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WO2024258916A1 - Agents de dégradation de stat3 et leurs utilisations - Google Patents

Agents de dégradation de stat3 et leurs utilisations Download PDF

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Publication number
WO2024258916A1
WO2024258916A1 PCT/US2024/033526 US2024033526W WO2024258916A1 WO 2024258916 A1 WO2024258916 A1 WO 2024258916A1 US 2024033526 W US2024033526 W US 2024033526W WO 2024258916 A1 WO2024258916 A1 WO 2024258916A1
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Prior art keywords
compound
patient
concentration
formulation
liquid formulation
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English (en)
Inventor
Sagar Agarwal
Christopher De Savi
Joyoti DEY
Vaishali DIXIT
Bradley ENERSON
Ashwin GOLLERKERI
Jared Gollob
Chris Ho
Rahul KARNIK
Michele Mayo
Haojing RONG
Bin Yang
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Kymera Therapeutics Inc
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Kymera Therapeutics Inc
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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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/02—Inorganic compounds
    • 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

Definitions

  • the present invention relates to formulation and dosage forms of STAT3 degrader (2-
  • UPP Ubiquitin-Proteasome Pathway
  • UPP is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins.
  • UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases.
  • Tire covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • STAT3 The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors upon binding to their cognate cell surface receptors resulting in the recruitment and phosphorylation of STAT3 by Janus kinase (JAK), dimerization, nuclear translocation and transcriptional regulation of STAT3 target genes. While in normal cells STAT3 activity is tightly controlled by feedback regulation, in diseases including cancer and auto-immunity, STAT3 activity becomes deregulated by mechanisms that result in persistent activation of STAT3 as evidence by high levels of phosphorylated STAT3 (pSTAT3). Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of pSTAT3.
  • STAT3 Aberrant activation of STAT3 has been shown to occur through direct mutation of the STAT3 gene, activation of upstream kinases such as JAK or ALK by mutation or translocation, reduced expression of negative regulators such as SOC3 and elevated receptor signaling from overexpression of cytokine and growth factors in the tumor microenvironment.
  • activated STAT3 also promotes a suppressive TME through direct regulation of immune cell function and regulation of cancer cell-TME crosstalk.
  • Activation of STAT3 in innate and adaptive immune cells generally favors expansion of immune suppressive cells while reducing the proliferation, maturation and function of cytolytic effector cells.
  • Targeting STAT3 with antisense oligonucleotides that are preferentially taken up by myeloid cells has been shown to reverse immune suppression and restore anti-tumor activity of cytotoxic T cells in mouse syngeneic tumor models.
  • STAT3 has been shown to be activated in response to both chemo- and targeted therapies such as EGFR inhibitors and contributes to the development of drug -resistance.
  • a liquid formulation or unit dosage fomi comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer.
  • a liquid formulation or unit dosage form of the invention is at about pH 6.5.
  • the present invention provides methods and uses for treating a hematological malignancy or solid tumor in a patient, comprising administering to the patient a therapeutically effect amount of compound A. or a pharmaceutically acceptable salt thereof, or a liquid formulation as described herein.
  • the hematological malignancy or solid tumor is a relapsed or refractory lymphoma.
  • the hematological malignancy or solid tumor is selected from large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL).
  • the method comprises administering up to about 3.0 mg/kg of Compound A. or a pharmaceutically acceptable salt thereof, to the patient per day. In other instances, the method comprises administering up to about 500 mg of Compound A, or a pharmaceutically acceptable salt thereof, to the patient per day. In some embodiments, the method comprises administering Compound A, or a pharmaceutically acceptable salt thereof, to the patient intravenously. In some embodiments, the method comprises administering Compound A, or a pharmaceutically acceptable salt thereof, to the patient once per week (QW). In some embodiments, the method comprises administering Compound A, or a phannaceutically acceptable salt thereof, to the patient on days 1, 8, 15, and 22 of a 28-day cycle.
  • the present disclosure provides a compound, which is Compound A ammonium hydrogen salt.
  • FIG. IB shows prcclinical PK/PD after QW intravenous administration of Compound A in NOD SCID mice bearing SU-DHL-1 xenografts.
  • FIG. 2 shows the antitumor activity after Q2W intravenous administration of Compound A in NOD SCID mice bearing SU-DHL-1 xenografts.
  • FIG. 3A and FIG. 3B show the antitumor activity after QW, 2 Days on/5 Days off, and Q2W intravenous administration of Compound A in NOD SCID mice bearing SUP-M2 xenografts.
  • FIG. 4 depicts a schematic of the drug product manufacturing process.
  • FIG. 5 depicts a schematic of the Phase 1 study design. * Solid tumor applies only to MTD/RP2D confirmation cohort. **RP2D not always the same as MTD.
  • FIG. 7 shows PK data for patients enrolled in DL1 to DL7.
  • FIG. 8A shows time course STAT3 degradation results in Peripheral Blood Mononuclear Cells (PBMCs) for patients enrolled in DL1 to DL5.
  • PBMCs Peripheral Blood Mononuclear Cells
  • FIG. 8B shows time course STAT3 degradation results in PBMCs for patients enrolled in DL1 to DL7.
  • FIG. 9 A shows maximum STAT3 degradation for patients enrolled in DL1 to DL5.
  • FIG. 9B shows maximum STAT3 degradation for patients enrolled in DL1 to DL7.
  • FIG. 10 shows that dose dependent degradation of STAT3 is observed across different peripheral immune cell types. Maximum degradation of STAT3 in peripheral immune cell subsets in individual patients across dose levels as measured using flow cytometric analysis.
  • FIG. 11 and FIG. 12 show that Compound A achieved STAT3 pathway inhibition and downregulation of inflammatory biomarkers in peripheral blood.
  • FIG. 13 shows a time course of IFNy plasma protein changes post Compound A infusion.
  • FIG. 14A and FIG. 14B show a time course of transcriptional induction of select IFNy stimulated genes post Compound A infusion.
  • FIG. 15 shows CXCL9 and CXCL10 plasma protein upregulation.
  • FIG. 16 shows representative ROIs from histological sections of tumor biopsies were analyzed using multiplex immunofluorescence (mIF) for STAT3, pSTAT3 and CD3.
  • t 24 ( ⁇ 3) hours post 2 nd dose of Compound 1 (C1D9); CTCL patient treated in DL4; Maximum STAT3 degradation in PBMCs by MS: 86% (CI); 91% (C2)
  • FIG. 17 shows that STAT3 and pSTAT3 % positive cells are reduced overall by 69% and 87% respectively in the C1D9 CTCL tumor biopsy vs. screening.
  • Compound A is a potent, highly selective, intravenously administered, heterobifunctional small molecule therapeutic targeting the protein STAT3 and the E3 ligase von Hippel-Lindau protein (VHL) to mediate the selective degradation of STAT3 via the ubiquitin-proteasome system (UPS).
  • VHL von Hippel-Lindau protein
  • Compound A has demonstrated potent and selective STAT3 protein degradation and antitumor activity in a battery of in vitro and in vivo studies. In vitro. Compound A degrades STAT3 in human ALCL cell lines, SU-DHL-1 and SUP -M2, at low nanomolar range ( ⁇ 11.8 ⁇ 2.3 nM), consistent with findings in the cellular phenotypic assays, where Compound A showed GI50 from 8.1 to 57.4 nM in several ALCL cell lines. Degradation of STAT3 in ALCL lines also induced caspase 3/7 activity, a marker of apoptosis, at similar concentrations.
  • Compound A exhibited comparable degradation potency of STAT3 in hepatocytes across human, rat, and dog.
  • PK/PD study in rats also demonstrated significant degradation of STAT3 protein in multiple tissues following IV administration of Compound A.
  • These data support the selection of rat and dog as nonclinical species for the safety evaluation of Compound A.
  • Compound A is a highly selective STAT3 degrader that does not degrade other STAT family members or other cellular proteins expressed in peripheral blood mononuclear cell (PBMC).
  • PBMC peripheral blood mononuclear cell
  • the present disclosure provides a method for treating a hematological malignancy or solid tumors in a patient, such as large granular lymphocytic leukemia (LGL- L), T-cell prolymphocytic leukemia (T-PLL), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL), comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.
  • LGL- L large granular lymphocytic leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • PTCL peripheral T-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • the present disclosure provides a method for treating a hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.
  • the present disclosure provides a method for treating relapsed or refractory lymphomas in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.
  • the present disclosure provides a method for treating solid tumors in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation thereof as described herein.
  • the present disclosure provides a method for treating LGL-L in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.
  • the present disclosure provides a method for treating T-PLL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation thereof as described herein.
  • the present disclosure provides a method for treating PTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation thereof as described herein.
  • the present disclosure provides a method for treating CTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation thereof as described herein.
  • the present disclosure provides a liquid fonnulation, which comprise Compound A, or a phannaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.
