Classifications

• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
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  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
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  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], 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
  • C07K16/2827—Immunoglobulins [IG], 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 B7 molecules, e.g. CD80, CD86
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
  • G01N33/57585—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites involving compounds identifiable in body fluids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• imidazoquinolinamines such as imiquimod and Compound A
• the imidazoquinolinamines are typically agonists of toll-like receptor (TLR) 7 and/or TLR8 and have both antiviral and anticancer activity in vitro.
• TLR toll-like receptor
• Imiquimod has been successfully developed into a topical treatment for actinic keratosis and genital and perianal warts.
• no imidazoquinolinamine has been successfully developed as a systemically administered drug, due to dose limiting toxicity (DLT).
• DLT dose limiting toxicity
• an imidazoquinolinamine drug 1-[4-amino-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]-2- methylpropan-2-ol, or a pharmaceutically aceptable salt thereof, collectively Compound A (unless context dictates otherwise), can be administered systemically as monotherapy for the treatment of cancer with therapeutic benefit and acceptable toxicity.
• Compound A is administered in the form of the free base or conjugate base.
• Compound A is administered in the form of a pharmaceutically acceptable salt.
• Further embodiments include formulations thereof. Dosages described herein are based on the free base, even when a salt, such as the sulfate salt, are being administered (unless otherwise noted). In some embodiments, dosages are adjusted based on the molecular weight of the particular species being administered.
• Some embodiments are methods of treating cancer in a patient in need thereof comprising administering Compound A at a dosage of from 0.10 to 1.2 mg/m 2 .
• the dosage is at least 0.10, 0.15, 0.30, 0.45, or 0.6 mg/m 2 .
• Some embodiments comprise administering Compound A at a dosage not exceeding 0.75, 0.9, 1.0, 1 .1 , or 1 .2 mg/m 2 .
• the administered dosage of Compound A is in a range bounded by any of these values.
• the patient is human.
• Compound A is used as monotherapy; that is, treatment with Compound A does not commence until after the last dose of any prior cancer therapy and no other anti-cancer drug is administered in the same time frame in which Compound A is being administered.
• treatment with Compound A does not commence until concentrations of the prior anti-cancer drug in the patient’s body have substantially subsided or have been eliminated.
• treatment with Compound A does not commence until at least 2 weeks or at least 4 weeks after the last administration of the prior anti-cancer drug.
• treatment with Compound A commences within 3 month or 6 months of the last administration of the prior anti-cancer drug.
• treatment with Compound A does not commence until after the point in time when a next dose of prior therapy would have been given had such treatment not been discontinued.
• Compound A is more effective after another cancer therapy (even if the patient’s cancer progressed on the other therapy).
• the prior therapy was chemotherapy, for example cytotoxic therapy or targeted therapy.
• the prior therapy was immune checkpoint inhibition therapy, for example PD-1 blockade.
• Some embodiments are methods of treating cancer in a patient in need thereof comprising administering Compound A after a course of treatment of immune checkpoint inhibitor therapy comprising at least 1 , 2, 3, 4, 5, or 6 doses of the immune checkpoint inhibitor (or any range of doses bound by those values).
• administration of the immune checkpoint inhibitor is discontinued at about, or prior to, the time treatment with Compound A is initiated. That is, Compound A is administered after a last dose of the immune checkpoint inhibitor, but not more than 3 months afterward.
• treatment with Compound A is initiated after the initial doses of the immune checkpoint inhibitor have been administered, but the immune checkpoint inhibitor therapy is not discontinued.
• the patient’s cancer progresses during the initial immune checkpoint inhibitor therapy, and treatment with Compound A is initiation after observation of that progression.
• the immune checkpoint inhibitor therapy is PD-1 blockade.
• PD-1 blockade comprises administration of an anti-PD-1 antibody. In other embodiments, PD-1 blockade comprises administration of an anti-PD- L1 antibody.
• Some embodiments are methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient to provide a plasma concentration profile in said patient comprsing: a. a maximum plasma concentration (C max ) of Compound A free base of_at least_8 ng/mL; or b. an area under the curve (AUC) of Compound A free base of_at least 3 ng/ml_*Day; or c. both; whereby the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• C max maximum plasma concentration
• AUC area under the curve
• Some embodiments are methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody to the patient to provide a plasma concentration profile in said patient comprsing: a. a maximum plasma concentration (C max ) of Compound A free base of_at least _7 ng/mL; or b. an area under the curve (AUC) of Compound A free base of_at least 2 ng/mL*Day; or c. both; whereby the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• C max maximum plasma concentration
• AUC area under the curve
• Some embodiments are methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody to the patient to provide a plasma concentration profile in said patient comprsing: a. a maximum plasma concentration (C max ) of Compound A free base of_at least 10 ng/mL; or b. an area under the curve (AUC) of Compound A free base of_at least 2 ng/mL*Day; or c. both; whereby the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• C max maximum plasma concentration
• AUC area under the curve
• Compound A is administered parenterally.
• parenteral administration comprises intravenous injection or infusion.
• Compound A is infused over 15-90 minutes, or over 30-60 minutes.
• Some embodiments further comprise determining a change in interferon inducible protein 10 (IP-10) plasma or whole blood concentration from before to after Compound A administration.
• Some embodiments further comprise determining a change in IP-10 transcripts in plasma or whole blood from before to after Compound A administration.
• IP-10 concentration or transcript level after Compound A administration is determined after 3 or 6 administrations of Compound A.
• the IP-10 is increased greater than 2-, 3-, 4-, or 5-fold.
• the dosage of Compound A is increased if IP-10 concentration in plasma or whole blood has not increased by a threshold level, for example, greater than 2-, 3-, 4-, or 5-fold.
• Compound A is administered at a dosage sufficient to produce a Cmax of Compound A free base in plasma that is at least 9.4 ng/ml in the patient. In some embodiments, Compound A is administered at a dosage sufficient to produce an AUC of Compound A free base in plasma that is at least 2.09 ng/ml_*day in the patient. If one or the other of these thresholds is not met, dosage of Compound A may be increased.
• Tmax is from 15 to 90 minutes after administration. In some embodiments, Tmax is within 60 minutes after administration. In some aspects, after administration refers to after beginning infusion.
• Compound A can be administered by 20-90 minute intravenous infusion, 1-6 times over a period of 3 to 6 weeks, with administration not occurring more often than once per week.
• Compound A is administered weekly in a 3-week cycle, that is, on days 1 , 8, and 15 of a 21 day cycle.
• the Compound A is administered once in a 3-week cycle, that is, on day 1 of a 21 -day cycle.
• Compound A is administered once in a 6-week cycle, that is, on day 1 of a 42 day cycle.
