WO2022167157A1 - Combinaisons d'éribuline-balixafortide pour le traitement du cancer - Google Patents

Combinaisons d'éribuline-balixafortide pour le traitement du cancer Download PDF

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WO2022167157A1
WO2022167157A1 PCT/EP2022/025045 EP2022025045W WO2022167157A1 WO 2022167157 A1 WO2022167157 A1 WO 2022167157A1 EP 2022025045 W EP2022025045 W EP 2022025045W WO 2022167157 A1 WO2022167157 A1 WO 2022167157A1
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tyr
pro
cys
ala
pharmaceutically acceptable
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PCT/EP2022/025045
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English (en)
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Francois RINGEISEN
Remco DIAB
Achim Wach
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Spexis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to pharmaceutical combinations comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject.
  • 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.
  • Metastatic breast cancer 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.
  • eribulin eribulin
  • a particular dose regimen of a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, such as e.g. eribulin mesylate and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof such as e.g.
  • the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll is useful for the prevention, delay of progression or treatment of cancer, in particular breast cancer
  • the present invention is herewith provided in its following aspects.
  • the present invention provides a pharmaceutical combination comprising:
  • the present invention provides pharmaceutical combinations comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer.
  • the present invention provides a pharmaceutical combination comprising:
  • the terms "individual,” “subject” or “patient” are used herein interchangeably.
  • 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.
  • dose refers to the total amount of an active ingredient (e.g., the compound of formula I, or a pharmaceutically acceptable salt thereof, or cyclo(-Tyr-His-Ala- Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, to be taken each time by a subject (e.g. a human).
  • an active ingredient e.g., the compound of formula I, or a pharmaceutically acceptable salt thereof, or cyclo(-Tyr-His-Ala- Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-
  • a subject e.g. a human
  • ORR object response rate
  • the ORR refers to the sum of complete response (CR) and partial response (PR).
  • CBR clinical benefit rate
  • CR complete response
  • Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to ⁇ 10 mm.
  • 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).
  • partial response refers to at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
  • PD progressive disease
  • progressive disease 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.
  • 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.
  • stable disease 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.
  • 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.
  • 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.
  • 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, 8 th edition) metastatic breast cancer is staged as stage IV breast cancer.
  • AJCC American Joint Committee on Cancer
  • 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.
  • 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.
  • the term "advanced breast cancer” as used herein includes metastatic breast cancer and locally advanced breast cancer, as used herein.
  • the compound of formula I formula I has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl- 20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy- 7, 9-ethano-12,15-methano-9/7, 15/7- furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one and is also referred to in the literature as (15,35,65,95,125,14/?,16/?,185,20/?,21/?,225,26/?,295,31/?,325,35/?,365)-20-[(25)-3-amino-2- hydroxypropyl]-21-methoxy- 14-
  • the amounts, concentrations and doses provided herein are all calculated on the basis of the respective free base. The amounts and concentrations are calculated for a 70 kg patient.
  • the compound of formula I is the compound of formula la formula la
  • the compound of formula la has the chemical name 2-(3-amino-2- hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)ll, 15-18, 21- 24,28-triepoxy-7,9-ethano-12,15-methano-9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3- b)(l,4)dioxacyclopentacosin-5-(4/7)-one methanesulfonate and is also referred to in the literature as ( IS, 35,65,95, 125,14/?, 16/?, 185,20/?, 21/?, 225,26/?, 295,31/?, 325,35/?, 365)-20-[(25)- 3-amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)- 2,19,30,34,37,
  • Eribulin mesilate is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It is a structurally modified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. It has a novel mode of action that is distinct from those of other tubulin-targeting agents: inhibiting the microtubule growth phase without affecting the shortening phase, resulting in tubulin sequestration into non-productive aggregates. The compound is approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Eribulin mesilate is marketed under the tradename Halaven®.
  • POL6326 Cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll 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 and is being developed as an IV treatment in combination with chemotherapy in patients with leukemias (autologous transplantation).
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that 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
  • 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.
  • Particularly suitable pharmaceutically acceptable salts of the compound of formula I are e.g. methane- or ethane-sulfonate. Most preferred is the methanesulfonate salt of the compound of formula I i.e. the compound of formula la.
  • Particularly suitable pharmaceutically acceptable salts of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll 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,
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Most preferred is the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is comprised by the pharmaceutical combination of the present invention.
  • the pharmaceutical combination of the present invention comprises a pharmaceutically acceptable salt of the compound of formula I.
