Treatment of platinum-resistant cancers

Abstract

A pharmaceutical composition for treating cancer is provided, which is characterized by using a specific dose at a specific administration interval. A pharmaceutical composition for treating cancer comprises a compound of formula I, or a pharmaceutically acceptable salt or ester thereof. JPEG2023065427000023.jpg42129 (i) the cancer is refractory or resistant to platinum-based therapy, and (ii) the pharmaceutical composition is administered in an amount of 1 to 30 mg / m per patient's body surface area per administration. 2 The compound is administered at a dose of 0.05 mg / kg. Methods of treatment using the pharmaceutical composition and novel dosage forms are also provided. In particular, ovarian cancer, including epithelial ovarian, fallopian tube, or peritoneal cancer, particularly those in which the alpha-folate receptor is overexpressed, is treated.

Description

[Technical field]

[0001] The present invention relates to a novel treatment for cancer, more particularly for cancers that are often resistant or refractory to platinum-based therapy. The cancers to be treated include, in particular, ovarian, endometrial, mesothelial and non-small cell lung (NSCL) cancers, and cancers derived therefrom. More particularly preferred treatments are provided for cancers derived from the ovary, such as epithelial ovarian, fallopian tube and peritoneal cancers. [Background technology]

[0002] Most particularly, the present invention provides novel treatments for cancers that possess alpha-folate receptors (FR-α), particularly those that express alpha-folate receptors at levels higher than background non-cancerous tissue levels, particularly those that have such FR-α on their cell membrane surfaces.Cancers suitable for treatment by the present invention also include breast and lung cancers that express FR-α, particularly triple-negative breast cancers.

[0003] The 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, usually with low / moderate and high expression levels, respectively, as reviewed in Non-Patent Document 4. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Cancer Res.51,5329-5338,1991(Campbell et al.,1991) [Non-Patent Document 2] Int.J.Cancer 74,193-198,1997(Toffoli et al.) [Non-Patent Document 3] Int.J.Cancer 79,121-126,1998(Toffoli et al.) [Non-Patent Document 4] Critical Rev.Therap.in Drug Carrier Systems 15,587-627,1998(Reddy and Low) Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention highly advantageously provides a treatment for patients with high-grade serous ovarian cancer (HGSOC), for example in a life-saving setting where there is a large unmet medical need for products that can extend life. [Means for solving the problem]

[0006] Ovarian cancer is a term for a group of tumors that originate from various types of tissue contained within the ovary. The most common type of ovarian cancer originates from epithelial cells on the surface of the ovary and can often spread to any surface within the peritoneal 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 stages III and IV, with stage III representing disease that has progressed locally and spread to the peritoneal cavity outside the pelvis, and stage IV representing 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 comprises a heterogeneous group 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 due to HGSOC, which is approximately 20 times more common than LGSOC.

[0008] Ovarian cancer is classified according to response to initial platinum chemotherapy as follows: Platinum-sensitive - the disease responds to platinum-based therapy but may recur after 6 months or more, which is ○ Completely platinum-sensitive - the disease responds to platinum-based therapy but recurs after 12 months or more, and Partially platinum-sensitive - disease can be subdivided into those that respond to platinum-based therapy but relapse within 6 to 12 months; and Platinum resistance - disease that recurs within 6 months of completing platinum-based chemotherapy, and • Platinum refractory – the disease does not respond to initial platinum-based chemotherapy.

[0009] A significant proportion of people have disease that responds to initial chemotherapy, but of these, 55-75% will relapse within two years of completing treatment. In addition to this situation, some patients cannot tolerate platinum-based drugs and therefore will need an alternative option to platinum, which the therapeutic regimen of the present invention now provides.

[0010] The initial therapeutic approach for HGSOC is usually surgical cytoreduction followed by chemotherapy. Optimal cytoreduction without macroscopic residual disease is the most important prognostic indicator. However, most patients present with advanced stage disease because HGSOC is asymptomatic in the early stages.

[0011] Most HGSOC (80%) respond well to platinum / taxane therapy initially and develop drug resistance during the next treatment cycle. On the other hand, a minority of HGSOC cases (20%) are initially refractory to platinum-based chemotherapy, but the basis of this drug resistance is unknown. Disease stages III and IV, which are the preferred target population for the treatment of the present invention, have a high recurrence rate.

[0012] Patients with optimally debulked (1 cm or less) stage III ovarian cancer are typically offered intraperitoneal (IP) chemotherapy after frontline surgery. Currently, there is no standard regimen for IP therapy, but regimens with drugs such as paclitaxel and cisplatin or carboplatin regimens may be used. If patients cannot tolerate IP delivery, they may be given intravenous drugs such as paclitaxel and carboplatin, or docetaxel and carboplatin.

[0013] Stage III and IV disease is usually treated with chemotherapy, and the choice of treatment depends on the time since the previous platinum-containing chemotherapy was completely successful. Liposomal doxorubicin is a good first choice, but there are many drugs with similar efficacy, and the final choice depends on the individual situation and the patient's and physician's preferences. Some of the drugs that can be used include gemcitabine, Topotecan, paclitaxel, docetaxel, etoposide, and nanoparticle albumin-bound paclitaxel. Bevacizumab may be considered as a single agent or in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

[0014] Other possible therapies in the pharmaceutical pipeline include PARP inhibitors, such as Lynparza (olaparib) and Rubraca (rucaparib) (both brands are restricted to BRCA-mutated cases) and Zejula (niraparib); and checkpoint inhibitors, such as Tecentriq (atezoizumab) and Bavercio (avelumab) for non-BRCA-mutated cases. However, many key opinion leaders expressed the view that such drugs need to be used with more clearly defined populations to be able to improve overall response rates. Keytruda (pembrolizumab) has also been found to have some efficacy when high levels of PD-1 are found on T lymphocytes and on tumors.

[0015] Several FR-α directed agents are in clinical trials. The FR-α directed monoclonal antibody farletuzumab failed to improve progression-free survival (PFS) in patients with platinum-sensitive epithelial ovarian cancer in a 1,100-patient phase III trial in combination with paclitaxel and carboplatin. Vintafolide, a conjugate of an α-folate receptor directed moiety and vinblastine, has shown some success in improving PFS in combination with docetaxel in folate receptor-positive non-small cell lung cancer (NSCLC) and has been tried with pegylated liposomal doxorubicin (PLD) in ovarian cancer, but the phase III trial failed to meet the pre-specified PFS criteria that would have allowed the study to continue. The antibody-drug conjugate IMGN853 (mirvetuximab-soravtansine) has also undergone phase I trials in platinum-resistant epithelial ovarian cancer and has shown some potential to increase PFS at a dose of 6 mg / kg every 3 weeks, with a PFS of 6.7 months in 39% of patients who had received ≤3 prior therapies.