• Further particular embodiments consistent with the above stated pattern are also contemplated. These embodiments are freely combinable with other variable aspects of the herein disclosed methods of treatment, including dosage, dose adjustment, and patient population, such as according to cancer type or prior therapy.
• FIGs 2A-B present analyses of interferon inducible protein 10 (IP-10) production in response to various doses of Compound A.
• Figure 2A depicts the induction from baseline IP-10 production in log scale in response to four dose levels of Compound A (1 - 0.30 mg/m 2 ; 2 - 0.45 mg/m 2 ; 3 - 0.60 mg/m 2 ; 4 - 0.75 mg/m 2 ).
• the parenthetical numeral following the Dose Level indicator is the number of subjects.
• the interquartile range is indicated by the exterior horizontal lines in each plot connected by a vertical line. Rectangle: interquartile range; Braces: min I max; Horizontal line: unity (no change from baseline.
• the interior horizontal line indicates the median, the lower line and the geometric mean, the upper line. * means p ⁇ 0.05 (Wilcoxon Rank-Sum Test in log domain).
• Figure 2B depicts a comparison of fraction of baseline induction of IP-10 production for various Compound A dose levels (D1-D4, corresponding to 1-4 in Figure 1). Calculations performed in log domain (Wilcoxon Rank-Sum Test). Each horizontal line represents the 95% confidence interval.
• the solid black circle is the estimate of fold-change in IP-10 production. P-value appears to the right of each horizontal line.
• the dashed vertical line is the null value.
• Figures 3A-B depict pharmacodynamic-pharmacokinetic (PD-PK) analysis of IP-10 changes versus plasma concentration of Compound A.
• Figure 3A depicts fraction of baseline IP-10 induction at Cycle 1 Day 1 and Day 8 (open circles with connecting lines for each subject) for PK of Compound A by Cmax (left panel) and AUEC quartiles (right panel).
• the parenthetical numeral indicated above is the number of subjects at Cycle 1 Day 1 and Day 8 in each quartile.
• Median (thick black line) and geometric mean (square) are displayed within the interquartile range (grey braces).
• Grey horizontal line represents unity (no change in IP-10 induction from baseline) and the filled circles indicate fold of induction ⁇ 1.
• Figure 3B depicts IP-10 fraction of baseline induction from baseline AUEC compared between quartiles for Cmax (left panel) and AUC (right panel) quartiles. Each horizontal line represents the 95% confidence interval. The solid black circle is the estimate. P-value appears to the right of each horizontal line. The dashed vertical line is the null value. Calculations performed in log domain (Wilcoxon Rank-Sum Test).
• FIG. 4 depicts IP-10 cytokine induction level of 32 patients post infusion on Cycle 1 were analyzed.
• IP-10 induction level was presented as fold induction from baseline and then divided into two groups in accordance with the pharmacokinetics parameter AUC for Compound A, 16 patients in a low AUC group (AUC below 2.09 ng/mL*Day) and 16 patients in a high AUC group (AUC above 2.09).
• IP-10 induction level of the two groups was calculated as mean +/- SEM and the statistical difference between two groups was analyzed by Student’s T-test.
• the mean value of induction level of IP-10 from baseline is 3.68-fold and 27.2-fold for the low AUC and high AUC groups, respectively.
• FIG. 5 depicts IP-10 cytokine induction level of 32 patients post infusion on Cycle 1 was analyzed.
• IP-10 induction level of was presented as fold induction from baseline and divided into two groups in accordance with the pharmacokinetics parameter Cmax for Compound A, 16 patients each in a low Cmax group (Cmax below 9.4 ng/mL) and a high Cmax group (Cmax above 9.4 ng/mL), respectively.
• IP-10 induction level of the two groups was calculated as mean +/- SEM and the statistical difference between two groups was analyzed by Student’s T-test. The mean value of induction level is 5.09-fold and 31 .9-fold for the low Cmax and high Cmax groups, respectively.
• Figures 6A-C depict the percentage of patients achieving a partial response or longterm stable disease above and below a threshold for AUC and Cmax of Compound A free base in plasma upon treatment with Compound A monotherapy (Figure 6A), combination therapy with Compound A and an anti-PD-1 mAb ( Figure 6B), and combination therapy with Compound A and an anti-PD-L1 mAb ( Figure 6C).
• Compound A is administered as monotherapy.
• the patient has been previously treated with an immune checkpoint inhibitor, for example, a PD-1/L1 axis immune checkpoint inhibitor.
• the immune checkpoint inhibitor therapy continues in conjunction with treatment with Compound A.
• the immune checkpoint inhibitor therapy is discontinued prior to initiation of treatment with Compound A.
• the patient has been treated with some other cancer therapy prior to the initiation of treatment with Compound A.
• the other therapeutic may be an immune checkpoint inhibitor, a chemotherapeutic such as a cytotoxic agent or a targeted therapeutic, or a therapeutic monoclonal antibody.
• the therapeutic monoclonal antibody can be an antagonist or agonist immune checkpoint inhibitor, an anti-cancer antigen antibody, a don’t-eat-me signal blocker, or an antibody mediating depletion of M2 macrophages.
• the other treatment is discontinued prior to commencing treatment with Compound A, as described above.
• the other treatment is continued in conjunction with treatment with Compound A.
• treatment with Compound A is suspended, the prior other treatment repeated and again discontinued, and treatment with Compound A resumed.
• Some embodiments specifically include one or more of the modes of treatment. Some embodiments specifically exclude one or more of the modes of treatment.
• monotherapy refers to a cancer treatment regimen utilizing a single anti-cancer therapeutic agent. It does not exclude prior (or subsequent) therapy with another therapeutic agent, but merely indicates that administration of the monotherapy agent is not coincident, or coordinated, in time with administration of another anti-cancer therapy. At a minimum, initiation of monotherapy does not commence until after the administration of a last dose of a prior agent. In some embodiments, treatment with Compound A does not commence until after the point in time when a next dose of prior anti-cancer therapy would have been given had such treatment not been discontinued. In some embodiments, initiation of the monotherapy does not commence until presence of a prior anti-cancer agent in the body has substantially subsided or been eliminated.
• monotherapy is with respect to another anti-cancer pharmaceutical agent; a composition of matter administered to the patient’s body.
• the monotherapy may overlap, or be coordinated, in time with surgical treatment or radiation therapy.
• chemotherapy refers to the use of small molecule drugs for the treatment of cancer.
• chemotherapeutics have been drugs that damaged DNA or otherwise disrupted the mechanisms of cell division, and were cytotoxic to dividing cells generally.
• Such drugs can be referred to as cytotoxic or DNA-damaging chemotherapeutics.
• targeted therapies have been developed. These also involve the use of small molecule drugs. However, these drugs act on specific proteins, very often kinases, involved in the regulation of cell division.
