402] Dosing of Pembrolizumab will remain constant (200 mg IV every 3 weeks). Balixafortide will be administered as a weekly intravenous infusion. Both agents will be continued until disease progression or unacceptable toxicity for up to 2 years.

[0403] We will evaluate serial tissue biopsies for exploratory endpoints utilizing our novel multiplex immunohistochemistry (IHC).

[0404] Correlative quantitative analysis of multiplex immunohistochemistry (mIHC) using a panel of 40 biomarkers will show significantly decreased CXCR4 expression and decreased immunosuppressive granulocytes and TAMs in exceptional responders.

[0405] STUDY OBJECTIVES AND ENDPOINTS

[0406] Primary Objectives To identify the MTD and RP2D of Balixafortide in combination with Pembrolizumab in patients with metastatic treatment refractory PDAC with progressive disease after SOC chemotherapy. Secondary Objectives

[0407] To assess the safety and toxicity profile of Balixafortide in combination with Pembrolizumab in patients with metastatic treatment refractory PDAC with progressive disease after SOC chemotherapy.

[0408] To evaluate the anti-tumor activity of combination Balixafortide and Pembrolizumab in patients with metastatic treatment refractory PDAC progressed on SOC chemotherapy.

[0409] Exploratory Objectives

[0410] To assess intratumoral and peripheral T-cell receptor clonality in pre- vs post-treatment biopsy specimens.

[0411] To assess changes of tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and T-reg cells with Balixafortide and Pembrolizumab following treatment initiation.

[0412] To assess activity of pancreatic stellate cells via a-Smooth muscle actin and fibroblast activate protein (FAP) IHC with Balixafortide and Pembrolizumab following treatment initiation.

[0413] To assess expression of PD-L1 / PD-1 and CD68 / CD8 ratio.

[0414] Endpoints

[0415] Primary Endpoints

[0416] MTD and RP2D

[0417] The occurrence of DLTs tabulated to determine MTD over a DLT period of 12 weeks.

[0418] Secondary Endpoints

[0419] Safety

[0420] The occurrence of treatment-related AEs as defined by CTCAE v5.0

[0421] Anti-tumor activity

[0422] ORR: Radiologic tumor responses (CR, PR) as determined by RECIST 1.1 criteria.

[0423] PFS: The length of time from the first dose of study treatment to disease progression according to RECIST 1.1 criteria

[0424] OS: The length of time from first dose of study treatment to death of any cause. Exploratory Endpoints

[0425] Identification and quantification of intratumoral and peripheral blood TCR clonality in pre- and post-treatment specimens using flow cytometry and multiplex IHC.

[0426] Identification and quantification of TAMs, MDSCs, and T-reg cells in pre- and posttreatment specimens using multiplex IHC.

[0427] Pancreatic stellate cell activity via identification and quantification of a-Smooth muscle actin and FAP in pre- and post-treatment specimens by multiplex IHC.

[0428] PD-L1 / PD-1 expression and CD68 / CD8 ratio in pre- and post-treatment specimens by multiplex IHC.

[0429] STUDY DESIGN

[0430] This is a single-center, open-label, phase 1 dose escalation and safety confirmation trial to evaluate the safety and tolerability of Balixafortide and Pembrolizumab in patients with metastatic PDAC who progressed after SOC chemotherapy.

[0431] In the dose escalation cohort, a maximum of 12 patients will be enrolled exploring three dose levels of Balixafortide to identify the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The MTD is defined as the dose level such that the probability of DLT at the MTD is 0 = 0.3. A dose limiting toxicity (DLT) is defined below based on NCI CTCAE v5.0 with a possible, probably, or likely causal relationship to administration of study drug(s), Balixafortide or Pembrolizumab. The following toxicities will be considered dose limiting in the event they are treatment-related and occur in the first 12 weeks of study treatment.

