WO2020049534A1 - Agoniste de sting et polythérapie correspondante pour le traitement du cancer - Google Patents

Agoniste de sting et polythérapie correspondante pour le traitement du cancer Download PDF

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Publication number
WO2020049534A1
WO2020049534A1 PCT/IB2019/057554 IB2019057554W WO2020049534A1 WO 2020049534 A1 WO2020049534 A1 WO 2020049534A1 IB 2019057554 W IB2019057554 W IB 2019057554W WO 2020049534 A1 WO2020049534 A1 WO 2020049534A1
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WIPO (PCT)
Prior art keywords
day
cancer
compound
dose
pharmaceutically acceptable
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PCT/IB2019/057554
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English (en)
Inventor
Nancy Lewis
Sarah McWHIRTER
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Novartis Ag
Aduro Biotech, Inc.
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Publication of WO2020049534A1 publication Critical patent/WO2020049534A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

  • the present invention relates to use of a STING agonist or a combination of therapeutic compounds useful for the treatment of cancer.
  • the invention relates to combination therapies comprising at least (a) the STING agonist COMPOUND A (dithio- Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]) or a pharmaceutically acceptable salt thereof and (b) one or more PD- 1 or CTLA-4 checkpoint inhibitors, suitably selected from spartalizumab, nivolumab and ipilimumab.
  • TME tumor microenvironment
  • TILs tumor infiltrating lymphocytes
  • CD28 facilitates and maintains a T cell response, partly through increased cytokine expression (Chambers and Allison (1999) Opin Cell Biol 11(2):203-210) mediated by interaction with its primary ligands B7-1 and B7- 2 on the surface of the APCs.
  • CTLA-4 signaling inhibits T cell activation, particularly during strong T cell responses.
  • CTLA-4 blockade, using anti-CTLA-4 antibody therapy, has been shown to suppress inhibitory signals resulting in the generation of an antitumor T cell response.
  • the inhibition of CTLA-4 shifts the immune system balance toward T cell activation, resulting in rejection of tumors by the host.
  • CTLA-4 is essential to the downregulation of autoreactive and potentially destructive peripheral T cell responses.
  • Treating patients with a CTLA-4 inhibitor can broaden the diversity of the peripheral T cell receptor repertoire following CTLA-4 blockade which has been associated with antitumor activity (Buchbinder and Desai (2016 ) Am J Clin Oncol 39:98-106; Robert etal (2014) Clin Cancer Res 20(9):2424- 2432).
  • the Programmed Death 1 (PD-l) protein is an inhibitory member of the CD28/CTLA- 4 family of T cell regulators (Okazaki etal. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). PD-l is expressed on activated B cells, T cells, and monocytes.
  • PD-L1 B7-H1
  • PD-L2 B7-DC
  • PD-L1 expressing tumor cells interact with PD-l expressing T-cells, which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med. 81 :281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-l with PD-L1 or PD-L2.
  • Immunotherapies employing checkpoint inhibitors currently in development have started to offer significant benefit to cancer patients, including those for whom conventional treatments are ineffective.
  • T cells attack and destroy tumor cells, tumors are able to inhibit T cell activation thereby escaping immune surveillance.
  • treatment failure is associated with upregulation of alternate immune checkpoint inhibitors that act to limit the antitumor immune response (Koyama et al (2016) Nat Commun 7(1): 10501), suggesting that many patients treated with single agent inhibitors do not benefit adequately from treatment.
  • the present invention relates to a method for the treatment of cancer.
  • the method comprises administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 50 pg to about 10,000 pg (e.g., 400 pg to about 10,000 pg) of COMPOUND A (dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, and (b) one or more PD-l or CTLA-4 checkpoint inhibitors, suitably or preferably selected from nivolumab, spartalizumab and ipilimumab, wherein COMPOUND A, or the pharmaceutically acceptable salt thereof, is administered intratumorally or intravesically.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • COMPOUND A dithio-Rp,Rp-cyclic-[A
  • the method comprises the separate or sequential administration of (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 400 pg to about 10,000 pg of Compound A (dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]) or a pharmaceutically acceptable salt thereof, and (b) one or more PD-l or CTLA-4 checkpoint inhibitors, suitably or preferably selected from nivolumab, spartalizumab and ipilimumab, for the treatment of cancer, e.g., a solid cancer or lymphoma, including, but not limited to, melanoma, e.g., metastatic melanoma, breast cancer, e.g., triple negative breast cancer (TNBC), squamous cell carcinoma (SCC), lymphoma, e.g., Hodgkin lymphoma, Merkel cell carcinoma, uveal mela
  • COMPOUND A is the compound with the following structure:
  • a dose e.g., a daily dose, a weekly dose, etc.
  • spartalizumab is administered intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • Compound A dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]
  • nivolumab is administered intravenously at a dose of about 480 mg on day 1 of a 28-day treatment cycle.
  • a pharmaceutical combination for use in the treatment of cancer comprising (a) COMPOUND A (dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof and (b) one or more checkpoint inhibitors selected from nivolumab, spartalizumab and ipilimumab, and wherein COMPOUND A or the pharmaceutically acceptable salt thereof is administered to a patient in need thereof at a dose (e.g., a daily dose, a weekly dose, etc.) of about 400 pg to about 10,000 pg, and wherein COMPOUND A or the pharmaceutically acceptable salt thereof is administered intratumorally or intravesically.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a method for the treatment of cancer comprising administering to a patient in need thereof a dose (e.g., a daily dose, a weekly dose, etc.) of about 300 pg to about 10,000 pg (e.g., about 400-10,000 pg) of COMPOUND A (dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, intratumorally or intravesically.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • COMPOUND A dithio-Rp,R
  • the cancer is, e.g., a solid cancer or lymphoma, including, but not limited to, melanoma, e.g., metastatic melanoma, breast cancer, e.g., triple negative breast cancer (TNBC), squamous cell carcinoma (SCC), lymphoma, e.g., Hodgkin lymphoma, Merkel cell carcinoma, uveal melanoma, renal cell cancer (RCC), colorectal cancer (CRC), e.g., microsatellite stable (MSS) colorectal cancer (CRC), ovarian cancer, pancreas cancer, bladder cancer, or head and neck cancer e.g., head and neck squamous cell carcinoma (HNSCC).
  • melanoma e.g., metastatic melanoma
  • breast cancer e.g., triple negative breast cancer (TNBC)
  • SCC squamous cell carcinoma
  • lymphoma e.g., Hodg
  • Figure 1 illustrates the study design on anti-tumor activity of Compound A in combination with an anti-CTUA-4 antibody in B16 Melanoma mouse model.
  • Figure 2 is a plot of tumor volume over time.
  • C57BU/6 mice were implanted with 5 10 4 B 16.F10 melanoma cells on the right flank at Day 0.
  • Mice were treated IP on days 20, and 24 with anti-CTUA4 (clone 9D9, 100 pg) or IgG isotype control (100 pg). Results are shown as mean tumor volume ⁇ SEM. Two-way ANOVA of mean at day 41, * P ⁇ 0.05.
  • Figures 3A and 3B illustrate the systemic IFN-b concentrations as PD biomarker.
  • Figure 3A is a plot demonstrating change of IFN-b concentrations at 6 hours post-treatment versus pre-dose.
  • Figure 3B is PK/PD analysis of IFN-b concentration change from pre-dose by AUCiast (which is the area under the concentration-time curve from time zero to time of last measurable concentration).
  • AUCiast which is the area under the concentration-time curve from time zero to time of last measurable concentration.
  • composition“comprising” X may consist exclusively of X or may include something additional e.g. X + Y.
  • composition“comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment can be more narrowly claimed using the intermediate term“consisting essentially of’ or the closed term“consisting of’.
  • the articles “a” and “an” refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.
  • “About” and “approximately” shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements, or when used in connection with a numerical value, means that a collection or range of values is included. Exemplary degrees of error are within 20 percent (%), more typically, within 10%, of a given value or range of values. This usage of“about” recognizes that the precise amount in a given dosage form may differ slightly from an intended amount for various reasons without materially affecting the in vivo effect of the administered therapeutic agent.
  • “about X” includes a range of values that are ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, ⁇ 0.2%, or ⁇ 0.1% of X, where X is a numerical value of the intended dose.
  • the term“about” refers to a range of values which are 10% more or less than the specified value.
  • the term“about” refers to a range of values which are 5% more or less than the specified value.
  • the term“about” refers to a range of values which are 1% more or less than the specified value.
  • ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
  • a range used herein, unless otherwise specified, includes the two limits of the range. For example, the terms“between X and Y” and“range from X to Y, are inclusive of X and Y and the integers there between.
  • any range including any of the two individual values as the two end points is also conceived in this disclosure.
  • the expression“a dose of about 800 pg, 1,200 pg, 1,600 pg, 2,000 pg, 2,400 pg, 2,800 pg, or 3,200 pg” can also mean “a dose ranging from 800 to 1,200 pg”,“a dose ranging from 1,200 to 2,400 pg”, or“a dose ranging from 800 to 3,200 pg”.
  • the terms“treat”,“treatment” and“treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disorder, e.g., a proliferative disorder, such as a cancer, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of the disorder resulting from the administration of one or more therapeutic agents.
  • a proliferative disorder such as a cancer
  • the terms“treat”,“treatment” and“treating” refer to the reduction or stabilization of the progression of a proliferative disorder, such as a cancer, either physically by, e.g., reduction or stabilization of a discernible symptom, physiologically by, e.g., reduction or stabilization of a physical parameter, or both.
  • the terms“treat,”“treatment” and“treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as a cancer, such as reduction or stabilization of tumor size or reduction or stabilization of cancerous cell count or reduction or stabilization of rate of cancer cell infiltration into peripheral organs or reduction or stabilization of tumor metastasis or reduction or stabilization of tumor growth, not necessarily discernible by the patient.
  • Such“treatment” therefore may result in the slowing, interrupting, arresting, controlling, delaying the onset (i.e., the period prior to clinical manifestation of a disease), reducing the risk of developing or worsening or stopping of the progression of a proliferative disorder, such as a cancer, as described herein, but does not necessarily indicate a total elimination of the proliferative disorder, such as a cancer, or the total elimination of symptoms of the proliferative disorder, such as a cancer.
  • administering is intended to refer to a method of giving a dosage of a pharmaceutically active ingredient, e.g., COMPOUND A or a checkpoint inhibitor as described herein, to a subject in need thereof.
  • a pharmaceutically active ingredient e.g., COMPOUND A or a checkpoint inhibitor as described herein
  • a“therapeutic agent” is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. It is also to be understood that a“therapeutic agent” may be a single compound or a combination or composition of two or more compounds.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject, e.g. a mammal or human, without excessive toxicity, irritation, allergic response and other problems or complications commensurate with a reasonable benefit/risk ratio.
  • a combination or“in combination with” it is not intended to imply that the therapy or the therapeutic agents (e.g., COMPOUND A or a pharmaceutically acceptable salt thereof, or a checkpoint inhibitor, such as ipilimumab, spartalizumab, nivolumab, etc.) must be physically mixed or administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope described herein.
  • a therapeutic agent in these combinations can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents.
  • the therapeutic agents can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the therapeutic agents utilized in this combination may be administered together in a single composition or administered separately in different compositions.
  • additional therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually.
  • the levels utilized in combination will be lower than those utilized as single-agent therapeutics.
  • the combinations of the invention have therapeutic or protective functions or both.
  • these molecules may be administered to a human subject, to treat and/or prevent a variety of disorders, such as cancers as described herein.
  • “combination therapy” and“therapeutic combination” refer to treatments in which the therapeutic agents, e.g., COMPOUND A, or a pharmaceutically acceptable salt thereof, and at least one checkpoint inhibitor, suitably selected from PD-l inhibitor or CTUA- 4 inhibitor, and optionally additional therapeutic agents, are administered to a patient in a coordinated manner, in order to treat a therapeutic condition or disorder described herein.
  • Such administration encompasses co-administration of these therapeutic agents in separate formulations (e.g., capsules and/or intravenous formulations) for each active ingredient.
  • such administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times.
  • the therapeutic agents are administered to the same patient as part of the same course of therapy.
  • the therapeutic agents of the combination therapy can be given jointly, separately or sequentially in such time intervals that they prefer such that the subject, especially human, to be treated, still show an (preferably synergistic) interaction (joint therapeutic effect).
  • joint therapeutic effect Whether this is the case can, inter alia, be determined by following the blood levels of the compounds, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • the treatment regimen will provide beneficial effects in treating the conditions or disorders, suitably cancer, as described herein.
