WO2006113172A1

WO2006113172A1 - Use of vascular endothelial growth factor receptor inhibitors for the treatment of gastrointestinal, genitourinary, lymphoid and pulmonary cancers

Info

Publication number: WO2006113172A1
Application number: PCT/US2006/013056
Authority: WO
Inventors: William Berg; David Lebwohl; Andrea Kay
Original assignee: Novartis Pharma GmbH Austria; Novartis AG
Current assignee: Novartis Pharma GmbH Austria; Novartis AG
Priority date: 2005-04-13
Filing date: 2006-04-10
Publication date: 2006-10-26
Anticipated expiration: 2007-10-13
Also published as: GT200600147A; AR053576A1; UY29471A1; TW200719914A; PE20061361A1

Abstract

The invention relates to the use of VEGF-R inhibitors alone or in combination with chemotherapy for the treatment of gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non-small cell) cancer patients having high LDH values and patients with cancers of neural crest origin having high LDH values.

Description

Use of Vascular Endothelial Growth Factor Receptor Inhibitors for the Treatment of Gastrointestinal. Genitourinary. Lymphoid and Pulmonary Cancers ,

The use of Vascular Endothelial Growth Factor Receptor (VEGF-R) inhibitors for the treatment of proliferative diseases is already known in the art. At the centre of the network regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth and in a wide number of pathological anomalies and diseases, lies the angiogenic factor known as "Vascular Endothelial Growth Factor", along with its cellular receptors (see Breier, G., et al., Trends in Cell Biology 6, 454- 6 [1996] and references cited therein). VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein. VEGF receptors are transmembranous receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Certain diseases are known to be associated with deregulated angiogenesis, for example diseases caused by ocular neovascularisation, such as retinopathies, age-related macula degeneration, psoriasis, arteriosclerosis and especially proliferative diseases, for example so-called solid tumours such as colorectal cancer and liquid tumours such as leukaemia. A large number of compounds inhibiting the VEGF-R tyrosine kinase activity has been described in the art.

Prognostic factors for survival have been identified for colorectal cancer suitable to determine the status of the disease and to predict the expected survival time of the patient (N. Kemeny et al, Prognostic variables in patients with hepatic metastases from colorectal cancer, Cancer 63(4), 1989, 742-7). Human colorectal cancer patients displaying certain prognostic factors upon diagnosis are considered as patients having a lower expected survival time compared to those patients lacking such prognostic factors. LDH (lactase dehydrogenase), bad performance status (PS), high number of metastases and liver metastases are the most commonly reported for, identifying poor prognosis colorectal cancer patients. For those colorectal cancer patients who had adjuvant chemotherapy, the time between the end of adjuvant therapy and first diagnosis of metastatic disease is another common prognosis factor, wherein shorter is worse.

Surprisingly, it has now been found that the benefit of the treatment with VEGF-R inhibitors alone or in combination with chemotherapy with respect to progression-free survival is significantly enhanced in gastrointestinal, genitourinary, lymphoid and pulmonary tsmall cell and non-small cell) cancer patients having high LDH values and in patients with cancer of neural crest origin having high LDH.

Hence, the present invention relates to the use of VEGF-R inhibitors alone, or in combination with chemotherapy for the treatment of gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non-small cell) cancer patients. having high LDH values and patients with cancers of neural crest origin. having high LDH values. The present invention further relates to the use of VEGF-R inhibitors alone or in a combination as mentioned above for the preparation of medicaments for the treatment of gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non -small cell) cancer patients having high LDH values, and patients with cancers of neural crest cell origin having high LDH values, a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use together with instructions to use such combination in the treatment of gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non-small cell) cancer patients having high LDH values and patients with cancers of neural crest cell origin having high LDH values, and to a method of treating gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non-small cell) cancer patients having high LDH values and patients having cancer of neural crest -cell origin having high LDH values.

