BRPI0913231A2 - pharmaceutical combination - Google Patents

Abstract

"pharmaceutical combination, its use, and pharmaceutical kit comprising the same." The present invention relates to a pharmaceutical combination which may be useful for treating diseases involving cell proliferation, involving myeloma cell migration or apoptosis, involving angiogenesis or involving fibrosis. The invention also relates to a method for treating said diseases comprising the simultaneous, separate or sequential administration of effective amounts of specific active compounds and / or co-treatment with radiation therapy, in such a manner as to confer an additive and synergistic effect, and to the combined use of these specific compounds and / or radiotherapy for the manufacture of corresponding pharmaceutical combination preparations.

Description

Invention Patent Specification Report for ’’ PHARMACEUTICAL COMBINATION *.

The present invention relates to a pharmaceutical combination that may be useful for the treatment of diseases that involve cell proliferation, which involve migration or apoptosis of myeloma cells, which involve anglogenesis or which involve fibrosis. The invention also relates to a method for the treatment of said diseases, comprising the simultaneous, separate or sequential administration of effective amounts of specific active compounds and / or co-treatment with radiation therapy, in a ratio that confers an additive and synergistic effect, and the combined use of these specific compounds and / or radiation therapy for the manufacture of corresponding pharmaceutical combination preparations.

The present invention more specifically relates to a pharmaceutical combination comprising the compound 3-Z ~ [1- (4- (N- (((4-methylpiperazin-1-yl) methylcarbonyl) N-methyl-amino) aniline) “1-phenyl-methyleneTSmetoxinafbonyl'2-indoiinone (compound A) or its pharmaceutically acceptable salt and the acid compound N- [4 ~ [2- (2-aminu ~ 4,7-dihydro-4-oxo-1H ~ pyrrole (2..3-d] pyrimidin-5-yl) ethyl] benzoyl-1 ..- glutamic acid (compound B) or its pharmaceutically acceptable salt, optionally in combination with radiotherapy.

Background of the Invention

The compound 3-Z- [1 “(4- (N - (((4-methyl-piperazin-1 -ii) -methylcarbonyl) N-methyl ~ amino) -aniline) -1-phenyl-niethytene] ^ - methoxycarbonyl ~ 2-indoininone (compound A) is an innovative compound with valuable pharmacological properties, particularly for the treatment of cancer diseases, immunological diseases or pathological conditions involving an immunological component or fibrotic diseases.

The chemical structure of this compound is shown below in Formula A leather.

Formula A

The basic furnaces of this compound are described in WO 01/27081, the monoethosulfonate salt form is described in WO 2004/013099, and various forms of additional salts are presented in WO 2007/141203. The use of this molecule for the treatment of immunological diseases or pathological conditions involving an immunological component is described in WO 2004/017948, the use for the treatment of uncological diseases is described in WO 2004/096224, and the use for the treatment of fibrotic diseases is described in WO 2006/067165 ..

The formula of the monoathanesulfonate salt of this compound has properties that make this salt particularly suitable for development as medically. The chemical structure of the 3-Z- [1- (4- (N - (((4-methyl - piperrinz-1-i) -methylcarbonyl) -N-methylamino) -anilino monoethanesulfonate> 1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone is represented below as Formula Al.

Formula A1

Preclinical studies have shown that this compound is a highly potent and bioavailable oral inhibitor of vascular endutelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (POGFRs) and oblast growth factor receptors. (FGFRs), which suppress tumor growth by inhibiting mechanisms of tumor neovascularization. This compound has also been shown to inhibit cell signaling to endothelial and smooth muscle pericytes and to reduce the density of tumor vessels.

In addition, this compound demonstrates anti-tumor efficacy in vivo in all 10 models tested so far at well-tolerated doses. The following table shows the results of the anti -urnal efficacy tests in vivo in xenograft models and in a model of synergic rat tumor. .

Cancer Model Efficiency Colorretel HT-29 large tumors HT-29 16% T / C at 160 mg / kg / d tumor volume reduction Glioblastoma Syngenic rat GS-9L 32% T / C at 50 mg / kg / d Head and neck FaDu 170 from 11% to 100 mg / kg / d Lung (non-small cell) NCI-H460 Calu-6 54% T / C at 25 mg / kg / g 24% T / C at 50 mg / kg / d Ovarian SKOV3 19% T / C at 50 mg / kg / d Prostate (hormone dependent) PAC-120 34% T / C at 100 mg / kg / d Renal Gaki-1 13% T / C at 100 mg / kg / d Pancreas (transgenic murldeo) Rip-Tag interference with tumor formation

This compound is, therefore, suitable for the treatment of diseases in which angiogenesis or cell proliferation is involved.

The compound N-14- {2- (2-ammo-4 _; 7-dihydro-4-oxo-1Hpirrola ^ .O-dlpyrimidin-E-ihethyljbenzoyl-L-glutamic (compound B) is an antifolate that inhibits the DNA synthesis pathways again and demonstrated clinical benefit in patients with advanced malignant pleural mesothelioma (in combination with oispíatina), whose disease is not operable unless they are eligible for curative treatment.This compound also demonstrated a similar effectiveness in comparison earn docetaxel in patients suffering from advanced non-small cell or metastatic lung cancer (NSCLC) who have failed previous first-line chemotherapy. The compound's pyrrolopinmidine base exerts its amphineoplastic activity 10 by disrupting folate-dependent metabolic processes essential for cell replication. In vitro data demonstrated that this molecule inhibits thymidylate synthetase (TS), dihydrofolate reductase (DHFR) and glycylamide ribonucleotide formyltranstera (GARFT). All of these enzymes are folate-dependent enzymes that are involved in the de novo biosynthesis of the n'15 hmidine and purine cleotides.

The structure of the acidic compound N '[4' {2- (2-amino-4.7-di-hydro-4 ~ oxO1H-pyrrolo [2,3-d] pyrimidin-5-i!) Ethyl] benzoyl] -L- glutamic acid is represented below as Formula B. This compound is described, for example, in EP 00432677 and also known as pemetrexed,

Formula B

Pemetrexed has been approved since 2004 in the USA in its form of disodium salt for use in combination with oysplatin for the treatment of patients with malignant pleural mesothelioma and, since 2005, for the treatment of patients with second-line NSCLC. It is marketed 25 under the trade name Alimta ^b

The approved active ingredient pemetrexed dlssódíico heptaidrata do has the clinical name acid N- (4- [2 ~ (2-am! No-4,7-dihydro ~ 4-oxo-1H ~ pyrruío ^ 2.3-d] pírimidin- 5-yl) ethylbenzailj ~ l ..- glutamic, disodium salt, hepiahydrated and is represented below with Formula EM, and a white to almost white solid, with a molecular formula of C ^ H ^ N & Na ^ Os.ZHsO and a weight lioness la r of 597.49.

