WO2022220841A1 - Composition and method for oral treatment of leukemia - Google Patents

Composition and method for oral treatment of leukemia Download PDF

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Publication number
WO2022220841A1
WO2022220841A1 PCT/US2021/027702 US2021027702W WO2022220841A1 WO 2022220841 A1 WO2022220841 A1 WO 2022220841A1 US 2021027702 W US2021027702 W US 2021027702W WO 2022220841 A1 WO2022220841 A1 WO 2022220841A1
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Prior art keywords
leukemia
compound
cytotoxic agent
pharmaceutically acceptable
cells
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PCT/US2021/027702
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English (en)
French (fr)
Inventor
Aru NARENDRAN
Dominic Rodrigues
Bruce Horowitz
Edward V. PERSHING
Eric A. Wachter
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Provectus Pharmatech, Inc.
Uti Limited Partnership
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Priority to AU2021440597A priority Critical patent/AU2021440597A1/en
Priority to CN202180038959.2A priority patent/CN115955969A/zh
Priority to EP21935450.3A priority patent/EP4117668A4/en
Priority to CA3175637A priority patent/CA3175637A1/en
Priority to MX2022012945A priority patent/MX2022012945A/es
Priority to KR1020227039851A priority patent/KR20230171854A/ko
Priority to PCT/US2021/027702 priority patent/WO2022220841A1/en
Priority to JP2022562946A priority patent/JP2023529262A/ja
Publication of WO2022220841A1 publication Critical patent/WO2022220841A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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

Definitions

  • This invention relates to an oral therapeutic regimen for treating blood (hematologic) cancers such as leukemia particularly effecting such treatments in children.
  • An adult human has about 7000 white blood cells per microliter ( ⁇ L) of blood. Of those white cells, about 65 percent are granulocytes (about 4500/mE), about 30 percent are monocytes (about 2100/m]1), and about five percent are lymphocytes (about 350/m ⁇ ).
  • granulocytes about 4500/mE
  • monocytes about 2100/m]1
  • lymphocytes about 350/m ⁇ .
  • the above cell number amounts are, of course, generalized average values, and granulocyte counts for normal patients, i.e., patients free of disease, typically are about 2000 to about 7000 cells/ ⁇ L.
  • ALL Acute lymphoblastic leukemia
  • B-ALL B cells
  • T-ALL T cells
  • 5UB5TITUTE SHEET (RULE 26) progresses rapidly and is typically fatal within weeks or months if left untreated.
  • ALL occurs in both children and adults, with highest rates seen between the ages three and seven years. About 75 percent of cases occur before the age of 6, with a secondary rise after the age of 40. The overall incidence of pediatric ALL in the United States during 2001-2014 was 34.0 cases per 1 million persons and among all racial/ethnic groups.
  • ALL is typically treated initially with chemotherapy aimed at bringing about remission. This is then followed by further chemotherapy typically over three years. Treatment usually also includes intrathecal chemotherapy (spinal cord injection), because systemic chemotherapy can have limited penetration into the central nervous system and the central nervous system is a common site for relapse of ALL.
  • intrathecal chemotherapy spinal cord injection
  • Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes, particularly B cells. Although it is generally considered incurable, CLL progresses slowly in most cases. CLL treatment consequently focuses on controlling the disease and its symptoms rather than on an outright cure. The decision to start CLL treatment is taken when the person's symptoms or blood counts indicate that the disease has progressed to a point where it may affect quality of life.
  • CLL is primarily a disease of older adults, most commonly occurring in people over the age of 50, with a median age of 70 years at the time of diagnosis. Though less common, CLL sometimes affects people
  • AML Acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • CGL chronic granulocytic leukemia
  • CML chronic myelogenous leukemia
  • CML is characterized by leukocytosis, the presence of increased numbers of immature granulocytes in the peripheral blood, splenomegaly and anemia.
  • immature granulocytes include basophils, eosinophils, and neutrophils.
  • the immature granulocytes also accumulate in the bone marrow, spleen, liver, and occasionally in other tissues. Patients presenting with this disease characteristically have more than 75,000 white blood cells per microliter ( ⁇ L), and the count can exceed 500,000/ ⁇ L.
  • CML accounts for about 20 percent of all leukemias in the United States. About 15 new cases per million people are reported each year, leading to about 3,000 to 4,000 new cases per year. The disease is rare in humans below age 45, but incidence rises rapidly to age 65, and remains elevated thereafter. The median
  • Blast crisis represents a manifestation of acute leukemia. The presence of certain markers on the blast cells sometimes suggests a lymphoid origin of these cells during the blast crisis.
  • Chemotherapeutic agents used for the treatment of the blast crisis are the same as those used for the treatment of other acute leukemias.
  • cytarabine and daunorubicin used for the treatment of acute myelocytic leukemia, are used to treat CML blast crisis.
  • Prednisone and vincristine a therapeutic regime used in the treatment of acute lymphocytic leukemias, is also used to treat CML blast crisis. Nevertheless, these drug therapies of the blast crisis stage of CML are even less successful than are the treatments of other acute leukemias.
  • Leukemias are the most common childhood cancers, accounting for about 30% of all pediatric deaths
  • ALL include pegylated asparginase, liposomal daunorubicin, liposomal annamycin, sphingosomal vincristine, and liposomal cytarabine.
  • current treatments include the use of all-trans-retinoic acid (ATRA), arsenic trioxide, anthracycline combined with ATRA, and idarubicin with high-dose cytarabine.
  • ATRA all-trans-retinoic acid
  • arsenic trioxide arsenic trioxide
  • anthracycline combined with ATRA
  • idarubicin with high-dose cytarabine.
  • Sorafenib (multikinase inhibitor) in combination with clofarabine and cytarabine has found success in a phase I study [ Inaba et al., J Clin Oncol 29:3293-3300 (2011)], and a calicheamicin-conjugated CD33 antibody, gemtuzumab ozogamicin, known commercially as Mylotarg®, has shown promise [Zwaan et al., Br J Haematol 148:768-776 (2010)].
  • Treatment of relapsed pediatric leukemia includes intensification of chemotherapeutic regimens and use of bone marrow transplantation (BMT).
  • BMT bone marrow transplantation
  • increasing the intensity of combination chemotherapies and introduction of second-line drugs is often accompanied by cumulative toxicity, with marginal incremental benefits.
  • 5UB5TITUTE SHEET (RULE 26) A key component for understanding immune system interactions against pediatric cancers is the availability of an applicable animal model. Current xenograft models are limited because they are established in severe combined immunodeficient (SCID) mice and so do not provide information on the contribution of the immune system. Other approaches such as human hematopoietic stem cell reconstitution in immunocompetent animals are cumbersome, expensive, and often introduce complex biological variables into the system.
  • SCID severe combined immunodeficient
  • One useful anti-cancer agent group for adult cancerous tumors are the halogenated xanthenes, or the pharmaceutically acceptable salts thereof. See, US Patents No. 6,331,286, No. 7,390,668, No. 7,648,695,
  • 5UB5TITUTE SHEET (RULE 26) solution in aqueous 0.9% sodium chloride for injection is a more recent formulation that is manufactured by Provectus Biopharmaceuticals, Inc. of Knoxville, TN.