More specifically, the present invention relates to

• a method of treating gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer comprising administering a therapeutically effective amount of a VEGF-R inhibitor to a human patient having high LDH values; and to

• a method of treating gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or patients having cancer of neural crest cell origin comprising administering a therapeutically effective amount of a 4-pyridylmethyl- phthalazine derivative to a human patient having high LDH values, -especially comprising administering a therapeutically effective amount of a 4-pyridylmethyl- phthalazine derivative to a human patient having LDH values of at least 1. S x upper normal limit.

The term "gastrointestinal, genitourinary, lymphoid, and pulmonary (small cell and non-small cell) cancer and cancer of neural crest cell origin" as used herein relates in particular to colorectal cancer, lung cancer, such as non-small cell lung -cancer and small cell lung cancer, melanoma, pheochromocytoma, neuroblastoma, pancreatic cancer, lymphoma, especially Burkitt, Hodgkins and Non-Hodgkins lymphoma, testicular cancer, mesothelioma, renal cell carcinoma, ovarian cancer and prostate cancer. In one preferred embodiment of the present invention the cancer type is colorectal cancer, especially metastatic colorectal cancer.

The term "high LDH values" as used herein means a value of above the upper normal limit (UNL), preferably at least 1.5 x UNL.

LDH units are usually expressed in IU/100 ml of serum (IU means international units). The normal laboratory values may change from one laboratory to the other and due to the method of analysis employed. For the present invention, the UNL is considered to be at 100, hence, the threshold for high LDH values applied herein is 150 IU/100 ml.

LDH values can be determined from plasma samples of the patients by standard laboratory serum evaluations known in the art. For that purpose, typically, blood samples (between 2 and 10 mL) is drawn from a vein or from a heel, finger, toe, or earlobe and -collected into pre- cooled (ice bath) heparinized tubes, gently inverted 8 to 10 times and immediately placed into an ice bath. Within 30 minutes, plasma is prepared by centrifugation (e.g. ca. 2,000 x g, 4⁰C, 10 min). Following centrifugation, the plasma sample can be stored frozen at < -18 ⁰C until analysis.

In a broader aspect, the present invention relates to the use of compounds which decrease by any kind of mechanism the activity of the VEGF in gastrointestinal, genitourinary, lymphoid and pulmonary (small cell and non-small cell) cancer patients with poor prognosis and patients having cancer of neural crest cell origin with poor prognosis, especially patients having high LDH values. Compounds which decrease the activity of the VEGF are especially compounds which inhibit the VEGF receptor tyrosine kinase, but also compounds which inhibit a VEGF receptor and compounds binding to VEGF, and are in particular those compounds, proteins and monoclonal antibodies generically and specifically disclosed in WO 98/35958, WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO OO/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; those as described by M. Prewettet al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27, no. 1 , pp 14-21 , 1999; in WO 00/37502 and WO 94/10202; Angiostatin™, described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; and Endostatin™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285; in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and claims is hereby incorporated into the present application by reference to these publications. The compounds used as active ingredients alone or in the combinations disclosed herein can be prepared and adm inistered as described in the cited documents, respectively.

In one embodiment, the present invention relates to the use of 4-pyridylmethyl-phthalazine derivatives alone or in combination with chemotherapy by administering agents contemporaneously, separately or sequentially to treat gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest cell origin in patients having high LDH values.

4-Pyridylmethyl-phthalazine derivatives being inhibitors of VEGF receptor tyrosine kinase and their preparation, pharmaceutical formulations thereof and methods of making such compounds are described in WO00/59509, EP02/04892, WO01/10859 and, in particular, in U.S. Patent No. 6,258,812, which are here incorporated by reference. Most preferred are the compounds of formula I

wherein r is 0 to 2, n is 0 to 2, m is 0 to 4,

Ri and R₂ (i) are lower alky I or

(ii) together form a bridge in subformula I* (I*)

Z)_n. the binding being achieved via the two terminal carbon atoms, or (iii) together form a bridge in subformula I**

wherein one or two of the ring members T₁, T₂, T₃ and T₄ are nitrogen, and the others are in each case CH, and the binding is achieved via T₁ and T₄;