[0432] • Any Grade 4 non-hematological toxicity

[0433] • Any Grade 3 non-hematological toxicity except Grade 3 fever or fatigue of < 72- hour duration, as well as suboptimally treated Grade 3 or 4 diarrhea, nausea, or vomiting (in investigator's assessment)

[0434] • Grade 3 or 4 hematologic toxicity of > 7-day duration

[0435] • Grade 3 or 4 neutropenia complicated by fever (> 100.4°F) or documented infection

[0436] • Grade 4 thrombocytopenia complicated by bleeding Any AE that is not a DLT per this definition, but is designated as a DLT by the

[0437] Data and Safety Monitoring Committee (DSMC)

[0438] A time to event escalation with overdose control (TITE-EWOC) algorithm will be utilized. The first patient will be enrolled at the lowest dose level of Balixafortide (5.5 mg / kg). The dose for each subsequent patient will be determined so that, based on all available data, the probability that it exceeds the MTD is equal to a prespecified value a. In this trial, we start at a = 0.3 and increase a in small increments of 0.05 until a = 0.5, this value being a compromise between the therapeutic aspect of the agent and its toxic side effects. No dose skipping will be permitted. The trial will be terminated if the posterior probability that the probability that DLT at dose level 1 exceeds 0 is 0.8 or more.

[0439] Once we determine the MTD, an additional 12 patients will be enrolled for additional experience with safety and efficacy.

[0440] Dosing of Pembrolizumab will remain constant (200 mg IV). Pembrolizumab will be given IV every 3 weeks and Balixafortide will be given IV weekly at the assigned dose (see Section 9), until disease progression or unacceptable toxicity for up to 2 years. In the safety confirmation cohort, an additional 12 patients will be treated at the established MTD. A Bayesian continuous monitoring for safety will be used and the objective response rate will be estimated with an exact 95% confidence interval.

[0441] History and physical exam (H&P), labs, and safety assessment will be obtained prior to each cycle. Computed tomography (CT) scans will be obtained every 6-9 weeks.

[0442] Inclusion of Women and Underrepresented Minorities

[0443] The total number of patients involved in the study will be up to 27. Of those, we estimate that approximately 54.0% will be cisgender women. The estimated racial / ethnic breakdown of the study may approximately be that 7.0% may be Black or African American, 21.8% may be Asian, 2.3% may be Native Hawaiian-Pacific Islander, 9.2% may be Hispanic or Latino, and 60% may be White. Estimates are a reflection of the racial / ethnic breakdown seen in our institution's pancreatic multidisciplinary clinic (PMDC, data unpublished). See Table 2 below. While this provides only an estimated breakdown of the study population, efforts will be made to ensure equitable recruitment of individuals that meet the above eligibility requirements.

[0444] Table 2: Estimated racial / ethnic breakdown of patients

[0445] Patients must have histologically (cytology) confirmed pancreatic ductal adenocarcinoma (PDAC) that is metastatic or unresectable, with disease progression after standard of care (SOC) chemotherapy. Patients with clinical, radiologic, and / or pathologic evidence of metastatic disease after SOC chemotherapy are eligible.

[0446] Example 3

[0447] BACKGROUND AND RATIONALE

[0448] Disease Background

[0449] Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease often requiring a multimodal treatment approach. PDAC is projected to be the second leading cause of cancer-related death by 2030 in the United States, surpassing prostate, breast, and colorectal cancerl. More than 50% of patients present with locally advanced or metastatic disease at the time of diagnosis 2-3. Surgical resection is the only curative option, yet the rate of recurrence is 80%, where systemic therapy remains the only treatment option. As a result, the 5-year survival rate is dismal at 11% and novel therapeutic approaches are desperately needed to address the treatment refractory nature of PDAC. Rationale

[0450] This trial is testing Balixafortide (POL6326, BLX), a more potent, best in class, highly selective synthetic peptide CXCR4 inhibitor (CXCR4i) administered IV weekly with anti-PDl therapy. It has been extensively studied in phase l-lll trials in multiple tumor types, particularly breast cancer which has shown to be safe both alone and in combination with chemotherapyl2-13. Balixafortide has the highest relative exposure to all other CXCR4 candidates. Additionally, Balixafortide is more potent than small molecular inhibitors, like AMD3100 (Plerixafor), with high selectivity, without any in-vitro off target effects and has high receptor occupancy and affinity compared to AMD3100.

