Classifications

• • 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 

Definitions

• This invention relates to a therapeutic regimen for treating blood (hematologic) cancers such as leukemia, lymphoma, and multiple myeloma, and particularly effecting such treatments in children.
• blood hematologic cancers such as leukemia, lymphoma, and multiple myeloma
• 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/ ⁇ l , about 30 percent are monocytes (about 2100/ ⁇ l and about five percent are lymphocytes (about 350/ ⁇ l . Geyton, Textbook of Medical Physiology, Seventh ed., W. B. Saunders Co., Philadelphia (1986).
• the above cell numbers are, of course, generalized average values, and granulocyte counts for normal patients; i.e., patients free of disease, typically have granulocyte counts of about 2000 to about 7000 cells/ ⁇ l.
• Chronic myelogenous leukemia also known as chronic granulocytic leukemia (CGL)
• CML chronic myelogenous leukemia
• CGL chronic granulocytic leukemia
• 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, rises rapidly to age 65, and remains high thereafter. The median life span of patients with chronic myelogenous leukemia from the time of diagnosis is approximately four years.
• 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.
• these drug therapies of the blast crisis stage of CML are even less successful than are the treatments of other acute leukemias.
• Cancer in children is rare with an incidence of 140-155 per million per year (age million per year (age ⁇ 15 years). This translates to ⁇ 1 in 7,000 children is diagnosed with cancer each year. Despite the rarity of cancer, malignant neoplasm is the most common cause of death after accidents in children aged 5 to 14 years, accounting for 23% of mortality.
• Leukemias are the most common childhood cancers, accounting for about 30% of all pediatric (ages 1-14) cancer diagnoses.
• Acute lymphoblastic leukemia (ALL) accounts for about 25% of childrens' cancers, and acute myeloid leukemia (AML) accounts for the remaining about 5%.
• NHL non-hodgkin lymphoma
• NHL Hodgkin lymphoma
• 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)].
• NHL non-Hodgkin's lymphoma
• NHL can be classified according to phenotype (B-cell vs. T-cell) and differentiation. It falls into three categories: (I) mature B-cell NHL including Burkitt/Burkitt-like lymphoma and diffuse large B-cell lymphoma (DLBCL);
• lymphoblastic lymphoma (mostly precursor T-cell); and (III) anaplastic large cell lymphoma (ALCL) (mature T-cell or null-cell).
• ACL anaplastic large cell lymphoma
• Burkitt lymphoma (BL) is most common, accounting for one-third of pediatric NHL [Saletta et al., Transl Pediatr 3(2):156- 182 (2014)].
• Hodgkin's lymphoma is the most common cancer in the 15 to 19 years age group and is four to five times more frequent than in the ⁇ 15 years age group. HL is typically categorized into classical and nodular lymphocyte predominant HL.
• HL was fatal until the 1960s when the MOPP (nitrogen mustard, vincristine, procarbazine and prednisone-containing) chemotherapy regimen was introduced.
• MOPP nitrogen mustard, vincristine, procarbazine and prednisone-containing
• the cure rate of HL in children has been >90% in the last two decades and is one of the most curable childhood cancers.
• survivors of childhood HL are at significant risk of long-term treatment-related morbidity and mortality.
• 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.
• 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.
• SCID severe combined immunodeficient
• Other approaches such as human hematopoietic stem cell reconstitution in immunocompetent animals are cumbersome, expensive and often introduce complex biological variables into the system.
• 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,
• PV-10 is a sterile 10% solution of RB in 0.9% saline that has been used clinically to measure liver function in infants [Yvart et al., Eur J Nucl Med 6:355-359 (1981)].
• Previous studies have shown that PV-10 accumulates in cancer cell lysosomes [Wachter, et al., Proceedings of SPIE, Multiphoton Microscopy in the Biomedical Sciences II, Periasamy, A. and So, P.T.C. (eds), Bellingham, Washington: 4620: 143-147 (2002)] and induces cell death in a range of adult cancers [Qin et al., Cell Death Dis 8:e2584 (2017); Toomey et al.,
• PV-10 has been used in a number of clinical trials, both as a single anti-cancer agent and in conjunction with both small molecule and monoclonal antibody anti-cancer agents. Several of those trials are discussed below. Phase I and phase II clinical studies using PV-10 alone as the cytotoxic agent illustratively reported "adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events" [Thompson et al., Ann Surg Oncol 22(1):2135-2142 (2015)], and "Treatment-Emergent Adverse Events (TEAEs) were consistent with established patterns for each drug, principally Grade 1-2 injection site reactions attributed to PV-10 and Grade 1-3 immune-mediated reactions attributed to pembrolizumab, with no significant overlap or unexpected toxicities: .
