MXPA06008954A - Anti-cancer therapies - Google Patents

Abstract

Methods for the treatment of cancer are described. In particular, methods for treatment of cancer comprising administration of glufosfamide alone or in combination with another anticancer agent are disclosed.

Description

TECHNICAL FIELD THERAPIES The present invention is generally concerned with methods for the treatment of cancer. In particular, the invention is concerned with methods for cancer treatment comprising the administration of glufosfamide alone or in combination with another anticancer agent.

BACKGROUND OF THE INVENTION "Cancer" generally refers to one of a group of more than 100 diseases caused by the uncontrolled abnormal growth of cells that can spread to attached tissues or other parts of the body. Cancer cells can form a solid tumor, in which the cancer cells are kneaded together or exist as dispersed cells, such as in leukemia. Normal cells divide (reproduce) until maturation is obtained and then only as necessary for the replacement of damaged or dead cells. Cancer cells are often referred to as "malignant," because they divide endlessly, eventually populating almost near the cells and dispersing to other parts of the body. The tendency of cancer cells to spread from one organ to another or from one part of the body to another distinguishes them from being benign tumor cells, which grow excessively but do not spread to other organs or parts of the body. Malignant cancer cells eventually metastasize and spread to other parts of the body via the bloodstream or the lymphatic system, where they can multiply and form new tumors. This kind of tumor advancement makes cancer a deadly disease. Although there have been great improvements in the diagnosis and treatment of cancer, many people die of cancer each year and their deaths are commonly due to metastases and cancers that are resistant to conventional therapies. Current methods for the treatment of advanced and / or metastatic malignancies previously treated with chemotherapy (that is, cancers refractory to chemotherapy are inappropriate). Curative therapy is not possible in patients with advanced malignancies who have relapsed after chemotherapy. There is a need in the art for improved methods for the treatment of advanced and / or metastatic malignancies previously treated with chemotherapy. The present invention addresses these needs and provides methods for the treatment of cancer.

BRIEF DESCRIPTION OF THE INVENTION The present invention is generally concerned with cancer treatment methods. In particular, the invention is concerned with the administration of glufosfamide alone or in combination with another anticancer agent for the treatment of cancer. In addition, the present invention provides methods for the treatment of advanced and / or metastatic malignancies previously treated with chemotherapy. In a first aspect, the present invention provides a method for the treatment of cancer, such method comprises administering glufosfamide and gemcitabine in combination to a subject in need of such treatment. A variety of cancers can be treated by this method, for example pancreatic cancer, colorectal cancer, breast cancer and the like. In one embodiment, glufosfamide is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than eight dosing cycles, each cycle comprising an infusion of glufosfamide in the range of: a) about 1.5 about 8.0 g / m2; approximately 1.5 to 6.0 g / m2; about 1.5 to 4.5 g / m2; about 4.5 to 8.0 g / m2; about 4.5 to about 6.0 g / m2 or about 4.5 to about 5.0 g / m2 or more in an infusion period of 1-6 hours once every three weeks; b) about 1.5 to about 3.0 g / m2 or about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours for three consecutive days (days 1, 2 and 3) every three weeks; c) approximately 1.5 to approximately 2.0 g / m2 in an infusion period of 1-6 hours once a week; or d) about 1.5 to about 8.0 g / m2; about 1.5 to about 6.0 g / m2 or about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks. In one embodiment, glufosfamide is administered by 1, 2, 3, 4 or more than four dosing cycles, wherein each cycle is a seven-week cycle. In one embodiment, glufosfamide is administered for 1, 2, 3, 4, 5, 6 or more than six dosing cycles, wherein each cycle is a three-week cycle. In one embodiment, glufosfamide is administered for 1, 2, 3, 4, 5, 6 or more than six dosing cycles, wherein each cycle is a four week cycle. In one embodiment, gemcitabine is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than eight dosing cycles and each cycle comprises an infusion of gemcitabine of: a) about 1000 mg / m2 over a period about 30 minutes; b) about 2200 mg / m2 over a period of about 30 minutes or c) about 1500 mg / m2 over a period of about 150 minutes. In one embodiment, gemcitabine is administered in weeks 1, 2, 3, 5, 6 and 7 of a dosing cycle of 1, 2, 3, 4 or more than four dosing cycles, where each cycle is a cycle of seven weeks In one embodiment, gemcitabine is administered in weeks 1, 2, and 3 of a dosing cycle for 1, 2, 3, 4, 5, 6, or more dosing cycles, wherein each cycle is a four-week cycle. Gemcitabine is administered one day before, one day after or on the same day with the administration of glufosfamide. In one embodiment, gemcitabine is administered on the same day as the administration of glufosfamide, about 30 minutes to about 4 hours after the administration of glufosfamide. In a second aspect, the present invention provides a method of treatment comprising administering glufosfamide to a subject in need of treatment of advanced and / or metastatic malignancies previously treated with chemotherapy. In one aspect, the present invention provides methods for the treatment of pancreatic cancer refractory to gemcitabine. In another aspect, the invention provides a method for the treatment of cancer comprising administering an agent with antitumor activity, such as bevacizumab, irinotecan, exatecan, pemetrexed or cisplatin, in combination with glufosfamide or in combination with glufosfamide and gemcitabine.