  • the pharmaceutical combination of the present invention comprises the compound of formula la (eribulin mesylate). Cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll or pharmaceutically acceptable salts thereof are comprised by the pharmaceutical combination of the present invention.
  • the pharmaceutical combination of the present invention comprises cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll in free form. More preferably the pharmaceutical combination of the present invention comprises cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll as acetate salt.
  • the most preferred pharmaceutical combination of the present invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject as described herein is a pharmaceutical combination comprising the compound of formula la (eribulin mesylate) and the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll.
  • the invention relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein.
  • a pharmaceutical combination according to the invention is for example a combined preparation or a pharmaceutical composition, for simultaneous, separate or sequential use.
  • combined preparation as used herein defines especially a "kit of parts” in the sense that the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, can be dosed independently, either in separate form or by use of different fixed combinations with distinguished amounts of the active ingredients.
  • the pharmaceutical combination according to the invention is a combined preparation.
  • the pharmaceutical combination according to the invention is a combined preparation wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are dosed independently from each other, i.e. are dosed in separate form.
  • the ratio of the amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, 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.
  • composition refers to a fixed-dose combination (FDC) that includes the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr- Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, combined in a single dosage form, having a predetermined combination of respective dosages.
  • FDC fixed-dose combination
  • additive-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.
  • a preferred add-on therapy of the present invention comprises adding a compound of formula I therapy to a patient already receiving cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) therapy.
  • the amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, respectively, 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 route of administration, the condition being treated, the target area being treated, and the subject or host being treated.
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in a therapeutically effective
  • an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention 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.
  • a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow 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.
  • the amount is sufficient to ameliorate, palliate, lessen,
  • 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.
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in an amount producing an additive
  • 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 anti-cancer agents, namely the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser- Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as a monotherapy.
  • an additive effect provides for greater efficacy at the same doses, and may lead to longer duration of response to the therapy.
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in an amount producing a
  • the term “synergistic” means that the effect achieved with the pharmaceutical combinations of this invention is approximately higher than the sum of the effects that result from using the anti-cancer agents, namely the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as a monotherapy.
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 0.1 to about 50 mg or from about 0.1 to about 20 mg or from about 0.1 to about 10 mg or from about 0.5 to about 8 mg or from about 0.5 to about 6 mg or from about 0.5 to about 4 mg or from about 0.75 to about 3 mg or from about 1.1 to about 2.4 mg, preferably from about 0.5 to about 4 mg, more preferably from
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is about 1 mg, about 1.2 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg.
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr- Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is from about 385 to about 2240 mg or from about 385 to about
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr- Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is about 385 mg, about 770 mg, about 1155 mg, about
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 0.1 to about 50 mg or from about 0.1 to about 20 mg or from about 0.1 to about 10 mg or from about 0.5 to about 8 mg or from about 0.5 to about 6 mg or from about 0.5 to about 4 mg or from about 0.75 to about 3 mg or from about 1.1 to about 2.4 mg, preferably from about 0.5 to about 4 mg, more preferably from
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is about 1 mg, about 1.2 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg; and wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser- Ala- D
  • the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 1.1 to about 2.4 mg; and wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is from about 385 to
  • the invention also relates to a pharmaceutical combination
  • a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, excipients or carriers for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein.
  • pharmaceutically acceptable diluent, excipient or carrier refers to a carrier or excipient or diluent that is 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. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject. In a further aspect the present invention provides a pharmaceutical combination comprising:
  • 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.
  • 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, by infusion, intravenously, intraperitoneally, parenterally, intramuscularly, 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.
  • agents having similar utilities including rectal, buccal, intranasal, transmucosal, transdermal, by intra-arterial injection, by infusion, intravenously, intraperitoneally, parenterally, intramuscularly, 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
  • One mode for administration is administration by injection or infusion, preferably intravenous administration by infusion.
  • the forms in which the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be incorporated for administration by injection or infusion include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, 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 or infusion, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer are used as aqueous solutions.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer
  • 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.
  • 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.
  • 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.
  • 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 sterile-filtered solution thereof.
  • sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 1000 mg, of the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser- Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount e.g., 0.1 to 1000 mg
  • 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.
  • a pharmaceutical combination for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein according to the invention is, preferably, suitable for injection, e.g. intravenous, intramuscular, intrathecal or intraperitoneal injection, or infusion, more preferably suitable for intravenous injection or infusion, and usually comprises a therapeutically effective amount of the active ingredients and one or more suitable pharmaceutically acceptable diluent, excipient or carrier.