Formula BI

Q ÇCX Na + p ‘W>

HN \ ^H k_____ r ρ ···· χ · · · LAm tes +

- Ν 'V'

H

Alímta * ' ¹ is supplied with a sterile lyophilized powder for intravenous infusion, available in single dose vials. The product is a white to light yellow or greenish yellow lyophilized solid. Each 500 mg vial of Aíimta ^ 'contains disodium pemetrexed equivalent to 500 mg pemetrexed and 500 mg mannitol. Hydrochloric acid and / or sodium hydroxide may have been added to adjust the pH.

The aim of the present invention is to provide a pharmaceutical combination for the treatment of diseases that involve cell proliferation, or involve migration or apoptosis of myeloma cells, or angiogenesis based on the compounds mentioned above. Such a specific pharmaceutical combination is not known in the prior art. Its advantages are the potential for a better clinical benefit for cancer patients treated with this pharmaceutical combination facilitated by one or more of the following mechanisms:

. additive or synergistic antitumor effect by combining two anti-cancer principles and different target structures;

. additive or synergistic antitumor effect through greater availability of BI compound in cancerous lesions by reducing antitumor pressure with compound Al;

. prevention of pro-anginal rejection after chemotherapeutic intervention with compound 81 with or without radiotherapy:

. maintenance of the tumor response or tumor stabilization achieved with the combination of both compounds Al and 81, or with only post Al after combination of compound Al and 81, or with only compound 81 by subsequent treatment with compound A1. A treatment effect of compound Al may prevail even after dose reductions determined by toxicity from the maximum tolerated dose in individual patients,

Summary of the Invention

A first object of the present invention is a pharmaceutical combination comprising an effective amount of the compound 3-Z- {1- (4 ~ (N - ((4-methyl-piperazin · -1 yl) -methylcarbonyl) -N -mefil- amine) -anilino) -1-phenylmethylmethoxy-6-methoxycarbonyl-2-indolinone or its pharmaceutically acceptable salt preferably in the form of the monoethanesuifonate salt, and an effective amount of the N- (442- (2-amino-4,7) acid compound -dihydro ~ 4Oxo ~ 1H-pin'010 [2,3 ~ 15 d] pyrimidin-5-yl) ethylbenzoxyyl-1-glutamic or its pharmaceutically acceptable salt, preferably in the form of disodium salt.

An additional object of the present invention is the pharmaceutical combination above, which, in addition, is in the form of a combination preparation for simultaneous, separate or sequential use.

An additional object of the present invention is a method for the treatment of diseases involving cell proliferation, involving migration or apoptosis of myeloma cells, involving angiogenesis or involving fibrosis, which comprises administering to a patient in need of an effective amount of the compound 3'Z'f1 (4- (N - ((4-methyl · · piperazln-1-ii) -methylsarb0nií) -N-methyl-amino) -anilin0) -1-fanyl-methylene} -6methoxycarbonii-Z- indolinone or its pharmaceutically acceptable salt is preferably the monoethanesulfonate salt form, and an effective amount of the acid compound N-f442- {2-amino-4,7-dihydra-4 ~ oxo-1H-pyrrhenium [2,3d] pyri.nüdin-5 -yl) ethylbenzoyl] -L-glutamic or its pharmaceutically acceptable salt, preferably in the form of disodium salt.

An additional object of the present invention is the pharmaceutical combination above or the method above, which, in addition, is adapted for an e-traiamenío with radiotherapy.

An additional object of the present invention is the pharmaceutical combination above and the method above, which is used for the treatment of diseases involving cell proliferation, involving migration or apoptosis of myeloma cells, involving angiogenesis or involving fibrous.

An additional object of the present invention is the pharmaceutical combination anima or the above method, which is used for the treatment of all types of cancer (including Kaposi's sarcoma, leukemia, multiple myeloa and lymphoma), diabetes, psoriasis, rheumatoid arthritis, hemangioma , acute and chronic naphropathies, atheroma, arterial restenosis., autoimmune diseases, acute inflammation, asthma, lymphedema, endometriosis, dysfunctional uterine bleeding, fibrosis, cirrhosis and eye diseases with proliferation of retinal vessels. including age-related macular degeneration.

An additional object of the present invention is the pharmaceutical combination above or the method above, which is used for the treatment of non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC). malignant peritoneal pleural mesothelicma, head and neck cancer, esophageal cancer, stomach cancer, colorectal cancer & L gastrointestinal tumor (GIST), pancreatic cancer, hepatocellular cancer, breast cancer, kidney cell cancer, urinary tract cancer, prostate cancer, ovarian cancer, brain tumors, sarcomas, skin cancers and hematological neoplasms (leukemias, myelodlplasm, myoma, lymphomas).

An additional object of the present invention is a pharmaceutical kit, comprising a first compartment comprising the compound 3Z-f1 ~ (4- (N - ((4-methyl "piperaxin-1yl) -methylcarbonyl) -N-methyl-amino) - amine) -1-phenyl-methylene-S-methoxycarbonyl-S-indulinone or its pharmaceutically acceptable salt, preferably in the form of the monoethanesulfonate salt. and a second compartment comprising the acid compound N ((4- (2- (2-amine-4,7-dhydro-4 oxo-1 H-pkfôío (2,3-d) pírimídín-5'íí) ethyl) benzyl] -L-gututamic or its pharmaceutically acceptable salt, preferably in the form of sodium salt, so that administration to a needy patient is to be simultaneous, separate or sequential.

An additional object of the present invention is the compound 3-2- (1 (4 (N - ((4-methyl-piperazin · 1 -ii) -methylcarbanyl) -N-methyl-xamrna) -anihiine) -1 -phenylmethylene- 6-methoxycarbanii-2-rndalinone or its pharmaceutically acceptable salt, preferably the monoethanesulfonate salt slurry, for simultaneous use, separated or sequentially in the treatment of diseases involving cell proliferation, migration in the apotosis of myeloma cells or angiogenesis, in a carp human or non-human mammal, in combination with acidic compound N44- (2- {2-amino-4 ₍ 7-dehydro% -oxo ~ 1Upirrolo [2,3 - '<i] plrimidin-'5''U) ^ tji] bfôn ^ ojO-L''gíutâmico or its pharmaceutically acceptable salt, preferably in the form of diodic salt, optionally also in combination with radiotherapy,

An additional object of the present invention is the use of the compound 3 ~ 2l- [1 (4- (N ~ ((4 ~ methyl-piperazin-1 "yl) -metiicarbanyl) N-methyl-amine) -anilir? O 1 phenyl ~ methylene] -8-methoxycarbunik2-indolinone or its pharmaceutically acceptable salt, preferably in the form of the monoethanesulfonate salt, in combination with the acid compound N- [4- [2- (2-aminí> 4.7-dihydro-4 -oxo-1Hpirroluf2 _! 3-d] pyrimidin-5-i) ethyl-L-glulamicn or its pharmaceutically acceptable salt, preferably in the form of disodium salt, for the manufacture of a pharmaceutical combination preparation, optionally adapted for a cut with a radiotherapy, for simultaneous use, separated or sequentially in the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, in a human or non-human mammalian body.

