Platinum-resistant cancer treatment

Abstract

To provide a pharmaceutical composition for treating cancer using a specific dose at specific dosing intervals.SOLUTION: A pharmaceutical composition for treatment of cancer contains a compound of formula I or a pharmaceutically acceptable salt or ester thereof, where (i) the cancer is refractory or resistant to platinum drug-based therapy and (ii) the pharmaceutical composition is used by administering a dose of 1-30 mg / m2 of the compound per patient body surface area per administration. A method of treatment and novel dosage forms based on the pharmaceutical composition are also provided. Particularly treated are ovarian cancers, particularly those overexpressing α-folate receptors, including epithelial ovarian, fallopian tube or peritoneal cancer.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a novel treatment for cancer, more particularly cancer that is often resistant or refractory to platinum-based therapy. Particularly included among the cancers to be treated are cancers of the ovary, endometrium, mesothelium and non-small cell lung (NSCL), and cancers derived therefrom. A more particularly preferred treatment is provided for cancers derived from the ovary, such as cancers of the epithelial ovary, fallopian tube and peritoneum, etc.

Background Art

[0002] Most particularly, the present invention provides a novel treatment for cancers that possess α-folate receptor (FR-α), especially those that exhibit α-folate receptor at levels higher than the non-cancerous tissue level in the background, specifically those that have such FR-α on the cell membrane surface. Cancers suitable for the treatment of the present invention also include breast cancer and lung cancer in which FR-α is expressed, particularly triple-negative breast cancer.

[0003] α-Folate receptor is overexpressed in many carcinomas, especially in those of ovarian origin where it is highly and uniformly overexpressed in 90% of cases (Non-Patent Document 1). Furthermore, high α-FR expression is associated with progressive platinum-resistant disease and poor prognosis (Non-Patent Documents 2, 3). The β-isoform is widely expressed in tumors of epithelial and non-epithelial origin, and it is reviewed in Non-Patent Document 4 that the expression levels are generally low / moderate and high, respectively.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non - Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] The present invention, very beneficially, provides treatment for patients with high - grade serous ovarian cancer (HGSOC) in life - saving situations where there is a large unmet medical need for products that can, for example, extend lifespan.

Means for Solving the Problems

[0006] Ovarian cancer is a term for a group of tumors caused by various types of tissue contained within the ovaries. The most common type of ovarian cancer originates from the epithelial cells on the surface of the ovary and can often spread to any surface within the abdominal cavity, including the fallopian tubes and peritoneal cavity. Fallopian tube cancer and primary peritoneal cancer are histologically equivalent diseases to epithelial ovarian cancer. Ovarian cancer is classified from stage I to stage IV. Advanced ovarian cancer corresponds to stage III and IV, where stage III represents a disease that has progressed locally and spread to the extra - pelvic abdominal cavity, and stage IV represents the occurrence of distant metastasis to other body organs such as the liver and lungs.

[0007] Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological malignancies in developed countries. EOC includes a heterogeneous mixture of neoplasms, including serous (68%), clear cell (13%), endometrioid (9%), and mucinous (3%) pathological subtypes. Serous ovarian cancer is further divided into low - grade (type I) and high - grade (type II) serous ovarian cancer (LGSOC and HGSOC, respectively). Most deaths are caused by HGSOC, which is approximately 20 times more common than LGSOC.

[0008] Ovarian cancer is classified as follows according to the response to first-line platinum chemotherapy: ● Platinum-sensitive - diseases respond to platinum-based therapy but may relapse more than 6 months later, which is ○ Completely platinum-sensitive - diseases respond to platinum-based therapy but relapse more than 12 months later, and ○ Partially platinum-sensitive - diseases respond to platinum-based therapy but can be further subdivided into those that relapse between 6 and 12 months; and ● Platinum-resistant - diseases that relapse within 6 months from the end of platinum-based chemotherapy, and ● Platinum-refractory - diseases do not respond to first-line platinum-based chemotherapy.

[0009] A significant proportion of people have diseases that respond to first-line chemotherapy, but 55 - 75% of these relapse within 2 years from the completion of treatment. In addition to such situations, some patients cannot tolerate platinum-based drugs, so alternative options to platinum that the treatment plan of the present invention will provide in the future will also be needed.

[0010] The first treatment approach for HGSOC is usually surgical tumor debulking followed by chemotherapy. Optimal tumor debulking without macroscopic residual disease is the most important prognostic indicator. However, since HGSOC is asymptomatic in the early stage, most patients present with advanced-stage diseases.

[0011] Most HGSOC (80%) initially respond well to platinum / taxane therapy, and drug resistance appears during the next treatment cycle. On the other hand, a small number of cases of HGSOC (20%) are refractory to platinum-based chemotherapy from the time of administration, but the principle of this drug resistance is not understood. The disease stages III and IV, which are the preferred target populations for the treatment of the present invention, have a high recurrence rate.

[0012] Patients with optimally debulked (less than 1 cm) stage III ovarian cancer are typically recommended to receive intraperitoneal (IP) chemotherapy after upfront surgery. At present, there is no standard treatment regimen for IP therapy, but dosing regimens with drugs such as paclitaxel and cisplatin or carboplatin dosing regimens may be used. If a patient cannot tolerate IP delivery, intravenous drugs such as paclitaxel and carboplatin, or docetaxel and carboplatin may be given.

[0013] Typically, the treatment of stage III and IV disease is carried out by chemotherapy, and the treatment options are influenced by the time elapsed since the previous platinum-containing chemotherapy was fully effective. Liposomal doxorubicin is a good first option, but there are many drugs with similar efficacy, and the final choice is influenced by the individual circumstances as well as the preferences of the patient and the physician. Some of the drugs available include gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, and nanoparticle albumin-bound paclitaxel. Bevacizumab may also be considered as a single agent or in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

[0014] Other possible therapies in the pharmaceutical company pipelines include PARP inhibitors such as Lynparza (olaparib) and Rubraca (rucaparib) (both trademarks are limited to BRCA mutant types), and Zejula (niraparib); and checkpoint inhibitors such as Tecentriq (atezolizumab) and Bavercio (avelumab) for non-BRCA mutant types. However, many important opinion leaders have stated that such drugs need to be used with a more precisely defined population in order to improve overall response rates. Keytruda (pembrolizumab) has also been found to have some efficacy when high levels of PD-1 are seen on T lymphocytes and on tumors.

[0015] Several FR-α directed drugs have been put into clinical trials. The FR-α directed monoclonal antibody, farletuzumab, was unable to improve the progression-free survival (PFS) of patients with platinum-sensitive epithelial ovarian cancer when combined with paclitaxel and carboplatin in a Phase III trial of 1,100 patients. Vintafolide, a conjugate of an α-folate receptor-directed moiety and vinblastine, has shown some success in improving PFS when combined with docetaxel in folate receptor-positive non-small cell lung cancer (NSCLC), and has been tried in ovarian cancer together with pegylated liposomal doxorubicin (PLD), but the Phase III trial was unable to meet the predefined PFS criteria to allow the trial to continue. The antibody-drug conjugate IMGN853 (mirvetuximab soravtansine) has also undergone a Phase I trial in platinum-resistant epithelial ovarian cancer, showing some potential to increase PFS at a dose of 6 mg / kg every three weeks, with a PFS of 6.7 months in 39% of patients who had received three or fewer prior therapies.

[0016] Although it is possible that the combination of these drugs may prove useful in platinum-resistant situations, there is a continuing need to treat platinum-resistant cancers, particularly ovarian cancers such as HGSOC, as it is the cause of most ovarian deaths and there has been little improvement in overall survival over decades. Potentially large drugs such as immune checkpoint inhibitors have produced remarkable clinical responses in melanoma and non-small cell lung cancer, probably due to an unusually high mutation burden, but in contrast, HGSOC is thought to have a moderate mutation burden and fewer neoantigens (Bowtell et al. Nat Rev Cancer 2016 June). Current monotherapy for HGSOC has an overall response rate (ORR) of 15 - 20% and a progression-free survival (PFS) of only 3 - 4 months.

[0017] Additional drug classes include the thymidylate synthase (TS) inhibitors CB3717, ZD1694 (raltitrexed), LY231514 Alimta (pemetrexed) and ZD9331 (previtrexed). All of these TS inhibitors have very clear clinical activity in various solid tumors (see Cancer Treatment Reports, 1986, 70, 1335 and Beale et al., “Tomudex: Clinical Development” in Antifolate Drugs in Cancer Therapy (ed. Jackman), Humana Press, Totowa, New Jersey, USA, pp. 177-181, 1999). The side effects of raltitrexed and ZD9331 are mainly related to the inhibition of TS in the gastrointestinal tract and bone marrow.

[0018] Raltitrexed and pemetrexed are examples of “classical” TS inhibitors defined by the following characteristics: the reduced folate carrier (RFC) is the main transporter into the cell; they are excellent substrates for folylpolyglutamate synthase (FPGS) and are thus extensively polyglutamylated in tissues / tumors to become polyglutamic acids, which are effective cytotoxic drug species; and they have a rather short half-life in plasma. Since these classical inhibitors are gradually removed from tissues due to polyglutamylation, they are often cytotoxic and are used in high-dose dosing regimens with low frequency and short duration infusions, for example, about 15 minutes.