  • the term“synergistic effect” as used herein, refers to action of two or more agents such as, for example, COMPOUND A, or a pharmaceutically acceptable salt thereof, and one or more checkpoint inhibitors, preferably selected from a PD- 1 inhibitor or a CTLA-4 inhibitor, suitably or preferably selected from ipilimumab, spartalizumab, and nivolumab, to produce an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a checkpoint inhibitors preferably selected from a PD- 1 inhibitor or a CTLA-4 inhibitor, suitably or preferably selected from ipilimumab, spartalizumab, and nivolumab
  • non-fixed combination or“kit of parts” means that the therapeutic agents of the combination of the invention are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of a subject in need thereof.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • sequential use is meant administration of at least two active ingredients at different times, the administration route being identical or different. More particularly by a sequential administration method is meant according to which the whole administration of one of the active ingredients is carried out before administration of the other or others commences.
  • treatment regimen As used herein, the terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy as disclosed herein.
  • the dosing regimen defines the amount of a drug and the number and frequency of its administrations over a specified period of time that is employed in the treatment of a disease.
  • dose refers to a specified amount of a drug administered.
  • dose or“dose per day” refers to a specified amount of a drug administered in one day. This term does not imply that the drug administration has to occur every day on consecutive days or only one administration per day.
  • The“daily dose” may be the amount administered into one lesion per day or the total amount per day if administered into multiple lesions (e.g., 2, 3, 4, 5, or 6 lesions).
  • the term“weekly dose” or“dose per week” refers to a specified amount of a drug administered in one week and this term does not imply that the drug administration has to occur only once per week or to occur on consecutive days of the week or on consecutive weeks.
  • pharmaceutical composition refers to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order or treat a particular disease or condition affecting the subject.
  • the present pharmaceutical combinations can be formulated in suitable pharmaceutical compositions for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art.
  • the pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • the amount of each carriers used may vary within ranges conventional in the art.
  • the pharmaceutical compositions provided herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in l,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in l,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions described herein are preferably formulated as pharmaceutical compositions for parenteral or enteral delivery.
  • a typical pharmaceutical composition for administration to an animal subject comprises a pharmaceutically acceptable vehicle such as aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like. See, e.g., Remington's Pharmaceutical Sciences, !5th Ed.. Easton ed., Mack Publishing Co., pp 1405-1412 and 1461- 1487 (1975); The National Formulary XIV. !4th Ed.. American Pharmaceutical Association, Washington, DC (1975).
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial agents, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components the pharmaceutical composition are adjusted according to routine skills in the art.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the therapeutic agents along with pharmaceutically acceptable carriers and excipients.
  • the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, or the like, administered to the patient at the same time.
  • the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient.
  • compositions may be prepared by any of the methods well known in the pharmacy art.
  • unit dose or “unit dosage” refers to a physically discrete unit that contains a predetermined quantity of active ingredient, e.g., COMPOUND A or a pharmaceutically acceptable salt thereof, calculated to produce a desired therapeutic effect.
  • the unit dose or unit dosage may be in the form of an injectable solution, tablet, capsule, sachet, etc. referred to herein as a "unit dosage form".
  • the pharmaceutical compositions described herein may include a“therapeutically effective amount” or “effective amount” of a compound disclosed herein.
  • pharmaceutically effective amount is an amount sufficient, at dosages and for periods of time necessary, to provide an observable or clinically significant improvement over the baseline of clinically observable signs and symptoms of the disorders treated with the combination.
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the therapeutic agents are outweighed by therapeutically beneficial effects.
  • a "therapeutically effective amount” preferably modulates a measurable parameter, such as tumor growth rate or disease progression in a desired manner.
  • the ability of a compound to modulate a measurable parameter may be evaluated in an animal model system predictive of efficacy in human tumors to help establish suitable dosing levels and schedules.
  • this property of a composition may be evaluated by examining the ability of the compound to modulate an undesired parameter by using in vitro assays known to the skilled practitioner.
  • the term“cancer” refers to a disease characterized by the undesired and uncontrolled growth of aberrant cells and is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathological type or stage of invasiveness. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body.
  • the term“cancer” or“tumor” includes premalignant, as well as malignant cancers and tumors.
  • the term“cancer” is used herein to mean a broad spectrum of tumors, including all solid tumors and lymphomas.
  • subject or“patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a cancer or any disorder involving, directly or indirectly, a cancer.
  • subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a proliferative disease, such as cancer and who would benefit from treatment.
  • the subject is a human patient in need of enhancement of an immune response.
  • the methods and compositions described herein are suitable for treating human patients having a disorder that can be treated by modulating (e.g., augmenting or inhibiting) an immune response.
  • immune response relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.
  • a subject is“in need of’ a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.
  • RECIST 1.1 Response Criteria means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or non-target lesions, as appropriate based on the context in which response is being measured.
  • %T/C refers to the percent change in tumor volume in a treated (e.g., treated with COMPOUND A or COMPOUND A in combination with a checkpoint inhibitor) versus control animal (e.g., treated with standard of care or treated with control vehicle).
  • inhibitortion includes a reduction in a certain parameter, e.g., an activity, of a given molecule, e.g., an immune checkpoint inhibitor, e.g., an inhibitor of PD-l or an inhibitor of CTLA-4.
  • an activity e.g., a PD- 1 or CTLA-4 activity
  • inhibition can be, but need not be 100%.
  • activation includes an increase in a certain parameter, e.g., an activity, of a given molecule, e.g., a costimulatory molecule.
  • a certain parameter e.g., an activity, of a given molecule
  • a costimulatory molecule e.g., a costimulatory molecule
  • increase of an activity, e.g., a costimulatory activity, of at least 5%, 10%, 25%, 50%, 75% or more is included by this term.
  • salts can be present alone or in mixture with free compounds of the combination of the invention, e.g., COMPOUND A, and are preferably pharmaceutically acceptable salts.
  • Such salts are formed, for example, by modifying the parent compound via converting an existing acid or base moiety to its salt form.
  • the pharmaceutically acceptable salt of Compound A is selected from the group consisting of the sodium, potassium, calcium, magnesium, zinc, aluminum, ammonium, diethylamine, isopropylamine, olamine, benzathine, benethamine, tromethamine (2-amino-2-(hydroxymethyl)propane-l,3-diol), morpholine, epolamine, piperidine, piperazine, picoline, dicyclohexylamine, N,N’-dibenzylethylenediamine, 2- hydroxyethylamine, tri-(2-hydroxyethyl)amine, chloroprocaine, choline, deanol, imidazole, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, dibenzylpiperidine, dehydroabietylamine, glucamine, collidine, quinine, quinolone, erbumine, lysine and arg
  • salts of compounds used in the combination of the invention are preferably pharmaceutically acceptable salts.
  • reference to therapeutic agents useful in the pharmaceutical combination provided herein includes both the free acid or base from of the compounds, and all pharmaceutically acceptable salts of the compounds.
  • antibody molecule refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain sequence.
  • the term“antibody molecule” includes, for example, a monoclonal antibody (including a full length antibody which has an immunoglobulin Fc region).
  • an antibody molecule comprises a full length antibody, or a full length immunoglobulin chain.
  • an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain.
  • an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope.
  • a multispecific antibody molecule is a bispecific antibody molecule.
  • a bispecific antibody has specificity for no more than two antigens.
  • a bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.
  • an antibody molecule is a monospecific antibody molecule and binds a single epitope, e.g. , a monospecific antibody molecule having a plurality of immunoglobulin variable domain sequences, each of which binds the same epitope.
  • an antibody molecule comprises a diabody, and a single-chain molecule, as well as an antigen-binding fragment of an antibody (e.g., Fab, F(ab’)2, and Fv).
  • an antibody molecule can include a heavy (H) chain variable domain sequence (abbreviated herein as VH), and a light (L) chain variable domain sequence (abbreviated herein as VL).
  • VH heavy chain variable domain sequence
  • VL light chain variable domain sequence
  • an antibody molecule comprises or consists of a heavy chain and a light chain (referred to herein as a half antibody).
  • an antibody molecule in another example, includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab’, F(ab’)2, Fc, Fd, Fd’, Fv, single chain antibodies (scFv for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g. , humanized) antibodies, which may be produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind with their respective antigen or receptor.
  • Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., IgGl, IgG2, IgG3, and IgG4) of antibodies.
  • the preparation of antibody molecules can be monoclonal or polyclonal.
  • An antibody molecule can also be a human, humanized, CDR-grafied, or in vitro generated antibody.
  • the antibody can have a heavy chain constant region chosen from, e.g., IgGl, IgG2, IgG3, or IgG4.
  • the antibody can also have a light chain chosen from, e.g., kappa or lambda.
  • the term“immunoglobulin” (Ig) is used interchangeably with the term“antibody” herein.
  • antigen-binding fragments of an antibody molecule include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see e.g., Bird el al.
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • a F(ab')2 fragment a bivalent fragment comprising two Fab fragment
  • antibody includes intact molecules as well as functional fragments thereof. Constant regions of the antibodies can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).
  • the VH and VL regions can be subdivided into regions of hypervariability, termed “complementarity determining regions” (CDR), interspersed with regions that are more conserved, termed “framework regions” (FR or FW).
  • CDR complementarity determining regions
  • FR framework regions
  • the extent of the framework region and CDRs has been precisely defined by a number of methods (see, Rabat, E. A., el al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. etal. (1987) J. Mol. Biol. 196:901- 917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See, generally, e.g. , Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-
  • CDR complementarity determining region
  • HCDR1, HCDR2, HCDR3 three CDRs in each heavy chain variable region
  • LCDR1, LCDR2, LCDR3 three CDRs in each light chain variable region
  • checkpoint inhibitor antibody molecules set forth herein can include any combination of one or more Rabat CDRs and/or Chothia hypervariable loops, e.g., described in Table 1, Table 2 or Table 3.
  • an“immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain.
  • the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain.
  • the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.
  • monoclonal antibody or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • a monoclonal antibody can be made by hybridoma technology or by methods that do not use hybridoma technology (e.g., recombinant methods).
  • a humanized or CDR-grafted antibody will have at least one or two but generally all three recipient CDRs (of heavy and or light immunoglobulin chains) replaced with a donor CDR.
  • the antibody may be replaced with at least a portion of a non-human CDR or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to PD-l or to CTLA-4.
  • the donor will be a rodent antibody, e.g., a rat or mouse antibody
  • the recipient will be a human framework or a human consensus framework.
  • the immunoglobulin providing the CDRs is called the "donor” and the immunoglobulin providing the framework is called the "acceptor".
  • the donor immunoglobulin is a non-human (e.g., rodent).
  • the acceptor framework is a naturally-occurring (e.g., a human) framework or a consensus framework, or a sequence about 85% or higher, preferably 90%, 95%, 99% or higher identical thereto
  • DAMPs damage-associated molecular patterns
  • PAMPs pathogen-associated molecular patterns
  • CDNs cyclic-di-nucleotides
  • PAMP pathogen associated molecular pattern
  • PRR pathogen recognition receptor
  • STING Stimulator of INterferon Genes
  • cGAS Upon recognition of cytosolic DNA, cGAS catalyzes the generation of the cyclic-dinucleotide 2'-3' cGAMP, an atypical second messenger that strongly binds to the ER-transmembrane adaptor protein STING. A conformational change is undergone by cGAMP-bound STING, which translocates to a perinuclear compartment and induces the activation of critical transcription factors IRF-3 and NF-kB.
  • Type I interferons and pro-inflammatory cytokines strongly potentiate T-cell activation by enhancing the ability of dendritic cells and macrophages to uptake, process, present and cross-present antigens to T-cells.
  • Type I interferons can significantly enhance anti tumor immune responses by inducing activation of both the adaptive and innate immune cells.
  • tumor invasiveness may be inhibited by interferons by modulating enzyme expression related to tissue remodeling. Examples of cyclic purine dinucleotides are described in some detail in, e.g., U.S. Patent Nos. 7,709458 and 7,592,326; W02007/054279; and Yan et al, Bioorg. Med. Chem Lett. 18: 5631 (2008), each of which is hereby incorporated by reference.
  • the present invention is based partially on the surprising finding that the combination of a STING agonist, e.g., COMPOUND A or a pharmaceutically acceptable salt thereof, and one or more checkpoint inhibitors, e.g., an anti -PD- 1 antibody or an anti-CTLA-4 antibody, leads to early and robust antitumor responses from the immunoactivation of STING agonism and the long-term benefit of immunotherapy.
  • a STING agonist e.g., COMPOUND A or a pharmaceutically acceptable salt thereof
  • one or more checkpoint inhibitors e.g., an anti -PD- 1 antibody or an anti-CTLA-4 antibody
  • the combinations disclosed herein can result in one or more of: an increase in antigen presentation, an increase in effector cell function (e.g., one or more of T cell proliferation, IFN- g secretion or cytolytic function), inhibition of regulatory T cell function, an effect on the activity of multiple cell types, such as regulatory T cell, effector T cells and NK cells), an increase in tumor infiltrating lymphocytes, an increase in T-cell receptor mediated proliferation, and a decrease in immune evasion by cancerous cells.