[0451] The starting dose of Balixafortide is 5.5 mg / kg IV weekly. This dose was found to be safe with an acceptable tolerability profile in a phase 1 dose escalation trial of Balixafortide plus Eribulin for HER2-negative, heavily pre-treated, metastatic breast cancer. Furthermore, objective response was higher compared to prior published data of eribulin alone. Trial investigators decided to explore further antitumor activity at the 5.5 mg / kg dose with the expansion cohort.

[0452] Study Hypothesis

[0453] For the current trial, study investigators hypothesize the addition of CXCR4i, Balixafortide, to anti-PD-Ll antibody, Cosibelimab will be a safe and well-tolerated regimen with significant potential of efficacy in future combinatorial phase II and registration clinical trials. This phase I trial is to evaluate the safety of combination Pembrolizumab and Balixafortide in patients with metastatic PDAC who progressed after standard of care (SOC) chemotherapy.

[0454] The dosing scheme is listed below in Table 3.

[0455] Table 3: Dosing scheme

[0456] Dosing of Cosibelimab will remain constant (800 mg IV every 2 weeks). Balixafortide will be administered as a weekly intravenous infusion. Both agents will be continued until disease progression or unacceptable toxicity for up to 2 years.

[0457] Correlative quantitative analysis of multiplex immunohistochemistry (mIHC) using a panel of 40 biomarkers will show significantly decreased CXCR4 expression and decreased immunosuppressive granulocytes and TAMs in exceptional responders.

[0458] STUDY OBJECTIVES AND ENDPOINTS

[0459] Primary Objectives

[0460] To identify the MTD and RP2D of Balixafortide in combination with Cosibelimab in patients with metastatic treatment refractory PDAC with progressive disease after SOC chemotherapy. Secondary Objectives

[0461] To assess the safety and toxicity profile of Balixafortide in combination with Cosibelimab in patients with metastatic treatment refractory PDAC with progressive disease after SOC chemotherapy.

[0462] To evaluate the anti-tumor activity of combination Balixafortide and Cosibelimab in patients with metastatic treatment refractory PDAC progressed on SOC chemotherapy.

[0463] Exploratory Objectives

[0464] To assess changes of tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and tumor associated neutrophils (TAN) with Balixafortide and Cosibelimab following treatment initiation.

[0465] To assess activity of pancreatic stellate cells via a-Smooth muscle actin and fibroblast activate protein (FAP) IHC with Balixafortide and Cosibelimab following treatment initiation.

[0466] To assess changes in expression of PD-L1 / PD-1 and CD68 / CD8 ratio with Balixafortide and Cosibelimab following treatment initiation.

[0467] Endpoints

[0468] Primary Endpoints

[0469] MTD and RP2D

[0470] The occurrence of DLTs tabulated to determine MTD over a DLT period of 4 weeks.

[0471] Secondary Endpoints

[0472] Safety

[0473] The occurrence of treatment-related AEs as defined by CTCAE v5.0

[0474] Anti-tumor activity

[0475] ORR: Radiologic tumor responses (CR, PR) as determined by RECIST 1.1 criteria.

[0476] PFS: The length of time from the first dose of study treatment to disease progression according to RECIST 1.1 criteria

[0477] OS: The length of time from first dose of study treatment to death of any cause. Exploratory Endpoints

[0478] Identification and quantification of TA Ms, MDSCs, and TANs in pre- and post-treatment specimens using multiplex IHC.

[0479] Pancreatic stellate cell activity via identification and quantification of a-Smooth muscle actin and FAP in pre- and post-treatment specimens by multiplex IHC.

