Platinum-resistant cancer treatment

Abstract

A compound of Formula I (I) or a pharmaceutically acceptable salt or ester thereof is provided for use in the treatment of cancer, wherein (i) the cancer is of a type that is predisposed to or becomes resistant or refractory to platinum-based therapy, and (ii) the treatment employs a dosage of 1 mg / m 2 to 30 mg / m 2 of the compound per patient body surface area per administration. Methods of treatment and novel dosage forms are also provided. Particularly treated is ovarian cancer, particularly those expressing a-folate receptor, including epithelial ovarian, fallopian tube, or peritoneal cancer.

Description

[0001] This application is a divisional application of CN201880030434.2.

[0002] This invention relates to cancer, and more particularly to novel treatments for cancers that frequently exhibit resistance to platinum-based therapies or are otherwise difficult to treat with platinum-based therapies. Specific cancers to be treated include ovarian cancer, endometrial cancer, mesothelial carcinoma, and non-small cell lung cancer (NSCL), as well as cancers derived from these. More particularly preferred treatments are provided for ovarian-derived cancers such as epithelial ovarian cancer, fallopian tube cancer, and peritoneal cancer.

[0003] Most notably, the present invention provides novel treatments for cancers carrying α-folate receptors (FR-α), particularly those exhibiting higher levels of α-folate receptors than in background non-cancerous tissue, especially those cancers possessing FR-α on their cell membrane surfaces. Cancers suitable for treatment with the present invention also include breast and lung cancer expressing FR-α, particularly triple-negative breast cancer.

[0004] Folate receptors are overexpressed in many cancers, particularly those of ovarian origin, where they are highly and uniformly overexpressed in 90% of cases; see Cancer Res. 51, 5329–5338, 1991 (Campbell et al., 1991). Furthermore, high α-FR expression is associated with aggressive platinum-resistant disease and poor prognosis—see Int. J. Cancer 74, 193–198, 1997 and Int. J. Cancer 79, 121–126, 1998 (both by Tofoli et al.). The β-isoform is widely expressed in both epithelial and non-epithelial tumors, with expression levels typically low / intermediate and high, as reviewed in Critical Rev. Therap. in Drug Carrier Systems 15, 587–627, 1998 (Reddy and Low).

[0005] This invention is particularly advantageous in providing treatment for patients with high-grade serous ovarian cancer (HGSOC), such as in resuscitation settings where there is a far from unmet medical need for life-prolonging products.

[0006] Ovarian cancer is a term for a group of tumors arising from various types of tissue contained within the ovary. 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 peritoneum). Fallopian tube cancer and primary peritoneal cancer are histologically equivalent diseases of epithelial ovarian cancer. Ovarian cancer is classified into stages I through IV. Advanced ovarian cancer falls into stages III and IV; stage III indicates locally advanced disease that has spread outside the pelvis and into the abdominal cavity, while stage IV indicates distant metastasis to other organs such as the liver and lungs.

[0007] Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancies in developed countries. EOC comprises a heterogeneous group of tumors, 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 attributable to HGSOC, which is approximately 20 times more common than LGSOC.

[0008] Ovarian cancer can be classified according to its response to initial platinum-based chemotherapy as follows:

[0009] • Platinum-sensitive type – The disease responds to platinum-based therapies but may relapse after 6 months or longer; this can be further subdivided into:

[0010] o Fully platinum-sensitive type - The disease responds to platinum-based therapies but may relapse after 12 months or longer.

[0011] o Some platinum-sensitive diseases respond to platinum-based therapies but relapse within 6 to 12 months; and

[0012] • Platinum-resistant type - Disease that relapses within 6 months after completion of platinum-based chemotherapy and

[0013] • Platinum-refractory diseases - diseases that do not respond to platinum-based initial chemical therapies.

[0014] Although a large percentage of people have diseases that respond to initial chemical therapy, 55% to 75% of them relapse within 2 years of completing treatment. In addition to these situations, some patients cannot tolerate platinum-based medications, thus necessitating the platinum-alternative options now provided by the solutions of this invention.

[0015] The initial treatment for HGSOC is usually surgical tumor debulking, followed by chemotherapy. Optimal debulking with no macroscopic residual disease is the most important prognostic indicator. However, because HGSOC is asymptomatic in its early stages, most patients have advanced disease.

[0016] Most HGSOC (80%) initially respond well to platinum / taxane therapy but develop resistance in subsequent treatment cycles. However, a minority of HGSOC cases (20%) have been difficult to treat with platinum-based chemotherapy since their inception, but the basis of this resistance is unclear. Relapse rates are high in stage III and IV disease (the preferred target population for this invention).

[0017] Following first-line surgery, intraperitoneal (IP) chemotherapy is typically administered to patients with stage III ovarian cancer who have achieved optimal reduction (≤1 cm). Currently, there is no standardized regimen for IP therapy; however, dosing regimens utilizing drugs such as paclitaxel and cisplatin or carboplatin may be used. If the patient cannot tolerate IP delivery, intravenous medications such as paclitaxel and carboplatin or docetaxel plus carboplatin may be given.

[0018] Treatment for stage III and IV disease typically involves chemotherapy; the choice of treatment depends on the time since a complete response to platinum-based chemotherapy. While liposomal doxorubicin is a good first-line treatment, many other drugs with similar efficacy exist, and the final choice depends on individual circumstances and patient and physician preferences. Some available drugs include gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, and paclitaxel bound to albumin nanoparticles. Bevacizumab may also be considered as a single agent or in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan.

[0019] Other potential therapies in pharmaceutical companies' pipelines include PARP inhibitors such as Lynparza (olaparib) and Rubraca (rucaparib) (limited to two markers for BRCA mutations) and Zejula (niraparib); and non-BRCA mutation checkpoint inhibitors such as Tecentriq (atezilumab) and Bavercio (averciumab). However, many leading opinion leaders believe that such drugs need to be used in more precisely defined populations to improve the overall response rate. Keytruda (pembrolizumab) has also been found to be effective when high levels of PD-1 are found on T lymphocytes and tumors.

[0020] Several FR-α targeted drugs have been put into clinical trials. Farletuzumab, an FR-α targeted monoclonal antibody, failed to improve progression-free survival (PFS) in a phase III clinical trial involving 1,100 patients in combination with paclitaxel and carboplatin. Vintafolide (a conjugate of α-folate receptor targeting and vincristine) has shown some success in improving PFS in folate receptor-positive non-small cell lung cancer (NSCLC) in combination with docetaxel, and has been tested in ovarian cancer in combination with pegylated liposomal doxorubicin (PLD), but the phase III trial failed to meet the predetermined PFS criteria and therefore could not be continued. The antibody-drug conjugate IMGN853 (mirvetuximab soravtansine) has also completed a phase I trial in platinum-resistant epithelial ovarian cancer, with indications of potential to increase PFS in 39% of patients who had received three or fewer prior therapies and had a PFS of 6.7 months, at a dose of 6 mg / kg every three weeks.