  • PV-10® aqueous RB disodium solution has been used in several clinical trials, both as a single anti- cancer agent and in conjunction with monoclonal antibody anti-cancer agents, where it has been administered into solid tumor cancers via intralesional (IL) administration. Several of those trials are discussed below.
  • intralesional administration of a halogenated xanthene compound into a tumor provides the active cytotoxic agent directly to the tumor at its highest concentration.
  • administration is often distant from the target cancerous hematologic cells, thereby possibly diminishing the effectiveness of the cancerocidal halogenated xanthene compound medication (agent).
  • Intralesional PV-10® aqueous RB disodium solution also demonstrated efficacy in combination with radiotherapy in a phase II clinical trial for patients with in-transit or metastatic melanoma, with an overall response rate of 86.6% [Foote et al., J Surg Oncol 115 (7): 891-897 (2017)].
  • PV-10® aqueous RB disodium solution intralesional administration has also been shown to induce a tumor-specific immune response in both mouse studies [Qin et al., Cell Death Dis 8:e2584 (2017); Toomey et al., PLoS ONE 8(7):e68561 (2013); and Liu et al., Oncotarget 7(25):37893-37905 (2016)] and in human clinical trials [Lippey et al., J Surg Oncol 114 (3):380-384 (2016); Ross, J Surg Oncol 109(4):314- 319 (2104); Liu et al., PLoS ONE 13 (4):e0196033 (2016); and Basel et al., Cancer Lett 412:256-263 (2016)].
  • That orally administered medicament could be in solid or liquid form.
  • the present invention contemplates a method of treating a mammalian subject having leukemia.
  • the method comprises the steps of administering to such a
  • HX halogenated xanthene
  • lactone a pharmaceutically acceptable salt
  • C4-C4 alkyl or aromatic ester thereof collectively referred to herein as an "HX compound”
  • HX compound a halogenated xanthene
  • a contemplated administration is typically repeated.
  • a contemplated treatment method can also be carried out in conjunction with administration to that same mammalian subject of a second therapeutically effective amount of a second, differently-acting systemic leukemia cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable medium.
  • the second systemic leukemia cytotoxic agent can be a small molecule, ionizing radiation, or an intact antibody or paratope-containing antibody portion such as those proteinaceous antibody molecules that inhibit inflammatory chemokine activity or immune checkpoint antibodies.
  • the first and the second leukemia cytotoxic agents can be administered together in the same or different medium, or in the same or different medium at different times.
  • the second leukemia cytotoxic agent can be administered in a solid tablet, capsule, pill or the like, in a liquid medium, or as an intravenous injection or infusion.
  • a small-molecule leukemia cytotoxic agent having a molecular weight of about 200 to about 1000 Da is contemplated.
  • Compounds that synergize with a HX Compound such as doxorubicin, etoposide and vincristine are preferred. Intact
  • 5UB5TITUTE SHEET (RULE 26) antibodies or paratope-containing antibody portions are a second group of leukemia cytotoxic agents. Preferred among these agents are those referred to as immune checkpoint inhibitors. [See, for example, Darvin et al., Exp Mol Med, 50:165 (2016).]
  • the present invention also contemplates use of a therapeutically effective amount of an HX compound as a first leukemia cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium for treatment of a mammalian subject having leukemia, wherein the halogenated xanthene compound (HX compound) is maintained in the mammalian subject for a period of time sufficient to induce death of leukemia cells.
  • the first leukemia cytotoxic agent HX compound is rose bengal, a pharmaceutically acceptable salt, lactone, or C 1 -C4 alkyl or aromatic ester thereof.
  • the HX compound is rose bengal disodium salt.
  • the typically treated leukemia cells are acute B-cell or T-cell lymphoblastic leukemia cells, chronic lymphocytic leukemia cells, or acute myeloid leukemia cells.
  • leukemia cells provide lower concentrations of more diffuse targets for the leukemia cytotoxic HX compound to "find" and be taken-up than are the cells of a solid tumor that are relatively more concentrated and directly fed by the tumor's arteries or are contacted by intralesional administration directly into the tumor.
  • Fig. 1 is a graph showing survival of CB17 SCID mice from Charles River Laboratories International, Inc., treated with orally-administered rose bengal disodium. Exponentially-growing SEM cells
  • the line nearest to the X-axis represents data for the controls
  • the middle line represents data for the Cohort II animals
  • the topmost line represents data for the Cohort I animals.
  • Fig. 2 is a log-log plot of data from several different studies that plots the log of the rose bengal concentration administered (molarity) versus the log of the duration of the HX compound in the subject up to the time of assessing solid tumor treatment, and is also present in an earlier form in US Application Serial No. 17/214,590, filed on March 26, 2021. "Intralesional Administration" represents data present
  • the present invention contemplates an orally administered pharmaceutical composition for use in treatment (killing) of leukemia cells present in a mammalian subject.
  • a principle cytotoxic agent in that oral pharmaceutical composition is a halogenated xanthene (HX), the lactone thereof, a pharmaceutically acceptable salt thereof, or a C 1 -C 4 alkyl or aromatic ester thereof, that are collectively referred to herein as an "HX compound" that is present in a leukemia-treating effective amount.
  • An orally administered pharmaceutical composition can be in solid or liquid form.
  • a contemplated halogenated xanthene molecule includes rose bengal (4,5,6,7-tetrachloro-2',4',5',7'- tetraiodofluorescein; RB) that is particularly preferred, erythrosin B, phloxine B, 4,5,6,7- tetrabromo-2',4',5',7'-tetra-iodofluorescein,
  • the lactone form of a contemplated halogenated xanthene can be formed synthetically and is a preferred precursor of very pure rose bengal.
  • the carboxylic acid form of a halogenated xanthene salt spontaneously forms the lactone form when in a strongly acidic aqueous environment such as that present in a mammalian stomach.
  • the lactone When formed in a mammalian stomach or similarly acidic aqueous medium from the carboxylic acid or carboxylate salt form, the lactone not only forms, but also appears to aggregate into clumps that do not readily dissolve in the duodenum and adjacent small intestinal region or in an agueous medium having a duodenal pH value.
  • a C 1 _-C4 alkyl ester of one of the above halogenated xanthene compounds can also be used, with the Cg; i.e., ethyl ester, being preferred.
  • Cg i.e., ethyl ester
  • ethyl-Red 3 erythrosine ethyl ester; 2',4',5',7'-tetraiodo-fluorescein ethyl
  • a contemplated aromatic ester is formed by a reaction between an HX molecule and an aromatic alcohol having a 5- or 6-membered aromatic ring (including benzyl alcohol), or a 5,6- or 6,6-fused aromatic ring system that contains 0, 1 or 2 hetero ring atoms that are independently nitrogen, oxygen or sulfur.
  • an aromatic ester is preferably a benzyl, phenyl, or a 2-, 3-, or 4-pyridyl (pyridyl) ester, other aromatic single and fused ring-containing esters are contemplated as discussed hereinafter. It is to be understood that although a benzyl ester is often considered to be an "aralkyl ester", for the purposes of this invention, a benzyl ester is deemed an aromatic ester.
