The present invention relates to the use of Volasertib or a salt thereof or a hydrate thereof in combination with Cisplatin or Carboplatin or a salt thereof or a hydrate thereof for treating patients suffering from advanced and/or metastatic solid tumours.

Background of the invention

Most advanced and/or metastatic solid tumours are incurable despite the availability of a variety of established treatment modalities like surgery, cytotoxic drugs, radiation therapy, and combinations of these. Objective responses in patients with advanced disease, though frequently seen using these treatments, are often followed by tumour progression and death. Therefore the search for new therapeutic strategies has become an urgent priority.

The efficacy of chemotherapeutic agents can be improved by combining anti-cancer drugs with different mode of action as well as by improving the dosage schedule. Even if the concept of combination therapies and improved dosage schedules already has been suggested, there is still a need for new and efficient therapeutic concepts for the treatment of cancer diseases, which show advantages over standard therapies.

Volasertib is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1 ), a key regulator of cell-cycle progression. Volasertib is a

dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for combination therapy of advanced and/or metastatic solid tumours..

Volasertib (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1 - piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro- 5-methyl-8-(1 -methylethyl)-

6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,

(I)-

This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.

Cisplatin (c/s-diamminedichloroplatinum(ll) (CDDP) (trade names Platinol and

Platinol-AQ) is a chemotherapy drug. It is used to treat various types of cancers, It reacts in vivo, binding to and causing crosslinking of DNA, which ultimately triggers apoptosis.

Carboplatin (cis-Diammine(1 ,1 -cyclobutanedicarboxylato)platinum(ll) (trade names Paraplatin and Paraplatin-AQ) is a chemotherapy drug used against different forms of tumours. Carboplatin interact with DNA, similar to the mechanism of alkylating agents.

Detailed Description of the Invention

In clinical trials with patients suffering suffering from advanced and/or metastatic solid tumours including NSCLC (non small cell lung cancer), sarcoma, colorectal cancer and melanoma it has been found that high dosages of Volasertib or a salt thereof or a hydrate thereof can be administered in combination with high dosages of cisplatin or carboplatin both having a profile of side effects (myelosuppression) which is overlapping to that of Volasertib without potentiation of those side effects. Therefore, a first object of the present invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 to 500 mg, preferably 300 or 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of 50 to 100 mg/m ² body surface area (BSA), preferably 75 to 100 mg/m ² BSA of Cisplatin at one day within the same treatment cycle, to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule I).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of 100 mg/m ² BSA of Cisplatin at one day within the same

treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule II).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of 75 mg/m ² BSA of Cisplatin at one day within the same

treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule III). Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of 100 mg/m ² BSA of Cisplatin at one day within the same

treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule IV).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of 75 mg/m ² BSA of Cisplatin at one day within the same

treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule V).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 to 500 mg, preferably 300 or 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of Carboplatin at a dose targeting AUC (area under the

concentration versus time curve) = 4 mg-min/mL to AUC = 6 mg-min/mL at one day within the same treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule VI). Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of Carboplatin at a dose targeting AUC = 6 mg-min/mL at one day within the same treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule VII).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 300 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of Carboplatin at a dose targeting AUC = 5 mg-min/mL at one day within the same treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule VIII).

Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of Carboplatin at a dose targeting AUC = 6 mg-min/mL at one day within the same treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule IX). Another object of the invention relates to a method of treating patients suffering from advanced and/or metastatic solid tumours characterized by the

a) administration of 350 mg of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof at one day within a 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 day treatment cycle and

b) administration of Carboplatin at a dose targeting AUC = 5 mg-min/mL at one day within the same treatment cycle

to a patient suffering from advanced and/or metastatic solid tumours (dosage schedule X).

For all of the above given dosage schedules, the preferred treatment cycles are 14, 21 or 28 day per treatment cycle, more preferably it is a 21 day treatment cycle. Volasertib and Cisplatin or Volasertib and Carboplatin can be administered at the same day or at different days during the treatment cycle. Preferably the compounds are administered at the same day. Preferably the compounds are administered at the same time or consecutively with a short break (about 30 min) between the

administrations. For example, as first medicament Cisplatin or Carboplatin is administered and after a 30 min break between the end of the administration of Cisplatin or Carboplatin Volasertib is administered.