  • an increase in antigen presentation an increase in effector cell function (e.g., one or more of T cell proliferation, IFN- g secretion or cytolytic function), inhibition of regulatory T cell function, an effect on the activity of multiple cell types, such as regulatory T cell, effector T cells and NK cells), an increase in tumor infiltrating lymphocytes, an increase in T-cell receptor mediated proliferation, and a decrease in immune evasion by cancerous cells.
  • an increase in antigen presentation e.g., an increase in effect
  • the method comprises administering to the subject a combination according to the methods disclosed herein (e.g., a combination comprising a therapeutically effective amount of an anti-PD-l antibody molecule and a therapeutically effective amount of COMPOUND A or a pharmaceutically acceptable salt thereof), such that the immune response in the subject is modulated.
  • the antibody molecule enhances, stimulates or increases the immune response in the subject.
  • the subject can be a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein).
  • the subject is in need of enhancing an immune response.
  • the subject has, or is at risk of, having a proliferative disorder described herein, e.g., a cancer, as described herein.
  • COMPOUND A in combination with a checkpoint inhibitor, e.g., an anti-PD-l antibody or an anti-CTUA-4 antibody in humans with diverse malignancies resulted in clinical systemic anti-tumor responses.
  • a checkpoint inhibitor e.g., an anti-PD-l antibody or an anti-CTUA-4 antibody in humans with diverse malignancies resulted in clinical systemic anti-tumor responses.
  • a STING agonist e.g., COMPOUND A or a pharmaceutically acceptable salt thereof
  • a checkpoint inhibitor e.g., an anti-PD-l antibody or an anti-CTUA-4 antibody
  • STING semulator of interferon genes
  • ERIS endoplasmic reticulum interferon stimulator
  • MIRF3 activation MIAA
  • MPYS MYS
  • TM173 transmembrane protein 173
  • STING is a transmembrane receptor protein and is encoded by the gene TMEM173 in human.
  • STAT6 signal transducer and activator of transcription 6
  • Tin-ty pe increase (IU-12), or decrease (IU-10) production of various cytokines, including the chemokines CCU2, CCU20, and CCU26 (Chen et al, 2011).
  • COMPOUND A which is dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p], or a pharmaceutically acceptable salt thereof, is a synthetic cyclic dinucleotide (CDN) molecule comprised of two adenosine purine nucleotides that can initiate a productive anti-tumor immune response through the STING pathway when delivered to the tumor microenvironment by acting on tumor-resident dendritic cells (DC) and other cell populations.
  • CDN synthetic cyclic dinucleotide
  • COMPOUND A a STING agonist
  • a STING agonist may therefore be useful in treating (e.g., one or more of reducing, inhibiting, or delaying progression) a proliferative disease, particularly a cancer, particularly a solid tumor or lymphoma.
  • the STING agonist is COMPOUND A, or a pharmaceutically acceptable salt thereof.
  • COMPOUND A has the following structure:
  • COMPOUND A is disclosed in WO2014/189805, which is incorporated herein by reference in its entirety.
  • COMPOUND A (also referred to herein as“Compound A”) is also known by the name of dithio-Rp,Rp-cyclic- [A(2’ ,5’ )pA(3’ 5’ )p] .
  • the pharmaceutically acceptable salt of COMPOUND A is a disodium salt.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered, e.g., as a single agent, at a dose of about 300 pg to about 10,000 pg (e.g., per injection or per day or per administration) for treating cancer in a subject in need thereof.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 pg to about 5,000 pg.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 pg to about 2000 pg.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 300 pg to about 1000 pg.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 pg to about 10,000 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 pg to about 7000 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 pg to about 4000 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1000 pg to about 5000 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5000 pg to about 10,000 pg.
  • COMPOUND A is administered at a dose of about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, about 800 pg, about 850 pg, about 900 pg, about 950 pg, about 1000 pg, about 1050 pg, about 1100 pg, about 1150 pg, about 1200 pg, about 1250 pg, about 1300 pg, about 1350 pg, about 1400 pg, about 1450 pg, about 1500 pg, about 1550 pg, about 1600 pg, about 1650 pg, about 1700 pg, about 1750 pg, about 1800 pg, about 1850 pg, about 1900 pg, about 1950 pg,
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 800 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1600 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 3200 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 6400 pg. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 9600 pg.
  • a combination with a checkpoint inhibitor e.g., an antibody molecule (e.g., ahumanized antibody molecule or ahuman antibody molecule) that binds to Programmed Death 1 (PD-l) and blocks the binding of PD-l to PD-U1 and/or PD-U2 or an antibody molecule (e.g., a humanized antibody molecule or a human antibody molecule) that binds to CTUA-4 and blocks the binding of CTUA-4 to CD80 and/or CD86, especially the exemplary antibody molecules as described below, can be useful in the treatment of patients with cancer, in particular with solid cancer or lymphoma.
  • a checkpoint inhibitor e.g., an antibody molecule (e.g., ahumanized antibody molecule or ahuman antibody molecule) that binds to Programmed Death 1 (PD-l) and blocks the binding of PD-l to PD-U1 and/or PD-U2 or an antibody molecule (e.g., a humanized antibody molecule or
  • a PD- 1 inhibitor in the combination inhibits, reduces or neutralizes one or more activities of PD-l, resulting in blockade or reduction of an immune checkpoint.
  • combinations comprising (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, and (b) at least one or more PD-l inhibitor can be used to treat or prevent disorders where enhancing an immune response in a subject is desired.
  • PD-l is a CD28/CTUA-4 family member expressed, e.g., on activated CD4 + and CD8 + T cells, Tregs, and B cells. It negatively regulates effector T cell signaling and function. PD-l is induced on tumor-infiltrating T cells, and can result in functional exhaustion or dysfunction (Keir et al. (2008) Anna. Rev. Immunol. 26:677-704; Pardoll et al. (2012) Nat Rev Cancer l2(4):252-64). PD-l delivers a coinhibitory signal upon binding to either of its two ligands, Programmed Death-Uigand 1 (PD-U1) or Programmed Death-Uigand 2 (PD-U2).
  • PD-U1 Programmed Death-Uigand 1
  • PD-U2 Programmed Death-Uigand 2
  • PD-U1 is expressed on a number of cell types, including T cells, natural killer (NK) cells, macrophages, dendritic cells (DCs), B cells, epithelial cells, vascular endothelial cells, as well as many types of tumors.
  • High expression of PD-U1 on murine and human tumors has been linked to poor clinical outcomes in a variety of cancers (Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardoll et al. (2012) Nat Rev Cancer l2(4):252-64).
  • PD-U2 is expressed on dendritic cells, macrophages, and some tumors.
  • Blockade of the PD-l pathway has been pre -clinically and clinically validated for cancer immunotherapy. Both preclinical and clinical studies have demonstrated that anti -PD-l blockade can restore activity of effector T cells and results in robust anti-tumor response.
  • Blockade of the PD-l pathway can be effected with an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide of PD-l, PD-L1 and/or PD-L2.
  • PD-l includes isoforms, mammalian, e.g., human PD-l, species homologs of human PD-l, and analogs comprising at least one common epitope with PD-l .
  • the amino acid sequence of PD-l, e.g., human PD-l is known in the art, e.g., Shinohara T et al. (1994) Genomics 23(3):704-6; Finger LR, et al. Gene (1997) 197(1-2): 177-87.
  • the antibody molecule binds to a mammalian, e.g., human, PD-l .
  • the antibody molecule binds specifically to an epitope, e.g., linear or conformational epitope on PD- 1.
  • COMPOUND A as described herein is administered in combination with a PD-l inhibitor.
  • the PD-l inhibitor is chosen from spartalizumab (PDR001, Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab (REGN2810, Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).
  • the anti -PD-l antibody molecule is spartalizumab (Novartis), also known as PDR001 or PDR-001.
  • Spartalizumab (PDR001) is a high-affinity, ligand-blocking, humanized anti -PD-l IgG4 antibody that blocks the binding of PD-L 1 and PD-L2 to PD-l .
  • the PD-l inhibitor is an anti-PD-l antibody molecule. In one embodiment, the PD-l inhibitor is an anti-PD-l antibody molecule as described in US 2015/0210769, published on July 30, 2015, entitled“Antibody Molecules to PD-l and Uses Thereof,” incorporated by reference in its entirety. In one embodiment, the PD-l inhibitor is spartalizumab (corresponding to BAP049-Clone-E, also known as PDR001) as disclosed in US 2015/0210769, incorporated by reference in its entirety.
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of spartalizumab, e.g., as disclosed in Table 1.
  • the anti-PD-l antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 (e.g. , from the heavy and light chain variable region sequences of BAP049-Clone-E or BAP049-Clone-B disclosed in Table 1), or encoded by a nucleotide sequence shown in Table 1.
  • the CDRs are according to the Kabat definition (e.g., as set out in Table 1).
  • the CDRs are according to the Chothia definition (e.g., as set out in Table 1).
  • the CDRs are according to the combined CDR definitions of both Kabat and Chothia (e.g., as set out in Table 1).
  • the combination of Kabat and Chothia CDR of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 543).
  • one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.
  • the anti -PD- 1 antibody molecule comprises a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 501, a VHCDR2 amino acid sequence of SEQ ID NO: 502, and a VHCDR3 amino acid sequence of SEQ ID NO: 503; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 510, a VLCDR2 amino acid sequence of SEQ ID NO: 511, and a VLCDR3 amino acid sequence of SEQ ID NO: 512, each disclosed in Table 1.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody molecule comprises a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 526; and a VL comprising a VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, a VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and a VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531, each disclosed in Table 1.
  • the anti -PD- 1 antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 506.
  • the anti-PD-l antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 520, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 520.
  • the anti-PD- 1 antibody molecule comprises a VL comprising the amino acid sequence of SEQ ID NO: 516, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 516.
  • the anti-PD-l antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 520. In one embodiment, the anti-PD-l antibody molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 506 and a VL comprising the amino acid sequence of SEQ ID NO: 516.
  • the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 507. In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 521 or 517. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
  • the anti -PD- 1 antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 508.
  • the anti- PD-l antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 522, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 522.
  • the anti-PD-l antibody molecule comprises a light chain comprising the amino acid sequence of SEQ ID NO: 518, or an amino acid sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 518.
  • the anti-PD-l antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 522. In one embodiment, the anti-PD-l antibody molecule comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 508 and a light chain comprising the amino acid sequence of SEQ ID NO: 518.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 509.
  • the antibody molecule comprises a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519, or a nucleotide sequence at least 85%, 90%, 95%, or 99% identical or higher to SEQ ID NO: 523 or 519.
  • the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
  • the antibody molecules described herein can be made by vectors, host cells, and methods described in US 2015/0210769, incorporated by reference in its entirety. Table 1. Amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
  • the anti -PD- 1 antibody molecule is Nivolumab (Bristol-Myers Squibb), also known as MDX-l 106, MDX-l 106-04, ONO-4538, BMS-936558, or OPDIVO®.
  • Nivolumab (Opdivo®) is a fully human IgG4 monoclonal antibody (mAb) binding PD-l, thereby blocking the binding of PD-L1 and PD-L2 to PD-l.
  • Opdivo® is approved for the treatment of various cancers, including unresectable or metastatic melanoma, renal cell carcinoma, Hodgkin lymphoma, Recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC), and Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC).
  • NRC Microsatellite instability-high metastatic colorectal cancer
  • Nivolumab clone 5C4
  • other anti-PD-l antibodies are disclosed in US 8,008,449 and WO 2006/121168, incorporated by reference in their entirety.
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Nivolumab, e.g., as disclosed in Table 2.
  • the anti-PD-l antibody molecule is Pembrolizumab (Merck & Co), also known as Lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®.
  • Pembrolizumab and other anti-PD-l antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009/114335, incorporated by reference in their entirety.
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pembrolizumab, e.g., as disclosed in Table 2.
  • the anti -PD- 1 antibody molecule is Pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti -PD- 1 antibodies are disclosed in Rosenblatt, J. etal. (2011) J Immunotherapy 34(5): 409-18, US 7,695,715, US 7,332,582, and US 8,686,119, incorporated by reference in their entirety.
  • the anti -PD- 1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of Pidilizumab, e.g., as disclosed in Table 2.
  • the anti -PD- 1 antibody molecule is MEDI0680 (Medimmune), also known as AMP-514.
  • MEDI0680 and other anti -PD- 1 antibodies are disclosed in US 9,205, 148 and WO 2012/145493, incorporated by reference in their entirety.