[0016] Although it is possible that combinations of these agents may prove useful in the platinum-resistant setting, there remains a need to treat platinum-resistant cancers, especially ovarian cancer such as HGSOC, which is responsible for most ovarian deaths and has shown little improvement in overall survival over the decades. Potential blockbuster drugs such as immune checkpoint inhibitors have produced impressive clinical responses in melanoma and non-small cell lung cancer, likely due to their exceptionally high mutational burden, whereas in contrast, HGSOC is expected to have a moderate mutational burden and a lower number of neoantigens. (Bowtell et al. Nat Rev Cancer 2016 June). Current single-agent HGSOC therapy has an overall response rate (ORR) of 15-20% and a progression-free survival (PFS) of only 3-4 months.

[0017] Further drug classes include 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 properties: reduced folate transporter (RFC) is the main transporter into cells; they are excellent substrates for folylpolyglutamate synthetase (FPGS) and are therefore extensively polyglutamylated in tissues / tumors to polyglutamates, which are effective cytotoxic drug species; and they have fairly short half-lives in plasma. Because these classical inhibitors are slowly cleared from tissues due to polyglutamination, they are often cytotoxic and are used in high-dose regimens with infrequent and short duration, e.g., about 15 minutes, infusions.

[0019] Previtrexed is a "non-classical" TS inhibitor in that it is not polyglutamylated and has the following properties: RFC is the primary transporter into cells; it is not a substrate for FPGS; it has a TS Ki of approximately 0.4 nM, i.e., similar to the polyglutamates of raltitrexed and pemetrexed; it is rapidly cleared from cells and therefore is poorly retained 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, 500 mg / m2 in a 21-day cycle is used in this indication. 2 of pemetrexed on day 1 and gemcitabine on day 8 (Clin Transl. Oncol (2009) 11:35-40), and 900 mg / m 2 was 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 included a 600 mg / m 2 The paper notes that a single-agent pemetrexed dose of 10 mg / kg / day was recommended. The paper also notes that at the time, antifolates (such as TS inhibitors) had not been approved for the treatment of ovarian cancer.

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

[0022] These inhibitors may also be used against other cells in which FR-β, as opposed to FR-α, is expressed, particularly those involved in rheumatoid arthritis and acute myeloid leukemia. For this purpose, US8466111 is available at doses of 50-25000 mg / m 2 However, the range of doses is 5 to 25,000 mg / m 2 also lists a 50 mg / mL agonist, but specifies that the dose is increased to 1-1000 mg / kg or 0.1-10 mg / kg for subcutaneous administration. Topical administration of 0.1-10 mg / kg is described, and lozenges containing 1, 10, 50 and 100 mg of the compound are disclosed, as are injectable solutions of 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, such as FR being the primary transporter; FR-mediated uptake is slower and more easily saturated than RFC-mediated uptake of other antifolates; not being a substrate for FPGS; and a TS Ki of approximately 1.4 nM, which is similar to the polyglutamate of raltitexed and pemetrexed. However, it was taught that higher dosages should be tolerated because the compounds are not retained in tissues / tumors and are rapidly cleared from cells.

[0024] Typically, TS requires at least 24 hours of inhibition to induce an antiproliferative effect, and TS inhibitors require sufficient intracellular exposure of at least 2-3 days, repeated frequently, e.g., weekly, to be effective. This is accomplished by the polyglutamylation of raltitrexed and pemetrexed, which overcomes their short plasma half-life and short extracellular exposure. For example, the long intracellular exposure of previtrexed is achieved by an exceptionally long terminal plasma half-life that results in extended extracellular exposure.

[0025] Surprisingly, the lead compound of this newer class of FR-α directed TS inhibitors was found to have exceptionally long half-life levels when administered to humans. This compound, ONX-0801 (hereafter BTG945), has high affinity for the alpha-folate receptor (FR-α) and enters cells by FR-α mediated transport. It has a modified glutamate ligand, L-glu-yD-glu dipeptide, and is therefore not a substrate for FPGS. It binds to the α-FR with 70% the affinity of folate (FA) (Theti et al., 2003), it binds to FR-β with similar affinity (van der Heijden et al., 2009), and it appears to have negligible affinity for the ubiquitous reduced folate transporter (RFC) except at high concentrations (Gibbs et al., 2005). This was found to lead to a concentration- and time-dependent inhibition of tumor cell proliferation in vitro.

[0026] Once inside the cell, BTG945 irreversibly binds to the active site of thymidylate synthase, which is then prevented from performing its normal role in generating thymidine monophosphate (dTMP), a vital step in DNA synthesis and repair that is also utilized by approved TS inhibitors.

[0027] A first in human Phase I clinical trial of BTG945, identified as ONX801, was initiated on September 30, 2009, with trial registration number ISRCCTN79302332, with the goal of finding a tolerated dose that would inhibit tumor cell growth upon 3-h infusion on days 1, 8, and 15 of a 21-day cycle. However, on March 30, 2011, the trial was terminated due to the development of bronchiolitis obliterans with organizing pneumonia (BOOP), which was reversible and potentially cumulative dose-related. 2 The drug was discontinued due to toxicity at the predicted therapeutically effective dose of 100 mg / kg / day, which led to the conclusion that the drug could not be used at the dose and dosing schedule previously envisaged, as this toxic dose was lower than indicated as the lowest dose preferred for treatment.

[0028] Considering the large unmet need in the targeted treatment cohort, the inventors re-evaluated the dosing regimen that could be applied to the drug BTG945 to make it clinically useful. Unpublished analysis of human plasma drug levels suggested that much lower doses of the drug would be necessary to avoid toxicity. The inventors and applicants have initiated a new Phase I clinical trial, EudraCT3941, at these presumably safe but predicted non-therapeutic doses and have now discovered unexpected efficacy against platinum-resistant tumors in human patients, particularly FR-α expressing tumors, at much lower levels of drug than previously thought necessary and without the occurrence of treatment-limiting BOOP. This efficacy has been expressed as partial responses and stable disease by RECIST criteria in a significant proportion of ovarian cancer patients exhibiting α-folate receptor expression, particularly when such expression presents receptors on the tumor membrane, resulting in periods of progression-free survival, and in particular partial responses and / or objective response rates (ORR).