• Some embodiments relate to patients who have received prior treatment with chemotherapy. In some of those embodiments, the chemotherapy was cytotoxic or DNA-damaging chemotherapy. In other of those embodiments the chemotherapy was targeted chemotherapy. Other embodiments specifically exclude prior treatment with any or all of these modes of chemotherapy.
• Immune checkpoint inhibition therapy refers to the use of pharmaceuticals, typically biologies, that act on regulatory pathways in the differentiation and activation of T cells to promote the passage of T cell developmental program through these checkpoints so that anti-tumor (or other therapeutic) activity can be realized.
• the agents bringing about immune checkpoint therapy are commonly called immune checkpoint inhibitors and it should be understood that it is the check on T cell development that is being inhibited.
• immune checkpoint inhibitors also inhibit the interaction of receptorligand pairs (e.g., programmed cell death 1 (PD-1) interaction with programmed deathligand 1 (PD-L1))
• other checkpoint inhibitors such as anti-OX40, anti GITR, anti-CD137, anti-CD122, anti-CD40, and anti-ICOS
• PD-1 programmed cell death 1
• other checkpoint inhibitors such as anti-OX40, anti GITR, anti-CD137, anti-CD122, anti-CD40, and anti-ICOS
• inhibition of some checkpoints has proven to be sufficient to mediate clinical improvement in some instances, inhibition of other checkpoints works best in combinations. Most commonly, antibodies against one member of the receptor-ligand pair are used.
• the antibody is replaced with another protein that similarly binds to the immune checkpoint target molecule.
• these non-antibody molecules comprise an extracellular portion of the immune checkpoint target molecule’s ligand or binding partner, that is, at least the extracellular portion needed to mediate binding to the immune checkpoint target molecule.
• this extracellular binding portion of the ligand is joined to additional polypeptide in a fusion protein.
• the additional polypeptide comprises an Fc or constant region of an antibody.
• Programed death-1 (PD-1) is a checkpoint protein on T cells.
• Non-limiting examples of monoclonal antibodies (mAbs) that target PD-1/PD-L1 include: the anti-PD-1 mAbs nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck & Co.), cemiplimab-rwlc (LIBTAYO®, Regeneron Pharmaceuticals), and the anti-PD-L1 mAbs durvalumab (MEDI4736, IMFINZITM, Medimmune), atezolizumab (MPDL3280A; TECENTRIQ®, Hoffmann-La Roche), avelumab (BAVENCIO®, EMD Serono), and BMS- 936559 (Bristol-Myers Squibb). These may be referred to as means for
• CTLA-4 is an immune checkpoint molecule expressed on the surface of CD4 and CD8 T cells and on CD25+, FOXP3+ T regulatory (Treg) cells.
• Non-limiting examples of monoclonal antibodies that target CTLA-4 include ipilimumab (YERVOY®; Bristol-Myers Squibb) and tremelimumab (Medimmune). These may be referred to as means for inhibiting CTLA-4, or means for immune checkpoint inhibition.
• TIM-3 T-cell immunoglobulin and mucin-domain containing-3 is a molecule selectively expressed on IFN-y-producing CD4 + T helper 1 (Th1) and CD8 + T cytotoxic 1 (Tc1) T cells.
• Th1 CD4 + T helper 1
• Tc1 CD8 + T cytotoxic 1
• Non-limiting, exemplary antibodies to TIM-3 are disclosed in U.S. Patent Application Publication 20160075783 which is incorporated by reference herein for all it contains regarding anti-TIM-3 antibodies.
• Other anti-TIM-3 antibodies include TSR-022 (Tesaro). These may be referred to as means for inhibiting TIM-3, or means for immune checkpoint inhibition.
• LAG-3 lymphocyte-activation gene 3; CD223 negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD- 1 and plays a role in Treg suppressive function.
• Non-limiting exemplary antibodies to LAG- 3 include GSK2831781 (GlaxoSmithKline), relatlimab (BMS-986016, Bristol-Myers Squibb), and the antibodies disclosed in U.S. Patent Application Publication 2011/0150892 which is incorporated by reference herein for all it contains regarding anti-LAG-3 antibodies. These may be referred to as means for inhibiting LAG-3, or means for immune checkpoint inhibition.
• TIGIT T cell immunoreceptor with Ig and ITIM domains
• Ig and ITIM domains TIGIT
• DAM-1 immune activating receptor CD226
• CD155 PVR or poliovirus receptor
• CD112 Nectin-2 or PVRL2
• Anti-TIGIT antibodies have demonstrated synergy with anti-PD-1/PD-L1 antibodies in pre-clinical models.
• Tiragolumab (Roche), etigilimab (OncoMed), vibostolimab (MK-7684; Merck), and EOS- 448 (iTeos Therapeutics) are non-limiting examples of an anti-TIGIT antibodies. They may be referred to as means for inhibiting TIGIT, or means for immune checkpoint inhibition.
• GITR glycocorticoid-induced TNFR-related protein promotes effector T cell functions and inhibits suppression of immune responses by regulatory T cells.
• the checkpoint inhibitor is an agonist of the target, in this case GITR.
• An agonistic antibody, TRX518 is currently undergoing human clinical trials in cancer. While by itself it may not be sufficient to mediate substantial clinical improvement in advanced cancer, combination with other checkpoint inhibition, such as PD-1 blockade was promising.
• immune checkpoint inhibitor targets include, but are not limited to, B- and T- cell attenuator (BTLA), CD40, CD122, inducible T-cell costimulator (ICOS), 0X40 (tumor necrosis factor receptor superfamily, member 4), Siglec-15, B7H3, CD137 (4-1 BB; as with CD40 and 0X40, checkpoint inhibition is accomplished with an agonist) and others are potentially useful in the disclosed methods.
• BTLA B- and T- cell attenuator
• CD40 CD122
• inducible T-cell costimulator IVS
• 0X40 tumor necrosis factor receptor superfamily, member 4
• Siglec-15 B7H3, CD137 (4-1 BB; as with CD40 and 0X40, checkpoint inhibition is accomplished with an agonist
• Anti-OX40 agonistic monoclonal antibodies are in early phase cancer clinical trials including, but not limited to, MEDI0562 and MEDI6469 (Medimmune), MOXR0916 (Genetech), and PF-04518600 (Pfizer); as is an anti-ICOS agonistic antibody, JTX-2011 (Jounce Therapeutics).
• Anti-CD40 agonistic antibodies under clinical investigation include dacetuzumab, CP-870,893 (selicrelumab), and Chi Lob 7/4.
• Anti-siglec-15 antibodies are also known (see, for example, US 8,575,531).
• Anti-CD137 agonistic antibodies include, but are not limited to, urelumab and utomilumab.