  • the anti -PD- 1 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of MEDI0680.
  • the anti-PD-l antibody molecule is cemiplimab , also known as REGN2810 (Regeneron).
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of cemiplimab (REGN2810).
  • the anti-PD-l antibody molecule is PF-06801591 (Pfizer). In one embodiment, the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of PF-06801591.
  • the anti-PD-l antibody molecule is tislelizumab, also known as BGB-A317 or BGB-108 (Beigene).
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of tislelizumab (BGB-A317) or BGB-108.
  • the anti-PD-l antibody molecule is INCSHR1210 (Incyte), also known as INCSHR01210 or SHR-1210. In one embodiment, the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of INCSHR1210.
  • the anti-PD-l antibody molecule is TSR-042 (Tesaro), also known as ANB011.
  • the anti-PD-l antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of TSR-042.
  • anti-PD-l antibodies include those described, e.g., in WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, WO 2018/020476, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727, incorporated by reference in their entirety.
  • the anti-PD-l antibody is an antibody that competes for binding with, and/or binds to the same epitope on PD-l as one of the anti-PD-l antibodies described herein.
  • the PD-l inhibitor is a peptide that inhibits the PD-l signaling pathway, e.g., as described in US 8,907,053, incorporated by reference in its entirety.
  • the PD-l inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-l binding portion of PD-U1 or PD-U2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • the PD-l inhibitor is AMP- 224 (B7-DCIg (Amplimmune), e.g., disclosed in WO 2010/027827 and WO 2011/066342, incorporated by reference in their entirety).
  • COMPOUND A as described herein is administered in combination with a CTLA-4 inhibitor.
  • the checkpoint inhibitor is an anti- CTLA-4 antibody molecule.
  • the anti-CTLA-4 antibody molecule is Ipilimumab.
  • Ipilimumab (Y ervoy®) is a fully human IgGl monoclonal antibody (mAb) binding CTLA-4, also known as MDX-010 (CAS No. 477202-00-9) that binds to human CTLA4 and prevent its interaction with CD80 and CD86.
  • Ipilimumab activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
  • Y ervoy® is approved for the treatment of unresectable or metastatic melanoma.
  • the antibody ipilimumab and other anti-CTLA-4 antibodies are disclosed in US 6,984,720, herein incorporated by reference.
  • the anti-CTLA-4 antibody molecule comprises one or more of the CDR sequences (or collectively all of the CDR sequences), the heavy chain or light chain variable region sequence, or the heavy chain or light chain sequence of ipilimumab, e.g., as disclosed in Table 3.
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 400 pg to about 10,000 pg of COMPOUND A (dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, and (b) one or more checkpoint inhibitors, preferably selected from the group consisting of ipilimumab, spartalizumab and nivolumab, and wherein administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, is intra-tumoral, peri-tumoral or into the tumor draining lymph node(s).
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a daily dose, a weekly dose, etc.
  • a dose e.g., a
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 400 pg to about 10,000 pg of COMPOUND A (dithio-Rp,Rp-cyclic-
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 50 pg to about 10,000 pg of COMPOUND A (dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, and (b) one or more PD-l checkpoint inhibitors, and wherein administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, is intra-tumoral, peri-tumoral or into the tumor-draining lymph node(s).
  • a dose e.g., a daily dose, a weekly dose, etc.
  • COMPOUND A dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]
  • PD-l checkpoint inhibitors one or more PD-l checkpoint inhibitors
  • the PD-l inhibitor is selected from the group consisting of spartalizumab, nivolumab, pembrolizumab, pidilizumab, MEDI0680, cemiplimab, TSR-042, PF-06801591, tislelizumab, BGB-108, INCSHR1210, or AMP-224.
  • the PD-l inhibitor is spartalizumab or nivolumab.
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 50 pg to about 10,000 pg of COMPOUND A (dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, and (b) spartalizumab, and wherein administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, is intra-tumoral, peri-tumoral or into the tumor-draining lymph node(s).
  • a dose e.g., a daily dose, a weekly dose, etc.
  • COMPOUND A dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]
  • spartalizumab spartalizumab
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose, a weekly dose, etc.) of about 50 pg to about 10,000 pg of COMPOUND A (dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, and (b) nivolumab, and wherein administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, is intra-tumoral, peri-tumoral or into the tumor-draining lymph node(s).
  • a dose e.g., a daily dose, a weekly dose, etc.
  • COMPOUND A dithio-Rp,Rp-cyclic- [A(2’,5’)pA(3’5’)p]
  • nivolumab nivolumab
  • the methods described herein are for first-line treatment in a patient in need thereof with cancer.
  • the cancer is treatment naive.
  • the methods described herein are for second-line or third-line treatment in a patient in need thereof with cancer, for example following treatment with a checkpoint inhibitor as monotherapy, or following treatment with chemotherapy or following treatment with a checkpoint inhibitor in combination with standard of care (e.g., platinum based therapy or targeted therapy or other chemotherapy) for said cancer.
  • the methods described herein are for the treatment of PD-l inhibitor refractory or relapsed cancer.
  • the methods described herein are for the treatment of PD-1/PD-U1 inhibitor naive cancer.
  • the term“first-line treatment” means that a patient has not been treated previously with a biotherapeutic or chemotherapeutic agent, targeted therapy, or hormonal therapy, i.e., is treatment-naive.
  • second-line or third-line treatment means treatment of a patient that has been treated previously with a biotherapeutic (e.g., checkpoint inhibitor) agent, chemotherapeutic agent (e.g., platinum-based therapy), targeted therapy (e.g., BRAF/MEK inhibitors), and/or hormonal therapy and has failed to achieve a sustained response after prior therapy, i.e., said patient is treatment-experienced.
  • a biotherapeutic e.g., checkpoint inhibitor
  • chemotherapeutic agent e.g., platinum-based therapy
  • targeted therapy e.g., BRAF/MEK inhibitors
  • hormonal therapy e.g., hormonal therapy
  • PD- 1 inhibitor refractory means that a patient is refractory to PD-l inhibitors.
  • PD- 1 inhibitor relapsed means that a patient has relapsed or progressed after an initial response to a PD-l inhibitor.
  • PD-l inhibitor refractory or relapsed means that a patient is refractory to PD-l inhibitor or has relapsed or progressed after an initial response to PD-l inhibitor”.
  • checkpoint inhibitor refractory or relapsed means that a patient is refractory to checkpoint inhibitor or has relapsed or progressed after an initial response to checkpoint inhibitor”.
  • PD-1/PD-L1 inhibitor naive cancer means that a patient has not been treated previously with a PD-l and/or PD-L1 inhibitor for treatment of that patient’s cancer.
  • the methods described herein may also be used prior to or following surgery to remove a tumor and may be used prior to, during, or after radiation treatment.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 pg to about 10,000 pg (e.g., per injection or per day or per administration) in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 pg to about 10,000 pg (e.g., per injection or per day or per administration) in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 pg to about 10,000 pg (e.g., per injection or per day or per administration) in combination with one or more checkpoint inhibitors.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 mg to about 10,000 mg (e.g., per injection or per day or per administration) in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 300 pg to about 10,000 pg (e.g., per injection or per day or per administration) in combination with one or more checkpoint inhibitors for treating cancer in a subject in need thereof. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 pg to about 5,000 pg in combination with one or more checkpoint inhibitors.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 pg to about 2000 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 pg to about 1000 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 pg to about 10,000 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 pg to about 7000 pg in combination with one or more checkpoint inhibitors.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 pg to about 4000 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1000 pg to about 5000 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 5000 pg to about 10,000 pg in combination with one or more checkpoint inhibitors.
  • COMPOUND A is administered at a dose of about 50 pg, about 100 pg, about 150 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, about 800 pg, about 850 pg, about 900 pg, about 950 pg, about 1000 pg, about 1050 pg, about 1100 pg, about 1150 pg, about 1200 pg, 1250 pg, about 1300 pg, about 1350 pg, about 1400 pg, about 1450 pg, about 1500 pg, about 1550 pg, about 1600 pg, about 1650 pg, about 1700 pg about
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 100 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 200 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 400 pg in combination with one or more checkpoint inhibitors.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1600 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 3200 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 6400 pg in combination with one or more checkpoint inhibitors. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 9600 pg in combination with one or more checkpoint inhibitors.
  • the dosages quoted herein may apply to the administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, per lesion or per day or per administration.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered non-parenterally or parenterally.
  • the administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is subcutaneous, intramuscular, intravenous, intradermal, intravesical, mucosal, vaginal, cervical, peri-tumoral, intra-tumoral, or intranode (lymph node), e.g., in the nearest lymph node(s) or directly into the tumor-draining lymph node(s).
  • the administration of COMPOUND A, or a pharmaceutically acceptable salt thereof is intra-tumoral, peri-tumoral, or directly into the tumor-draining lymph node(s).
  • the administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is intra-tumoral.
  • the administration of COMPOUND A, or a pharmaceutically acceptable salt thereof is by intra-tumoral visceral injection.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered into one tumor lesion. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered into the same tumor lesion on each day of administration. In one embodiment, COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof, is administered into a single lesion on each day of administration.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered into a single lesion on each day of administration per treatment cycle.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered into multiple lesions (e.g., 2, 3, 4, 5, or 6 lesions) on each day of administration per treatment cycle.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered into the same multiple lesions on each day of administration per treatment cycle.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof, or a composition comprising COMPOUND A, or a pharmaceutically acceptable salt thereof is administered into different one or more lesions on each day of administration per treatment cycle.
  • the dose of COMPOUND A, or a pharmaceutically acceptable salt thereof, administered per lesion may be between about 50 pg and 10,000 pg, with the total daily dose of COMPOUND A, or a pharmaceutically acceptable salt thereof, not exceeding about 10,000 pg.
  • the dose of COMPOUND A, or a pharmaceutically acceptable salt thereof, administered per lesion may be between about 50 pg and 10,000 pg, with the total weekly dose of COMPOUND A, or a pharmaceutically acceptable salt thereof, not exceeding about 10,000 pg.
  • a dose of about 200 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 400 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 800 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 1600 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 3200 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 6400 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • a dose of about 9600 pg of COMPOUND A, or a pharmaceutically acceptable salt thereof may be administered per lesion, e.g., per day or per week.
  • COMPOUND A is administered on day 1 only of a 21 -day treatment cycle.
  • COMPOUND A is administered on day 1 and on day 8 of a 21 -day treatment cycle.
  • COMPOUND A is administered on day 1 only of a 28 -day treatment cycle.
  • COMPOUND A is administered on day 1 and day 15 of a 28-day treatment cycle.
  • COMPOUND A is administered on day 1, day 8, and day 15 of a 28-day treatment cycle.
  • COMPOUND A is administered on day 1, day 8, day 15, and day 21 of a 28-day treatment cycle.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered for treating a bladder disorder (e.g., bladder cancer).
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered on day 1 and day 8 of a 21 -day treatment cycle for at least one, at least two, at least three, at least four, at least five, or at least six 2l-day treatment cycles.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles, followed by administration once per month for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles, followed by administration once every four weeks for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles, followed by administration once every three weeks for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles, followed by administration once every 8 weeks for at least two months, at least four months, at least six months, at least eight months, at least ten months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 21 -day treatment cycles, followed by administration once every 12 weeks for at least three months, at least six months, at least nine months, or at least 12 months.
  • COMPOUND A or a pharmaceutically acceptable salt thereof, is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered on day 1, day 8, and day 15 of a 28-day treatment cycle for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles, followed by administration once per month for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles, followed by administration once every four weeks for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles, followed by administration once every three weeks for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least 11 months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles, followed by administration once every 8 weeks for at least two months, at least four months, at least six months, at least eight months, at least ten months, or at least 12 months.
  • COMPOUND A is administered for at least one, at least two, at least three, at least four, at least five, or at least six 28-day treatment cycles, followed by administration once every 12 weeks for at least three months, at least six months, at least nine months, or at least 12 months.
  • COMPOUND A or a pharmaceutically acceptable salt thereof, may be administered as a single dose per lesion or per day or per administration or COMPOUND A, or a pharmaceutically acceptable salt thereof, may be administered in multiple doses per lesion or per day or per administration.
  • a method for the treatment of cancer comprising administering to a patient in need thereof (a) a dose (e.g., a daily dose or weekly dose) of about 50 mg to about 10,000 mg of COMPOUND A (dithio-Rp,Rp-cyclic-[A(2’,5’)pA(3’5’)p]), or a pharmaceutically acceptable salt thereof, (b) one or more checkpoint inhibitors, preferably selected from nivolumab, ipilimumab and spartalizumab, and (c) at least one further therapeutic agent, and wherein administration of COMPOUND A, or a pharmaceutically acceptable salt thereof, is intra-tumoral, peri -tumoral or into the tumor-draining lymph node(s).