A, B, D₁ and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N ;

G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH₂-O-, -CH₂-S-,

-CH₂-NH-, oxa (-O-), thia (-S-), or imino (-NH-);

Q is lower alkyl;

R is H or lower alky I;

X is imino, oxa, or thia;

Y is aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and

Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present; and wherein the bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein one or more N atoms carry an oxygen atom; with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, G is selected from the group comprising lower alkylene,

-CH₂-O-, -CH₂-S-, oxa and thia; and their pharmaceutically acceptable salts. The radicals and symbols as used in the definition of a compound of formula I have the meanings as disclosed in WO 98/35958 which publication is hereby incorporated into the present application by reference.

The term "PTK787" or "PTK/ZK" or "PTK787/ZK222584" as used herein means a VEGF receptor tyrosine inhibitor of formula I wherein r, n and m are each 0, R₁ and R₂ together form a bridge of subformula I*, A₁ B, D and E are each CH, G is methylene, X is imino, Y is 4-chlorophenyl, and the bonds characterized by a wavy line are double bonds^ Such VEGF receptor tyrosine inhibitor of formula I is very preferred for the present invention. Most preferably, PTK787 is employed in the form of its succinate salt.

Studies in humans have shown PTK787 to be well tolerated and to reduce tumor vascular permeability. It is understood that further references to PTK787 are intended to include pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, the activity of the VEGF is decreased by administration of "AVAST ATIN"®.

Chemotherapy for the treatment of proliferative diseases is known in the art. When applied in combination with chemotherapy, the agents are administered contemporaneously, separately or sequentially.

In a preferred embodiment of the present invention, the chemotherapy comprises a platinum compound and/or an antineoplastic antimetabolite and, optionally, folinic acid. In a specific embodiment of the present invention, the chemotherapy comprises a platinum compound, 5- fluorouracil and folinic acid. In a further specific embodiment of the present. invention, the chemotherapy comprises a platinum compound, capecitabine and folinic acid.

In another embodiment of the present invention, the chemotherapy comprises a topoisomerase I inhibitor and/or an antineoplastic antimetabolite and, optionally, folinic acid. In a specific embodiment of the invention, the chemotherapy comprises a topoisomerase I inhibitor, 5-fluorouracil or capecitabine, and folinic acid. The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6- mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of such compounds, and furthermore ZD 1694 (RALTITREXED™), LY231514 (ALIMTA™), LY264618 (LOMOTREXOL™) and OGT719.

5-Fluorouracil can be prepared, e.g., as described in US 2,802,005. It can be employed in the present invention as marketed, e.g., under the trademark EFUDEX™, FLURACI L™ or FLUROBLASTIN™. Tegafur can be employed especially in the form of a composition as disclosed in US 5,116,600 and U S 5,525,603. Furthermore, tegafur can be administered, e.g., in the form as it is marketed under the trademarks FTORAFUR™, LAMAR™ or NEBEREK™. Capecitabine can be administered, e.g., in the form as disclosed in US 5,472,949 or in the form as it is marketed, e.g., under the trademark XELODA™. Cladribine can be prepared, e.g., as disclosed in US 4,760,135. It can be administered, e.g., in the form as it is marketed under the trademarks LEUSTATIN™ or LEUSTAT™. Cytarabine can, e.g., be prepared as disclosed in US 3,116,282 or by Hessler in J. Org. Chem. 4J. (1970) 1828. It can be administered, e.g., in the form as it is marketed under the trademarks ARA-C™, CYTOSAR™ or UDICIL™. A suitable salt of such compound is cytarabine ocfosfate (STARASID™) which can be prepared as described in US 4,812,560. Fludarabine phosphate can be prepared as described in US 4,357,324, It -can be applied as marketed under the trademark FLUDARA™. Gemcitabine can be administered, e.g., in accordance with the disclosure of US 5,464,826 or in the form as it is marketed, e.g., under the trademark GEMZAR™. 6-Mercaptopurine (6-purinethiol) can, e.g., be prepared as disclosed in US 2,933,498. It can be employed as marketed, e.g., under the trademark LEUKERIN™ or PURINETHOL™. Hydroxyurea can, e.g., be prepared as disclosed in US 2,705,727. Methotrexate can be employed as marketed, e.g., under the trademark FOLEX™ or MTX™. Edatrexate can, e.g., be prepared as disclosed in US 4,369,319.