DETAILED DESCRIPTION OF THE INVENTION In one aspect of the invention, glufosfamide and gemcitabine are administered in combination to a subject in need of cancer treatment, a variety of cancers can be treated by this method, an example of a cancer that can be treated by This method is pancreatic cancer. A third agent with antitumor activity, such as benazizumab; topoisomerase I inhibitors, for example, irinotecan and exatecan; Antifoliates, for example, methotrexate, raltitrexed, lometrexol and pemetrexed or platinum-based antineoplastic agent, for example, carboplatin and cisplatin, may be administered in combination with glufosfamide and gemcitabine. In one aspect of the invention, glufosfamide and bevacizumab are administered in combination to a subject in need of cancer treatment. A variety of cancers can be treated by this method. An example of a cancer that can be treated by this method is colorectal cancer. In one aspect of the invention, glufosfamide and another anticancer agent selected from the group consisting of topoisomerase I inhibitors, for example, irinotecan and exatecan; antifoliates for example, metatrexate, raltitrexed, lometrexol and pemetrexed; or platinum-based antineoplastic agent, for example carboplatin and cisplatin are administered in combination to a subject in need of cancer treatment. In one aspect of the invention, glufosfamide is administered to a subject in need of treatment for breast cancer. In another aspect of the invention, glufosfamide is administered to a subject in need of colorectal cancer treatment. In another aspect of the invention, glufosfamide is administered to a subject in need of treatment of pancreatic cancer refractory to gemcitabine. For the aforementioned treatment of breast cancer, colorectal cancer and pancreatic cancer refractory to gemcitabine, glufosfamide is administered as a single agent (that is, not in combination with another antineoplastic agent or another anticancer agent). Glufosfamide, gemcitabine, bevacizumab, irinotecan, exatecan, pemetrexed and cisplatin, as used in the present invention can be administered at any dose that is therapeutically effective, such as doses comparable to those used clinically systematically. Specific dosage regimens for known and approved antineoplastic agents (eg, the recommended effective dose) are known to physicians and are provided for example, in the descriptions found in PHYSICIANS 'DESK REFERENCE, 2003 57th edition, Medical Economics Company, Inc. , Oradell, NJ; Goodman and Gilman's "THE PHARMACOLOGICAL BASIS OF THERAPEUTICS" 2001, 10th edition, Me Graw-Hill, New York; and / or available from the Federal Drug Administration and / or are discussed in the medical literature. In one aspect, the invention provides a method of treatment in which a glufosfamide alone or in combination with another anticancer agent is administered according to a schedule or administration regime discovered as being particularly effective for treatment.