  • a dose e.g., a daily dose or weekly dose
  • a dose e.g., a daily dose or weekly dose
  • a dose e.g., a daily dose or weekly dose
  • a dose
  • the at least one further therapeutic agent includes, but is not limited to, one or more of standard of care treatment (e.g., for a cancer), targeted therapy (e.g., for cancer), an antibody molecule (e.g., for cancer), an immunomodulator (e.g., a checkpoint inhibitor, an activator of a costimulatory molecule or an inhibitor of a costimulatory molecule); a vaccine, e.g., a therapeutic cancer vaccine.
  • standard of care treatment e.g., for a cancer
  • targeted therapy e.g., for cancer
  • an antibody molecule e.g., for cancer
  • an immunomodulator e.g., a checkpoint inhibitor, an activator of a costimulatory molecule or an inhibitor of a costimulatory molecule
  • a vaccine e.g., a therapeutic cancer vaccine.
  • cancerous disorders include, but are not limited to, solid tumors, hematological cancers, soft tissue tumors, and metastatic lesions.
  • solid tumors include malignancies, e.g., sarcomas, lymphomas, and carcinomas (including adenocarcinomas and squamous cell carcinomas), of the various organ systems, such as those affecting liver, lung, breast, lymphoid, gastrointestinal (e.g., colon), genitourinary tract (e.g., renal, urothelial, or bladder cells), prostate, CNS (e.g., brain, neural, or glial cells), skin, pancreas, and pharynx.
  • malignancies e.g., sarcomas, lymphomas, and carcinomas (including adenocarcinomas and squamous cell carcinomas)
  • gastrointestinal e.g., colon
  • genitourinary tract e.g., renal, urothelial, or bladder cells
  • Adenocarcinomas include malignancies, such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, and cancer of the esophagus.
  • Squamous cell carcinomas include malignancies, e.g., in the lung, esophagus, skin, head and neck region, oral cavity (e.g., gingiva), anus, and cervix. Metastatic lesions of the aforementioned cancers can also be treated or prevented using the methods of the invention.
  • Exemplary cancers whose growth can be inhibited using the methods, as disclosed herein, include cancers typically responsive to immunotherapy.
  • Non-limiting examples of typical cancers for treatment include skin cancer (e.g., a Merkel cell carcinoma or a melanoma, e.g., a cutaneous melanoma), breast cancer (e.g., a metastatic breast carcinoma or a stage IV breast carcinoma, e.g., a triple negative breast cancer (TNBC)), squamous cell carcinoma, lymphoma, an eye cancer (e.g., uveal melanoma), kidney cancer (e.g., renal cell carcinoma), colorectal cancer (e.g., relapsed colorectal cancer or metastatic colorectal cancer, e.g., a microsatellite unstable colorectal cancer, a microsatellite stable colorectal cancer, a mismatch repair proficient colorectal cancer, or a mismatch repair deficient colorectal cancer),
  • the methods as disclosed herein are also useful for treating metastatic lesions associated with the aforementioned cancers. Additionally, refractory or recurrent or relapsed malignancies can be treated using methods as described herein.
  • the cancer is a metastatic cancer. In other embodiments, the cancer is an advanced cancer. In other embodiments, the cancer is a relapsed or refractory cancer. In one embodiment, the cancer is advanced/metastatic solid tumor. In another embodiment, the cancer is advanced/metastatic lymphoma.
  • the cancer is a solid tumor or a lymphoma. In one embodiment, the cancer is a solid tumor. In some embodiments, the cancer is a skin cancer, e.g., a melanoma (e.g., a cutaneous melanoma, a non-cutaneous melanoma, a stage II-IV melanoma, an HLA- A2 positive melanoma, an unresectable melanoma, or a metastatic melanoma), or a Merkel cell carcinoma. In one embodiment, the cancer is a melanoma. In one embodiment, the cancer is an advanced stage melanoma. In another embodiment, the cancer is metastatic melanoma.
  • a melanoma e.g., a cutaneous melanoma, a non-cutaneous melanoma, a stage II-IV melanoma, an HLA- A2 positive melanoma, an unresectable melanoma, or
  • the cancer is PD-l inhibitor refractory or relapsed (R/R) metastatic melanoma. In another embodiment, the cancer is checkpoint inhibitor refractory or relapsed (R/R) metastatic melanoma. In one embodiment, the cancer is cutaneous melanoma. In one embodiment, the cancer is non-cutaneous melanoma. In one embodiment, the cancer is visceral metastatic melanoma. In one embodiment, the cancer is a Merkel cell carcinoma. In some embodiments, the cancer is a breast cancer, e.g., a metastatic breast carcinoma or a stage IV breast carcinoma, e.g., a triple negative breast cancer (TNBC). In one embodiment, the cancer is triple negative breast cancer.
  • TNBC triple negative breast cancer
  • the cancer is metastatic triple negative breast cancer.
  • the cancer is metastatic triple negative breast cancer that has progressed on prior therapy, e.g., prior chemotherapy with or without checkpoint inhibitors, such as PD-l or PD-L1 inhibitors.
  • the cancer is a cervical cancer (e.g., a squamous cell carcinoma of the cervix).
  • the cancer is a colorectal cancer, e.g., a relapsed colorectal cancer or a metastatic colorectal cancer, e.g., a microsatellite unstable colorectal cancer, a microsatellite stable colorectal cancer, a mismatch repair proficient colorectal cancer, or a mismatch repair deficient colorectal cancer.
  • the cancer is a microsatellite instability-high colorectal cancer (MSI-high CRC) or a microsatellite stable colorectal cancer (MSS CRC).
  • the cancer is a microsatellite stable (MSS) colorectal cancer (CRC).
  • the cancer is a sarcoma. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is gastric cancer. In some embodiments, the cancer is an ovarian cancer. In some embodiments, the cancer is a pancreatic cancer, e.g., an advanced pancreatic cancer. In some embodiments, the cancer is a renal cancer, e.g., a renal cell carcinoma (RCC) (e.g., a metastatic renal cell carcinoma) or a treatment-naive metastatic kidney cancer. In some embodiments, the cancer is a head and neck cancer (e.g., an HPV positive or negative squamous cell cancer of the head and neck (SCCHN)).
  • RCC renal cell carcinoma
  • SCCHN head and neck cancer
  • the cancer is a head and neck squamous cell carcinoma (HNSCC). In another embodiment, the cancer is an advanced/metastatic head and neck squamous cell carcinoma (HNSCC). In another embodiment, the cancer is recurrent head and neck squamous cell carcinoma. In one embodiment, the cancer is a SCC of the scalp. In some embodiments, the cancer is a lymphoma, e.g., a Hodgkin lymphoma (HL) or a diffuse large B cell lymphoma (DLBCL) (e.g., a relapsed or refractory HL or DLBCL) or a non- Hodgkin lymphoma. In one embodiment, the cancer is lymphoma. In one embodiment, the cancer is extranodal lymphoma. In another embodiment, the cancer is Hodgkin lymphoma. In another embodiment, the cancer is non-Hodgkin lymphoma.
  • HNSCC head and neck squamous cell carcinoma
  • treatment according to the methods described herein results in the improvement of at least one of overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
  • ORR is the proportion of patients with a best overall response of complete response (CR) or partial response (PR).
  • DCR disease control rate
  • PFS progression-free survival
  • OS overall survival
  • the methods as disclosed herein increases median PFS compared to patients not receiving the treatment as put forth herein, i.e., patients receiving standard of care. In one embodiment, the methods as disclosed herein increases median OS compared to patients not receiving the treatment as put forth herein, i.e., patients receiving standard of care.
  • the treatment regimen as described herein that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject.
  • a method for the treatment of visceral metastatic melanoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 400 pg to about 10,000 mg intratumorally on day 1 only of a 21 -day treatment cycle and (b) ipilimumab intravenously at a dose of about 3 mg/kg on day 1 of a 21 -day treatment cycle.
  • a dose e.g., a daily dose
  • a method for treating visceral metastatic melanoma comprising administering to in a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally on day 1 only of a 28-day treatment cycle and (b) one or more PD-l checkpoint inhibitors, preferably spartalizumab or nivolumab, intravenously on day 1 of a 28- day treatment cycle.
  • a dose e.g., a daily dose
  • PD-l checkpoint inhibitors preferably spartalizumab or nivolumab
  • a method of treating PD-l inhibitor refractory or relapsed metastatic melanoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose of about 400 pg to about 10,000 pg intratumorally on day 1 of a 21 -day treatment cycle and (b) ipilimumab intravenously at a dose of about 3 mg/kg on day 1 of a 21 -day treatment cycle.
  • a method of treating PD-l inhibitor refractory or relapsed metastatic melanoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 400 pg to about 10,000 pg intratumorally on day 1 and on day 8 of a 21 -day treatment cycle and (b) ipilimumab intravenously at a dose of about 3 mg/kg on day 1 of a 21 -day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically at on day 1 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, day 8 and day 15 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating triple negative breast cancer comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 mg to about 10,000 mg intratumorally (e.g., from about 400 mg to about 6,400 mg, e.g., about 800 mg, 1,200 mg, 1,600 mg, 2,000 mg, 2,400 mg, 2,800 mg, or 3,200 mg) on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating bladder cancer comprising administering, e.g., intravesically, to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intravesically (e.g., from about 400 pg to about 6,400 pg, e.g., about 800 pg, 1,200 pg, 1,600 pg, 2,000 pg, 2,400 pg, 2,800 pg, or 3,200 pg) on day 1, and optionally on day 8, day 15, and day 21 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • COMPOUND A in treating bladder cancer, is intravesically administered only on day 1 of a 28-day treatment cycle, only on day 1 of a 35-day treatment cycle, or only on day 1 of a 42-day treatment cycle.
  • COMPOUND A, or a pharmaceutically acceptable salt thereof in treating bladder cancer, is intravesically administered only on day 1, day 8, day 15, and day 21 of a 28-day treatment cycle.
  • a method of treating recurrent or metastatic head and neck squamous cell carcinoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28 -day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating unresectable or metastatic melanoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating microsatellite stable colorectal cancer comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating cancer comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, day 8 and day 15 of a 28-day treatment cycle and (b) spartalizumab intravenously at a dose of about 400 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1 of a 28-day treatment cycle and (b) nivolumab intravenously at a dose of about 480 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, day 8 and day 15 of a 28-day treatment cycle and (b) nivolumab intravenously at a dose of about 480 mg on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) an anti -PD- 1 antibody selected from the group consisting of pembrolizumab, pidilizumab, MEDI0680 (Medimmune), cemiplimab, TSR-042 (Tesaro), PF- 06801591 (Pfizer), tislelizumab, BGB-108 (Beigene), INCSHR1210 (Incyte), and AMP-224 (Amplimmune), for example, on day 1 of a 28-day treatment cycle, on day 1 of a 21 -day treatment cycle, or on day 1 of a l
  • a dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) an anti -PD- 1 antibody selected from the group consisting of pembrolizumab, pidilizumab, MEDI0680 (Medimmune), cemiplimab, TSR-042 (Tesaro), PF- 06801591 (Pfizer), tislelizumab, BGB-108 (Beigene), INCSHR1210 (Incyte), and AMP-224 (Amplimmune) on day 1 of a 28-day treatment cycle.
  • a dose e.g., a daily dose
  • an anti -PD- 1 antibody selected from the group consisting
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 of a 21 -day treatment cycle and (b) an anti -PD- 1 antibody selected from the group consisting of pembrolizumab, pidilizumab, MEDI0680 (Medimmune), cemiplimab, TSR-042 (Tesaro), PF- 06801591 (Pfizer), tislelizumab, BGB-108 (Beigene), INCSHR1210 (Incyte), and AMP-224 (Amplimmune) on day 1 of a 2l-day treatment cycle.
  • a dose e.g., a daily dose
  • an anti -PD- 1 antibody selected from the group consisting of
  • HNSCC head and neck squamous cell carcinoma
  • a method of treating head and neck squamous cell carcinoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 400 pg to about 6,400 pg (e.g., 800 pg, 1,200 pg, 1,600 pg, 2,000 pg, 2,400 pg, 2,800 pg, or 3,200 pg) intratumorally on day 1 and day 8 of a 21 -day treatment cycle and (b) about 200 mg pembrolizumab on day 1 of a 21 -day treatment cycle.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 of a l4-day treatment cycle and (b) an anti -PD- 1 antibody selected from the group consisting of pembrolizumab, pidilizumab, MEDI0680 (Medimmune), cemiplimab, TSR-042 (Tesaro), PF- 06801591 (Pfizer), tislelizumab, BGB-108 (Beigene), INCSHR1210 (Incyte), and AMP-224 (Amplimmune) on day 1 of a 14-day treatment cycle.