The term "folinic acid" relates to "N-[4-[[(2-amino-5-formyl-1 ,4,5,6,7,8-hexahydro-4-oxo-6- pteridinyl)methyl]amino]benzoyl-L-glutamic acid, which is marketed, e.g., under the trademark LEUCOVORIN™.

The term "platinum compound" as used herein means carboplatin, cisplatin or oxaliplatin. Preferably, the platinum compound is oxaliplatin. The term "carboplatin" as used herein relates to the antineoplastic agent c/s-diamine (1 ,1- cyclobutane dicarboxylato) platinum(ll), which is disclosed, e.g., in US 4,140,707 or by R.C. Harrison et al. in Inorg. Chim. Acta 46, L15 (1980). This drug can be administered e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT™ or PARAPLATIN™.

The term "oxaliplatin" as used herein relates to the antineoplastic agent also known as oxalatoplatinum, which is disclosed, e.g., in US 5,716,988. This drug can be administered e.g., in the form as described in the cited US patent or in the form it is marketed, e.g. under the trademark ELOXANTINE™ or 1-OHP™.

The term "cisplatin" as used herein relates to the antineoplastic agent also known as cis- diaminedichloroplatinum, which compound and its use as antineoplastic agent is disclosed, e.g., in DE 2,318,020.

The term "topoisofn erase I inhibitors" as used herein includes, but is not limited to topotecan,. irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU- 166148 (compound A1 in WO99/17804). Irinotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark CAMPTOSAR™. Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN™.

In a broader sense of the invention, the term "chemotherapy" refers to the administration of an antineoplastic agent selected from the group that includes, but is not limited to topoisomerase Il inhibitors, microtubule active agents, protein kinase C inhibitors, gonadorelin agonists, anti-androgens, bisphosphonates, histone deacetylase inhibitors, S- adenosylmethionine decarboxylase inhibitors, and trastuzumab.

The term "topoisomerase Il inhibitors" as used herein includes, but is not limited to the antracyclines doxorubicin (including liposomal formulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, arid the podophillotoxines etoposide and teniposide. Etoposide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposide can be administered, e.g., in the form as it is marketed, e.g. under the trademark VM 26-BRISTOL ™. Doxorubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ADRIBLASTIN™. Epirubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMORUBICIN™. ldarubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™. Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g_; under the trademark NOVANTRON™.

The term "microtubule active agents" relates to microtubule stabilizing and microtubule destabilizing agents selected from the group consisting of paclitaxel, docetaxel, eleutherobin, the vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine and discodermolide. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN RP. ™. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTΪN™.

The term "protein kinase C inhibitors", refers in particular to staurosporine derivatives, and preferably to those disclosed in US 5,093,330. Such compounds can be administered in the form as disclosed in WO99/48896.

The term "anti-angiogenic compounds" as used herein relates to thalidomide (THALOMID™) and SU5416.

The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelix can be formulated, eg. as disclosed in US 5,843,901.

The term "anti-androgens" as used herein includes, but is not limited to bicalutamide (CASODEX™), which can be formulated, e.g. as disclosed in US 4,636,505.

The term "bisphosphonates" as used herein includes, but is not limited to etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. "Etridonic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL™. "Clodronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS™. "Tiludronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID™. "Pamidronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark AREDIA™. "Alendronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™. "Ibandronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT™. "Risedronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL™. "Zoledronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZO META™.