  • a unit dosage form which comprise Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and/or carrier.
  • the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • Compound A refers to STAT3 degrader (2-(((5S,8S, 10aR)-3-acetyl-8-(((5 - 5-amino-l-(2-chloro-3-(4-(((.S -l-((2S,4RJ-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)- 5-oxopentan-2-yl)carbamoyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)-lH-indole-5- carbonyl)phosphonic acid, of
  • Compound A is provided in solid fonn. In some embodiments, Compound A is amorphous.
  • ‘'Compound A ammonium hydrogen salt’ refers to STAT3 degrader ammonium hydrogen (2-(((5S, 8S, 10aR)-3-acetyl-8-(((S)-5-amino-l-(2-chloro-3- (4-(((.S7-l-((2S,4R -4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrroli din-1- yl)-3,3-dimethyl-l-oxobutan-2-yl)amino)-4-oxobutyl)phenoxy)-5-oxopentan-2-yl)carbamoyl)-6- oxo
  • Compound A ammonium hydrogen salt is provided in solid form. In some embodiments, Compound A ammonium hydrogen salt is amorphous.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge etal.. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 4alkyl) salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Tire term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • the temr “subject,” as used herein, has the same meaning as the tenn “patient”.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • a patient or subject “in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non-human mammals), would reasonably benefit from a given treatment or therapy.
  • an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non-human mammals
  • a “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent, such as Compound A. or a pharmaceutically acceptable salt thereof, is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as LGL-L, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • a therapeutically effective amount of the drug promotes regression to the point of eliminating the disease.
  • the tenns “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the Compound A, or a pharmaceutically acceptable salt thereof, to treat the disease in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • therapeutic benefit refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • Tire phase “woman of childbearing potential” are considered fertile: 1. following mcnarchc; 2. from the time of menarche until becoming postmenopausal unless pennanently sterile.
  • a postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
  • a high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required.
  • FSH follicle-stimulating hormone
  • Permanent sterilization methods include: documented hysterectomy; documented bilateral salpingectomy’ documented bilateral oophorectomy; for individuals with permanent infertility due to an alternate medical cause other than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion should be applied to determining study entry.
  • the present invention provides a method for treating hematological and solid tumors in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation as described herein.
  • the hematological and solid tumors are relapsed and/or refractory lymphomas, large granular lymphocytic leukemia, and advance solid tumors.
  • the hematological and solid tumors are selected from large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL).
  • LGL-L large granular lymphocytic leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • PTCL peripheral T-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • the present disclosure provides a method for treating hematological and solid tumors in a patient, such as large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphoma (CTCL), comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation as described herein.
  • LGL-L large granular lymphocytic leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • PTCL peripheral T-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • the present disclosure provides a method for treating LGL-L in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation as described herein.
  • the present disclosure provides a method for treating T-PLL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation as described herein.
  • the present disclosure provides a method for treating PTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid formulation as described herein.
  • the present disclosure provides a method for treating CTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a liquid fonnulation as described herein.
  • the patient is male or female aged > 18 years.
  • the patient has cytologically or pathologically confirmed Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma.Small Lymphocytic, or NK-cell Lymphomas, LGL-L , histologically or pathologically confmned solid tumor, or T-cell prolymphocytic leukemia (T-PLL).
  • fresh or archival formalin fixed paraffin embedded (FFPE) tumor tissue or 15 slides are preferably collected within ideally 6 months or 2 years prior to first dose of the study drug (for lymphoma and solid tumor patients, respectively).
  • pre-dose biopsy will be perfomred (optional for Phase la, required for Phase lb), and a blood sample collected during screening for STAT3 pathway mutational analysis and potentially for central pathology review.
  • the lymphoma or solid tumor patient has relapsed and/or refractory' disease to at least 2 prior systemic standard of care treatments or for whom standard therapies are not available.
  • the LGL-L or T-PLL patient has relapsed and/or refractory disease to at least 1 prior systemic standard of care treatment or for whom standard therapies are not available.
  • the patient of all disease types has relapsed and/or refractory disease to at least 1 prior systemic standard of care treatments or for whom standard therapies are not available.
  • the LGL-L patient has hematology specific criteria selected from one of severe neutropenia ⁇ 500/mm 3 , symptomatic anemia and/or, transfusion-dependent anemia; ANC > 200/p.L at Screening and CID 1 (pre dose); or platelet count > 100,000/pL (assessed > 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).
  • the LGL-L patient has baseline disease characteristics selected from CD3+CD8+ cell population >650/mm 3 ; CD3+CD8+CD57+ population >500/mm 3 ; presence of a clonal T- cell receptor (within 1 month of diagnosis); and Natural-Killer (NK) LGL is also permitted, provided there is a clonal NK-cell population noted with >500 cells/mm 3 .
  • baseline disease characteristics selected from CD3+CD8+ cell population >650/mm 3 ; CD3+CD8+CD57+ population >500/mm 3 ; presence of a clonal T- cell receptor (within 1 month of diagnosis); and Natural-Killer (NK) LGL is also permitted, provided there is a clonal NK-cell population noted with >500 cells/mm 3 .
  • solid tumor and PTCL patients have measurable disease per Lugano for PTCL and Response evaluation criteria in solid tumors (RECIST) version 1. 1 for solid tumors at Screening.
  • T-PLL patients have measurable disease per Lugano and/or atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow.
  • patients have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at Screening and C1D1 (pre-dose).
  • EOG Eastern Cooperative Oncology Group
  • patients have adequate bone marrow function at Screening and C1D1 (pre-dose) for all patients except those with LGL-L defined as: absolute neutrophil count (ANC) > 1000/pL; hemoglobin > 8 g/dL (forthose patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion); and platelet count > 100, 000/ qL (assessed > 7 days following last platelet transfusion in patients with thrombocytopenia requiring platelets).
  • ANC absolute neutrophil count
  • RBC red blood cell
  • patients have adequate organ function at Screening and CID1 (predose) for all patients including those with LGL-L including aspartate aminotransferase (AST), alanine transaminase (ALT) ⁇ 3x upper limit of normal (ULN) or ⁇ 5 x ULN in cases of documented lymphoma involvement of liver; total serum bilirubin ⁇ 3x ULN or ⁇ 5x ULN if secondary' to Gilbert’s syndrome or documented lymphoma involvement of liver; and serum creatinine clearance > 50 niL/min/1.73 m2 either measured or calculated using standard Cockcroft-Gault formula.
  • AST aspartate aminotransferase
  • ALT alanine transaminase
  • the patient tests negative to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test at Screening.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus-2
  • WOCBP childbearing potential
  • WOCBP must agree to use highly effective contraceptive methods for the duration of treatment and 6 months after the last dose of Compound A.
  • WOCBP must have a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 72 hours prior to first dose of Compound A.
  • male patients must agree to use highly effective contraceptive methods during the treatment and for 6 months after the last dose of Compound A if the partner is a WOCBP.
  • the patient does not have known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
  • CNS central nervous system
  • the patient does not have a diagnosis of Chronic Lymphocytic Leukemia (CLL).
  • CLL Chronic Lymphocytic Leukemia
  • the patient does not have a history of or active concurrent malignancy other than lymphoma or solid tumors unless the patient has been disease-free for > 2 years. Exceptions to the > 2-year time limit include treated basal cell or localized squamous cell skin carcinoma, localized prostate cancer, or other localized carcinomas such as carcinoma in situ of cervix, breast, or bladder.
  • the patient has not recovered from any clinically significant adverse events (AEs) of previous treatments to pre-treatment baseline or Grade 1 prior to first dose of Compound A.
  • AEs adverse events
  • the patient does not have ongoing unstable cardiovascular function: symptomatic ischemia, or uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic drugs is excluded: 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or congestive heart failure of New York Heart Association Class > III, or myocardial infarction within 3 months prior to Screening.
  • symptomatic ischemia or uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic drugs is excluded: 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or congestive heart failure of New York Heart Association Class > III, or myocardial infarction within 3 months prior to Screening.
  • the patient does not have congenital long QT syndrome, or a QT interval corrected by Fridericia’s formula (QTcF) >450 ms (average of triplicate electrocardiograms) at Screening and/or on C1D1 (pre-dose) with the exception of a documented bundle branch block or unless secondary to pacemaker.
  • QTcF Fridericia
  • the patient does not have a history of thromboembolic or cerebrovascular event (i.e., transient ischemic attacks, cerebrovascular accidents, pulmonary emboli, or clinically significant deep vein thrombosis) within 2 years prior to screening.
  • thromboembolic or cerebrovascular event i.e., transient ischemic attacks, cerebrovascular accidents, pulmonary emboli, or clinically significant deep vein thrombosis
  • the patient does not have an infection requiring antibiotics, antivirals, or antifungals within 1 week prior to first dose of Compound A. Prophylactic use of these agents is acceptable even if parenteral.