  • a dose e.g., a daily dose
  • an anti -PD- 1 antibody selected from the group consisting of
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 of a 21 -day treatment cycle and (b) a checkpoint inhibitor on day 1 of a 21 -day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 21 -day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and on day 8 of a 21 -day treatment cycle and (b) a checkpoint inhibitor on day 1 of a 21 -day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 21 -day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and on day 8 of a 21 -day treatment cycle and (b) ipilimumab on day 1 of a 2l-day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 21 -day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a dose e.g., a daily dose
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) a checkpoint inhibitor on day 1 of a 28-day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 28-day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a dose e.g., a daily dose
  • a checkpoint inhibitor on day 1 of a 28-day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 28-day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks,
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a
  • a dose e.g., a daily dose
  • 28-day treatment cycle and (b) spartalizumab on day 1 of a 28-day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 28-day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a method of treating solid tumor or lymphoma comprising administering to a patient in need thereof (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, at a dose (e.g., a daily dose) of about 50 pg to about 10,000 pg intratumorally or intravesically on day 1, and optionally on day 8 and day 15 of a 28-day treatment cycle and (b) nivolumab on day 1 of a 28-day treatment cycle for at least one, at least two, at least three, at least four, at least five or at least six 28-day treatment cycles, followed by administration of the checkpoint inhibitor once every six weeks, once every nine weeks, once every twelve weeks or once every sixteen weeks.
  • a dose e.g., a daily dose
  • a commercial package kit or a non-fixed combination comprising as active ingredients (a) COMPOUND A, or a pharmaceutically acceptable salt thereof, and (b) one or more checkpoint inhibitors, suitably selected from the group consisting of nivolumab, spartalizumab and ipilimumab, optionally together with instructions for separate or sequential administration of said pharmaceutical combination to a patient in need thereof for use in the treatment of a cancer comprising administering intratumorally or intravesically a daily dose or weekly dose of about 400 pg to about 10,000 pg COMPOUND A, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Additional embodiments include pharmaceutical compositions, combinations, and uses of the methods set forth above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.
  • Example 1 A Phase lb, open label, multicenter study of the safety and efficacy of COMPOUND A administered by intratumoral injection with spartalizumab (PDR001) to patients with advanced/metastatic solid tumors or lymphomas
  • COMPOUND A Intravenous dose of spartalizumab (PDR001), to determine safety, tolerability and the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of the combination.
  • PDR001 spartalizumab
  • MTD maximum tolerated dose
  • RDE recommended dose for expansion
  • Group A Dose escalation in solid tumor or lymphoma patients with cutaneous or subcutaneous accessible lesions. Patients received 400mg spartalizumab (PDR001) intravenously (i.v.) as a fixed dose administered on day 1 of each 28 day cycle. COMPOUND A was administered via intratumoral injection on days 1, 8 and 15 of each 28-day cycle.
  • Group B Dose escalation in solid tumor or lymphoma patients with cutaneous or subcutaneous accessible lesions. Patients received 400mg spartalizumab (PDR001) i.v. as a fixed dose and COMPOUND A administered on day 1 only of each 28-day cycle.
  • PDR001 spartalizumab
  • Group C Dose confirmation in solid tumor patients with visceral lesions accessible by ultrasound (US) or computed tomography (CT) guidance or endoscopically accessible lesions. Patients receive spartalizumab (PDR001) i.v. as a fixed dose and COMPOUND A is administered on day 1 only of each 28-day cycle as a fixed dose at the MTD/RDE determined in Group B.
  • US ultrasound
  • CT computed tomography
  • the injected lesion (Ll) must be an accessible cutaneous or subcutaneous lesion for baseline and on-treatment biopsies.
  • the second (distal) lesion (L2) must be an accessible cutaneous or subcutaneous lesion for baseline and on-treatment biopsy and must be distinct from the injected lesion.
  • Tumors encasing major vascular structures such as the carotid artery or tumors in locations that are at high risk for adverse events (i.e. pneumothorax), are not considered appropriate for intratumoral injection.
  • Dose escalation/dose confirmation part of study Patients with advanced/metastatic solid tumors or lymphomas, who have progressed despite standard therapy or are intolerant to standard therapy, for whom no standard therapy exists or for whom standard therapy is not reasonably effective.
  • the study treatment is the combination of COMPOUND A and spartalizumab
  • a treatment cycle is defined as 28 days for the purpose of scheduling procedures and evaluations.
  • the first dose of study drug is Cycle l-Day 1 (C1D1) and defines the patient’s treatment cycle for the study.
  • the last day of each treatment cycle is day 28 (D28).
  • Spartalizumab (PDR001) is administered as a 30 minute infusion or up to two hours, if clinically indicated.
  • the intratumoral injection is given as soon as possible following the completion of the infusion.
  • the intratumoral injection of COMPOUND A should take no more than 5 minutes to complete.
  • Group C is administered spartalizumab (PDR001) i.v. followed by COMPOUND A intratumorally in a visceral lesion on day 1 of each 28 day cycle.
  • the intratumoral injection is given as soon as possible following the completion of the infusion.
  • the intratumoral injection of COMPOUND A is performed by experienced interventional personnel using US or CT guidance or using endoscopic techniques into a visceral lesion on day 1 of each cycle.
  • the longest diameter of the injected lesion will be measured and the injection volume is based on the size of that lesion (Table 5). As another example, the injection volume is a fixed volume for different sizes of lesions.
  • the dose of COMPOUND A is administered as described in Table 4.
  • efficacy endpoints are defined and analyzed based on tumor assessment by RECIST 1.1 (primary) and irRC (secondary). All efficacy endpoints for lymphoma patients are defined and analyzed based on Cheson (2014) criteria. Efficacy endpoints include best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and time to response (TTR).
  • ORR objective response rate
  • DCR disease control rate
  • PFS progression free survival
  • TTR time to response
  • irRC the key difference in the assessments of these endpoints is the requirement for confirmation of PD no less than 4 weeks after the criteria for PD are first met. The date of the first of these two assessments is then the date of confirmed progression. For patients who have ended study without a valid confirmation assessment, for the purposes of analysis the single assessment of PD will be treated as a confirmed PD.
  • the immune-related response criteria use unidimensional measurements to assess tumor response and are an adaptation of the original irRC (Wolchok el al (2009) Clin Cancer Res; 15:7412-20; Nishino et al (2013) Clin Cancer Res; 19:3936-3943).
  • the primary difference between irRC and RECIST 1.1 is the definition of progressive disease.
  • the definitions of baseline target/non target lesions, number of lesions selected at baseline, the criteria for lesion measurement method of evaluation of response and definition of response are the same for irRC and RECIST 1.1. In irRC a new lesion does not automatically indicate progressive disease.
  • New measurable lesions are added to the sum of diameters of the previously existing target lesions, and the sum of diameters is followed at each subsequent tumor assessment.
  • New measureable lesions are defined using the same criteria as for baseline target lesions in RECIST vl . l .
  • New measurable lesions shall be prioritized according to size, and the largest lesions shall be selected as new measurable lesions. Up to five new measurable lesions (and a maximum of two per organ) are allowed in total and will be included in the overall tumor assessment.
  • Non-target lesions baseline and new non-measurable lesions are used primarily for determination of Complete Response (CR).
  • CR Complete Response
  • a CR requires that all non-target lesions disappear (both those present at baseline and any new non-measurable lesions that have appeared during the study). If after worsening a non-target lesion becomes measurable, it should still be followed as a non-target lesion. Worsening of non-target lesions and new non- measurable lesions only indicate disease progression if there is unequivocal evidence of disease progression.
  • the sum of diameters for all target lesions is calculated (at baseline and throughout the study). The diameters of any new measurable lesions are included in the sum of diameters at each assessment to provide the total tumor burden.
  • percent change in the sum of diameters is calculated and compared to baseline or to nadir in order to evaluate the target lesion response (including new measurable lesions). This evaluation combined with the status of non-target lesions (baseline and new non- measurable lesions) is then used to determinate the overall lesion response.
  • the thresholds for irPR and irPD assessment are the same as for RECIST vl . l . In irRC, the overall response is primarily based on target lesions (baseline and new measurable lesions). The non-target lesions only contribute to define irCR, and irPD in the case of unequivocal progression, as shown below in Table 6.
  • irCR and irPR must be confirmed at a new assessment after at least 4 weeks.
  • irPD also requires confirmation at a new assessment after at least 4 weeks.
  • the irRC response categories are defined as follows:
  • irCR Disappearance of all non-nodal target lesions and non-target lesions in two consecutive observations not less than 4 weeks apart.
  • any pathological lymph nodes assigned as target lesions must have a reduction in short axis to ⁇ 10 mm. (Sum of diameters may be greater than zero at the time of CR, if nodal lesions are included as target lesions).
  • irPR At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions in two consecutive observations not less than 4 weeks apart, taking as reference the baseline sum of diameters.
  • irPD At least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.
  • the irPD must be confirmed in a second evaluation not less than 4 weeks later, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline (nadir).
  • the sum In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Worsening of non-target lesions (existing or new) only indicates PD when there is unequivocal evidence of progression, confirmed in a second evaluation not less than 4 weeks later.
  • Unknown Progression has not been documented and one or more target lesions or new measurable lesions observed at earlier assessment have not been/could not be assessed, or have been assessed using a method significantly different from baseline (target lesions) or assessment of first occurrence (for new measurable lesions) that prevents reasonable comparison to the prior assessments.
  • Group A COMPOUND A at the dose indicated in Table 7 on day 1, day 8 and day 15 of every 28-day cycle and 400 mg spartalizumab (PDR001) on day 1 of every 28-day cycle
  • Group B COMPOUND A at the dose indicated in Table 7 on day 1 of every 28-day cycle and 400 mg spartalizumab (PDR001) on day 1 of every 28-day cycle
  • Tumors were evaluated before treatment according to the dose and treatment schedule detailed in Table 4 as well as on day 1 of cycle 3 (evaluation 1), day 1 of cycle 5 (evaluation 2), day 1 of cycle 7 (evaluation 3), day 1 of cycle 9 (evaluation 4), and day 1 of cycle 11 (evaluation 5) as indicated.
  • Patient 1 Cutaneous melanoma (PD1-R/R) with PR, ongoing 30 weeks
  • Prior therapy included pembrolizumab (4 months with CR), trametinib/dabrafenib (9 months with CR), nivolumab/ipilimumab (3 months with SD), nivolumab/ BMS IDOi (2 months with SD)
  • TL1 Target Lesion 1
  • TL2 Target Lesion 2
  • TL3 Target Lesion 3
  • TL4 Target Lesion 4
  • TL5 Target Lesion 5
  • TNBC triple negative breast cancer
  • TL1 Target Lesion 1
  • TL2 Target Lesion 2
  • TL3 Tar get Lesion 3
  • TL4 Target Lesion 4 •Cohort 1B
  • TLl Target Lesion 1
  • TL2 Target Lesion 2
  • TL1 Target Lesion 1
  • TL2 Target Lesion 2
  • TL3 Tar get Lesion 3
  • TL4 Target Lesion 4 •Cohort 2
  • TL1 Target Lesion 1
  • TL2 Target Lesion 2
  • TL3 Target Lesion 3
  • TL4 Target Lesion 4
  • TL5 Target Lesion 5
  • LTP longest transverse diameter
  • LPD longest perpendicular diameter -
  • Patient 6 Melanoma with PR of locoregional disease, ongoing 15 weeks o 93 year old female with cutaneous melanoma
  • TL1 Target Lesion 1
  • TL2 Target Lesion 2
  • 2019 data cut-off (based on findings from 83 enrolled patients, with 53 patients in the weekly group, i.e., Group A, and 30 patients in the monthly group, i.e., Group B or C):
  • IP-10 interleukin-6
  • MCP-l monocyte chemoattractant protein 1
  • Example 2 A Phase I, open label, multicenter study of the safety and efficacy of COMPOUND A administered by intratumoral injection as a single agent or in combination with ipilimumab to patients with advanced/metastatic disease
  • This study is a Phase I, first-in-human (FIH), multi-center, open-label study of COMPOUND A as a single agent in patients with advanced/metastatic solid tumors and COMPOUND A in combination with ipilimumab in patients with in patients with metastatic melanoma who are relapsed/refractory (R/R) to PD-l inhibitors.
  • FH first-in-human
  • This study consists of a dose escalation part and a dose expansion part.
  • Group A includes patients with advanced/metastatic solid tumors or lymphomas with cutaneous, SC and/or nodal lesions that are visible, palpable or detectable by ultrasound (US) guidance. Patients are administered COMPOUND A as a single agent, via intratumoral injection on days 1, 8 and 15 of each 28 day cycle
  • Group B includes patients with metastatic melanoma with cutaneous, SC and/or nodal lesions who are R/R to PD-l inhibitors.