[0021] Despite the potential for combinations of these agents to prove useful in a platinum-resistant context, treatment remains necessary for platinum-resistant cancers, particularly ovarian cancers such as HGSOC, which account for the highest rate of ovarian death and have seen little improvement in overall survival over decades. Potential blockbuster drugs, such as immune checkpoint inhibitors, have generated impressive clinical responses in melanoma and non-small cell lung cancer, likely due to their exceptionally high mutational burden, compared to HGSOC's moderate mutational burden and expected number of neoantigens (Bowtell et al., Nat Rev Cancer, June 2016). Current single-dose HGSOC therapy has an overall response rate (ORR) of 15–20% and a progression-free survival (PFS) of only 3–4 months.

[0022] Another class of drugs includes thymidylate synthase (TS) inhibitors CB3717, ZD1694 (raltitrexed), LY231514 (pemetrexed), and ZD9331 (pretrexed). All of these TS inhibitors have demonstrated clinical activity in a range of solid tumors (see Treatment Reports, 1986, 70, 1335 and Beale et al., “Tomudex: Clinical Development” in Antifolate Drugs in Cancer Therapy (edited by Jackman), Humana Press, Totowa, New Jersey, USA, pp. 177–181, 1999). The side effects of raltitrexed and ZD9331 are primarily associated with TS suppression in the gut and bone marrow.

[0023] Raltitrexed and pemetrexed are examples of "classic" TS inhibitors, characterized by the following: reduced foliated carriers (RFCs) are major transporters into cells; they are excellent substrates for foyl polyglutamate synthase (FPGS), and are therefore extensively polyglutamicized in tissues / tumors to polyglutamate, which is a potent class of cytotoxic drugs; and they have a relatively short half-life in plasma. Because these classic inhibitors are slowly cleared from tissues due to polyglutamate formation, they are generally cytotoxic and are used infrequently in short infusions, e.g., administered at high doses over approximately 15 minutes.

[0024] Pretrexed is an “atypical” TS inhibitor because it is not polyglutamate-treated and has the following characteristics: RFC is the main transporter into cells; it is not a substrate of FPGS; TS Ki ~0.4 nM, which is similar to the polyglutamate salt of raltitrexed and pemetrexed; it is readily expelled from cells and therefore does not remain well in tissues / tumors; and it has a long plasma half-life.

[0025] Pemetrexed is approved for non-small cell lung cancer and pleural mesothelioma, but has also been proposed for the treatment of platinum-resistant ovarian cancer. For example, in this indication, 500 mg / m² is administered on day 1 of a 21-day cycle. 2 Pemetrexed was administered, along with gemcitabine (Clin Transl. Oncol (2009) 11:35-40) on day 8, followed by 900 mg / m² every 21 days. 2Pemetrexed (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 states that the recommended single-dose pemetrexed dose is 600 mg / m². 2 The article also points out that at the time, antifolate drugs (TS inhibitors are a type of antifolate drug) had not been approved for the treatment of ovarian cancer.

[0026] Another subgroup of this group of TS inhibitor compounds is FR-α-targeting cyclopenteno[g]quinazoline compounds, described in patent applications WO-A-94 / 11354, WO-A-95 / 30673, and WO-A-03 / 020748. For the purposes of this patent application, US5789417, US5747499, US7250511, US7297701, US7528141, US7705006, US7863284, US8063056, US8486955, and US8552016 are incorporated herein by reference. These documents teach that, at doses of 50–25000 mg, particularly 50–5000 mg / m² of patient body surface area (mg / m²),... 2 (That is, approximately 1500 mg / m²) 2 These compounds are administered at doses in the range of 1–100 mg / kg, particularly. Higher doses may be used, and in the case of subcutaneous infusion, the dose range may be increased to 1–1000 mg / kg, preferably 10–250 mg / kg, and especially 30–150 mg / kg.

[0027] Unlike FR-α, these inhibitors can also be used to target other cells expressing FR-β, particularly those associated with rheumatoid arthritis and acute myeloid leukemia. For this purpose, US8466111 teaches a dosage of 50-25000 mg / m². 2 Dosage ranges are listed, but 5-25000 mg / m² are also included. 2 However, it states that for subcutaneous administration, the dose should be increased to 1-1000 mg / kg or 0.1-10 mg / kg. Topical administration at 0.1 to 10 mg / kg is discussed, and oral tablets containing 1, 10, 50, and 100 mg of the compound, as well as injectable solutions at 1, 10, and 50 mg / ml, are disclosed.

[0028] The higher doses used are consistent with raltitrexed and pemetrexed, and this subgroup of TS-inhibiting compounds shares similar characteristics, such as: FR is the major transporter; uptake via FR is slower and more easily saturated than other RFC-mediated antifolate drugs; they are not substrates for FPGS; and the TS Ki is approximately 1.4 nM, similar to the polyglutamate salts of raltitrexed and pemetrexed. However, because this compound is readily expelled from cells that have never been retained in the tissue / tumor, the higher doses are taught to be tolerable.

[0029] Typically, TS requires inhibition for at least 24 hours to induce antiproliferative effects, and sufficient intracellular exposure to the drug for at least 2–3 days of frequent repetition (e.g., weekly) for TS inhibitors to be effective. This is achieved through the polyglutamylation of raltitrexed and pemetrexed, which overcomes the problems of short plasma half-life and short extracellular exposure time. For example, long intracellular exposure for pretrexed is achieved by providing an exceptionally long plasma final half-life with prolonged extracellular exposure.

[0030] Surprisingly, an unusually long half-life was found in the lead compound for the administration of this novel class of FR-α-targeted TS inhibitors to humans. The compound, ONX-0801 (hereinafter referred to as BTG945), has a high affinity for the α-folate receptor (FR-α) and enters cells via FR-α-mediated transport. It possesses a modified glutamate ligand, the L-glu-yD-glu dipeptide, and is therefore not a substrate for FPGS. It binds to α-FR with 70% affinity for folate (FA) (Theti et al., 2003); it binds to FR-β with a similar affinity (van der Heijden et al., 2009), and its affinity for the ubiquitous reduced folate carrier (RFC) is negligible except at high concentrations (Gibbs et al., 2005). This has been found to lead to concentration- and time-dependent inhibition of tumor cell proliferation in vitro.

[0031] Once inside the cell, BTG945 irreversibly binds to the active site of thymidine synthase, which in turn prevents it from playing its normal role in the generation of thymidine monophosphate (dTMP), a key step in DNA synthesis and repair that is also utilized by approved TS inhibitors.

[0032] The first human Phase I clinical trial of BTG945 (identified as ONX801 in this paper) was initiated on September 30, 2009, with trial registration number ISRCCTN79302332. The aim was to find a tolerable 3-hour infusion dose on days 1, 8, and 15 of a 21-day cycle that inhibited tumor cell growth. However, due to the 45 mg / m²... 2The trial was abandoned on March 30, 2011, because the expected effective therapeutic dose was toxic (in which irreversible bronchiolitis obliterans with tissue pneumonia (BOOP) occurred and was believed to increase with cumulative dose). It was concluded that the drug could not be used at the intended dose and regimen because the toxic dose was less than the taught minimum therapeutic dose.