The primary determinant of carboplatin clearance is glomerular filtration rate (GFR). GFR is a parameter of the renal function and is often decreased in elderly patients. Dosing formulas incorporating estimates of GFR to provide predictable carboplatin plasma AUCs should be used, especially in elderly patients, to minimize the risk of toxicity.

The dosing of carboplatin by target AUC is described in the current drug label. A simple formula for calculating dosage, based upon a patients glomerular filtration rate (GFR in mL/min) and carboplatin injection target area under the concentration versus time curve (AUC in mg/mL ^» min), has been proposed by Calvert Based on the Calvert formula, the Carboplatin doses can be calculated as:

Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula] If a patient's GFR is estimated based on serum creatinine measurements by the IDMS (Isotope Dilution Mass Spectrometry ) method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing as follows:

The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used.

For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg

For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg

For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg

Another object of the invention refers to Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof for the use in treating advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours characterized in that Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof is administered according to one of the dosage schedules I to X.

Another object of the invention refers to Cisplatin for the use in treating advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours characterized in that Cisplatin is administered according to one of the dosage schedules I to X.

Another object of the invention refers to Carboplatin for the use in treating a advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours characterized in that Carboplatin is administered according to one of the dosage schedules I to X.

Another object of the invention refers to the use of Volasertib or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of a medicament for treating advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours wherein the medicament is prepared for administration according to one of the dosage schedules I to X.

Another object of the invention refers to the use of Cisplatin or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of a medicament for treating advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours wherein the medicament is prepared for administration according to one of the dosage schedules I to X.

Another object of the invention refers to the use of Carboplatin or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of a medicament for treating advanced and/or metastatic solid tumours in patients suffering from advanced and/or metastatic solid tumours wherein the medicament is prepared for administration according to one of the dosage schedules I to X.

Another object of the invention is a pharmaceutical composition comprising an effective amount of Volasertib and an effective amount of Cisplatin together with an instruction for administration of both active ingredients to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and/or Cisplatin is to be administered according to the above mentioned dosage schedules I to X.

Another object of the invention is a pharmaceutical composition comprising an effective amount of Volasertib and an effective amount of Carboplatin together with an instruction for administration of both active ingredients to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and/or Carboplatin is to be administered according to the above mentioned dosage schedules I to X.

Another object of the invention is a pharmaceutical composition comprising an effective amount of Volasertib together with an instruction for administration of Volasertib and Cisplatin to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and Cisplatin is to be administered according to the above mentioned dosage schedules I to X.

Another object of the invention is a pharmaceutical composition comprising an effective amount of Volasertib a together with an instruction for administration of Volasertib and Carboplatin to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and Carboplatin is to be administered according to the above mentioned dosage schedules I to X.

Another object of the invention is a pharmaceutical kit, comprising a first

compartment which comprises an effective amount of Volasertib and a second compartment which comprises an effective amount of Cisplatin, together with an instruction for administration of both active ingredients to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and Cisplatin is to be administered according to one of the above mentioned dosage schedules I to X.

Another object of the invention is a pharmaceutical kit, comprising a first

compartment which comprises an effective amount of Volasertib and a second compartment which comprises an effective amount of Carboplatin, together with an instruction for administration of both active ingredients to a patient suffering from advanced and/or metastatic tumours, wherein according to said instruction Volasertib and Carboplatin is to be administered according to one of the above mentioned dosage schedules I to X.

This treatment cycle can be repeated as long as patients are eligible for repeated cycles, i.e. until progression of disease, or unacceptable toxicity and as long as neither patient nor investigator requests treatment discontinuation.

If platinum treatment needs to be stopped the patient might be switched to Volasertib monotherapy The instruction for administration may be in any form suitable for pharmaceuticals, e.g. in form of a leaflet added to the dosage form within secondary packaging or an imprint on the primary or secondary packaging.