  • Rose bengal is a preferred HX molecule and its disodium salt, rose bengal disodium, is a most preferred HX compound.
  • a structural formula of rose bengal disodium is shown below:
  • RB when RB is administered in vivo by intralesional injection to a range of solid tumors (e.g., melanoma, hepatocellular carcinoma, breast carcinoma) acute tumor cytotoxicity is evident within approximately 30 minutes for intratumoral RB concentrations of approximately 25-50 mg/g tumor tissue (25-50 mM) [Thompson et al, Melanoma Res 18:405-411 (2008)].
  • solid tumors e.g., melanoma, hepatocellular carcinoma, breast carcinoma
  • 5UB5TITUTE SHEET (RULE 26) Extended exposure to RB in the context of continuous oral feeding has been shown to prevent formation of colon cancer (prophylactic activity) and to arrest colon cancer (therapeutic activity) in the murine Apc Min colorectal tumor model as disclosed in parental US Application Serial No. 17/214590, filed on March 26, 2021.
  • symptomatic mice receiving RB ad libitum in drinking water at a concentration of 1 mg/mL had an approximate 38% increase in mean survival relative to untreated mice (12.3 ⁇ 0.5 weeks vs 9.8 ⁇ 0.8 weeks). Presuming a daily drinking water consumption rate of approximately 2 mL/10 g body weight, this corresponds to consumption of approximately 2 mg RB/10 g (200 mg/kg).
  • Bioavailability of RB disodium administered in aqueous solution via the oral route appears to be limited based on mass balance studies conducted by the inventors, and can be estimated at 0.1-1 percent, corresponding to a daily systemic exposure of 0.2-2 mg/kg. Presuming this amount is distributed through the bloodstream, and that blood volume comprises approximately 10 percent of body weight, this equates to an estimated concentration of 2-20 mM RB in the blood.
  • FIG. 1 of the present application shows survival of CB17 SCID mice with established xenografts of a pediatric B acute lymphoblastic leukemia (ALL) tumor cell line; therapeutic activity was observed for mice in two treatment groups receiving RB by gavage twice weekly for two consecutive weeks.
  • ALL acute lymphoblastic leukemia
  • 5UB5TITUTE SHEET (RULE 26) Assuming 1% bioavailability of this oral RB, an intestinal transit time of 6 hours per administration, and a blood volume of approximately 10 percent of body weight, the two treatment groups correspond to an estimated 125-250 mM RB in the blood.
  • this functional relationship permits prediction of dose level and schedule appropriate to achieve either an anti-tumor therapeutic outcome upon systemic administration.
  • low micromolar concentrations i.e., about 10 mM
  • micromolar to submicromolar concentrations i.e., about 1 mM
  • Fig. 2 illustrates that standard approaches routinely used by those of skill in the art in pharmaceutical development can be applied to select an
  • 5UB5TITUTE SHEET (RULE 26) appropriate dose level and schedule that maximizes therapeutic outcome while minimizing potential safety risk.
  • the Apc Min data of Application Serial No. 17/214590 and the oral leukemia treatment data of the present application show that a simple formulation of the disodium salt of RB is sufficient to deliver a therapeutically active level of RB; however, this may be less than ideally efficient as to bioavailability. Determining a suitable formulation to achieve efficient liberation and absorption of an orally delivered HX compound is thus a matter of standard pharmaceutical development familiar to those of skill in the art, where the properties of the formulation can be varied to achieve desired bioavailability by control of liberation (disintegration, disaggregation and dissolution) at an appropriate point within the GI tract so as to maximize absorption of the dissolved HX compound into the bloodstream.
  • Formulary optimization can be guided by standard pharmacokinetic study of absorption such that dose level and formulation are adjusted to achieve the necessary systemic exposure on the desired dose schedule (e.g., about 100 mM in the bloodstream for short duration exposure on the order of several days, about 1 to about 10 mM for intermediate duration exposure on the order of several months, to about ⁇ 1 mM or lower for long-term exposure on the order of a year or more).
  • dose schedule e.g., about 100 mM in the bloodstream for short duration exposure on the order of several days, about 1 to about 10 mM for intermediate duration exposure on the order of several months, to about ⁇ 1 mM or lower for long-term exposure on the order of a year or more.
  • the dibasic salt forms of the HX compounds exist in solution having a pH greater than
  • the intraluminal pH value rapidly increases from highly acidic in the stomach to around pH 6 in the duodenum, and further increases in the small intestine from pH 6 to about pH 7.4 in the terminal ileum; pH drops to 5.7 in the caecum before gradually increasing to pH 6.7 in the rectum.
  • the necessary PO dose is reduced to approximately 15 mg daily.
  • a target blood concentration of approximately 10 mM (10 mg/L) is achieved. Presuming 1% bioavailability, then 7 g HX compound PO is required daily, whereas at 50% bioavailability, the necessary dose is reduced to approximately 150 mg daily.
  • One contemplated pharmaceutical composition comprises a 0.1 % to about 20 % (w/v) aqueous medium (as a liquid) of a first leukemia cytotoxic agent that is a halogenated xanthene compound (HX compound). More preferably, that concentration is about 0.2 to about 10 % (w/v), most preferably, the concentration is about 0.2 to about 5 % (w/v).
  • a first leukemia cytotoxic agent that is a halogenated xanthene compound (HX compound).
  • HX compound halogenated xanthene compound
  • a particularly preferred halogenated xanthene salt is rose bengal (4,5,6,7-tetrachloro-2',4',5',7'- tetraiodofluorescein) disodium (RB disodium) salt.
  • the pharmaceutical composition is administered orally to provide a therapeutically effective amount of a first leukemia cytotoxic agent to a mammal such as a human having leukemia, or more specifically, acute lymphoblastic leukemia (ALL) as T-ALL or B-ALL, chronic lymphocytic leukemia (CLL), or acute myeloid leukemia (AML).
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • AML acute myeloid leukemia
  • 5UB5TITUTE SHEET (RULE 26) The mammalian subject is typically treated multiple times.
  • the fact and relative amount of leukemia cell killing can be determined by usual means for assaying the status of a given leukemia mammalian subjects. Both the duration of maintenance and the choice to conduct further administrations can depend upon the species of mammal, individual mammalian subjects, the severity of disease, type of disease, age and health of the subject, and the observed effect on the burden of leukemic cells caused by the treatment. These factors are commonly dealt with by physicians skilled in the art of treating leukemia.
  • the data provided hereinafter illustrate that the IC50 value for use of RB against several leukemia cell lines in vitro is about 50 to about 100 mM for exposures of one to several days. Given that the molecular weight of RB disodium is 1018 g/mole, the above IC50 value calculates to about 50 to about 100 mg of RB/liter. It is preferred to achieve that concentration for contacting leukemic cells during an in vivo treatment.
  • 5UB5TITUTE SHEET 1500 mg delivered IV.
  • the standard adult blood volume is approximately 5 L.