Administration Regimens It will be appreciated that chemotherapy for cancer sometimes involves multiple "rounds" or "dosing cycles" of administration of a drug, wherein each cycle comprises administration of the drug one or more times according to a specific schedule. A cycle is in general (but not necessarily) measured in weeks and may for example be 1, 2, 3, 4, 5, 6, 7, or 8 weeks in length. In some modalities, a cycle is longer than eight weeks. For example, chemotherapeutic drugs can be administered from 1 to 8 dosing cycles or for a longer period. In some modalities, the dosing cycle is a three-week cycle, a four-week cycle or a seven-week cycle. In a dosage cycle, a drug is administered according to a specified schedule or schedule, for example daily, once a week, multiple times a week on consecutive days or non-consecutive days; once each cycle; multiple times each cycle such as every three weeks for three consecutive days; etc. When more than one drug (eg, two drugs) can be administered to a subject, each can be administered according to its own schedule as illustrated above (weekly, once every three weeks, etc.). It will be clear that the administration of drugs, even those administered with different periodicity, can be coordinated in such a way that both drugs were administered on the same day or at least some of the time or alternatively, such that the drugs are administered on consecutive days. at least some of the time. In treatment regimens in which glufosfamide, gemcitabine (or another drug) are administered in combination, they can be administered in a certain order. In certain modalities, glufosfamide is administered one day before, or on the same day as the administration of gemcitabine. In certain embodiments, gemcitabine administered is administered on the same day as glufosfamide and the administration of gemcitabine is commenced before, concurrently with or after the administration of glufosfamide. In certain embodiments, gemcitabine is delivered (ie, administration will begin) between about 30 minutes to about 4 hours after the administration of glufosfamide. It will be understood that other schedules may be used as determined by the physician. In various embodiments, glufosfamide is administered to a patient in need of cancer treatment at 1, 2, 3, 4, 5, 6, 7, 8 or more than eight dosing cycles, each cycle comprising an infusion of glufosfamide in the range from: a) approximately 1.5 approximately 8.0 g / m2; approximately 1.5 to 6.0 g / m2; about 1.5 to 4.5 g / m2; about 4.5 to 8.0 g / m2; about 4.5 to about 6.0 g / m2 or about 4.5 to about 5.0 g / m2 or more in an infusion period of 1-6 hours once every three weeks; b) about 1.5 to about 3.0 g / m2 or about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours for three consecutive days (days 1, 2 and 3) every three weeks; c) about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours once a week; or d) about 1.5 to about 8.0 g / m2; about 1.5 to about 6.0 g / m2 or about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks. In one embodiment, glufosfamide is administered by 1, 2, 3, 4 or more than four dosing cycles, wherein each cycle is a seven-week cycle. In one embodiment, glufosfamide is administered for 1, 2, 3, 4, 5, 6 or more than 6 dosing cycles, wherein each cycle is a three-week cycle. In one embodiment, glufosfamide is administered for 1, 2, 3, 4, 5, 6 or more than 6 dosing cycles, wherein each cycle is a four-week cycle. As used in this context, an "infusion period of 1-6 hours" includes an infusion period of about 1, about 2, about 3, about 4, about 5 and about 6 hours. In various embodiments, gemcitabine is administered by 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosing cycles and each cycle comprises an infusion of gemcitabine of: a) about 1000 mg / m2 over a period about 30 minutes; b) about 2200 mg / m2 over a period of about 30 minutes or c) about 1500 mg / m2 over a period of about 150 minutes. In one embodiment, gemcitabine is administered in weeks 1, 2, 3, 5, 6 and 7 of a dosing cycle of 1, 2, 3, 4 or more than four dosing cycles, where each cycle is a cycle of seven weeks In one embodiment, gemcitabine is administered in weeks 1, 2, and 3 of a t-cycle, dosing for 1, 2, 3, 4, 5, 6, or more dosing cycles, wherein each cycle is a four-week cycle. Gemcitabine is administered one day before, one day after or on the same day with the administration of glufosfamide. In one embodiment, gemcitabine is administered on the same day as the administration of glufosfamide, about 30 minutes to about 4 hours after the administration of glufosfamide. As will be understood in the art, treatment with cancer therapeutic drugs may be temporarily suspended if toxicity is observed or for the convenience of the patient, without deviating from the scope of the invention and then resuming.

Administration in combination Two or three drugs are administered to a subject "in combination" when the drugs are administered as part of the same course of therapy.

A course of therapy refers to the administration of drug combinations that are believed by the medical professional to work together in an additive manner, in a complementary manner, synergistically or otherwise to produce a result more likely than anticipated for the administration of a drug. only drug. A course of therapy may be for one or a few days, but more often prolonged for several weeks. Thus, an example of administration in combination is the administration of glufosfamide once every three weeks for 1 to 8 cycles of three weeks starting on day 1 and the administration of gemcitabine once every week for weeks 2, 3, 4, 5, 6 and 7 of a seven-week cycle for one or more seven-week cycles. In one embodiment, gemcitabine administration begins on day 1, day-1 (one day after day 1) or day 2 or another day, such as administration of glufosfamide. Another example of administration in combination is the administration of glufosfamide once every four weeks beginning at week 1 (on day 1) of a four-week cycle for 1 to 8 four-week cycles and administration of gemcitabine at weeks 1, 2 and 3 (on days 1, 8 and 15) of a four-week cycle for 1 to 8 four-week cycles. In one embodiment, gemcitabine is administered on the same day as glufosfamide between about 30 minutes to about 4 hours after administration of glufosfamide. When two drugs are administered in combination, a variety of schedules can be used. In one case, for example and without limitation, Drug 1 is first administered prior to administration of Drug 2 and administration of Drug 2; alternatively, Drug 1 is administered after the start or completion of therapy with Drug 2; alternatively, Drug 1 is first administered contemporaneously with the initiation of the other cancer therapy. As used in this context "contemporaneously" means that the two drugs are administered on the same day or on consecutive days. For example, glufosfamide is administered to treat advanced or metastatic malignancies previously with chemotherapy. In one embodiment, the invention provides a method of administering glufosfamide for the treatment of locally advanced or metastatic non-receptive pancreatic adenocarcinoma previously untreated with chemotherapy. In one embodiment, the invention provides a method of administering glufosfamide for the treatment of metastatic pancreatic adenocarcinoma refractory to gemcitabine.

Cancers The methods of the present invention can be used for the treatment of any breast cancer, pancreatic cancer, colon cancer and / or rectal cancer, leukemia, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, laryngeal cancer, gall bladder cancer, paratoid, thyroid, adrenal, neural tissue, head and neck, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both the ulcerative type and papillary, metastatic skin carcinoma, osteosarcoma, Ewins sarcoma, ventricle cell sarcoma, myeloma, giant cell tumor, small cell lung tumor, islet cell carcinoma, primary brain tumor, and acute and chronic lymphocytic tumors and granulocytic tumors, hair cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuroma, intestinal ganglioneuroma, corneal nerve tumor h iperplastic, marfanoid habit tumor, Wilm tumor, seminoma, ovarian tumor, leiomyoma, cervical dysplasia and carcinoma in situ, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoides, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforme, leukemias, lymphomas, malignant melanomas and squamous cell carcinomas. Certain treatment regimens of the invention are particularly suitable for the treatment of pancreatic cancer, breast cancer or colorectal cancer as indicated above. Thus, in certain embodiments of the invention the subject to whom the treatment is administered has colorectal cancer or metastatic colorectal cancer. Colorectal cancer or metastatic colorectal cancer is currently through radiation therapy, surgery or chemotherapy (for example, administration of fluorouracil). In certain embodiments of the invention, the subject to whom the treatment is administered has breast cancer.

