US20160082012A1 - Combination of a PI3 Kinase Inhibitor with Pacitaxel for Use in the Treatment or Prevention of a Cancer of the Head and Neck - Google Patents
Combination of a PI3 Kinase Inhibitor with Pacitaxel for Use in the Treatment or Prevention of a Cancer of the Head and Neck Download PDFInfo
- Publication number
- US20160082012A1 US20160082012A1 US14/785,995 US201414785995A US2016082012A1 US 20160082012 A1 US20160082012 A1 US 20160082012A1 US 201414785995 A US201414785995 A US 201414785995A US 2016082012 A1 US2016082012 A1 US 2016082012A1
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- United States
- Prior art keywords
- neck
- treatment
- cancer
- head
- paclitaxel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
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Definitions
- 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.
- PI3K phosphatidylinositol-3-kinase
- HNSCC head and neck squamous cell carcinoma
- Treatment modalities for HNSCC include surgery, radiation and chemotherapy. With advanced HNSCC, only 35% to 55% of patients survive and remain disease-free for three years, despite aggressive therapy. Locoregional recurrence develops in 30% to 40% of patients and distant metastases develop in 12% to 22% ⁇ of patients. Palliative treatment of recurrent/metastatic HNSCC remains largely ineffective, and little progress has been made.
- 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.
- aggressive induction therapies e.g., combination of 5-FU, cisplatin and docetaxel
- the recurrence rate ranges from 35-50%. Patients usually relapse locally and develop symptoms such as difficulties in swallowing, eating and speaking.
- the median survival for patients with recurrent disease is six months and can reach 10 months in patients with good general status. Thus, improving the clinical benefit in patients with head and neck cancer is important to improve the patient's quality of life.
- the combination of the compound of formula (I) and paclitaxel will provide improved and effective treatment as compared to each monotherapy for patients suffering from a cancer of the head and neck, particularly those suffering from a cancer of the head and neck or head and neck squamous cell carcinoma resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention relates to a pharmaceutical combination
- 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 or prevention of a cancer of the head and neck.
- PI3K phosphatidylinositol-3-kinase
- the present invention further pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a cancer of the head and neck.
- the present invention provides a pharmaceutical combination comprising (a) a phosphatidylinositol-3-kinase (PI3K) inhibitor compound of formula (I) and (b) paclitaxel, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer of the head and neck.
- PI3K phosphatidylinositol-3-kinase
- the present invention provides a COMBINATION OF THE INVENTION for use in the treatment or prevention of a cancer of the head and neck.
- the present invention relates to a method of treating or preventing a cancer of the head and neck comprising administering a jointly therapeutically effective amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- the present invention pertains to a pharmaceutical composition
- a pharmaceutical composition comprising a quantity of the COMBINATION OF THE INVENTION, which is jointly therapeutically effective against a cancer of the head and neck.
- the present invention further provides a commercial package comprising as therapeutic agents a COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the treatment or prevention of a cancer of the head and neck.
- FIG. 1 shows the IC50 values for Compound A for several cancer cell lines.
- FIG. 2 shows the results of administration of Compound A in squamous cancer cells.
- the present invention relates to a pharmaceutical combination
- 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 or prevention of a cancer of the head and neck.
- PI3K phosphatidylinositol-3-kinase
- combination or “pharmaceutical combination”, as used herein, defines either a fixed combination in one dosage unit form or a kit of parts for the combined administration where the compound of formula (I), particularly Compound A, and paclitaxel may be administered independently at the same time or separately within time intervals that allow that the therapeutic agents (i.e, the compound of formula (I), particularly Compound A, and paclitaxel and pharmaceutically acceptable salts thereof) show a cooperative, e.g., synergistic, effect.
- the therapeutic agents i.e, the compound of formula (I), particularly Compound A, and paclitaxel and pharmaceutically acceptable salts thereof
- composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the mammal.
- pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
- a combined preparation is defined herein to refer to especially a “kit of parts” in the sense that the therapeutic agents (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the therapeutic agents (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.