[0029] Thus, while BTG945 has a comparable Ki to raltitrexed and pemetrexed against the isolated target thymidine synthase (1.2 nM versus 1.4 nM), the dose required for efficacy in humans is significantly lower than previously expected, yet in the favorable control population where FR-α is expressed, the efficacy of the compound appears to be much superior to that seen with other members of the TS inhibitor class.

[0030] Of particular surprise and benefit is the discovery that the side effect profile of BTG945 is exceptionally favorable. There were no dose-limiting effects other than BOOP, which may prove to be manageable and / or may be eliminated by optimized dosing regimens, e.g., using dosing twice or three times a week. Side effects typically associated with thymidine synthetase inhibitors, e.g., neutropenia, diarrhea, and alopecia, were not observed, nor were side effects associated with alpha-folate receptor antibody complexes, e.g., diarrhea, blurred vision, and nausea. Moreover, common toxicities associated with cytotoxic chemotherapy, e.g., myelotoxicity, nephrotoxicity, and neurotoxicity, were not observed.

[0031] Some study patients have had cancer at 1 mg / m2 with the treatment regimen outlined below. 2 It has been shown that the efficacy is as low as 100 mg / kg / day. The side effects determined to date suggest that this dosing regimen may be used as a monotherapy or in combination with any currently employed therapy that is taught herein to have no overlapping toxicities. Such findings in clinical practice now provide a treatment for platinum-resistant cancer that can be used as a monotherapy or in combination with other available treatments, with the promise of extending PFS in a patient population that remains in unmet need. The treatment of the present invention can be used in combination with first-line therapeutic agents, particularly paclitaxel or carboplatin, for example.

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

[0033] [ka]

[0034] or a pharma- ceutically acceptable salt or ester thereof, wherein (i) the cancer is characterized as being of a type that is, or is predisposed to be, refractory or resistant to platinum-based therapy, and further wherein (ii) the treatment is administered at a dose of 1-30 mg / m2 of patient body surface area per administration.2 This is due to the dose of the compound.

[0035] Treatment is preferably with a dosing regimen that achieves a plasma concentration of the drug above 0.5 μM for at least 72 hours. More preferably, the dosing regimen results in a plasma concentration of the drug immediately after dosing of 1-5 μM for up to 72 hours, preferably up to 60 hours. Most preferably, the dosing regimen maintains a plasma concentration of the drug between 0.1-2 μM for at least 50% of the treatment cycle duration.

[0036] The treatment preferably comprises: 1-10 mg / m administered on days 1, 8, 15, and 22 at 7-day intervals in a 28-day cycle 2 The dose of 6-14 mg / m administered on days 1 and 15, 14 days apart, in a 28-day cycle 2 The dose of 10-30 mg / m administered on day 1 of a 21-day cycle 2 The dosage regimen is selected from the following doses:

[0037] The cancer is preferably platinum-refractory or resistant. Preferably, the cancer is selected from ovarian, endometrial, mesothelial, non-small cell lung cancer, or a cancer derived from one of these.

[0038] More preferably, the cancer is selected from those expressing alpha-folate receptor (FR-α), particularly those expressing alpha-folate receptor higher than background non-cancerous tissue levels. Most preferably, FR-α is expressed on the surface membrane of cancer cells. Most preferably, the cancer is ovarian cancer, such as epithelial ovarian, fallopian tube or peritoneal cancer, but may also be breast cancer or lung cancer, such as triple-negative breast cancer or non-small cell lung cancer. A particularly preferred cancer to be treated is serous ovarian cancer, such as high-grade serous ovarian cancer (HGSOC) found in salvage settings.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] In a further preferred embodiment, the compound is conveniently administered by injecting the contents of the vial provided by the original pharmaceutical company into a sterile saline bag as part of a saline infusion. Typically, the "drug product" is a sterile aqueous solution of the drug substance BTG945 as the trisodium salt, preferably the dihydrate, in solid form. The drug product is housed, for example, in a Type 1 clear glass vial with a stopper and an aluminum crimped closure. The strength of each vial as labeled, for example, contains 2 mL of solution containing the appropriate mg of 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.

[0043] Typically, drug product vials are stored at low temperature and thawed prior to use, after which a desired aliquot is 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. Once diluted in the infusion bag, the prepared solution should be administered to the patient, preferably within 24 hours at room temperature. The vials and bags should be protected from light prior to administration.

[0044] In one preferred embodiment for IP infusion, aliquots are added directly to infusion bags for further dilution with 10 ml, 15 ml, 25 ml, or 50 ml of 0.9% sterile saline (USP) for IP injection or infusion. Once diluted, these bags are handled as described above.

[0045] More particularly, the present invention provides treatment with the above calculated doses by infusion, particularly intravenous infusion (IV), or as single or multiple injections, with dosing intervals of 10 to 28 days as set forth above, more preferably 10 to 21 days, and most preferably about 14 or 21 days. Even more preferably, when administered IV, the present invention provides treatment with a dose of 150 mg / m2 of patient body surface area throughout all infusions. 2 More preferably, this limit also applies to IP dosing. More preferably, the maximum cumulative dose is 144 mg / m 2 It is.

[0046] Treatment according to the invention preferably provides the compound in infusions spaced 14 or 21 days apart in a 21 or 28 day cycle, most preferably in two infusions per 28 day cycle, one on day 1 and one on day 15. These cycles are preferably repeated until a maximum cumulative dose is reached. Infusions are preferably administered over a period of 0.5 to 3 hours. Treatment is at a dose of 1 mg / m 2 It will be appreciated that as little as 1 hour may be effective, so an infusion rate of 1 hour may be sufficient. Thus, the infusion may be over 0.5 to 1 hour, over 1 hour, but not longer than 3 hours.