[0033] Given the significant unmet need for targeted treatment cohorts, the inventors have re-evaluated dosing regimens applicable to the drug BTG945 to make it clinically useful. Analysis of undisclosed human plasma drug levels indicates that much lower drug doses are necessary to avoid toxicity. The inventors and the applicant initiated a new Phase I trial, EudraCT3941, at these presumed safe but predicted non-therapeutic doses, in which unexpected efficacy against platinum-resistant tumors, particularly those expressing FR-α, has now been found in human patients at drug levels far below those previously considered necessary and without treatment that restricts BOOP. Using RECIST criteria, this efficacy has been shown as a partial response and disease stabilization, providing progression-free survival, particularly in a high percentage of ovarian cancer patients exhibiting α-folate receptor expression, providing partial response and / or objective response rates (ORR), especially when this expression presents a receptor on the tumor membrane.

[0034] Therefore, although BTG945 has a Ki (1.2 nM vs. 1.4 nM) against isolated target thymidine synthases comparable to raltitrexed and pemetrexed, the dose required to be effective in humans is much lower than previously expected in the preferred target group expressing FR-α, and the efficacy of this compound appears to be far superior to that seen for other members of the TS inhibitor class.

[0035] A particularly surprising and favorable finding was the exceptionally favorable side effect profile of BTG945. No dose-limiting effects were observed, except for BOOP, which itself has been shown to be manageable and / or eliminated with optimized regimens (e.g., dosing 2 or 3 times weekly). No side effects typically associated with thymidine synthase inhibitors, such as neutropenia, diarrhea, and hair loss, were observed, nor were side effects associated with alpha-folate receptor antibody conjugates, such as diarrhea, blurred vision, and nausea. Furthermore, no conventional toxicities associated with cytotoxic chemotherapy, such as myelotoxicity, nephrotoxicity, and neurotoxicity, were observed.

[0036] Some trial patients with cancer received treatment regimens as low as 1 mg / m² in the treatment outlined below. 2The following shows the response. The side effects identified to date indicate that, due to the non-overlapping toxicities, this regimen can be used as a monotherapy or in combination with any currently employed therapy described herein. Such findings in the current clinical context offer a treatment for platinum-resistant cancers that can be used as a monotherapy or in combination with other available treatments, with the potential to prolong PFS in a patient group where a large unmet need remains. In particular, the treatment of the present invention can be used in combination with first-line therapies such as paclitaxel or carboplatin.

[0037] In a first aspect, the present invention provides a compound of formula I for treating cancer.

[0038]

[0039] Or its pharmaceutically acceptable salts or esters, wherein

[0040] (i) The cancer is characterized by being a type of cancer that tends to or becomes refractory or resistant to platinum-based therapies, and

[0041] (ii) The treatment used was at a dose of 1 mg / m². 2 Up to 30mg / m 2 Compound / patient body surface area / application.

[0042] The treatment preferably employs a dosing regimen that results in a sustained plasma drug concentration of 0.5 μM or higher for at least 72 hours. More preferably, the dosing regimen results in a plasma drug concentration of 1 μM to 5 μM immediately after administration for no more than 72 hours, preferably no more than 60 hours. Most preferably, the dosing regimen maintains a plasma drug concentration of 0.1 μM to 2 μM for at least 50% of the treatment cycles.

[0043] The treatment is preferably administered using a dosage regimen selected from the following:

[0044] • Administer 1 to 10 mg / m² at 7-day intervals on days 1, 8, 15, and 22 within a 28-day cycle. 2 The dosage.

[0045] • Administer 6 to 14 mg / m² on days 1 and 15 at 14-day intervals over a 28-day cycle. 2 The dosage.

[0046] • Administer 10 to 30 mg / m² on day 1 within a 21-day cycle. 2 The dosage.

[0047] The cancer is preferably platinum-refractory or drug-resistant. Preferably, the cancer is selected from ovarian cancer, endometrial cancer, mesothelial carcinoma, non-small cell lung cancer, or cancers originating from one of these.

[0048] More preferably, the cancer is selected from those cancers that express α-folate receptor (FR-α), especially those cancers that show higher levels of α-folate receptor than in background non-cancerous tissue. Most preferably, FR-α is expressed on the surface membrane of cancer cells. Most preferably, the cancer is ovarian cancer, such as epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer, but it can also be breast cancer or lung cancer, such as triple-negative breast cancer or non-small cell lung cancer. Particularly preferred cancers to be treated are serous ovarian cancers, such as high-grade serous ovarian cancer (HGSOC), such as those found in a salvage setting.

[0049] To avoid any doubt, platinum-based therapies include, but are not limited to, cisplatin or carboplatin.

[0050] Although 1mg / m 2 Up to 30mg / m 2 Treatment with this dosage is included within the scope of the invention, but a preferred dosage is 3 mg / m². 2 Up to 30mg / m 2 The preferred dosage for the compound / patient body surface area / administration is 5 mg / m². 2 Up to 20 mg / m 2 For the compound / patient body surface area / administration, a more preferred dose is still 8 mg / m². 2 Up to 15 mg / m 2 The optimal concentration of the compound / patient body surface area / administration is 10 mg / m². 2 Up to 15 mg / m 2 And specifically about 12 mg / m 2 For example, 11.5 mg / m³ 2 Up to 12.5 mg / m 2 Compound / patient body surface area / application.

[0051] The dose is preferably administered intraperitoneally (IP) or intravenously (IV). Ip administration reduces the risk of systemic side effects, particularly those affecting the lungs, such as BOOP. Typically, the dose is administered intravenously.

[0052] In a preferred embodiment of the invention, a suitable volume, for example 1 ml to 10 ml, more preferably 2 ml to 6 ml (containing the mg / m³ content), is used. 2An appropriate amount of the compound (as required by dosage) is administered intraperitoneally (IP) by injection (particularly a single injection). Typical such doses are solutions of 2 ml, 3 ml, 4 ml, or 5 ml. These are typically aqueous solutions in saline or water for injection. The compound referred to here is the "active pharmaceutical ingredient," and the "medicine" is a vial having an appropriate volume suitable for a single IP administration. In another preferred embodiment, multiple IP injections are given, each from 1 ml to 10 ml, but more preferably from 2 ml to 6 ml, of a solution (containing an appropriate mg of the active pharmaceutical ingredient). Typical such doses are solutions of 2 ml, 3 ml, 4 ml, or 5 ml. Each "medicine" is provided for single or multiple IP injections and is a vial containing the drug, such as a glass bottle, for example a clear glass bottle, with a stopper, and properly secured to hold the stopper in place, such as an aluminum crimp seal.

[0053] In another preferred embodiment, the compound is conveniently administered by injecting the contents of a vial supplied by a pharmaceutical company into a sterile saline bag as part of a saline droplet. Typically, the "medicine" is a sterile aqueous solution of the active pharmaceutical ingredient BTG945, present in the form of a trisodium salt (preferably a solid dihydrate). The medicine is contained, for example, in a type I clear glass vial (with a stopper and aluminum crimp seal). Each vial is labeled with a strength indicating, for example, a 2-mL solution containing an appropriate mg of the drug substance. Conveniently, the only excipient in the BTG945 trisodium salt medicine can be sterile water for injection. Other components conventional to be found in pharmaceutical compositions can, of course, be provided.