[0019] Previtrexed is a “non-classical” TS inhibitor in that it is not polyglutamylated and has the following characteristics: RFC is the main transporter into the cell; it is not a substrate for FPGS; its TS Ki is about 0.4 nM, i.e., similar to the polyglutamates of raltitrexed and pemetrexed; it is rapidly excreted from cells and is thus not retained much in tissues / tumors; and it has a long plasma half-life.

[0020] Pemetrexed is approved for use in non-small cell lung cancer and pleural mesothelioma, but has also been proposed as a treatment for platinum-resistant ovarian cancer. For example, in this condition, 500 mg / m 2 of pemetrexed is given on day 1 and gemcitabine on day 8 in a 21-day cycle (Clin Transl.Oncol(2009)11:35-40), and 900 mg / m 2 is given once every 21 days (J.Clin Oncol 27:2686-2691). Further discussion of these and other trials is provided in Expert Opin.Investig.Drugs(2012)21(4), and Expert Opin.Investig.Drugs(2013)22(9), the latter of which notes that a single-agent pemetrexed dose of 600 mg / m 2 is recommended. This paper also notes that at that time, antifolate drugs (such as TS inhibitors) were not approved for the treatment of ovarian cancer.

[0021] A further subset of this group of TS inhibitor compounds is the FR-α-directed cyclopenta[g]quinazolines described in patent applications WO-A-94 / 11354, WO-A-95 / 30673 and WO-A-03 / 020748. US5789417, US5747499, US7250511, US7297701, US7528141, US7705006, US7863284, US8063056, US8486955 and US8552016 are incorporated herein by reference for the purposes of United States patent rights. These documents teach that these compounds are administered at a dose in the range of 50 to 25000, particularly 50 to 5000 mg per square meter of patient body surface area (mg / m 2 ), i.e., approximately 1500 mg / m 2 , particularly at a dose of 1 to 100 mg / kg. It is taught that higher dosages could be employed and that when subcutaneous infusion is used, the dosage range could be increased to 1 to 1000 mg / kg, preferably 10 to 250 mg / kg, particularly 30 to 150 mg / kg.

[0022] These inhibitors can also be used for other cells expressing FR-β as opposed to FR-α, particularly those associated with rheumatoid arthritis and acute myeloid leukemia. For this purpose, US8466111 teaches dosages in the range of 50 to 25000 mg / m 2 although dosages in the range of 5 to 25000 mg / m 2 are also mentioned, but it specifies increasing the dosage to 1 to 1000 mg / kg or 0.1 to 10 mg / kg for subcutaneous administration. There is a description of topical administration at 0.1 to 10 mg / kg, and oral tablets containing 1, 10, 50, and 100 mg of the compound are disclosed in the same way as injection solutions at 1, 10, and 50 mg / ml.

[0023] The use of higher dosages is consistent with raltitrexed and pemetrexed, and this subset of TS inhibitor compounds share similar properties, for example, FR is the main transporter; uptake via FR is slower and can reach saturation more easily compared to uptake of other antifolates mediated by RFC; it is not a substrate for FPGS; and the TS Ki is about 1.4 nM which is similar to the polyglutamates of raltitexed and pemetrexed. However, it was taught that high dosages should be tolerated because the compound is not retained in tissues / tumors and is rapidly excreted from cells.

[0024] Typically, to induce an antiproliferative effect, TS requires at least 24 hours of inhibition, and for a TS inhibitor to be effective, it is often necessary to repeat a sufficient intracellular exposure to the drug for at least 2 to 3 days, for example, weekly. This is achieved by the polyglutamination of raltitrexed and pemetrexed which overcomes the short plasma half-life and short extracellular exposure. For example, the long intracellular exposure by premetrexed is achieved by an unusually long terminal plasma half-life which results in an extended extracellular exposure.

[0025] Surprisingly, it has been found that when the lead compound of this newer class of FR-α-directed TS inhibitors is administered to humans, the half-life levels become unusually long. This compound, ONX-0801 (hereinafter referred to as BTG945), has a high affinity for the alpha-folate receptor (FR-α) and enters cells by FR-α-mediated transport. It has the modified glutamate ligand L-glu-γ-D-glu dipeptide and is therefore not a substrate for FPGS. It binds to α-FR with an affinity of 70% of folic acid (FA) (Theti et al., 2003), it binds to FR-β with a similar affinity (van der Heijden et al., 2009), and furthermore it appears to have negligibly small affinity for the ubiquitous reduced folate carrier (RFC) except at high concentrations (Gibbs et al., 2005). This has been found to lead to the desired concentrations and time-dependent inhibition of tumor cell growth in vitro.

[0026] Upon entering the cell, BTG945 irreversibly binds to the active site of thymidylate synthase, which then interferes with the normal performance of its role in the production of thymidine monophosphate (dTMP), an essential step in DNA synthesis and repair that approved TS inhibitors also utilize.

[0027] The first human Phase I trial of BTG945, identified as ONX801, was initiated on September 30, 2009, with the trial registration number ISRCCTN79302332, aiming to find tolerable doses that would inhibit tumor cell growth in 3-hour infusions on days 1, 8, and 15 of a 21-day cycle. However, on March 30, 2011, this trial was terminated due to the occurrence of bronchiolitis obliterans organizing pneumonia (BOOP) with fibrosis, which is reversible and may be exacerbated by cumulative doses, at a predicted therapeutic effective dose of 45 mg / m 2 due to toxicity. From this, it was concluded that the drug could not be used at the previously considered doses and dosing schedules because this toxic dose was lower than the lowest dose shown to be preferable for treatment.

[0028] Considering the still unmet great need for the treatment cohort of interest, the inventors re-evaluated the dosing regimens applicable to the drug BTG945 to make it clinically useful. Analysis of unpublished drug levels in human plasma suggested that much lower doses of the drug would be required to avoid toxicity. The inventors and applicants initiated a new Phase I trial, EudraCT 3941, at doses predicted to be such safe but non-therapeutic doses, and have now discovered that unexpected efficacy against platinum-resistant tumors in human patients, particularly FR-α-expressing tumors, is achieved at levels of the drug much lower than previously thought necessary, without the occurrence of BOOP that limits treatment. This efficacy is demonstrated as partial response and stable disease according to RECIST criteria in a significant proportion of ovarian cancer patients showing α-folate receptor expression, particularly when such expression presents receptors on the tumor membrane, resulting in a period of progression-free survival and in particular partial response and / or objective response rate (ORR).

[0029] Therefore, BTG945 has a Ki comparable to that of raltitrexed and pemetrexed (1.2 nM versus 1.4 nM) against isolated target thymidylate synthase, but the dose required for efficacy in humans is considerably lower than previously expected, and nevertheless, in the preferred control group where FR-α is expressed, the efficacy of the compound appears to be far superior to that seen in other members of the class of TS inhibitors.

[0030] Particularly surprisingly beneficial is the finding that the side effect profile of BTG945 is unusually favorable. There were no dose-limiting effects other than BOOP, and BOOP itself has been shown to be manageable and / or may be eliminated by an optimized dosing schedule using, for example, twice or three times weekly dosing. Side effects commonly associated with thymidylate synthase inhibitors, such as neutropenia, diarrhea, and alopecia, were not observed, nor were side effects associated with α-folate receptor antibody complexes, such as diarrhea, blurred vision, and nausea. Moreover, general toxicities associated with cytotoxic chemotherapy, such as myelotoxicity, nephrotoxicity, and neurotoxicity, were not observed.

[0031] The cancers of several trial patients have been shown to respond at a low dose of 1 mg / m 2 as outlined in the treatment plan below. It is suggested by the side effects determined to date that this dosing plan may be used as monotherapy or in combination with any of the currently employed therapies taught herein to have no overlapping toxicities. Such findings in the clinical setting provide a treatment for platinum-resistant cancers that can be used as monotherapy or in combination with other available treatments, promising to extend the PFS of patient groups with unmet needs remaining here. The treatment of the present invention can be used in combination with first-line therapeutic agents, particularly, for example, paclitaxel or carboplatin.

[0032] In a first aspect, the present invention provides a compound of formula I for the treatment of cancer

[0033] [Chemical formula] or a pharmaceutically acceptable salt or ester thereof, wherein (i) the cancer is of a type that is refractory or resistant to platinum-based therapy or has a tendency to become so, and further (ii) the treatment is by a dose of the compound of 1 to 30 mg / m 2 per patient body surface area per administration.

[0034] The treatment is preferably by a dosing regimen that maintains the plasma concentration of the drug at 0.5 μM or more for at least 72 hours. More preferably, as a result of the dosing regimen, the plasma concentration of the drug becomes 1 to 5 μM over 72 hours or less, preferably over 60 hours or less, immediately after dosing. Most preferably, the dosing regimen maintains a plasma concentration of the drug of 0.1 to 2 μM for at least 50% of the treatment cycle period.

[0035] The treatment is preferably ● A dose of 1 to 10 mg / m administered on days 1, 8, 15 and 22 at 7-day intervals in a 28-day cycle 2 of the dose, ● A dose of 6 to 14 mg / m administered on days 1 and 15 at 14-day intervals in a 28-day cycle 2 of the dose, ● A dose of 10 to 30 mg / m administered on day 1 in a 21-day cycle 2 selected from the dosing regimens.