  • an adult patient would need to receive approximately 500 mg of RB IV to achieve the IC50 value in the bloodstream.
  • t 1/2 is about 30 minutes
  • an IV administration can require continuous infusion to maintain peak levels of RB in circulation (i.e., for up to several hours or more).
  • IC50 value level would not be toxic to all circulating hematologic, non- tumorous leukemic cells; i.e., only approximately half of cells would be affected at the IC50 value. It can therefore be preferred to administer RB at a multiple of the IC50 value, up to approximately 1500 mg (i.e.,
  • the leukemia cell debris caused by the cytotoxicity to leukemia cells of a halogenated xanthene releases intracellular contents such as potassium, causing non-specific cell death.
  • This process may also activate the immune system specifically against the malignant cells.
  • the similarly useful halogenated xanthene compounds previously-listed and their pharmaceutically acceptable salts can have molecular weights that differ
  • 5UB5TITUTE SHEET (RULE 26) from each other by about a factor of three (See, Table 3, US Patent No. 7,390,688 at columns 15-16). It is preferred that an exact amount of other than RB halogenated xanthene to be used is calculated based on published molecular weights for each such compound and that of RB or RB disodium.
  • a mammalian subject having leukemia in need of treatment (a mammalian subject) and to which a pharmaceutical composition containing a halogenated xanthene compound can be administered can be a primate such as a human, an ape such as a chimpanzee or gorilla, a monkey such as a cynomolgus monkey or a macaque, a laboratory animal such as a rat, mouse or rabbit, a companion animal such as a dog, cat, horse, or a food animal such as a cow or steer, sheep, lamb, pig, goat, llama or the like.
  • a contemplated HX compound for oral administration is typically used dissolved or dispersed in a sterile aqueous pharmaceutical composition.
  • Sterile tap water or sterile water from another source can be used.
  • An HX compound is typically present in a contemplated aqueous pharmaceutical composition at about 0.1 to about 20 % (w/v). More preferably, that concentration is about 0.2 to about 10 % (w/v), most preferably, the concentration is about 0.2 to about 5 % (w/v).
  • the above dose of 150 mg daily could readily be achieved by use of 3 mL of a 5 % (w/v) aqueous solution.
  • a liquid pharmaceutical composition for oral administration have an osmolality
  • composition is free of tonicity agents (or tonicity-adjusting agents) such as sugars like mannitol and dextrose, C3-C6 polyhydroxy compounds such as propylene glycol, glycerol and sorbitol, isotonic salts such as sodium or potassium chloride, and/or buffering agents other than those such as citric acid, malic acid, acetic acid and other food acids and their salts that can be provided for flavor and mild buffering (less than 5 mmol of buffering agent).
  • the stomach and lower GI tract are well adapted to provide the proper tonicity to materials flowing through such that further salts and/or buffers are not needed.
  • One or more pharmaceutically acceptable taste-masking agents or flavorants as are well-known can be present at up to about 5% by weight to enhance the potability of the composition.
  • the pH value of a pharmaceutically acceptable aqueous diluent be about 5 to about 9, to yield maximum solubility of the HX compound in an aqueous vehicle and assure compatibility with biological tissue.
  • a particularly preferred pH value is about 5 to about 8, and more preferably between about 6 to about 7.5. At these pH values, the halogenated xanthenes typically remain in dibasic form, rather than the lactone that forms at low pH values.
  • HX compound such as rose bengal is dibasic, having pKa values of 2.52 and 1.81. pKa value determinations for several contemplated halogenated
  • the specific amount of halogenated xanthene compound in a pharmaceutical composition is not believed to be as important as was the case where the composition was injected intralesionally to a tumor because the object here is to ultimately provide a cytotoxic concentration of halogenated xanthene compound to the environment of the leukemic cells and in which those leukemic cells can be contacted with the halogenated xanthene compound.
  • the data provided hereinafter indicate that an IC50 concentration of disodium rose bengal is about 50 to about 100 mM for in vitro cultured leukemia cells.
  • PV-10® aqueous RB disodium solution-treated cells at 96 hours post treatment of 65-85 mM for the neuroblastoma lines assayed and 49 mM for the neuroepithelioma line SK-N-MC.
  • Those authors also examined toxicity toward human epithelial cells from three tissue sources and reported IC50 values of 93-143 mM.
  • 5UB5TITUTE SHEET (RULE 26) In clinical studies of PV-10® aqueous RB disodium solution, RB has been tolerated at 1500 mg delivered IL. Due to the rapid clearance of RB from circulation (t 1/2 about 30 minutes) an IV administration can require continuous infusion to maintain peak levels of RB in circulation (i.e., for up to several hours or more) during a single administration.
  • the HX compound such as RB or disodium RB, or a HX compound lactone such as RB lactone be administered in a solid pharmaceutical composition for oral administration that is enterically-coated to pass through the stomach and release the HX compound in the intestines.
  • the HX compound is typically dissolved in or dispersed in or on a solid diluent medium.
  • Gastric transit can range from 0 to 2 hours in the fasted state and can be prolonged up to 6 hours in the fed state.
  • the transit time in the small intestine is considered relatively constant at around 3 to 4 hours, but can range from 2 to 6 hours in healthy individuals.
  • Colonic transit times can be highly variable, with ranges from 6 to 70 hours reported [Hua, Front Pharmacol 11 :Article 524 (April 2020)].
  • Drugs must pass or permeate through the epithelial cells that line the inner walls of the GI tract in order to be absorbed into the circulatory system.
  • a cellular barrier that can prevent epithelial cell absorption of a given drug is the cell membrane.
  • Cell membranes are essentially lipid bilayers that form a semipermeable membrane.
  • ions cannot passively diffuse through the gastrointestinal tract because the epithelial cell membrane is made up of a phospholipid bilayer.
  • the bilayer is made up of two layers of phospholipids in which the charged hydrophilic heads face outwards and the non-charged hydrophobic fatty acid chains are in the middle of the layer.
  • the uncharged fatty acid chains repel ionized, charged molecules. This means that the ionized molecules cannot easily pass through the intestinal membrane and be absorbed.
  • C2-C4 alkyl and aromatic ester forms of an HX compound typically have decreased solubility in aqueous liquids, and because of their neutral ionic charge, are typically better taken-up by intestinal epithelial cells than their carboxylate forms. Later, esterases in the GI tract wall and blood hydrolyze these esters to release the parent drug.
  • coating films on a tablet or a pellet can act as a barrier to reduce the rate of dissolution and/or disintegration of the composition in aqueous media, generally, and particularly within the stomach.
  • a coating can also be used to modify where dissolution takes place.
  • enteric coatings can be applied to a drug-containing medicament, so that the coating and the drug only dissolve in the basic environment of the intestines.
  • 5UB5TITUTE SHEET (RULE 26) predictable release of a drug from a medicament in the intestinal portion of the GI tract and/or at a particular location in the GI tract relies upon pH- specific coatings and matrices that dissolve or disintegrate at preselected GI tract pH values such as those noted previously.