[0054] The vials are typically stored at low temperatures and thawed before use. The required aliquot is then removed from one or more stoppered vials using a sterile syringe. This aliquot is then added directly to the infusion bag for further dilution in 250 mL of 0.9% sterile saline (USP) for injection (whether IP or IV). Once diluted in the infusion bag, the prepared solution should preferably be administered to the patient at ambient temperature within 24 hours. The vials and bag should be protected from light before administration.

[0055] In a preferred embodiment for IP infusion, aliquots are added directly to the infusion bag for further dilution in 10 ml, 15 ml, 25 ml, or 50 ml of 0.9% sterile saline (USP) for IP injection or infusion. Once diluted, the bags are processed as described above.

[0056] More specifically, the present invention treats the patient by infusion (particularly intravenous infusion (IV)) or by single or multiple injections at dosing intervals of 10 to 28 days, more preferably 10 to 21 days, and most preferably about 14 or 21 days. More preferably, when administered IV, the present invention uses 150 mg / m² throughout all infusions. 2 Treatment is administered based on the maximum cumulative concentration of the compound per patient's body surface area. More preferably, this limitation also applies to IP dose administration. More preferably, the maximum cumulative dose is 144 mg / m². 2 .

[0057] The treatment according to the invention preferably delivers the compound in infusions at 14 or 21-day intervals in 21 or 28-day cycles (most preferably a 28-day cycle with two infusions per cycle, once on day 1 and once on day 15). These cycles are preferably repeated until the maximum cumulative dose is reached. Infusions are preferably administered over 0.5 to 3 hours. This is due to the use of doses as low as 1 mg / m². 2 The treatment can be effective, and it will be recognized that an infusion rate of 1 hour will be sufficient. Therefore, infusions can be administered over 0.5 to 1 hour, or over 1 hour but less than 3 hours.

[0058] A more preferred dose for each administration (e.g., infusion) is 1 mg / m². 2 Up to 20 mg / m 2 3mg / m 2 Up to 20 mg / m 2 More preferably 6mg / m 2 Up to 18 mg / m 2 8 mg / m² is still preferred. 2 Up to 16 mg / m 2 For example, 10mg / m 2 Up to 15 mg / m 2 and 10mg / m 2 Up to 12 mg / m 2 The optimal dose is approximately 12 mg / m². 2 Administer 12 mg / m² every 14 days during a 28-day cycle. 2 At the given dosage, it can be seen that the maximum cumulative recommended dose is reached in less than 6 months. Another preferred dosage is 12 mg / m² administered once every 21 days in a 21-day cycle. 2Dosage. Further dosing may be considered if the attending clinician is monitoring for irreversible BOOP or similar side effects. When a patient exhibits signs of BOOP, such as if a CT scan shows an accumulation of inflammatory cellular exudate (AICE), the dose of the drug compound should be reduced. It is also advisable to cautiously discontinue dosing for a short period (e.g., 2 or 4 weeks) and then restart at a lower, preferred dose. ACIE has been observed on radiographic scans, and the patient was found to have stopped developing or by discontinuing 12 mg / m². 2 The medication was administered for 2 weeks, followed by a dose of 6 mg / m². 2 Restart until 144 mg / m 2 At the maximum cumulative dose, the patient's condition was alleviated.

[0059] In a particularly preferred embodiment, the administered preferred dose achieves a blood concentration of about 0.5 µM or greater of the compound for at least 72 hours, preferably less than 2.0 µM for at least 36 hours, more preferably about 0.7 µM or greater for at least 36 hours, or even more preferably about 0.9 µM or greater for at least 24 hours, with a blood concentration of less than about 1.5 µM also being more preferred. This level is particularly preferred for IV administration. Preferably, the plasma level of the drug is maintained above 1 µM for no more than 72 hours. Most preferably, the dosing regimen maintains a plasma concentration of the drug at 0.1 µM to 2 µM for at least 50% of the treatment cycles. Most preferably, it is 0.1 to 1 µM for 50% of the cycles.

[0060] A particularly preferred cohort of suitable cancers for the treatment of this invention is those of female patients with newly diagnosed, histologically confirmed high-risk advanced (FIGO III-IV) BRCA-mutated high-grade serous or high-grade endometrioid ovarian cancer, primary peritoneal cancer, and / or fallopian tube cancer.

[0061] Stage III patients preferably have undergone optimal debulking surgery (early or intermittent debulking). Stage IV patients preferably have undergone biopsy and / or early or intermittent debulking surgery.

[0062] Especially preferred are cancers in patients who have completed first-line platinum (e.g., carboplatin or cisplatin) therapy (intravenous or intraperitoneal).

[0063] This therapy is most effective for treating cancers that express the alpha-folate receptor, particularly those expressing it in at least 25% of the cancer cells in their membranes and / or cytoplasm. It is more effective for cancers expressing the alpha-folate receptor in at least 50% of the cancer cells, and most effective for those expressing it in at least 75% of the cancer cells. These levels can be determined by histological studies of biopsy tissue using an alpha-folate-specific antibody linked to an indicator known in the art. For maximum efficacy, the cancer should express FR-α on its cell membrane.

[0064] Kurosaki et al. (2016) Int. J Cancer: 138, 1994–2002 VC 2015 UICC described an example of a method for assessing α-folate receptor expression on the membrane and in the cytoplasm, in which the expression of FR-α in the tumor was studied on a total of 164 EOCs (including marginal malignancies) in FFPE (formalin-fixed paraffin-embedded) specimens using the specific antibody NCL-L-FRα (clone BN3.2; Leica Biosystems, UK). Immunohistochemical staining of whole slides was performed using a BenchMark XT automated slide stainer and an iView DAB assay kit, according to the manufacturer's instructions (Ventana Medical Systems, Tucson, AZ). Sections were dewaxed, water-replenished, and antigen-retrieved with Cell Conditioning Solution 1 (Ventana Medical Systems), followed by incubation for 30 min with 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 as follows: <1% positive tumor cells stained negative, 1–25% positive tumor cells stained weakly positive (11), 25–75% stained moderately positive (21), and >75% stained strongly positive (31). Fr-α staining was scored by two independent observers in a blinded manner. Any discrepancies could be resolved by combined examination with a dual-head microscope.

[0065] Alternative methods for noninvasively determining a patient's suitability for treatment use, employing the assay of the present invention targeting α-folate receptors 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 for ovarian cancer. At the site where α-folate receptors are found on the membrane, they can fall into circulating physiological fluids (such as serum). In the case of ovarian cancer, the research team found elevated levels of circulating α-folate receptors (FRα) in patients with ovarian cancer. This was the case even in the early stages of cancer.

[0066] Kurosaki et al. (2016) Int. J. Cancer: 138, 1994-2002 further confirmed that serum α-folate receptor levels can be used to diagnose epithelial-originating ovarian cancer and associated high serum FR-α with shorter PFS.