[0480] PD-L1 / PD-1 expression and CD68 / CD8 ratio in pre- and post-treatment specimens by multiplex IHC.

[0481] CD8+ T cell and CXCR4+ cell densities in pre- and post-treatment specimens by multiplex IHC.

[0482] STUDY DESIGN

[0483] This is a single-center, open-label, phase 1 dose escalation and dose expansion (safety confirmation) trial to evaluate the safety and tolerability of Balixafortide and Cosibelimab in patients with metastatic PDAC who progressed after SOC chemotherapy.

[0484] In the dose escalation cohort, a maximum of 12 patients will be enrolled exploring three dose levels of Balixafortide to identify the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The MTD is defined as the dose level such that the probability of DLT at the MTD is 0 = 0.3. A dose limiting toxicity (DLT) is defined below based on NCI CTCAE v5.0 with a possible, probably, or likely causal relationship to administration of study drug(s), balixafortide or cosibelimab. The following toxicities will be considered dose limiting in the event they are treatment-related and occur in the first 4 weeks of study treatment.

[0485] • Any Grade 4 non-hematological toxicity

[0486] • Any Grade 3 non-hematological toxicity except Grade 3 fever or fatigue of < 72-hour duration, as well as suboptimally treated Grade 3 or 4 diarrhea, nausea, or vomiting (in investigator's assessment);

[0487] • Grade 3 or 4 hematologic toxicity of > 7-day duration

[0488] • Grade 3 or 4 neutropenia complicated by fever (> 100.4°F) or documented infection

[0489] • Grade 4 thrombocytopenia complicated by bleeding; • Endocrine toxicity that can be reversed with hormone replacement is not considered a DLT. Endocrine toxicity that requires hospitalization (or cannot be managed in the outpatient setting) is considered a DLT.

[0490] • Any AE that is not a DLT per this definition, but is designated as a DLT by the Data and Safety Monitoring Committee (DSMC).

[0491] An escalation with overdose control (EWOC) algorithm will be utilized.30, 31 The first patient will be enrolled at the lowest dose level of Balixafortide (7.5 mg / kg). The dose for each subsequent patient will be determined so that, based on all available data, the probability that it exceeds the MTD is equal to a prespecified value a. In this trial, we start at a = 0.3 and increase a in small increments of 0.05 until a = 0.5, this value being a compromise between the therapeutic aspect of the agent and its toxic side effects. No dose skipping will be permitted. The trial will be terminated if the posterior probability that the probability that DLT at dose level 1 exceeds 0 is 0.8 or more. If the probability of DLT is less than 0.3 at the highest dose level of Balixafortide (16 mg / kg) and the MTD has not been determined, newly accrued patients can then be assigned to previously determined higher doses of Balixafortide.

[0492] Once we determine the MTD, an additional 12 patients will be enrolled for additional experience with safety and efficacy.

[0493] Dosing of Cosibelimab will remain constant (800 mg IV). Cosibelimab will be given IV every 2 weeks and Balixafortide will be given IV weekly at the assigned dose, until disease progression or unacceptable toxicity for up to 2 years. In the dose expansion (safety confirmation) cohort, an additional 12 patients will be treated at the established MTD. A Bayesian continuous monitoring for safety will be used and the objective response rate will be estimated with an exact 95% confidence interval.

[0494] History and physical exam ( H &P), labs, and safety assessment will be obtained prior to each cycle. Computed tomography (CT) scans will be obtained every 8 weeks. Inclusion of Women and Underrepresented Minorities

[0495] The total number of patients involved in the study will be up to 27. Of those, we estimate that approximately 54.0% will be cisgender women. The estimated racial / ethnic breakdown of the study may approximately be that 7.0% may be Black or African American, 21.8% may be Asian, 2.3% may be Native Hawaiian-Pacific Islander, 9.2% may be Hispanic or Latino, and 60% may be White. Estimates are a reflection of the racial / ethnic breakdown seen in our institution's pancreatic multidisciplinary clinic (PMDC, data unpublished). See Table 4 below. While this provides only an estimated breakdown of the study population, efforts will be made to ensure equitable recruitment of individuals that meet the above eligibility requirements.