An additional object of the present invention is the use of the compound 3-2- (t - (4- (N - ((4-methyl-piperazin ~ 1-yl) -metifearbonyl) ~ N-methyl-ammonium) -aniline) - 1 phenyl-mefilenu] -6-methoxycarbonyl-2-intrinone or its pharmaceutically acceptable salt, preferably in the form of monoelane & ulphonate salt, in combination with the acid compound N [4- (2- (2-amino-4,7- dihydro-4axo-1H ·· pyrrole | 2,3 '<í] pyr'imidin-'5-'íl) ethyl] benzuilj'L-gíutâmíco with its pharmaceutically acceptable salt, preferably in the form of disodium salt, for the manufacture of a pharmaceutical combination preparation, optionally adapted for subgroups of patients characterized by genetic polymorphisms in the target structures of the aforementioned compounds or by specific expression profiles of the respective target structures of the aforementioned compounds, various of the Figures

Figure 1: Evolution of tumor volume with the time of Üalu-6 NSCIC xenografts without treatment (T / C value of the treated control group is equal to 100% at the end of the experiment), after treatment with compound A1 (T / C value of 33%), after treatment with compound Bi (T / C value of 46%) and after treatment with a combination of compound A1 and compound B1 (T / C value of 1 fMyra.2:% change in body weight of more during the treatment as shown in figure 1.

PesçriÇàg ... Detected, da, Invention

As mentioned above, the present invention relates to a pharmaceutical combination comprising an effective amount of compound 3-Z · {1- (4 (1M - ((4-methyl · ρíρeraziπ-'1-ii) ~ methylcateoπil) -N ~ methyl-amino) anilinoj-1-phenÜ-methylenaj-B-methoxycisyl ^ -induiinuna or its pharmaceutically acceptable salt and an effective amount of the acid compound N- [4- (2 - (2-aminu-4 _> 7-dihydro-4oxo-1H ~ pyrrole [2,3 "d] pyrimidin-5" yl) ethyl | benzoyl] -glutamic acid or its family-acceptable salt,

A combination treatment of the present invention, as defined herein, can be achieved by means of simultaneous, sequential or separate administration of the individual components of said treatment. A combination treatment, as defined herein, may be applied as the sole therapy or may involve surgery or radiation therapy or an additional chemotherapy or targeted agent, in addition to a combination treatment of the invention. Surgery may comprise the stage of partial or tumor resection complete before naked after administration of the combination treatment as described herein.

In accordance with another aspect of the present invention, the effect of a treatment method of the present invention is expected to be at least equivalent to the addition of the effects of each of the components of said treatment used alone, i.e.. of each of the compounds and ionizing radiation used alone

According to another aspect of the present invention, the effect of a treatment method of the present invention is expected to be greater than the addition of the effects of each of the components of said treatment used alone, that is, of each of the compounds and ionizing radiation used alone.

In accordance with another aspect of the present invention, the effect of a method of treatment of the present invention is expected to be a synergistic offering. A combination treatment is defined as providing a synergistic effect if the effect is superior ferapeutioameute, as measured, by example, by the extent of the response, the duration of the response, the rate of response, the rate of stabilization, the duration of stabilization, the time for disease progression, progression-free survival or overall survival, as achieved with the dosage of one or other of the components of the combination treatment at its conventional dose. For example, the effect of the combination treatment is synergistic if the effect is therapeutically 20 greater than the effect achieved with a component alone. Furthermore, the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients who do not respond (or respond poorly) to a component in isolation. In addition, the effect of the combination treatment is defined as providing a synergistic effect if one of the components is dosed at its conventional dose, the other component (s) is dosed at a reduced dose. , and the therapeutic effect, as measured, for example, by the extent of the response, the duration of the response, the response rate, the stabilization rate, the duration of stabilization, the time for disease progression, progression-free survival or the overall brevity is equivalent to that achieved with dosing conventional amounts of the components of the combination treatment.

In particular, it is considered that the synergy is present if the conventional dose of one of the components can be reduced earn damage to one or more of the response length, response duration, response rate, stabilization rate, stabilization duration, time for disease progression, progression-free survival or overall survival, 5 in particular, without prejudice to the duration of the response, but with fewer side effects and / or less concern than those that occur when conventional doses of nothing are used.

As stated above, the combination treatments of the present invention, as defined herein, are of interest for their anti-angiogenic and / or vascular permeability effects.

Angiogenesis and / or increased vascular permeability is present in a wide range of pathological conditions, including cancer (including Kaposi's sarcoma, leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, hemangioma, acute and chronic nephropaiias, 15 atheroma, artenal restenosis, autoimmune diseases, acute inflammation, asthma, iinfedema, endometriosis, dysfunctional uierine bleeding, fibrosis, cirrhosis and eye diseases with proliferation of retinal vessels. including age-related macular degeneration. Combination treatments of the present invention are expected to be particularly useful in the prophylaxis and treatment of diseases such as cancer and Kaposi's sarcoma. In particular, these combination treatments of the invention are expected to advantageously slow the growth of primary and recurrent solid tumors. , for example, the colon, pancreas, brain, bladder, ovary, breast, prostate, lungs and skin. The combination treatments of the present invention are expected to delay25 the advantage of tumor growth in lung cancer, including malignant pleural mesothelioma, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), head and neck cancer, esophageal cancer, stomach cancer, gastrointestinal tumor (GIST) coloratal cancer, pancreatic cancer, hepatocellular cancer, breast cancer, kidney cell cancer and urinary tract cancer, prostate cancer, cancer ovarian, brain tumors, sarcomas, skin cancers and hematological neoplasms (leukemias, myelodysplasia.

myeloma, lymphomas),

More particularly, these combination treatments of the invention are expected to inhibit any form of cancer associated with VEGF. including leukemia, multiple myeloma and lymphoma and also, for example, inhibit the growth of those solid primary and recurrent tumors that are associated with VEGF, particularly those tumors that are significantly dependent on VEGF for their growth and spread, including, for example, certain tumors of the colon (including the rectum), pancreas, brain, kidneys, hepatocellular cancer, bladder, ovary, breast, prostate, 10 lung, volva, skin and, particularly, malignant pleural mesothelioma and NSCLC, More particularly, treatments are expected combinations of the present invention advantageously delay the growth of tumors in malignant pleural mesothelioma. More particularly, it is expected that the combination treatments of the present invention will advantageously slow the growth of tumors in non-small cell lung cancer (NSCLC).