The term "histone deacetylase inhibitors" as used herein includes, but is not limited to MS- 275, SAHA, FK228 (formerly FR901228), Trichostatin A and the compounds disclosed in WO 02/22577, in particular NVP-LAQ824 or its lactate salt and NVP-LBH589.

The term "S-adenosylmethionine decarboxylase inhibitors" as used herein includes, but is not limited to the compounds disclosed in US 5,461 ,076.

"Trastuzumab" can be administered, e.g., in the form as it is marketed, e.g. under the trademark HERCEPTIN™.

The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International or other IMS World Publications. The corresponding content thereof is hereby incorporated by reference.

The term "a combined preparation", as used herein defines especially a "kit of parts" in the sense that the combination partners (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Thus, the present invention further includes a commercial package comprising 1-(4- chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof in a form suitable for oral administration and instructions to administer the 1-(4-chloroanilinό)-4- (4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof to a gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non -small -cell) cancer patients having high LDH values or patients having cancer of neural crest cell origin having high LDH values.

The present invention also relates to the use of a combination as disclosed herein for the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest cell origin in a patient having high LDH values and for the preparation of a medicament for the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest cell origin characterized by high LDH values.

The term "metastatic growth" as used herein comprises the metastatic spread of tumors and the growth and development of micrometastases in other organs of the cancer patients.

It will be understood that references to the combination partners (a) and (b) are meant to also include the pharmaceutically acceptable salts of the compounds.

In general, for the treatment of colorectal cancer, the 4-pyridylmethyl-phthalazine derivative can be given orally on a continuous basis, for example once daily. For 1-(4-chloroanilino)-4- (4-pyridylmethyl)phthalazines succinate, a daily oral dose in the range from 750 mg to 2500 mg, especially in the range from 1000 mg to 1500 mg/day, more preferably in the range from 1200 mg to 1300 mg/day, most preferably 1250 mg/day, are contemplated as a pharmaceutically effective dose. However, other administration schedules are also likely to be effective and are included within the scope of the present invention.

When the combination partners employed in the combinations as disclosed herein are applied in the form as marketed as single drugs, their dosage and mode of administration can take place in accordance with the information provided on the package insert of the respective marketed drug in order to result in the beneficial effect described herein, if not mentioned herein otherwise.

The chemotherapy is generally administered according to established administration regimen. Such administration regimens, for example the deGramont regimen for colorectal cancer, are known in the art (A De Gramont et al, J. Clin. One. 18(16), 2000, 2938-47). In a specific embodiment, the chemotherapy comprises the administration of oxaliplatin, folinic acid and 5-fluorouracil according to an established administration regimen, such as those known in the art. A particular chemotherapy regimen whereby 85 mg/m² of oxaplatin is administered on day 1 , 200 mg/m² of folinic acid is given as a 2 hour infusion on days 1 and 2, and 5-fluorouracil is administered as a bolus at a dose of 400 mg/m² followed by 600 mg/m² over 22 hours on days 1 and 2 and is given every 14 days is particularly useful.

5-Fluorouracil may be administered to a human in a dosage range varying from about 50 to 1000 mg/m²day, e.g. 500 mg/m²day.

Capecitabine may be administered to a human in a dosage range varying from about 10 to 1000 mg/m²day.

Gemcitabine hydrochloride may be administered to a human in a dosage range'varying from 10 to about 1000 mg/week.

Methotrexate may be administered to a human in a dosage range varying from about 5 to 500 mg/m²day.

ZD 1694 (RALTITREXED™) can be administered to a human in a dosage range varying from about 2.0 to 4.0 mg/m², e.g., 3.5 mg/m², every 3 weeks as a 15 minute infusion.

Carboplatin may be administered intravenously to a human in a dosage range varying from about 100 to 400, e.g. 200, mg/m² body surface about every four to six weeks.

Oxaliplatin may be administered intravenously to a human in a dosage range varying from about 25 to 135, e.g. 45 or 85, mg/m² body surface about every two to three weeks.