Breast cancer is commonly treated through various combinations of surgery, radiation therapy, chemotherapy and hormone therapy. In certain embodiments of the invention, the subject to whom the treatment is given has pancreatic cancer. Within pancreatic cancer, pancreatic cancers refractory to chemotherapy such as pancreatic cancers refractory to treatment with gemcitabine (see, for example, Araneo et al., 2003, Cancer Invest. 489-96: Kozuch et al., 2001, The Oncologist 6: 488-95; Noble and Goa, 1997, Drugs 54: 447-72N; Stephens et al., 1998, Oncol. Nurs Forum 25: 87-93; Burris and Storniolo, 1997, Eur. J.

Cancer 33: Suppl 1: S18-22; Rothemberg et al., 1996, Ann. Oncol. 1: 347-53) can be treated using the methods disclosed herein, for example by administration of glufosfamide. Reportedly, serum carbohydrate 19-9 may be a useful marker for evaluating the response to gemcitabine therapy in pancreatic cancer (Ziske et al., 2003, Br. J. Cancer 89: 1413-17). In one embodiment, the response to glufosfamide therapy for cancer, wherein glufosfamide is administered as a single agent or in combination with another anticancer agent is characterized by measuring the serum carbohydrate levels 19-9 of the subject during treatment.

SUBJECT As used herein, "subject" is a mammal in need of cancer treatment. In general, the subject is a human cancer patient. In some embodiments of the invention, the subject may be a non-human mammal, such as a non-human primate, an animal used in a model system (e.g., animals such as mice and rats used in the selection, characterization and evaluation of the medication) and other mammals.

Treatment As used herein and as is well understood in the art, "treatment" is a procedure for obtaining beneficial or desired medical results in which clinical outcomes are included. For purposes of this invention, beneficial or desired clinical outcomes include but are not limited to relief or improvement of one plus symptoms, prevented extension of disease, stabilized state (ie, does not worsen) of disease, prevention of disease dispersion, improvement or alleviation of disease status and remission (either partial or total), either detectable or undetectable. "Treatment" can also mean prolonging survival in comparison with the expected survival if the treatment is not received or if a different treatment is received.

Chemotherapeutic Agent The following section describes drugs used in various embodiments of the invention. Since these drugs are well known, only brief discussions are provided. The publications cited in this section are proposed to illustrate aspects of the drug for the benefit of the physician; however, the citation to a particular publication in this section or elsewhere in this publication is not intended to limit the scope of the present invention in any aspect, in which doses, combinations and indications are included.

Glufosfamide The antitumor drug glufosfamide (ß-D-glucosyl-ifosfamide mustard; glc-IPM) is an alkylating agent used to treat cancer (see, U.S. Patent No. 5,622,936 incorporated by reference herein and Niculescu-Duvaz, 2002, Curr Opin Investig Drugs 3: 1527-32). The alkylation moiety (isophosphamide mustard, IPM) is glycosidically linked to beta-D-glucose and the cellular uptake of glufosfamide can be mediated by a glucose-dependent transmembrane transport protein (Briasoulis et al., 2000, J. Clin, Oncol. 18: 3535 44) In Phase II clinical trials, glufosfamide has been administered from pancreatic cancer receiving first-line treatment and in patients with non-small-cell lung cancer receiving second line chemotherapies , as well as glioblastoma, patients with breast cancer and patients with colon cancer (see Niculescu-Duvaz, 2002, supra). Glufosfamide is administered systematically intravenously; it is contemplated that in the practice of the present invention other routes of administration may be used, such as intrathecal administration, intratumoral injection, oral administration and others. The -glufosfamide can be administered at doses comparable to those systematically clinically (see Niculescu-Duvaz, 2002, supra). In preferred embodiments, glufosfamide is administered as described elsewhere herein.

Gemcitabine Gemcitabine (2 '-deoxi-2', 2 '-difluoro-cytidine, also known as 1- (4-amino-2-oxo-lH-pyrimidin-1-yl) -2-deoxy-2,2-difluororibose ) is an analogue of the nucleoside that alters the process of cell replication. See US Patent Nos. 4,808,826 and 5,424,826, each of which is incorporated by reference herein. Gemcitabine HCl (Gemzar ™; Lilly) has been used for the treatment of patients with non-small cell lung cancer and pancreatic cancer. Gemcitabine HCl is formulated systematically as a sterile solution and is administered by intravenous infusion. Other forms of salt, for example, monophosphate, sulfate, malonate, citrate, and succinate are readily prepared and may be used if desired. It is contemplated that other routes of administration may be used, including intratumor injection, intrathecal administration and others. In preferred embodiments, gemcitabine is administered as described in part herein.