• CD122 has been targeted in cancer clinical trials with bempegaldesleukin (NKTR-214, a pegyltated-IL-2 used as a CD122-biased agonist).
• B7H3 has been targeted both for immune checkpoint inhibition and as a tumor antigen with reagents such as enoblituzumab, 131 l-omburtamab, 177 Lu-DTPA-omburtamab, 131 1- 8H9, 124 I-8H9, MCG018, and DS-7300a. These may be referred to as means for immune checkpoint inhibition or means for inhibiting (or activating (agonizing), as appropriate) their respective targets.
• Compound A therapy may also follow treatment with other types of therapeutic monoclonal antibodies.
• the therapeutic monoclonal antibody blocks the so-called “Don’t eat me” signal; these include antibodies recognizing ILT2 (for example, BND-22), ILT4 (for example MK-4830), CD47 (for example, Hu5F9-G4), and SIRPa (for example, KWAR23).
• the Don’t-eat-me signal can also be blocked with products such as TTI-621 , a fusion protein of the SIRP protein and the antibody Fc region, which act similarly to an anti-CD47 antibody by blocking binding of SIRPa to CD47.
• the therapeutic monoclonal antibody recognizes a cancer antigen, such as, but not limited to, Her2, CD133/prominin, TROP2, claudin 18.2 (for example, claudiximab (IMAB362) or zolbetuximab), CD73/NT5E (for example, MEDI9447, BMS986179, SRF373/NZV930, CPI-006/CPX-006, IPH5301 , or TJ004309; CD73/NT5E is also considered an immune checkpoint), crypto-1 , or CEACAM5.
• the anti-cancer antigen antibody is conjugated to a cytotoxic agent.
• Non-limiting examples include: SAR408701 , an antibody-drug conjugate (ADC) combining a humanized antibody targeting CEACAM5 with the potent cytotoxic maytansinoid derivative DM4; PF-06664178, an antibody-drug conjugate targeting Trop-2 and delivering Aur0101 , an auristatin microtubule inhibitor; Sacituzumab govitecan (IMMU-132), an ADC targeting Trop-2 and delivering SN-38; DS-1062a, an ADC targeting Trop-2 and delivering DXd, a topoisomerase I inhibitor and derivative of exatecan; and AC133-vcMMAF, a murine antihuman CD133 antibody (AC133) conjugated to a potent cytotoxic drug, monomethyl auristatin.
• ADC antibody-drug conjugate
• AC133 murine antihuman CD133 antibody
• the therapeutic monoclonal antibody can be used for M2 macrophage depletion, such as an anti-CD206 antibody.
• the anti- CD206 antibody is conjugated to a toxin such as diphtheria toxin.
• Pharmaceutically acceptable salts include hydrochloride, sulfate, acetate, phosphate, diphosphate, chloride, maleate, citrate, mesylate, nitrate, tartarate, and gluconate.
• Various embodiments of Compound A salts are genera comprising these salts, any subset thereof, or any individual species.
• the individual Compound A salt is a chloride, a hydrochloride, a sulfate, an acetate, or a phosphate.
• Compound A dosages are commonly expressed in units of mg/kg, largely for convenience. However, this is actually a rather inaccurate way to estimate drug exposure.
• TD50/ED50 the ratio of tolerated dose to effective dose, each for 50% of the population
• the variation in drug exposure may be inconsequential.
• the therapeutic index is smaller, more precise dosing is needed to attain effectiveness while avoiding unacceptable toxicity.
• Drug dosages expressed in units of mg/m 2 can provide this greater precision as drug exposure scales more closely to the subject’s body surface area (BSA) than it does to body weight. To achieve this greater precision in Compound A exposure, Compound A dosages are expressed herein in units of mg/m 2 .
• the dosage of Compound A is from 0.10 mg/m 2 to 1.2 mg/m 2 , or 0.15 mg/m 2 to 1.0 mg/m 2 (0.2-1.3 mg/m 2 by mass of the sulfate salt), administered weekly by intravenous infusion. In some embodiments, the dosage does not exceed 0.75, 0.80, 0.90, or 1.0 mg/m 2 . In some embodiments, the dosage is at least 0.15, 0.30, 0.45, or 0.60 mg/m 2 . In some embodiments, the dosage is in a range bounded by any pair of these values. In other embodiments, Compound A is administered weekly, biweekly, every third week, or an interval of any integer number of days between weekly and every third week.
• efficacy when used in combination with PD-1 blockade, efficacy can be achieved with a dosage of Compound A of 0.5-0.9 mg/m 2 (or 0.66-1 .2 mg/m 2 by mass of the sulfate salt).
• Compound A is administered by intravenous infusion, for example, in 100 mL of normal saline.
• an appropriate volume of a more concentrated solution would be added to the intravenous solution to provide the required dosage for the individual patient.
• the manufactured dosage form can be a solution of Compound A, or a pharmaceutically acceptable salt thereof, at a concentration, for example, of 0.5, 1 .0, 1 .5, 2.0, 2.5 mg/ml, or in a range bound by any pair of those values.
• the solution is contained in a vial (or similar container) filled with 1-2 mL of the solution.
• the dosage form comprises Compound A sulfate.
• the concentration of Compound A sulfate in the dosage form solution is 1 .0 to 2.5 mg/ml_.
• the concentration of Compound A sulfate in the dosage form solution is 1.31 mg/ml (equivalent to 1 mg Compound A free base/mL).
• the dosage form comprises a 2 mL injection vial containing 1 .5 mL of the dosage form solution.
• the dosage form solution further comprises 9.1 mg/ml sodium chloride, 0.71 mg/ml sodium citrate dehydrate, sufficient citrate dehydrate or citric acid to adjust the pH to between 4.0 and 5.0 (inclusive), and water for injection to volume.
• Compound A dosage is adjusted during treatment based on IP-10 induction level. In some embodiments, Compound A dosage is increased if the foldinduction of IP-10 is less than two-fold, five-fold, 10-fold, 20-fold, 30-fold, or 40-fold. In some embodiments, the Compound A dosage adjustment is 0.15 mg/m 2 . In some embodiments, the Compound A dosage adjustment is 0.10 mg/m 2 or 0.05 mg/m 2 . In some embodiments involving more than one dosage adjustment, the initial dosage adjustment(s) are 0.15 mg/m 2 , but as the desired fold-induction of IP-10 is approached the size of the dosage adjustment is reduced, for example, to 0.10 mg/m 2 or 0.05 mg/m 2 .
• Therapeutic window is the dose range from the lowest dose that exhibits a detectable therapeutic effect up to the maximum tolerated dose (MTD); the highest dose that will the desired therapeutic effect without producing unacceptable toxicity.
