Combined application of ecteinascidin-743 and platinum-containing anti-tumour compounds

FIELD: medicine.

SUBSTANCE: invention relates to method of treating human patient with cancer by means of combined therapy with application of ET-743 in doses smaller than 1200 mcg/ m2 per day and platinum anti-tumour agent - carboplatin in doses from 200 to 400 mcg/ m2 per day. Application of ET-743 in combination with carboplatin in the same range of dosage as it is used in case of individual carboplatin introduction results in overcoming of resistance to platinum anti-tumour compound without increase of toxicity of each medication.

EFFECT: invention also relates to medical set which includes combination of ET-743 and carboplatin in said dosages, pharmaceutically acceptable carrier and treatment scheme instruction.

29 cl, 10 tbl, 5 ex

 

The invention relates to the treatment, more targeted and better use of anticancer drugs in cancer treatment.

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to the use of ecteinascidin-743-containing drugs in cancer therapy, in particular to the use of ecteinascidin-743 in combination with anticancer coordination complexes of platinum in the treatment of cancer.

The prior art INVENTIONS

Cancers are a group of malignant tumors that can be divided into two categories: carcinoma, most commonly observed in the clinic, and others are not so frequently observed types of cancer, including leukemia, lymphoma, tumors of the Central nervous system and sarcoma. Carcinoma occur in epithelial tissues, whereas sarcomas develop in the connective tissues and structures that are associated with mesodermal fabrics. Sarcoma can affect, for example, muscle or bone tissue, and to meet on the bone, bladder, kidney, liver, lung, parotid gland, spleen, etc.

Cancer is aggressive and has a tendency to metastasize to new places. It spreads to the surrounding tissue and may spread through whether the lymph and circulatory system.

For cancer treatment you can use many methods, including surgery and radiation therapy for localized foci of the disease, as well as drug therapy.

However, the effectiveness of available methods of treatment of many types of cancer is small, and the need for new, improved methods of treatment that are useful for clinical practice. This is especially important for patients with advanced disease and/or metastasis. This is also true for patients with recurrence, expressed in the progression of the disease after taken generally recognized therapy, further repetition which is impractical due to acquired resistance to the drugs or concomitant toxicity.

The role of chemotherapy in cancer treatment is very significant, especially when you want to cure cancer at the stage with much metastasized, and chemotherapy often helps to reduce the tumor before surgery. Developed many anticancer drugs with different mechanisms of action.

The most commonly used are the following anticancer drugs: DNA-alkylating tools (e.g., cyclophosphamide, ifosfamide), antimetabolites (structural analogues) (for example, methotrexate antagonist of folic is islote and 5-fluorouracil - a pyrimidine antagonist), depolymerization microtubules (stop mitosis in metaphase, disrupt the normal formation of the mitotic spindle) (e.g., vincristine, vinblastine, paclitaxel), bind to the DNA tools (through embedding between nucleic bases or separating chains of DNA (e.g., doxorubicin, daunomycin, cisplatin), hormonal drugs (for example, tamoxifen, flutamide). Ideal anticancer drug should selectively kill cancer cells, have a wide range and high value therapeutic index, not to have toxicity to non-cancerous cells. It must also retain its efficacy against malignant cells even after prolonged exposure to drugs. Unfortunately, none of the modern chemotherapeutic regimens are not perfect. Most funds have a very narrow range and low values of therapeutic index, and in almost every case, the cancer cells develop resistance to the chemotherapeutic agent used in sublethal doses, and quite often there is cross-resistance - preventing treatment resistance to other anticancer drugs.

Combination therapy, which uses drugs is a means with different mechanisms of action, - a common therapeutic technique to help prevent the development of resistance of tumor during treatment.

Ecteinascidin (abbreviated as ET) are promising anticancer means, isolated from marine tunicates Ecteinascidia turbinata. Some members of Ecteinascidia mentioned previously in the patent and scientific literature. For example, in U.S. patent No. 5089273 described new compounds that are produced by the method of extraction of tropical marine invertebratesEcteinascidia turbinataand who called ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are of interest as an antibacterial and/or anticancer agents for mammals. In U.S. patent No. 5478932 described ecteinascidin isolated from the Caribbean tunicatesEcteinascidia turbinataand are able to provide in vivo protection (model xenografts) from lymphoma P388, B16 melanoma, sarcoma M5076 ovarian, lung carcinoma Lewis, as well as human lung carcinoma LX-1 human breast carcinoma MX-1.

One of these substances, ecteinascidin-743 (ET-743)is a new tetrahydroisoquinoline alkaloid isolated from marine ascidiansEcteinascidia turbinata,manifests in the case of human tumors and rats in vitro and in vivo antitumor activity and is currently undergoing clinical trials.

The potential is th antitumor activity has been demonstrated on a large number of models of tumors in vivo including human tumor xenograft in Nude mice. ET-743 has a new complex mechanism of action at the level of gene transcription. ET-743 is associated with a small groove in the area of the guanine-cytosine-rich DNA sequences and performs the alkylation of guanine residues in position No. 2.