Bevacizumab Bevacizumab (Avastatin ™, Genentech) is a monoclonal antibody (VEGF) of anti-vascular endothelial growth factor that has been developed as an anti-angiogenesis agent for the treatment of cancers such as colorectal cancer, non-small cell lung cancer, cancer of chest and other solid tumors. See Salgaller, 2003, Curr Opin Mol Ther, 5: 657-67 and PCT applications WO 96/30046 and WO 98/45331. Bevacizumab as used in the present invention can be administered at doses comparable to those used clinically systematically (see, for example, Yang, 2003, N. Eng. J. Med. 349: 419-21 and Cobleigh et al., 2003 , Semen Oncol 30 (5 supplements 16): 117-24 Irinotecan Irinotecan (CPT-11, Camptosar®, Pharmacia &Upjohn) is a semi-synthetic derivative of the alkaloid camptothecin plant that inhibits topoisomerase I. It has been developed as an anticancer drug, for the treatment of colorectal cancer. Irinotecan can be administered at doses comparable to those systematically used clinically. For example, and without limitation, patients can receive Camptosar® in a 90-minute infusion once every 3 weeks. The initial dose for most patients can be 350 mg / m2, but the dose can be reduced to 300 mg / m2 for patients 70 years of age or longer. Camptosar® can also be administered according to a weekly administration schedule that starts at 125 mg / m2. The dose can be administered for approximately 2 to 4 weeks with the course repeated every 7 weeks. See http: // .meds. co / colon / camptosar / treatment. htlm See also Rothemberg et al., 1996 J. Clin Oncol. 14: 1128-35.

Exatecan Extecan mesylate (DX-8951f, Daiichi Pharmaceutical Co.) is a water soluble analogue of the alkaloid camptothecin plant that inhibits topoisomerase I. Extecan mesylate has been developed as a therapeutic agent for the treatment of lung cancer. non-small cells, ovarian, tubal or peritoneal cancer and breast cancer. Various dosages and administrations of exatecan mesylate for the treatment of cancer have been described. See for example, Verschaegen et al., 2004, Cancer Chemother Pharmacol. 53: 1-7, Esteva et al. , - 2003, Cancer 98: 900-7; Braybrroke et al. , 2003, Luna Cancer, 41: Royce et al. , 2004, Invest New Drugs 22: 53-61.

Pemetrexed Pemetrexed (Alimta ™) is an antifoliast that inhibits thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase and aminoimidazole carboxamide ribonucleotide formyltransferase. Pemetrexed is active against pancreatic cancer cell lines in vitro and has shown activity in patients with advanced pancreatic cancer. See Kindler, 2002, Semen Oncol. 29: 49-53 and Adjei, 2003, Expert Rev Anticancer Ther. 3: 145-56.

Cisplatin Cisplatin (cis-diaminodichloroplatinum (II)) is a complex containing divalent inorganic water soluble platinum with broad activity as an antineoplastic agent (see Go and Adjei, 199, J Clin Oncol. 17: 409-22). The present invention has been described in detail in the preceding sections, the following examples are provided to illustrate certain aspects of, but not limiting the invention.

Example 1 Combination therapy of glufosfamide and gemcitabine A combination of glufosfamide and gemcitabine was administered daily for seven days to female NMRI mice nu / nu that were carriers of tumors derived from HS766-T or pancreatic human cells As-PC-1. The mice were given vehicle control doses (0.9% sodium chloride solution, i.v.), gemcitabine (i.p.), glufosfamide (iv) or combinations of gemcitabine / glufosfamide once daily for seven consecutive days . A dose of 1.25 mg / kg was used as the standard dose for gemcitabine throughout the study. In the HS766-T tumor model, administration of 10 mg / kg glufosfamide caused a dramatic delay in the onset of tumor growth compared to the gemcitabine alone or vehicle control groups. Treatment with gemcitabine alone had only a marginal inhibitory effect on tumor progression. The combined administration of 10 mg / kg glufosfamide and 1.25 mg / kg gemcitabine resulted in a statistically significant (P = 0.009) reduction in tumor size of the test animals at the end of the study period (Day 42) compared with treatment with glufosfamide alone. In the tumor model of AS-PC-1, the dosing regimens of glufosfamide and gemcitabine, either alone or in combination, had no obvious inhibitory effect on tumor growth. These results demonstrate that in the tumor model HS766-T is sensitive to the combined administration of glufosfamide and gemcitabine.