[0067] In addition to the ovarian tissue-derived cancers specified above, cancers overexpressing FR-α suitable for treatment by the methods and protocols of this invention include uterine cancer, mesothelial carcinoma, renal cell carcinoma, gastric cancer, lung cancer, colon cancer, choroid plexus cancer, and brain cancer. The highest level of overexpression was detected in non-mucinous ovarian cancer (Toffoli et al., 1998), where >90% of patients' tumors showed FR-α overexpression, but high levels of expression were also shown in papillary serous endometrial carcinoma (Allard et al., 2007), renal cell carcinoma, and NSCLC (Parker et al., 2005). Furthermore, breast cancer, primary CNS, colon cancer, and gastric cancer showed varying degrees of expression (Low and Kularatne, 2009).

[0068]

[0069] Table 1: α-Folic acid receptor expression in selected tumors (Weitman 1994; Garin-Chesa 1993; Bueno 2001)

[0070] The compounds used in this invention have the IUPAC nomenclature N-{N-{4-[N-((6S)-2-hydroxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenteno[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoyl}-L-γ-glutamyl}-D-glutamic acid or its salts, and are referred to herein as BTG945, wherein its trisodium salt has the general formula II.

[0071]

[0072] The alternative name is D-glutamic acid, N-[4-[2-propyn-1-yl-[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenteno[g]quinazolin-6-yl]amino]benzoyl]-L-γ-glutamyl-, sodium salt.

[0073] It is also known that the (6RS) racemic mixture is the active form containing the said active (6S). It will be appreciated that if they are used as racemates, the dosage may need to be at the upper limit of the said range, since they contain only 50% of the (6S) form.

[0074] When the compound is provided in ester form, it can be a simple alcohol conjugated with one or more carboxylate groups, or it will be at the sodium-bonded position in the above formula. For regulatory purposes, the resulting alkyl ester can be any of those alkyl esters equivalent to the parent compound. A suitable pharmaceutically acceptable ester form of cyclopentenyl[g]quinazoline for use in the treatment of the present invention is, for example, an ester with an aliphatic alcohol having up to 6 carbon atoms, such as a methyl ester, ethyl ester, or tert-butyl ester. Due to the presence of three carboxyl groups, the salt or ester can be a mono-acid-di-salt or mono-acid-di-ester, or a di-acid-mono-salt or di-acid-mono-ester, or even a tri-salt or tri-ester.

[0075] Suitable pharmaceutically acceptable salt forms of the compounds used in the treatment of this invention are, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, or maleic acid; or alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., calcium) salts, or ammonium (e.g., tetra(2-hydroxyethyl)ammonium) salts. The most preferred form is the trisodium salt.

[0076] The cyclopentene[g]quinazoline or salts described in the treatment of this invention are believed to be used at least in part as anticancer agents due to their ability to inhibit the enzyme thymidylate synthase.

[0077] Cyclopenteno[g]quinazoline or salt compositions may be in forms suitable for oral use, such as tablets, capsules, aqueous or oily solutions, suspensions, or emulsions; forms suitable for topical use, such as creams, ointments, gels, or aqueous or oily solutions or suspensions; forms suitable for nasal use, such as nasal sprays, nasal drops, or nasal suppositories; forms suitable for vaginal or rectal use, such as suppositories; forms suitable for inhalation, such as fine powders like dry powder, microcrystalline forms, or liquid aerosols; forms suitable for sublingual or oral use, such as tablets or capsules; or forms suitable for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular, or infusion use), such as sterile aqueous or oily solutions, emulsions, or suspensions. Typically, these compositions can be prepared in a conventional manner using conventional excipients.

[0078] The preferred form of the compound is for parenteral administration. Particularly preferred are compounds for infusion, wherein the compound is preferably formulated with saline or water for injection. Alternatively, it may be provided in a solid form readily miscible with said water or saline. For example, a dihydrate of a trisodium salt.

[0079] In addition to the cyclopenteno[g]quinazoline used in this invention, the composition may also contain one or more other anticancer or palliative substances selected from, for example, other antimetabolites, DNA interactors, immunotumor agents, tumor angiogenesis inhibitors or signal transduction inhibitors or other inhibitors of dysregulated pathways in tumors.

[0080] However, those skilled in the art will recognize that, more routinely, such combinations are applied separately, but in a manner that is coordinated with treatment visits to the application site.

[0081] A preferred approach used in conjunction with the compounds for treating cancer according to the first aspect of the invention is to utilize one or more other anticancer agents selected from cisplatin, carboplatin, doxorubicin, bevacizumab / gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, and paclitaxel bound to albumin via nanoparticles, olaparib, Rubraca (rucaparib), Zejula (niraparib), Tecentriq (atezilumab), and Bavercio (avercitabine).

[0082] Various combinations may also include bevacizumab with paclitaxel, pegylated liposomal doxorubicin, or topotecan. Other examples of such combinations are illustrated in the following examples.

[0083] Particularly advantageous is that the dosage of these combination drugs used in the first aspect of the invention is lower than that currently prescribed. This is especially true because resistance to BTG945 has been found to be non-cross-linked with resistance to these other drugs, and the expected toxicity to target cancer cells is often cumulative. Therefore, in addition to the exemplary dosing regimens provided in the embodiments herein, other drugs at lower doses or lower dose frequencies may be used.

[0084] In a second aspect, the present invention provides a method for treating a patient suffering from cancer, wherein the cancer is characterized as being a type that tends to or becomes refractory to or resistant to platinum-based therapies, and wherein the treatment is performed at a dose of 1 mg / m². 2 Up to 30mg / m 2 Compounds / Patient body surface area / Compound of formula I administered

[0085]

[0086] Or its pharmaceutically acceptable salts or esters are used to treat cancer.

[0087] The cancer to be treated is as described above with respect to the first aspect of the invention. The method is preferably performed by intraperitoneal (IP) or intravenous (IV) administration of a compound, salt, or ester.

[0088] The treatment preferably employs a dosing regimen that results in a sustained plasma drug concentration of 0.5 μM or higher for at least 72 hours. More preferably, the dosing regimen results in a plasma drug concentration of 1 μM to 5 μM immediately after administration for no more than 72 hours, preferably no more than 60 hours. Most preferably, the dosing regimen maintains a plasma drug concentration of 0.1 μM to 2 μM for at least 50% of the treatment cycles.

[0089] The treatment is preferably administered using a dosage regimen selected from the following:

[0090] • Administer 1 to 10 mg / m² at 7-day intervals on days 1, 8, 15, and 22 within a 28-day cycle. 2 The dosage.

[0091] • Administer 6 to 14 mg / m² on days 1 and 15 at 14-day intervals over a 28-day cycle. 2 The dosage.

[0092] • Administer 10 to 30 mg / m² on day 1 within a 21-day cycle. 2 The dosage.

[0093] Although 1mg / m 2 Up to 30mg / m 2 Treatment with this dosage is included within the scope of the invention, but a preferred dosage is 3 mg / m². 2 Up to 30mg / m 2 The preferred dosage for the compound / patient body surface area / administration is 5 mg / m². 2 Up to 20 mg / m 2 For the compound / patient body surface area / administration, a more preferred dose is still 6 mg / m². 2 Up to 18 mg / m 2 For the compound / patient body surface area / administration, a more preferred dose is still 8 mg / m². 2 Up to 15 mg / m 2 The optimal concentration of the compound / patient body surface area / administration is 10 mg / m². 2 Up to 15 mg / m 2 And specifically about 12 mg / m 2 For example, 11.5 mg / m³ 2 Up to 12.5 mg / m 2Compound / patient body surface area / application.