In another aspect of the present invention, the combination is expected to inhibit the growth of those primary and recurrent solid tumors that are associated with VEGF, particularly those tumors that are significantly dependent on VEGF for their growth and spread;

The advantages of the present invention are the potential for a better clinical benefit for cancer patients treated with. this pharmaceutical combination involving one or more of the following mechanisms:

. Additive or synergistic anti-tumor effect mediated by the combination of two anti-cancer principles and different target structures: the compound Al is an anti-angiogenic compound directed towards tumor vasuularization (endothelial cells, perfect cells and muscle cells with suppression of tumor (re) growth and metastatic spread ; compound 81 is a cytotoxic agent that interacts with DMA synthesis pathways again. Unlike normal cells, cancer cells are genetically unstable, causing them to replicate inaccurately, As tumors progress, genetic instability leads to subpopulations of tumor cells with different biological characteristics.An antitumeral treatment with compound B1 asks to finish even most of the tumor tissue, however, in the end, some cell clones will become refractory.5 After the cells sensitive to treatment have been dead, resistant cells they can divide quickly again to restore a tumor that is inherently resistant to therapy. Consequently, The simultaneous targeting of different principles that cause cancer growth and spread with the described combination of compound Al and compound 81 reduces the risk of primary and secondary tumor resistance and also tumor escape. The validity of these approaches has been demonstrated for combination and multimodal treatment in various solid and hemostatic human forms, but not for the object of combination of the present invention, that is, the combination of compound Ale compound 15 B2. Of importance in the context of the present invention may be the fact that the compound Al acts mainly on genetically stable cells of tumor vasculature, which are less prone to spontaneous mutation and the development of resistance compared to malignant cells.

. Additive or synergistic antitumor effect due to a greater availability 2.0 of compound B1 in cancerous lesions by reducing the irrtratumoral pressure with compound A1. Treatment with compound Al can significantly reduce vessel density and permeability, thus contributing to an increase in liquid tumor perfusion and a reduction in intratumor pressure. This process can lead to a greater availability of 25 molecules such as compound B1 within tumor lesions.

. Prevention of pro-angiogenic rejection by compound A1 after chemotherapeutic intervention with compound BI, with or without radiotherapy. Conventional chemotherapy with BI compound or with radiotherapy can be followed by a so-called pro-angiogenic rejection of soluble pro-angiogenic factors 30 and circulating endothelial cells derived from bone marrow, which can decrease the therapeutic effect and help the tumor to compensate for the damage caused by compound 81 or radiotherapy. The elimination of this effect during boulders free of BI compound or free of radiotherapy by continuous treatment with compound Al pado compromises this robust repair process and leads to an increased and more sustainable antitumor effect, Maintenance of the tumor response or the achieved tumor stabilization 5 with the combination of both compounds A1 and 81 ₁ or with only compound A1 after the combination of compounds A1 and BI. or with only BI compound for subsequent treatment with compound A.

Despite its proven merits, treatment with conventional chemotherapeutics, such as compound B1, is mainly limited by its 10 unavoidable toxicities to healthy dividing tissues and the often relatively rapid emergence of tumor resistance and subsequent tumor relapse or progression. Consequently, an approach to maintaining the benefits achieved with chemotherapy, here with compound 81, is of high importance and value for the cancer patient. Treatment 15 with compound Al as an addition to treatment with compound BI and also after the end of treatment with compound BI has the potential to achieve this goal, as can be assessed by prolonging the duration of the tumor response or tumor stabilization, survival free of progression and overall survival. The Phase II clinical data below on the maintenance treatment with only compound A1, which were collected in patients with ovarian cancer relapse after α chemotherapy ended, further support the concept of maintenance treatment.

Results of the Preclinical Study

To analyze the anti-tumor effects of the combination of inhibition 25 of tumor angiogenesis, by interference with the VEGFR signaling cascade. with the established antiproliferative treatment modality of NSLC with compound B1, the following experiment was performed in vivo. Naked mice bearing established subeutaneous Caiu-6 xenografts (human NSCLC tumor cell line) were randomized 3Q and treated with BI compound or A1 compound alone or with a combination of both drugs. After 3 days of treatment, doses in control-treated mice had reached their end point and were, on average, -1400 mm ° in volume. The results in Figure 1 show that the combination of suboptimal doses of compound Ale compound B1 results in better antitumor efficacy, with a T / C value of 15%, compared to treatments with individual agents (T / C values of 33% and 46%). %, respectively5).

The results in Figure 2 show that the doses applied during this tumor experiment did not wash away the weight loss in the treated mice. The weight gain of the mice in the treatment groups, compared to the weight of the control oamundongus, was reduced, but nevertheless well tolerated.

Results of the Phase I Study

An additional study was carried out, namely, a dose escalation study, of the open label. Phase I, to investigate the combination of compound A1 together with a standard dose of compound 81 in patients previously treated with recurrent advanced stage NSCL.C. The potential additive or synergistic effects of new therapeutic regimens may make combinations of these agents particularly attractive for the treatment of patients with advanced NSCLC compared to a single agent alone,

The main objectives of this test were to determine safety, tolerability. Maximum Tolerated Dose (BAT) and pharmacuciretics of compound Al in combination with a standard dose of compound 81, Methods

Patients with advanced stage WSCLC, PS 0-1, previously treated with a first-line platinum-based chemotherapy regimen were eligible for this trial. The trial was an open label dose escalation project with compound Al at a starting dose of 100 mg twice a day, taken on days 2 - 21, combined with a standard dose of compound 81 (500 mg / m ² ) _: given as an intravenous infusion of 30 10 minutes on day 1 of a 21-day cycle. Patients could be treated for a minimum of four and a maximum of six cycles of the combination therapy, with an option of monotherapy with compound Al after the completion of the combination stage. Compound Al was scaled at doses of mg per group, until the MTD dose was determined. MTD was defined as the dose of compound A1 which was a dose group below the dose in which two nu plus six out of six patients experienced limited toxicity5 dose (DLT) in the first cycle of treatment. Tumor evaluations were performed during screening and after each second treatment cycle, according to RECIST (Response Evaluation Criteria in Solid Tumors).

B.êey.ífedqs

Twenty-six patients (13 men, 13 women, median age 61.5 years) in total and 12 in BAT were treated in this study. The MTD dose of compound A1 was determined to be 200 mg twice daily in combination with a standard dose of compound 81. Geraimente. the combination of compound Al and compound 81 was well tolerated. During the first course of treatment, 7 patients developed Limitative Dose Toxicity (DLT): 1 out of 6 patients at 100 mg of compound A1 twice daily. 1 out of 6 patients to 150 mg of compound Al twice daily, 3 out of 12 patients to 200 mg of compound A1 twice daily, and 2 out of 2 patients to 250 mg of compound Λ1 twice daily.

These DLTs included elevated liver enzymes, gastrointestinal events, including vomiting and nausea, fatigue and confusion, and were all CTC (Common Toxicity Criteria of the National Institute of Health) Grade 3. These events resolved after the study medication was stopped. There was no Grade 4 CTC event in the study. The best answers by

RECIST included (20 evaluable per response): 1 Complete Response (CR) and 13 patients with Stable Disease (DS). The patient with CR was kept on monotherapy with compound Al for a period of more than 63 weeks. Half of the 26 treated patients had Stable Disease (DS) as the best global response according to the investigators' assessments, with the Maximum Tolerated Dose (BAT) group with 58.3% SD as the best global response. Median Progression-Free Survival (PFS) for all patients was 5.4 months.