In in vitro tests, for example bone marrow cells of human, rat, dog was demonstrated similar sensitivity to ET-743 erythroid and myeloid cells. Prolonged or repeated exposure of medicines has led to toxicity in relation to blood cells-the precursors to a greater extent than a single hour exposure. Therapeutic results ET-743 was preferred during prolonged use.

The clinical studies on the effects of ET-743 on cancer patients began with phase I, which was used for intravenous drug within 1 hour, 3 hours, 24 hours and 72 hours, and within 5 days, an hour a day. In phase I and in phase II clinical trials with ET-743 has shown significant antitumor activity against several types of human malignancies, including soft tissue sarcoma, ovarian carcinoma. Additional details about the use of ET-743 in treating people the century in malignant tumors described in WO 0069441 and presents here a specific example.

Platinum compounds are well known and commonly used anticancer drugs. Cisplatin (CIS-diaminedichloroplatinum (II)) is a coordination complex of platinum, first described in 1965 as a cytotoxic agent. He has a wide spectrum of antitumor activity and is particularly effective in the treatment of epithelial malignancies. Other platinum coordination complexes, have undergone clinical trials are carboplatin, tetraploid, ormaplatin, iproplatin and oxaliplatin.

Treatment of cancer patients such anticancer remedies relating to the coordination complexes of platinum, as cisplatin or carboplatin, is particularly active in the last decade. Cisplatin was effective in the treatment of many malignant tumors, including cancer of the testis, ovarian cancer and small cell lung cancer, whereas carboplatin is effective in the treatment of brain tumors, endometrial cancer, genocidal, as well as cancer of the head and neck. The mechanism of action today is not known, but may be associated with the ability of these compounds to bind to DNA with the formation of different types of intra - and miaocheng relations, which ultimately can inhibit both DNA synthesis and RNA synthesis.

Oncologicas the e patients eventually become insensitive to the treatment of coordination complexes of platinum, such as cisplatin and carboplatin. The mechanism of resistance to these compounds is unclear, but may be associated with weakening of the accumulation of drugs that increase intracellular concentrations of metallothionein or glutathione, which bind and inactivate drugs, or associated with a weakening of the formation of adducts drug-DNA or inhibition of repair. Thus, it is necessary to develop effective treatments to overcome this resistance.

For cancer cell lines grown in vitro, the combined effects of ET-743 and cisplatin had an additive effect or synergistic effect, quantification were based on the analysis of isobologram. The synergistic effect was confirmed also in vivo studies: Erba E. et al. "ET-743 and cisplatm (DDP) show in vitro and in vivo synergy against human sarcoma and ovarian carcinoma cell lines", Proceed. AACR-NCI-EORTC Nov. 2001, abstract 406; Faircloth, Glynn Thomas, Jr., et al. "In vivo combinations of chemotherapeutic agents with Ecteinascidin 743 (Et743) against solid tumors", proceed. AACR-NCI-EORTC Nov. 2001, abstract 387; Dincalci M. et al. "The combination of ET-743 and cisplatin (DDP): From a molecular pharmacology study to a phase I clinical trial", proceed. AACR March 2002, abstract 404; Dincalci, M. et al. "In Human tumor xenografts the resistance to ET-743 or to cisplatm can be overcome by giving the two drugs in combination", proceed. AACR-NCI-EORTC, Nov. 2002, abstract 97. Combination therapy with the use of ET-743 is described in international application WO 0236135, in its entirety, is included in the present description put the m citation.

The aim of the invention is the provision of effective methods and products to prevent blindness or overcome acquired resistance in humans to the coordination of the platinum complexes as anticancer agents. Another aim of the invention is the provision of effective methods and products to enhance the cytotoxic effect of the coordination of platinum complexes as anticancer agents in clinical practice.

The INVENTION

The inventors have found that when combined, maximum dose of ET-743 and platinum compounds, in particular cisplatin or carboplatin, does not improve or the emergence of additional toxicity. This is confirmed by clinical tests, in which the total dose of cisplatin and carboplatin successfully used along with increasing doses of ET-743.

Thus, the subject invention relates to a new method of treatment of cancer patients, in which platinum compounds administered in combination with ET-743.

The invention additionally relates also to a method of treating a cancer patient, involving the use of platinum compounds and ET-743 in such quantities that the percentage of platinum compounds is at least 50%, at least 75%, at least 85%, at least 90%, the e less than 95%, not less than 100% of the recommended dose of platinum compounds in the absence of ET-743, and the amount of ET-743 is at least 50%, at least 75%, at least 85%, at least 90%, at least 100% of the recommended dose for ET-743 in the absence of platinum compounds. The magnitude of the recommended doses are based on studies of doses of minimal toxicity. The preferred quantity as platinum compounds, and ET-743 comprise at least 85%, at least 90%, at least 95% or at least 100% of the respective recommended doses.

From another point of view, the present invention is directed to the use of ET-743 in the preparation of drugs for effective treatment of cancer by combination therapy, with the use of ET-743 with platinum compounds, in which process overcomes the resistance to platinum antitumor compounds without increasing toxicity of each drug.

In this aspect of the invention, a method for treating a cancer patient man with platinum compounds, wherein ET-743 is introduced for combination therapy without compensation to reduce the dose of platinum compounds.