• Most typically therapeutic index is calculated as the ratio of LD 5 O:EDSO when based on animal studies and TD 5 o:EDso when based on studies in humans (though this calculation could also be derived from animal studies and is sometime called the protective index), where LD50, TD50, and ED50 are the doses that are lethal, toxic, and effective in 50% of the tested population, respectively.
• the dosage of Compound A avoids or reduces the severity or incidence of toxicity and related adverse events.
• the toxicity is an observable toxicity, a substantial toxicity, a severe toxicity, or an acceptable toxicity, or a dose-limiting toxicity (such as but not limited to a MTD).
• an observable toxicity it is meant that while a change is observed the effect is negligible or mild.
• substantial toxicity it is meant that there is a negative impact on the patient’s overall health or quality of life.
• a substantial toxicity may be mitigated or resolved with other ongoing medical intervention.
• a severe toxicity it is meant that the effect requires acute medical intervention and/or dose reduction or suspension of treatment. The acceptability of the toxicity will be influenced by the particular disease being treated and its severity and the availability of mitigating medical intervention.
• Toxicities and adverse events are sometimes graded according to a 5-point scale.
• a grade 1 or mild toxicity is asymptomatic or induces only mild symptoms; may be characterized by clinical or diagnostic observations only; and intervention is not indicated.
• a grade 2 or moderate toxicity may impair activities of daily living (such as preparing meals, shopping, managing money, using the telephone, etc.) but only minimal, local, or non- invasive interventions are indicated.
• Grade 3 toxicities are medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization is indicated; activities of daily living related to self-care (such as bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden) may be impaired.
• Grade 4 toxicities are life-threatening and urgent intervention is indicated.
• Grade 5 toxicity produces an adverse event-related death.
• use of Compound A in the herein disclosed regimen, or at a specified dosage reduces the grade of a toxicity associated with treatment by at least one grade as compared to use of the drug according to another regimen.
• a toxicity is confined to grade 2 or less, grade 1 or less, or produces no observation of the toxicity.
• Compound A dosage is reduced if an unacceptable level of toxicity is observed. In some embodiments, the Compound A dosage is reduced 0.15 mg/m 2 . In some embodiments, the Compound A dosage is reduced 0.10 mg/m 2 or 0.05 mg/m 2 . In some embodiments, infusion time is increased to mitigate adverse reactions. Cytokine induction
• induction refers to an increase in expression that is >2-fold the baseline level of expression before initiation of Compound A monotherapy.
• induction refers to an increase in expression that is >5-fold the baseline level of expression before initiation of Compound A monotherapy.
• fold induction is based on IP-10 AUC.
• IP-10 induction is based on Cmax.
• IP-10 induction was associated with prior immune checkpoint inhibition, specifically PD-1 blockade therapy (with either anti-PD-1 or anti-PD-L1). Greater IP-10 induction was also associated with prior chemotherapy, specifically DNA-damaging chemotherapy. Greater IP-10 induction was also associated with prior targeted therapies. Additionally, higher baseline levels of IP-10 may indicate a higher probability of response via further IP-10 induction to Compound A monotherapy.
• cytokine induction is monitored during Compound A monotherapy.
• Monitoring can include assaying plasma or serum levels of cytokines, such as IFN-y and IP-10, or IFN-y inducible gene products, such as CXCL10 (IP-10) orCXCLU .
• Monitoring can include quantification of whole blood RNA transcripts encoding these proteins.
• a baseline reading is established before the first infusion of Compound A monotherapy and samples can be collected as specified time points thereafter.
• Cytokine induction can be assessed after the first infusion of Compound A, after the second infusion of Compound A, after 6 weeks of treatment, at the time of the first efficacy evaluation scan, at the time of disease progression, at the time of clinical response, at the time of an adverse event, or on a regular schedule, for example, every 3 or 6 weeks, counting from either initiation of treatment or from a first measurement after initiation of treatment.
• Compound A dosage could then be changed for the next infusion to either increase the probability of response and/or decrease the risk of severe adverse events.
• IP-10 induction Importance of IP-10 induction to immune response and how IP-10 induction correlates with response in cancers
• IP-10 is known for exerting antitumor immunity by binding CXCR3, which is expressed on immune cells such as monocytes, CD4 + Th1 T cells, effector CD8 + T cells, NK, and dendritic cells. IP-10 is inducible by both IFN-y and type I interferons and is produced by CD4 + T cells, NK/NKT cells, monocytes, dendritic cells, fibroblasts, endothelial, and epithelial cells. IP-10 induction triggers CXCR3-mediated Th1 polarization, which in turn facilitates the maturation and activation of cytotoxic T lymphocytes, NK, and macrophages and their migration to the tumor microenvironment. IP-10 induction can also activate CXCR3 + CD47CD8 + T cells to enhance antitumor immunity.
• IP-10 bound to CXCR3 expressed on cancer cells can promote survival and metastasis through autocrine signaling.
• Enhanced IP-10-CXCR3 signaling in the tumor microenvironment is considered a negative predictor of response whereas IP-10- CXCR3 paracrine signaling axis in immune cells elicit antitumor immune response. Therefore, IP-10 induction in the blood may be predictive for paracrine signaling for antitumor immunity; however, migration of activated immune cells and CXCR3 expression in the tumor microenvironment must be assessed to fully correlate IP-10 induction with antitumor response.
• IFN-y-mediated gene signature which includes IP-10
• IP-10 is a well-studied predictive biomarker for response in cancer patients.
• IFN-y/IP-10 induction was associated with increased antitumor immunity, leading to clinical response in various solid tumors.
• immunomodulatory agents such as anti-PD-(L)1 mAb, anti-CTLA-4 mAb, IFN-a, poly- 1 :C, and a DNA vaccine to elicit antitumor immunity via IFN- y/IP-10 induction.
• PD-1 and CTLA-4 blockade induced macrophage-derived IP-10, which correlated with antitumor immune response.
• IFN-y/IP-10 induction may depend on the tumor and treatment types (e.g., immunotherapy versus chemotherapy) that may shift the balance between Treg and Th1- mediated immune cells.
• kits for treating cancer in a mammal comprising administering Compound A by intravenous infusion as monotherapy.
• Dosage is specified in units of mg/m 2 , in order to more precisely control patient exposure to the Compound A.
• dosage can be in the range of 0.10 mg/m 2 to 1.2 mg/m 2 .
• This amount of drug is typically infused over 20-90 minutes, for example 30 minutes, or 60 minutes or any range bound by a pair of these values.
• Compound A will be administered by infusion 1-6 times over a period of 3 to 6 weeks, with administration not occurring more often than once per week.
• Compound A monotherapy after a prior therapy can commence any time after the last administration of the prior therapy and the decision to adopt a new therapeutic approach is made.