[0036] The cancer is preferably refractory or resistant to platinum. Preferably, the cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, or cancer derived from one of these.

[0037] More preferably, the cancer is one in which the alpha-folate receptor (FR-α) is expressed, particularly one that shows the alpha-folate receptor higher than the non-cancerous tissue level in the background. Most preferably, FR-α is expressed on the surface membrane of cancer cells. Most preferably, the cancer is ovarian cancer, for example, epithelial ovarian, fallopian tube or peritoneal cancer, but may also be breast cancer or lung cancer, for example triple-negative breast cancer or non-small cell lung cancer. A specifically preferred cancer to be treated is serous ovarian cancer, for example, high-grade serous ovarian cancer (HGSOC) found in a salvage situation.

[0038] For the avoidance of doubt, platinum-based therapy includes, but is not limited to, the drugs cisplatin or carboplatin. The scope of the present invention is 1 to 30 mg / m 2 However, the preferred dose is 3-30 mg / m2 per patient body surface area per administration. 2 of the compound, more preferably 5 to 20 mg / m2 of the patient's body surface area per administration. 2 and more preferably, the dose of the compound is 8 to 15 mg / m2 of patient body surface area per administration. 2 , and most preferably 10 to 15 mg / m 2 , especially about 12 mg / m 2 , for example 11.5 to 12.5 mg / m 2 is the dose of the compound.

[0039] The dose is preferably administered intraperitoneally (IP) or intravenously (IV). IP administration would allow dosing with less risk of systemic side effects, especially those that would affect the lungs, such as BOOP. Typically, the dose is administered intravenously.

[0040] In one preferred embodiment of the invention, the compound is administered by injection, particularly as a single injection, intraperitoneally (IP), at a dose of about 1 mg / m 2 The compound is administered in a suitable size, e.g., 1-10 ml, more preferably 2-6 ml, volume, containing an appropriate amount of compound to meet dosing requirements. Typical such doses would be 2, 3, 4 or 5 ml of solution. Typically, it is an aqueous solution, which may be in saline or water for injection. The compound herein is the "drug substance" and the "drug product" is a vial having an appropriate volume for a single IP administration. In a further preferred embodiment, multiple IP injections are given as 1-10 ml, more preferably 2-6 ml of solution each containing the appropriate mg of drug substance. Typical such doses would be 2, 3, 4 or 5 ml of solution. Each "drug product" provides single or multiple IP injections, and the drug product is a vial, e.g., a glass vial, e.g., a clear glass vial, containing the drug substance with a stopper and an appropriate device to keep the stopper in place, e.g., an aluminum crimped closure.

[0041] In a further preferred embodiment, the compound is conveniently administered by injecting the contents of the vial provided by the supplying pharmaceutical company into a sterile saline bag as part of an intravenous drip of saline. Typically, the "drug product" is a sterile aqueous solution of the drug substance BTG945 as the trisodium salt, which is preferably in the form of the dihydrate in solid form. The drug product is contained, for example, in a type 1 clear glass vial equipped with a stopper and an aluminum crimp seal. The strength of each vial stated on the label includes, for example, a 2 mL solution containing the appropriate mg of the drug substance. For convenience, the only excipient in the BTG945 trisodium salt drug product can be sterile water for injection. Of course, other ingredients that are common in pharmaceutical compositions may be provided.

[0042] Typically, the drug product vials are stored at a low temperature, thawed before use, and then the desired aliquots are removed from one or more stoppered vials using a sterile syringe. This aliquot is then added directly to an infusion bag for further dilution with 250 mL of 0.9% sterile saline (USP) for IP or IV injection. Immediately after dilution in the infusion bag, the prepared solution should preferably be administered to the patient within 24 hours at room temperature. The vials and bags must be protected from light before administration.

[0043] In one preferred embodiment for IP infusion, the aliquot is added directly to an infusion bag for further dilution with 10 mL, 15 mL, 25 mL or 50 mL of 0.9% sterile saline (USP) for IP injection or infusion. These bags are handled as described above immediately after dilution.

[0044] More specifically, the present invention treats with the calculated dosage at dosing intervals of 10 to 28 days, more preferably 10 to 21 days, most preferably about 14 or 21 days, as presented above, by infusion, particularly intravenous infusion (IV), or as single or multiple injections. Even more preferably, when administered by IV, the present invention treats with a cumulative maximum amount of 150 mg / m 2 of the compound per patient body surface area throughout all infusions. More preferably, this limit also applies to IP dosing. More preferably, the maximum cumulative dose is 144 mg / m 2 .

[0045] Treatment according to the present invention preferably provides the compound in infusions at 14 or 21 day intervals in 21-day cycles or 28-day cycles, most preferably two infusions on day 1 and day 15 per cycle in 28-day cycles. These cycles are preferably repeated until the maximum cumulative dose is reached. Infusions are preferably carried out over 0.5 to 3 hours. It will be understood that a 1-hour infusion rate may be sufficient since treatment can be effective at as little as 1 mg / m 2 . Thus, the infusion can be carried out over 0.5 to 1 hour, over 1 hour, but less than 3 hours.

[0046] A more preferred dosage for each administration, for example for infusion, is 1 to 20 mg / m 2 , preferably 3 to 20 mg / m 2 , more preferably 6 to 18 mg / m 2 , even more preferably 8 to 16 mg / m 2 , for example, 10 to 15 mg / m 2 , and 10 to 12 mg / m 2 . The most preferred dosage is about 12 mg / m 2 . It can be seen that a dosage of 12 mg / m 2 administered once on day 14 in a 28-day cycle will reach the maximum cumulative recommended dose just before 6 months. An even more preferred dosage is 12 mg / m 2 administered once on day 21 in a 21-day cycle.is the dosage. Further dosing may be considered if the attending clinician is monitoring for irreversible BOOP or similar side effects. If the patient exhibits signs of BOOP, for example, if there is evidence of accumulation of inflammatory cell exudate (AICE) on a CT scan, the dosage of the drug compound must be reduced. It may also be advisable to interrupt drug administration for a short period, for example, 2 or 4 weeks, and then resume at a lower preferred dosage. ACIE has been observed on radiological scans, and symptoms have been found to stop progressing and be alleviated by discontinuing dosing at 12 mg / m 2 for 2 weeks and then resuming at 6 mg / m 2 until the maximum cumulative dose of 144 mg / m 2 is achieved.

[0047] In a particularly preferred embodiment, by administering a preferred dosage amount, a blood concentration of the compound of at least about 0.5 μM is achieved over at least 72 hours, preferably less than 2.0 μM, more preferably at least about 0.7 μM is achieved over at least 36 hours, or even more preferably at least about 0.9 μM, more preferably less than about 1.5 μM is achieved over at least 24 hours. This level is particularly preferred for IV administration. It is preferred that the plasma level of the drug does not remain above 1 μM for more than 72 hours. Most preferably, the dosing schedule maintains a plasma concentration of the drug of 0.1 - 2 μM over at least 50% of the treatment cycle period. More preferably, 0.1 - 1 μM over 50% of said period.

[0048] One particularly preferred cohort of cancers suitable for the treatment of the present invention is a cohort of female patients newly diagnosed and histologically confirmed with advanced high-risk (FIGO stage III-IV) BRCA-mutated high-grade serous and high-grade endometrioid ovarian cancer, primary peritoneal cancer, and / or fallopian tube cancer.

[0049] Stage III patients preferably have had one attempt at optimal cytoreductive surgery (primary and intermediate cytoreduction). Stage IV patients preferably have had either a biopsy and / or primary or intermediate cytoreductive surgery.

[0050] Particularly preferred are cancers in patients who have completed first-line platinum (e.g., carboplatin or cisplatin) therapy (intravenous or intraperitoneal). The cancers most effectively treated by the therapy of the present invention are cancers in which the α-folate receptor is expressed, particularly cancers in which the α-folate receptor is expressed in the membrane and / or cytoplasm of at least 25% of the cancer cells. More effectively treated are cancers in which the α-folate receptor is expressed in at least 50% of the cancer cells on or within the cancer, and most effectively are cancers in which the α-folate receptor is expressed in at least 75% of the cancer cells on or within the cancer. Such levels can be determined by histological studies of biopsy tissue using an α-folate specific antibody conjugated to a visualizing agent as known in the art. The cancers with maximum efficacy are those in which FR-α is expressed on the cell membrane.

[0051] An example of a method for evaluating α-folate receptor expression on the cell membrane and in the cytoplasm is described in Kurosaki et al (2016) Int. J. Cancer: 138, 1994-2002 VC 2015 UICC, which studied tumor FR-α expression in FFPE (formalin-fixed paraffin-embedded) specimens from a total of 164 cases of EOC, including borderline malignancies, using the specific antibody NCL-L-FR alpha (clone BN3.2, Leica Biosystems, UK). Immunohistochemical staining was performed on whole-section slides using a BenchMark XT automated slide stainer and an iView DAB detection kit according to the manufacturer's instructions (Ventana Medical Systems, Tucson, AZ). The sections were deparaffinized, hydrated, antigen was retrieved using Cell Conditioning Solution 1 (Ventana Medical Systems), and then incubated for 30 minutes with a mouse monoclonal anti-FRA antibody (1:40 dilution). Positive staining was defined as the presence of membrane staining or membrane and cytoplasmic staining in tumor cells. Slides were scored with <1% positive tumor cell staining as negative, 1-25% positive tumor cell staining as weak (1+), 25-75% staining as moderate (2+), and >75% staining as strong (3+). Scoring of FR-α staining was evaluated in a blinded fashion by two independent observers. Disagreements were resolved by joint re-examination using a binocular microscope.