In another implementation of the present invention, a method for reducing resistance to platinum antineoplastics connections among individuals with neoplastic disease, on the emitting introduction to the individual ET-743 and platinum compounds in the range of doses, similar to those that would be imposed if each of the connections - ET-743, or a platinum compound is administered to be separate.

The present invention also proposed a pharmaceutical composition with a content of the recommended doses of ET-743 for weekly use in combination with a platinum compound and pharmaceutically acceptable carrier.

In an additional aspect of the present invention proposed a set of medical instruments for the introduction of ET-743 in combination with antineoplastics a platinum compound, provided with printed instructions for use of ET-743 on the basis of the following dosing schedules, and the provision of ET-743 in doses sufficient to not less than one course of treatment, with each unit dose contains appropriate amount of ET-743 for the treatment, as defined above, and pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

ET-743 is a compound of natural origin, its structure can be represented by the following formula:

The term "ET-743" also is intended here to denote any kind pharmaceutically acceptable salt, ester, MES, hydrate or any other compound, which, when appointments to the recipient is able to provide its (directed or indirectly) the compound is AutoRAE described in this document. However, it should be taken into account that the pharmaceutically unacceptable salts also fall within the scope of the present invention, because they can be used in obtaining pharmaceutically acceptable salts. Obtaining salts and prodrugs and derivatives thereof can be made known in this field means.

ET-743 is supplied and stored as a sterile liofilizirovannogo product containing ET-743 and a filler in the composition suitable for therapeutic use.

Combinations of drugs in the present invention include ET-743 and antineoplastics platinum compound, preferably a coordination complex. Preferred complexes are cisplatin, carboplatin, tetraploid, ormaplatin, iproplatin, oxaliplatin, etc. the Most preferred such coordination complexes of platinum as cisplatin and carboplatin, preferably cisplatin.

Two drugs can be given simultaneously or one after another in any order, preferably in sequence.

As mentioned, the invention is a method of treatment of a person who has cancer. Preferred patients with relapsed or resistant to prior chemotherapy. Most preferably, if patients have ovarian cancer, head and neck cancer, carcinoma NSCL or IU anomy. In a particularly preferred implementation of the patients have ovarian cancer, and prior therapy have included platinum compounds.

In addition, in the present invention, a method for treating cancer in humans, including intravenous infusion of a composition containing ET-743 man with malignant disease, regular doses (in the period up to 4 hours)before or after continuous intravenous infusion of a composition containing antineoplastics the platinum compound and drug administration is repeated on a weekly basis and is performed periodically.

The injections are usually periodically repeat. Periodically alternate two phases: phase a weekly infusion and phase without infusion, called the resting phase. During the phase of relaxation for patients reconstructed. Usually phase of the cycle last week, but it is possible that the phase of the infusion will take one or more weeks, and the rest phase is one or more weeks. The rest period may be longer or shorter than the phase of the infusion. The preferred duration of each cycle of treatment is 2 to 4 weeks; multiple cycles is provided as needed. Most preferred is 3 - or 4-week cycles with one - or 2-week duration of infusions.

In that case, if ET-743 is administered in combination with cisplatin, R is komandoa dose of ET-743 preferably does not exceed 700 mg/m 2/a day 1 and 8 every 3 days or 4 weeks of treatment, preferably from 400 to 650 g/m2/in a day or even more preferably from 500 to 650 g/m2/day and even more preferably from 550 to 650 g/m2/day. In this case, it is advisable to use both compounds daily at 1 and 8 days of treatment every 4 weeks.

On the other hand, when ET-743 is administered in combination with carboplatin, the recommended dose of ET-743 preferably should not exceed 1200 mg/m2/day, on day 1 of each 3-week treatment cycle, preferably from 650 to 1200 mg/m2/in a day or even more preferably from 800 to 1000 g/m2/day and more preferably from 800 to 900 g/m2/day.

With regard to the dose of cisplatin, use the entire range of doses depending on the treatment regimen. The preferred dose is 30-60 mg/m2/day, more preferably 40-50 mg/m2/day, more preferably 40 mg/m2/day.

Dose carboplatin can be any in the used dose interval and depends on the treatment regimen. The preferred dose is about 200-400 mg/m2per day, more preferred are a dose of 250-300 mg/m2/day.

In a particular embodiment, the time infusions of ET-743 is from 1 to 3 hours, preferably from 2 to 3 hours. Especially preferred time SOS is to place about 3 hours.

The above regimens and doses for effective combination therapy of cancer in humans, at the same time allowing you to avoid toxicity. The inventors have found that ET-743 in combination with cisplatin or carboplatin effective in the treatment of several types of cancer, including the stage of progression or metastasis. Preferably using a combination of ET-743 with platinum compounds according to the above regimens and doses for the treatment of sarcoma, osteosarcoma, ovarian cancer, breast cancer, melanoma, head and neck cancer, cancer of the colon and rectum, mesothelioma, cancer of the kidney, endometrial (uterine) cancer and lung cancer.

Depending on the type of tumor and the stage of its development, methods of treatment described in the invention, is effective in the prevention of the risk of tumor growth, reduce tumor, stop tumor growth and/or prevent metastasis.