- the ratio of the total amounts of the therapeutic agent (a) to the therapeutic agent (b) to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient.
- combined administration is defined to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
- treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a cancer of the head and neck.
- treatment can be the diminishment of one or several symptoms of a cancer of the head and neck or complete eradication of a cancer of the head and neck.
- the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a cancer of the head and neck) and/or reduce the risk of developing or worsening a cancer of the head and neck.
- prevention is used herein to mean prevent, delay or treat, or all, as appropriate, development or continuance or aggravation of a cancer of the head and neck in a subject.
- joint therapeutic effect or “jointly therapeutic effective” means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both or all therapeutic agents are present in the blood of the human to be treated at least during certain time intervals.
- an “effective amount” of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the cancer of the head and neck treated with the combination.
- subject or “patient” as used herein includes animals, which are capable of suffering from or afflicted with a cancer of the head and neck or any disorder involving, directly or indirectly, a cancer of the head and neck.
- subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits rats and transgenic non-human animals.
- the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from cancer of the head and neck.
- the term “about” or “approximately” usually means within 20%, more preferably within 10%, and most preferably still within 5% of a given value or range. Alternatively, especially in biological systems, the term “about” means within about a log (i.e., an order of magnitude) preferably within a factor of two of a given value.
- the present invention relates to a pharmaceutical combination
- 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 or prevention of a cancer of the head and neck.
- PI3K phosphatidylinositol-3-kinase
- WO07/084786 describes specific pyrimidine derivatives which have been found to inhibit the activity of PI3K.
- the compound 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine (hereinafter also referred to as “COMPOUND A”) has the chemical structure of formula (I)
- the phosphatidylinositol 3-kinase inhibitor compound of formula (I) may be present in the pharmaceutical combination in the form of the free base or a pharmaceutically acceptable salt thereof.
- Such salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively.
- Suitable salts of the compound of formula (I) include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi-sulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2 naphth-alenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 phenylproionate, picrate, pivalate
- the basic nitrogen-containing groups can be quaternized with such agents as alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.
- alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
- long chain halides such as decyl, lauryl, myristyl,
- inorganic acids as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid and phosphoric acid
- organic acids as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, methanesulfonic acid, succinic acid, malic acid
- Pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, pyridine, picoline, triethanolamine and the like, and basic amino acids such as arginine, lysine and ornithine.
- the compound of formula (I) is in the form of its hydrochloride salt.
- Paclitaxel (TAXOL®) is a natural product with antitumor activity. Paclitaxel is obtained via a semi-synthetic process from Taxus baccata . The chemical name for paclitaxel is 5 ⁇ , 20-Epoxy1,2a,4,7 ⁇ , 10 ⁇ , 13a-hexahydroxytax-11-en-9-one 4, 10,-diacetate 2-benzoate 13-ester with (2R,3S)—N-benzoyl-3-phenylisoserine. Also included are the generic forms of paclitaxel, as well as various dosage forms of paclitaxel. Various dosage forms of paclitaxel include, but are not limited to, albumin nanoparticle paclitaxel marketed as ABRAXANE® and ONXOL®.
- the present invention particularly pertains to a COMBINATION OF THE INVENTION useful for separate, simultaneous or sequential administration to a subject in need thereof for treating or preventing a cancer of the head and neck.
- the present invention further pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a pharmaceutical composition or medicament for the treatment or prevention of a cancer of the head and neck.
- the present invention relates to a method of treating or preventing a cancer of the head and neck comprising administering a jointly therapeutically effective amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- the present invention further provides a commercial package comprising as therapeutic agents a COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the treatment or prevention of a cancer of the head and neck.
- the present invention particularly pertains to a COMBINATION OF THE INVENTION useful for treating or preventing a cancer of the head and neck in a subject in need thereof.
- the COMBINATION OF THE INVENTION is used for the treatment or prevention of a cancer of the head and neck comprising administering to the subject a combination therapy, comprising an effective amount of the combination of formula (I) or a pharmaceutically acceptable salt thereof and paclitaxel.