[0047] A more preferred dosage for each administration, e.g., infusion, is 1 to 20 mg / m 2 , preferably 3 to 20 mg / m 2 , more preferably 6 to 18 mg / m 2 , and 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 12 mg / m given every 14 days in a 28-day cycle 2 It is understood that at a dose of 12 mg / m given once every 21 days in a 21-day cycle, the maximum cumulative recommended dose would be reached just short of 6 months. A more preferred dose is 12 mg / m given once every 21 days in a 21-day cycle. 2If the attending clinician monitors for irreversible BOOP or similar side effects, further dosing may be considered. When a patient shows signs of BOOP, for example if there is evidence of accumulation of inflammatory cell exudate (AICE) on a CT scan, the dose of the drug compound must be reduced. It may be prudent to discontinue drug administration for a short period, for example 2 or 4 weeks, and then resume at a lower preferred dose. ACIE has been observed on radiological scans and can be as low as 12 mg / m 2 After 2 weeks of cessation of dosing at 144 mg / m 2 until a maximum cumulative dose of 6 mg / m is achieved 2 It has been shown that resuming treatment at 100 mg / kg / day halts the progression of symptoms and alleviates them.

[0048] In particularly preferred embodiments, administration of the preferred dosage achieves a blood concentration of the compound of about 0.5 μM or more for at least 72 hours, preferably less than 2.0 μM, more preferably about 0.7 μM or more for at least 36 hours, or even more preferably about 0.9 μM or more, more preferably less than about 1.5 μM for 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 longer than 72 hours. 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 duration. More preferably, it is 0.1-1 μM for 50% of said period.

[0049] One particularly preferred cohort of cancers suitable for treatment with the present invention is that of female patients with newly diagnosed, histologically confirmed, advanced, high-risk (FIGO stages III-IV) BRCA mutated, high-grade serous and high-grade endometrioid ovarian cancer, primary peritoneal cancer, and / or fallopian tube cancer.

[0050] Stage III patients have preferably undergone one attempt at optimal cytoreductive surgery (pre- and interim cytoreductive surgery), and Stage IV patients have preferably undergone biopsy and / or either pre- or interim cytoreductive surgery.

[0051] Particularly preferred are cancers in patients who have completed first-line platinum (eg, carboplatin or cisplatin) therapy (intravenously or intraperitoneally). The most effective cancers treated by the present invention are those in which alpha-folate receptors are expressed, particularly those in which at least 25% of the cancer cells express alpha-folate receptors on the membrane and / or cytoplasm.More effective cancers are those in which at least 50% of the cancer cells express alpha-folate receptors on or in the cells, and most effective cancers are those in which at least 75% of the cancer cells express alpha-folate receptors on or in the cells.Such levels can be determined by histological studies of biopsy tissue using alpha-folate specific antibodies coupled with visualization agents as known in the art.The cancers that are most effective are those in which FR-α is expressed on the cell membrane.

[0052] An example of a method to evaluate alpha-folate receptor expression on cell membranes and in the cytoplasm is described in Kurosaki et al (2016) Int. J. Cancer: 138, 1994-2002 VC 2015 UICC, who studied tumor FR-alpha expression in FFPE (formalin-fixed paraffin-embedded) specimens using the specific antibody NCL-L-FRalpha (clone BN3.2, Leica Biosystems, UK) for a total of 164 cases of EOC, including borderline malignancies. Immunohistochemical staining was performed on whole section slides using a BenchMark XT automated slide stainer and iView DAB detection kit according to the manufacturer's instructions (Ventana Medical Systems, Tucson, AZ). Sections were deparaffinized, hydrated, and antigen retrieved using Cell Conditioning Solution 1 (Ventana Medical Systems), followed by incubation with mouse monoclonal anti-FRA antibody (1:40 dilution) for 30 minutes. Positive staining was defined as the presence of membrane staining or membrane and cytoplasmic staining in tumor cells. Slides were scored as negative for <1% positive tumor cell staining, weak for 1-25% positive tumor cell staining (11), moderate for 25-75% staining (21), and strong for >75% staining (31). FR-α staining scores were assessed in a blinded fashion by two independent observers. Any discrepancies were resolved by collaborative review under a binocular microscope.

[0053] An alternative method to non-invasively confirm a patient's suitability for treatment with the present invention is to test for α-folate receptors in the blood. Such an assay is described, for example, in Basal et al (2009) PLoS ONE 4(7):e6292. Doi:10.1371 / journal.pone.0006292, at least for ovarian cancer. When α-folate receptors are found on membranes, they can be excreted into circulating physiological fluids such as serum. In the case of ovarian cancer, our team found that patients with ovarian cancer have elevated levels of circulating α-folate receptors (FRα). This was found to be true even when the cancer was in its early stages.

[0054] Kurosaki et al (2016) Int. J. Cancer:138,1994-2002 further supported the application of serum α-folate receptor levels in the diagnosis of ovarian cancer of epithelial origin, correlating high serum FR-α with shorter PFS.

[0055] In addition to the cancers originating from ovarian tissues specified above, FR-α overexpressing cancers suitable for treatment with the methods and dosing regimens of the present invention also include uterine, mesothelial, renal, gastric, lung, colon, choroid plexus and brain cancers. The highest levels of overexpression were detected in non-mucinous ovarian cancers, where more than 90% of patients' tumors exhibit FR-α overexpression (Toffoli et al., 1998), but high levels were also shown in papillary serous endometrial cancers (Allard et al., 2007), renal cell carcinoma and NSCLC (Parker et al., 2005). In addition, breast cancer, primary CNS, colon cancer and gastric cancer show varying degrees of expression (Low and Kularatne, 2009).

[0056] Table 1: Alpha-folate receptor expression in selected tumors (Weitman 1994, Garin-Chesa 1993, Bueno 2001)

[0057] [Table 1]

[0058] The compound used in the present invention has the IUPAC name N-{N-{4-[N-((6S)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-yl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid or a salt thereof, referred to herein as BTG 945, the trisodium salt of which has the general formula II

[0059] [ka]

[0060] has. Another name is D-glutamic acid, N-[4-[2-propyn-1-yl-[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-L-gamma-glutamyl-, sodium salt.

[0061] The (6RS) racemate is also known to be an active form containing the activity (6S) as depicted. It will be understood that when the racemate is used, it contains only 50% of the (6S) form and therefore the dosage may need to be at the higher end of the ranges described.

[0062] When the compound is provided as an ester, it may be an ester of a simple alcohol that is bound to one or more of the carboxylate moieties that would otherwise be the sodium binding sites in the formula above. The resulting alkyl ester may be any equivalent to the parent compound for regulatory purposes. Pharmaceutically acceptable ester forms of cyclopenta[g]quinazolines suitable for the treatment of the present invention are, for example, esters with aliphatic alcohols of six or fewer carbon atoms, such as methyl, ethyl or tert-butyl esters. Due to the presence of three carboxyl groups, the salt or ester may be a monoacid di-salt or ester, a diacid mono-salt or ester, or even a tri-salt or ester may be used.