Conclusions

The combination of At compound and 81 compound in previously treated NSCLC patients has been shown to be safe and well tolerated in this study. The Maximum Tolerated Dose (BAT) of compound Al was 200 mg twice daily when given in a compound 81 at a dose of 500 mg / m ^z (recommended dose of pemetrexed for treatment of NSCL.C). Signs of clinical efficacy were observed in the small number of patients treated in this trial, one patient with a complete response three years ago.

Results of the H rase study

Phase II trial in patients with advanced non-small cell lung cancer

This study was conducted as a randomized double-blind Phase II study of two different doses of compound Al administered orally in patients with advanced non-small cell lung cancer who failed at least one previous chemotherapy regimen. The primary efficacy endpoints assessed were response rate and time to progression. Important secondary end points were the survival and tolerability of the compound Al.

Methods

Patients were randomly assigned to receive compound A1 at a dose of 250 mg twice daily or 150 mg twice daily. The dose of compound A1 could be reduced in stages to a minimum of 100 mg twice a day in case of excessive toxicity that would prevent chronic treatment. Patients were treated for the diagnosis of progression of the underlying lung cancer disease. Progressive disease, for the analysis of the primary final panto, was defined as radtological evidence of tumor progression according to the RECIST criteria.

This randomized study enrolled 73 patients in total. · 36 patients at the dose of 250 mg twice daily and 37 patients at the dose of 150 mg twice daily.

The ECOG performance status score is a scale from 0 to 5 with criteria used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the patient's daily life skills and determine a treatment and prog5 appropriate diagnostics (Oken, MM, Creech, RH, Tormey, DC, Horton, J. „Davis, TE, McFadden, ET, Carbona, PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: 649- 655. 1982). Progression-Free Survival Time (PFS) is defined as the period of time during and after treatment in which a patient is experiencing a disease that does not get worse. Global Survival Time (OS) is defined as the length of time a patient lives after being diagnosed with or treated for a disease.

Compound A1 at 150 mg twice daily and 250 mg twice daily were equivalent in terms of median Pro15 grade survival (PFS) time (48 versus 53 days). The corresponding Global Survival (OS) times are 144 days for patients who received the 150 mg dose and 208 days for patients who received the 250 mg dose. When considering patients with a baseline ECOG of 0 or 1. the median PFS was higher compared to all patients; 20 for all patients, the median PFS was dose independent (150 mg twice daily: 81 days; 250 mg twice daily; 85 days). In the subgroup with ECOG 0 or 1, the clinical benefit was reached by almost 60% of patients; one of the 17 patients with baseline line ECOG of 2 had stable disease One patient treated with 250 mg of compound A1 twice a day maintained a 74% reduction (partial response) of the tumor size for 9 months. The median overall survival (OS) of all patients was 153 days. (ECOG 0-2) and patients with an ECOG count of 0 -1 had a median OS of 264 days.

Conclusion

Compound A1 showed encouraging signs of efficacy in non-small cell lung cancer patients with an ECOG performance count of 0 to 1. There was no evidence of difference in efficacy between the two dosages of compound A1.

Assay of maintenance of Phase II in patients with advanced ovarian cancer

A randomized double-ego Phase H trial was conducted to assess the efficacy and safety of compound A1 as maintenance therapy in a population of patients who had experienced an early ovarian cancer relapse (<12 months after previous chemotherapy, indicating refractoriness standard platinum-based therapy). Therapy with compound Al was to start as maintenance after reaching a clinical benefit to the treatment of cytotoxic induction of relapse. The aim of the trial was to explore the therapeutic potential of compound Al compared to a placebo, that is, whether compound Al showed signs of maintaining clinical benefit (objective response or tumor stabilization) to relapse therapy induced by an octotoxic regimen. immediately preceding. The end point of primary efficacy for this trial was the Progression-Free Survival Rate (PFSR) 9 months after starting treatment with compound A1. As secondary end points, the PFS rate at 3 months and 6 months, respectively, and the time until the next anti-tumor treatment were evaluated.

Methods

Patients were randomly assigned to receive compound A1 at a dose of 250 mg twice daily or a corresponding placebo. The dose of compound A1 or corresponding placebo could be reduced per step to a minimum of 100 mg twice daily in case of toxicity. excessive amount that would prevent chronic treatment. Patients were treated until the diagnosis of progression of the underlying ovarian cancer disease Progressive disease, for the analysis of the primary endpoint, was defined as progression radiologies or progression of the tumor marker (CA-125), Results

In total 84 patients entered a trial. 44 patients were randomly assigned to receive compound Al at a dose of 250 mg twice daily, to 40 patients to receive a corresponding placebo. One patient had to be excluded from the analysis in the compound group Al. In total, the characteristics of the patients were well balanced between the two treatment groups, there was some tendency for patients with a worse prognosis in the group of compound Al (more patients with metastases, particularly with hepatic metastases, higher mean baseline CA-125, higher percentage of patients with subsequent therapy lines (2 or more previous therapies)).

According to preliminary data presented on November 19, 2008, the 9-month (26-week) PFS rate was 16,535 in the Al compound group, and 6.4% in the placebo group. The PFS rate at 6 months (24 weeks) was 28.3% in the A1 compound group, and 19.2% in the placebo group. The PFS rate was no different between groups at 3 months 912 weeks; the first moment of routine image). In total, the likelihood of remaining progression-free was greater for patients treated with compound Al. All five patients who remained on treatment until the end of the 9-month study period were treated in the group of compound A1.

Progressive disease could be diagnosed due to an elevation of the tumor marker only ('' progression of the tumor marker '). Based on radiological data, disregarding the progression of the tumor marker, the median time to progression was 143 days (95% of Cl 82-175 days) for patients treated with compound A1, and 65 days (95% CI 78-89 days) for placebo. The time between the progression of the tumor marker and the radiological progression was also longer in the group of compound Al.

Conclusion

Analysis of the trial suggests that compound Al, given as a long-term treatment, may be active in maintaining the clinical benefit achieved with chemotherapy, delaying the aditional progression of the tumor disease under treatment. Certain dose reductions for toxicity to a minimum of 106 mg twice daily are appropriate.

Attaché modalities at is

Additional pharmaceutically acceptable salts of the compounds of the combination according to the present invention in addition to those described above can, for example, include acid addition salts. Such acid addition salts include, for example, salts with inorganic or organic acids that provide pharmaceutically acceptable anions, such as with hydrogen halides or with sulfuric or phosphoric acid, or with trifluoroacetic acid, citric or maleic acid. Besides that. pharmaceutically acceptable salts can be formed with an inorganic or organic base which provides a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include, for example, an alkali metal salt, such as a sodium or potassium salt, and an alkaline earth metal salt, such as a calcium or magnesium salt.