Although the above and made recommendations on doses, but refined dose of the compounds will vary in accordance with individual formulations of drugs, method of application depend on the location of the tumor, from the owner and from the type of tumor to be treated. Other factors, such as age, body weight, sex, diet, time of administration, rate is evegenia substances from the body, the condition of the body, drug combination, reaction sensitivities and severity of the disease should be taken into account. The administration of a medicinal product may be carried out continuously or intermittently, within the maximum tolerated dose.

EXAMPLES

Example 1

In order to assess the impact of the combination of ET-743 and cisplatin (DDP) in vivo, the inventors chose the xenografts that are relatively resistant to a dose of DDP and moderately resistant to a single dose of ET-743. Infusion used suitable for injection media, using the circuit and method of using injection, as is customary in pharmacotherapy. ET-743 and DDP was administered within 1 hour, separately, sequentially or simultaneously. In xenografts controlled the growth of subcutaneously (s.c.) the transplanted tumors in standard conditions, the tumor weight (TW) was determined as follows: conducted measurement of the diameter of the tumors with a caliper every 2-4 days, the mass was calculated by the formula TW=d2x D/2 (where d and D are the smallest and the largest diameters of the tumor, respectively).

Maximum single intravenous (i.v.) dose DDP and ET-743, do not result in toxic death was 12 mg/kg and 0.2 mg/kg, respectively. The same dose of each drug can be entered in the case when the two drugs are administered in combination at such doses celebrated tolerant toxicity, maximum weight loss in the range from 10% to 26% in different experiments (n=14), the average weight loss of 15%. Unexpectedly, it was found that treatment with a combination of drugs caused only a slightly greater mass loss than treatment with each drug separately. In toxicity was not observed differences for the cases of simultaneous or sequential administration of drugs with an interval of 1 hour, as in that, and in a different sequence.

In all models, the antitumor activity of the combination of drugs was greater than their individual application. In the case of rhabdomyosarcoma TE-671 and neuroblastoma SK-N-DZ all three options of drug administration (i.e. ET-743 was injected 1 hour before the introduction of the DDP, or were introduced simultaneously, or ET-743 was administered within 1 hour after administration of DDP) was compared, and did not observe noticeable differences in antitumor activity. Also in the case of H & N FADU, NSCLC LX-1, melanoma H-187, ovarian SKOV did not observe significant differences when comparing the two variants of the drug.

In summary, it can be noted that the antitumor activity of the combination of drugs was higher than each drug separately, and the sequence of the introduction does not affect therapeutic effect, and magnitude of toxicity at different introduction comparable.

Example 2

What is the current which was mentioned by using a combination of drugs was shown very sparingly, led the authors to investigate the impact of the combination of ET-743 and DDP when splitting the dose of each drug to three injections every 4 days.

The xenografts of ovarian carcinoma A were relatively resistant to these two drugs in the case of monotherapy. In contrast, DDP dose of 4 mg/kg (Q4x3), in a total dose of 12 mg/kg, with simultaneous introduction of ET-743 in a dose of 0.1 mg/kg (Q4x3), in a total dose of 0.3 mg/kg, caused a significant level of TWI, leaving 73%.

And again, in the case of the combined use of drugs was not observed toxic death or severe toxicity (average body weight loss was 16%) compared with the use of one drug (average body weight loss of 14% and 12% when using the ET-743 and DDP, respectively).

Thus, combination therapy allows the use of high doses of drugs, and even for those tumors that are treated with each of these two medications does not show appreciable activity for individual use, has been proven therapeutic activity when using combinations of these tools.

Example 3

In patients with ovarian carcinoma, the tumor spreads into the abdominal cavity. Therefore, to create a clinical model of the disease, the authors chose the xenograft is echnical person HOC 8, which is transplanted into the abdominal cavity of ascites and disseminators into the abdominal cavity. The growth is partly sensitive to DDP (ILS = 139%) and not sensitive to ET-743 (ILS=21% and 23% in the case of doses of 0.05 mg/kg and 0.15 mg/kg, Q4x3).

In the case of a combination of these two drugs, the effect was much greater, with a significant increase in the duration of survival than in the case of individual use of each medication. How low (ILS=258% in comparison with control (medium))and high (ILS=322% in comparison with the carrier) dose of ET-743, used in combination with DDP, increased the survival time of mice with HOC8, which is a marked improvement compared with monotherapy DDP ( ILS=49% and 76% when compared DDP with low and high doses of ET-743, respectively). Three animals were alive after 12 months, two of them belonged to the group treated with high doses of ET-743. They were scored and conducted a detailed analysis of macro - and mikrobiologicheskikh changes. In mice, related to the group treated with lower dose of ET-743, conducted a microscopic analysis of the liver, spleen, pancreas, bone marrow, charts, ovaries, uterus, omentum, lymph nodes were negative. In contrast to this case, other long-lived mouse had residual tumors of the omentum, and one of the mice were found the metastases in the uterus, while in other organ metastases were not detected.

This example shows the possibilities of combination therapy in the case of ovarian cancer, even in the presence of metastases.

Example 4

The authors organized a multicenter trials actions doses of 1 and 8 days every 3 weeks schedule treatment with increasing doses of ET, introduced by 3-hour infusion with steroids and prophylactic antiemetic means, the introduction of which was carried out on 30 minutes later by 1-hour infusion of cisplatin at a fixed dose of 40 mg/m2with 2 l of saline.