• TEAEs Treatment-Emergent Adverse Events
• intralesional administration of a halogenated xanthene into a tumor provides the active cytotoxic agent directly to the tumor at its highest concentration.
• administration is often distant from the target cancerous hematiologic cells, thereby possibly diminishing the effectiveness of the cancerocidal halogenated xanthene agent.
• PV-10 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 human clinical trials [Lippey et al., J Surg Oncol 114(3):380-384 (2016);
• the present invention contemplates a method of treating a mammalian subject having hematologic, non-tumorous cancer cell.
• Illustrative hematologic, non-tumorous cancers include leukemia, lymphoma and myeloma.
• the method comprises the steps of: (A) administering to such a mammalian subject a therapeutically effective amount of a halogenated xanthene, a pharmaceutically acceptable salt or a Cy-C4 alkyl ester thereof as a first cancer cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium.
• the mammalian subject is maintained for a period of time sufficient to induce death of hematologic, non-tumorous cancer cells.
• a contemplated administration is typically repeated.
• a contemplated treatment method can also be carried out in conjunction with administration to that mammalian subject of a second therapeutically effective amount of a second, differently-acting cancer cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable medium.
• the second cancer cytotoxic agent can be a small molecule or an intact antibody or paratope-containing antibody portion.
• the first and the second cancer cytotoxic agents can be administered together in the same or different media, or at different times.
• the second cancer cytotoxic agent can be administered in a solid tablet, capsule, pill or the like or in a liquid medium.
• a small molecule cancer cytotoxic agent having a molecular weight of about 200 to about 1000 Da is contemplated.
• Compounds that synergize with a halogenated xanthene such as doxorubicin, etoposide and vincristine are preferred.
• Intact antibodies or paratope-containing antibody portions are a second group of cancer cytotoxic agents. Preferred among these agents are those referred to as immune check point 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 a halogenated xanthene, a pharmaceutically acceptable salt or a C 1 -C 4 alkyl ester thereof as a first cancer cytotoxic agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium for treatment of a mammalian subject having hematologic, non-tumorous cancer cells, wherein the halogenated xanthene is maintained in the mammalian subject for a period of time sufficient to induce death of hematologic, non-tumorous cancer cells.
• the first cancer cytotoxic agent halogenated xanthene, pharmaceutically acceptable salt or C 1 -C 4 alkyl ester thereof is rose bengal, a pharmaceutically acceptable salt or C 1 -C 4 alkyl ester thereof.
• the rose bengal is rose bengal disodium salt.
• the hematologic, non-tumorous cancer cells are leukemia, lymphoma or myeloma.
• the hematologic, non- tumorous cancer cells, leukemia, lymphoma or myeloma is selected from the group consisting of acute B-cell or T-cell lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.
• the present invention contemplates a pharmaceutical composition for use in the treatment (killing) of hematologic, non-tumorous cancer cells, e.g., leukemia, lymphoma and myeloma.
• a contemplated pharmaceutical composition comprises a 0.1 % to about 20 % (w/v) aqueous medium (as a liquid) of a first cancer cytotoxic agent that is a halogenated xanthene, a physiologically acceptable salt of the halogenated xanthene, or a C 1 -C 4 alkyl ester thereof.
• a particularly preferred halogenated xanthene salt is rose bengal (4,5,6,7-tetrachloro-2 ' ,4',5',7'- tetraiodofluorescein) disodium salt, as is present in PV-10.
• the composition is administered to provide a therapeutically effective amount of a first cancer cytotoxic agent to a mammal such as a human having a hematologic, non-tumorous cancerous disease such as leukemia, lymphoma and myeloma, or more specifically, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or Hodgkin's lymphoma (HL).
• ALL acute lymphoblastic leukemia
• AML acute myeloid leukemia
• NHL non-Hodgkin's lymphoma
• NHL Hodgkin's lymphoma
• the mammalian subject is maintained for a time sufficient to kill hematologic, non-tumorous cancerous cells.