According to the present invention, combinational compounds can be formulated using one or more pharmaceutically acceptable excipients or vehicles, where appropriate. Formulations suitable for both compounds A1 and B1 that can be used within the scope of the present invention have already been described in the literature and in patent applications related to these compounds. These formulations are incorporated herein by reference.

In a further preferred embodiment according to the present invention, the formulation for the compound of formula A1 is a lipid suspension of the active substance, preferably comprising a multi-carrier, a thickener and a de-thinning / solubilizing agent, more preferably in that the multi-vehicle is selected from corn oil glycerides, diethylene glycolmonoethyl ether, ethanol, glycerol, glycofural, maorogolglioerolcaprilocaprate, macrogollycerololeate, medium-chain partial glycerides, medium-chain glycerides, polyethylene glycol, polyethylene glycol 300, polyethylene glycol 300 castor oil, polluxil 3D hydrogenated castor oil. propylene glycol rnonocaprylate, pre-pi ··lene glycol monolsurafo, refined soybean oil, triasetine, triethyl citrate or mixtures thereof; the thickener is selected from excipients that form oleogel, such as colloidal silica or bentonin, on lipophilic or amphiphilic exoipients of high viscosity, such as polyoxy hydrogenated castor oil, macroglycerol hydroxystearates of hydrogenated vegetable oil, macrogulglycerol or ricinoyl or ricinoyl or ricineal oil. solubilization 5 lecithin is selected. optionally also comprising one or more macrogolgicericerels, preferably selected from macrogolglycerol-hydroxystearate or macrogolglycerol-riainoleate. The lipid suspension formulation can be prepared by conventional methods of producing formulations known in the literature, that is, by mixing the ingredients at a predetermined temperature in a predetermined order, to obtain a homogenized suspension.

The above formulation can preferably be incorporated into a pharmaceutical capsule, preferably a soft gelatin capsule, characterized by the fact that the capsule shell comprises, for example, glycerol as a plasticizer, or a gelatin capsule hard or hydroxypropylmethylcellulose (HPMC), optionally with a seal or bandage, The pharmaceutical dosage form of the capsule can be prepared by conventional capsule production methods known in the literature. The soft gelatin capsule can be prepared by conventional non-conventional methods of producing soft gelatin capsules known in the literature such as, for example, the rotating matrix procedure ”, described, for example, in Swarbrick, Boyiann, Encyclopedia of pharmaceutical technology , Marcel Dekker, 1990, Vol. 2, pp. 269 et seq., Or phenylamino Lachmann et al., The Theory and Practice of Industrial Pharmacy, ^3rd Edition 2, pages 404-419, 25 , 1976, or other procedures., Such as those described, for example,

Jimerson R. F. et al., Soft gelatin capsule update. Drug Dev .. Ind. Pharm., Vol. 12, No. 8-9, pp. 1133-44, 1986.

The formulation defined above or the capsule defined above can be used in a dosage range of 0.1 mg to 20 µg active substance / kg body weight, preferably 0.5 mg to 4 mg active substance kg body weight.

The capsules defined above can be packed in a suitable reel of the appropriate glass or flexible plastic container or in an aluminum raft or double polybag.

The following examples of vehicle systems (formulations), soft gelatin capsules, packaging materials and a manufacturing process are illustrative of the present invention and should in no way be construed as limiting its scope.

Examples of vehicle systems (formulations), soft gelatin capsules, packaging materials and a manufacturing process for the preparation of a formidic suspension formulation of At compound

The active substance in all Examples 1 to 10 is 3-Z- [1 - (4- (N ~ ((4 ~ methyl-piperaz.in-1 -yl) -methylcarbenyl) -N-methylamsnoyanjIinGi-l monoethanesulfonate -fend-methyleneH-methoxycarbanyl-Z-indolinone (Compound A1).

Example 1

Lipid-based Vehicle System

Formulation THE B Ç Ingredients (%] (%] ιγζίιβΙγι ;! Active substance 43.48 43.48 ...... 43.48 Triglycerides, medium chain 2870 37.83 38,045 Hard fat '18 .26 18.26 Lecithin 0.43 0.43 0.215 Total (filling mixture) 100.00 100.00 180.00

Example 2

Lipid-based vehicle system with additional surfactant

Ingredients BI Active substance 42.19 Triglycerides, medium chain 41.77 Hard fat 12.66 Cremaphor RH40 2.95 Lecithin 0.42

Ingredients [Bi ........: ....................................: .. ... Total (filling mixture) 100.00

Hydraulic vehicle system

Ingredients ................. ZZz ......... ^ zzzZiiizz Z ................ ² ... ..... Active substance 31.75 85% glycerol 3.17 Purified water 4.76 Macrogol 600 58.10 Macrogol 4000 2.22 Total (filling mixture) 100.00

ÈKtLQPfo.4

Atin mote gel capsule containing 50 mg of active substance

Zii ^...... ................ ² Formulation A Formulation B Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule Active substance Active ingredient 60.20 60.20 60.20 Triglycerides, medium chain Vehicle 40.56 53.70 54.00 Hard fat Thickener 38.25 25.50 25.50 Lecithin Urgent / sliding agent 0.66 0.60 The" Gelatine Film former 72.25 72.25 ..... 72.25 85% glycerol Plasticizer 32.24 32.24 32.24 Titanium dioxide Dye 0.20 0 _: 20 0.20 Iron oxide A Dye 0.32 0.32 0.32. Iron Oxide B Dye 0.32 0.32 0.32 Total Weight Capsule 245.33 245.33 245.33

Soft gelatin capsule containing WO mg of active substance

Formulation A Formulation B Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule Active substance Active ingredient 120.40 120.40 120.40 Triglycerides, medium chain Vehicle 81.90 107.40 106.8 Hard fat Thickener 76.50 51.00 51.00 Lecitlns Umeotanto / sliding agent 1.20 1.20 1.80 Gelatine Film former 111.58 111.58 111.58 85% glycerol Fastifier 48.79 48.79 48.79 Titanium dioxide Dye 0.36 0.36 0.38 Iron oxide A Dye 0.06 0.06 0.06 Iron oxide B Dye 0.17 0.17 0.17 Total Weight Capsule 440.95 440.96 440.96

Mote gelatin capsule containing 125 mg of active substance

Formulation A Formulation B Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule ί Active substance Active ingredient 150.50 150.50 150.50 ί Triglycerides. i medium chain Vehicle 102,375 134.25 133.5 Hard fat Thickener 95,625 6375 63.75 i lecithin Upstream / sliding agent 1.50 1.50 2.25 i Gelatin Trainer 142.82 142.82 142.82

Formulation A Formulation B Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule film 85% glycerol Plastifíoarrte 62.45 62.45 62.45 Titanium dioxide Dye 0.47 0.47 0.47 Iron oxide A Dye 0.08 0.08 0.08 Iron oxide B Dye 0.22 0.22 0.22 Total Weight of Capsule ...... / ......... // ......................... 556.04 556.04 556.04

ExemnlsZ

Soft gelatin capsule contains 150 mg of active substance

Formulation A Formulation 8 Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule Active substance ingredient active 180.60 180.60 180.60 Triglioerides, medium chain Vehicle 122.85 161/10 160.20 Hard fat Thickener 114.75 78.50 76.50 Leoitin Wetting / Sliding Agent 1.80 1.80 2.70 Gelatine Film former 142.82 142.82 142.82 85% glycerol Piastifying 62.45 62.45 62.45 Titanium dioxide Dye 0.47 0.47 0.47 iron oxide A Dye 0.08 0.08 tos Iron Oxide 8 Dye 0.22 0.22 0.22 Total Weight Capsule 826.04 626.04 ____________ 626.04 ........................................