The study involved 36 patients (15 with ovarian cancer, 6 with uterus cancer, 14 with soft tissue sarcoma and 1 with another type of tumor). Prior to treatment patients was as follows:

Prior treatment
The number of patients who have been pre-chemotherapy in the case of running of the disease.35
The number of distributed groups of patients with pre-chemotherapy in the case of running diseaseAverage 1
The amplitude 0-2
To the number of patients pre-treated with drugs containing platinum22 (61%)
The number of patients
- responsible for the treatment
- stable
9
13
The number of patients pre-treated with carboplatinum16
The number of patients
- responsible for the treatment
- stable
6
10

Dose of ET-743 has reached the following levels: 300, 400, 500, 600 and 700 mg/m2/day, 3-6 patients were treated with doses close to the toxic level.

Increase the dose of ET-743 to the level of 500 ug/m2took place without any complications, at 600 mg/m2the patients were divided into two risk groups, depending on the duration of the preceding chemotherapeutic treatment: low risk = 1 (LR) and high risk ≥2 (HR).

The table below reflects the data obtained about the hematologic toxicity:

Hematologic toxicity
ET-743
on day 1 and 8 mg/m2
The number of registered patients The number of patients treatedThe number of patients with toxicity in 1 treatment cycle
G3G4
30033nono
40034*#nono
50082 ANCno
6001515°8 ANCno
700772 ANC 1Hb2 ANC 1 PLT

* 7 days of neutropenia in G4 → DLT

° 1 patient at 500 and 1 patient at 600 not recovered from neutropenia 35 days → DLT

# 1 the patient's initial dose was recorded 500, but it took 400 in 1 cycle.

The table below reflects detected not hematological toxicity:

The table below reflects the other received data is not hematological toxicity:

Other species not hematological toxicity depending on the dose and regimen
ET-743
dose
a day
1 and 8,
mg/m2
The number of patients treatedG1G2
3003
4004*1 anorexia
1 phlebitis
5007*
600153 SNP1 abdominal
cramps
1 abdominal pain
70071 anorexia

Limiting toxic doses (DLT):

- 500: 1/7 treated patients was not cured within 35 days

- 600: 3/15 treated patients

--1 not withdrawl the al due to hematological toxicity for 35 days

--stage 1 G3 ALT, recovery was not B/L

--1 was not recovered in 8 days, bilirubin G1 phase, stage G3 ALT

-700: 2/7 treated patients ANS stage G4, deterioration was not >7 days in 1 patient was associated G4 thrombocytopenia, and recovery was not due to hematological toxicity 35 day).

The table below shows the observed efficiency:

TumorPrior therapyET-743
dose
a day
1 and 8 mg/m2
Localization of the diseaseBest resultsTTP, months
OvaryCarboplatin + TaxolNE600The pelvis, liverPR6+
paclitaxelPD
STS - gyneco-logyAdriamycin/ ifosfamidAD700easyPR 3+
OvaryCarboplatin + TaxolNC400easyPR6
topotecanPD
OvaryCarboplatin + TaxolPR600Liver
Abdominal area
Unconditional PRQuickly
STS - gyneco-logyEpirubicin+ ifosfamideAD500Abdominal areaRoentgenological-
Kai PR, no support is present to measure pathological changes
5+
gemcitabinePD
Uterus
Colon
carboplatinNE400Bone region t is for, easyRoentgenological-
Kai PR, no support is present to measure pathological changes
1
Taxol + epirubicin + cisplatinCR

(PR: partial sensitivity; PD: progressive disease; CR: complete sensitivity; NC: no change; AD: adjuvant (stimulator, synergist); NE: not measurable; TTP: time to progression of the disease).

In this study, the authors made the following conclusions:

from the investigated values MTD 700 mg/m2for treatment of previously treated patients at 1 and 8 days every 4 weeks;

- recommended dose (RD) for treatment of previously treated patients is 500 mg/m21 and 8 days every 4 weeks;

- DLT called myelosuppression, particularly neutropenia;

at doses ≥600 mg/m21 and 8 days every 3 weeks protracted recovery from neutropenia was observed in the vast majority of patients;

- most not hematological toxicities are dose-dependent, accompanied by nausea and vomiting (N&V), asthenia and hepatic toxicity (always reversible and are moderately to a dose of 600 mg/m2/day);

- most not hematological toxicities were accompanied addicted to the s nausea and vomiting (N& V), and asthenia;

- the optimal interval between treatments is 28 days.

Example 5

The authors organized a multicenter trials of dosages, administered 1 day every 3 weeks schedule treatment using carboplatin constant dose of 300 mg/m2the infusion over 1 hour, and with a concomitant increase doses of ET, administered at 3-hour infusion with steroids and prophylactic antiemetic agents.

The study involved 11 patients (6 with ovarian cancer, 1 with lung cancer, 4 with soft tissue sarcoma). Prior to treatment patients was as follows:

The number of patients11
Tumor type
Non-small cell lung cancer (NSCLC)1
Epithelial carcinoma of the ovary6
Soft-tissue sarcoma4
Prior treatment
Once chemotherapy6
Twice or more chemotherapy 5
Pre-treatment carboplatinum6 (all patients with ovarian carcinoma)

Dose of ET-743 has reached the following levels: 500, 650 and 800 mg/m2/day, 3-6 patients were treated with doses close to the toxic level.