Example 2 Combination therapy of glufosfamide and gemcitabine A combination of glufosfamide and gemcitabine was administered to nude mice bearing tumors derived from human pancreatic cancer cells type MiPaca2. The mice were administered vehicle control doses, gemcitabine, glufosfamide or combinations of gemcitabine / glufosfamide, as tabulated in Table 1 below (10 mice / group). Glufosfamide was administered to i. v. daily for 14 days (Groups 1-4 and 7-12). Gemcitabine was administered at 300 mg / kg i .p. once a week for three weeks (Groups 6 and 10-12). Gemcitabine was administered at 150 mg / kg, i .p. , twice a week for three weeks (Groups 5 and 7-9).

Table 1 * = vehicle Groups 3 and 4 resulted in a moderate reduction in tumor size. An approximately 50% reduction in tumor size was observed in Group 6. Group 10 was comparable to Group 6. Groups 11 and 12 showed a reduction in tumor size compared to Group 6 (Group 12 seemed be toxic). Gemcitabine at 150 mg / kg (Groups 5, 7-9 resulted in rapid deaths of the animals). These results demonstrate that the administration of an administration of glufosfamide and gemcitabine results in tumor reduction in the animals.

Example 3 Glufosfamide and gemcitabine combination therapy in advanced solid tumors and pancreatic adenocarcinoma The following prophetic example is provided to illustrate the treatment of cancer with combination therapy of glufosfamide and gemcitabine. A clinical study is carried out to evaluate the safety and demonstrate the efficacy of glufosfamide in combination with gemcitabine. The pharmacokinetic parameters of glufosfamide (in which isofosforamide mustard, IPM) and gemcitabine (including dFdü) are included when they are administered in combination are also evaluated.

A multi-center study is carried out in which the groups are divided into two groups: (i) subjects who have locally advanced and / or metastatic solid tumors that have been previously treated or for whom there is no standard treatment available (Group 1); and (ii) subjects who have advanced / metastatic pancreatic adenocarcinoma previously untreated with chemotherapy (Group II). The subjects are assigned to cohorts. The total duration of the study for each subject is up to 29 weeks, including up to three weeks before dosing (selection period). The treatment period is eight weeks in which glufosfamide is administered on day 1 of each four-week cycle and gemcitabine is administered on days 1, 8 and 15 of each four-week cycle. Glufosfamide (1500, 2500, 3500 and 4500 mg / m2 - one cut at each dose level) is administered intravenously for four hours once every four weeks on day 1 of each cycle. A quarter of the dose is administered during the first 30 minutes. The remaining three quarters of the doses are administered in the following three and a half hours. Gemcitabine (1000 mg / m2) is administered intravenously weekly for 30 minutes on days 1, 8 and 15 of each four-week cycle. On day 1 of each cycle the infusion of gemcitabine begins 30 minutes after the completion of the glufosfamide infusion. In subjects with a stable response or a complete or partial response after two cycles, the treatment is optionally extended for up to a period of four additional four-week cycles. This dosing schedule is shown in Table 2 below Table 2 Vital signs, electrocardiograms, results of clinical laboratory tests and adverse events are used to determine safety. Tumor measurements, which include scans or computed tomography (CT) scans, are carried out at a reference week and every eight weeks while the subjects are in the study. Pharmacokinetic parameters are determined from plasma concentrations of glufosfamide and gemcitabine obtained at specific time intervals after dosing. Serial blood samples are collected from each subject for review of glufosfamide / IPM plasma concentrations (0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 4.5, 6, 8, 12, 16 and 24 hours after initiation of glufosfamide infusion on day 1 of cycles 1 and 2) and gemcitabine / dFdU (15, 30, 40, 50 minutes and 1, 1.5, 3.5, 7.5, 7.5, 11.5 and 19.5 hours after the beginning of infusion of gemcitabine on days 1 and 8 of cycles 1 and 2). Blood samples are analyzed for glufosfamide and gemcitabine levels. All statistical tests used for the analysis of efficacy and safety data are two-sided and are performed at a significance level of 0.05 and calculated at a confidence interval of 90%. The following pharmacokinetic parameters of glufosfamide / IPM and gemcitabine / dFdU are calculated for each subject: time at maximum concentration (Tmax); observed maximum peak concentration (Cmax); the magnitude of the slope of the linear regression of the logarithmic concentration against time profile during the terminal phase (Kel); average life, calculated as In (2) / Kel / (T? / 2); area under the concentration-time curve (AUCuitimo) of Hour 0 through the last quantifiable concentration time (LQCT), where LQCT is the time at which the last sample with a quantifiable concentration was extracted; area under the concentration-time curve (AUC) from 0 to infinity, calculated using a linear trapezoidal rule such as AUCü? tim0 + C1QCT + Ke ?; clearance (Cl) calculated as the dose divided by AUC (glufosfamide and gemcitabine only); volume of apparent steady-state distribution (Vss), calculated as the dose multiplied by AUCM / AUC2, where AUMC is the area under the first moment of the time curve of plasma concentrations (glufosfamide and gemcitabine only); apparent distribution volume in the postdistribution phase (Vß) calculated as the ratio of Cl to the terminal elimination rate constant, Kel (glufosfamide and gemcitabine only). The AUC adjusted to the dose and Cmax is calculated for each subject by dividing AUC and Cmax by the dose. Efficacy results are evaluated as determined by response speed, duration of response, progression-free survival, overall survival for subjects with pancreatic cancer (survival of 6 and 12 months and changes in serum carbohydrate 19-9). The combination therapy of glufosfamide with gemcitabine is improved with respect to treatment with gemcitabine as the sole agent.