  • the pharmaceutical combination is administered to the subject intravenously, i.e.
  • compositions or combined preparations in separate form comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be manufactured by means of conventional mixing, dissolving, granulating, coated tabletmaking, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions or combined preparations in separate form may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active ingredient into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
  • the compounds can be readily formulated by combining the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His- Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated.
  • suitable excipients include fillers such as sugars, e.
  • 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.
  • desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added.
  • the composition may take the form of tablets, lozenges, etc. formulated as usual.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof 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.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • 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.
  • 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.
  • suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.
  • 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.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • 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.
  • additional strategies for protein stabilization may be employed.
  • 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, as described herein, 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.
  • 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 as described herein 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.
  • 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.
  • prevention e.g. preventive treatments comprise prophylactic treatments.
  • the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer.
  • 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.
  • treatment 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.
  • 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.
  • 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.
  • 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").
  • 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.
  • 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, as described herein, 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, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.
  • the cancer to be treated by the method for the prevention, delay of progression or treatment of cancer of the present invention expresses CXCR4.
  • CXCR4 expression of a cancer can be assessed by e,g, immunohistochemistry on tumour tissue (archival primary tumour, metastatic tissue, or from a fresh biopsy). Any level of expression of CXCR4 of the cancer to be treated by the method of the present invention is considered as cancer expressing CXCR4 in the context of the invention.
  • 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, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.
  • 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, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.
  • 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, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.
  • the breast cancer is selected from the group consisting of HER2- negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2- ER+PR-) breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2-ER+PR+) breast cancer.
  • the advanced breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) advanced breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) advanced breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) advanced breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2- ER+PR+) advanced breast cancer
  • the locally advanced breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) locally advanced breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) locally advanced breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) locally advanced breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2-ER+PR+) locally advanced breast cancer.
  • the metastatic breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) metastatic breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) metastatic breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) metastatic breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2- ER+PR+) metastatic breast cancer.
  • the subject who has cancer is (i) refractory to at least one chemotherapy treatment, or (ii) is in relapse after treatment with chemotherapy, or a combination thereof.
  • 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), preferably the subject is refractory to one to three or one to two anti-cancer therapies (including, for example, standard or experimental chemotherapies), more preferably the subject is refractory to one to three or one to two anti-cancer therapies for the treatment of locally recurrent breast cancer or metastatic breast cancer.
  • the subject who is in relapse after treatment with chemotherapy has received at least two, at least three, or at least four anti-cancer therapy (including, for example, standard or experimental chemotherapies), preferably the subject who is in relapse after treatment with chemotherapy has received one to three or one to two anticancer therapies (including, for example, standard or experimental chemotherapies), more preferably the subject who is in relapse after treatment with chemotherapy has received one to three or one to two anti-cancer therapies for the treatment of locally recurrent breast cancer or metastatic breast cancer.
  • anti-cancer therapy including, for example, standard or experimental chemotherapies
  • the subject who is in relapse after treatment with chemotherapy has received one to three or one to two anticancer therapies for the treatment of locally recurrent breast cancer or metastatic breast cancer.
  • 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.
  • 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 anti-cancer therapies prior to treatment using the methods described herein (e.g., prior to the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulf
  • 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, wherein each of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is independently administered to the subject on days 1 and 8 of a 21-day cycle administration.
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ⁇ 1 day.
  • administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.
  • the dosing regimen of the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, 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.
  • the amount e.g. the therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, may be provided in a single dose or multiple doses to achieve the desired treatment endpoint.
  • 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.
  • pharmacokinetic and pharmacodynamic information about the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials.
  • a therapeutically effective dose can be estimated initially from biochemical and/or cell-based 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.
  • Toxicity and therapeutic efficacy of the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, 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.