[0052] An alternative method for non-invasively confirming a patient's suitability for treatment using the present invention is to test for α-folate receptor in the blood. Such assays are described, for example, in Basal et al (2009) PLoS ONE 4(7):e6292. Doi:10.1371 / journal.pone.0006292, at least with respect to ovarian cancer. When the α-folate receptor is found on the membrane, it can be excreted into the circulating physiological fluid such as serum. The team discovered that in cases of ovarian cancer, the levels of circulating α-folate receptor (FRα) are elevated in patients with ovarian cancer. This was found to be true even when the cancer was in its early stages.

[0053] Kurosaki et al (2016) Int. J. Cancer: 138, 1994 - 2002 further supports the applicability of serum α-folate receptor levels for the diagnosis of epithelial ovarian cancer, correlating high serum FR-α with shorter PFS.

[0054] In addition to the cancers derived from the ovarian tissue specified above, FR-α overexpressing cancers suitable for treatment by the methods and dosing regimens of the present invention also include cancers of the uterus, mesothelium, kidney, stomach, lung, colon, choroid plexus, and brain. The highest levels of overexpression were detected in non-mucinous ovarian cancers in which tumors of over 90% of patients exhibit overexpression of FR-α (Toffoli et al., 1998), but high levels have also been shown in papillary serous endometrial cancer (Allard et al., 2007), renal cell carcinoma, and NSCLC (Parker et al., 2005). In addition, breast cancer, primary CNS, colon cancer, and gastric cancer exhibit varying degrees of expression (Low and Kularatne, 2009).

[0055] Table 1: Alpha-folate receptor expression in selected tumors (Weitman 1994, Garin-Chesa 1993, Bueno 2001)

[0056]

Table 1

[0057]

Chemical formula

[0058] (6RS) The racemate is also known to be the active form containing the active (6S) as depicted. When using the racemate, it will be understood that since it contains only 50% of the (6S) form, it may be necessary to use the higher end point of the dosage range as described.

[0059] When the compound is provided as an ester, this may be a simple alcohol ester that is bound to one or more of the carboxylate moieties that would be the sodium binding sites in the above formula if not an ester. The resulting alkyl ester may be any that is equivalent to the parent compound for regulatory purposes. Pharmaceutically acceptable ester forms of the cyclopenta[g]quinazoline suitable for the treatment of the present invention are, for example, esters with aliphatic alcohols having 6 or fewer carbon atoms, such as methyl, ethyl or tert-butyl esters. Since there are three carboxyl groups, the salt or ester may be a monoacid dibasic salt or ester, or a diacid monobasic salt or ester, or more preferably a tribasic salt or ester may be used.

[0060] Pharmaceutically acceptable salt forms of the compound suitable for the treatment of the present invention are, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid or maleic acid; or salts of alkali metals, such as sodium, alkaline earth metals, such as calcium or ammonium, such as tetra(2-hydroxyethyl)ammonium. Most preferred is the trisodium salt.

[0061] In the treatment of the present invention, the cyclopenta[g]quinazoline or salt is considered to function at least in part as an anticancer agent due to its ability to inhibit the enzyme thymidylate synthase.

[0062] The composition of cyclopenta[g]quinazoline or salt may be in a form suitable for oral use, such as tablets, capsules, aqueous or oily solutions, suspensions or emulsions; a form suitable for topical use, such as creams, ointments, gels or aqueous or oily solutions or suspensions; a form suitable for intranasal use, such as nasal sprays or nasal drops; a form suitable for intravaginal or rectal use, such as suppositories; a form suitable for administration by inhalation, such as fine powders, such as dry powders, microcrystalline forms or liquid aerosols; a form suitable for sublingual or buccal use, such as tablets or capsules; or a form suitable for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion use), such as sterile aqueous or oily solutions, emulsions or suspensions. Generally, the above compositions can be prepared by conventional methods using conventional excipients.

[0063] A preferred form of the compound is a form for parenteral administration. Particularly preferred is the compound for infusion, in which case the compound is preferably formulated using physiological saline or water for injection. Alternatively, it is provided in a solid state that can be immediately mixed with the above water or physiological saline. For example, it is the dihydrate of trisodium salt.

[0064] In addition to the cyclopenta[g]quinazoline used in the present invention, the composition may contain one or more other anticancer substances or palliative substances selected from, for example, other antimetabolites, DNA-interacting agents, immuno-oncology agents, tumor angiogenesis inhibitors or signal transduction inhibitors, or other inhibitors of deregulated pathways in tumors.

[0065] However, those skilled in the art will understand that it is more convenient to administer such combinations separately while coordinating them at the time of a treatment visit to the administration site. A specific dosing regimen that is preferably employed in combination with a compound for the treatment of cancer according to one aspect of the present invention is by one or more additional anti-cancer agents selected from cisplatin, carboplatin, doxorubicin, bevacizumab, gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, nanoparticle albumin-bound paclitaxel, Lynparza (olaparib), Rubraca (rucaparib), Zejula (niraparib), Tecentriq (atezolizumab), Bavercio (avelumab).

[0066] The combination therapy may include the combination of bevacizumab with paclitaxel, pegylated liposomal doxorubicin or topotecan. Further such combination examples are illustrated in the following examples.

[0067] Particularly advantageously, in a first aspect of the present invention, the doses employed in these combination drugs are lower than those currently prescribed. This is particularly due to the finding that resistance to BTG945 is not cross-resistant with respect to resistance to these other drugs, and that the desired toxic effects on the target cancer cells will often be cumulative. Thus, in addition to the exemplary dosing regimens provided in the examples herein, lower doses or less frequent doses of the additional drugs may be employed.

[0068] In a second aspect of the present invention, there is provided a method of treating a patient suffering from cancer that is of a type that is refractory or resistant or tends to be refractory or resistant to platinum-based therapy, where the treatment is, per administration, from 1 to 30 mg / m 2 of a dose of a compound of formula I for the treatment of cancer

[0069]

Chemical formula

[0070] The treatment preferably is by a dosing regimen that maintains the plasma concentration of the drug at 0.5 μM or more for at least 72 hours. More preferably, as a result of the dosing regimen, the plasma concentration of the drug becomes 1 - 5 μM over 72 hours or less, preferably 60 hours or less, immediately after dosing. Most preferably, the dosing regimen maintains a plasma concentration of the drug of 0.1 - 2 μM for at least 50% of the treatment cycle period.

[0071] The treatment preferably is ● a dose of 1 - 10 mg / m 2 administered on days 1, 8, 15 and 22 at 7 - day intervals in a 28 - day cycle, ● a dose of 6 - 14 mg / m 2 administered on days 1 and 15 at 14 - day intervals in a 28 - day cycle, ● a dose of 10 - 30 mg / m 2 administered on day 1 in a 21 - day cycle,

[0072] Treatment with a dose of 1 - 30 mg / m 2 is within the scope of the present invention, but the preferred dose is 3 - 30 mg / m 2 per patient body surface area per administration of the compound, more preferably 5 - 20 mg / m 2 per patient body surface area per administration of the compound, even more preferably 6 - 18 mg / m 2 per patient body surface area per administration of the compound, still more preferably 8 - 15 mg / m 2 , most preferably 10 - 15 mg / m 2 , particularly about 12 mg / m 2 , for example 11.5 - 12.5 mg / m 2 per patient body surface area per administration of the compound.

[0073] More preferably, specifically, the method treats by infusion of a dose at an interval of 10 to 28 days, more preferably at an interval of 10 to 21 days, and most preferably at an infusion interval of about 14 or 21 days. Even more preferably, when administered IV, the present invention treats with a cumulative maximum amount of 150 mg / m per patient body surface area taking into account all infusions 2 of the compound. More preferably, this limit also applies to IP dosing. More preferably, the maximum cumulative dose is 144 mg / m 2 .

[0074] The method according to the present invention preferably provides the compound as an infusion at 14-day or 21-day intervals in a 21-day cycle or a 28-day cycle, most preferably an infusion in a 28-day cycle. These cycles are preferably repeated until the maximum cumulative dose is reached. The infusion is preferably carried out over 0.5 to 3 hours. The infusion can be carried out over 0.5 to 1 hour, 1 hour, or less than 1 to 3 hours. The treatment can be effective at as little as 1 mg / m 2 or 3 mg / m 2 , so it will be understood that an infusion rate of 1 hour will be sufficient.

[0075] A more preferred dosage for each infusion is 1 to 20 mg / m 2 , more preferably 10 to 15 mg / m 2 . The most preferred dose is about 12 mg / m 2 . It can be seen that a dose of 12 mg / m 2 given once every 14 days in a 28-day cycle will reach the maximum cumulative recommended dose just before 6 months. This consists of 12 infusions of the compound at 12 mg / m 2 providing a total cumulative amount of 144 mg / m 2 . An even more preferred dosing schedule is a dose of 12 mg / m 2 given once every 21 days in a 21-day cycle. Further dosing may be considered, preferably as long as the attending clinician monitors for irreversible BOOP or similar side effects.