Cisplatin may be administered to a human in a dosage range varying from about 25 to 100 mg/m² about every three weeks.

Topotecan may be administered to a human in a dosage range varying from about 1 to 5 mg/m²day. . lrinotecan may be administered to a human in a dosage range varying from about 50 to 350 mg/m²day.

Vinblastine may be administered to a human in a dosage range varying from about 1.5 to 10 mg/m²day. Vincristine sulfate may be administered parenterally to a human in a dosage range varying from about 0.025 to 0.05 mg/kg body weight • week. Vinorelbine may be administered to a human in a dosage range varying from about 10 to 50 mg/m²day. Etoposide phosphate may be administered to a human in a dosage range varying from about 25 to 115 mg/m²day, e.g. 56.8 or 113.6 mg/m²day. Teniposide may be administered to a human in a dosage range varying from about 75 to 150 mg about every two weeks. Doxorubicin may be administered to a human in a dosage range varying from about 10 to 100 mg/m²day, e.g. 25 or 50 mg/m²day. Epirubicin may be administered to a human in a dosage range varying from about 10 to 200 mg/m²day. ldarubicin may be administered to a human in a dosage range varying from about 0.5 to 50 mg/m²day. Mitoxantrone may be administered to a human in a dosage range varying from about 2.5 to 25 mg/m²day. Paclitaxel may be administered to a human in a dosage range varying from about 50 to 300 mg/m²day. Alendronic acid may be administered to a human in a dosage range varying from about 5 to 10 mg/day. Clodronic acid may be administered to a human e.g. in a dosage range varying from about 750 to 1500 mg/day. Etridonic acid may be administered to a human in a dosage range varying from about 200 to 400 mg/day. lbandronic acid may be administered to a human in a dosage range varying from about 1 to 4 mg every three to four weeks. Risedronic acid may be administered to a human in a dosage range varying from about 20 to 30 mg/day. Pamidronic acid may be administered to a human in a dosage range varying from about 15 to 90 mg every three to four weeks. Tiludronic acid may be administered to a human in a dosage range varying from about 200 to 400 mg/day. Trastuzumab may be administered to a human in a dosage range varying from about 1 to 4 mg/m²week. Bicalutamide may be administered to a human in a dosage range varying from about 25 to 50 mg/m²day.

It is one objective of this invention to provide a pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against a proliferative disease comprising a combination as described herein. In this composition, the combination partners (a) and <b) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.

The pharmaceutical compositions for separate administration of the combination partners (a) and (b) and for the administration in a fixed combination, i.e. a single pharmaceutical composition comprising at least two combination partners (a) and (b), according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral adm inistration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carries, especially suitable for enteral or parenteral application.

Novel pharmaceutical composition contain, for example, from about 10 % to about 100 %, preferably from about 20 % to about 60 %, of the active ingredients. Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, -capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.

It can be shown by established test models that VEGF-R inhibitors alone or in combination with chemotherapy result in the beneficial effects described herein before. The person skilled in the pertinent art is fully enabled to select a relevant test model to prove such beneficial effects. The pharmacological activity may, for example, be demonstrated in a clinical study or in a test procedure as essentially described hereinafter .

Suitable clinical studies are, for example, randomized, double-blind, placebo-controlled, parallel studies in patients with metastatic colorectal cancer, but also dose -escalation studies. For treatment schemes including chemotherapy, optionally a standard antiemetic regimen for the prophylaxis of acute emesis can be given to the patient on the day of chemotherapy, e.g. a 5HT₃ antagonist such as granisetron or ondansetron with or without a corticosteroid. The primary endpoints in such studies can be the performance status, Quality of Life scores, time to progression of the disease, morbidity, mortality or an increase in the perod of progression -free survival. Tumor assessment in the form of dynamic contrast- enhanced Magnetic Resonance Imaging (MRI) is a suitable approach to determine the effect of the treatment.