• Compound A therapy commences after a rest period to allow the amount of the prior therapy drug in the body to become substantially reduced or eliminated, to recover from surgery, or for any adverse events produced by the prior therapy to resolve.
• the interval between the last administration of the prior therapy and commencing Compound A monotherapy is at least 2, 3, or 4 weeks, or a month.
• Compound A monotherapy does not commence until toxicity from the prior therapy has reduced to grade 1 or less, or to baseline.
• the prior therapy caused permanent damage to an organ and Compound A monotherapy is not initiated until mitigating therapy for the impaired or lost function of the damaged organ is established.
• the thyroid gland or pituitary gland may be damaged and hormone replacement therapy undertaken.
• the prior therapy was immunotherapy, for example, immune checkpoint inhibition therapy.
• the prior therapy was chemo therapy, for example cytotoxic or DNA-damaging chemotherapy.
• Compound A monotherapy is used to treat patients coming off of immune checkpoint inhibition therapy (for example, due to progressive disease or unacceptable toxicity).
• the patients have also had prior treatment with chemotherapy, for example, cytotoxic or DNA-damaging chemotherapy.
• Compound A monotherapy is commenced within 12 weeks or within 24 weeks (or within 3 months or within 6 months) of the last dose of the prior therapy, or within 12 weeks or within 24 weeks (or within 3 months or within 6 months) of the last dose of the prior immune checkpoint inhibition therapy.
• the prior immune checkpoint inhibition therapy was anti-PD-1 therapy, anti-PD-L1 therapy, or either. In some embodiments, the prior immune checkpoint inhibition therapy, was anti-CTLA-4 therapy. In still further embodiments, the prior immune checkpoint inhibition therapy was anti-LAG-3, anti-Siglec- 15, anti-TIGIT, oranti-TIM-3. In further embodiments, the prior immune checkpoint inhibition therapy can be anti-B7H3, anti-CD137, anti-OX40, anti- CD40, anti-CD122, anti-ICOS, or anti-CD73/NT5E.
• immune checkpoint inhibition therapy and treatment with Compound A are undertaken as sequential treatments, in which at least 1-3 doses of the immune checkpoint inhibitor are administered before treatment with Compound A commences.
• immune checkpoint inhibition therapy is discontinued before commencing treatment with Compound A.
• administration of the immune checkpoint inhibitor continues concurrently with treatment with Compound A.
• the immune checkpoint inhibitor is administered according to its usual schedule.
• a window during which Compound A monotherapy or sequential therapy is initiated is defined by any of the above teachings regarding earliest administration and periods within which it should be commenced.
• the effectiveness of treatment can be monitored over the course of treatment. Monitoring can be accomplished by imaging the tumor(s), for example, by simple X-ray, CAT or CT scan, PET scan, or MRI. In some embodiments, these scanning technologies can be referred to as means for imaging, and taking such a scan can be referred to as a step for imaging.
• the effectiveness of cancer therapy is typically measured in terms of "response.”
• the techniques to monitor responses can be similar to the tests used to diagnose cancer such as, but not limited to:
• a lump or tumor involving some lymph nodes can be felt and measured externally by physical examination.
• Some internal cancer tumors will show up on an x-ray, CT scan, PET scan, CT/PET scan or MRI and can be measured with a ruler.
• a tumor marker test can be done for certain cancers. [0065] Regardless of the test used, whether blood test, cell count, or tumor marker test, it is repeated at specific intervals so that the results can be compared to earlier tests of the same type.
• Stable disease the cancer has neither grown, nor shrunk; the amount of disease has not changed.
• a tumor marker (if applicable) has not changed significantly.
• Other measures of the efficacy of cancer treatment include intervals of overall survival (that is time to death from any cause, measured from diagnosis or from initiation of the treatment being evaluated)), cancer-free survival (that is, the length of time after a complete response cancer remains undetectable), and progression-free survival (that is, the length of time after disease stabilization, partial response, or complete response that resumed tumor growth is not detectable).
• a Cmax in plasma of Compound A free base of 8.3 ng/mL and/or an area under the curve (AUC) in plasma of Compound A free base of 3.4 ng/ml_*Day is associated with greater likelihood of clinical benefit from monotherapy with Compound A.
• some embodiments are methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to the patient to provide a plasma concentration profile in said patient comprsing: a maximum plasma concentration (Cmax) of Compound A free base of_>8.3 ng/mL, an AUC of Compound A free base of >3.4 ng/ml_*Day, or both.
• Cmax maximum plasma concentration
• the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• the Cmax profile attained is >5, >6, >7, >8, >9, >10, >11 , or >12 ng/mL.
• the AUC profile attained is >1 , >2, >3, >4, or >5 ng/mL*Day.
• a Cmax in plasma of Compound A free base of 7.6 ng/mL and/or an AUC in plasma of Compound A free base of 2.2 ng/mL*Day is associated with greater likelihood of clinical benefit from combination therapy with Compound A and an anti-PD1 antibody.
• methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody to the patient to provide a plasma concentration profile in said patient comprsing: a maximum plasma concentration (Cmax) of Compound A free base of_7.6 ng/mL, an area under the curve (AUC) of Compound A free base of _2.2 ng/mL*Day, or both.
• the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• the Cmax profile attained is >5, >6, >7, >8, >9, or >10 ng/mL.
• the AUC profile attained is >1 , >2, >3, >4, or >5 ng/mL*Day.
• a C max in plasma of Compound A free base of 10.5 ng/mL and/or an AUC in plasma of Compound A free base of 2.1 ng/mL*Day is associated with greater likelihood of clinical benefit from combination therapy with Compound A and an anti-PD-L1 antibody.
• methods of treating cancer comprising administering an therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody to the patient to provide a plasma concentration profile in said patient comprsing: a maximum plasma concentration (C max ) of Compound A free base of_10.5 ng/mL, an area under the curve (AUC) of Compound A free base of _2.1 ng/mL*Day, or both.
• the likelihood of clinical benefit is increased as compared to treatment with Compound A that does not attain the plasma concentration profile.
• the Cmax profile attained is >5, >6, >7, >8, >9, >10, >11 , or >12 ng/mL.
• the AUC profile attained is >1 , >2, >3, >4, or >5 ng/mL*Day.
• “clinical benefit” means complete response, partial response, or stable disease > 18 weeks according to RECIST version 1.1.
• treating broadly includes any kind of treatment activity, including the diagnosis, mitigation, or prevention of disease, or aspect thereof, in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
• Treatment activity includes the administration of the medicaments, dosage forms, and pharmaceutical compositions described herein to a patient, especially according to the various methods of treatment disclosed herein, whether by a healthcare professional, the patient his/herself, or any other person.
• Treatment activities include the orders, instructions, and advice of healthcare professionals such as physicians, physician’s assistants, nurse practitioners, and the like, that are then acted upon by any other person including other healthcare professionals or the patient him/herself.