[0094] More preferably and particularly, the method involves infusion of the dose at intervals of 10 to 28 days, more preferably 10 to 21 days, and most preferably at dosing intervals of about 14 or 21 days. More preferably, when administered IV, the present invention uses a dose of 150 mg / m², taking into account all infusions. 2 Treatment is performed based on the maximum cumulative dose of the compound / patient body surface area. More preferably, this limitation also applies to IP dose administration. More preferably, the maximum cumulative dose is 144 mg / m². 2 .

[0095] The method according to the invention preferably provides the compound in an infusion form at intervals of 14 or 21 days, most preferably 28 days, within a 21 or 28-day cycle. These cycles are preferably repeated until the maximum cumulative dose is reached. Infusion is preferably performed over 0.5 to 3 hours. Infusion can be performed over 0.5 to 1 hour, more than 1 hour, or within 1 to 3 hours. This is achieved by using doses as low as 1 mg / m³. 2 Or 3mg / m 2 The treatment can be effective, so it will be recognized that an infusion rate of 1 hour will be sufficient.

[0096] The preferred dose for each infusion is 1 mg / m². 2 Up to 20 mg / m 2 More preferably 10 mg / m 2 Up to 15 mg / m 2 The optimal dose is approximately 12 mg / m². 2 Administer 12 mg / m² every 14 days during a 28-day cycle. 2 At this dosage, it can be seen that the maximum cumulative recommended dose can be reached in less than 6 months. This is achieved by 12 doses of 12 mg / m². 2 Infusion of the compound (providing 144 mg / m²) 2 The total cumulative amount is composed of [amount not specified]. Another preferred dosing schedule is to administer 12 mg / m² every 21 days in a 21-day cycle. 2 Dosage. If the attending clinician is monitoring for irreversible BOOP or similar side effects, further dosing may preferably be considered.

[0097] The second aspect of the invention also provides a treatment using a compound of formula I in combination with a therapeutically effective amount of one or more other anticancer agents.

[0098] The other anticancer agents used in this combination therapy are preferably selected from cisplatin, carboplatin, doxorubicin, bevacizumab / gemcitabine, topotecan, paclitaxel, docetaxel, etoposide, paclitaxel bound to albumin nanoparticles, olaparib, Rubraca (rucaparib), Zejula (niraparib), Tecentriq (atezil), Bavercio (avezil), and Keytruda (pembrolizumab).

[0099] Various combinations may also include bevacizumab with paclitaxel, pegylated liposomal doxorubicin, or topotecan. Other examples of such combinations are illustrated in the following examples.

[0100] The preferred combination is to use paclitaxel or carboplatin or both.

[0101] In view of the nature of the side effects observed in the lungs in failed trials, the inventors also envision that the dosing regimen of the present invention could also incorporate the administration of steroids to reduce lung inflammation.

[0102] In a third aspect, the present invention provides a method for treating a patient suffering from cancer, wherein the cancer is characterized as being a type that tends to or becomes refractory to or resistant to platinum-based therapies, and wherein the treatment is performed at a dose of 1 mg / m². 2 Up to 30mg / m 2 Compounds / Patient body surface area / Compound of formula I administered

[0103]

[0104] Or, in combination with a pharmaceutically acceptable salt or ester thereof, an anti-inflammatory corticosteroid. Preferred corticosteroids are selected from the group consisting of: prednisone, methylprednisolone, dexamethasone, and prednisolone and hydrocortisone.

[0105] In a fourth aspect, the present invention provides a novel dosage form of the compound of formula I.

[0106]

[0107] The dosage form comprises a single dose unit containing the compound or a pharmaceutically acceptable salt or ester thereof, characterized in that the amount of the compound in the dose unit is from 0.5 mg to 40 mg.

[0108] More preferably, the dosage unit of the present invention comprises 1 mg to 30 mg of a compound of formula I or a salt or ester thereof. Even more preferably, the dosage unit comprises 5 mg to 26 mg of a compound of formula I. Most preferably, the dosage unit comprises 10 mg to 24 mg of a compound of formula I or a salt or ester thereof.

[0109] The preferred dosage form will be a container for a Formula I compound or its salt or ester, more preferably a sodium salt, in the form of a sterile solid or an aqueous solution in a medium such as water for injection or saline. The sterile solid is preferably BTG945 or its salt or ester free of other substances. Such a container should allow the liquid contained therein, or added thereto when provided in solid form, to be drawn into the syringe in an amount appropriate to the patient's body surface area to transfer 1 mg / m². 2 Up to 30mg / m 2 The required dose.

[0110] Preferably, the dosage is provided in an aqueous solution in a vial. Such a dosage form or formulation would preferably be a vial containing 1 ml to 30 ml, more preferably 1 ml to 20 ml, still more preferably 1 ml to 10 ml, and most preferably 2 ml to 6 ml of an aqueous solution of the compound for treatment. Alternatively, the dosage is provided in solid form of the compound, which can be used for treatment without liquid. Thus, the preferred vial of the present invention would contain 0.5 mg to 40 mg of the compound in an aqueous solution of 1 ml to 30 ml, still more preferably 5 mg to 26 mg of the compound in an aqueous solution of 1 ml to 20 ml, and most preferably 10 mg to 24 mg of the compound in an aqueous solution of 1 ml to 10 ml, for example, about 6 mg or 12 mg of the compound in an aqueous solution of 2 ml to 6 ml.

[0111] Those skilled in the art will recognize that pharmaceuticals are expensive commodities, and it is desirable not to waste compounds unnecessary for a given treatment. Since BTG945 may be toxic above the currently taught doses, exceeding the doses required in a clinical setting is inappropriate. Therefore, the preferred dose per patient surface area is 6 mg / m². 2 Or 12mg / m 2 Furthermore, patients in developed countries typically have 1m 2 Up to 2.5m 2 The surface area of ​​patients with abnormally high BMI is typically limited to 2m². 2 It can be seen that, whether in dry solid or solution form, the novel preferred vials contain 6 mg to 24 mg of the drug compound, more preferably 10 mg to 24 mg. Therefore, vials containing 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 invention. Particularly those drugs in which the drug is in the form of dry BTG945 salt and / or its dehydrated form, or a simple solution in water for injection or saline.

[0112] The compounds used for the treatment of the present invention can be synthesized as described in the aforementioned patent application or as described in the most recent patent US8809526 (Onyx) and patent application US2013 / 0345423 (Onyx). Attached Figure Description

[0113] Figures 1 to 5 Clinical results of trials using the treatment of this invention in humans are shown.

[0114] Figure 1 : Shows the percentage change in tumors generated in patients using RECIST criteria during the dose escalation phase of the trial in Example 1, with weekly schedules indicated by asterisks and tumors expressing α-folate indicated by crosses.

[0115] Figure 2 : Shows the percentage change in tumor size as measured by CA125 levels during the escalation phase of the trial as in Example 1. Numbers represent doses in mg / m2, letters indicate once-weekly (w) or once-bi-weekly (f), and crosses indicate tumors expressing α-folate.