In one aspect, the present invention provides a commercial package comprising a A- pyridylmethyl-phthalazine derivative and at least one compound selected from the group consisting of a platinum compound and/or an antineoplastic antimetabolite and, optionally, folinic acid, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier together with instructions for simultaneous, separate or sequential use thereof in the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary .(small cell and non-small cell) cancer or cancer of neural crest cell origin in patients having high LDH values.

In a further aspect, the present invention provides a method to diagnose subjects suffering from gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially metastatic colorectal cancer, who may be suitable candidates for the treatment with VEGF-R inhibitors, preferably those of formula I, alone or in combination with chemotherapy, comprising assaying LDH levels in a biological sample from said subject, especially a blood or serum sample, wherein subjects having high LDH values compared to controls would be suitable candidates for treatment with VEGF-R inhibitors alone or in combination with chemotherapy.

Example 1 : Progression-free survival (PFS) results from a randomized, double-blind, placebo-controlled, phase III study in patients with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK222584 or placebo (CQ NFIRM-D

Methods: A multinational, randomized double-blind, placebo controlled phase III study was performed to evaluate PTK787/ZK222584 (PTK/ZK) in combination with the FOLFOX-4 regimen (oxaliplatin/5-FU/LV) in patients with metastatic adenocarcinoma of the colon or rectum.

Patients received oxaliplatin/5-FU/LV every 2 weeks according to the FOLFOX4 regimen with either PTK/ZK or placebo, given at a dose of 1250 mg, administered orally on a once- daily continuous schedule. The pre-planned early primary endpoint, progression-free survival, was assessed by the investigators and independently by a central radiology review every 8 weeks.

Results: 1168 patients were randomized. Baseline characteristics were similar between the two arms. Key efficacy and selected safety results are as follows:

hazard ratio is the relative risk of progression on PTK/ZK compared to placebo The PFS results suggest a positive effect of PTK/ZK. An exploratory analysis performed by pooling the preplanned strata for randomization showed that patients with high LDH experienced the greatest improvement in PFS.

Claims

What is claimed is:

1. A method of treating gastrointestinal, genitourinary, lymphoid or pulmonary (small-cell and non-small cell) cancer or a cancer of neural crest origin comprising administering a therapeutically effective amount of a VEGF-R inhibitor to a human patient having high LDH values.

2. A method of treating colorectal cancer comprising administering a therapeutically effective amount of a VEGF-R inhibitor to a human patient having high LDH values.

3. A method of treating gastrointestinal, genitourinary, lymphoid or pulmonary tsmall cell and non-small cell) cancer or a cancer of neural crest origin comprising administering a therapeutically effective amount of a 4-pyridylmethyl-phthalazine derivative to a human patient having high LDH values.

4. A method of treating colorectal cancer comprising administering a therapeutically effective amount of a 4-pyridylmethyi-phthalazine derivative to a human patient having high LDH values.

5. The method of claim 3 or 4 comprising administering a therapeutically effective amount of a 4-pyridylmethyl-phthalazine derivative to a human patient having LDH values of at least 1.5 x upper normal limit.

6. The method according to any one of claims 3 to 5 comprising administering a therapeutically effective amount of a 4-pyridylmethyl-phthalazine derivative of formula I

wherein r is 0 to 2, n is 0 to 2, m is 0 to 4,

R₁ and R₂ (i) are lower alkyl or (ii) together form a bridge in subformula I*

the binding being achieved via the two terminal carbon atoms, or (iii) together form a bridge in subformula I**

A, B, D, and E are, independently of one another, N or CH, with the stipulation that not more than 2 of these radicals are N;

G is lower alkylene, lower alkylene substituted by acyloxy or hydroxy, -CH₂-O-, -CH₂-S-, -CH₂-NH-, oxa (-O-), thia (-S-), or imino (-NH-); Q is lower alkyl; R is H or lower alkyl; X is imino, oxa, or thia;

Y is unsubstituted or substituted aryl, pyridyl, or unsubstituted or substituted cycloalkyl; and

Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present; and wherein the bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom, or the salt of such compound having at least one salt-forming group, to a warm-blooded animal in need thereof.

