Combination of a PI3 Kinase Inhibitor with Pacitaxel for Use in the Treatment or Prevention of a Cancer of the Head and Neck

Abstract

A pharmaceutical combination comprising (a) a phosphatidylinositol-3-kinase (PI3K) inhibitor compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) paclitaxel or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use, for the treatment of a cancer of the head and neck; a pharmaceutical composition comprising said combination; the use of said combination for the preparation of a medicament for the treatment of a cancer of the head and neck; a method of treating or preventing a cancer of the head and neck comprising administering a jointly therapeutically effective amount of such a combination to a subject in need thereof; and a commercial package thereof.

Description

FIELD OF THE INVENTION[0001]A pharmaceutical combination comprising (a) a phosphatidylinositol-3-kinase (PI3K) inhibitor compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) paclitaxel or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use, for the treatment of a cancer of the head and neck; a pharmaceutical composition comprising said combination; the use of said combination for the preparation of a medicament for the treatment of a cancer of the head and neck; a method of treating or preventing a cancer of the head and neck comprising administering a jointly therapeutically effective amount of such a combination to a subject in need thereof; and a commercial package thereof.BACKGROUND OF THE INVENTION[0002]Cancer of the head and neck includes all cancers arising from the upper aerodigestive tract. Squamous cell carcinomas originating from mucosal surfaces represent more than 90% of cases. The incidenc...

AI Technical Summary

Benefits of technology

[0058]The nature of cancer is multifactorial. Under certain circumstances, drugs with different mechanisms of action may be combined. However, just considering any combination of therapeutic agents having different mode of action does not necessarily lead to combinations with advantageous effects.

[0059]The administration of a pharmaceutical combination of the invention may result not only in a beneficial effect, e.g. a synergistic therapeutic effect, e.g. with regard to alleviating, delaying progression of or inhibiting the symptoms, but also in further surprising beneficial effects, e.g. fewer side-effects, more durable response, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically therapeutic agents used in the combination of the invention.

[0060]Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the therapeutic agent (a) and (b), in particular a synergism (e.g., a more than additive effect), additional advantageous effects, less side effects, a combined therapeutic effect in a non-effective dosage of one or both of the therapeutic agent (a) and (b), and very preferably a strong synergism of the therapeutic agent (a) and (b).

[0061]The term “synergistic effect” or “synergism” as used herein, refers to action of two therapeutic agents such as, for example, a compound of formula (I), e.g., compound A, and paclitaxel, producing an effect, for example, slowing the symptomatic progression of a proliferative disease or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[0062]It can be shown by established test models that a COMBINATION OF THE INVENTION results in the beneficial effects described herein before. The person skilled in the art is fully enabled to select a relevant test model to prove such beneficial effects. The pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be demonstrated in a clinical study or in an animal model as essentially described hereinafter.

[0063]Determining a synergistic interaction between one or more components, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different w / w ratio ranges and doses to patients in need of treatment. For humans, the complexity and cost of carrying out clinical studies on patients may render impractical the use of this form of testing as a primary model for synergy. However, the observation of synergy in one species can be predictive of the effect in other species and animal models exist, as described herein, to measure a synergistic effect and the results of such studies can also be used to predict effective dose ratio ranges and the absolute doses and plasma concentrations required in other species by the application of pharmacokinetic / pharmacodynamic methods. Established correlations between tumor models and effects seen in man suggest that synergy in animals may be demonstrated, for example, by xenograft models or in appropriate cell lines.

Problems solved by technology

Palliative treatment of recurrent / metastatic HNSCC remains largely ineffective, and little progress has been made.

Although HNSCC can be considered a chemosensitive disease as shown by high response rates with aggressive induction therapies (e.g., combination of 5-FU, cisplatin and docetaxel, the results are poor at relapse.

Patients usually relapse locally and develop symptoms such as difficulties in swallowing, eating and speaking.

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