[0116] Figure 3 : Shows the percentage change in tumor size in patients using RECIST criteria during the extended phase of the trial in Example 1, which administered 12 mg / m² every 14 days over a 28-day period. 2 Dosage. A cross indicates tumors expressing α-folate.

[0117] Figure 4 This shows the percentage change in tumor size in patients measured using CA125 levels, as in the extended phase of the trial described in Example 1, which administered 12 mg / m² every 14 days over a 28-day period. 2 Dosage. A cross indicates tumors expressing α-folate.

[0118] Figure 5 : Shows the mean blood concentration (µM) of compound ONX-0801 / BTG 945 in patients over time (hours) at different dosing regimens during the escalation phase of the trial prior to selecting the extended dose.

[0119] Example

[0120] The invention will now be illustrated by way of the following non-limiting embodiments. Other embodiments will arise in the minds of those skilled in the art based on these embodiments.

[0121] The preferred target cancers to be treated with the following example regimens will be present in patients with the following conditions:

[0122] • Histologically confirmed epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer.

[0123] Platinum-resistant / refractory disease is defined as disease progression (resistance) within 180 days after the last dose of platinum-based therapy, or disease progression without response or despite recent platinum-based therapy (refractory).

[0124] • Received up to three chemotherapy treatments for platinum-sensitive diseases, the most recent platinum-containing, and had no prior treatment for platinum-resistant diseases.

[0125] Example 1: Using 1 mg / m 2 Up to 12 mg / m 2 BTG 945 (the trisodium salt form of compound II) as a monotherapy Treatment of patients

[0126] Methods: A 3+3 dose-escalation design was used, and two IV schedules were explored. Schedule A, once-weekly (QW), and Schedule B, once-every-two-week (Q2W). In both schedules, cycles consisted of 4 weeks, and treatment was discontinued after 6 cycles. An expanded cohort was initiated to evaluate clinical activity in patients with high-grade serous ovarian cancer (HGSOC) that overexpressed FR-α.

[0127] Results: Each of the 21 patients was treated according to schedules A and B, which used doses ranging from 1 to 6 mg / m². 2 and 2-12 mg / m 2 The dose-limiting toxicity for timetable A was G3 cellulitis; no dose-limiting toxicity was observed for timetable B. The most common toxicities were fatigue (15 / 42, 36%), nausea (9 / 42, 21%), and dyspepsia (5 / 42, 12%). In timetable A, at a dose of 4 mg / m², two patients experienced suspected drug-related changes (Dlco decrease >15%) in pulmonary function tests at cycles 5 and 6, respectively. No suspected drug-related Dlco decreases were observed in patients treated in timetable B. Grade 3–4 diarrhea, mucositis, or neutropenia were observed in either cohort. 12 mg / m² 2 The Cmax, AUC, and half-life were 4952 ng / mL, 85170 h*ng / mL, and 26 h, respectively. Preclinical PK-PD modeling aimed to achieve concentrations of 0.05–1 μM, and at 4 mg / mL... 2 At doses of 0.05-1 μM and above, a concentration of 0.05-1 μM was achieved for 48 hours.

[0128] Above 6 mg / m 2At the specified dose, concentrations above 0.5 µM were achieved for 72 hours. Evidence of thymidine synthase inhibition was observed using FLT PET imaging. See Cancer Res 68.3827-3834.2008 (Pillai et al.).

[0129] Based on safety and pharmacokinetic considerations, the Phase II recommended dose (RP2D) for BTG945 (then ONX801) was 12 mg / m². 2 Q2W was initiated, and an expansion cohort of HGSOC patients was started. Five HGSOC patients achieved partial remission (PR) in the dose escalation cohort. In the expanded cohort of HGSOC patients, as of the date of this application, 5 out of 11 patients had PR. A sample of the patient records from 8 out of 11 patients in the expanded cohort was analyzed. Following BTG945 treatment, 4 out of 4 AFR+ve patients had PR and 4 out of 4 AFR-ve patients did not have PR. RECIST and CA125 remission were shown... Figures 1 to 4 middle.

[0130] Conclusion: The RP2D of BTG945 is 12 mg / m². 2 Q2W. In RP2D, multiple HGSOC patients with AFR overexpression achieved PR, thus necessitating further randomized, pre-specified phase II clinical trials with biomarkers.

[0131] Example 2: Combination therapy using BTG945 and other anticancer therapies

[0132] On days 1 and 15 of a 28-day cycle, the medication was administered in saline solution at a concentration of 12 mg / m³. 2 BTG945 is administered intravenously over 1 hour, for a maximum of 6 cycles. One or more of the following exemplary treatment regimens may be used in conjunction with this treatment:

[0133] Example 2.1 at 40-50 mg / m 2 IV administration of liposomal doxorubicin 30 minutes later; one cycle is every 21 days.

[0134] Example 2.2 Gemcitabine was administered intravenously at 1000 mg / m² for 30 minutes on days 1 and 8; each cycle lasted 21 days.

[0135] Example 2.3 1.25-1.5 mg / m² on days 1-5 2 IV. Topotecan administered 30 minutes later; one cycle lasts 21 days.

[0136] Example 2.4 Once a week at 80 mg / m² 2 IV. Paclitaxel administered 1 hour later

[0137] Example 2.5 75-100 mg / m² every 21 days 2 IV. Docetaxel administered 1 hour ago

[0138] Example 2.6 50 mg / m² every 28 days 2 Etoposide was administered daily for 21 days.

[0139] Example 2.7 Paclitaxel nanoparticles bound to albumin were administered IV at 100 mg / m² every 28 days, once a week (days 1, 8, and 15), for 30 minutes.

[0140] Example 2.8 Administer Keytruda and 945 intravenously at 200 mg every 3 weeks in any form of chemotherapy.

[0141] Example 3: Combination therapy using BTG945 and other anticancer therapies for platinum-sensitive cancers

[0142] On days 1 and 15 of a 28-day cycle, the medication was administered in saline solution at a concentration of 12 mg / m³. 2 BTG945 is administered intravenously over 1 hour, for a maximum of 6 cycles. One or more of the following exemplary treatment regimens may be used in conjunction with this treatment:

[0143] Example 3.1 Day 1 at 135 mg / m 2 IV. Administer paclitaxel 24 hours later, plus on day 2 at 100 mg / m². 2 Cisplatin administered via intraperitoneal injection (can reduce the dose to 75 mg / m²) 2 ) plus 60 mg / m² on day 8 2 Paclitaxel is administered via IP for 6 or more cycles, as long as there is a disease response. On day 2, the cisplatin dose can be reduced to 75 mg / m² IP; some clinicians use 135 mg / m². 2 Paclitaxel was administered IV 3 hours later, followed by cisplatin at 75 mg / m² IP. Both administrations were performed on day 1 and were based on outpatient settings.

[0144] Example 3.2 Carboplatin Treatment. The normal range for the AUC of carboplatin used in the treatment of ovarian cancer is 5 to 7.5; patients who have received extensive prior chemotherapy or radiotherapy should start with an AUC < 5.