• the fact and relative amount of cancer killing can be determined by usual means for assaying the status of hematologic, non-tumorous cancers .
• the mammalian subject is typically thereafter treated again, usually multiple times. 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 like. These factors are commonly dealt with by physicians skilled in the art of treating hematologic, non-tumorous cancers.
• the data provided hereinafter illustrates that the value for use of RB against several leukemia cell lines in vitro is about 50 to about 100 mM. Given that the molecular weight of RB is 1018 g/mole, the above IC 50 value calculates to about 50 to about 100 mg of RB/liter. It is preferred to achieve that concentration for contacting cancerous cells during an in vivo treatment.
• IV intravenous
• RB has been tolerated at 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 IC 50 value in the bloodstream.
• an IV administration would require continuous infusion to maintain peak levels of RB in circulation (i.e., for up to several hours or more).
• Administration at the IC 50 value level would not be toxic to all circulating hematologic, non- tumorous cancerous cells; i.e., only approximately half of cells would be affected at the IC 50 value. It can therefore be preferred to administer RB at a multiple of the IC50 value, up to approximately 1500 mg (i.e.,
• cancerous cells it can be sufficient to kill only a fraction of the cancerous cells to initiate a functional immune response against remaining tumor burden.
• the latter case can be preferable to avoid toxic reaction (i.e., so-called "tumor lysis syndrome" due to presence of an abundance of rapidly killed cancer cells.
• the cancer cell debris caused by the cytotoxicity to cancer cells of a halogenated xanthene induces an immune reaction that in turn kills further cancerous hematologic, non-tumorous cells.
• halogenated xanthene compounds listed below and their pharmaceutically acceptable salts can have molecular weights that differ 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.
• a contemplated halogenated xanthene includes rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodo- fluorescein) that is particularly preferred, erythrosin B, phloxine B, 4,5,6,7-tetrabromo-2',4',5',7'-tetra- iodofluorescein, 2',4,5,6,7-pentachloro-4',5',7'- triiodofluorescein, 4,4',5,6,7-pentachloro-2',5',7'- triiodofluorescein, 2',4,5,6,7,1'-hexachloro-4',5'- diiodofluorescein, 4,4',5,5',6,7-hexachloro-2',1'- diiodofluorescein, 2',4,5,5',6,7-hexach
• a C 1 -C 4 alkyl ester of one of the above halogenated xanthene compounds can also be used, with the C2; i.e., ethyl ester, being preferred.
• C2 i.e., ethyl ester
• ethyl-Red 3 erythrosine ethyl ester; 2',4',5',7'-tetraiodo- fluorescein ethyl ester
• 4,5,6,7-tetrabromo- 2 ',4',5',7'-tetraiodofluorescein and ethyl-Pholoxine B 4,5,6,7-tetrachloro-2',4',5',1’-tetrabromofluorescein ethyl ester
• rose bengal disodium that has the structural formula below:
• a contemplated halogenated xanthene or its pharmaceutically acceptable salt is typically used dissolved or dispersed in an aqueous pharmaceutical composition.
• the halogenated xanthene is typically present at 0.1 to about 20 % (w/v) in an aqueous 0.9 % saline pharmaceutical composition.
• a contemplated pharmaceutical composition is typically intended for parenteral administration as by intravenous methods, such a composition should contain an electrolyte, and preferably have approximately physiological osmolality and pH value.
• a preferred concentration of singly charged electrolyte ions in a pharmaceutically acceptable aqueous medium is about 0.5 to about 1.5% (w/v), more preferably at about 0.8 to about 1.2%
• the electrolyte in a chemoablative pharmaceutical composition is sodium chloride.
• Electrolytes at such levels increase the osmolality of a pharmaceutically acceptable aqueous medium.
• osmolality can be used to characterize, in part, the electrolyte level of the composition. It is preferred that the osmolality of a composition be greater than about 100 mOsm/kg, more preferably that the osmolality of the composition be greater than about 250 mOsm/kg, and most preferably that it be about 300 to about 500 mOsm/kg.
• the pH value of a pharmaceutically acceptable aqueous medium be about 4 to about 9, to yield maximum solubility of the halogenated xanthene 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 water-insoluble lactone that forms at low pH values.