Maximum tolerated dose (MTD) was defined as the highest dose value found for combinations of drugs, in which not less than 2 patients experienced a DLT in cycle 1. If one patient was found to have caused by drugs DLT in cycle 1 or 2, up to 6 patients can be treated at the same level of drug dose. If DLT was not observed in additional patients, new patients can be treated by following a high dose.

The table below presents the results of cycle 1 for hematologic toxicity platelet and absolute number of polymorphonuclear leukocytes (ANC):

LevelThe number of patientsNeutropeniaTrombopenia
G0G1G2G3 G0G1G2G3
500320100210
650301200300
800521111112

Two patients manifested DLT during the first course of treatment at G3 thrombocytopenia dose level 3. Both patients had carcinoma of the ovary, pre-treatment which is carried out by carboplatinum.

The table below presents the results of haematological toxicity for platelets and ANT for all courses of treatment, and the e and the number of cycles without returning to normal hematological 21 and 28 days:

The applied dose of ET-743The number of treatment coursesThe number of courses without returning to normal hematological 21 days +1 dayThe number of courses without returning to the hematological normal 28 day +1 day
400*41/40/3
50013 No.1/135/13
650)4/40/3
80093/60/5

*all after reducing the dose; No. - 8 after reducing the dose; I - 1 after dose reduction

The applied dose of ET-743NeutropeniaTrombopenia
G0G1G2G3 G0G1G2G3
400*02200310
50043515521
65001300301
80041133213

*all after reducing the dose; No. - 8 after reducing the dose; I - 1 after dose reduction

And the following table shows the number of patients with tolerated dose (and easier is Oh) in cycle 2, indicating reasons for delay for each level doses:

LevelThe number of patients receiving treatment in cycle 2Portable dose (and lightweight) in cycle 2The reason
5003/31 patientANC G2
6503/33 patientTrombopenia G1
ANC G2
ANC G2
8004/5*
*one patient before
2 patientANC G3
ANC G3

On the basis of data on the treatment of 11 patients in cycle 1, you can conclude the following:

according to the data obtained quantitative value for MTD ET-743 is 800 mg/m2when using it with carboplatinum at a fixed dose (300 mg/m2);

- DLT accompanied by thrombocytopenia 3rd grade (G3);

- we see patients at the second level of metering in 100% of subjects the dose was delayed and reduced the dose in the second cycle of treatment because of hematological toxicity;

- at the third level doses 50% of patients tolerated dose and low dose in the second cycle of treatment C is hematologic toxicity.

Given gematologichesky safe profile, with long, though moderate, neutropenia, which can be prevented by adequate doses of intensity of ET-743, and 2DLT compatible with trombopenia 3rd grade (G3) two patients with ovarian carcinoma previously treated with carboplatinum, we propose the following scheme:

for patients previously treated with carboplatinum: introduction carboplatin constant dose (250 mg/m2with infusionum for one hour, followed by an intravenous infusion of ET-743 for 3 hours on day 1, every 3 weeks.

- for patients not pre-treated with carboplatinum: introduction carboplatin constant dose (300 mg/m2) infusion for one hour, followed by infusion of ET-743 for 3 hours on day 1, every 3 weeks.

1. The effective way of treating a cancer patient, which man, through combination therapy with the use of ET-743 and carboplatin, where the dosage carboplatin is approximately from 200 to 400 mg/m2/day, and the dosage of ET-743 is less than 1200 mg/m2/day.

2. The method according to claim 1, in which the dosage carboplatin is approximately 250 to 300 mg/m2/day.

3. The method according to claim 2, in which the dosage carboplatin is 250 mg/m2/day.

4. The method according to claim 2, in which doser the WHC carboplatin is 300 mg/m 2/day.

5. The method according to any of claim 2 to 4, in which ET-743 is administered at day 1 of each 3-week cycle in combination with carboplatinum.

6. The method according to claim 5, in which the dosage of ET-743 is from about 650 to 1200 mg/m2/day.

7. The method according to claim 6, in which the dosage of ET-743 is from about 800 to 1000 mg/m2/day.

8. The method according to claim 6, in which the dosage of ET-743 is approximately 800 to 900 mg/m2/day.

9. The method according to claim 6, in which the dosage of ET-743 is about 800 mg/m2/day.

10. The method according to claim 7, in which carboplatin administered every 3 or 4 weeks.

11. The method according to claim 9, in which carboplatin administered every 3 or 4 weeks.

12. The method according to claim 10, in which ET-743 and carboplatin is administered at day 1 of each 3-week cycle.

13. The method according to claim 11, in which ET-743 and carboplatin is administered at day 1 of each 3-week cycle.

14. The method according to any of PP or 13, in which the introduction is carried out by intravenous infusion.

15. The method according to 14, in which time infusion of ET-743 is from 1 to 3 p.m.

16. The method according to item 15, in which time infusion of ET-743 is approximately 3 hours

17. The method according to clause 16, in which time infusion of ET-743 is 3 hours, and the time of infusion carboplatin is 1 o'clock

18. The method according to claim 1, in which carboplatin and ET-743 is administered sequentially.

19. The method according to claim 1, in which the patient is watching what I relapse or resistant to prior chemotherapy.

20. The method according to claim 1, in which the patient has a malignant disease is selected from sarcoma, osteosarcoma, ovarian cancer, breast cancer, NSCL carcinoma, melanoma, head and neck cancer, cancer of the colon and rectum, mesothelioma, cancer of the kidney, endometrial cancer and lung cancer.