  • the table below shows some examples of pH- dependent polymer coatings that have been used for the purpose of targeting release (local treatment) either alone or in combination, including some methacrylic resins (commercially available from Evonik Industries,
  • the enteric coating can protect the incorporated active agent against the harsh GI tract environment (e.g., gastric juice, bile acid, and microbial degradation) and can create an extended and delayed drug release profile to enhance therapeutic efficiency.
  • harsh GI tract environment e.g., gastric juice, bile acid, and microbial degradation
  • the "published pH release” value for each polymer is from the manufacturer.
  • the “published pH release” values are not absolute for all compositions or environments, and pH values for dissolution or disintegration stated herein are based on those published values.
  • colon-targeted drug delivery systems For colonic release, colon-targeted drug delivery systems have been actively pursued because conventional non-targeted therapy can have undesirable side-effects and low efficacy due to the systemic absorption of drug before reaching the target site.
  • Eudracol® is another example of a multi-unit technology providing targeted drug delivery to the colon, with delayed and uniform drug release. This system is based on coating the pellet with Eudragit® RL/RS and Eudragit® FS 30D, providing colon-specific drug release in a pH-and time-dependent manner [Patel, Expert Opin. Drug Deliv. 8:1247-1258 (2011)].
  • composition that targets the small intestine comprises a diluent medium of sugar/sucrose beads coated with particulate rose bengal (RB) that is coated with one or a plurality of layers of a (meth)acrylate copolymer that is composed of about 60 to about 95% by weight free radical polymerized C4-C4- alkyl esters of acrylic or methacrylic acid and about 5 to about 40% by weight (meth)acrylate monomers with an acidic group in the alkyl radical.
  • a (meth)acrylate copolymer that is composed of about 60 to about 95% by weight free radical polymerized C4-C4- alkyl esters of acrylic or methacrylic acid and about 5 to about 40% by weight (meth)acrylate monomers with an acidic group in the alkyl radical.
  • Particularly suitable (meth)acrylate copolymers include about 10 to about 30% by weight methyl methacrylate, about 50 to about 70% by weight methyl acrylate and about 5 to about 15% by weight methacrylic acid (Eudragit® FS type).
  • (meth)acrylate copolymers of about 20 to about 40% by weight methacrylic acid and about 80 to about 60% by weight methyl methacrylate (Eudragit® S)
  • (meth)acrylate is used herein to mean that either or both of acrylate and methacrylate monomers can be used.
  • the pH value of the fluid within the duodenum typically is about 6 and rises to about 7.4 toward the ileum.
  • a usual tablet or lozenge can be prepared by admixture of lactose (20%) and active ingredient (80%; HX compound) mixed in a high-speed mixer (DIOSNA type P10, Osnabruck, Germany).
  • An aqueous solution containing the excipient polyvinylpyrrolidone (PVP) such as povidone (Sigma-Aldrich International GmbH, Buchs, CH) is added in small amounts until a homogeneous composition is obtained.
  • the moist powder mixture is screened. Tablets are subsequently made therefrom as is well-known, and dried.
  • the resulting tablets or lozenges are thereafter preferably coated with a protective polymer film, often using fluidized bed equipment.
  • Film ⁇ forming polymers are normally mixed with plasticizers and release agents by well-known processes.
  • the film formers can in this case be in the form of a solution or suspension.
  • the excipients for the film formation can likewise be dissolved or suspended.
  • Organic or aqueous solvents or dispersants can be used.
  • Stabilizers can be used in addition to stabilize the dispersion (for example: Tween® 80 or other suitable emulsifiers or stabilizers).
  • release agents are glycerol monostearate or other suitable fatty acid derivatives, silicic acid derivatives or talc.
  • plasticizers include propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, and other substances mentioned above and in the literature.
  • Another preferred type of medicament is a water-soluble capsule or blister that contains a plurality of particles of an HX compound such as rose bengal disodium or rose bengal lactone that are covered with one or more layers of polymeric resin that release the HX compound quickly upon dissolution or disintegration of the capsule in water or body fluid.
  • Capsules are typically made of gelatin and are often referred to as gelcaps.
  • Gelatin is an animal product.
  • Vegetarian capsules are often made of hydroxypropyl methyl cellulose (HPMC).
  • the HX compound is directly layered with one or more coats of the polymer to form particles that are generally spherical in shape. Such particles are often referred to as beads.
  • pH value-sensitive coating polymeric resins are discussed above.
  • the pH value- sensitivity of coating polymeric resins is to be understood in terms of physiologically present pH
  • 5UB5TITUTE SHEET (RULE 26) values along the GI tract such as those discussed above.
  • small pellets such as sugar/starch seeds, non-pareils or prills, which are small, generally spherically-shaped cores, are coated with one or a plurality of layers of the HX compound and one or more layers of polymeric coating.
  • Illustrative sugar/starch cores are sugar spheres NF that pass through an about 40 mesh sieve (425 mm opening) screen to an about 50 mesh sieve (300 mm opening) screen, that contain not less than 62.5 percent and not more than 91.5 percent sucrose, calculated on the dry basis, the remainder consisting primarily of starch. (USP NF 19952313).
  • a 100 kilogram (kg) quantity of disodium rose bengal, a 7.1 kg quantity of cross-linked carboxymethyl cellulose (preferably croscarmellose sodium NF), and an 11.9 kg quantity of starch NF are each divided in half, and the three constituents are blended together to form two identical batches.
  • Each of the batches is milled through an 80 mesh screen using a mill such as a Fitzpatrick Mill.
  • the two milled batches are then blended to form a mixture, which is tested for composition in accordance with accepted quality assurance testing methods that are well-known by those skilled in the art.
  • the disodium rose bengal mixture is subsequently divided into three equal parts, with a first part remaining whole, and second and third parts each divided into lots of 50 percent, 30 percent and 20 percent.
  • 5UB5TITUTE SHEET (RULE 26) seeds (e.g., sugar spheres NF) is placed in a stainless steel coating pan. An 80 liter (L) quantity of 5 percent povidone/iso-propanol (IPA) solution is prepared for spraying onto the particles.
  • IPA povidone/iso-propanol
  • the coating pan is started with the sugar spheres, onto which is sprayed an application (approximately 0.173 kg per application) of the povidone-alcohol solution, and onto which is sifted an application (approximately 0.32 kg) of the disodium rose bengal mixture from the first part (that part that remained whole). Sifting is done using a standard sifter. The spraying and sifting steps are continued until the first part of the mixture has been applied to the sugar spheres to form a batch of partially coated spheres.
  • the partially coated spheres are then divided into two equal lots, each lot being placed in a coating pan. Separately for each of the two lots, spraying of the povidone/IPA solution and sifting of the disodium rose bengal mixture as divided into the 50 percent lots continues until the 50 percent lots have been applied to the spheres. Following application of the 50 percent lots, the spheres can be screened using a 25 mesh screen if necessary.
  • the spraying of the povidone/IPA solution and sifting of the disodium rose bengal mixture as divided into the 30 percent lots commences and continues until the 30 percent lots have been applied to the spheres.
  • the coated spheres can be rescreened using a 25 mesh screen.