[0496] Table 4: Estimated racial / ethnic breakdown of patients

[0497] Patients must have histologically (cytology) confirmed pancreatic ductal adenocarcinoma (PDAC) that is metastatic or unresectable, with clinical, radiologic, and / or pathologic disease progression after at least one line of standard of care (SOC) chemotherapy are eligible.

[0498] Example 4

[0499] Cell lines

[0500] Mouse EO771 breast cancer cells (mammary tumor cells) and C57BL / 6J mouse mammary fibroblasts (gift from Harold L. Moses, Vanderbilt University, Nashville, Tennessee, United States) were cultured in DMEM base media (Gibco, #11965, Thermo Fisher Scientific, Waltham, Massachusetts, United States) supplemented with 10% FBS, 1% GlutaMAX (Gibco #35050061, Thermo Fisher Scientific, Waltham, Massachusetts, United States) and 1% plasmocin (InvivoGen, San Diego, California, United States).

[0501] Mouse tumor model

[0502] For the orthotopic model mouse mammary tumor cells (5 x 105) of EO771 mouse mammary tumor cell line and 1 x 105mouse mammary fibroblasts were implanted orthotopically into 4thinguinal mammary fat pads of 6-8-week-old female C57BL / 6J mice (The Jackson Laboratory, Bar Harbor, Maine, United States) (J. Fenner et al., Macroscopic Stiffness of Breast Tumors Predicts Metastasis, Sc / Rep, 2024, 4: 5512). Mice were housed in specific pathogen-free housing facilities maintained by the Unit for Laboratory animal Medicine at the University of Michigan. Two days after implanting cells, mice were randomly assigned to treatment with anti-PD-1 antibody CD279 (BioXCell, Lebanon, New Hampshire, United States) (5 mg / kg, intraperitoneal), or vehicle control administered every three days for four total doses. In particular, Group 1 (Balixafortide / anti-PD-1 antibody) and Group 3 (anti-PD-1 antibody) received four doses of anti-PD-1 antibody at 5mg / kg per dose every three days for 4 cycles. Group 1 and Group 2 received 20 mg / kg Balixafortide through subcutaneous injection in the rear flank daily. The administration of Balixafortide ended between day 50-55. Control mice (Group 4) received matched vehicle only.

[0503] Growth of orthotopic tumors were measured by use of calipers quantifying tumor size for each mouse as mm3by V (volume) measurements. Mice were euthanized for a predetermined human endpoint of tumor size, which defined time of censoring for survival analysis. To account for differences in days required to reach pre-defined study endpoints the reported duration of each experiment to fraction experiment progression was normalized (defined as 1.0). The presented data (Figure 2) are mean values + SEM combined from two different experiments. Differences across the groups at each time point were compared by ANOVA corrected for multiple comparisons (*: p < 0.05; **: p< 0.01).

[0504] Figure 3 shows overall survival of mice in different treatment groups with log-rank p-values calculated using a Mantel-Cox test. Asterisks in legend symbolize significance (*: p < 0.05; **: p< 0.01). The data to fraction of days to reach the study endpoint (defined as 1.0) were normalized in order to combine two different experiments.

[0505] Table 5 shows survival calculations using log-rank p-values and hazard ratios from the survival study presented in Figure 3.