ΒίΐΏώΟ

Male gelatin capsule contains .200 mg of active substance

Formulation A Formulation B Formulation C Ingredients Occupation mg per capsule mg per capsule mg per capsule Active substance Active ingredient 240.80 240.80 240.80 Triglíoendeos. media chain Vehicle 163.30 214.80 216.00 Hard fat Thickener 153.50 102.00 ...... wlo ............ Lecithin Urgent / slippery agent 2.40 2.40 1.20 Gelatine Film former 263.19 203.19 203.19 85% glycerol Plasticizer 102.61 102.61 102.61 Titanium dioxide Dye 6.57 0.57 0.57 Iron oxide A Dye 0.90 0.90 0.90 Iron Oxide B Dye 0.90 0.90 op Total Weight Capsule 868.17 868.17 868.17

exgnmfei

The packaging materials for packaging the best gelatin capsules of examples 1 to 4 above can be double aluminum pouches or pouches.

Example ^ LÍÊ '

In the following, a manufacturing process for the preparation of a formulation of the lipid suspension of the active substance and a process for encapsulation are described.

The. Hard fat and part of the medium chain trigücerides are pre-mixed in the processing unit. Subsequently, lecithin is added. the rest of the medium chain triglycerides and the active substance. The suspension is mixed, homogenized, de-aerated and, finely, sieved to produce the phonnulation (filling mixture).

B. The components of the basic mass of oelatin are mixed * χλ ...... ....... .. ύ and dissolved at elevated temperature. Then, the corresponding colors and more water are added and mixed., Producing the colored gelatin mass.

ç. After adjustment of the encapsulation machine, the filling mixture and the colored gelatin mass are processed in soft gelatin capsules using the rotary matrix process. This process is described, for example, in Swaforick, Boylann, Encyclopedia of pharmaceutical technology. Marcel Dekker, 1990, Vol. 2, pp. 269 et seq.

d. After encapsulate residues of lubricating medium chain triglycerides are removed from the surface of the capsule, using acetone denatured with acetone, containing small amounts of Phosal® 53 MCT, used here as an antipegajosidads agent,

and. Initial drying is carried out using a rotary dryer. For the final drying step, the capsules are placed on trays. Drying is carried out at 15 - 2S ° C and low relative humidity.

f. After visual inspection of 100% of the capsules to separate deformed or leaking capsules, the capsules are classified by size and once again washed using acetone denatured with acetone,

g. Finally, the capsules are printed using an offset printing technology or an inkjet printing technology. Alternatively, the capsule can be printed using ribbon printing technology, a technology in which the gelatin bands are printed before the encapsulation step c.

Compound 81 (perrtetrexed) can be administered according to known clinical practice. For example, in NSCl.C, the recommended dose of pemetrexed is 500 mg <W given by 10-minute intravenous infusion, administered on the first day of each 21-day cycle.

The desages and cranagrams can vary according to the particular pathological state and the general condition of the patient. Dosages and chronograms may also vary if, in addition to a combination treatment of the present invention, one or more chemotherapeutic agents are used. The schedule can be determined by the doctor treating any particular patient.

Radiotherapy can be administered according to known practices in clinical radiotherapy. Dosages of ionizing radiation will be those known for use in clinical radiotherapy. The radiation therapy used will include, for example, the use of y-rays, X-rays and / or the targeted distribution of radiation by radioisotopes. Other forms of DNA damaging factors are also included in the present invention, such as microwave and UV irradiation. For example, X-rays can be dosed in daily doses of 1.8 ·· 2.0 Gy, 5 days a week for 5 - 6 weeks. Normally, a total dose of fradonado will be in the range of 45 - 00 Gy. Larger single doses, for example, 5 -10 Gy can be administered as part of a radiotherapy course. Single doses can be administered during surgery. Hypertracic radiotherapy can be used, in which small doses of X-rays are administered regularly over a period of time, for example, 0.1 Gy per hour over a number of days. The dosage ranges for radioisotopes vary widely and depend on the isotope half-strength, the strength and type of radiation emitted and the uptake by cells.

The dose size of each therapy that is required for the therapeutic or prafilmatic treatment of a particular pathological condition will necessarily vary depending on the treated host, the route of administration and the severity of the disease being treated. Therefore, the optimum dosage can be determined by the physician treating any particular patient. For example, it may be necessary or desirable to reduce the above-mentioned doses of the components of the combination treatments to reduce toxicity.

Claims (17)