21. The method according to claim 20, in which the patient has a malignant disease is selected from ovarian cancer, NSCL carcinoma, melanoma and cancer of the head and neck.

22. The method according to item 21, in which the patient has ovarian cancer.

23. The method according to item 22, in which the patient has metastatic ovarian cancer.

24. The method according to 17, in which the patient has a malignant disease is selected from sarcoma, osteosarcoma, ovarian cancer, breast cancer, NSCL carcinoma, melanoma, head and neck cancer, cancer of the colon and rectum, mesothelioma, cancer of the kidney, endometrial cancer and lung cancer.

25. The method according to paragraph 24, in which the patient has a malignant disease is selected from ovarian cancer, NSCL carcinoma, melanoma and cancer of the head and neck.

26. The method according A.25 in which the patient has ovarian cancer.

27. The method according to p in which the patient has metastatic ovarian cancer.

28. Combination for treatment of cancer, comprising ET-743 and carboplatin, where the dosage carboplatin is approximately from 200 to 400 mg/m2/day, and the dosage of ET-743 is less than 1200 mg/m2/day.

29. IU is izinski set for the introduction of ET-743 in combination with carboplatinum, includes ET-743 in dosage units for at least one treatment cycle, where each dosage unit contains the appropriate amount of ET-743 for the treatment defined in claim 1, and a pharmaceutically acceptable carrier, and printed instructions for the introduction of ET-743 in combination with carboplatinum, according to the scheme of treatment defined in claim 1.



 

Same patents:

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to biotechnology, specifically obtaining hemopoietic cells from blood, and may be used in medicine. The homopoietic cell CD34+ is extracted from peripheral blood of cancer patients undergone a growth factor treatment course. The obtained cell is transduced by a ligand which induces apoptosis with participation of the tumour necrosis factor, and is used to treat tumours.

EFFECT: invention enables to obtain a hemopoietic cell CD34+ which has anti-tumuor activity.

6 cl, 3 dwg, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to ophthalmology and concerns treating conjunctiva nevus. That is ensured by administration of tabletted or capsulated chitosan in a dose 125-300 mg 2-3 times a day within a month.

EFFECT: method provides effective treatment of the disease without surgical intervention.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new condensed compounds (versions) or their pharmaceutically acceptable salts having inhibitory effect on HER2 and/or EGFR kinase, having the following formula, for example: or , where R1a is a hydrogen atom; R2a is a C1-8alkyl group, C2-8alkenyl group or C2-8alkynyl group, each of which is substituted with substitute(s), R3a is a hydrogen atom or C1-6alkyl group; or R1a and R2a are optionally bonded with formation or R2a and R3a are optionally bonded with formation of C2-4alkylene; Ba is a benzene ring optionally substituted with 1-4 substitutes selected from halogen and optionally halogenated C1-4alkyl; Ca is a phenyl group substituted with 1-5 substitutes selected from (i) halogen, (ii) optionally halogenated C1-4alkyl, (iii) hydroxy- C1-4alkyl, (iv) a 5-8-member heterocycle- C1-4alkyl, where the said 5-8-member heterocycle contains 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and optionally oxidised sulphur atom, (v) optionally halogenated C1-4alkyloxy, (vi) cyano and (vii) carbamoyl, optionally substituted with C1-8alkyl, and, respectively, R2e is a C1-4alkyl group optionally substituted with -O-(CH2)n-OH, where n is an integer from 1 to 4; R3e is a hydrogen atom; Be is a benzene ring optionally substituted with a halogen; and Ce is a phenyl group optionally substituted with halogenated C1-4alkyl.

EFFECT: obtained new compounds can be used for treating cancer.

22 cl, 2 tbl, 280 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used in treating the patients with Non Hodgkin Lymphoma. That is ensured by administration of a combination containing an effective amount of CCI-779 and rituximab in the form of a dosage form with one or more neutral components added. The combination is introduced simultaneously, separately or consistently with the other agents.

EFFECT: method allows improving clinical effectiveness for the given pathology, including in the patients resistant to rituximab due to synergetic interactions of these preparations.

5 cl

Cancer treatment // 2389507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.

EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.

48 cl, 25 tbl

Cancer treatment // 2389507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.

EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.

48 cl, 25 tbl

FIELD: medicine.

SUBSTANCE: group of the inventions refers to medicine, namely to oncology and immunology and can be used for treating renal cell carcinoma or thymoma. The method is implemented as follows: Polypeptide containing amino acid precipitations 1-182 of a sequence SEQ ID NO:29 or precipitations 1-176 of a sequence SEQ ID NO: 159, is used for preparing a drug for treating renal cell carcinoma. Another aspect of the invention concerns application of polypeptide containing amino acid precipitations 1-176 of the sequence SEQ ID NO: 159 for preparing a drug for treating thymoma.