- these therapeutic agents are administered at therapeutically effective dosages which, when combined, provide a beneficial effect.
- the administration may be separate, simultaneous or sequential.
- the COMBINATION OF THE INVENTION is useful for the treatment or prevention of a cancer of the head and neck.
- cancer of the head and neck is used herein to mean a broad spectrum of tumors arising from the upper aerodigestive tract. Examples of such tumors include but are not limited to cancer or tumor of the oral cavity, lips, pharynx (including nasopharynx, oropharynx, and hypopharynx), larynx, paranasal sinuses, nasal cavity, throat and salivary glands. Further, depending on the tumor type and particular combination used, a decrease of the tumor volume can be obtained.
- the COMBINATION OF THE INVENTION disclosed herein is also suited to prevent the metastatic spread of tumors and the growth or development of micrometastases.
- the COMBINATION OF THE INVENTION disclosed herein is used for the treatment or prevention of a cancer of the head and neck.
- the cancer of the head and neck is a squamous cell carcinoma.
- Squamous cell carcinoma of the head and neck is used herein to mean a cancer of the head and neck that begins in squamous cells.
- squamous cell carcinoma of the head and neck include but are not limited to squamous cell cancers or tumors of the oral cavity, lips, pharynx (including nasopharynx, oropharynx, and hypopharynx), larynx, paranasal sinuses, nasal cavity, throat and salivary glands.
- the cancer of the head and neck is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), and/or platinum-based therapies.
- resistant to prior treatment with paclitaxel, fluorouracil (5-FU), and/or platinum-based therapies is defined to refer to cancer or tumor progression in a patient suffering from said cancer or tumor while receiving treatment with paclitaxel, fluorouracil (5-FU), or platinum-based therapy.
- prior platinum-based therapies include, but are not limited to, prior treatment with cisplatin, carboplatin, oxaliplatin, or a combination thereof.
- the cancer is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), and/or platinum-based therapies is defined as growth or progression of the cancer while exposed to paclitaxel, fluorouracil (5-FU), and/or platinum-based therapies.
- the cancer of the head and neck is a squamous cell carcinoma of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the COMBINATION OF THE INVENTION disclosed herein is used for the treatment or prevention of a squamous cell carcinoma of the head and neck.
- the COMBINATION OF THE INVENTION disclosed herein is suitable for the treatment or prevention of poor prognosis patients, especially such poor prognosis patients having a cancer of the head and neck.
- the cancer of the head and neck is a squamous cell carcinoma of the head and neck.
- the cancer of the head and neck is a squamous cell carcinoma of the head and neck that is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the COMBINATION OF THE INVENTION is particularly useful for the treatment or prevention of cancers of the head and neck having a genetic alteration of the phosphatidylinositol-3-kinase pathway such as, for example, amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha that serve to up-regulate the p85-p110 complex.
- a genetic alteration of the phosphatidylinositol-3-kinase pathway such as, for example, amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha that serve to up-regulate the p85-p110 complex.
- the cancer of the head and neck is characterized by amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha that serve to up-regulate the p85-p110 complex.
- the cancer of the head and neck is a squamous cell carcinoma of the head and neck that is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof and that is characterized by amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha that serve to up-regulate the p85-p110 complex.
- the present invention relates to a method of treating or preventing a cancer of the head and neck comprising administering a jointly therapeutically effectivel amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- a subject in need of a particular treatment includes subjects suffering from or diagnosed with the identified cancer of the head and neck in such embodiment.
- the present invention relates to a method of treating or preventing a cancer of the head and neck characterized by amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha, comprising administering a jointly therapeutically effectively amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- the present invention relates to a method of treating or preventing a cancer of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof comprising administering a jointly therapeutically effectively amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- a subject in need of a particular treatment includes subjects suffering from or diagnosed with the identified cancer of the head and neck in such embodiment.
- the present invention relates to a method of treating or preventing a squamous cell carcinoma of the head and neck comprising administering a jointly therapeutically effective amount of a combination of: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) paclitaxel, to a subject in need thereof.