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, followed by
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for less
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-) having
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for about
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys--D Pro
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys--D Pro
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-A
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-A
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-A
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-A
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-Ala-Cys-Ser
  • Exemplary doses of the compound of formula I, or a pharmaceutically acceptable salt thereof, above, e.g. for a human subject may be from about 0.1 to about 50 mg/m 2 or from about 0.1 to about 20 mg/m 2 or from about 0.1 to about 10 mg/m 2 or from about 0.5 to about 8 mg/m 2 or from about 0.5 to about 6 mg/m 2 or from about 0.5 to about 1.6 mg/m 2 or from about 0.5 to about 1.5 mg/m 2 about 0.6 mg/m 2 or about 0.7 mg/m 2 , about 0.8 mg/m 2 , about 0.9 mg/m 2 , about 1 mg/m 2 , about 1.1 mg/m 2 , about 1.2 mg/m 2 , about 1.3 mg/m 2 , about 1.4 mg/m 2 , about 1.5 mg/m 2 , about 2 mg/m 2 , about 3 mg/m 2 , about 4 mg/m 2 , about 5 mg/m 2 , about 6 mg/m 2 , about 7 mg/m 2 , about
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to the subject after the end of the second phase of administration of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as described above, wherein the doses of the compound of formula I, or a pharmaceutically acceptable salt thereof, are from about 0.1 to about 50 mg/m 2 or from about 0.1 to about 20 mg/m 2 or from about 0.1 to about 10 mg/m 2 or from about 0.5 to about 8 mg/m 2 or from about 0.5 to about 6 mg/m 2 or from about 0.5 to about 1.6 mg/m 2 or from about 0.5 to about 1.5 mg/m 2 or about 0.7 mg/m 2 , about 0.8 mg/m 2 , about 0.9 mg/m
  • the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the administration of cyclo(-Tyr-His-Ala-Cys- Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.
  • the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the second phase of administration as described above of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.
  • the dosing regimen of the above embodiments relating to a first and a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and the compound of formula I, or a pharmaceutically acceptable salt thereof, are usually administered to the subject on days 1 and 8 of a 21-day cycle administration.
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ⁇ 1 day.
  • administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to the subject (e.g. a human) usually over about 1 to about 60 minutes, preferably over about 2 to about 30 minutes, more preferably over about 2 to about 10 minutes, most preferably over about 2 to about 5 minutes.
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-A
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cycl
  • D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cycl
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-T
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cycl
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-T
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cycl
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysl , or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Ty
  • a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m 2 , preferably about 0.6 mg/m 2 , about 1.1 mg/m 2 or about 1.2 mg/m 2 , for 2 to about 10 minutes.
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Ty
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Ty
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Ty
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of of cyclo(-
  • the compound of formula I is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the second phase of administration as described above of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.
  • the dosing regimen of the above embodiments relating to a first and a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, are usually administered to the subject on days 1 and 8 of a 21-day cycle administration.
  • cyclo(-Tyr- His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ⁇ 1 day.
  • administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.
  • An exemplary treatment regimen 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 regimen in which the subject receives cycles of treatment (administration cycles) interrupted by a drug holiday or period of nontreatment.
  • 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.
  • a preferred administration cycle in the methods of the present invention is a period of three weeks i.e. a 21-day cycle.
  • the cycle is repeated one or more times, usually one, two, three, for, five, six, seven, eight , nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or twenty one times, preferably at least two, at least three, at least four, at least five, at least six seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty or at least twenty one times, more preferably at least two times.
  • the cycle is repeated at least two times, so that the treatment comprises at least three 21-day cycles.
  • the present invention provides a pharmaceutical combination comprising:
  • the present invention provides a pharmaceutical combination comprising:
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-C
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-C
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-C
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-C
  • the cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of
  • a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m 2 , preferably about 0.6 mg/m 2 , about 1.1 mg/m 2 or about 1.2 mg/m 2 , for 2 to about 10 minutes.
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of
  • cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose
  • the compound of formula I or a pharmaceutically acceptable salt thereof, in combination with cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered to a subject (e.g. a human) in additional combination with one or more additional therapies.
  • a subject e.g. a human
  • the method for treating cancer in a subject e.g.
  • a human comprises administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- D Pro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys- D Pro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, 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 anticancer agents.
  • LA locally advanced
  • BC metastatic, HER2- negative breast cancer
  • balixafortide were assessed as well tolerated.
  • IRR infusion-related reactions
  • Typical IRR manifestations include mucocutaneous symptoms in up to 90% of patients (flushing, urticaria, pruritus), respiratory in 40% (wheezing), circulatory in 30%-35% (hypotension) and abdominal symptoms (nausea, vomiting, cramps, diarrhea), minutes to hours after exposure to the drug.
  • the IRR observed with balixafortide at the therapeutic dose of 5.5 mg/kg are mainly localized at the infusion site and of mild to moderate nature.