[0076] The method of the second aspect of the present invention further provides treatment with a compound of formula I in combination with a therapeutically effective amount of one or more additional anti-cancer agents. One or more additional anti-cancer agents used in this combination therapy are preferably selected from cisplatin, carboplatin, doxorubicin, bevacizumab, gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, nanoparticle albumin-bound paclitaxel, Lynparza (olaparib), Rubraca (rucaparib), Zejula (niraparib), Tecentriq (atezoizumab), Bavercio (avelumab), and Keytruda (pembrolizumab).

[0077] The combination of multiple agents may include the combination of bevacizumab with paclitaxel, pegylated liposomal doxorubicin, or topotecan. Further such combination examples are illustrated in the following examples.

[0078] Combination with paclitaxel or carboplatin or both is preferred. Considering the nature of the side effects observed in the failed clinical trials in the lungs, the inventor further contemplates that the dosing regimen of the present invention may incorporate the administration of a steroid that alleviates lung inflammation.

[0079] The third aspect of the present invention provides a method for treating a patient suffering from cancer, which is characterized by being of a type that is refractory or resistant or tends to be so to platinum-based therapy, wherein the treatment is administered once in combination with an anti-inflammatory corticosteroid, at a dose of 1 to 30 mg / m per patient's body surface area, of a compound of formula I 2 of the compound

[0080]

Chemical formula

[0081] In a fourth aspect of the present invention, the compound of formula I

[0082]

Chemical formula

[0083] More preferably, the dosage unit of the present invention contains 1 to 30 mg of the compound of formula I or a salt or ester thereof. Even more preferably, the dosage unit contains 5 to 26 mg of the compound of formula I. Most preferably, the dosage unit contains 10 to 24 mg of the compound or salt or ester of formula I.

[0084] Preferred dosage forms will be containers of the compound of formula I or a salt or ester thereof, more preferably the sodium salt, as a sterile solid or an aqueous solution in a medium such as water for injection or physiological saline. The sterile solid is preferably BTG945 or a salt or ester thereof that does not contain other materials. Such a container is capable of collecting in a syringe in an amount suitable for the patient's body surface area so as to transfer the required dose of 1 to 30 mg / m 2 of the liquid contained therein or the liquid added thereto when the solid state is provided.

[0085] Preferably, a dosage is provided as an aqueous solution within a vial. Such a dosage form or formulation will preferably be a vial containing an aqueous solution of the compound for treatment in an amount of 1 to 30 ml, more preferably 1 to 20 ml, even more preferably 1 to 10 ml, and most preferably 2 to 6 ml. Alternatively, a dosage is provided as a solid form of the compound for treatment without liquid. Thus, a preferred vial of the present invention will contain 0.5 to 40 mg of the compound in 1 to 30 ml of an aqueous solution, even more preferably 5 to 26 mg in 1 to 20 ml of an aqueous solution, most preferably 10 to 24 mg in 1 to 10 ml of an aqueous solution, for example about 6 mg or 12 mg in 2 to 6 ml of an aqueous solution.

[0086] One skilled in the art will understand that pharmaceuticals are expensive commodities and it is desirable not to waste compounds that are not necessary for a given treatment. Since BTG945 is potentially toxic when exceeding the dosages taught herein, it would be inappropriate to provide more than necessary in a clinical setting. Thus, a preferred dosage per unit surface area of the patient is 6 mg / m 2 or 12 mg / m 2 and in developed countries patients typically have a surface area of 1 to 2.5 m 2 and patients with an unusually high BMI are often capped at 2 m 2 so that a novel preferred usable vial content will be 6 to 24 mg of the drug compound, more preferably 10 to 24 mg of the drug compound, whether in dry solid or solution form. Thus, vials with drug contents of 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg and 24 mg are disclosed as novel embodiments of the present invention. In particular, those in which the drug is in the form of dry BTG945 salt and / or its hydrate, or a simple solution thereof in water for injection or physiological saline are disclosed.

[0087] The compound for treatment of the present invention can be synthesized as described in the aforementioned patent applications or as shown in the more recent patents US8809526 (Onyx) and patent application US2013 / 0345423 (Onyx).

[0088] Figures 1 to 5 show the clinical results of the clinical trials of the treatment according to the present invention in humans.

Brief Description of the Drawings

[0089]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0090] (Example) The present invention will be illustrated herein by the following non-limiting examples. Those skilled in the art will be able to conceive of further embodiments in view of these.

[0091] The preferred target cancers to be treated by the dosing regimens of the following examples would be those of patients having the following: ● Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer.

[0092] ● Platinum-resistant / refractory diseases, defined respectively as disease progression (resistance) within 180 days after the last administration of platinum therapy, or lack of response or disease progression (refractoriness) during the most recent platinum-based therapy.

[0093] ● Having received no more than three chemotherapies for platinum-sensitive diseases, with the most recent one containing platinum, and having not previously received therapy for platinum-resistant diseases. Example 1: Treatment of patients with 1 - 12 mg / m 2 of BTG945 (compound of formula II in trisodium salt form).

[0094] Method: Using a 3 + 3 dose-escalation design, two IV schedules were investigated. Schedule A was weekly dosing (QW), and Schedule B was once every two weeks dosing (Q2W). The cycle consisted of four weeks, and treatment was ended after six cycles in both schedules. An expanded cohort was initiated to evaluate the clinical activity of patients with high-grade serous ovarian cancer (HGSOC) overexpressing FR-α.

[0095] Results: Twenty-one patients were treated each in Schedules A and B, investigating doses in the ranges of 1 - 6 mg / m 2 and 2 - 12 mg / m 2 respectively. The dose-limiting toxicity in Schedule A was G3 cellulitis, and no dose-limiting toxicity was seen in Schedule B. The most common toxicities were fatigue 15 / 42 (36%), nausea 9 / 42 (21%), and taste disturbance 5 / 42 (12%). Among the patients in Schedule A at 4 mg / m2, two patients each developed drug-related changes suspected in pulmonary function tests (decrease in Dlco > 15%) in Cycles 5 and 6. No cases of suspected drug-related decrease in Dlco were observed in the patients treated in Schedule B. Grade 3 - 4 diarrhea, mucositis, or neutropenia were not seen in either cohort. 12 mg / m 2The Cmax, AUC, and half-life were 4952 ng / mL, 85170 h·ng / mL, and 26 hours, respectively. Preclinical PK-PD modeling aimed to achieve concentrations of 0.05 - 1 μM, which was achieved over a 48-hour period at a dose of 4 mg / m 2 or higher. Concentrations higher than 0.5 μM were achieved over 72 hours at a dose of 6 mg / m

[0096] or higher. Evidence of thymidylate synthase inhibition was observed using FLT PET imaging. See Cancer Res 68.3827-3834.2008 (Pillai et al). 2 Based on safety and PK, the recommended Phase II dose (RP2D) of BTG945 (which was ONX801) was 12 mg / m

[0097] Q2W, and an expansion in patients with HGSOC was initiated. Five patients with HGSOC had a partial response (PR) in the dose-escalation cohort. In the expansion cohort of patients with HGSOC, 5 / 11 patients had a PR as of the date of this application. Archived samples from 8 / 11 patients in the expansion cohort were analyzed. Four out of four AFR+ve patients had a PR after treatment with BTG945, while none of the four AFR-ve patients had a PR. RECIST and CA125 responses are shown in Figures 1 - 4. 2 Conclusion: The RP2D of BTG945 is 12 mg / m

[0098] Q2W. At the RP2D, multiple patients with AFR-overexpressing HGSOC had a PR, warranting further randomized Phase II trials defined by biomarkers. Example 2: Combination therapy with BTG945 and other anticancer therapies. 2 On days 1 and 15 of a 28-day cycle, administer 12 mg / m

[0099] of BTG945 IV over 1 hour in injection saline up to a maximum of 6 cycles. Along with this treatment, administer one or more of the following exemplary dosing schedules as follows: 2 ​Example 2.1 Liposomal doxorubicin at 40 - 50 mg / m is administered IV over 30 minutes 2 ; every 21 days Example 2.2 Gemcitabine at 1000 mg / m is administered IV over 30 minutes on days 1 and 8 2 ; every 21 days Example 2.3 Topotecan at 1.25 - 1.5 mg / m is administered IV over 30 minutes on days 1 - 5 2 ; every 21 days Example 2.4 Paclitaxel at 80 mg / m is administered IV over 1 hour weekly 2 Example 2.5 Docetaxel at 75 - 100 mg / m is administered IV over 1 hour every 21 days 2 Example 2.6 Etoposide at 50 mg / m is administered PO daily for 21 days every 28 days 2 / day Example 2.7 Nanoparticle albumin - bound paclitaxel at 100 mg / m is administered IV over 30 minutes weekly (days 1, 8, and 15) every 28 days Example 2.8 In any cycle of chemotherapy, Keytruda at 200 mg is administered IV with 945 every 3 weeks

[0100] Example 3: Combination therapy with BTG945 and other anticancer therapies for platinum - sensitive cancer BTG945 at 12 mg / m in injectable saline is administered IV over 1 hour on days 1 and 15 of a 28 - day cycle up to a maximum of 6 cycles 2 This treatment is combined with one or more of the following exemplary dosing schedules as follows: Example 3.1 Subject to the disease being responsive, paclitaxel at 135 mg / m is administered IV over 24 hours on day 1, and cisplatin at 100 mg / m 2 is administered IP on day 2 (the dose may be reduced to 75 mg / m 2 ), and paclitaxel at 60 mg / m 2 is administered IP on day 8 over 6 cycles or more. The cisplatin dose on day 2 may be reduced to 75 mg / m2 IP. Some clinicians may administer 135 mg / m 2 IV over 3 hours2 On the first day, both paclitaxel [[ID=]] 2 is given to outpatients, followed by cisplatin at 75 mg / m2 IP Example 3.2 Carboplatin treatment. The normal range of carboplatin AUC for the treatment of ovarian cancer is 5 - 7.5. Patients who have previously received extensive chemotherapy or radiation must start with AUC < 5.