• the orders, instructions, and advice aspect of treatment activity can also include encouraging, inducing, or mandating that a particular medicament, or combination thereof, be chosen for treatment of a condition - and the medicament is actually used - by approving insurance coverage for the medicament, denying coverage for an alternative medicament, including the medicament on, or excluding an alternative medicament, from a drug formulary, or offering a financial incentive to use the medicament, as might be done by an insurance company or a pharmacy benefits management company, and the like.
• treatment activity can also include encouraging, inducing, or mandating that a particular medicament be chosen for treatment of a condition - and the medicament is actually used - by a policy or practice standard as might be established by a hospital, clinic, health maintenance organization, medical practice or physicians group, and the like. All such orders, instructions, and advice are to be seen as conditioning receipt of the benefit of the treatment on compliance with the instruction.
• a financial benefit is also received by the patient for compliance with such orders, instructions, and advice.
• a financial benefit is also received by the healthcare professional for compliance with such orders, instructions, and advice.
• Non-limiting examples of cancers which can be treated by the disclosed methods may include, but are not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, an AIDS-related malignancy, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, a brain tumor (e.g., astrocytoma, cerebellar astrocytoma; cerebral astrocytoma/malignant glioma, ependymoma brain tumor, supratentorial primitive brain tumor, a neuroectodermal tumor, visual pathway and hypothalamic glioma, etc.), breast cancer, a bronchial adenoma/carcinoid, carcinoid tumor, carcinoma (adrenocortical, gastrointestinal, islet cell, skin, unknown primary, etc.); cervical cancer, a childhood cancer, chronic lymphocytic leukemia,
• Each of the herein disclosed methods of treatment may be expressed as a corresponding composition for use in treating cancer, use of a composition in treating cancer, or use of a composition in the manufacture of a medicament for treating cancer, etc.
• compositions comprising Compound A can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
• buffers include, without limitation, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline.
• antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
• Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition, such as, e.g., sodium chlorite and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA- bisamide.
• Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
• Liquid formulations suitable for infusion may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile infusable solutions or dispersions.
• aqueous and non-aqueous carriers, diluents, solvents or vehicles include, but are not limited to, water, ethanol, polyols (propylene glycol, polyethyleneglycol (PEG), glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), polymers, liposomes, nanoparticles, nanomicellar formulation, pegylation, aluminum gel, associated proteins or polypeptides such as albumins, and injectable organic esters such as ethyl oleate.
• PEG polyethyleneglycol
• suitable mixtures thereof vegetable oils (such as olive oil)
• polymers such as liposomes, nanoparticles, nanomicellar formulation, pegylation, aluminum gel, associated proteins or polypeptides such as albumins
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required
• a pharmaceutical composition of Compound A can optionally include a pharmaceutically acceptable carrier that facilitates processing of the active compound into pharmaceutically acceptable compositions.
• a pharmaceutically acceptable carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound.
• aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solvents; dispersion media; polymers, liposomes, nanoparticles, nanomicellar formulation, pegylation, aluminum gel; associated proteins or polypeptides such as albumins; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
• the dosage appropriate amount of Compound A based on the patient’s BSA is diluted into 100 ml normal saline for infusion.
• Compound A injectable solution is a sterile, preservative-free, colorless solution containing Compound A and inactive ingredients, sodium chloride and sodium citrate, for intravenous use.
• the primary packaging consists of a 2-mL glass vial containing 1.5 mL of Compound A Injectable Solution.
• the concentration of Compound A free base can be 1.0 mg/ml (although the solution may be made by dissolution of a pharmaceutically acceptable salt, such as the sulfate salt) and the volume of the drug solution in the vial to be added to 100 mL normal saline is calculated based on 1.0 mg/mL in the vial and the mass or BSA of the pateint.
• Directions can be provided in a pharmacy manual or prescribing information (package insert) for dosing solution preparation and infusion requirements.
• Compound A injectable solution vials are for single use only and can be supplied in a 2 ml clear vial.
• the vial is capped with a 13-mm rubber stopper and sealed with a 13-mm plastic aluminum seal.
• An aluminum seal with a plastic flip-off cap can be used to secure the closure in place.
• Vials can be shipped in small cardboard cartons containing a plurality of vials, for example six vials each.
• the vials are to be stored at room temperature (15° - 25°C) and protected from light in a secure, temperature controlled, limited access area.
• the final compound A sulfate salt concentration can be about 1 .3 mg/mL This is equivalent to a free base of approximately 1 .0 mg/mL.
• the ongoing Phase 1 dose-escalation trial has so far enrolled 36 subjects treated with at least one dose of the Compound A salt as monotherapy.
• Subject population summary (Table 2) shows the demographics, and prior lines of therapy recorded at screening. (A line of therapy consists of >1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens.) Enrolled subjects had 15 solid tumor types with most frequent being NSCLC, endometrial carcinoma/sarcoma, and ovarian cancer.
• BSA body surface area
• IP-10 induction was more likely in subjects with prior anti-PD-(L)1 mAb and/or chemotherapy treatments (Table 3); however, such immune activation favored clinical response in subjects with prior anti-PD-(L)1 mAb treatment.
• cytokine biomarkers implicated in inflammatory responses, immune system regulation, and other biological processes. Assays for cytokine quantification were performed by Frontage Laboratories, Inc. utilizing Meso Scale Discovery (MSD) V-PLEX and U-PLEX plates pre-coated with capture antibodies for IL-5, IL-17A, IFN-y, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-a, IFN-a, IFN-p, and IP-10. Plasma samples were added directly to the plate to allow the analytes in the samples to bind to the capture antibodies.
• MSD Meso Scale Discovery
• Electrochemiluminiscent label (MSD SOLFO- TAGTM)-conjugated detection antibodies were then added to visualize the plates by a MSD plate reader. The luminescence intensity was measured to quantify the amount of captured analytes (or cytokine levels) in each sample.
• RNA extracted from whole-blood samples was analyzed via the NanoString nCounter platform of high-plex assay designed to quantify gene expression using the predesigned Human Pan Cancer Immune Profiling panel of genes. Intra-patient comparisons among various time points was performed. The relative transcript levels of selected genes were analyzed based on the data from cytokine quantification.
• GCP Good Clinical Practice
• GLP Good Laboratory Practice
• Peak cytokine levels were normalized to Cycle 1 Day 1 baseline for each subject and compared based on Compound A dose levels (Table 4). The greater peak cytokine level from either Cycle 1 Days 1 or 8 were selected for the analysis to be inclusive of all subjects. There was a dose-dependent increase in IP-10 and IFN-y, indicating immune activation by Compound A. Medians and ranges of peak cytokine levels I baseline from each dose level are shown in Table 4. Cytokine induction also correlated to peak plasma concentration of Compound A ( Figure 3).