  • the patient does not have an active hepatitis B and/or hepatitis C infection as detected by positive hepatitis B surface antigen (HbsAg) or antibody to hepatitis C virus (anti HCV) with confirmation testing (e.g., anti-HBc, IgM anti- HBc, anti-HBs, HCV RNA), known seropositivity for human immunodeficiency virus (HIV).
  • HbsAg positive hepatitis B surface antigen
  • anti HCV antibody to hepatitis C virus
  • confirmation testing e.g., anti-HBc, IgM anti- HBc, anti-HBs, HCV RNA
  • HIV human immunodeficiency virus
  • the patient does not have concurrent medical conditions including psychiatric disorders that in the judgment of the Investigator will interfere with the patient’s ability to participate or with achieving the objectives of the study or pose a safety risk.
  • the patient is not pregnant or breast feeding.
  • the patient has not had an autologous hematopoietic stem cell transplant less than 3 months prior to first dose of Compound A.
  • the patient has not had prior allogenic hematopoietic or bone marrow transplant.
  • the patient has not had radiation treatment within 4 weeks prior to first dose of Compound A.
  • the patient has not had major surgery requiring general anesthesia within 4 weeks prior to first dose of Compound A.
  • the patient has not received a live vaccine within 1 month prior to the first dose of Compound A.
  • the patient has not had exposure to investigational or non-investigational anti -cancer therapy within 4 weeks or within at least 5 half-lives (up to a maximum of 4 weeks) prior to the first dose of Compound A, whichever is shorter. In all situations, the maximum washout period will not exceed 4 weeks prior to first dose of Compound A.
  • the patient has not completed a course of SARS-CoV-2 vaccine within 14 days prior to first dose of Compound A.
  • the patient has not used strong CYP3A4 inhibitors or inducers within 14 days or 5 half-lives of the first dose of Compound A (whichever is longer) within prior 14 days prior to first dose.).
  • the patient has not used OATP1B inhibitors or inducers within 14 days or 5 half-lives of the first dose of Compound A (whichever is longer) within prior 14 days prior to first dose.).
  • a patient received a prior brentuximab vedotinand at least one regimen containing a check point inhibitor.
  • a patient has NK-Cell lymphoma and comprises a mutation a STAT3 mutation.
  • a method of the present invention comprises intravenously administering a liquid formulation as described herein. In some embodiments, a method of the present invention comprises administering a unit dosage form as described herein. In some embodiments, a method of the present invention comprises administering daily to a patient a liquid fonnulation or a unit dosage form as described herein.
  • the invention provides a liquid formulation comprising a STAT3 degrader of this invention (c.g., Compound A) or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable excipient (e.g., a buffer) and/or carrier (e.g., water).
  • a pharmaceutically acceptable excipient e.g., a buffer
  • carrier e.g., water
  • the amount of Compound A in liquid formulations of this invention is such that it is effective to measurably degrade and/or inhibit STAT3 protein, or a mutant thereof, in a patient.
  • a liquid formulation of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for parenteral (e.g., intravenous) administration to a patient.
  • a liquid formulation of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 0.5%-I.5% w/w of the total weight of the formulation.
  • a liquid formulation of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 0.6%-1.4%, about 0.7%-1.3%, about 0.8%-l .2%, or about 0.9%-l . 1% w/w of the total weight of the formulation.
  • a liquid formulation of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.9%, about 0.95%, about 1.00%, about 1.05%, about 1.10%, about 1.15%, about 1.20%, about 1.25%, about 1.30%, about 1.35%, about 1.40%, about 1.45%, or about 1.50% w/w of the total weight of tire formulation.
  • a liquid formulation of the invention comprises Compound A at a concentration of about 0.995% w/w of the total weight of the formulation.
  • a liquid formulation of the invention comprises Compound A ammonium hydrogen salt at a concentration of about 1.00% w/w of the total weight of the formulation.
  • a liquid formulation of the invention comprises Compound A, or a phannaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 5-15 mg/mL.
  • a liquid formulation of the invention comprises Compound A. or a pharmaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 6-14 mg/mL, about 6.5-13.5 mg/mL, about 7- 13 mg/mL, about 7.5-12.5 mg/mL, about 8-12 mg/mL, about 8.5-11.5 mg/mL, about 9-11 mg/mL, or about 9.5-10.5 mg/mL.
  • a liquid formulation of the invention comprises Compound A, or a pharmaceutically acceptable salt thereof (such as Compound A ammonium hydrogen salt), at a concentration of about 8 mg/mL, about 8.5 mg/mL, about 9 mg/mL, about 9.5 mg/mL. about 10 mg/mL, about 10.5 mg/mL, about 11 mg/mL, about 11.5 mg/mL. or about 12 mg/mL.
  • a liquid formulation of the invention comprises Compound A at a concentration of about 10 mg/mL.
  • a liquid formulation of the invention comprises Compound A ammonium hydrogen salt at a concentration of about 10.14 mg/mL.
  • the liquid fonnulation of the present invention may be administered parenterally by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, or the like) as the liquid formulation or in unit dosage forms or via suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.
  • a provided liquid formulation for parenteral use are provided in unit dosage fonns (e.g., in single-dose ampoules), or in vials containing several doses and in which a suitable preservative may be added (see below).
  • such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid and liquid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution or dilution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
  • tire liquid formulation or unit dosage forms thereof are administered intravenously. The preparation of such liquid formulations and unit dosage forms is described herein such as in Example 3.
  • the liquid formulations or unit dose forms are packaged in solutions with one or more aqueous buffer.
  • the liquid formulations or unit dosage fomrs are packaged in solutions with sterile isotonic aqueous buffers.
  • the liquid fonnulations or unit dosage fonns are buffered at about pH 5-8 or about pH 6-7 for parenteral administration upon dilution.
  • a buffering agent is at an amount to adjust the pH of a liquid formulation or a unit dosage form of the invention to about 6-8.
  • a provided liquid formulation or unit dosage form is at about pH 6.5.
  • a provided liquid formulation or unit dosage form is at pH 6.5 ⁇ 0.3. In some embodiments, a provided liquid formulation or unit dosage fomi is at about pH 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7.0. In some embodiments, the pH of a provided liquid formulation or unit dosage form can be adjusted by adding minute amounts of an acid (e.g., IN hydrochloric acid) or a base (e.g., IN sodium hydroxide).
  • an acid e.g., IN hydrochloric acid
  • a base e.g., IN sodium hydroxide
  • Suitable buffers or buffering agents include, but are not limited to, phosphate buffers, citrate buffers, acetate buffers, histidine buffers, or succinate buffers.
  • the buffer is one or more phosphate buffer.
  • the one or more phosphate buffer is disodium phosphate (e.g., disodium phosphate heptahydrate) and monobasic sodium phosphate (e.g., sodium phosphate monobasic monohydrate).
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 25-75 mM, about 30-70 mM, about 35-65 mM, about 40-60 mM, or about 45-55 mM.
  • a liquid formulation or unit dosage fomi of the invention comprises a sodium phosphate buffer at a concentration of about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, or about 75 mM.
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 50 mM.
  • a liquid fonnulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 0.2%- 1.1% w/w of the total weight of the formulation.
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 0.3%-1.0%, about 0.4%-0.9%, about 0.5%-0.8%, or about 0.6%-0.7% w/w of the total weight of the formulation.
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.05%, or about 1. 1% w/w of the total weight of the fonnulation.
  • a liquid fonnulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 0.64% w/w of the total weight of the formulation.
  • a liquid fonnulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of 0.636% w/w of the total weight of the formulation.
  • a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 2-f f mg/mL of the total weight of the fonnulation. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 3-10, about 4-9, about 5-8, or about 6-7 mg/mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7. about 7.5, about 8, about 8.5.
  • a liquid formulation or unit dosage fonn of the invention comprises a sodium phosphate buffer at a concentration of about 6.4 mg/mL. In some embodiments, a liquid formulation or unit dosage form of the invention comprises a sodium phosphate buffer at a concentration of 6.36 mg/mL.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 0.995% w/w of the total weight of the formulation, and a sodium phosphate buffer at a concentration of about 50 mM.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 10 mg/mL, and a sodium phosphate buffer at a concentration of about 50 mM. [00117] In some embodiments, the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 0.995% w/w of the total weight of the formulation, and a sodium phosphate buffer at a concentration of about 0.64% w/w of the total weight of the formulation.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 10 mg/mL, and a sodium phosphate buffer at a concentration of about 0.64% w/w of the total weight of the formulation.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 0.995% w/w of the total weight of the formulation, and a sodium phosphate buffer at a concentration of about 6.4 mg/mL.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A at a concentration of about 10 mg/mL, and a sodium phosphate buffer at a concentration of about 6.4 mg/mL.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 1.00% w/w of the total weight of the formulation, and a sodium phosphate buffer at a concentration of about 50 mM.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 10.14 mg/mL, and a sodium phosphate buffer at a concentration of about 50 mM.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 1.00% w/w of the total weight of the formulation, and a sodium phosphate buffer at a concentration of about 0.64% w/w of the total weight of the formulation.