  • Patients receive ipilimumab, i.v., on day 1 of each 21 day cycle for the first 4 cycles and COMPOUND A, via intratumoral injection, on days 1 and 8 of each 2 l-day cycle.
  • patients with SD/PR/CR may continue to receive COMPOUND A on days 1 and 8 of each cycle and ipilimumab maintenance on day 1, every 12 weeks, until disease progression.
  • Group 1 includes patients with UV-induced cancers that have cutaneous, SC and/or nodal lesions that are visible, palpable or detectable by US guidance.
  • Group 2 includes patients with non UV-induced cancers that have cutaneous, SC and/or nodal lesions that are visible, palpable or detectable by US guidance.
  • Group 3 includes patients with metastatic melanoma that is R/Rto PD-l inhibitors. Patients must have cutaneous, SC and/or nodal lesions that are visible, palpable or detectable by US guidance.
  • COMPOUND A is administered on days 1 and 8 of every 21 day cycle and ipilimumab is administered on day 1 of each 21 day cycle through cycle 4. Patients may continue on maintenance ipilimumab on day 1 every 12 weeks thereafter if they have SD/PR/CR.
  • Group 4 includes patients with metastatic melanoma that is R/Rto PD-l inhibitors. Patients must have US, CT, or endoscopically accessible visceral lesions. COMPOUND A is administered on day 1 of every 21 day cycle and ipilimumab is administered on day 1 of each 21 day cycle for the first four cycles. After the first four cycles, patients with SD/PR/CR may continue to receive COMPOUND A on day 1 of each 21 -day cycle and ipilimumab maintenance on day 1 every 12 weeks, until disease progression.
  • the injected lesion (Ll) must be an accessible cutaneous or subcutaneous lesion for baseline and on-treatment biopsies. In dose expansion, the injected lesion can be an accessible cutaneous or subcutaneous lesion or a visceral lesion.
  • the second (distal) lesion (L2) must be an accessible cutaneous or subcutaneous lesion for baseline and on-treatment biopsy and must be distinct from the injected lesion.
  • Tumors encasing major vascular structures such as the carotid artery or tumors in locations that are at high risk for adverse events (i.e. pneumothorax), are not considered appropriate for intratumoral injection.
  • Dose escalation part of study includes patients with:
  • o PD-l refractory is defined as progressive disease at the first radiological imaging assessment after initiation of an anti -PD-l -directed therapy and PD-l relapsed is defined as any PD- 1 -treated patient with progression that did not meet the definition ofPD-l refractory.
  • the study treatment is COMPOUND A as a single agent or the combination of
  • a treatment cycle is defined as 28 days for patients receiving COMPOUND A as a single agent and 21 days for patients receiving COMPOUND A in combination with ipilimumab for the purpose of scheduling procedures and evaluations.
  • the treatment cycle calendar is continuous. There is no break in administration of study treatment between cycles.
  • the first dose of COMPOUND A is Cycle 1 Day 1 (C1D1) and defines the patient’s treatment cycle for the study.
  • the last day of each treatment cycle is day 28 for patients receiving COMPOUND A, as a single agent, and day 21 for patients receiving COMPOUND A in combination with ipilimumab.
  • COMPOUND A is administered via intratumoral injection.
  • Ipilimumab (3mg/kg) is administered as an i.v. infusion, given over 90 minutes.
  • the intratumoral injection of COMPOUND A should be given as soon as possible following the completion of the ipilimumab infusion.
  • the longest diameter of the injected lesion will be measured and the injection volume is based on the size of that lesion (Table 15). As another example, the injection volume is a fixed volume for different sizes of lesions.
  • the dose of COMPOUND A is administered as described in Table 14.
  • the same lesion should be injected until an on-treatment biopsy of that lesion has been obtained (Cycle 2 between days 18 and 25) for patients receiving COMPOUND A as a single agent.
  • the same lesion should be injected until an on-treatment biopsy of that lesion has been obtained (Cycle 2 between days 12 and 18) for patients receiving COMPOUND A in combination with ipilimumab. If the first injected lesion shows signs of significant regression that precludes the ability to reinject the lesion, other accessible lesions may be injected after documented discussions.
  • Injection of treatment into visceral lesions should be performed by a qualified interventional radiologist with experience in US and CT guided techniques. Some lesions may be best accessed using endoscopic techniques by qualified endoscopists. In patients with multiple accessible lesions, the same lesion should be injected until an on-treatment biopsy of that lesion has been obtained (Cycle 2 between days 12 and 18). If the first injected lesion shows signs of significant regression that precludes the ability to reinject the lesion, other accessible lesions may be injected after documented discussions. Efficacy objectives
  • the evaluations of tumor responses are based on criteria according to irRC (see criteria in example 1), RECIST vl. l (European Journal of Cancer, Vol.45: 228-47), or Cheson (2014) for lymphoma patients.
  • BOR is defined as the best response recorded from the start of the treatment until disease progression/recurrence as defined for irRC, RECIST vl.l.
  • BOR will be analyzed both as the best response recorded from the start of treatment until disease progression/recurrence as defined by Cheson 2014 criteria and as best response recorded at any time on treatment.
  • CR and PRs must be confirmed by repeat assessments that should be performed not less than 4 weeks after the criteria for response are first met. Additionally, for irRC, progressive disease should be confirmed in a similar manner.
  • ⁇ ORR defined as the proportion of patients with best overall response of CR or PR.
  • PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression, or death due to any cause. Progressive disease should be confirmed by a repeat assessment that should be performed not less than 4 weeks after the criteria for progression are first met. The date of progression will then be the date of the first of these two assessments. For patients without a confirmation assessment, and with no subsequent assessments of SD, or better, a single assessment will be used as date of progression. If a patient has not had an event, PFS will be censored at the date of the last adequate tumor evaluation.
  • PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause.
  • PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause.
  • DOR defined for responder as the time between the date of first documented response (CR or PR) and the date of first documented progression or death due to underlying cancer. If progression or death due to underlying cancer has not occurred, then the patient is censored at the date of last adequate tumor assessment.
  • DCR defined as the proportion of patients with best overall response of CR or PR or SD.
  • Example 3A A Phase lb/II, open label, multicenter study of the safety and efficacy of COMPOUND A administered by intratumoral injection in combination with nivolumab to patients with advanced cancer
  • This study is a Phase II, multi-center, open-label study of COMPOUND A in combination with nivolumab in patients with PD- 1/PD-L1 -naive recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) or treatment-naive unresectable or metastatic melanoma.
  • Group 1 includes patients with PD- 1/PD-L1 -naive recurrent or metastatic SCCHN. Patients receive 480 mg nivolumab, i.v., on day 1 of each 28-day cycle and COMPOUND A, via intratumoral injection, on days 1, 8 and 15 of each 28-day cycle at a dose of e.g., 200 pg, 400 pg, or 800 pg per lesion per day.
  • Group 2 includes patients with treatment naive unresectable or metastatic melanoma. Patients receive 480 mg nivolumab, i.v., on day 1 of each 28-day cycle and COMPOUND A, via intratumoral injection, on days 1, 8 and 15 of each 28-day cycle at a dose of e.g., 200 pg, 400 pg, or 800 pg per lesion per day.
  • SCCHN Histological or cytological confirmation of recurrent or metastatic SCCHN that has progressed on or after a platinum-based therapy
  • melanoma Histological or cytological confirmation of unresectable (Stage IIIB/C/IIID or metastatic (Stage IV) melanoma (per American Joint Committee on Cancer Staging, 8th ed)
  • o lesion must be >10 millimeters (mm) and ⁇ 100 mm in longest diameter; nodal lesions must be >15 mm (post-biopsy) at short axis.
  • o Lesion accessible for intratumoral injection Tumors encasing major vascular structures such as the carotid artery or tumors in locations that are at high risk for adverse events (i.e. pneumothorax), are not considered appropriate for intratumoral injection.
  • the study treatment is the combination of COMPOUND A and nivolumab.
  • total dose level assumes maximum number of four (4) lesions are injected; total dose varies by subject depending on number of accessible target lesions, but does not exceed 2400 meg. All designated lesions are injected on every dosing day.
  • progression-free survival time from first dose of study drug to first documentation of disease progression or death due to any cause
  • duration of response time from first tumor assessment that supports the subject’s objective disease response to the time of disease progression or death due to any cause
  • disease control rate DCR
  • DCR disease control rate
  • DODC duration of disease control
  • OS overall survival
  • Example 3B A Phase II, open label, multicenter study of the safety and efficacy of COMPOUND A administered by intratumoral injection in combination with pembrolizumab to patients with advanced cancer
  • This study is a Phase II, multi-center, open-label study of COMPOUND A in combination with pembrolizumab in the first-line setting in adult patients with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).
  • HNSCC head and neck squamous cell carcinoma
  • o 10 millimeters (mm) and ⁇ 100 mm in longest diameter; nodal lesions must be >15 mm (post-biopsy) at short axis.
  • Tumors encasing or abuting major vascular structures such as the carotid artery
  • tumors in locations that are at high risk for adverse events i.e. pneumothorax, brain lesions
  • An irradiated mass cannot be used for intratumoral injection unless radiotherapy was completed at least 28 days prior to first dose of study drug and/or the lesion demonstrates evidence of growth (metabolically active by positive positron emission tomography or an unambiguous increase in size)
  • hematopoietic colony-stimulating growth factors e.g. granulocyte colony- stimulating factor (G-CSF), GM-CSF, macrophage colony-stimulating factor (M-
  • Erythroid stimulating agents may be maintained if initiated more than 4 weeks prior to the first dose of study drug and the dose is stable.
  • the study treatment is the combination of COMPOUND A and pembrolizumab.
  • total dose level assumes maximum number of two (2) lesions are injected; total dose varies by subject depending on number of accessible target lesions, but does not exceed 1600 meg. All designated lesions are injected on every dosing day.
  • PFS progression-free survival
  • DCR disease control rate
  • DODC duration of disease control
  • mice Female C57BL/6 mice (Charles River Laboratories) and were acclimated to laboratory conditions for at least 72 hours before the start of the study.
  • B16.F10 melanoma cells were purchased from ATCC (Manassas, VA) and thawed at passage 4 into a 15 cm cell culture dish. Cells were maintained at 37°C with 5% C02 in DMEM media containing L-glutamine (Hyclone), with 10% heat-inactivated FCS, IX penicillin and streptomycin (Hyclone). Upon reaching confluence, cells were washed with IX DPBS, harvested with 0.25% Trypsin-EDTA, and washed with DMEM media.
  • IT injections were initiated when tumors grew to between 75-100 mm 3 (day 17). On day 17, 20 and 24 all groups of mice were administered a single intratumoral (IT) injection of 40 pL HBSS vehicle, or 40 pL COMPOUND A as described in Table 20 below.
  • mice were administered intraperitoneal (IP) injections of 100 pL of antibody (polyclonal Rat IgG (isotype control) or anti -mouse CTLA4 (9D9)) on day 20 and day 24 as described in Table 21 below. Table 21.
  • IP intraperitoneal
  • Tumor measurements were performed twice weekly using electronic calipers (Fowler, Newton, MA). Tumor volume was calculated using the modified ellipsoid formula l/2(length x width 2 ). Mice were euthanized if tumor size reached >20% of body weight or became necrotic.
  • mice bearing established B16.F10 flank tumors received a single IT injection into the right flank tumor on day 17, 20 and 24 with 50 pg COMPOUND A or HBSS control (see Table 19 and Table 20).
  • Groups of mice received injections of either 100 pg isotype control IgG or anti- CTUA4 IP on day 20 and 24 (see Table 19 and Table 21).
  • Example 5 Anti-tumor activity of COMPOUND A as a single agent or in combination with an anti-PD-1 antibody in multiple mouse tumor models
  • Intratumoral injection of COMPOUND A induces a potent antitumor immune response and significant tumor regression in multiple mouse tumor models, including B16.F10 (B 16) melanoma, 4T1 mammary carcinoma, and CT26 colon carcinoma.
  • Treatment with COMPOUND A inhibited the primary treated tumor and primed an effective systemic CD8+ Tcell immune response that significantly inhibited the growth of distal, untreated lesions, or conferred protection against autologous tumor challenge.
  • induction of CD8+ T cell immunity and antitumor efficacy by COMPOUND A was shown to be completely STING dependent.
  • COMPOUND A was given as a subcutaneous injection in the 4T1 mammary carcinoma model, no tumor efficacy was noted.
  • COMPOUND A and anti-PD-l antibody has been evaluated in the MC38 colon carcinoma and the 4T1 mammary carcinoma syngeneic mouse tumor models and demonstrated enhanced anti-tumor immunity and tumor regression as compared to treatment with MIW815 or anti-PD-l antibody alone.