[0063] Pharmaceutically acceptable salt forms of the compounds 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.

[0064] The cyclopenta[g]quinazolines or salts taught in the present treatments are believed to function as anti-cancer agents at least in part due to their ability to inhibit the enzyme thymidylate synthase.

[0065] The cyclopenta[g]quinazoline or salt composition may be in a form suitable for oral use, such as a tablet, capsule, aqueous or oily solution, suspension or emulsion; a form suitable for topical use, such as a cream, ointment, gel, or aqueous or oily solution or suspension; a form suitable for intranasal use, such as a snuff, nasal spray or nasal drops; a form suitable for vaginal or rectal use, such as a suppository; a form suitable for administration by inhalation, such as a finely divided powder, e.g., a dry powder, microcrystalline form or liquid aerosol; a form suitable for sublingual or buccal use, such as a tablet or capsule; or a form suitable for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion use), such as a sterile aqueous or oily solution, emulsion or suspension. In general, the compositions may be prepared in a conventional manner using conventional excipients.

[0066] The preferred form of the compound is the form for parenteral administration.Particularly preferred is the compound for infusion, in which case the compound is preferably formulated with physiological saline or water for injection.Alternatively, it is provided in a solid state that can be mixed immediately with said water or physiological saline.For example, the dihydrate of trisodium salt.

[0067] The compositions may contain, in addition to the cyclopenta[g]quinazoline used in the present invention, one or more other anti-cancer or palliative agents selected, for example, from other antimetabolites, DNA interactors, immuno-oncological agents, tumor vascular or signal transduction inhibitors, or other inhibitors of deregulated pathways in tumors.

[0068] However, those skilled in the art will appreciate that it may be more convenient to administer such combinations separately, yet simultaneously, at a treatment visit to the administration site. Particular dosing regimens preferably employed with the compounds for the treatment of cancer of one aspect of the present invention are with 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 (atezoizumab), Bavercio (avelumab).

[0069] Combinations of multiple drugs may include bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan. Further examples of such combinations are illustrated in the Examples below.

[0070] Particularly advantageously, the first aspect of the present invention employs lower doses of these combination drugs than currently prescribed.This is especially because resistance to BTG945 has been found not to be cross-resistant with respect to resistance to other of these drugs, and the desired toxic effects on target cancer cells will often be cumulative.Thus, in addition to the exemplary dosing regimen provided in the examples herein, lower or less frequent doses of additional drugs may be employed.

[0071] In a second aspect of the invention, there is provided a method of treating a patient suffering from a cancer characterized as being of a type that is, or is predisposed to being, refractory or resistant to platinum-based therapy, wherein the treatment comprises administering to the patient a single dose of 1 to 30 mg / m2 of body surface area of ​​the patient. 2 A compound of formula I for the treatment of cancer,

[0072] [ka]

[0073] or by a pharma- ceutically acceptable salt or ester thereof. The cancer to be treated is as described above for the first aspect of the invention. The method is preferably by administering the compound, salt or ester intraperitoneally (IP) or intravenously (IV).

[0074] Treatment is preferably with a dosing regimen that achieves a plasma concentration of the drug above 0.5 μM for at least 72 hours. More preferably, the dosing regimen results in a plasma concentration of the drug immediately after dosing of 1-5 μM for up to 72 hours, preferably up to 60 hours. Most preferably, the dosing regimen maintains a plasma concentration of the drug between 0.1-2 μM for at least 50% of the treatment cycle duration.

[0075] The treatment preferably comprises: 1-10 mg / m administered on days 1, 8, 15, and 22 at 7-day intervals in a 28-day cycle 2 The dose of 6-14 mg / m administered on days 1 and 15, 14 days apart, in a 28-day cycle 2 The dose of 10-30 mg / m administered on day 1 of a 21-day cycle 2 The dosage regimen is selected from the following doses:

[0076] 1-30mg / m 2 Although treatment with doses of 3 to 30 mg / m2 per patient's body surface area per administration is within the scope of the present invention, the preferred dose is 3 to 30 mg / m2 per patient's 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, a dose of the compound of 6 to 18 mg / m2 per patient body surface area per administration. 2 of the compound, and even more preferably, 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 / m2 is the dose of the compound.

[0077] More preferably, and more particularly, the method is by infusion of doses at intervals of 10-28 days, more preferably 10-21 days, and most preferably at dosing intervals of about 14 or 21 days. Even more preferably, when administered IV, the present invention provides a dose of 150 mg / m2 of patient body surface area, taking into account all infusions. 2 More preferably, this limit also applies to IP dosing. More preferably, the maximum cumulative dose is 144 mg / m 2 It is.

[0078] The method of the present invention provides the compound as an infusion, preferably at 14 or 21 day intervals in a 21 day or 28 day cycle, most preferably in a 28 day cycle. These cycles are preferably repeated until a maximum cumulative dose is reached. The infusion is preferably administered over 0.5 to 3 hours. The infusion may be administered over 0.5 to 1 hour, 1 hour, or less than 1 to 3 hours. Treatment is at a dose of 1 mg / m 2 or 3 mg / m 2 It will be appreciated that as little as 1 hour may be effective, so that a 1 hour infusion rate may be sufficient.

[0079] The preferred dosage for each infusion is 1 to 20 mg / m 2 , more preferably 10 to 15 mg / m 2 The most preferred dosage is about 12 mg / m 2 12 mg / m given every 14 days in a 28-day cycle 2 At this dose, it appears that the maximum cumulative recommended dose will be reached just before 6 months, which is 144 mg / m 2 Twelve doses provide a cumulative total of 12 mg / m 2 A more preferred dosing schedule comprises the infusion of 12 mg / m given once every 21 days in a 21 day cycle. 2Preferably, further dosing may be considered provided the attending clinician monitors for irreversible BOOP or similar side effects.

[0080] The method of the second aspect of the invention further provides for treatment with a compound of formula I in combination with a therapeutically effective amount of one or more additional anti-cancer agents. Preferably, the one or more additional 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 (atezoizumab), Bavercio (avelumab), and Keytruda (pembrolizumab).

[0081] Combinations of multiple drugs may include bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan. Further examples of such combinations are illustrated in the Examples below.

[0082] Combination with paclitaxel or carboplatin or both is preferred. Given the nature of the pulmonary side effects seen in the failed clinical trials, the inventors further contemplate that the dosing regimen of the present invention may incorporate administration of steroids to reduce pulmonary inflammation.