  • a 7.5 percent povidone/IPA solution is prepared and applied to the spheres as a sealant.
  • the sealed spheres are tumble dried for about one hour, weighed, and placed in an oven at about 122 °F (50 °C) for 24 hours. After drying, the spheres are screened through a 20 mesh screen and a 38 mesh screen to form the immediate (quick or fast as compared to delayed) release particles.
  • HX compound-containing spheres or their capsule (or blister) can also be coated with a pH value-sensitive enteric coating polymer as discussed previously so that once released in the GI tract, the spheres do not provide their active ingredient, HX compound, to their surroundings unless the pH value is at least that of a desired GI tract location.
  • HX compound release Another way to control the location of HX compound release is to further coat the spheres (HX- coated particles) discussed above, with a dissolution ⁇ controlling coat of polymeric resin applied to the surface of the spheres such that the release of the HX compound from the spheres is controlled and released over a 6-10 hour period.
  • the materials used for this purpose can be, but are not limited to, ethylcellulose,
  • 5UB5TITUTE SHEET (RULE 26) hydroxypropylethyl-cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, nitrocellulose, carboxymethyl-cellulose, as well as copolymers of ethacrylic acid and methacrylic acid (Eudragit®), or any other acrylic acid derivative (Carbopol®, etc.) can be used.
  • an enteric coating material can also be employed, either singularly, or in combination to the above non-pH-sensitive coatings.
  • These materials include, but are not limited to, hydroxypropylmethylcellulose phthalate and the phthalate esters of all the cellulose ethers.
  • These coating materials can be employed in coating the surfaces in an amount of about 1.0 percent (w/w) to about 25% (w/w). Preferably, these coating materials are present at about 8.0 to about 12.0 percent (w/w).
  • Excipients customary in pharmacy can be employed in a manner known per se in the production of the HX compound-containing medicament. These excipients can be present in the core or in the coating agent.
  • Polymeric materials used as adhesives in helping to adhere an HX compound to a sugar prill or sphere is deemed to be an excipient where coating layers of an HX compound are employed.
  • Dryers have the following properties: they have large specific surface areas, are chemically inert, are free- flowing and comprise fine particles. Because of these properties, they reduce the tack of polymers containing polar comonomers as functional groups. Examples of dryers are: alumina, magnesium oxide, kaolin, talc, fumed silica, barium sulphate and cellulose.
  • Disintegrants are added to oral solid dosage forms to aid in their disaggregation. Disintegrant are formulated to cause a rapid break-up of solids dosage forms on contacting moisture. Disintegration is typically viewed as the first step in the dissolution process.
  • Illustrative disintegrants include sodium croscarmellose, an internally cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone (crospovidone) and sodium starch glycolate.
  • release agents are: esters of fatty acids or fatty amides, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, montan waxes or paraffin waxes and metal soaps; particular mention should be made of glycerol monostearate, stearyl alcohol, glycerol behenic acid ester, cetyl alcohol, palmitic acid, carnauba wax, beeswax, and the like.
  • the usual proportionate amounts are: esters of fatty acids or fatty amides, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, montan waxes or paraffin waxes and metal soaps; particular mention should be made of glycerol monostearate, stearyl alcohol, glycerol behenic acid ester, cetyl alcohol, palmitic acid, carnauba wax, beeswax, and the like.
  • the usual proportionate amounts are: esters of fatty acids or
  • 5UB5TITUTE SHEET (RULE 26) are in the range from 0.05 percent by weight to 5, preferably 0.1 to 3 percent by weight based on the copolymer.
  • stabilizers for example, stabilizers, colorants, antioxidants, wetting agents, pigments, gloss agents. They are typically used as processing aids and are intended to ensure a reliable and reproducible production process and good long-term storage stability. Further excipients customary in pharmacy may be present in amounts from 0.001% by weight to 10% by weight, preferably 0.1 to 10% by weight, based on the polymer coating.
  • plasticizers ordinarily have a molecular weight between 100 and 20,000 and comprise one or more hydrophilic groups in the molecule, e.g. hydroxyl, ester or amino groups.
  • Citrates, phthalates, sebacates, castor oil are suitable.
  • further suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, dibutyl sebacate and polyethylene glycols 4000 to 20 000.
  • Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate.
  • the amounts used are between 1 and 35, preferably 2 to 10, % by weight, based on the (meth)acrylate copolymer.
  • the amount of HX compound delivered by a solid medicament composition is substantially the same as that from an aqueous composition.
  • 5UB5TITUTE SHEET (RULE 26) sufficient RB, as an illustrative HX compound, to achieve a circulating RB concentration at the IC50 level would not by definition be toxic to all circulating leukemic cells (i.e., only approximately half of the leukemic cells would be affected at the IC50). In some embodiments it can be preferred to administer RB in an amount that is a multiple of the IC50 level, up to approximately 1500 mg (i.e., 300 mM).
  • tumor lysis syndrome is the most common disease-related emergency encountered by physicians treating hematologic cancers such as leukemia.
  • a RB-initiated functional immune system response is believed to occur due at least in part from the action of RB-caused necrotic cell debris circulating in the body induces an immune response that can prolong the effects of an initial administration of a halogenated xanthene such as RB.
  • An induced immune response can take a longer time to develop than the more immediate killing of the
  • 5UB5TITUTE SHEET (RULE 26) contacted leukemic cells. That delay in effect can occur because of the time needed for induction the appropriate B and T cell populations to attack and kill the leukemic cells as well as to induce long lasting memory T cells whose continued circulation can protect the patient from relapse. Such an initial delay can be augmented for the subject's life-time due to the memory immune cells so induced.
  • an above pharmaceutical composition is used in conjunction with a second, differently-acting systemic cytotoxic anti-leukemia agent; i.e., a cytotoxic anti-leukemia agent whose mechanism of action is different from that of the first cytotoxic agent, the HX compound.
  • a second, differently-acting systemic cytotoxic anti-leukemia agent i.e., a cytotoxic anti-leukemia agent whose mechanism of action is different from that of the first cytotoxic agent, the HX compound.
  • the halogenated xanthenes localize in cancer cell lysosomes, increase the percentage of cells in G1 phase of the cell cycle and induces cell death by apoptosis [Swift et al., Oncotargets Ther, 12:1293-1307 (February 2019)].
  • a first type of second anti-leukemia systemic cytotoxic agent is a so-called "small molecule.”
  • small molecules can be viewed as semi-specific cellular poisons in that they are only generally more specific at killing leukemia cells than non-leukemic cells.
  • Almost all small molecule anticancer agents are less leukemia-specific than a contemplated HX compound, and can result in causing sickness, baldness and other trauma to their recipient subjects that can lead to subjects leaving their treatment regimens.
  • 5UB5TITUTE SHEET (RULE 26) These small molecules typically have molecular weights of about 150 to about 1000 Daltons (Da), and preferably about 250 to about 850 Da.