  • the present invention provides a liquid fonnulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 10.14 mg/mL, and a sodium phosphate buffer at a concentration of about 0.64% w/w of the total weight of the formulation.
  • the present invention provides a liquid formulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 1.00% w/w of the total weight of the fonnulation, and a sodium phosphate buffer at a concentration of about 6.4 mg/mL.
  • the present invention provides a liquid fonnulation at about pH 6.5, comprising Compound A ammonium hydrogen salt at a concentration of about 10.14 mg/mL, and a sodium phosphate buffer at a concentration of about 6.4 mg/mL.
  • the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of about 10 niL. In some embodiments, the present invention provides a unit dosage form, which is a liquid fonnulation of the present invention, as described above, with a volume of about 10.5 mL.
  • the present invention provides a unit dosage form, which is a liquid formulation of the present invention, as described above, with a volume of about 10.1 mL, about 10.2 mL, about 10.3 mL, about 10.4 mL, about 10.6 mL, about 10.7 mL, about 10.8 mL, about 10.9 mL, about 11 mL, about 11.1 mL, about 11.2 mL, about 11.3 mL, about 11.4 mL, or about 11.5 mL.
  • the present invention provides a unit dosage form, which can be prepared by combining 101.4 mg Compound A ammonium hydrogen salt, 47.8 mg disodium phosphate heptahydrate, 44.1 mg sodium phosphate monobasic monohydrate, and water to about 10 mg/mL concentration of Compound A, and adding hydrochloride acid and sodium hydroxide to adjust pH to about 6.5.
  • the present invention provides a liquid formulation or a unit dosage form as described in the examples herein, such as Example 3.
  • the present invention provides a liquid formulation or a unit dosage form, which can be prepared by the process as described in the examples herein, such as Example 3.
  • the unit dosage form comprises a liquid volume of about 10 mL.
  • the liquid formulation may also include a solubilizing agent.
  • the components of the formulation can be either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder (which can be reconstituted before use with a carrier such as saline) or concentrated solution in a hermetically sealed container such as an ampoule or sachet indicating the amount of active agent.
  • a dry lyophilized powder which can be reconstituted before use with a carrier such as saline
  • concentrated solution in a hermetically sealed container
  • an ampoule or sachet indicating the amount of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle or bag containing sterile pharmaceutical grade water or saline .
  • an ampoule of sterile water or saline can be provided so that the ingredients may be mixed prior to injection.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, com oil, sesame oil, etc.), and combinations thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
  • water is added to the formulation or unit dosage form of the present invention. In certain embodiments, the amount of water added to tire fonnulation or unit dosage form is listed in Table 1 below.
  • Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to buffers, surfactants, dispersants, emulsifiers, viscosity modifying agents, and combination thereof.
  • Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenyl ether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol buty l ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl-.beta. -alanine, sodium N-lauryipiminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.
  • Hie formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s).
  • Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
  • Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above.
  • the preferred methods of preparation are vacuum-dry ing and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art.
  • the liquid formulation or unit dose form of the present invention is mixed with an IV infusion vehicle.
  • the liquid formulation or unit dose form is mixed with an injectable medium such as normal saline (0.9% sodium chloride), 5% dextrose (D5W), or lactated ringer’s injection.
  • the invention provides a liquid pharmaceutical composition prepared by mixing a liquid formulation or unit dose form of the invention with water, followed by dilution with saline or 5% dextrose.
  • a liquid pharmaceutical composition is diluted into a saline or 5% dextrose IV bag for IV administration.
  • a liquid phannaceutical composition in a saline or 5% dextrose IV bag is stored under room temperature (about 20-25 °C) for up to about 4 hours before IV administration.
  • a liquid pharmaceutical composition in a saline or 5% dextrose IV bag is stored under refrigerated (about 2-8 °C) conditions for up to about 20 hours before IV administration.
  • a liquid pharmaceutical composition in a saline or 5% dextrose IV bag is stored under refrigerated (about 2-8 °C) conditions for up to about 20 hours, followed by storage under room temperature (about 20-25 °C) for up to about 4 hours, before IV administration.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular STAT3 degrader in the composition.
  • the liquid formulation or unit dosage form of the present invention is a stabilized liquid formulation or a stabilized unit dosage form.
  • a liquid formulation or unit dosage form of the present invention is in frozen form.
  • the liquid formulation or unit dosage fomi of the present invention is stable after 3 freeze/thaw cycles.
  • the liquid formulation or unit dosage form of the present invention is stable for at least 3 months at 2-8 °C.
  • the liquid formulation or unit dosage form of the present invention is stable for at least 12 months at -20 °C.
  • the stability of the liquid formulation or unit dosage form of the present invention is shown in Example 4 below.
  • an STAT3 degrader e.g., Compound A
  • a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to a patient at a dose and schedule appropriate to give the desired cancer regression effect with minimum side effects.
  • a method of the present invention comprises administering daily to a patient up to about 3.0 mg/kg or up to about 5.0 mg/kg of Compound A (e.g., up to 201 mg or 350 mg for a 70 kg patient), for example about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 1 .5 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, or about 4.5 mg/kg of Compound A.
  • Compound A e.g., up to 201 mg or 350 mg for a 70 kg patient
  • Compound A e.g., up to 201 mg or 350 mg for a 70 kg patient
  • the amount of Compound A administered daily to a patient is about 0.05, about 0.1, about 0.2, about 0.4, about 0.7, about 1.1, about 1.5, about 2.0, or about 2.7 mg/kg. In certain embodiments, the amount of Compound A administered daily to a patient is listed in Table 8 below. It will be appreciated that references to “administered daily” refer to a total daily dose, but not necessarily administration each day. For example, in some embodiments, an amount administered daily is administered once per week.
  • a method of the present invention comprises administering daily to a patient up to about 500 mg of Compound A, for example up to about 25 mg, up to about 50 mg, up to about 75 mg, up to about 100 mg, up to about 150 mg, up to about 200 mg, up to about 300 mg, up to about 400 mg, or up to about 500 mg of Compound A.
  • a method of the present invention comprises administering daily to a patient about 10-500 mg (for example, about 10-400 mg, about 50-400 mg, about 100-400 mg, about 200-400 mg, about 50-300 mg, about 100-300 mg, about 200-300 mg, about 25-200 mg, about 75-200 mg. about 100-200 mg. about 150-300 mg.
  • a method of the present invention comprises administering daily to a patient about 50 mg of Compound A, for example 0.5x100 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 100 mg of Compound A, for example IxlOOmg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 150 mg of Compound A, for example 1.5x100 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 200 mg of Compound A, for example 2x1 OOmg unit dosage forms.
  • a method of the present invention comprises administering daily to a patient about 250 mg of Compound A, for example 2.5x100 mg unit dosage fonns. In some embodiments, a method of the present invention comprises administering daily to a patient about 300 mg of Compound A, for example 3x1 OOmg unit dosage fomis. In some embodiments, a method of the present invention comprises administering daily to a patient about 350 mg of Compound A, for example 3.5x100 mg unit dosage forms. In some embodiments, a method of the present invention comprises administering daily to a patient about 400 mg of Compound A, for example 4x1 OOmg unit dosage forms.
  • a method of the present invention comprises administering a liquid fonnulation or a unit dosage fonn as described herein once daily. In some embodiments, a method of the present invention comprises administering a fonnulation or a unit dosage form as described herein twice daily. In some embodiments, a method of the present invention comprises administering a formulation or a unit dosage form as described herein three times daily. In some embodiments, a method of the present invention comprises administering a formulation or a unit dosage fomr as described herein four to fourteen times daily.
  • the dosing is twice daily or BID, z.e., two separate about 100 mg doses.
  • the dosing is thrice daily or TID, i.e. , three separate about 100 mg doses.
  • the dosing is four-times daily or QID, i.e., four separate about 100 mg doses.
  • a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein there is about 4-24 hours between two consecutive administrations. In some embodiments, there is about 4, about 6, about 8, about 12, about 18, or about 24 hours between two consecutive administrations.
  • a method of the present invention comprises administering a liquid formulation or a unit dosage fomr as described herein, wherein there are about 1-7 days between two consecutive administrations. In some embodiments, there are about 1, about 2. about 3, about 4. about 5, about 6, or about 7 days between two consecutive administrations. In certain embodiments, a liquid formulation or a unit dosage form as described herein is administered every 7 days between two consecutive administrations.
  • a method of the present invention comprises administering a liquid formulation or a unit dosage form as described herein, wherein there is about 1-4 weeks between two consecutive administrations. In some embodiments, there is about I. about 2, about 3, or about 4 weeks between two consecutive administrations. In some embodiments, a liquid formulation or a unit dosage form as described herein is administered once every two weeks (Q2W).