  • the most common occurring adverse events reported to have occurred in conjunction with an IRR are, e.g., acute infusion related reactions, injection site erythema, injection site pain, injection site pruritus, scalppruritus, whole body-pruritus, rash, rash at the chest, rash on the extremities, anaphylactoid skin reactions, flushing, facial edema, tight throat, tight upper chest wall, dyspnea, bronchospasm, edema, sensation of warmth, perioral numbness, paresthesia, "periorbital"- headache and urticaria (incl. large body surface areas).
  • HER2-negative advanced breast cancer should include locally advanced stages IIIB/C or metastatic stage IV disease by American Joint Committee on Cancer (AJCC) criteria (8th edition).
  • AJCC American Joint Committee on Cancer
  • Prior therapies should have included at least 1 but no more than 3 prior chemotherapy-based lines of treatment for advanced or metastatic disease.
  • HER2-negative advanced breast cancer should include locally advanced stages IIIB/C or metastatic stage IV disease by American Joint Committee on Cancer (AJCC) criteria (8th edition).
  • AJCC American Joint Committee on Cancer
  • Prior therapies should have included at least 1 but no more than 2 prior chemotherapy-based lines of treatment for advanced or metastatic disease.
  • the study has 2 parts: a phase Ib-part and a phase ll-part.
  • Patients will be administered a fixed eribulin dose of 1.23 mg/m 2 (equivalent to 1.4 mg/m 2 eribulin mesylate) combined with increasing doses of balixafortide starting at a dose of 5.5 mg/kg. Both drugs will be administered on day 1 and 8 of each 21-day cycle (+/- 1 day), see table below.
  • Balixafortide will be administered intravenously (IV) following a biphasic regimen (4.5% of balixafortide dose during the first 30 minutes of treatment, 95.5% of balixafortide dose during the following 3 hours and 30 minutes for a total of 4 hours; e.g. a balixafortide dose of 11 mg/kg will be administered as follow: 0,5 mg/ kg during the first 30 minutes and the remaining 10.5 mg/kg during the following 3 hours and 30 minutes.
  • a biphasic regimen (4.5% of balixafortide dose during the first 30 minutes of treatment, 95.5% of balixafortide dose during the following 3 hours and 30 minutes for a total of 4 hours; e.g. a balixafortide dose of 11 mg/kg will be administered as follow: 0,5 mg/ kg during the first 30 minutes and the remaining 10.5 mg/kg during the following 3 hours and 30 minutes.
  • Eribulin will be both administered IV over 2 to 5 minutes.
  • Up to 4 additional cohorts (balixafortide dose: 11 mg/kg, 16.5 mg/kg, 23 mg/kg, 32 mg/kg) are to be introduced to evaluate and establish the optimum exposure of balixafortide combined with eribulin, see table below.
  • eribulin is expected to be the same during the phase lb and phase II part of the study, it could be adjusted in response to safety observations during phase lb of the study and in line with the instructions for dose adjustment given in the eribulin summary of product characteristics (SmPC).

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Abstract

La présente invention concerne des combinaisons pharmaceutiques comprenant un composé de formule I, ou un sel pharmaceutiquement acceptable de celui-ci, et un cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) ayant une liaison disulfure entre Cys4 et Cys11, ou un sel pharmaceutiquement acceptable de celui-ci, destinées à être utilisées dans un procédé pour la prévention, le retardement de la progression ou le traitement du cancer chez un sujet.
PCT/EP2022/025045 2021-02-05 2022-02-07 Combinaisons d'éribuline-balixafortide pour le traitement du cancer WO2022167157A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024061946A3 (fr) * 2022-09-20 2024-05-02 Spexis Ag Applications à dose élevée d'un inhibiteur de cxcr4 peptidique

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018149552A1 (fr) * 2017-02-20 2018-08-23 Polyphor Ag Combinaisons pharmaceutiques pour traiter le cancer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018149552A1 (fr) * 2017-02-20 2018-08-23 Polyphor Ag Combinaisons pharmaceutiques pour traiter le cancer

Non-Patent Citations (1)

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Title
SONIA PERNAS ET AL: "Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial", THE LANCET ONCOLOGY, vol. 19, no. 6, 1 June 2018 (2018-06-01), AMSTERDAM, NL, pages 812 - 824, XP055722882, ISSN: 1470-2045, DOI: 10.1016/S1470-2045(18)30147-5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024061946A3 (fr) * 2022-09-20 2024-05-02 Spexis Ag Applications à dose élevée d'un inhibiteur de cxcr4 peptidique

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