[0506] Table 5 Statistics

[0507] All data processing were performed in Prism GraphPad V9 (Dotmatics, Boston, Massachusetts, United States). A t test was performed for statistical comparisions among groups of mormally distributed samples, and a Mann-Whitney test for mon-parametric means. Asterisks (ns = p > 0.05; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001) indicate p-values shown in figure legends. Kaplan-Meier plots were generated and differences in survival were analysed using the Mantel-Cox test and the Mantel- Haenszal test. In assessing statistical differences of tumor burden over time between in-vivo groups, analysis of variance (ANOVA) was used. Similarly, ANOVA was used for the suprssion assay. Results

[0508] In order to evaluate effects of CXCR4 inhibition to improve checkpoint inhibitor immunotherapy in breast cancer, in particular triple negative breast cancer (TNBC), murine E0771 TNBC cells, a transplantable tumor model derived from C57BL / 6J mice were used. E0771 tumors exhibit an immunologically active tumor microenvironment like TNBC im humans. Monotherapy with the CXCR4 inhibitor Balixafortide (group 2) or anti-PD-1 antibody (group 3) modestly decreases tumor growth when compared with the control group (group 4, Figure 2). In contrast, combination treatment with Balixafortide and anti- PD-1 antibody (group 1) significantly reduced tumor growth compared with all other groups at later growth times (p < 0.01 by ANOVA, Figure 2).

[0509] In order to determine the effects of treatment on the relative likelihood of mortality among various treatment groups the overall survival of mice was analyzed (Figure 3). Combination treatment with Balixafortide and anti-PD-1 antibody (group 1) significantly increased the probability of survival or reduced hazard ratios for death relative to all other groups

[0510] (p < 0.05). As shown in Table 5, relative to the combination treatment group (group 1), all other groups showed a roughly 2.5-fold or higher risk of death.

[0511] Overall, these data establish that adding Balixafortide to anti-PD-1 immunotherapy provides benefits to anti-PD-1 therapy alone, in particular offering a potential means to improve outcomes in breast cancer, in particular TNBC.