[0145] Example 4: Utilization of BTG945 and other anti-inflammatory drugs for platinum-sensitive cancers in which patients cannot tolerate IP administration. Combination therapy for cancer

[0146] On days 1 and 15 of a 28-day cycle, the medication was administered in saline solution at a concentration of 12 mg / m³. 2 BTG945 is administered intravenously over 1 hour, for a maximum of 6 cycles. One or more of the following exemplary treatment regimens may be used in conjunction with this treatment:

[0147] Example 4.1 On day 1, paclitaxel was administered IV at 175 mg / m² for 3 hours, followed by cisplatin IV at AUC 7.5 for 1 hour; each cycle lasted 21 days, for a total of 6 cycles, or

[0148] Example 4.2 On day 1, docetaxel was administered IV at 75 mg / m² for 1 hour, followed by cisplatin IV at AUC 5 for 1 hour; each cycle lasted 21 days, for a total of 6 cycles.

[0149] Example 5: Utilization of BTG945 and other anticancer drugs for platinum-sensitive stage III and IV platinum-sensitive recurrent cancer Combination therapy

[0150] Platinum-sensitive relapse: If relapse occurs >6 months after initial or subsequent complete clinical remission with platinum-based chemotherapy, 12 mg / m² should be administered intravenously in saline solution over 1 hour on days 1 and 15 of a 28-day cycle (up to 6 cycles) in combination with one of the following platinum-based IV regimens. 2 BTG945 is used to treat patients. The choice depends on several factors, such as pre-existing comorbidities, previous toxicities, and physician and patient preferences. The regimen is as follows:

[0151] Example 5.1 Cisplatin AUC 5 IV injection plus 30 mg / m 2 IV administration of liposomal doxorubicin 30 minutes later; one cycle is every 28 days, for a total of 6 cycles.

[0152] Example 5.2 Paclitaxel was administered IV at 175 mg / m² 3 hours later, followed by carboplatin AUC 5 (Calvert) IV 1 hour later; each cycle lasted 21 days, for a total of 6 cycles.

[0153] Example 5.3 Once a week, on days 1, 8, and 15, at 80 mg / m² 2 IV paclitaxel 1 hour later, followed by carboplatin IV administration on day 1 with an AUC of 6 1 hour later; one cycle is every 21 days, for a total of 6 cycles.

[0154] Example 5.4 at 75 mg / m 2 IV docetaxel 1 hour later, followed by IV carboplatin AUC 5 1 hour later; one cycle every 21 days, for 6 cycles.

[0155] Example 5.5 Day 1 and Day 8 at 1000 mg / m 2 IV gemcitabine 30 minutes after administration, plus carboplatin IV administration on day 1 with an AUC of 4 1 hour; one cycle is 21 days, for a total of 6 cycles.

[0156] Example 6: Utilization of BTG945 and other anticancer drugs for platinum-sensitive stage III and IV platinum-sensitive recurrent cancer Combination therapy

[0157] Bevacizumab alone or in combination with carboplatin / gemcitabine can be considered, but its use remains controversial. Platinum-sensitive relapse: If relapse occurs > 6 months after initial or subsequent complete clinical remission with platinum-based chemotherapy, 12 mg / m² should be administered intravenously in saline solution over 1 hour on days 1 and 15 of a 28-day cycle (up to 6 cycles) in combination with one of the following platinum-based IV regimens. 2 BTG945 was used to treat the patient.

[0158] Example 6.1 Bevacizumab was administered IV at 15 mg / kg (initially for 90 minutes, then for 60 minutes, and finally for 30 minutes for subsequent infusions); every 21 days was one cycle until disease progression, regardless of prior platinum-based responses.

[0159] Example 6.2 Day 1 and Day 8 at 1000 mg / m 2 Gemcitabine was administered intravenously 30 minutes after the first dose of carboplatin (AUC 4) on day 1; this was repeated every 21 days for 6–10 cycles, followed by bevacizumab intravenously at 15 mg / kg on day 1 before gemcitabine and carboplatin, and continued until disease progression or unacceptable toxicity occurred.

[0160] Example 6.3 Bevacizumab was administered IV at 10 mg / kg every 14 days, in combination with one of the following IV chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan (topotecan was administered once weekly).

[0161] Example 6.4 Bevacizumab was administered IV at 15 mg / kg every 21 days in combination with topotecan (one cycle every 21 days).

[0162] Example 6.5 Bevacizumab was administered IV at 15 mg / kg (initially for 90 minutes, then for 60 minutes, and finally for 30 minutes for subsequent infusions); every 21 days was one cycle until progression.

[0163] Example 6.6 Bevacizumab was administered IV at 10 mg / kg on days 1 and 15, followed by topotecan IV at 4 mg / m² on days 1, 8, and 15, in a cycle of 28 days.

[0164] Example 7: Stage III and IV platinum-sensitive recurrent cancer with platinum-sensitive, drug-resistant, or refractory BRCA mutations Combination therapy using BTG945

[0165] For patients diagnosed with BRCA mutations in patients who have received three or more prior chemotherapy treatments (as detected by an FDA-approved test, BRACAnalysis CDx™): Administer 12 mg / m² intravenously in saline solution on days 1 and 15 of a 28-day cycle. 2 BTG945 1 hour, for up to 6 cycles, while continuing PO BID administration of olaparib 400 mg.

[0166] In the European Union, olaparib 400 mg PO BID is approved as a monotherapy for maintaining the treatment of patients with platinum-sensitive, recurrent BRCA-mutated (germ cell and / or somatic) advanced serous epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who have shown a response (complete or partial) to platinum-based chemotherapy.

Claims

1. A compound of formula (I) for the treatment of cancer. Or its pharmaceutically acceptable salts or esters, wherein (i) The cancer is characterized by being a type of cancer that tends to or becomes refractory or resistant to platinum-based therapies, and (ii) The dosage used in the treatment is 1 mg / m². 2 Up to 30mg / m 2 Compound / patient body surface area / application.

2. The compound for treatment as claimed in claim 1, characterized in that... The cancer is platinum-refractory or platinum-resistant.

3. The compound for treatment as described in claim 1, characterized in that... The cancers mentioned are selected from ovarian cancer, endometrial cancer, mesothelial carcinoma, non-small cell lung cancer, and cancers derived from one of these.

4. The therapeutic compound as described in claim 1, 2, or 3, characterized in that... Selected from those that express α-folate receptor (FR-α).

5. The compound for treatment as described in claim 4, characterized in that... The cancer expressed α-folate receptors at levels higher than those in background non-cancer tissue.

6. The compound for treatment as described in any one of the preceding claims, characterized in that... The cancer in question is ovarian cancer.

7. The compound for treatment as described in any one of the preceding claims, characterized in that... The cancer in question is epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer.

8. The therapeutic compound as described in claim 6 or claim 7, characterized in that... The cancer in question is serous ovarian cancer.

9. The compound for treatment as claimed in claim 8, characterized in that... The cancer in question is high-grade serous ovarian cancer (HGSOC).

10. The compound for treatment as described in any one of the preceding claims, characterized in that... The dose is administered intraperitoneally (IP) or intravenously (IV).

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