  • Compound A is administered to a patient once every' 1, 2, 3, 4, 5, 6, or 7 days.
  • a liquid formulation or a unit dosage form of the invention is administered to a patient biweekly (BIW).
  • Biweekly doses can be administered hours apart (e.g., 1. 3, 6, 12 hours) or days apart (e.g.. 1. 2, 3, or 4 days).
  • biweekly doses are administered on day 1 and day 2.
  • biweekly doses are administered on day 1 and day 4.
  • a liquid formulation or a unit dosage form as described herein is administered once per week (QW).
  • Compound A is intravenously administered is administered to a patient once every 1, 2, 3, or 4 weeks, or once every 7, 10, 14, 17, 21, 24, or 28 days.
  • a liquid formulation or a unit dosage form as described herein is administered once every two weeks (Q2W).
  • a liquid formulation or a unit dosage form is administered once weekly for two or three out of four weeks.
  • a liquid formulation or a unit dosage form as is administered twice weekly for two or three out of four weeks.
  • a liquid formulation or a unit dosage form is administered once weekly for two out of three weeks.
  • a liquid formulation or a unit dosage form is administered twice weekly for two out of three weeks.
  • a liquid formulation or a unit dosage form is administered once weekly even' other week out of four weeks.
  • a liquid formulation or a unit dosage form is administered twice w eekly every other week out of four weeks.
  • a liquid formulation or a unit dosage form is administered to the patient once weekly in week 1 and week 2 in a 3 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient once weekly in week 1 and week 2 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient once weekly in week 1 and week 2 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage fonn is administered to the patient once w eekly in week 1 and week 3 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient once weekly in weeks 1-3 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient once weekly in weeks 1-4 in a 4 week administration cycle (e.g., on days 1, 8, 15, and 22 of a 28-day cycle).
  • a liquid formulation or a unit dosage fonn is administered to the patient twice weekly in week 1 and week 2 in a 3 week administration cycle. In some embodiments, a liquid formulation or a unit dosage fonn is administered to the patient twice weekly in week 1 and week 2 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient once weekly in week 1 and week 2 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage form is administered to the patient twice weekly in week 1 and week 3 in a 4 week administration cycle. In some embodiments, a liquid formulation or a unit dosage fonn is administered to the patient twice weekly in eeks 1-3 in a 4 week administration cycle. In some embodiments, the dosing schedule shown in FIG. 5.
  • an IV infusion of a unit dosage form of the invention lasts about 5-180 minutes. In some embodiments, an IV infusion of a pharmaceutical composition of the invention lasts about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, or 180 minutes, or any range of time created by using two of the aforementioned times as endpoints. In some embodiments, an IV infusion of a unit dosage form of the invention lasts about 60-120 minutes.
  • an IV infusion of a unit dosage form of the invention lasts about 120-180 minutes. In some embodiments, an IV infusion of a unit dosage form of the invention lasts about 1, 2, 2.5, 3, 3.5, or 4 hours. In some embodiments, an IV infusion of a unit dosage form of the invention lasts about 2 hours.
  • a liquid fonnulation or a unit dosage form described herein is administered to the patient for up to about 9 doses. In some embodiments, a liquid formulation or a unit dosage form described herein is administered to the patient for up to about 8 doses. In some embodiments, a liquid formulation or a unit dosage form described herein is administered to the patient for up to 9 doses. In some embodiments, a liquid formulation or a unit dosage fomr described herein is administered to the patient for up to 8 doses. In some embodiments, a liquid fonnulation or a unit dosage form described herein is administered to the patient for about 9 doses.
  • a liquid formulation or a unit dosage form described herein is administered to the patient for about 8 doses. In some embodiments, a liquid formulation or a unit dosage form described herein is administered to the patient for between about 7 to about 10 doses. In some embodiments, a liquid formulation or a unit dosage form described herein is administered to the patient for between about 8 to about 9 doses. In some embodiments, a liquid formulation or a unit dosage fomr described herein is administered to the patient for between 7 to 10 doses. In some embodiments, a liquid formulation or a unit dosage form described herein is administered to the patient for between 8 to 9 doses.
  • a liquid fonnulation or a unit dosage form described herein is administered to the patient for at least about 7 doses. In some embodiments, a liquid formulation or a unit dosage fonn described herein is administered to the patient for at least about 8 doses. In some embodiments, a liquid fonnulation or a unit dosage fomr described herein is administered to tire patient for at least about 9 doses.
  • the present invention provides a method for treating a hematological malignancy (e.g., such as various leukemias and lymphomas) or solid tumor in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • a hematological malignancy or solid tumor disease is large granular lymphocytic leukemia (LGL-L), T-cell prolymphocytic leukemia (T-PLL), peripheral T-cell lymphoma (PTCL), or cutaneous T-cell lymphoma (CTCL).
  • the present disclosure provides a method for treating hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the hematological malignancy is leukemia, diffuse large B-ccll lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, or MDS.
  • DLBCL diffuse large B-ccll lymphoma
  • CLL chronic lymphocytic lympho
  • the present disclosure provides a method for treating relapsed or refractory lymphomas in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for treating solid tumors in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for treating LGL-L in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for treating T-PLL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for treating PTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for treating CTCL in a patient, comprising administering to the patient a therapeutically effective amount of Compound A.
  • the present invention provides a method for treating of a proliferative disease selected from a benign or malignant tumor, solid tumor, liquid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid
  • B-cell prolymphocytic leukemia B-cell prolymphocytic leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • lymphoplasmacytic lymphoma Waldenstrom’s macroglobulinemia (WM)
  • WM macroglobulinemia
  • splenic marginal zone lymphoma multiple myeloma
  • plasmacytoma plasmacytoma
  • intravascular large B-ccll lymphoma intravascular large B-ccll lymphoma
  • the cancer which can be treated according to the methods of this invention is selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, and ovarian cancer.
  • abnormal STAT3 activation also correlates with the progression of diverse hematopoietic malignancies, such as various leukemias and lymphomas, and STAT3 is frequently activated in both multiple myeloma cell lines and tumor cell lines derived from patient bone marrows.
  • the present invention provides a method of treating a cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies include lymphomas, leukemias, myelomas, myeloproliferative neoplasms and myelodysplastic syndromes.
  • a cancer selected from glioma, breast cancer, prostate cancer, head and neck squamous cell carcinoma, skin melanomas, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer, urothelial cancer, liver cancer, bile duct cancer, kidney cancer, colon cancer,
  • the present invention provides a method of treating a JAK-associated disease.
  • the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma etc ), hematological cancers (e g., lymphoma, leukemia Such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or multiple myeloma), and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
  • CTCLs include Sezary' syndrome and mycosis fimgoides.
  • the present invention provides a method of treating histologically or pathologically confirmed lymphomas (including Hodgkin’s, B-cell, T-cell, Small Lymphocytic, orNK-cell Lymphomas).
  • the present invention provides a method of treating histologically or pathologically confirmed T-PLL, PTCL, CTCL, LGL-L [T-cell LGL-L or Chronic Lymphoproliferative Disorder of NK-cells (CLPD-NK)J, or solid tumors.
  • the administration of Compound A to a patient in need thereof according to the present invention comprises modulating one or more protein markers (e.g., protein or mRNA biomarkers) in the patient.
  • the present invention provides a method of modulating one or more protein markers (e.g., CRP, SAA, S0CS3, CXCL10, IRF1, STAT1) in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.
  • the method of modulating one or more protein markers e.g.. CRP.
  • the present invention provides a method of decreasing one or more protein markers (e.g., S0CS3, CRP, SAA, CXCL10, IRF1, STAT1) in a patient in need thereof, comprising administering Compound A of tire present invention, or a pharmaceutically acceptable salt thereof.
  • protein markers e.g., S0CS3, CRP, SAA, CXCL10, IRF1, STAT1
  • the method of decreasing one or more protein markers comprises treating a hematological malignancy or solid tumor in a patient as described herein.
  • the protein marker is a protein marker found in peripheral blood.
  • the present invention provides a method of decreasing S0CS3 in a patient in need thereof, comprising administering Compound A of the present invention, or a pharmaceutically acceptable salt thereof.
  • the method of decreasing S0CS3 comprises treating a hematological malignancy or solid tumor in a patient as described herein.
  • the present invention provides a method of decreasing CRP in a patient in need thereof, comprising administering Compound A of the present invention, or a phannaceutically acceptable salt thereof.
  • the method of decreasing CRP comprises treating a hematological malignancy or solid tumor in a patient as described herein.
  • the present invention provides a method of decreasing SAA in a patient in need thereof, comprising administering Compound A of the present invention, or a phannaceutically acceptable salt thereof.
  • the method of decreasing SAA comprises treating a hematological malignancy or solid tumor in a patient as described herein.