[0101] Example 4: Combination therapy with BTG945 and other anticancer therapies for platinum - sensitive cancers where the patient cannot tolerate IP administration. On days 1 and 15 of a 28 - day cycle, 12 mg / m 2 of BTG945 in injectable saline is administered IV over 1 hour up to a maximum of 6 cycles. Along with this treatment, one or more of the following exemplary dosing regimens are carried out as follows: Example 4.1 Paclitaxel at 175 mg / m2 IV over 3 hours and carboplatin at AUC 7.5 IV over 1 hour on day 1; every 21 days for 6 cycles, or Example 4.2 Docetaxel at 75 mg / m2 IV over 1 hour and carboplatin at AUC 5 IV over 1 hour on day 1; every 21 days for 6 cycles.

[0102] Example 5: Combination therapy with BTG945 and other anticancer therapies for platinum - sensitive stage III and IV platinum - sensitive recurrent cancers. Platinum - sensitive recurrence: If recurrence occurs more than 6 months after the first or subsequent complete clinical response to platinum - containing chemotherapy, 12 mg / m 2 of BTG945 in injectable saline is administered IV over 1 hour on days 1 and 15 of a 28 - day cycle up to a maximum of 6 cycles. The patient must be treated according to one of the following IV platinum - containing combination therapy regimens. The choice is influenced by factors such as existing comorbidities, previous toxicities, and the preferences of the physician and patient. The dosing regimens are as follows: Example 5.1 IV of carboplatin at AUC 5 and liposomal doxorubicin at 30 mg / m IV over 30 minutes2 ; Every 28 days over 6 cycles Example 5.2 Paclitaxel at 175 mg / m2 over 3 hours IV and carboplatin (Calvert) of AUC5 over 1 hour IV; Every 21 days over 6 cycles Example 5.3 Paclitaxel at 80 mg / m over 1 hour IV on days 1, 8, and 15 every week 2 and carboplatin at AUC6 over 1 hour IV on day 1; Every 21 days over 6 cycles Example 5.4 Docetaxel at 75 mg / m over 1 hour IV 2 and carboplatin at AUC5 over 1 hour IV; Every 21 days over 6 cycles Example 5.5 Gemcitabine at 1000 mg / m over 30 minutes IV on days 1 and 8 2 and carboplatin at AUC4 over 1 hour IV on day 1; Every 21 days over 6 cycles.

[0103] Example 6: Combination therapy with BTG945 and other anticancer therapies for platinum-sensitive stage III and IV platinum-sensitive recurrent cancer Bevacizumab may be considered alone or in combination with carboplatin / gemcitabine, but the use of this agent is still under discussion. Platinum-sensitive recurrence: If recurrence occurs more than 6 months after the first or subsequent complete clinical response to platinum-containing chemotherapy, 12 mg / m in normal saline for injection administered over 1 hour IV on days 1 and 15 of a 28-day cycle up to a maximum of 6 cycles 2 of BTG945, in combination with one of the following IV platinum-containing combination therapy regimens, the patient must be treated.

[0104] Example 6.1 Bevacizumab at 15 mg / kg IV (initially over 90 minutes, then over 60 minutes, and finally over 30 minutes for the next infusion); Every 21 days until disease progression regardless of prior platinum response Example 6.2 Gemcitabine at 1000 mg / m over 30 minutes IV on days 1 and 8 until disease progression or unacceptable toxicity 2On the first day, carboplatin of AUC4 was administered by intravenous injection; every 21 days for 6 to 10 cycles, and furthermore, 15 mg / kg of bevacizumab was administered IV on the first day prior to gemcitabine and carboplatin. Example 6.3 One of the following IV chemotherapy regimens in combination with 10 mg / kg of bevacizumab IV every 14 days: paclitaxel, pegylated liposomal doxorubicin or topotecan (topotecan is administered once a week). Example 6.4 Topotecan (every 21 days) in combination with 15 mg / kg of bevacizumab IV every 21 days. Example 6.5 15 mg / kg of bevacizumab IV (initially over 90 minutes, then over 60 minutes, and finally over 30 minutes for the next infusion); every 21 days until disease progression. Example 6.6 Every 28 days, 10 mg / kg of bevacizumab IV on days 1 and 15, and 4 mg / m² of topotecan IV on days 1, 8 and 15.

[0105] Example 7: Combination therapy with BTG945, and platinum-sensitive or resistant or refractory BRCA-mutated stage III and IV platinum-sensitive recurrent cancers. Among patients previously treated with chemotherapy three or more times, for patients diagnosed with BRCA mutation (detected by the FDA-approved test, BRACAnalysis CDxTM): 12 mg / m in IV over 1 hour in normal saline for injection on days 1 and 15 of a 28-day cycle, up to a maximum of 6 cycles of BTG945 are administered, and at the same time, 400 mg of olaparib is administered PO twice daily continuously. 2 In the European Union, 400 mg of olaparib twice daily PO is approved as a monotherapy for maintenance therapy in adult patients with platinum-sensitive recurrent BRCA mutations (germline and / or somatic), high-grade serous epithelial, fallopian tube or primary peritoneal cancer who have shown (complete and partial) response to platinum-based chemotherapy.

[0106]

[0107] (Appendix) (Appendix 1) A compound of formula I for the treatment of cancer

[0108] [Chemical formula] or a pharmaceutically acceptable salt or ester thereof, wherein, (i) the cancer is of a type characterized by being refractory or resistant to platinum-based therapy or having a tendency to become so, and further (ii) the treatment is by a dose of the compound of 1 to 30 mg / m per patient body surface area per administration 2 of the compound.

[0109] (Appendix 2) A compound for the treatment according to Appendix 1, characterized in that the cancer is platinum-refractory or resistant.

[0110] (Appendix 3) A compound for the treatment according to Appendix 1, characterized in that the cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, and cancers derived from one of these.

[0111] (Appendix 4) A compound for the treatment according to Appendix 1, Appendix 2 or Appendix 3, characterized in that it is selected from those in which α-folate receptor (FR-α) is expressed.

[0112] (Appendix 5) A compound for the treatment according to Appendix 4, characterized in that the cancer expresses α-folate receptor at a level higher than that of non-cancerous tissue background.

[0113] (Appendix 6) A compound for the treatment according to any one of the preceding appendices, characterized in that the cancer is ovarian cancer.

[0114] (Appendix 7) A compound for the treatment according to any one of the preceding claims, wherein the cancer is an epithelial ovarian, fallopian tube or peritoneal cancer.

[0115] (Appendix 8) A compound for the treatment according to Appendix 6 or Appendix 7, wherein the cancer is a serous ovarian cancer.

[0116] (Appendix 9) A compound for the treatment according to Appendix 8, wherein the cancer is a high-grade serous ovarian cancer (HGSOC).

[0117] (Appendix 10) A compound for the treatment according to any one of the preceding claims, wherein the dose is administered intraperitoneally (IP) or intravenously (IV).

[0118] (Appendix 11) The dose is 3 - 30 mg / m per patient body surface area per administration 2 A compound for use according to any one of the preceding claims, wherein the compound is such.

[0119] (Appendix 12) A compound according to any one of the preceding claims, wherein the treatment administers each dose as individual infusions at 10 - 28 day intervals.

[0120] (Appendix 13) A compound according to Appendix 12, wherein the infusion is at 10 - 21 day intervals. (Appendix 14) A compound according to Appendix 13, wherein the infusion is performed at a dosing interval of about 14 days.

[0121] (Appendix 15) The treatment is with a compound having a cumulative maximum amount of 150 mg / m per patient body surface area throughout all said infusions 2 A compound according to Appendix 14, wherein the compound is such.

[0122] (Supplementary Note 16) wherein the maximum cumulative dose is 144 mg / m 2 The compound according to Supplementary Note 15, characterized in that it is as described above.

[0123] (Supplementary Note 17) wherein the treatment is by infusion at 1 to 20 mg / m per administration 2 The compound according to any one of the preceding supplementary notes, characterized in that it is as described above.

[0124] (Supplementary Note 18) wherein the treatment is by infusion at 10 to 15 mg / m per administration 2 The compound according to Supplementary Note 17, characterized in that it is as described above.

[0125] (Supplementary Note 19) wherein the treatment is by infusion at approximately 12 mg / m per administration 2 The compound according to Supplementary Note 16, characterized in that it is as described above.

[0126] (Supplementary Note 20) The compound according to any one of Supplementary Notes 1 to 19, characterized in that the dose is added to the drip of physiological saline.