• the pH value of a pharmaceutically acceptable aqueous medium can be regulated or adjusted by any suitable means known to those of skill in the art.
• the composition can be buffered or the pH value adjusted by addition of acid or base or the like.
• the halogenated xanthenes, or physiologically acceptable salts thereof are weak acids, depending upon halogenated xanthene concentration and/or electrolyte concentration
• the pH value of the composition may not require the use of a buffer and/or pH modifying reagent. It is especially preferred, however, that the composition not contain any buffer, permitting it to conform to the biological environment once administered.
• the specific amount of halogenated xanthene 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 to the environment of the cancerous cells and in which those cancerous cells can be contacted with the halogenated xanthene.
• 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.
• IC 50 half maximal inhibitory concentration
• IV dosing is a preferred method of administering a halogenated xanthene-containing composition to a mammalian subject in need.
• RB administered in an amount that is a multiple of the IC50 level, up to approximately 1500 mg
• tumor lysis syndrome is the most common disease-related emergency encountered by physicians treating hematologic cancers.
• a mammal having leukemia, lymphoma or myeloma in need of treatment (a mammalian subject) and to which a pharmaceutical composition containing a halogenated xanthene or its pharmaceutically acceptable salt 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 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 contacted cancerous 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.
• an above pharmaceutical composition is used in conjunction with a second, differently-acting cytotoxic anticancer agent; i.e., a cytotoxic anticancer agent whose mechanism of action is different from that of the first cytotoxic agent, the haiogenaed xanthene.
• a second, differently-acting cytotoxic anticancer agent i.e., a cytotoxic anticancer agent whose mechanism of action is different from that of the first cytotoxic agent, the haiogenaed xanthene.
• 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 cytotoxic agent is a so-called "small molecule".
• small molecules can be viewed as semi-specific cellular poisons in that they are generally more specific at killing cancer cells than non-cancerous cells.
• small molecule anticancer agents are less cancer-specific than a contemplated halogenated xanthene, and can result in causing sickness, baldness and other trauma to their recipient subjects that can lead to subjects leaving their treatment regimens.
• These small molecules typically have molecular weights of about 200 to about 1000 Daltons (Da), and preferably about 250 to about 850 Da.
• This group of small molecules includes many of the previously noted molecules used to treating hematologic cancers such as calicheamicin (1368 Da), vinblastine (811 Da), vincristine (825 Da), monomethyl auristatin (718 Da), etoposide (589 Da), daunorubicin (528 Da), doxorubicin (544 Da), annamycin (640 Da), sorafenib (465 Da), clofarabine (304 Da), cisplatin (300 Da), irinotecan (587 Da) and cytabarine (243 Da). 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 cytotoxic anti-cancer 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 cancerous 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 cancerous cells and/or be endocytosed by the cancer cell.
• This group of encapsulated and conjugated small molecules' is included with the previously discussed small molecule group of second cytotoxic agents as their active cytotoxic agent is a small molecule.
• second 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 cytotoxic agent to assist delivery. See, Akbarzadeh et al., Nanoscale Res Lett, 8:102 (2013).
• 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 [IC50 ⁇ 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 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-cancer 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 as compared to the localized administration that occurs with an intralesional administration of a halogenated xanthene.
• Intravenous administration is a preferred method to achieve that spread of medication.
• Illustrative small molecule anti-cancer medications include doxorubicin, etoposide, vincristine, cisplatin, irinotecan and cytarabine that were used herein, whereas an exemplary proteinaceous molecule is egasparaginase. Of those medications, doxorubicin, etoposide and vincristine appeared to synergize with treatment with a sub-lethal dose of PV-10, and are preferred.
• any of the second cancer cytotoxic agents discussed herein can be undertaken multiple times. Such multiple administrations are within the purview of the treating physician, and can be made in conjunction with an administration of a first cancer cytotoxic agent or can be carried out separately.
• a useful effective dosage of a small molecule systemic anti-cancer 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.
• the combination therapies 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.
• a halogenated xanthene and a second cytotoxic anti-cancer agent need not be administered together nor by the same means of administration.
• a pill or capsule can be used to administer the second cytotoxic anti-cancer agent, while the halogenated xanthene is administered IV.