Example 4 Glufosfamide therapy for metastatic pancreatic adenocarcinoma refractory to gemcitabine The following prophetic example is provided to illustrate the treatment of metastatic pancreatic adenocarcinoma refractory to gemcitabine. A multicenter, randomized, open-label study is conducted to evaluate the safety and efficacy of glufosfamide in subjects with metastatic pancreatic adenocarcinoma refractory to gemcitabine as measured by overall survival compared to the best supportive care. Subjects are divided into two groups of 150 subjects per treatment group (i) glufosfamide treatment group (Group I) and (ii) best supportive care (BSC, Group II). Glufosfamide Group I subjects are administered with a duration of up to 51 weeks. Glufosfamide is administered intravenously for 6 hours once every three weeks at 4500 mg / m2 for up to 17 doses. One quarter of the dose is infused for 30 minutes and the rest in the next five and a half hours. Subjects can receive palliative radiotherapy but not within 48 hours of a dose of glufosfamide. In order to determine the efficacy of glufosfamide treatment, Group II subjects are not administered with any medication that has antitumor effects, for example, chemotherapy or other cytotoxic / cytostatic systemic therapies. However, other appropriate supportive measures and concomitant medications that do not have antitumor effects, such as analgesics, antibiotics, transfusions, haematopoietic colony stimulating factors (as therapy, but not as prophylaxis), erythropoietin, megestrol acetate for appetite stimulation are supplied when appropriate. The subjects in Group I also receive the best supportive care. This dosing schedule is shown in Table 3 below: Table 3 The determination of the tumor is made in the references and every six weeks during the first 24 weeks and then every 9 weeks until the progress of the disease is documented. Pharmacokinetic samples are collected from subjects in Group I during cycles 1 and 2. Blood samples for glufosfamide / IPM plasma concentrations are collected at the following times on day 1 in cycles 1 and 2 of the subjects in the Group I at the following time points: predose and immediately before the completion of glufosfamide infusion. Additional pharmacokinetic parameters are measured for a subset of 24 subjects in Group I (AUC, Cmax, and T? / 2 for glufosfamide / IPM). Blood samples are collected from this subset at the following times on days 1 of cycles 1 and 2: predosis, 0.5 (immediately before changing the infusion rate), 1, 3, 6 (immediately before the infusion of glufosfamide), 6.25, 6.5, 7, 8, 10, 16, 24 hours after the start of the infusion of glufosfamide. The pharmacokinetic parameters (as described in Example 3 above) for glufosfamide / IPM (day 1 of cycles 1 and 2) are calculated for each subject in the subset of 24 subjects. Efficacy results are evaluated based on response speed (complete response and partial response), response duration, progression-free survival, survival of 6 and 12 months, changes in VAS pain score and serum carbohydrate response. 19 -9 compared to the best support care. Subjects treated with glufosfamide with metastatic pancreatic adenocarcinoma refractory to gemcitabine have improved overall survival compared to the best supportive care.

Equivalents and incorporation by reference Wherein the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without departing from the scope of the invention. . In addition, many modifications can be made to adapt to a particular situation, material, composition of matter, process, step or process steps, to obtain the benefits provided by the present invention without deviating from the scope of the present invention. It is intended that all such modifications be within the scope of the claims appended hereto. All publications and patent documents cited herein are incorporated herein by reference as if each of such publications or documents were specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to be an indication that any such document is a prior relevant technique, nor does it constitute any admission as to the content and date thereof.

Claims (21)