[0083] A third aspect of the invention provides a method of treating a patient suffering from a cancer characterized as being of a type that is, or is prone to be, refractory or resistant to platinum-based therapy, wherein the treatment comprises administering to the patient a single dose of 1 to 30 mg / m2 of body surface area of ​​the patient in combination with an anti-inflammatory corticosteroid. 2 of the compound of formula I

[0084] [ka]

[0085] or a pharma- ceutically acceptable salt or ester thereof.Preferred corticosteroids are selected from the group consisting of prednisone, methylprednisolone, dexamethasone and prednisolone and hydrocortisone.

[0086] In a fourth aspect of the invention, there is provided a compound of formula I

[0087] [ka]

[0088] A novel dosage form comprising: The dosage form is provided comprising a single dosage unit containing the compound or a pharma- ceutically acceptable salt or ester thereof, characterized in that the amount of the compound in the dosage unit is 0.5 to 40 mg.

[0089] More preferably, a dosage unit of the invention contains 1 to 30 mg of a compound of formula I or a salt or ester thereof. Even more preferably, a dosage unit contains 5 to 26 mg of a compound of formula I. Most preferably, a dosage unit contains 10 to 24 mg of a compound of formula I or a salt or ester thereof.

[0090] A preferred dosage form would be a container of the compound of formula I or a salt or ester thereof, more preferably the sodium salt, as a sterile solid or aqueous solution in a vehicle such as water for injection or saline. The sterile solid is preferably BTG945 or a salt or ester thereof, free of other materials. Such containers can be used to administer the liquid contained therein, or to which a liquid is added if a solid form is provided, at a concentration of 1-30 mg / m 2 The patient will be able to draw up into a syringe an amount appropriate for the patient's body surface area to deliver the required dose.

[0091] Preferably, the dose is provided as an aqueous solution in a vial. Such a dosage form or formulation will preferably be a vial containing 1-30 ml, more preferably 1-20 ml, even more preferably 1-10 ml, most preferably 2-6 ml of an aqueous solution of the compound for treatment. Alternatively, the dose is provided as a solid form of the compound for treatment, without a liquid. Thus, a preferred vial of the invention will contain 0.5-40 mg of compound in 1-30 ml of aqueous solution, more preferably 5-26 mg in 1-20 ml of aqueous solution, most preferably 10-24 mg in 1-10 ml of aqueous solution, for example about 6 mg or 12 mg in 2-6 ml of aqueous solution.

[0092] Those skilled in the art will appreciate that pharmaceuticals are expensive commodities and it is desirable to avoid wasting compounds that are not needed for a given treatment. Because BTG945 is potentially toxic above the doses just taught, it would be inappropriate to provide more than is necessary in a clinical setting. Thus, a preferred dose per unit patient surface area of ​​6 mg / m 2 or 12 mg / m 2 In developed countries, patients typically live for 1–2.5 m 2 and patients with exceptionally high BMI have a surface area of ​​2m 2 Since the upper limit of the drug content is often set at 6-24 mg, more preferably 10-24 mg of drug compound, whether in dry solid or solution form, a new preferred usable vial content would be 6-24 mg, more preferably 10-24 mg of drug compound. 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 new embodiments of the invention. In particular, those in which the drug is in the form of a dry BTG945 salt and / or its dehydrated form, or a simple solution thereof in water or saline for injection are disclosed.

[0093] The compounds for treatment of the present invention may be synthesized as described in the aforementioned patent applications or as shown in the more recent patent US8809526 (Onyx) and patent application US2013 / 0345423 (Onyx).

[0094] 1-5 show the clinical results of human trials of the treatment of the present invention. [Brief description of the drawings]

[0095] [Figure 1] FIG. 1 shows % tumor change by RECIST criteria for patients in the dose escalation phase of the trial of Example 1. Weekly schedules are represented by stars and alpha-folate expressing tumors are represented by crosses. [Diagram 2] Figure 1 shows the % change in tumors as measured by CA125 levels during the escalation phase of the trial in Example 1. Numbers represent dose in mg / m2, letters represent weekly (w) or biweekly (f), and alpha-folate expressing tumors are represented by a cross symbol. [Diagram 3] Figure 1 shows % tumor change by RECIST criteria in patients in the expansion phase of the trial of Example 1 using a 12 mg / m2 dose once every 14 days in a 28 day cycle. Alpha-folate expressing tumors are represented by cross symbols. [Figure 4] Figure 1 shows the % change in tumors measured using CA125 levels in patients in the expansion phase of the trial of Example 1 using a 12 mg / m2 dose once every 14 days in a 28 day cycle. Alpha-folate expressing tumors are represented by cross symbols. [Diagram 5] 1 shows the mean blood concentration (μM) of compound ONX-0801 / BTG945 versus time (hours) for patients under different dose regimens during the titration phase of the clinical trial prior to selection of the expansion dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0096] (Example) The present invention will now be illustrated by the following non-limiting examples, and further embodiments will occur to those of skill in the art in light of these.

[0097] Preferred target cancers to treat with the exemplary dosing regimens below would be those in patients with: • Histologically documented epithelial ovarian, fallopian tube or peritoneal carcinoma.

[0098] ● Platinum-resistant / refractory disease, defined as disease progression within 180 days after the last dose of platinum therapy (resistance), or lack of response or disease progression while receiving most recent platinum-based therapy (refractory), respectively.

[0099] Have received three or fewer chemotherapy regimens for platinum-sensitive disease, the most recent of which contained platinum, and have not received any previous therapy for platinum-resistant disease. Example 1: 1-12 mg / m as monotherapy 2 Treatment of patients with BTG945 (the trisodium salt form of the compound of formula II).

[0100] Methods: Two IV schedules were investigated using a 3+3 dose escalation design. Schedule A was weekly dosing (QW) and Schedule B was once every 2 weeks (Q2W). Cycles consisted of 4 weeks, with treatment terminating after 6 cycles for both schedules. An expansion cohort was initiated to evaluate clinical activity in patients with FR-α-overexpressing high-grade serous ovarian cancer (HGSOC).