• a second type of second cytotoxic agent useful for combination treatment with a halogenated xanthene such as that present in PV-10 is an immune checkpoint inhibitor, that can also be viewed as a special systemic anti-cancer medication.
• An immune checkpoint inhibitor is a drug that binds to and blocks certain checkpoint proteins made by immune system cells such as T cells and some cancer cells. When not blocked, those proteins inhibit immune responses, helping keep immune responses in check and keeping T cells from killing cancer cells. Blocking those immune checkpoint proteins releases the "brakes" on the immune system permitting T cells to become activated and kill cancer 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, thereby permitting the immune system to recognize the cancer cells as foreign and assist in eliminating those cancer 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 cancer.
• PD-1 programmed death 1
• PD-Ll immune checkpoint protein ligand
• Another group of antibodies with checkpoint inhibitor-like activity immunoreact with the cell surface receptor 0X40 (CD134) to stimulate proliferation of memory and effector T-lymphocytes, and thereby stimulate a T-cell-mediated immune response against cancerous cells.
• exemplary such humanized anti-OX40 monoclonal antibodies include those presently referred to in the literature as gsk3174998 (IgGl), pogalizumab (MOXR0916), MED10562 and the human anti- 0X40 IgG2 antibody designated PF-04518600 (PF-8600).
• 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.
• Intact checkpoint inhibiting monoclonal antibodies have half-lives in a human body of about one to three weeks
• both medicaments can be administered in a single composition or in separate compositions. If administered separately, it is preferred to administer both types of anticancer 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 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 anticancer agent is an immune checkpoint inhibitor such as a monoclonal antibody
• the halogenated xanthene and the second cytotoxic anticancer agent immune checkpoint inhibitor can be administered together or one before the other, with the second cytotoxic anticancer agent immune checkpoint inhibitor being administered up to about one month prior to the halogenated xanthene.
• the two cytotoxic anticancer agents are administered together or with the second cytotoxic anticancer agent immune checkpoint inhibitor being administered within a few days after the halogenated xanthene.
• a second cytotoxic anticancer agent immune checkpoint inhibitor can also be administered about one month after the halogenated xanthene.
• PV-10 decreased cancer cell viability in a concentration and time dependent manner in the eleven pediatric leukemia cell lines (mean IC 50 92.8 mM), and three primary leukemia samples (mean IC50122.5 mM) examined.
• the results show that 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 IC 50 value of 122.5 mM (Table 2, below).
• Table 1*
• a panel of eleven cell lines derived from patients with either primary or relapsed pediatric leukemia CEM-C1, CCRF-SB, Kasumi-1, KOPN8, Molm-13, Molt-3, Molt-4, MV4-11, SEM, SUP-B15 and TIB-202
• T-ALL, AML, Infant AML three primary leukemia patient specimens
• Target modulation and induction of cell death pathways were investigated by western blot, phase-contrast microscopy and time-lapse video microscopy.
• A. l x 10 4 cells/mL were injected subcutaneously into BALB/c nude mice. 2-3 Weeks were required for tumors to grow to treatable volume.
• halogenated xanthene solutions (0.01, 0.001 or 0.1% w/v) was injected until tumor was completely infiltrated. One could see the tumor begin to turn red as the agent was injected.
• Laser Coherent, Verdi 5W, 532nm CW laser, 200mW/cm 2 , lOOJ/cm 2 , 4cm2 treatment zone.
• the 532 nm exciting wavelength was removed using a Melles Griot filter Part No. 03 FIM 008. Fluorescence of the compounds was recorded using an Olympus® digital camera (Model 0-300-L).
• Results *PH-12 2 ,4',5',7'-tetrabromo-4,5,6,7- tetraiodoerythrosin prepared and supplied by Molecular Probes Inc.
• **Phloxine B the unesterified parent compound of Ethyl- phloxine B has been examined previously and is not retained in tumors.

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  • 2019-11-19 AU AU2019474803A patent/AU2019474803A1/en active Pending
  • 2019-11-19 WO PCT/US2019/062184 patent/WO2021101521A1/en active Application Filing
  • 2019-11-19 CA CA3158221A patent/CA3158221A1/en active Pending
  • 2019-11-19 JP JP2022555613A patent/JP2023506609A/ja active Pending
  • 2019-11-19 MX MX2022005828A patent/MX2022005828A/es unknown

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