  • the present invention provides a process for preparing Compound A ammonium hydrogen salt.
  • the process for preparing Compound A ammonium hydrogen salt comprises treating intermediate F:
  • the suitable salt exchange conditions used to prepare Compound A ammonium hydrogen salt from intermediate F include conditions known in the art to exchange a DIPEA salt with an ammonium salt.
  • the suitable salt exchange conditions include subjecting intermediate F to an ammonium source, such as a solution containing ammonium hydrogen carbonate.
  • the suitable salt exchange conditions are described in the examples herein, such as Example 1.
  • the process for preparing Compound A ammonium hydrogen salt further comprises preparing Intermediate F, the process comprising treating intermediate D: with intermediate E:
  • the process for preparing intermediate F from intermediates D and F further comprises a base, such DIPEA.
  • a base such as DIPEA.
  • the process for preparing intermediate F from intennediates D and F is described in the examples herein, such as Example 1.
  • the present invention provides the DIPEA salt of
  • Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2020/206424, the contents of which, including below intermediates A, B, C, D, and E, are incorporated herein by reference in their entireties.
  • Step 1 Preparation of Intermediate C.
  • amine A 2-chloro-4,6-diraethoxy-l,3,5-triazine (CDMT) in dichloromethane was added 4-methylmorpholine (NMM) slowly.
  • Hie reaction mixture was stirred at this temperature until complete conversion of A to C is achieved (IPC, reaction conversion monitoring by HPLC).
  • IPC reaction conversion monitoring by HPLC.
  • deionized water was added. The layers w ere separated, and the organic phase was successively washed with aqueous solutions of sodium phosphate monobasic, sodium bicarbonate, and sodium chloride.
  • Step 2 Preparation of Intermediate D.
  • DCM dichloromethane
  • hydrochloric acid in dioxane
  • Step 3 Preparation of Intermediate F.
  • DIPEA N,N-diisopropylethylamine
  • NMP N- methylpyrrolidinone
  • IPC reaction conversion monitoring by HPLC
  • the reaction mixture was transferred slowly to a room temperature solution of MeCN and the DIPEA salt of Compound A (intermediate F) precipitated.
  • the suspension was then stirred at room temperature for at least 1 hour before filtration. Hie filtered solid was rinsed with MeCN and dried (IPC, purity by HPLC, residual solvents by GC).
  • Step 3 Preparation of Compound A ammonium hydrogen salt.
  • Intermediate F was purified by reverse phase preparative chromatography using ammonium bicarbonate and MeCN as the eluants (IPC, fraction purity by HPLC). Tire conforming fractions were combined and concentrated. The combined conforming fractions were concentrated (IPC, purity by HPLC) and lyophilized to yield Compound A ammonium hydrogen salt (IPC, water content by KF, residual solvent (MeCN) by GC, residual solvent (NMP and DIPEA) by GC).
  • IPC ammonium hydrogen salt
  • the antitumor activity of Compound A ammonium hydrogen salt was evaluated in a human SU-DHL- 1 cell-line xenograft model established in NOD SCID female mice.
  • the antitumor activity of Compound A ammonium hydrogen salt was evaluated in a human SUP-M2 cell-line xenograft model established in NOD SCID female mice.
  • Animals administered Compound A QW or 2 on/5 off were monitored until Day 25 post first dose, and those administered Compound A Q2W were monitored until Day 52 post first dose.
  • Compound A demonstrated significant, dose-dependent anti-tumor activity in SUP-M2 xenografts.
  • Animals administered IV doses of Compound A at 10 mg/kg QW achieved TGI of 83.8%, while those administered 20 and 30 mg/kg QW achieved complete tumor regression in 4 of 5 and 5 of 5 animals, respectively, which was sustained until study end (FIG. 3A).
  • Administration of Compound A according to a 2 day on/5 days off regimen at 10 and 20 mg/kg achieved complete tumor regression in all animals, which w as sustained until study end (FIG. 3A).
  • Q2W administration of Compound A at 20 and 40 mg/kg achieved complete tumor regression in 4 of 5 and 5 of 5 animals, respectively, which was sustained until study end (FIG. 3B).
  • Tire drug product Compound A Injection (Concentrate Solution for Infusion), consists of a clear colorless solution of Compound A in clear Type I glass vials fitted with a rubber stopper and sealed with a flip-off aluminum cap.
  • the drug product is fonnulated as 10 mg/mL of Compound A free acid (equivalent to 10.14 mg/mL of ammonium salt) dissolved in water for injection (WFI) containing disodium phosphate heptahydrate, and sodium phosphate monobasic monohydrate, adjusted to the target of pH 6.5 with either hydrochloric acid (HO) or sodium hydroxide (NaOH).
  • WFI water for injection
  • HO hydrochloric acid
  • NaOH sodium hydroxide
  • Tire label fill volume is 10 mL.
  • Each glass vial contains at a minimum 10.5 mL of sterile Compound A solution designed to deliver nominally 10.0 mL of the solution.
  • the drug product solution is intended to be diluted to the required concentration with a diluent for intravenous infusion.
  • Tire drug product is manufactured by dissolving Compound A (off-white amorphous solid) into the solution of WFI, disodium phosphate heptahydrate and sodium phosphate monobasic monohydrate. The final pH is adjusted with HCl/NaOH to 6.5 ⁇ 0.3 and q.s. to 10 mg/ml with WFI.
  • the solution is made in a 20 L glass vessel with stirring.
  • the prepared solution is filtered through two sterilizing filters attached in series to obtain a sterile solution.
  • the sterile solution is then filled into glass vials, stoppered, and crimped aseptically. Each vial is filled by weight to contain 10.5 mL of the sterile solution.
  • the finished product is 100% visual inspected and labeling is perfonned. Tire vials are cooled to ensure unifonn freezing at -20 °C.
  • a flow diagram of the manufacturing process is shown in FIG. 4.
  • Compound A injection was manufactured as a frozen concentrated solution containing 10 mg/mL of free acid intended to be diluted with IV infusion vehicle. It has aqueous solubility greater than 10 mg/mL at pH 4.5 to 9.0 but less than 10 mg/mL at pH less than or equal to 3.
  • a buffer screening study was performed as part of the development work. To demonstrate an acceptable short-term stability of Compound A solution, several 50 mM buffers were examined including phosphate (pH 6.5), citrate (pH 6.5), histidine (pH 6.5), and succinate (pH 6.0). 10 mg/mL of Compound A solution in different buffer type was stored at -20 °C, 2-8 °C, 25 °C, and 40 °C. After 14 days, the changes in assay and impurity profile are minimum for up to 25 °C and comparable across the evaluated buffers. However, significant color change was noted in histidine and succinate buffers when stored past 7 days at 40° C storage condition.
  • Container Closure System The drug product was sterile filtered and filled into glass vials fitted with stopper with Flurotec barrier film secured by a flip-cap aluminum seal.
  • Microbiological Attribute Drug product was manufactured aseptically and tested for Bacterial Endotoxin and Sterility for release and stability.
  • Compound A Injection IV Dosing Solutions To assess the stability and compatibility of Compound A Injection IV dosing solutions with the IV administration supplies (bag, tubing and close system transfer device) that are intended for use in the clinical trials, laboratory experiments were carried out under conditions representative of clinical dose preparation.
  • the IV bag, administration sets (tubing), and close system transfer device (CSTD) that were utilized in this study are provided in Table 4.
  • the IV infusion set (tubing) with an aireliminating filter extension and a catheter was connected to the IV bag and filled with the drug saline solution (primed).
  • the catheter end of the IV tubing up to stop the drug solution flow
  • removed the IV tubing from the IV bag held both end of the IV tubing up in a “U” position to retain the diluted drug saline solution inside the IV tubing and to allow full contact between the drug solution and IV tubing in the stationary stage as a worst-case scenario.
  • the drug solution in the IV tubing was then analyzed.
  • the IV tubing with filter and catheter was flushed (filled and drained) 4 times with approximately 20 mL/flush of drug solution.
  • the drug solution was collected and analyzed for assay to determine any assay drop of Compound A in the IV tubing.
  • the IV tubing was then filled with the drug solution, put the catheter end of tire IV tubing up to stop the drug solution flow, removed the IV tubing from the IV bag, held both end of the IV tubing up in a “U” position to retain the diluted drug saline solution inside the IV tubing and to allow full contact between the drug solution and IV tubing in the stationary stage as a worst-case scenario.
  • the drug solution in the IV tubing was then analyzed.
  • Compound A Injection Dosing Solution (2 mg/mL) in IV Bag and infusion tubing As presented in Table 5, IV dosing solutions at the concentration of 2 mg/mL prepared in IV bag and filled in IV tubing showed acceptable physicochemical stability and compatibility up to 48 hours and 8 hours, respectively. All stability-indicating parameters remained within established product specification at each time point and showed little to no change.