Dosages / Volasertib:

For intraveneous treatment Volasertib may be administered to the human patient in a daily dose of 300 to 500 mg/application, preferably 300 or 350 mg/application. For instance, Volasertib can be administered as a slow intravenous infusion over several hours, e.g. over about 1 , 2, 4, 6, 10, 12 or 24 hours, preferably about 1 or 2 hours.

However, it may optionally be necessary to deviate from the dosage amounts specified for Volasertib, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses.

Dosage Forms and Formulation Aspects

Regarding any aspects of the invention for Volasertib pharmaceutically acceptable salts or hydrates thereof may be used, preferably trihydrochloride salt forms and hydrates thereof as disclosed in WO 07/090844. Dosages or amounts of the actives provided in the context of this invention refer in any case to the free base equivalent, that is Volasertib in the free base form.

The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue system, animal or human that is being sought by a researcher or clinician, resulting in a beneficial effect for at least a statistically significant fraction of patients, such as a improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass, extension of life, or improvement in quality of life. For Volasertib the therapeutically effective amount within the meaning of the present invention is between 300 and 500 mg per day of administration. For Cisplatin the therapeutically effective amount within the meaning of the present invention is between 50 and 100 mg/m ² BSA per day of administration. For Cisplatin the therapeutically effective amount within the meaning of the present invention is between 50 and 100 mg/m ² BSA per day of administration. For Carboplatin the therapeutically effective amount within the meaning of the present invention is calculation according to the Calvert formula:

Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula].

Day 1 of a e.g. 21 day treatment cycle is defined as that day at which the first dose of Volasertib is administered.

The term "advanced and/or metastatic solid tumours" is defined as histologically or cytologically confirmed diagnosis of advanced, non resectable and/or metastatic relapsed or refractory solid malignant tumour, not amenable to standard therapy or for which no therapy of proven efficacy exists.

In accordance with the present invention Volasertib, Cisplatin and Carboplatin may be administered by parenteral (e.g. intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection), preferably intravenous application, and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. Dosage forms and formulations of both actives suitable within the present invention are known in the art. For instance, such dosage forms and formulations include those disclosed for Volasertib in WO

2006/018221 .

The following Examples serve to illustrate the invention without restricting it:

Example 1 : Clinical Trial Sequential cohorts of three to six patients (pts) received a single 2-hour infusion of Volasertib (V) in combination with Cisplatin (Cis) (arm A) or Carboplatin (Ca) (arm B), on day 1 every 3 weeks. Cis and Ca were given for up to six cycles (Cy), V was continued until disease progression or unacceptable toxicity.

Results:

46 patients have received Volasertib in combination with either Cisplatin or

Carboplatin. The maximum tolerated dose for volasertib in combination with cisplatin or carboplatin in patients with advanced and/or metastatic solid tumours was at or above 300 mg. Patients have received between one and 16 cycles of treatment with volasertib, with a median (range) of three (one, six) cycles in combination with cisplatin and two (one, six) cycles in combination with carboplatin

Efficacy

Four partial responses (PR) have been observed: two in patients with CHOP- resistant follicular dendritic reticulum cell sarcoma in arm A (dose level [DL] A2, A4), one in a heavily-pretreated head and neck carcinoma in arm B (DL B4), and one in a patient with pretreated lung cancer (DL A5)

- one patient with dendritic reticulum cell sarcoma (DL A2) achieved a PR, remaining on treatment until discontinuation at the end of cycle 15 due to progressive disease (PD)

- another patient with dendritic reticulum cell sarcoma (DL A4; volasertib dose reduced to 200 mg from fifth cycle onwards due to febrile neutropenia) had stable disease (SD) at first evaluation and relevant tumor shrinkage at second evaluation. This patient achieved PR at cycle 4, and remains on treatment in cycle 16

- one patient with hypopharynx carcinoma (DL B4; volasertib dose reduced to 200 mg in cycle 2 due to DLT in cycle 1 ) achieved a PR in cycle 2, which was confirmed in cycle 4. The patient continues to have PR in cycle 12

- one patient with lung adenocarcinoma (DL A5) is receiving treatment in cycle 4 having achieved a PR in cycle 2 that has yet to be confirmed. These results demonstrate the beneficial effect of the combined administration of Volasertib and Cisplatin or Volasertib and Carboplatin according to the dosage schedules I to X.