Claims

CLAIMS1) A pharmaceutical combination comprising:(a) a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14-Xaa15-Pro16-)(I), in whichXaa3is Ala; Tyr; or Tyr(Me);Xaa6is Ala or Acc;Xaa7isDPro;DTyr; orDTyr(Me);Xaa8is Dab; or Orn(iPr);Xaa14is Lys; or Lys(iPr);Xaa15isDPro; orDLys(iPr); whereinTyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;Acc is 1-aminocyclopropane-l-carboxylic acid;Dab is (2S)-2,4-diaminobutyric acid;Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11;(b) an inhibitor of PD-1; and(c) optionally one or more pharmaceutically acceptable diluents, excipients or carriers.2) A pharmaceutical combination according to claim 1, wherein said peptidic CXCR4 inhibitor is a backbone cyclized peptidic compound, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Ala6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)(la), in whichXaa3is Ala; Tyr; or Tyr(Me);Xaa7isDPro;DTyr; orDTyr(Me);Xaa8is Dab; or Orn(iPr);Xaa14is Lys; or Lys(iPr);Xaa15isDPro; orDLys(iPr); wherein Tyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;Dab is (2S)-2,4-diaminobutyric acid;Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;DLys(iPr) is (2 / ?)-l\T-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues, and wherein the compound of formula la has a disulfide bond between Cys4and Cys11.3) A pharmaceutical combination according to claim 1, wherein said backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-)having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(l\ / le)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof.4) A pharmaceutical combination according to claims 1 and 3, wherein said backbone cyclized peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DLys(iPr)-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:3), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:4), cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr-Dab-Arg-Tyr-Cys-Tyr-Gln Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:5), cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:6), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:7),cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:8), cyclo(-Tyr-His-Tyr -Cys-Ser-Ala-DTyr-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:9), cyclo(-Tyr-His-Tyr(Me)-Cys-Ser-Ala-DTyr(Me)-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro- Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NQ:10), cyclo(-Tyr-His-Tyr-Cys-Ser-Acc-DPro-Orn(iPr)-Arg-Tyr-Cys-Tyr-Gln-Lys(iPr)-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:11), or pharmaceutically acceptable salts thereof.5) A pharmaceutical combination according to claim 1 to 3, wherein said peptidic CXCR4 inhibitor is selected from the group consisting of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), and cyclo(-Tyr-His-Tyr-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:2), or pharmaceutically acceptable salts thereof.6) A pharmaceutical combination according to any one of claims 1 to 3 or 5, wherein said peptidic CXCR4 inhibitor is cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4and Cys11, (SEQ ID NO:1), or pharmaceutically acceptable salts thereof.7) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Avelumab, Atezolizumab, Durvalumab, Vopratelimab, INCMGA00012, AMP-224, AMP- 514, Acrixolimab and Sugemalimab.8) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, Cosibelimab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ-053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS-1480 (PD-L1 / EGFR).9) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Tislelizumab, Toripalimab, Camrelizumab, Sintilimab, Retifanlimab, Prolgolimab (BCD-100), Serplulimab (HLX10), Spartalizumab, Penpulimab, Vopratelimab, INCMGA00012, AMP-224, AMP-514, Acrixolimab, Atezolizumab, Avelumab, Envafolimab, Durvalumab, lodapolimab, Garivulimab, Opucolimab, Manelimab, Pacmilimab (CX-072), CBT-502, MSB-2311, SHR-1316, Sugemalimab, A167, STI-A1015, FAZ- 053, BMS-936559, INCB086550, GEN-1046 (PD-L1 / 4-1BB), FBT-155 (CTLA4 / PD-L1 / CD28), Bintrafusp alpha (M7824; PD-L1 / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-2 / PD-L1), INBRX-105 (4-1BB / PD-L1), MAX10181 and GNS- 1480 (PD-L1 / EGFR).10) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, RMP1-14, Cemiplimab, Dostarlimab and Retifanlimab11) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab,Cemiplimab, Dostarlimab, Retifanlimab, Avelumab, Atezolizumab, Durvalumab, Sugemalimab and Cosibelimab.12) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is Pembrolizumab.13) A pharmaceutical combination according to any one of claims 1 to 6, wherein the inhibitor of PD-1 is Cosibelimab.14) A pharmaceutical combination according to any one of claims 1 to 13, for use as a medicament.15) A pharmaceutical combination according to any one of claims 1 to 13 for use in a method for the prevention, delay of progression or treatment of cancer in a subject.16) A pharmaceutical combination for use according to claim 15, wherein the cancer is a solid tumor.17) A pharmaceutical combination for use according to claim 16, wherein the solid tumor is selected from the group consisting of pancreatic cancer, breast cancer and colon cancer.18) A pharmaceutical combination for use according to claim 16, wherein the solid tumor is selected from the group consisting of pancreatic cancer and breast cancer.19) A pharmaceutical combination for use according to claim 16, wherein the solid tumor is pancreatic cancer.20) A pharmaceutical combination for