  • Compound A Injection Dosing Solution (0.03 mg/mL) in IV Bag As presented in Table 6, IV dosing solutions at the concentration of 0.03 mg/mL prepared in IV bag showed acceptable physicochemical stability and compatibility up to 48 hours. In the study of IV infusion tubing with fdter and catheter, it appeared that the assay was dropped by 12% in the first flush fraction which indicated that Compound A was potentially adsorbed on the IV tubing after the first flush with 20 mL drug solution. However, % assay was closed 100% at 2 to 4 flushes as well as after 8 hours of drug solution holding in the IV administration set. These results indicated that amount of Compound A adsorbed on the IV administration set is minimum and only happens in the first 20 mL of drug solution at 0.03 mg/mL.
  • Example 5 A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Intravenously Administered Compound A in Adult Patients with Relapsed or Refractory Lymphomas, Large Granular Lymphocytic Leukemia, and Solid Tumors
  • Targeted protein degraders represent a new therapeutic class of compounds that utilize the ubiquitin proteasome system to target the specific degradation of proteins.
  • Compound A is a protein degrader that targets signal transducers and activators of transcription (STAT)3, a transcription factor that plays an important role in hematological malignancies such as lymphomas and in solid tumors.
  • Compound A is administered via intravenous infusion (IV) at the dose levels defined in the protocol on Days 1, 8, 15, and 22 of each 28-day cycle.
  • IV intravenous infusion
  • Phase la dose escalation
  • lb dose expansion
  • F1H first-inhuman
  • the primary objective of the Phase la portion of the study is to identify the maximum tolerated dose [MTD]/recommended Phase 2 dose [RP2D]
  • Phase lb will consist of separate cohorts of patients with R/R peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGL-L). and solid tumors.
  • PTCL peripheral T-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • LGL-L large granular lymphocytic leukemia
  • Fresh/archival FFPE tumor tissue will be obtained.
  • pre-dose biopsy will be performed (optional for Phase la, required for Phase lb).
  • One on- treatment biopsy will be required in Phase lb unless medically contraindicated or is unattainable due to lack of feasibility.
  • This biopsy will be optional in Phase la.
  • An additional biopsy at time of disease progression will be optional for all patients. Any issues with collection of biopsies are to be discussed with medical monitor.
  • the end of treatment/safety follow-up visit will be scheduled within 30 days from the last dose of Compound A and prior to initiation of a new anticancer therapy, whichever occurs first. Further, patients will be contacted every 3 months to collect data on survival status and subsequent therapies for up to one year after their last dose of Compound A.
  • Uris part aims to characterize the safety and tolerability of IV weekly doses of Compound A in sequential cohorts.
  • the dose escalation stage will be conducted in patients with R/R lymphoma, LGL-L or advanced tumors and will utilize an accelerated titration followed by a 3+3 design with tire ultimate objectives of defining the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).
  • MTD maximum tolerated dose
  • R2D recommended Phase 2 dose
  • Enrollment in phase lb may not be initiated until the following criteria are met:
  • Enrollment in PTCL, CTCL, LGL-L, and solid tumor cohorts may be initiated independently as soon as criteria have been met for the respective cohorts.
  • Table 8 Phase la Planned Dose Levels a Planned dose levels are shown. Doses may be adjusted higher or lower based on emerging safety/PK/PD data from the study as determined by the SRC. b In case a dose reduction is required in the first cohort, a lower dose may be explored as recommended by the SRC.
  • SRC Safety Review Committee
  • PK pharmacokinetic
  • MTD/RP2D is determined in 3-6 patients, it will be confirmed by enrolling additional R/R lymphoma, LGL-L, and advanced solid tumor patients (see above) until a total of 9 patients are enrolled prior to initiation of Phase lb.
  • Phase lb, Dose Expansion After establishing the RP2D in patients with R/R lymphoma, LGL-1 and solid tumors, up to 80 additional patients will be treated to further characterize treatment- emergent adverse events (TEAEs) and to evaluate tire relative clinical activity of Compound A in the following cohorts:
  • Phase lb expansion may start at separate times in Cohorts 1-3 and Cohort 4 and will be dependent on when the RP2D has been established in the R/R lymphoma, LGL-L and solid tumor confirmation portion of the Phase la. Patients will be treated at the RP2D as detennined in the respective patient populations in Phase la.
  • the starting dose in patients in Cohort 3 (LGL-L) will be the RP2D as determined in the lymphoma, LGL-L, and solid tumor patients in Phase la. If the DLTs in lymphoma across all patients are predominantly hematologic (i.e.. neutropenia) or infectious in nature, a starting dose below the RP2D alternate regimens (e.g., IV every 2 weeks) or lower doses may be used evaluated in LGL-L patients following discussion with the SRC.
  • Patient understands signed and dated, written informed consent and provides voluntary consent prior to any mandatory study-specific procedures, sampling, and analyses.
  • Patient is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • ICF informed consent form
  • NDL indolent non-Hodgkin’s lymphoma
  • SLL small lymphocytic lymphoma
  • T-cell prolymphocytic leukemia Phase lb Only: Histologically or pathologically confirmed PTCL, CTCL (WHO/EORTC Classification), LGL-L [T-cell LGL-L or Chronic Lymphoproliferative Disorder of NK-cells (CLPD-NK) - see inclusion #7, 9, 10], or solid tumors.
  • Fresh or archival formalin fixed paraffin embedded (FFPE) tumor tissue or 15 slides preferably collected within ideally 6 months or 2 years prior to first dose of the study drug (for lymphoma and solid tumor patients, respectively).
  • Phase la Relapsed and/or refractory' disease to at least 2 prior systemic standard of care treatments or for whom standard therapies are not available.
  • Phase la LGL-L/T-PLL: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatment or for whom standard therapies are not available.
  • Phase lb Only All disease types: Relapsed and/or refractory disease to at least 1 prior systemic standard of care treatments or for whom standard therapies are not available.
  • patients with T-LGLL may be included with PI approval even if CD3+CD8+ cell population is ⁇ 650/mm 3 or CD3+CD8+CD57+ population is ⁇ 500/mm 3 . though +TCR is required;
  • NK LGL Natural-Killer (NK) LGL is also permitted, provided there is a clonal NK-cell population noted with >500 cells/mm 3
  • Solid tumors and PTCL Measurable disease per Lugano for PTCL and Response evaluation criteria in solid tumors (RECIST) version 1.1 for solid tumors at Screening.
  • T-PLL Measurable disease per Lugano and/or atypical T lymphocytes quantifiable by flowcytometry or morphology in the peripheral blood or bone marrow.
  • Hemoglobin > 8 g/dL for those patients undergoing red blood cell [RBC] transfusion, hemoglobin must be evaluated after at least 14 days after the last RBC transfusion).
  • AST Aspartate aminotransferase
  • ALT alanine transaminase
  • UPN upper limit of normal
  • 5 x ULN ⁇ 5 x ULN in cases of documented lymphoma involvement of liver
  • COVID Coronavirus disease
  • WOCBP must have a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 72 hours prior to first dose of the study drug.
  • CNS central nervous system
  • Patients with solid tumors are eligible if their CNS metastases or cord compression have been treated (e.g., radiotherapy, stereotactic surgery) and they are clinically stable, off steroids for at least 4 weeks before first dose of study drug and have no evidence of progression at time of study enrollment.
  • CNS metastases or cord compression have been treated (e.g., radiotherapy, stereotactic surgery) and they are clinically stable, off steroids for at least 4 weeks before first dose of study drug and have no evidence of progression at time of study enrollment.
  • CLL Chronic Lymphocytic Leukemia
  • small lymphocytic leukemia small lymphocytic leukemia
  • Active hepatitis B and/or hepatitis C infection as detected by positive hepatitis B surface antigen (HbsAg) or antibody to hepatitis C virus (anti HCV) with confirmation testing (e.g., anti-HBc. IgM anti- HBc, anti-HBs, HCV RNA), known seropositivity for human immunodeficiency virus (HIV).
  • HbsAg positive hepatitis B surface antigen
  • anti HCV antibody to hepatitis C virus
  • confirmation testing e.g., anti-HBc. IgM anti- HBc, anti-HBs, HCV RNA
  • HIV human immunodeficiency virus
  • Patient is pregnant or breast feeding. Autologous hematopoietic stem cell transplant less than 3 months prior to first dose of study drug. Prior allogenic hematopoietic or bone marrow transplant. Radiation treatment within 4 weeks prior to first dose of study drug. Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug. If patient required general anesthesia within the prior 4 weeks, consultation with the Medical Monitor is required prior to enrollment. Received live vaccine within 1 month prior to the first dose of study drug. Exposure to investigational or non-investigational anti-cancer therapy within 4 weeks or within at least 5 half-lives (up to a maximum of 4 weeks) prior to the first dose of study drug, whichever is shorter.