EFFECT: application of the inventions allows improving clinical effectiveness in said diseases due to tumour induction polypeptide reaction with reducing cytotoxic by-effects.

5 cl, 35 tbl, 6 dwg, 46 ex

FIELD: medicine.

SUBSTANCE: invention concerns biochemistry and medicine. There is offered therapeutic application of yessotoxins as inhibitors of human tumour cell growth. The mechanism of action of yessotoxin (YTX) is associated with activation of cell phosphodiesterases and respectively with decreasing the content of cyclic adenosine monophosphate in cytosol. This cytotoxic effect of YTX with respect to tumour cells can be applied as a strategy to develop preparation effective in treating tumour processes.

EFFECT: inhibition of human hepatocellular carcinoma cell growth following introduction of YTX.

3 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns medicine. Transdermal compositions containing varenicline or pharmaceutically acceptable salt thereof.

EFFECT: obtaining of transdermal compositions beneficial in terms of nausea amelioration and enhancement of the preparation availability among a larger population of patients requiring it.

14 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutics, more specifically a prolonged-release composition of tedisamil or its pharmaceutically acceptable salt to be used in prevention and treatment of atrial fibrillation, atrial flutter and myocardial ischemia, containing 5 to 40 wt % of tedisamil or its pharmaceutically acceptable salt, 30 to 85 wt % of a water-swellable polymeric matrix containing hydroxypropylmethylcellulose (HPMC) of high or medium viscosity and hydrohyethyltcellulose (HEC) of high or medium viscosity in the ratio HPMC/HEC=1/0.85-1/1.2, 2.5 to 5 wt % of a salt capable to recover carbon-dioxide gas in the gastric medium, and 0.5 to 10 wt % of alginic acid.

EFFECT: invention allows providing tedisamil composition expressing improved bioavailability and causing less by-effects of gastrointestinal tract.

5 cl, 6 ex, 4 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: medicine.

SUBSTANCE: invention relates to composition for treating malignant disease, which contains ecteinascidin of general formula and disaccharide.

EFFECT: invention allows to provide compositions, which have high stability in storage, and essentially reduce formation of admixtures during liophylisation process and storage of ecteinascidin compositions.

36 cl, 5 ex, 19 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions concerns medicine, in particular to oncology, and concerns cancer treatment with pegylated liposomal Doxorubicinum (PLD) in a combination with ecteinescidin 743 (ET-743). Versions of the method of treatment, versions of compositions, and also medical sets are offered for this purpose.

EFFECT: maintenance of effective suppression of a cancer tissue at the expense of combined influence of PLD and E-743 at depression of toxic effects.

41 cl, 1 dwg, 9 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a method for treatment of nicotine dependence in a person using a medicinal formulation with controlled release (MFCR) comprising 5,8,14-triazatetracyclo[10.3.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene or its pharmaceutically acceptable salt taken in the effective dose, and to a method for reducing adverse effect of this active component. Method involves using MFCR that comprises agents of this active component for its administration to a patient at the rate less about 6 mg/h resulting to administration of at least about 0.1 mg of compound or its salt for 24 h. The initial administration of MFCR results to plasma maximal concentration (Cmax) of active component in average from 10% to 80% of the corresponding Cmax determined for the equal dose of active component in form of bolus with immediate release, and to increasing time of value Cmax in plasma (Tmax) in initial administration in average by 50% relatively to the corresponding Tmax value determined for the equal dose of active component in form of bolus of immediate release. Also, MFCR releases active component in vireo at the rate less 6 mg/h in the dissolving testing using device USP-2 (USA Pharmacopoeia) in order to provide the dissolving time of 50 wt.-% of active component from 1 to 15 h. Indicated agents comprise a tablet with matrix, multi-particles, covered multi-particles or tablet with a cover. Invention provides carrying out the effective treatment of nicotine dependence and without symptoms of adverse effects of active component, in particle, without nausea.

EFFECT: improved method of treatment.

7 cl, 19 tbl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compositions and methods for treatment of depressive disorder in subject using the therapeutically effective dose of agonist(s) of delta-receptors of the general formula: wherein Ar1 represents a 6-membered carbocyclic aromatic ring with a substitute Y at its carbon atom wherein Y represents carboxamide of the formula: CONR9R10 wherein both R9 and R10 represent ethyl group; Z is chosen from group consisting of hydrogen atom (H), -OH and alkoxy-group; Ar2 represents a 6-membered carbocyclic aromatic ring with a substitute X at its carbon atom wherein X represents H, or pharmaceutically acceptable ester or salt of such compound. Invention provides antidepressant effect in a patient in using indicated compounds in lower doses as compared with the known agonists of delta-receptors showing the related chemical structure with compounds proposed.

EFFECT: improved method of treatment, enhanced and valuable medicinal properties of compounds.

17 cl, 1 tbl, 21 ex

Cancer treatment // 2389507

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to new drugs and preparations containing effective anticancer agent with anti-Hsp90 antibody.

EFFECT: invention improves clinical effectiveness in treating cancer and leukemia.

48 cl, 25 tbl

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