  • a study in the MC38 colon carcinoma model evaluated a single intratumoral injection of COMPOUND A in combination with the mouse anti-PD-l antibody administered intraperitoneally twice weekly. Results demonstrated partial tumor control with either COMPOUND A or anti-PD-l antibody alone, and complete tumor control when COMPOUND A was combined with anti-PD-l antibody.
  • COMPOUND A was administered by single intratumoral injection and combined with a twice weekly regimen of anti-PD-l antibody. These data demonstrated partial control of the distal, uninjected tumor with COMPOUND A alone, and complete primary and distal tumor clearance from COMPOUND A in combination with anti-PD-l antibody. The combined efficacy was evident when anti-PD-l antibody was administered at the time of COMPOUND A intratumoral treatment, not when anti-PD-l antibody treatment was delayed by three days.

Abstract

La présente invention concerne des méthodes de traitement du cancer comprenant l'administration à un patient en ayant besoin (a) d'un COMPOSÉ A (dithio-Rp,Rp-cyclique-[A(2',5')pA(3'5')p]), ou d'un sel pharmaceutiquement acceptable de celui-ci, et éventuellement (b) d'un ou plusieurs inhibiteurs de point de contrôle PD-1 ou CTLA-4, de manière appropriée ou de préférence choisis dans le groupe constitué par le nivolumab, le spartalizumab et l'ipilimumab.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022107027A1 (fr) * 2020-11-18 2022-05-27 Takeda Pharmaceutical Company Limited Administration d'un agoniste de sting, d'inhibiteurs de point de contrôle et de rayonnement

Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
WO2006121168A1 (fr) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies
WO2007054279A2 (fr) 2005-11-08 2007-05-18 Helmholtz-Zentrum für Infektionsforschung GmbH Dinucleotides cycliques et leurs conjugues utiles en tant qu'adjuvants et leurs utilisations dans des compositions pharmaceutiques
US7332582B2 (en) 2002-05-23 2008-02-19 Curetech Ltd. Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
WO2009114335A2 (fr) 2008-03-12 2009-09-17 Merck & Co., Inc. Protéines de liaison avec pd-1
US7592326B2 (en) 2004-03-15 2009-09-22 Karaolis David K R Method for stimulating the immune, inflammatory or neuroprotective response
WO2010027827A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer
US7695715B2 (en) 1999-03-31 2010-04-13 Mor Research Applications Ltd. Monoclonal antibodies, antigens and diagnosis and therapy of malignant diseases
US7709458B2 (en) 2004-03-15 2010-05-04 David K. R. Karaolis Method for inhibiting cancer cell proliferation or increasing cancer cell apoptosis
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8686119B2 (en) 2011-07-24 2014-04-01 Curetech Ltd. Variants of humanized immunomodulatory monoclonal antibodies
US8735553B1 (en) 2013-09-13 2014-05-27 Beigene, Ltd. Anti-PD1 antibodies and their use as therapeutics and diagnostics
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
WO2014189805A1 (fr) 2013-05-18 2014-11-27 Auro Biotech, Inc. Compositions et procédés d'activation de la signalisation dépendante de « stimulateur de gènes d'interféron »
WO2014194302A2 (fr) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Protéines de liaison à l'antigène qui se lient à pd-1
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
WO2014209804A1 (fr) 2013-06-24 2014-12-31 Biomed Valley Discoveries, Inc. Anticorps bispécifiques
US8927697B2 (en) 2008-09-12 2015-01-06 Isis Innovation Limited PD-1 specific antibodies and uses thereof
US8993731B2 (en) 2010-03-11 2015-03-31 Ucb Biopharma Sprl PD-1 antibody
WO2015085847A1 (fr) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
US20150210769A1 (en) 2014-01-24 2015-07-30 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2015112800A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains se liant à pd-1
US9102727B2 (en) 2008-09-26 2015-08-11 Emory University Human anti-PD-1 antibodies and uses therefor
WO2015200119A1 (fr) 2014-06-26 2015-12-30 Macrogenics, Inc. Dianticorps liés par covalence, présentant une immunoréactivité avec pd-1 et lag-3 et leurs procédés d'utilisation
WO2016092419A1 (fr) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anticorps anti-pd1 et méthodes d'utilisation de ceux-ci
US20180028553A1 (en) * 2013-11-19 2018-02-01 The University Of Chicago Use of sting agonist as cancer treatment
WO2018020476A1 (fr) 2016-07-29 2018-02-01 Aduro Biotech Holdings, Europe B.V. Anticorps anti-pd-1

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7695715B2 (en) 1999-03-31 2010-04-13 Mor Research Applications Ltd. Monoclonal antibodies, antigens and diagnosis and therapy of malignant diseases
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
US7332582B2 (en) 2002-05-23 2008-02-19 Curetech Ltd. Humanized immunomodulatory monoclonal antibodies for the treatment of neoplastic disease or immunodeficiency
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US7592326B2 (en) 2004-03-15 2009-09-22 Karaolis David K R Method for stimulating the immune, inflammatory or neuroprotective response
US7709458B2 (en) 2004-03-15 2010-05-04 David K. R. Karaolis Method for inhibiting cancer cell proliferation or increasing cancer cell apoptosis
WO2006121168A1 (fr) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Anticorps monoclonaux humains pour mort programmee 1 (mp-1) et procedes pour traiter le cancer en utilisant des anticorps anti-mp-1 seuls ou associes a d’autres immunotherapies
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
WO2007054279A2 (fr) 2005-11-08 2007-05-18 Helmholtz-Zentrum für Infektionsforschung GmbH Dinucleotides cycliques et leurs conjugues utiles en tant qu'adjuvants et leurs utilisations dans des compositions pharmaceutiques
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
WO2009114335A2 (fr) 2008-03-12 2009-09-17 Merck & Co., Inc. Protéines de liaison avec pd-1
WO2010027827A2 (fr) 2008-08-25 2010-03-11 Amplimmune, Inc. Polypeptides co-stimulateurs ciblés et leurs procédés d'utilisation dans le traitement du cancer
US8927697B2 (en) 2008-09-12 2015-01-06 Isis Innovation Limited PD-1 specific antibodies and uses thereof
US9102727B2 (en) 2008-09-26 2015-08-11 Emory University Human anti-PD-1 antibodies and uses therefor
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
US8993731B2 (en) 2010-03-11 2015-03-31 Ucb Biopharma Sprl PD-1 antibody
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
US9205148B2 (en) 2011-04-20 2015-12-08 Medimmune, Llc Antibodies and other molecules that bind B7-H1 and PD-1
WO2012145493A1 (fr) 2011-04-20 2012-10-26 Amplimmune, Inc. Anticorps et autres molécules qui se lient à b7-h1 et à pd-1
US8686119B2 (en) 2011-07-24 2014-04-01 Curetech Ltd. Variants of humanized immunomodulatory monoclonal antibodies
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
WO2014189805A1 (fr) 2013-05-18 2014-11-27 Auro Biotech, Inc. Compositions et procédés d'activation de la signalisation dépendante de « stimulateur de gènes d'interféron »
WO2014194302A2 (fr) 2013-05-31 2014-12-04 Sorrento Therapeutics, Inc. Protéines de liaison à l'antigène qui se lient à pd-1
WO2014209804A1 (fr) 2013-06-24 2014-12-31 Biomed Valley Discoveries, Inc. Anticorps bispécifiques
US8735553B1 (en) 2013-09-13 2014-05-27 Beigene, Ltd. Anti-PD1 antibodies and their use as therapeutics and diagnostics
US20180028553A1 (en) * 2013-11-19 2018-02-01 The University Of Chicago Use of sting agonist as cancer treatment
WO2015085847A1 (fr) 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
WO2015112800A1 (fr) 2014-01-23 2015-07-30 Regeneron Pharmaceuticals, Inc. Anticorps humains se liant à pd-1
US20150210769A1 (en) 2014-01-24 2015-07-30 Novartis Ag Antibody molecules to pd-1 and uses thereof
WO2015200119A1 (fr) 2014-06-26 2015-12-30 Macrogenics, Inc. Dianticorps liés par covalence, présentant une immunoréactivité avec pd-1 et lag-3 et leurs procédés d'utilisation
WO2016092419A1 (fr) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anticorps anti-pd1 et méthodes d'utilisation de ceux-ci
WO2018020476A1 (fr) 2016-07-29 2018-02-01 Aduro Biotech Holdings, Europe B.V. Anticorps anti-pd-1

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"Antibody Engineering Lab Manual", SPRINGER-VERLAG, article "Protein Sequence and Structure Analysis of Antibody Variable Domains"
"Remington's Pharmaceutical Sciences", 1985, AMERICAN PHARMACEUTICAL ASSOCIATION, pages: 1405 - 1412,1461-1487
AL-LAZIKANI ET AL., JMB, vol. 273, 1997, pages 927 - 948
BENNETT ET AL., J. IMMUNOL., vol. 170, 2003, pages 711 - 8
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BLANK ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 54, 2005, pages 307 - 314
BUCHBINDERDESAI, AM J CLIN ONCOL, vol. 39, 2016, pages 98 - 106
CARTER ET AL., EUR. J. IMMUNOL., vol. 32, 2002, pages 634 - 43
CHAMBERSALLISON, OPIN CELL BIOL, vol. 11, no. 2, 1999, pages 203 - 210
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 477202-00-9
CHESON ET AL., J CLIN ONCOL, vol. 32, no. 27, 2014, pages 3059 - 68
CHOTHIA, C. ET AL., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
CORRALES ET AL., CELL REPORTS, vol. 11, 2015, pages 1018 - 1030
CORRALES LETICIA ET AL: "The host STING pathway at the interface of cancer and immunity", THE JOURNAL OF CLINICAL INVESTIGATION : JCI, AMERICAN SOCIETY FOR CLINICAL INVESTIGATION, US, vol. 126, no. 7, 1 July 2016 (2016-07-01), pages 2404 - 2411, XP002790392, ISSN: 1558-8238, DOI: 10.1172/JCI86892 *
DONG ET AL., J. MOL. MED., vol. 81, 2003, pages 281 - 7
DONG ET AL., NAT. MED., vol. 8, 2002, pages 787 - 9
EISENHAUER ET AL., EUR J CANCER, vol. 45, 2009, pages 228 - 47
EISENHAUER, E.A. ET AL., EUR. J. CANCER, vol. 45, 2009, pages 228 - 247
FINGER LR ET AL., GENE, vol. 197, no. 1-2, 1997, pages 177 - 87
FREEMAN ET AL., J. EXP. MED., vol. 192, 2000, pages 1027 - 34
GALON ET AL., J TRANSL MED, vol. 10, 2012, pages 205
HAMID, O. ET AL., NEW ENGLAND JOURNAL OF MEDICINE, vol. 369, no. 2, 2013, pages 134 - 44
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
KABAT, E. A. ET AL.: "Sequences of Proteins of Immunological Interest", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH
KEIR ET AL., ANNU. REV. IMMUNOL., vol. 26, 2008, pages 677 - 704
KONISHI ET AL., CLIN. CANCER RES., vol. 10, 2004, pages 5094 - 100
KOYAMA ET AL., NAT COMMUN, vol. 7, no. 1, 2016, pages 10501
NISHINO ET AL., CLIN CANCER RES, vol. 19, 2013, pages 3936 - 3943
OKAZAKI ET AL., CURR OPIN IMMUNOL, vol. 14, 2002, pages 391779 - 82
PARDOLL ET AL., NAT REV CANCER, vol. 12, no. 4, 2012, pages 252 - 64
ROBERT ET AL., CLIN CANCER RES, vol. 20, no. 9, 2014, pages 2424 - 2432
ROSENBLATT, J. ET AL., J IMMUNOTHERAPY, vol. 34, no. 5, 2011, pages 409 - 18
SEYMOUR ET AL., LANCET ONCOL, vol. 18, 2017, pages e 143 - e52
SHINOHARA T ET AL., GENOMICS, vol. 23, no. 3, 1994, pages 704 - 6
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
WOLCHOK ET AL., CLIN CANCER RES, vol. 15, 2009, pages 7412 - 20
WOLCHOK ET AL., N ENGL J MED, vol. 369, no. 2, 2013, pages 122 - 133
WOLCHOKSAENGER, THE ONCOLOGIST, vol. 13, no. 4, 2008, pages 2 - 9
WOO ET AL., J IMMUNITY, vol. 41, 2014, pages 830 - 842
YAN ET AL., BIOORG. MED. CHEM LETT., vol. 18, 2008, pages 5631

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022107027A1 (fr) * 2020-11-18 2022-05-27 Takeda Pharmaceutical Company Limited Administration d'un agoniste de sting, d'inhibiteurs de point de contrôle et de rayonnement

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