  • Compound A was well tolerated with primarily Grade 1 and 2 adverse events. Tire most common AEs were stomatitis, nausea, ALT increase, constipation and fatigue. Two DLTs occurred in LGL- L patients at DL5 and one DLT was observed in a lymphoma patient treated at DL7. Dose escalation is ongoing at DL7 in solid tumor/lymphoma patients and complete at DL4 in leukemia patients.
  • CR Complete response
  • PR partial response
  • FIG. 6A shows duration on exemplary treatment for patients with response of SD or better.
  • FIG. 6B shows duration of time on treatment in dsiease evaluable CTCL and Hodgkin’s Lymphoma patients.
  • the patient totals listed above represent the number of patients enrolled that were disease evaluable for response assessment at the time of cut-off: 2 PET-CR; 3 Cutaneous T-Cell lymphoma; 4 Peripheral T-Cell lymphoma; Large granular lymphocytic leukemia/T-Cell polymorphic leukemia; includes one patient with clinical progression
  • FIG. 7 and the following Tables 12a and 12b show PK data for patients enrolled in DL1 to DL7.
  • Compound A exposure increased approximately dose proportionally between the 0.05 mg/kg to 1.5 mg/kg doses, with a half-life of 4-7 hours. Exposure at the 1.5 mg/kg dose was higher than that predicted to be efficacious based on preclinical data.
  • %CV Mean
  • Compound A leads to mean maximum STAT3 degradation of up to 84% in peripheral blood mononuclear cells (PBMCs) at dose levels 4-5, and mean maximum STAT3 degradation of up to 95% in PBMCs at dose level 9, demonstrating proof-of-mechanism.
  • FIG. 8A and FIG. 8B show exemplary time course of STAT3 degradation in PBMCs.
  • Table 13 shows exemplary mean max degradation of STAT3 in PMBCs.
  • FIG. 9A shows exemplary maximum degradation across individual patients; maximum STAT3 degradation was greater than 90% in 4 patients in DL3-DL5 in Cycle 1; and
  • FIG. 9B shows exemplary maximum degradation across individual patients; maximum STAT3 degradation was greater than 90% in 9 patients in DL3-DL7 in Cycle 1.
  • Percent change in STAT3 represents mean percent change of two STAT3 peptides from baseline measured using targeted mass spectrometry (MS) assay. Screening sample was used as baseline when C1D1 predose was not available. When both samples were available, C1D1 predose data served as baseline. For measurements BLOQ, 50% of LLOQ values for the respective STAT3 peptides were used for computation of change from baseline.
  • DL5 data includes PD after dose reductions in two LGL-L patients (i) on C1D22 for one patient and (ii) on C1D8 and C2D1 for the other patient, both due to AEs.
  • FIG. 10 shows that dose dependent degradation of STAT3 is observed across different peripheral immune cell types. Maximum degradation of STAT3 in peripheral immune cell subsets in individual patients across dose levels as measured using flow cytometric analysis.
  • Compound A achieves STAT3 pathway inhibition and acute downregulation of inflammatory biomarkers in peripheral blood.
  • FIG. 11 shows that Compound A achieved dose-dependent reduction in SOCS3 mRNA during Cycles 1 and 2 and a correlation between changes in STAT3 protein and S0CS3 mRNA.
  • FIG. 12 shows that Compound A achieved reductions in plasma SAA and CRP during Cycle 1.
  • Plasma levels of C Reactive protein (CRP) and serum amyloid A (SAA) decreased transiently following Compound A infusion as measured in Cycle 1.
  • Maximum decrease in week 1 (between Days 2-5) was measured w.r.t. to CID 1 predose, and maximum decrease in week 2 (between Days 9-12) was measured w.r.tto C1D8 predose.
  • Compound A achieved up to 84% mean maximum STAT3 degradation in peripheral blood mononuclear cells at DL4-5 and maximum degradation up to 96% with evidence of STAT3 pathway inhibition (decrease in S0CS3) and downregulation of inflammatory biomarkers in peripheral blood.
  • Compound A leads to induction of IFNy, a central cytokine involved in anti-tumor immunity, and IFNy stimulated genes as detected in peripheral blood.
  • IFNy and an IFNy-related mRNA profile that corresponds to a signature predictive of response to anti PD1 was transiently induced following Compound A dosing, as measured in peripheral blood [Ayers et. al. (2017) J. Clin. Invest.].
  • IFNy protein levels were measured using a SIMOA assay in plasma isolated from the same whole blood samples used for mass spec analysis of STAT3 in PBMCs (baseline levels: mean 0.37 pg/ml ⁇ 0.097 SEM). For measurements BLOQ, 50% of LLOQ values were used for computational purposes.
  • Gene expression profiling was done using RNA sequencing of whole blood.
  • FIG. 13 shows a time course of IFNy plasma protein changes post Compound A infusion.
  • FIG. 14A and FIG. 14B show a time course of transcriptional induction of select IFNy stimulated genes post Compound A infusion.
  • CXCL9 and CXCL10 Key IFNy regulated chemokines, CXCL9 and CXCL10, plasma protein upregulation corresponded to respective transcriptional upregulation post Compound A infusion.
  • CXCL9 and CXCL10 were also measured at the protein level in using Luminex assay in plasma isolated from same whole blood samples used for mass spec analysis of STAT3 degradation in PBMCs.
  • FIG. 15 shows CXCL9 and CXCL10 plasma protein upregulation.
  • Compound A leads to marked reductions in STAT3, pSTAT3, and SOC3 levels with concomitant induction of IFNy stimulated genes including chemokines, CXCL9 and CXCL10 in tumor tissue from a CTCL patient.
  • FIG. 16 shows representative ROIs from histological sections of tumor biopsies were analyzed using multiplex immunofluorescence (mIF) for STAT3, pSTAT3 and CD3. Images include epidermal region, dermal region and CD3+ tumor infdtrate. DAPI was used as nuclear counterstain. Scale bars: 2 mm for H&E; 300 pm for mIF and 80 pm for high magnification ROI showing STAT3/CD3 co-stain. White arrows indicate STAT3+CD3+ cells.
  • mIF multiplex immunofluorescence
  • FIG. 17 shows that STAT3 and pSTAT3 % positive cells are reduced overall by 69% and 87% respectively in the C1D9 CTCL tumor biopsy vs. screening.
  • HALO image analysis platform was used for analysis of mIF data. Intensity-based thresholds were set to derive classifiers for CD3, STAT3, pSTAT3 that delineated biomarker positive versus negative DAPI+ cells in both the screening and C1D9 biopsies. The epidermis was excluded from quantitative analysis.
  • FIG. 18 shows that Compound A leads to induction of IFNy pathway response and downregulation of SOCS3 in CTCL tumor.
  • Compound A resulted in substantial reduction of STAT3, pSTAT3 and SOCS3 in a CTCL patient tumor with concomitant induction of IFNy stimulated genes including chemokines, CXCL9 and CXCL10 suggestive of immunomodulatory responses in the TME.
  • Results overall show' robust STAT3 knockdown and favorable immunomodulation in blood and tumor at doses that were well-tolerated and predicted to be clinically efficacious, with promising antitumor activity in heavily pre-treated cHL, CTCL and STAT3mut NK-Cell Lymphoma patients.

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Abstract

La présente invention concerne des agents de dégradation de STAT3, leurs formulations liquides, et leurs méthodes d'utilisation pour le traitement du cancer.
PCT/US2024/033526 2023-06-12 2024-06-12 Agents de dégradation de stat3 et leurs utilisations Pending WO2024258916A1 (fr)

Applications Claiming Priority (14)

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US202363507641P 2023-06-12 2023-06-12
US63/507,641 2023-06-12
US202363516596P 2023-07-31 2023-07-31
US63/516,596 2023-07-31
US202363595185P 2023-11-01 2023-11-01
US63/595,185 2023-11-01
US202363598399P 2023-11-13 2023-11-13
US63/598,399 2023-11-13
US202463559380P 2024-02-29 2024-02-29
US63/559,380 2024-02-29
US202463646158P 2024-05-13 2024-05-13
US63/646,158 2024-05-13
US202463656030P 2024-06-04 2024-06-04
US63/656,030 2024-06-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060210536A1 (en) * 2003-04-17 2006-09-21 Curt Horvath Methods and compositions for inhibiting stat signaling pathways
WO2020206424A1 (fr) * 2019-04-05 2020-10-08 Kymera Therapeutics, Inc. Agents de dégradation de stat et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060210536A1 (en) * 2003-04-17 2006-09-21 Curt Horvath Methods and compositions for inhibiting stat signaling pathways
WO2020206424A1 (fr) * 2019-04-05 2020-10-08 Kymera Therapeutics, Inc. Agents de dégradation de stat et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 19 December 2020 (2020-12-19), ANONYMOUS: "SCHEMBL22525985", XP093258984, Database accession no. 439223877 *

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