1. Pharmaceutical combination comprising the compound 3-Z [1 - (4 - (N4 (4-meiibpiperazin-1-iO-metHcarboniO-N-methyl-amylnohaniiino) -! -Phen * methylene] -6-methoxycarboni-2-indoline or your pharmaceutically accepted salt - 5 and the compound N-phenyl S-CZ-amino-AJ-dihydro-á'OXU-1H-pyrrole (2 _; 3 ··dididinin-S-iOethylbenzoylH-L-glutamic or its pharmaceutically acceptable salt). Pharmaceutical combination according to claim 1, wherein the pharmaceutically acceptable salt of compound 3-Z- [1- {4 · (Ν - ((4- 10?? Pharmaceutical combination according to claim 1, wherein the pharmaceutically acceptable salt of the acid compound N- (4- (2- (2 amino-4 / Z-dihydro-á-axo-1 H-p5rrola [2 , 3 ~ d] pinmídin-5-yl) ethyl} benzoill 'L- 15 giutamic is its form of disodium exit. Pharmaceutical combination according to claim 1, comprising the 3-Ζ-Ή - (4 (N - (((4-methyl-piperazin-1-ii) -methylcarbonyl) -N-methylamirm monoethanesulfonate form) ) “ArHlino) -1-phenylmethylenol-e-methoxyterbonyl-Z-'indolinone and the form of disodium out of the com ·· 20 acid post N44- (2- (2-amino ~ 4 ₍ 7-dihydro ~ 4 oxo-1 H-pyrrole (2,3-d] pyrimidin-5fl} etiiJbenzoii] -L-glutamic). Pharmaceutical combination according to any one of claims 1 to 4, which is in the form of a combined preparation for simultaneous, separate or sequential use, 25 6, Pharmaceutical combination according to any one of claims 1 to 4, which is also adapted for co-treatment with radiotherapy, 7. Pharmaceutical combination according to any one of claims 1 to 4, which is used for the treatment of diseases involving cell proliferation, involving migration or apoptosis of myeloma cells, involving angiogenesis or involving fibrosis, 3. Pharmaceutical combination, according to any of claims 1 to 4. which is used for the treatment of a selected disease from cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma. hemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, asthma, lymphedema, endomeirio5 .se, dysfunctional uterine bleeding, fibrosis, cirrhosis and eye diseases with proliferation of retinal vessels. 9. Pharmaceutical combination according to any one of claims 1 to 4, which is used for the treatment of a selected non-small cell lung cancer (NSCtC) disease, 10 small cell lung (SCLC), pleural mesothelioma! or malignant peritoneal, head and neck cancer, esophageal cancer, stomach cancer, colorectal cancer, gastrointestinal stromal tumor (GIST), pancreatic cancer, hepatocellular cancer, breast cancer, renal cell cancer, urinary tract cancer, cancer prostate cancer, advanced cancer, cerebral tumors, sarcomas, skin cancers and hematoldgioma neoplasms. 10. Compound 3-Ζ (1- (4 »(Ν · '(((4-ΓηαΙίΚρίροΓ» ζίπ-1-ΙΙ) ~ πι & 0Ιο ^ η> θΓ »Ι) ~ N“ metií-srnino} -anihno) -1- fenj | -methylene] »6mrretaxicartjonih2-indolinana or its pharmaceutically acceptable salt, for simultaneous, separate or sequential use in the treatment of diseases involving cell proliferation, 20 myeloma cell angulation or aptosis or angiogenesis. in a human or non-human mammalian body, in combination with the acidic compound N44- {2- (2 - amino-4 T-dihydro-et-oxa-1 H-pyrrole ^ ritoijpirimidin-Sil) -glutamic acid or its pharmaceutically acceptable salt. 11. Use of compound 3-Z41 ~ (4- (N - (((4-methyl-piperazin-1-yl) 25 methyl-methylbenzyl} -N-methylamine) -anilino) ~ 1-phenyl-methylenu] -6-methoxycarbonyl-2- indalinone or its pharmaceutically acceptable salt in combination with the acid compound N44- (2 '(2-amino-4,7-dihydro-4-oxo- 1 H-pyrrolo [2,3d} pyrimidin-5-i!) efil] bensoil] -L-glutamic to its pharmaceutically acceptable salt, for the manufacture of a pharmaceutical combination preparation, for simultaneous, separate or sequential use in the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or anglogenesis, in a human or non-human mammal body. 12. Use according to claim 11, in that the pharmaceutical combination preparation is adapted for cutting with radiotherapy. 13. Use according to claim 11 or 12, wherein the The pharmaceutical combination comparison is adapted for subgroups of patients characterized by genetic poHmorphisms in the target structures of the compounds of the combination or characterized by specific expression profiles of the respective target structures of the compounds of the combination. 14. Pharmaceutical kit, comprising a first comparison 10 to which comprises the compound 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) r? Ethylcarbonyl) -Nmefií arrfirm) -anilino) -1-phenyl-mefylene] - 6-methoxycarbonyl-2indinone or its pharmaceutically acceptable salt and a second compartment comprising the compound N- [4-p42-amino-4 acid _; 7-dihydro ~ 4Qxo-1.H-pyrrolu (2,3-d) pinmidin-5-ii) ethyl] benzoyl ~ glutamic or its pharmaceutically acceptable salt, as a matter of fact that administration to a patient needy can be simultaneous, separate or sequential. Pharmaceutical kit according to claim 14, wherein the first compartment comprises the monoethanesulfonatu salt form of the compound 3-Z- [i - (4- (N ^ (4 ~ methyl-piperezjn-1-i) - methylcarannii) -N-methyl · 20 amiau) anilino) -1-phenyl-methyl-6-methoxycarbanyl-2-indoiinone. Pharmaceutical kit according to claim 14, wherein the second compartment comprises the dissolved salt form of the acid compound N ~ [4- {2- (2-amino-4,7-dihydro-4-oxo -1 H-pyrrolo [2,3d] pyrimidin-5yl) ethyl] benzo-glutamic. 25 17, Method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis, which comprises administering to a patient in need of an effective amount of compound 3-Z- (1 ”(4- (N- ((4-methyl “piperazin-1áí} -metilcartQníl) Ν '<ηοΐίΙ-οϊηΙηο) -? ^ Ν11ηη) ~ 1-ίοηίΙ- ^ ίθΙίΙοηοΕ5-ηχήοχίοο ^ οη3ϋ-2“ ηη6 ϋ 30 its pharmaceutically acceptable salt, before, after and simultaneously with an effective amount, of the acid compound N- [4- [2- (2-amino-4,7-dihydro-4 · nxo-IH-pyrophojZEEdjpismidin-ã- iDetitJbenzoiíj-L-gluíâmicu or its pharmaceutically acceptable salt4 18. The method of claim 17, wherein the pharmaceutically acceptable salt of compound 3-Z- [1 “(4- (N - ((4-methyl-piperazin-1-yl)“ methylcarbonyl) 'Nmethyl-anvno ) -anilins) 1-phenyl-methylene] -e-methoxycarbonyl-2indelinena is its monethanesulfonate salt. 19. The method of claim 17, wherein the pharmaceutically acceptable salt of the acid compound N- (4> {2- (2-aminO4,7dihydro-4-oxo-1 H-pyrrole (2,3d] pyrimidine) 5-yl) ethyl) benzoH] L-glutamic is its disodium salt; 20. Method according to claim 17, which is also adapted for use with radiation therapy. 21. Method, according to any of the claims of 17 to 20, in which the disease is selected from cancers, diabetes, psoriasis, rheumatic arthritis, ayoid, Kaposi's sarcoma, hemangioma, acute and chronic kidney diseases, atheroma, arterial restenosis autoimmune diseases, acute inflammation, asthma, lymphedema, endometriosis, bleeding dysfunctional uierinosis, fibrosis, cirrhosis and eye diseases with proliferation of retinal vessels. 22. Method, according to any of claims 17 to 2D, wherein the disease is selected from non-small cell lung cancer (NSCI..C), small cell lung cancer (SCLC), pleural mesoielioma or malignant peritoneal, head and neck cancer, esophageal cancer, stomach cancer, co-rectal cancer, gastrointestinal sstromal tumor (GIST), pancreatic cancer, hepatocellular cancer, breast cancer, renal cell cancer, urinary tract cancer, cancer of prostate, ovarian cancer, brain tumors, sarcomas, skin caner and hematological cancer.