[0101] Results: 1-6 mg / m 2 and 2 to 12 mg / m 2 Twenty-one patients each were treated on schedules A and B, investigating doses ranging from 0.1 mg / m2 to 0.2 mg / m2. The dose-limiting toxicity on schedule A was grade 3 cellulitis, and no dose-limiting toxicities were seen on schedule B. The most common toxicities were fatigue 15 / 42 (36%), nausea 9 / 42 (21%), and dysgeusia 5 / 42 (12%). Two patients in schedule A at 4 mg / m2 developed suspected drug-related changes in pulmonary function tests in cycles 5 and 6, respectively (decrease in Dlco >15%). No cases of suspected drug-related decrease in Dlco were observed in patients treated on schedule B. No grade 3-4 diarrhea, mucositis, or neutropenia were seen in either cohort. 2The Cmax, AUC and half-life at 4 mg / mL were 4952 ng / mL, 85170 h·ng / mL and 26 h, respectively. Preclinical PK-PD modelling aimed to achieve concentrations of 0.05–1 μM; 2 This was achieved over a 48 hour period with doses of 100 mg / kg or more.

[0102] Concentrations above 0.5 μM are 6 mg / m 2 At higher doses, this was achieved over 72 hours. Evidence of thymidylate synthase inhibition was observed using FLT PET imaging. See Cancer Res 68.3827-3834.2008 (Pillai et al).

[0103] Based on safety and PK, the recommended phase II dose (RP2D) of BTG945 (which was ONX801) is 12 mg / m 2 Q2W and expansion of patients with HGSOC was initiated. Five patients with HGSOC had partial responses (PR) in the dose escalation cohort. In the expansion cohort of patients with HGSOC, 5 / 11 patients had PR by the date of this filing. Archived samples from 8 / 11 patients in the expansion cohort were analyzed. 4 / 4 AFR+ve and 4 / 4 AFR-ve patients had PR after treatment with BTG945, respectively. RECIST and CA125 responses are shown in Figures 1-4.

[0104] Conclusion: The RP2D for BTG945 is 12 mg / m 2 Q2W. At RP2D, multiple patients with AFR-overexpressing HGSOC had PR and further biomarker-predefined randomized Phase II trials are warranted. Example 2: Combination therapy with BTG945 and other anti-cancer therapies.

[0105] 12 mg / m on days 1 and 15 of a 28-day cycle 2 of BTG945 will be administered IV in injectable saline over 1 hour for up to 6 cycles. One or more of the following exemplary dosing schedules will be administered in conjunction with this treatment as follows: Example 2.1 Liposomal doxorubicin IV 40-50 mg / m over 30 minutes 2 ; Every 21 days Example 2.2 Gemcitabine 1000 mg / m IV over 30 minutes on days 1 and 8 2 ; Every 21 days Example 2.3 Topotecan 1.25-1.5 mg / m IV over 30 minutes on days 1-5 2 ; Every 21 days Example 2.4 Paclitaxel 80 mg / m IV over 1 hour weekly 2 Example 2.5 Docetaxel 75-100 mg / m IV over 1 hour every 21 days 2 Example 2.6 Etoposide 50 mg / m PO for 21 days every 28 days 2 / day Example 2.7 Nanoparticle albumin-bound paclitaxel 100 mg / m2 given IV over 30 minutes weekly (days 1, 8, and 15) every 28 days Example 2.8 Keytruda 200 mg with 945 IV every 3 weeks during any chemotherapy session.

[0106] Example 3: Combination therapy with BTG945 and other anti-cancer therapies for platinum-sensitive cancers. 12 mg / m on days 1 and 15 of a 28-day cycle 2 of BTG945 will be administered IV in injectable saline over 1 hour for up to 6 cycles. One or more of the following exemplary dosing schedules will be administered in conjunction with this treatment as follows: Example 3.1 Paclitaxel 135 mg / m IV over 24 hours on Day 1 for 6 or more cycles provided disease is responsive. 2 and cisplatin 100 mg / m IP on day 2. 2 (Dose 75 mg / m 2 on day 8) and paclitaxel 60 mg / m IP on day 8. 2 On day 2, the cisplatin dose may be reduced to 75 mg / m2 IP. Some clinicians recommend administering 135 mg / m2 IV over 3 hours.2 paclitaxel followed by 75 mg / m2 cisplatin IP, both on day 1 on an outpatient basis. 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 should start with an AUC<5.

[0107] Example 4: Combination therapy with BTG945 and other anti-cancer therapies for platinum-sensitive cancers where patients cannot tolerate IP administration. 12 mg / m on days 1 and 15 of a 28-day cycle 2 of BTG945 will be administered IV in injectable saline over 1 hour for up to 6 cycles. One or more of the following exemplary dosing schedules will be administered in conjunction with this treatment as follows: Example 4.1 Paclitaxel 175 mg / m2 IV 3 hours with carboplatin AUC 7.5 IV 1 hour on day 1; every 21 days for 6 cycles, or Example 4.2 Docetaxel 75 mg / m2 IV over 1 hour on day 1 and carboplatin AUC5; IV over 1 hour every 21 days for 6 cycles.

[0108] Example 5: Combination therapy with BTG945 and other anti-cancer therapies for platinum-sensitive stage III and IV platinum-sensitive recurrent cancer. Platinum-sensitive recurrence: 12 mg / m in injectable saline given IV over 1 hour on days 1 and 15 of a 28-day cycle for up to 6 cycles if recurrence occurs more than 6 months after the first or next complete clinical response to platinum-containing chemotherapy. 2 Patients should be treated with one of the following IV platinum-containing combination therapy regimens in conjunction with BTG945. Selection will depend on factors such as existing comorbidities, previous toxicities, and physician and patient preferences. The dosing regimens are as follows: Example 5.1 Carboplatin IV at AUC5 and liposomal doxorubicin 30 mg / m IV over 30 minutes2 every 28 days for 6 cycles Example 5.2 Paclitaxel 175 mg / m2 IV over 3 hours with carboplatin (Calvert) AUC5 IV over 1 hour; every 21 days for 6 cycles Example 5.3 Paclitaxel 80 mg / m IV over 1 hour on days 1, 8, and 15 of each week 2 and carboplatin AUC6 administered IV over 1 hour on day 1 every 21 days for 6 cycles. Example 5.4 Docetaxel 75 mg / m IV over 1 hour 2 and carboplatin AUC5;6 administered intravenously over 1 hour every 21 days for 6 cycles. Example 5.5 Gemcitabine 1000 mg / m IV over 30 minutes on Days 1 and 8 2 and carboplatin AUC4; given IV over 1 hour on day 1, every 21 days for 6 cycles.