7. Method of claim 6 wherein the 4-pyridylmethyl-phthalazine derivative of formula I is PTK/ZK.

8. The method of claim 7 wherein between 1200 mg/day to 1300 mg/day of PTK/ZK is administered.

9. The method of claim 7 wherein 1250 mg/day of PTK/ZK is administered.

10. Use of a VEGF-R inhibitor for the manufacture of a medicament for the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, characterized by high LDH values.

11. The use of a VEGF-R inhibitor for the manufacture of a medicament for the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, in human patients having LDH values of at least 1.5 x upper normal limit.

12. Use of a combination comprising a VEGF-R inhibitor and at least one compound selected from the group consisting of a platinum compound and/or an antineoplastic antimetabolite and, optionally, folinic acid, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier for the preparation of medicaments for contemporaneous, separate or sequential use in the treatment of human gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, patients having high LOH values.

13. Use according to claim 12, wherein the combination comprises a VEGF-R inhibitor, a platinum compound, especially oxaliplatin, 5-fluorouracil and folinic acid.

14. Use according to claim 12, wherein the combination comprises a VEGF-R inhibitor, a platinum compound, especially oxaliplatin, capecitabine and folinic acid.

15. Use of a combination comprising a VEGF-R inhibitor and at least one-compound selected from the group consisting of a topoisom erase I inhibitor and/or an antineoplastic antimetabolite and, optionally, folinic acid, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier for the preparation of medicaments for contemporaneous, separate or sequential use in the treatment of human gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, patients having high LDH values.

16. Use according to claim 15, wherein the combination comprises a VEGF-R inhibitor, a topoisomerase I inhibitor, 5-fluorouracil or capecitabine, and folinic apid.

17. Use according to any one of claims 10 to 16 wherein the VEGF-R inhibitor is a 4- pyridylmethyl-phthalazine derivative of formula I

wherein r is 0 to 2, n is 0 to 2, m is 0 to 4,

Ri and R₂ (i) are lower alkyl or

(ii) together form a bridge in subformula I*

A, B, D, and E are, independently of one another, N or CH₁ with the stipulation that not more than 2 of these radicals are N;

-CH₂-NH-, oxa (-O-), thia (-S-), or imino (-NH-);

Q is lower a Iky I;

R is H or lower alkyl;

X is imino, oxa, or thia;

Z is amino, mono- or disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sύlfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfonyl, phenyl-lower alkylsulfinyl or alkylphenylsulfinyl, substituents Z being the same or different from one another if more than 1 radical Z is present; and wherein the bonds characterized, if present, by a wavy line are either single or double bonds; or an N-oxide of the defined compound, wherein 1 or more N atoms carry an oxygen atom, or the salt of such compound having at least one salt-forming group.

18. Use according to any one of claims 10 to 16 wherein the VEGF-R inhibitor is PTK/ZK.

19. Use according to any one of claims 10 to 16 wherein the VEGF is decreased by administration of "AVAST ATIN"®.

20. A commercial package comprising a 4-pyridylmethyl-phthalazine derivative and at least one compound selected from the group consisting of a platinum compound and/or an antineoplastic antimetabolite and; optionally, folinic acid, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable carrier together with instructions for simultaneous, separate or sequential use thereof in the treatment of gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, in patients having high LDH values.

21. A method of diagnosing subjects suffering from gastrointestinal, genitourinary, lymphoid or pulmonary (small cell and non-small cell) cancer or a cancer of neural crest origin, especially colorectal cancer, who may be suitable candidates for the treatment with VEGF-R inhibitors alone or in combination with chemotherapy, comprising assaying LDH levels in a biological sample from said subject, wherein subjects having high LDH values compared to controls would be suitable candidates for treatment with VEGF-¹R inhibitors alone or in combination with chemotherapy.