use according to claim 16, wherein the solid tumor is metastatic pancreatic cancer.21) A pharmaceutical combination for use according to any one of claims 17 to 19, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC) and / or metastatic pancreatic ductal adenocarcinoma (PDAC).22) A pharmaceutical combination for use according to claim 21, wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) comprises liver metastasis.23) A pharmaceutical combination for use according to claim 21, wherein the metastatic pancreatic ductal adenocarcinoma (PDAC) is refractory metastatic pancreatic ductal adenocarcinoma (PDAC).24) A pharmaceutical combination for use according to claim 16, wherein the solid tumor is breast cancer.25) A pharmaceutical combination for use according to any one of claims 17, 18, or 24, wherein the breast cancer is triple negative breast cancer (TNBC).26) A pharmaceutical combination for use according to any one of claims 15 to 25, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1, 8 and 15 of a 21-day cycle administration.27) A pharmaceutical combination for use according to any one of claims 15 to 26, wherein the inhibitor of PD-1 is administered to the subject on day 1 of a 21-day cycle administration.28) A pharmaceutical combination for use according to any one of claims 15 to 27, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 5.5 to about 11 mg / kg.29) A pharmaceutical combination for use according to any one of claims 15 to 27, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 5.5 mg / kg.30) A pharmaceutical combination for use according to any one of claims 15 to 27, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 8.25 mg / kg.31) A pharmaceutical combination for use according to any one of claims 15 to 27, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 11 mg / kg.32) A pharmaceutical combination for use according to any one of claims 15 to 31, wherein the inhibitor of PD-1 is administered to the subject at a dose of about 200 mg.33) A pharmaceutical combination for use according to any one of claims 15 to 28, or 32, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 5.5 to about 11 mg / kg for about 2 hours.34) A pharmaceutical combination for use according to any one of claims 15 to 33, wherein the inhibitor of PD-1 is administered to the subject at a dose of 200 mg for about 30 minutes.35) A pharmaceutical combination for use according to any one of claims 15 to 25, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject on days 1 and 8 of a 14-day cycle administration.36) A pharmaceutical combination for use according to any one of claims 15 to 25, or 35, wherein the inhibitor of PD-1 is administered to the subject on day 1 of a 14-day cycle administration.37) A pharmaceutical combination for use according to any one of claims 15 to 25, 35, or 36, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 7.5 to about 16 mg / kg.38) A pharmaceutical combination for use according to any one of claims 15 to 25, 35 or 36, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 7.5 mg / kg.39) A pharmaceutical combination for use according to any one of claims 15 to 25, 35 or 36, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 11 mg / kg.40) A pharmaceutical combination for use according to any one of claims 15 to 25, 35 or36, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose of about 16 mg / kg.41) A pharmaceutical combination for use according to any one of claims 15 to 25, or 35 to 40, wherein the inhibitor of PD-1 is administered to the subject at a dose of about 800 mg.42) A pharmaceutical combination for use according to any one of claims 15 to 25, 35 to37, or 41, wherein the backbone cyclized peptidic CXCR4 inhibitor or pharmaceutically acceptable salts thereof is administered to the subject at a dose from about 5.5 to about 11 mg / kg for about 2 hours.43) A pharmaceutical combination for use according to any one of claims 15 to 25, 35 to 42, wherein the inhibitor of PD-1 is administered to the subject at a dose of 800 mg for about 60 minutes.44) A kit of parts comprising a first container, a second container and a package insert, wherein the first container comprises at least one dose of a medicament comprising a backbone cyclized peptidic CXCR4 inhibitor, built up from 16 amino acid residues, or pharmaceutically acceptable salts thereof, of the formula cyclo(-Tyr1-His2-Xaa3-Cys4-Ser5-Xaa6-Xaa7-Xaa8-Arg9-Tyr10-Cys11-Tyr12-Gln13-Xaa14- Xaa15-Pro16-)(I), in whichXaa3is Ala; Tyr; or Tyr(Me);Xaa6is Ala or Acc;Xaa7isDPro;DTyr; orDTyr(Me);Xaa8is Dab; or Orn(iPr);Xaa14is Lys; or Lys(iPr);Xaa15isDPro; orDLys(iPr); whereinTyr(Me) is (2S)-2-amino-3-(4-methoxyphenyl)-propanoic acid;DTyr(Me) is (2 / ?)-2-amino-3-(4-methoxyphenyl)-propanoic acid;Acc is 1-aminocyclopropane-l-carboxylic acid;Dab is (2S)-2,4-diaminobutyric acid;Orn(iPr) is (2S)-N“-isopropyl-2,5-diaminopentanoic acid;Lys(iPr) is (2S)-N“-isopropyl-2,6-diaminohexanoic acid;DLys(iPr) is (2 / ?)-N“-isopropyl-2,6-diaminohexanoic acid; wherein all of the amino acid residues, which are not explicitly designated as D-amino acid residues, are L-amino acid residues; and wherein the compound of formula I has a disulfide bond between Cys4and Cys11; the second container comprises at least one dose of a medicament comprising an inhibitor of PD-1, and the package insert comprises optionally instructions for treating a subject for cancer using the medicaments.

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