  • This group of small molecules includes many of those used to treating hematologic leukemias such as calicheamicin (1368 Da), vinblastine (811 Da), vincristine (825 Da), imatinib (494 Da), monomethyl auristatin (718 Da), etoposide (589 Da), daunorubicin (528 Da), doxorubicin (544 Da), cladribine (286 Da),fludarabine (365 Da), mitoxantrone (444 Da), 6-thioguanine (167 Da), methotrexate (454 Da),6-mercaptopurine (152 Da), azacytidine (244 Da), annamycin (640 Da), sorafenib (465 Da), clofarabine (304 Da), cisplatin (300 Da), irlnotecan (5
  • One or more of the above small molecule anti-leukemia can comprise a second leukemia cytotoxic agent. It is noted that many of these small molecules are used as their salts, prodrugs and/or esters, which consequently have greater molecular weights than those rounded values above.
  • a pharmaceutical composition having a second systemic cytotoxic anti-leukemia agent can also contain a small molecule as above-described that is conjugated to a lager molecule such as a protein, detergent and/or polymer such as poly(ethylene glycol) [PEG]. Such conjugations often minimize the toxicity of the small molecule and enhance situs of delivery as use of an antibody that binds to a leukemic cell. Additionally, a small molecule cytotoxic agent can be enveloped within a liposome, micelle or cyclodextrin molecule that can be adapted to bind specifically bind to leukemic cells and/or be endocytosed by the leukemia
  • 5UB5TITUTE SHEET (RULE 26) cell This group of encapsulated and conjugated small molecules is included with the previously discussed small molecule group of second systemic cytotoxic agents as their active cytotoxic agent is a small molecule.
  • cytotoxic agents are liposomal daunorubicin, liposomal annamycin, sphingosomal vincristine, liposomal cytarabine, a calicheamicin- conjugated CD33 antibody called gemtuzumab ozogamicin and a chimer of CD30 antibody and monomethyl auristatin E called brentuximab vedotin.
  • liposomes are generally spherically- shaped artificial vesicles typically prepared from cholesterol and phospholipid molecules that constitute one or two bilayers and encapsulate the small molecule second systemic cytotoxic agent to assist delivery.
  • Calicheamicin is a high molecular weight small molecule (1368 Da), and contains four linked saccharides interrupted by a benzothioate S-ester linkage as well as an ene-diyne group that cleaves DNA sequences. Calicheamicin is too toxic to be used alone, LD50 in nude mice of 320 mg/kg [DiJoseph et al.,
  • monomethyl auristatin exhibits general (broad range), high toxicity [IC 50 ⁇ 1 nM for several cancer cell lines; ApexBio Technology Product Catalog (2013)] that is mediated by linkage to an antibody against CD30 (a TNF receptor-family member that is a cell membrane protein
  • 5UB5TITUTE SHEET (RULE 26) and cancer marker) was reported useful against large cell lymphoma and Hodgkin's disease [Francisco et al., Blood 102:1458-1465 (2003)], whereas linkage to an anti-CD79b monoclonal provided an advantage in treating three xenograft models of NHL [Dornan et al., Blood 114:2721-2729 (2009)].
  • a systemic anti-leukemia medication that is a small molecule (non-proteinaceous, less than about 1000 grams/mole) or a larger proteinaceous molecule, is administered to the subject mammal to be treated such that the medication spreads throughout the subject's body. Intravenous administration is one preferred method to achieve that spread of medication. On the other hand, imatinib is usually administered orally.
  • Illustrative small molecule anti-cancer medications useful for treating leukemia include doxorubicin, etoposide, vincristine, cisplatin, irinotecan and cytarabine were used in parental application Serial No. 16/688,319, whereas an exemplary proteinaceous molecule is egasparaginase.
  • doxorubicin, etoposide and vincristine each of which would be administered IV to a mammalian subject appeared to synergize in treatment with a sub-lethal dose of PV-10® aqueous RB disodium solution, and are preferred.
  • Such multiple administrations are within the purview of the treating physician, and can be made in conjunction with an administration of the HX compound first
  • 5UB5TITUTE SHEET (RULE 26) leukemia cytotoxic agent or can be carried out separately.
  • a useful effective dosage of a small molecule systemic anti-leukemia medication is the dosage set out in the labeling information of a FDA-, national- or international agency-approved medication.
  • monotherapy dose schedules are set by determining the maximum tolerated dose (MTD) in early-stage clinical trials.
  • MTD maximum tolerated dose
  • the MTD (or a close variation thereon) is then promulgated to later-stage clinical trials for assessment efficacy and more detailed assessment of safety.
  • MTDs frequently become the established therapeutic dose upon completion of clinical testing.
  • a MTD is the maximal amount that would normally be used, and that amount is to be titrated downward following usual procedures.
  • Exemplary dosing schedules for several systemic anti-cancer (anti-leukemia) medications (agents) that can be combined with halogenated xanthene therapy in the present invention are provided in Table A, below. It is noted that several of the medications listed below are "small molecules" as defined above, whereas others are large, proteinaceous molecules such as antibodies, preferably monoclonal antibodies, inhibit inflammatory chemokine activity. They are nonetheless administered systemically.
  • the medications of Table A are usually used as single active agents. However, one or more can also be used together, particularly the antibodies, as is the case with the
  • the combination therapy and method of treatment of the present invention generally permit use of the systemic agent at a level at or below the typical dose schedule for the systemic agent, such as those described in Table A, when used with an IV administration therapy, such as that described below.
  • the dosing schedules provided in Table A provide a useful guide for beginning treatment from which dosages can be titrated to lessened amounts as seen appropriate by the physician caring for a given patient.
  • HX compound and a second cytotoxic anti-leukemia agent need not be administered together nor by the same means of administration.
  • a pill or capsule form can be used for can be used to administer the HX compound first cytotoxic anti-leukemia agent, whereas the small or large molecule second anti-leukemia agent is administered by IV or orally, like imatinib.
  • Those skilled in the art are aware of the various methods of administering antileukemia agents.
  • a second type of second systemic cytotoxic agent useful for combination treatment with a halogenated xanthene such as that present in aqueous RB disodium solution or a before-described solid dosage form is an immune checkpoint inhibitor, that can also be viewed as a special systemic anti-leukemia medication.
  • An immune checkpoint inhibitor is a drug that binds to and blocks certain checkpoint proteins
  • 5UB5TITUTE SHEET made by immune system cells such as T cells and some leukemia cells. When not blocked, those proteins inhibit immune responses, helping keep immune responses in check and keeping T cells or other immune cells from killing leukemia cells. Blocking those immune checkpoint proteins releases the "brakes" on the immune system permitting immune cells to become activated and kill leukemia cells.
  • a useful immune checkpoint inhibitor is preferably a human or humanized monoclonal antibody or binding portion thereof whose administration blocks the action of those certain proteins. That blockage permits the immune system to recognize the leukemia cells as foreign and assist in eliminating those leukemia cells from the body.
  • Illustrative immune checkpoint inhibitors include the anti-CTLA-4 (cytotoxic T lymphocyte- associated antigen 4) monoclonal antibodies ipilimumab and tremelimumab that are designed to counter down- regulation of the immune system by blocking CTLA-4 activity and thus augment T cell response against leukemia.