[0127] (Supplementary Note 21) Trisodium salt of Formula II

[0128] [Chemical formula] The compound for use according to any one of the preceding supplementary notes, characterized in that it is as described above. (Supplementary Note 22) A method for treating a patient suffering from cancer, which has the characteristic of being refractory or resistant to platinum-based therapy or having a tendency to become so, wherein the treatment is, per administration, a compound of 1 to 30 mg / m per patient's body surface area 2 for the treatment of cancer of the compound of Formula I

[0129] [Chemical formula] The method as described above, which is by the compound or a pharmaceutically acceptable salt or ester thereof. (Appendix 23) The method as described in Appendix 22, wherein the treatment is as described in any one of Appendices 1 to 21.

[0130] (Appendix 24) The method as described in Appendix 22 or Appendix 23, wherein the treatment by the compound of formula I is provided in combination with a dosing regimen that administers one or more additional anti-cancer agents in a therapeutically effective amount.

[0131] (Appendix 25) The method as described in Appendix 24, wherein the treatment comprises administering a composition comprising the compound of formula I and the one or more additional anti-cancer agents.

[0132] (Appendix 26) The method as described in Appendix 24, wherein the compound of formula I and the one or more additional anti-cancer agents are administered separately.

[0133] (Appendix 27) The method as described in Appendix 24, wherein the administration of the compound of formula I and the administration of the one or more additional anti-cancer agents are separated by 12 hours.

[0134] (Appendix 28) The method as described in Appendix 24, wherein the administration of the compound of formula I and the administration of the one or more additional anti-cancer agents are separated by 24 hours.

[0135] (Appendix 29) The method as described in Appendix 24, wherein the administration of the compound of formula I and the administration of the one or more additional anti-cancer agents are separated by 36 hours.

[0136] (Appendix 30) The method according to appended claim 24, wherein the administration of the compound of formula I and the administration of the one or more further anti-cancer agents are separated by 38 hours.

[0137] (Appended claim 31) The method according to appended claim 24, wherein the administration of the compound of formula I and the administration of the one or more further anti-cancer agents are carried out in alternating weeks of a 7-day dosing schedule.

[0138] (Appended claim 32) The method according to appended claim 24, wherein the administration of the compound of formula I and the administration of the one or more further anti-cancer agents are carried out in alternating weeks of a 14-day dosing schedule.

[0139] (Appended claim 33) The method according to appended claims 24 to 32, wherein the one or more further anti-cancer agents used in this combination therapy are selected from cisplatin, carboplatin, doxorubicin, bevacizumab, gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, nanoparticle albumin-bound paclitaxel, Lynparza (olaparib), Rubraca (rucaparib), Zejula (niraparib), Tecentriq (atezolizumab), Bavercio (avelumab).

[0140] (Appended claim 34) The method according to appended claims 24 to 32, wherein the treatment comprises a combination of administering the compound of formula I together with a dosing regimen of administering bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan.

[0141] (Appended claim 35) Compound of formula I

[0142]

Chemical formula

[0143] (Appendix 36) The dosage form according to Appendix 35, containing 0.5 to 40 mg of the compound of formula I or a salt or ester thereof.

[0144] (Appendix 37) The dosage form according to Appendix 35 or 36, containing 1 to 30 mg of the compound of formula I or a salt or ester thereof.

[0145] (Appendix 38) The dosage form according to Appendix 35, 36, or 37, containing 5 to 26 mg of the compound of formula I or a salt or ester thereof.

[0146] (Appendix 39) The dosage form according to Appendix 35, 36, 37, or 38, containing 10 to 24 mg of the compound of formula I or a salt or ester thereof.

[0147] (Appendix 40) The dosage form according to any one of Appendices 35 to 39, characterized by comprising a container of the compound of formula I or a salt or ester thereof.

[0148] (Appendix 41) The dosage form according to Appendix 40, characterized by containing a sodium salt as a sterile solid or aqueous solution.

[0149] (Appendix 42) The dosage form according to Appendix 41, characterized in that the aqueous solution is an aqueous solution of the compound in water for injection or physiological saline.

[0150] (Appendix 43) The dosage form according to any one of Appendices 35 to 42, characterized by being a vial containing an aqueous solution of the compound, salt, or ester.

[0151] (Appendix 44) The dosage form described in Appendix 43, containing 1 to 40 mg of the compound of formula I or a salt or ester thereof.

[0152] (Appendix 45) The dosage form described in any one of Appendices 35 to 44, characterized by comprising a vial containing 1 to 40 mg of the compound of formula I or a salt or ester thereof in the form of a dry solid or an aqueous solution.

[0153] (Appendix 46) The dosage form described in Appendix 45, containing 5 to 30 mg of the compound of formula I or a salt or ester thereof.

[0154] (Appendix 47) The dosage form described in any one of Appendices 35 to 46, characterized by comprising a vial containing 5 to 30 mg of the compound of formula I or a salt or ester thereof in the form of a dry solid or an aqueous solution.

[0155] (Appendix 48) The dosage form described in Appendix 47, containing 10 to 24 mg of the compound of formula I or a salt or ester thereof.

[0156] (Appendix 49) The dosage form described in any one of Appendices 35 to 48, characterized by comprising a vial containing 10 to 24 mg of the compound of formula I or a salt or ester thereof in the form of a dry solid or an aqueous solution.

[0157] (Appendix 50) For the treatment of cancer Formula I

[0158] [Chemical formula] and formula II

[0159] [Chemical formula] and a compound selected from the group consisting of a pharmaceutically acceptable salt or ester thereof, (i) characterized in that said cancer is of a type that is refractory or resistant or tends to become so to platinum-based therapy; (ii) said treatment being by a dose of the compound of 1 to 30 mg / m 2 per patient body surface area per administration; (iii) said dose being administered intraperitoneally (IP), said compound.

[0160] (Appendix 51) A method of treating a patient suffering from a cancer characterized in that it is of a type that is refractory or resistant or tends to become so to platinum-based therapy, said treatment being by a dose of the compound of 1 to 30 mg / m 2 per patient body surface area per administration of a compound of formula I for said treatment of cancer

[0161]

Chemical formula

[0162] (Appendix 52) The method according to Appendix 51, wherein said treatment with said compound of formula I is given in combination with a dosing regimen that administers one or more additional anti-cancer agents in a therapeutically effective amount.

[0163] (Appendix 53) For said treatment of cancer Formula I

[0164]

Chemical formula

[0165] [Chemical] and a compound selected from the pharmaceutically acceptable salts or esters thereof, (i) having the feature that said cancer is of a type that is refractory or resistant to platinum-based therapy or tends to become so; (ii) said treatment being by a dose of the compound of 1 to 30 mg / m 2 per patient body surface area per administration; (iii) said compound in which at least one side effect associated with classical thymidylate synthase inhibitors or alpha folate receptor antibody-drug conjugates is not observed.

[0166] (Appendix 54) The compound according to Appendix 53, wherein said at least one side effect is selected from neutropenia, diarrhea, alopecia, blurred vision or nausea.

[0167] (Appendix 55) The compound for the treatment according to Appendix 53 or Appendix 54, characterized in that said cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, and cancers derived from one of these.

[0168] (Appendix 56) The compound for the treatment according to Appendix 53, Appendix 54 or Appendix 55, characterized in that it is selected from those in which alpha-folate receptor (FR-α) is expressed.

[0169] (Appendix 57) The compound for the treatment according to Appendix 56, characterized in that said cancer expresses alpha-folate receptor at a level higher than that of non-cancerous tissue background.

[0170] (Appendix 58) The compound for the treatment according to any one of Appendices 53 to 57, characterized in that said cancer is ovarian cancer.

[0171] (Supplementary Note 59) A compound for treatment according to any one of Supplementary Notes 53 to 58, wherein the cancer is an epithelial ovarian, fallopian tube or peritoneal cancer.

[0172] (Supplementary Note 60) A compound for treatment according to Supplementary Note 58 or Supplementary Note 59, wherein the cancer is a serous ovarian cancer.

[0173] (Supplementary Note 61) A compound for treatment according to Supplementary Note 60, wherein the cancer is a high-grade serous ovarian cancer (HGSOC).

[0174] (Supplementary Note 62) A compound for treatment according to any one of Supplementary Notes 53 to 61, wherein the dose is administered intraperitoneally (IP) or intravenously (IV).

[0175] (Supplementary Note 63) The dose is 3 - 30 mg / m per patient body surface area per administration 2 A compound for use according to any one of Supplementary Notes 53 to 62, which is a compound of.

[0176] (Supplementary Note 64) A compound according to any one of Supplementary Notes 53 to 63, wherein the treatment is administered as individual infusions at 10 - 28 day intervals for each dose.

[0177] (Supplementary Note 65) A compound according to Supplementary Note 64, wherein the infusions are at 10 - 21 day intervals. (Supplementary Note 66) A compound according to Supplementary Note 65, wherein the infusions are performed at a dosing interval of about 14 days.

[0178] (Supplementary Note 67) The treatment is 150 mg / m per patient body surface area throughout all the infusions 2The compound according to appended note 66, characterized in that it is by the compound with the maximum cumulative amount.