1. CLAIMS 1. The use of glufosfamide and gemcitabine, characterized in that it is for the manufacture of a drug for use in the treatment of cancer.
2. 2. The use of glufosfamide, characterized in that it is for the manufacture of a medicament for use in combination with gemcitabine in the treatment of cancer.
3. 3. The use of gemcitabine, characterized in that it is for the manufacture of a medicament for use in combination with glufosfamide in the treatment of cancer.
4. 4. The use according to any of the preceding claims, characterized in that the cancer is a metastatic and / or locally advanced solid tumor.
5. 5. The use according to any of the preceding claims, characterized in that the cancer is pancreatic cancer.
6. 6. The use according to any of the preceding claims, characterized in that the treatment comprises the administration of glufosfamide by one or more dosing cycles, each cycle comprising an infusion of glufosfamide in the range of: a) about 1.5 about 8.0 g / m2; approximately 1.5 to 6.0 g / m2; about 1.5 to 4.5 g / m2; about 4.5 to 8.0 g / m2; about 4.5 to about 6.0 g / m2 or about 4.5 to about 5.0 g / m2 or more in an infusion period of 1-6 hours once every three weeks; b) about 1.5 to about 3.0 g / m2 or about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours for three consecutive days (days 1, 2 and 3) every three weeks; c) about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours once a week; or d) about 1.5 to about 8.0 g / m2; about 1.5 to about 6.0 g / m2 or about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks.
7. The use according to any of the preceding claims, characterized in that the treatment comprises the administration of gemcitabine once each week of a seven-week dosing cycle, wherein the administration is for one or more of seven-week cycles and wherein each cycle comprises an infusion of gemcitabine of: a) about 1000 mg / m2 over a period of about 30 minutes; b) about 2200 mg / m2 over a period of about 30 minutes or c) about 1500 mg / m2 over a period of about 150 minutes.
8. 8. The use according to each of claims 1-4, characterized in that the treatment comprises the administration of gemcitabine in weeks 1, 2 and 3 of a cycle of four weeks by one or more cycles of four weeks and in each cycle comprises an infusion of gemcitabine of: a) about 1000 mg / m2 over a period of about 30 minutes; b) about 2200 mg / m2 over a period of about 30 minutes or c) about 1500 mg / m2 over a period of about 150 minutes.
9. The use according to any of the preceding claims, characterized in that the cancer is a locally advanced solid tumor and / or advanced metastatic solid tumor and the treatment comprises the administration of glufosfamide and gemcitabine in combination to a subject in need of such treatment. , wherein the glufosfamide is administered by one or more dosage cycles, each cycle comprising: a) an infusion of glufosfamide in the range of about 1.5 to about 8.0 g / m2; about 1.5 to about 6.0 g / m2; about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks and b) an infusion of gemcitabine of approximately 1000 g / m2 in a period of about 30 minutes.
10. The use according to any of the preceding claims, characterized in that the cancer is pancreatic cancer and the treatment comprises the administration of glufosfamide and gemcitabine in combination to a subject in need of such treatment wherein the glufosfamide is administered by one or more Dosing cycles, each cycle comprises: a) an infusion of glufosfamide in the range of approximately 1.5 to approximately 8.0 g / m2; about 1.5 to about 6.0 g / m2; about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks and b) an infusion of gemcitabine of about 1000 g / m2 in a period of approximately 30 minutes.
11. The use according to any of claims 7 to 10, characterized in that each cycle comprises an infusion of glufosfamide in the range of about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four hours. weeks
12. 12. The use according to claim 11, characterized in that the treatment comprises the administration of gemcitabine on the same day as the administration of glufosfamide.
13. 13. The use according to claim 12, characterized in that the treatment comprises the administration of gemcitabine between about 30 minutes to about 4 hours after the administration of glufosfamide.
14. The use according to any of claims 9 to 13, characterized in that the treatment comprises the administration of glufosfamide every four weeks as an infusion in the range of about 1.5 to about 4.5 g / m2 in an infusion period of 1- 6 hours once every four weeks.
15. 15. The use of glufosfamide for the manufacture of a medicament for use in the treatment of pancreatic cancer refractory to chemotherapy.
16. 16. The use of glufosfamide for the manufacture of a medicament for use in the treatment of pancreatic cancer refractory to gemcitabine.
17. 17. The use according to claim 15 or claim 16, characterized in that the treatment comprises the administration of glufosfamide for one or more dosage cycles, each cycle comprising an infusion of glufosfamide in the range of: a) approximately 1.5 approximately 8.0 g / m2; approximately 1.5 to 6.0 g / m2; about 1.5 to 4.5 g / m2; about 4.5 to 8.0 g / m2; about 4.5 to about 6.0 g / m2 or about 4.5 to about 5.0 g / m2 or more in an infusion period of 1-6 hours once every three weeks; b) about 1.5 to about 3.0 g / m2 or about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours for three consecutive days (days 1, 2 and 3) every three weeks; c) about 1.5 to about 2.0 g / m2 in an infusion period of 1-6 hours once a week; or d) about 1.5 to about 8.0 g / m2; about 1.5 to about 6.0 g / m2 or about 1.5 to about 4.5 g / m2 in an infusion period of 1-6 hours once every four weeks.
18. 18. The use according to claim 16, characterized in that the treatment comprises the administration of glufosfamide to a subject in need of this treatment, wherein the administration of glufosfamide is by one or more dosage cycles, each cycle comprising an infusion of glufosfamide in the range of about 1.5 to about 6.0 g / m2 in an infusion period of 1-6 hours once every three weeks.
19. The use according to claim 18, characterized in that the treatment comprises the administration of glufosfamide by one or more dosage cycles, each cycle comprising an infusion of approximately 4.5 g / m2 of glufosfamide in an infusion period of 1-6. hours once every three weeks.
20. 20. A product characterized in that it contains glufosfamide and gemcitabine for simultaneous, separate or sequential use in the treatment of cancer.
21. 21. The combination of glufosfamide and gemcitabine, characterized because it is for use in the treatment of cancer.