[0109] 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 with carboplatin / gemcitabine, but the use of this agent remains controversial. Platinum-sensitive recurrence: If recurrence occurs more than 6 months after the first or next complete clinical response to platinum-containing chemotherapy, 12 mg / m2 in injectable saline given IV over 1 hour on days 1 and 15 of a 28-day cycle for up to 6 cycles. 2 Patients must be treated with one of the following IV platinum-containing combination therapy regimens in conjunction with BTG945:

[0110] Example 6.1 Bevacizumab 15 mg / kg IV (first 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 1000 mg / m IV over 30 minutes on days 1 and 8 until disease progression or unacceptable toxicity. 2and carboplatin AUC4 IV on day 1; every 21 days for 6 to 10 cycles, plus bevacizumab 15 mg / kg IV on day 1 prior to gemcitabine and carboplatin. Example 6.3 Bevacizumab 10 mg / kg IV every 14 days in combination with one of the following IV chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin or topotecan (topotecan given once a week) Example 6.4 Topotecan (every 21 days) in combination with bevacizumab 15 mg / kg IV every 21 days Example 6.5 Bevacizumab 15 mg / kg IV (first 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 Bevacizumab 10 mg / kg IV on days 1 and 15 and topotecan 4 mg / m2 IV on days 1, 8, and 15 every 28 days.

[0111] Example 7: Combination Therapy with BTG945 and Platinum-Sensitive or Resistant or Refractory BRCA Mutated Stage III and IV Platinum-Sensitive Recurrent Cancer For patients diagnosed with a BRCA mutation (as detected by the FDA-approved test, BRACAnalysis CDx™) who have been previously treated with 3 or more lines of chemotherapy: 12 mg / m IV over 1 hour in saline on days 1 and 15 of every 28-day cycle. 2 Patients will receive up to six cycles of BTG945 concomitantly with olaparib 400 mg PO twice daily continuously.

[0112] In the European Union, olaparib 400 mg twice daily PO is approved as monotherapy for the maintenance treatment of adult patients with platinum-sensitive recurrent BRCA-mutated (germline and / or somatic) high-grade serous epithelial, fallopian tube or primary peritoneal cancer who have a response (complete and partial) to platinum-based chemotherapy. (Additional Note) (Appendix 1) Compounds of Formula I for the Treatment of Cancer

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Claims

1. 1. A pharmaceutical composition for treating cancer, comprising: The pharmaceutical composition comprises a compound of formula I, 【Chemistry 21】 or a pharma- ceutically acceptable salt or ester thereof, the cancer is refractory or resistant to platinum-based therapy; The compound or a pharma- ceutical acceptable salt or ester thereof is present in the pharmaceutical composition in a therapeutically effective amount at a dose of 6 mg / m2 to 14 mg / m2 of patient body surface area per administration, and the compound or a pharma- ceutical acceptable salt or ester thereof is administered every 14 days in a 28 day cycle.

2. 2. The pharmaceutical composition of claim 1, wherein the administration is performed with a first dose on day 1 of the 28-day cycle and with a second dose on day 15 of the 28-day cycle.

3. The pharmaceutical composition of claim 1, further comprising a therapeutically effective amount of one or more additional anticancer agents formulated to be administered together with the compound or a pharma- ceutically acceptable salt or ester thereof or separately from the compound or a pharma- ceutically acceptable salt or ester thereof.

4. The pharmaceutical composition of claim 2, further comprising a therapeutically effective amount of one or more additional anticancer agents formulated to be administered together with the compound or a pharma- ceutically acceptable salt or ester thereof or separately from the compound or a pharma- ceutically acceptable salt or ester thereof.

5. The pharmaceutical composition of claim 3, characterized in that the one or more further anticancer agents include a PARP inhibitor.

6. 6. The pharmaceutical composition of claim 5, wherein the PARP inhibitor is selected from olaparib, rucaparib, and niraparib.

7. The pharmaceutical composition of claim 4, characterized in that the one or more further anticancer agents include a PARP inhibitor.

8. 8. The pharmaceutical composition of claim 7, wherein the PARP inhibitor is selected from olaparib, rucaparib, and niraparib.

9. The pharmaceutical composition according to claim 1, wherein the cancer is selected from cancers in which alpha-folate receptor (FR-α) is expressed.

10. The pharmaceutical composition according to claim 1 , wherein the cancer is ovarian cancer.

11. The pharmaceutical composition according to claim 1, characterized in that the cancer is epithelial ovarian, fallopian tube or peritoneal cancer.

12. The pharmaceutical composition according to claim 1 , wherein the cancer is serous ovarian cancer.

13. The pharmaceutical composition according to claim 1, wherein the cancer is high-grade serous ovarian cancer (HGSOC).

14. 2. The pharmaceutical composition according to claim 1, characterized in that it is adapted for administration of said dose by intraperitoneal (IP) or intravenous (IV) infusion.

15. 11.5-12.5 mg / m2 per patient's body surface area per dose ２ 2. The pharmaceutical composition according to claim 1, characterized in that a dose of said compound or a pharma- ceutically acceptable salt or ester thereof is administered by infusion.

16. 12 mg / m2 per patient's body surface area per dose ２ 2. The pharmaceutical composition according to claim 1, characterized in that a dose of said compound or a pharma- ceutically acceptable salt or ester thereof is administered by infusion.

17. The maximum cumulative dose of said compound, or a pharma- ceutical salt or ester thereof, is 150 mg / m2 of patient body surface area throughout all said administrations. ２ The pharmaceutical composition according to claim 1, characterized in that it is used as follows:

18. The compound is the trisodium salt of formula II 【Chemical 22】 The pharmaceutical composition according to claim 1, characterized in that it is 19. The pharmaceutical composition of claim 18, further comprising a PARP inhibitor formulated to be administered together with the trisodium salt of formula II or separately from the trisodium salt of formula II.

20. 20. The pharmaceutical composition of claim 19, wherein the PARP inhibitor is selected from olaparib, rucaparib, and niraparib.

21. 20. The pharmaceutical composition of claim 19, wherein the trisodium salt of formula II and the PARP inhibitor are administered separately.

22. 21. The pharmaceutical composition of claim 20, wherein the trisodium salt of formula II and the PARP inhibitor selected from olaparib, rucaparib, and niraparib are administered separately.

23. The maximum cumulative dose of said compound, or a pharma- ceutical salt or ester thereof, is 150 mg / m2 of patient body surface area throughout all said administrations. ２ 19. The pharmaceutical composition according to claim 18, characterized in that it is used as follows:

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