[0179] (Appended note 68) The compound according to appended note 67, characterized in that the maximum cumulative dose is 144 mg / m 2

[0180] (Appended note 69) The compound according to any one of appended notes 53 to 68, characterized in that the treatment is by infusion of 1 to 20 mg / m per administration 2

[0181] (Appended note 70) The compound according to appended note 69, characterized in that the treatment is by infusion of 10 to 15 mg / m per administration 2

[0182] (Appended note 71) The compound according to appended note 68, characterized in that the treatment is by infusion of about 12 mg / m per administration 2

[0183] (Appended note 72) The compound according to any one of appended notes 53 to 71, characterized in that the dose is added to the drip of physiological saline

[0184] (Appended note 73) Trisodium salt of formula II

[0185]

Chemical formula

[0186] (Appended note 74) For the treatment of cancer Formula I

[0187]

Chemical formula

[0188] [Chem.] , and a compound selected from the pharmaceutically acceptable salts or esters thereof, wherein (i) said cancer is of a type that is refractory or resistant to platinum-based therapy or has a tendency to become so, (ii) said treatment is by a dose that achieves a concentration of about 0.5 μM or more of said compound over at least 72 hours, said compound.

[0189] (Appendix 75) The compound according to Appendix 74, wherein said treatment is by a dose that achieves a concentration of about 0.7 μM or more of said compound over at least 36 hours.

[0190] (Appendix 76) The compound according to Appendix 74, wherein said treatment is by a dose that achieves a concentration of about 0.9 μM or more of said compound over at least 24 hours.

[0191] (Appendix 77) The compound for the treatment according to Appendix 74, Appendix 75 or Appendix 76, wherein said cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, and cancer derived from one of these.

[0192] (Appendix 78) The compound for the treatment according to Appendix 74, Appendix 75, Appendix 76 or Appendix 77, wherein it is selected from those in which α-folate receptor (FR-α) is expressed.

[0193] (Appendix 79) A compound for the treatment according to appended note 78, wherein the cancer expresses higher than the non-cancerous tissue level with α-folate receptor as the background.

[0194] (Appended note 80) A compound for the treatment according to any one of appended notes 74 to 79, wherein the cancer is ovarian cancer.

[0195] (Appended note 81) A compound for the treatment according to any one of appended notes 74 to 80, wherein the cancer is cancer of the epithelial ovary, fallopian tube or peritoneum.

[0196] (Appended note 82) A compound for the treatment according to appended note 80 or appended note 81, wherein the cancer is serous ovarian cancer.

[0197] (Appended note 83) A compound for the treatment according to appended note 82, wherein the cancer is high-grade serous ovarian cancer (HGSOC).

[0198] (Appended note 84) A compound for the treatment according to any one of appended notes 74 to 83, wherein the dosage is administered intraperitoneally (IP) or intravenously (IV).

[0199] (Appended note 85) The dosage is 3 to 30 mg / m per patient body surface area per administration 2 A compound for use according to any one of appended notes 74 to 84, which is a compound characterized by this.

[0200] (Appended note 86) A compound according to any one of appended notes 74 to 85, wherein the treatment is administered with each dosage as individual infusions at 10 to 28-day intervals.

[0201] (Appended note 87) A compound according to appended note 86, wherein the infusion is at 10 to 21-day intervals. (Supplementary Note 88) The compound according to Supplementary Note 87, characterized in that the infusion is carried out at a dosing interval of about 14 days.

[0202] (Supplementary Note 89) The compound according to Supplementary Note 88, characterized in that the treatment is with a compound having a cumulative maximum amount of 150 mg / m per patient body surface area throughout all the infusions. 2

[0203] (Supplementary Note 90) The compound according to Supplementary Note 89, characterized in that the maximum cumulative dose is 144 mg / m. 2

[0204] (Supplementary Note 91) The compound according to any one of Supplementary Notes 74 to 90, characterized in that the treatment is by an infusion of 1 to 20 mg / m per administration. 2

[0205] (Supplementary Note 92) The compound according to Supplementary Note 91, characterized in that the treatment is by an infusion of 10 to 15 mg / m per administration. 2

[0206] (Supplementary Note 93) The compound according to Supplementary Note 90, characterized in that the treatment is by an infusion of about 12 mg / m per administration. 2

[0207] (Supplementary Note 94) The compound according to any one of Supplementary Notes 74 to 93, characterized in that the dose is added to an intravenous drip of physiological saline.

[0208] (Supplementary Note 95) Trisodium salt of Formula II

[0209]

Chemical Formula

[0210] (Appendix 96) A compound of formula I for manufacturing a medicament for the treatment of cancer

[0211] [Chemical formula] Or use of a pharmaceutically acceptable salt or ester thereof, (i) having the feature that the cancer is of a type that is refractory or resistant to platinum-based therapy or tends to become so, (ii) the treatment being by a dose of the compound of 1 to 30 mg / m per patient body surface area per administration, 2 said use.

[0212] (Appendix 97) The treatment is ● A dose of 1 to 10 mg / m administered on days 1, 8, 15, and 22 at 7-day intervals in a 28-day cycle, 2 ● A dose of 6 to 14 mg / m administered on days 1 and 15 at 14-day intervals in a 28-day cycle, ● A dose of 10 to 30 mg / m administered on day 1 in a 21-day cycle, 2 ● A dose of 10 to 30 mg / m administered on day 1 in a 21-day cycle, ● A dose of 10 to 30 mg / m administered on day 1 in a 21-day cycle, 2 The compound according to Appendix 1, which is by a dosing schedule selected from the group of doses.

[0213] (Appendix 98) The dosing schedule is a dose of 10 to 14 mg / m administered on days 1 and 15 at 14-day intervals in a 28-day cycle, 2 The compound according to Appendix 97.

[0214] (Appendix 99) The dosing schedule is a dose of 10 to 14 mg / m administered on day 1 in a 21-day cycle, 2 The compound according to Appendix 97.

[0215] (Appendix 100) A compound of formula I for the treatment of cancer

[0216] [Chemical formula] A pharmaceutical composition for the treatment of cancer, comprising the compound of formula I or a pharmaceutically acceptable salt or ester thereof, (i) having the characteristic that the cancer is of a type that is refractory or resistant to platinum-based therapy or tends to become so, (ii) the treatment being by a dose of the compound of 1 to 30 mg / m 2 per patient body surface area per administration, said pharmaceutical composition.

Claims

1. A pharmaceutical composition for treating cancer, comprising: The pharmaceutical composition comprises a compound of formula I: 【Chemical 21】 A compound of formula II, 【Chemical 22】 and a pharmaceutically acceptable salt or ester thereof, the cancer is characterized as being of a type that is or is prone to become refractory or resistant to platinum-based therapy; The compound or the pharmaceutically acceptable salt or ester thereof is A pharmaceutical composition formulated for administration to a patient at a dose that achieves a blood concentration of the compound of 0.5 μM or greater for at least 72 hours.

2. The pharmaceutical composition of claim 1, wherein the blood concentration level of the compound does not exceed 1 μM for longer than 72 hours.

3. The pharmaceutical composition of claim 1, wherein the compound or the pharmaceutically acceptable salt or ester thereof is formulated for administration to a patient at a dose that achieves a blood concentration of the compound of 0.7 μM or greater for at least 36 hours.

4. The pharmaceutical composition of claim 1, wherein the compound or the pharmaceutically acceptable salt or ester thereof is formulated for administration to a patient at a dose that achieves a blood concentration of the compound of 0.9 μM or greater for at least 24 hours.

5. The pharmaceutical composition described in claim 1, wherein the cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, and cancers derived from one of these.

6. The pharmaceutical composition described in claim 1, wherein the cancer is selected from those in which the alpha-folate receptor (FR-α) is expressed.

7. The pharmaceutical composition described in claim 6, wherein the cancer expresses alpha-folate receptors at levels higher than background non-cancerous tissue levels.

8. The pharmaceutical composition described in claim 1, wherein the cancer is ovarian cancer.

9. The pharmaceutical composition described in claim 8, wherein the ovarian cancer is epithelial ovarian, fallopian tube or peritoneal cancer.

10. The pharmaceutical composition described in claim 9, wherein the ovarian cancer is serous ovarian cancer.

11. The pharmaceutical composition described in claim 10, wherein the serous ovarian cancer is high-grade serous ovarian cancer (HGSOC).

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for intraperitoneal (IP) or intravenous (IV) administration.

13. The pharmaceutical composition of claim 1, wherein the dose per administration is 3 to 30 mg / m 2 of the compound or the pharmaceutically acceptable salt or ester thereof per patient's body surface area.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for administration as an infusion with each dose administered at intervals of 10 to 28 days.

15. The pharmaceutical composition of claim 14, wherein the infusion is at 14-day intervals.

16. The pharmaceutical composition of claim 15, wherein said treatment is said compound or said pharmaceutically acceptable salt or ester thereof at a cumulative maximum amount of 150 mg / m 2 of patient body surface area throughout all said infusions.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for administration by infusion at a dose of 1 to 20 mg / m 2 of the compound or the pharmaceutically acceptable salt or ester thereof per patient body surface area per administration.

18. The pharmaceutical composition of claim 17, wherein the dose is 12 mg / m 2 of the compound or the pharmaceutically acceptable salt or ester thereof per patient body surface area per administration.

19. The pharmaceutical composition of claim 1, wherein the dose is added to an infusion of saline.

20. The compound of claim 1, wherein the compound is a trisodium salt of Formula II 【Chemical 23】 The pharmaceutical composition of claim 1, wherein

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