  • CTLA-4 cytotoxic T lymphocyte- associated antigen 4
  • monoclonal antibodies such as pidilizumab, nivolumab, tislelizumab, spartalizumab, cemiplimab, pembrolizumab, camrelizumab, sintilimab, toripalimab, and dostarlimab bind to PD-1 (programmed death 1) receptor to counter down-regulation of the immune system and augment T cell responses to cancerous cells.
  • PD-1 receptor Three monoclonal antibodies that target the immune checkpoint protein ligand (anti-PD-Ll) for the PD-1 receptor (anti-PD-1) are atezolizumab, avelumab, and durvalumab.
  • 5UB5TITUTE SHEET (RULE 26) 936559 and MEDI4736 (durvalumab) to PD-L1, also indicate inhibition of down-regulation of the immune system and an augmented T cell response against leukemia.
  • AMERICAN SOCIETY of CLINICAL ONCOLOGY (ASCO) 2020 VIRTUAL SCIENTIFIC PROGRAM May 29-31, 2020 provided data from a study that utilized rose bengal disodium that was injected intratumorally into uveal melanoma tumors metastatic to the liver along with either a systematic administration of anti-PD-1, or systemic administrations of both anti-PD-1 and CTLA-4 antibodies.
  • lymphocyte activation gene 3 protein Another group immunoreacts with lymphocyte activation gene 3 protein (anti-LAG-3; CD223) that
  • 5UB5TITUTE SHEET (RULE 26) negatively regulates T lymphocytes by binding to the extracellular domain of the ligand, thus avoiding autoimmunity caused by T cell overactivation.
  • LAG-3 is an important immune checkpoint in vivo and plays a balanced regulatory role in the human immune system [Shan et al., Oncol Lett 20:207 (2020)].
  • LAG-3 blocks the signal transduction pathway of T cell activation; however, the intracellular segment of the LAG-3 molecule produces immunosuppressive signals, which have been found to regulate CD4+T cell activity.
  • LAG-3 regulates the immune response of T cells in three ways: First, it directly inhibits the proliferation and activation of T cells via negative regulation of T cells. Second, it can promote the inhibitory function of regulatory T cells (Tregs), and the T cell response can then be indirectly inhibited. Third, it can prevent T cell activation by regulating the function of antigen presenting cells (APCs) [Joller et al., Curr Top Microbiol Immunol 410:127-156 (2017)].
  • APCs antigen presenting cells
  • a still further type of immune checkpoint inhibitor is a monoclonal antibody against CD47 and macrophage checkpoint inhibitor that interferes with recognition of CD47 by the SIRPa receptor on macrophages, thus blocking the "don't eat me” signal used by cancer cells to avoid being ingested by
  • 5UB5TITUTE SHEET (RULE 26) macrophages.
  • This monoclonal, whose INN name is magrolimab, is being developed by Giliad Sciences, Inc. in several hematologic and solid tumor malignancies, including myelodyspiastic syndrome (MDS).
  • Magrolimab has been granted Fast Track Designation by the FDA for the treatment of myelodyspiastic syndrome (MDS), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
  • Magrolimab has also been granted Orphan Drug Designation by the FDA for MDS and AML and by the European Medicines Agency for AML.
  • Anti-TIM-3 T cell immunoglobulin and mucin domain 3
  • INN INN name sabatolimab (earlier MBG-453) for use in MDS and AML therapy based on differential leukemic stem cell expression, its role as a co-inhibitory T-cell co-receptor, and possibly a role in promoting antibody-dependent cellular phagocytosis (ADCP).
  • TIM-3 is expressed on AML leukemic progenitors but is not seen on normal hematopoietic stem cells and its expression has been correlated with severity of myelodyspiastic syndromes as well as the likelihood of progression to AML.
  • TIM-3 antibody MBG-453 in frontline myelodyspiastic syndromes and AML, with encouraging antileukemic activity presented when used in combination with decitabine.
  • Intact monoclonal antibodies as well their paratope-containing portions (binding site-containing portions) such as Fab, Fab', F(ab')2 and Fv regions, as well as single-stranded peptide binding sequences can be useful as immune checkpoint protein inhibitors.
  • both medicaments can be administered in a single composition or in separate compositions. If administered separately, it is preferred to administer both types of anti-cancer (anti-leukemia) agent within minutes to about 3 hours of each other. More preferably, both are administered within less than one hour of the other.
  • administration is used herein to mean the beginning of a treatment regimen.
  • swallowing a tablet or other per os dosage form is the beginning of a treatment regimen, as is the time at which an IV flow is begun.
  • administration begins when that unitary composition enters the subject's body.
  • the second cytotoxic systemic anti ⁇ leukemia agent is an immune checkpoint inhibitor such as a monoclonal antibody, the halogenated xanthene compound and the second cytotoxic anti-leukemia agent
  • 5UB5TITUTE SHEET (RULE 26) immune checkpoint inhibitor can be administered together or one before the other, with the second cytotoxic antileukemia agent immune checkpoint inhibitor being administered up to about one month prior to the halogenated xanthene.
  • the two cytotoxic anti-leukemia agents are administered together or with the second systemic cytotoxic anti ⁇ leukemia agent immune checkpoint inhibitor being administered within a few days after the halogenated xanthene.
  • a second systemic cytotoxic anti-leukemia agent immune checkpoint inhibitor can also be administered about one month after the halogenated xanthene.
  • the SEM cell line was initially established from a 5 year old female with B acute lymphoblastic leukemia.
  • mice 2.5xl0 6 exponentially growing SEM cells [labelled with green fluorescent protein (GFP)] were injected intravenously into each animal and the establishment of tumors was monitored. After 4 weeks to permit the growth of the tumors, mice were randomized to three groups.
  • GFP green fluorescent protein
  • PV-10® (10% rose bengal disodium w/v in 0.9 percent in aqueous saline) diluted in PBS to a final volume of 100 ⁇ L and given orally by gavage twice a week for 2 weeks.
  • PV-10® administration decreased leukemia cell viability in a concentration and time dependent manner in the eleven pediatric leukemia cell lines (mean IC 50
  • PV-10 is cytotoxic to leukemia cell lines with a mean IC 50 value of 92.8 mM (Table 1, below) and is cytotoxic to two primary leukemia samples with a mean IC50 value of 122.5 mM (Table 2, below).

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CN202180038959.2A CN115955969A (zh) 2021-04-16 2021-04-16 用于口服治疗白血病的组合物和方法
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CA3175637A CA3175637A1 (en) 2021-04-16 2021-04-16 Composition and method for oral treatment of leukemia
MX2022012945A MX2022012945A (es) 2021-04-16 2021-04-16 Composición y método para el tratamiento de la leucemia oral.
KR1020227039851A KR20230171854A (ko) 2021-04-16 2021-04-16 백혈병의 경구 치료를 위한 조성물 및 방법
PCT/US2021/027702 WO2022220841A1 (en) 2021-04-16 2021-04-16 Composition and method for oral treatment of leukemia
JP2022562946A JP2023529262A (ja) 2021-04-16 2021-04-16 白血病の経口処置のための組成物及び方法

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