• IP-10/IFN-y changes are higher in partial response and prolonged stable disease (SD) subjects (data not shown), indicating that IP-10 and IFN-y induction correlates with clinical response to Compound A.
• the window of immune activation necessary for response could be defined by IP-10 induction of 5- to 40-fold increase, which was seen in PR (2 of 2) and prolonged SD subjects (6 of 7).
• An out of window induction of IP-10 higher than 100-fold increase may instead require dose reduction to minimize the risks of toxicity such as cytokine release syndrome.
• a disease control rate of 63% (2 partial response [PR] + 18 stable disease [SD]) was achieved according to irRECIST. 7 subjects (22%) had prolonged disease control (study duration >18 weeks), one of whom who had the longest study duration of 68 weeks on Compound A salt monotherapy treatment. There were 12 subjects with progressive disease (PD, 38%) as best response. Both partial response subjects received the higher dose of Compound A salt at 0.75 mg/m 2 .
• ADME absorption, distribution, metabolism, and excretion
• patients receiving the same dosage may have very different Compound A (measured as free base) AUC or Cmax values, which in turn will produce very different downstream pharmacodynamic effects, such as IP-10 induction.
• patient A dosed with dose level 2 with slower metabolism may have higher AUC and/or Cmax than patient B who was dosed with dose level 3, as a result patient A may produce higher level of IP-10 induction from baseline.
• IP-10 induction level presented as the induction from baseline, divided into two groups in accordance with the AUC for Compound A , with 16 patients in a low AUC group (AUC below 2.09 ng/ml_*Day) and 16 patients in the ahigh AUC group (AUC above 2.09 ng/ml_*Day) groups respectively.
• the mean value of induction level of IP-10 is 3.68-fold in the low AUC group but 27.2-fold in the high AUC group, indicating that a minimum of AUC 2.09 ng/ ng/ml_*Day is required to induce IP-10 that in turn results in clinical benefit in patients, and this difference is statistically significant with p ⁇ 0.05.
• IP-10 induction level of was presented as the induction from baseline and divided into two groups in accordance with the Cmax of Compound A, with 16 patients in a low Cmax group (Cmax below 9.4 ng/mL) and 16 patients in the a high AUC group (Cmax above 9.4 ng/mL) group.
• the mean value of induction level of IP-10 is 5.09-fold for the low Cmax group but 31 .9-fold for the high Cmax group, indicating that a minimum of Cmax of 9.4 ng/mL is required to induce enough IP-10 that in turn results in clinical benefit in patients, and this difference is statistically significant with p ⁇ 0.05.
• IFN-y Median IP-10 induction (peak concentration between C1 D1 and C1 D8) relative to baseline for subjects with clinical beneift (irPR + irSD > 18 weeks) was 13.5-fold compared to 4.0-fold and 3.4-fold in subjects with irSD ⁇ 18 weeks and uirPD, respectively. Likewise, median IFN-y induction relative to baseline for subjects with clinical beneifts (irPR + irSD > 18 weeks) was 7.5-fold compared to 3.0-fold and 2.5-fold in subjects with irSD ⁇ 18 weeks and uirPD, respectively. It is clear that higher dose levels produce greater IP-10 or IFN-y induction which in turn correlates to better clinical efficacy.
• a dosage form was manufactured to provide 1.5 mL of solution of Compound A sulfate at a concentration of 1.31 mg/ml (1 mg free base per mL) in a 2 mL injection vial.
• the master formula for making the solution was (per 1 mL):
• Compound A sulfate is C17H22N4O2 H2SO4, molecular weight 412.46.
• the crystal form was confirmed during the production (crystal form A, as identified in WO2018232725, which is hereby incorporated by reference).
• an appropriate volume is withdrawn from the injection vial and injected into an intravenous solution container (for example, 100 mL of normal saline), which is infused intravenously into the patient.
• an intravenous solution container for example, 100 mL of normal saline
• a volume of 1 .35 mL of the Compound A sulfate solution would be withdrawn from the injection vial and injected into the intravenous solution container.
• Compound A has been evaluated in monotherapy and in combination with an anti- PD-1 mAb (pembrolizumab) or an anti-PD-L1 mAb (atezolizumab) in subjects with advanced solid tumors.
• An analysis was performed to investigate the correlation between clinical benefit and the pharmacokinetic parameters of the free base form of Compound A when administered in monotherapy or in combination with the anti-PD-1 mAb or anti-PD- L1 mAbs.
• Clinical benefit was defined as radiographic complete response, partial response or stable disease > 18 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Compound A was evaluated in monotherapy in 32 patients with advanced solid cancers.
• the patients divided into two groups in accordance with the AUC for Compound A, with 18 patients in a low AUC group (AUC below 3.42 ng/ml_*Day) and 14 patients in the high AUC group (AUC above 3.42 ng/ml_*Day).
• Clinical benefit to the treatment was observed in 11% of patients in the low AUC group compared to 50% of patients in the high AUC group, indicating that a minimum of AUC 3.42 ng/ml_*Day is more likely to produce clinical benefit in patients.
• Compound A was evaluated in combination with pembrolizumab in 26 patients with advanced solid cancers.
• the patients divided into two groups in accordance with the AUC for Compound A, with 11 patients in a low AUC group (AUC below 2.19 ng/mL*Day) and 15 patients in the high AUC group (AUC above 2.19 ng/mL*Day).
• Clinical benefit to the treatment was observed in 27% of patients in the low AUC group compared to 47% of patients in the high AUC group, indicating that a minimum of AUC 2.19 ng/mL*Day is more likely to produce clinical benefit in patients.
• Cmax Evaluation of Cmax in the same patients divided into two groups in accordance with the Cmax for Compound A, with 10 patients in a low Cmax group (Cmax below 7.65 ng/mL) and 16 patients in the high Cmax group (Cmax above 7.65 ng/mL). Clinical benefit to the treatment was observed in 30% of patients in the low Cmax group, compared to 44% of patients in the high Cmax group, indicating that a minimum of Cmax 7.65 ng/mL is more likely to produce clinical benefit in patients.
• Compound A was evaluated in combination with atezolizumab in 25 patients with advanced solid cancers.
• the patients divided into two groups in accordance with the AUC for Compound A, with 15 patients in a low AUC group (AUC below 2.14 ng/mL*Day) and 10 patients in the high AUC group (AUC above 2.14 ng/mL*Day).
• Clinical benefit to the treatment was observed in 20% of patients in the low AUC group compared to 50% of patients in the high AUC group, indicating that a minimum of AUC 2.14 ng/mL*Day is more likely to produce clinical benefit in patients.

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