- the present invention relates to a method of treating or preventing a squamous cell carcinoma of the head and neck characterized by amplification of PI3K alpha, somatic mutation of PIK3CA, germline mutations or somatic mutations of PTEN, or mutations and translocation of p85-alpha, comprising administering a jointly therapeutically effectively amount of a COMBINATION OF THE INVENTION to a subject in need thereof.
- the present invention relates to a method of treating or preventing a squamous cell carcinoma of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof, comprising administering a jointly therapeutically effective amount of a combination of: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) paclitaxel, to a subject in need thereof.
- 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.
- 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.
- 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).
- a 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).
- synergistic effect 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.
- 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.
- 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.
- 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.
- Suitable clinical studies are, for example, open label non-randomized, dose escalation studies or multi-center, randomized, double-blind, placebo-controlled studies in patients with a cancer of the head and neck. Such studies can prove the additive or synergism of the active ingredients of the COMBINATIONS OF THE INVENTION.
- the beneficial effects on proliferative diseases can be determined directly through the results of these studies or by changes in the study design which are known as such to a person skilled in the art.
- Such studies are, in particular, suitable to compare the effects of a monotherapy using the active ingredients and a COMBINATION OF THE INVENTION.
- the therapeutic agent (a) is administered with a fixed dose and the dose of the therapeutic agent (b) is escalated until the Maximum Tolerated Dosage is reached.
- the compound of formula (I) is preferably administered daily at a dose in the range of from 1.0 to 30 mg/kg body weight.
- the dosage of compound of formula (I) is in the range of about 60 mg/day to about 120 mg/day, especially if the warm-blooded animal is an adult human.
- the dosage of compound of formula (I) is in the range of about 80 mg/day to about 100 mg/day for an adult human.
- the Compound of formula (I) may be administered orally to an adult human once daily continuously (each day) or intermittently (e.g, 5 out of 7 days) in a suitable dosage.
- the dose range in the adult human suitably corresponds to a dose range of about 15 to 200 mg/m 2 , e.g., about 50 to 175 mg/m 2 , about 60 to 100 mg/m 2 , or about 70 to 100 mg/m 2 per week.
- the dose is 80 mg/m 2 per week.
- the present invention pertains to a pharmaceutical composition or combined preparation comprising a jointly therapeutically effective amount of the COMBINATION OF THE INVENTION and optionally at least one pharmaceutically acceptable carrier, for use in the treatment or prevention of a cancer of the head and neck.
- the therapeutic agents of the compound of formula (I), particularly COMPOUND A, or a pharmaceutically acceptable salt thereof and paclitaxel can be administered together in a single formulation or unit dosage form, administered concurrently but separately, or sequentially by any suitable route.
- a therapeutically effective amount of the therapeutic agents of the COMBINATION OF THE INVENTION may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
- the method of treatment or prevention of a cancer of the head and neck according to the invention may comprise (i) administration of the first therapeutic agent in free or pharmaceutically acceptable salt form and (ii) administration of the second therapeutic agent in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts.
- the individual therapeutic agents of the COMBINATION OF THE INVENTION can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The invention is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
- the compound of formula (I) and paclitaxel are administered separately.
- compositions 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 administration to mammals (warm-blooded animals), including man.
- enteral such as oral or rectal
- parenteral administration to mammals (warm-blooded animals), including man.
- the agents when the agents are administered separately, one can be an enteral formulation and the other can be administered parenterally.
- the 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 one of the therapeutic agents 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.
- any of the usual pharmaceutically acceptable carriers may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents; or carriers such as starches, sugars, microcristalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed.
- disintegrants examples include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL from International Specialty Products (Wayne, N.J.); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum.
- the disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1% to about 5% by weight of composition.
- binders examples include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PH from FMC (Philadelphia, Pa.), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCEL from Dow Chemical Corp. (Midland, Mich.); sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
- the binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.
- Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
- the lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1% to about 1.5% by weight of composition.
- the glidant may be present in an amount from about 0.1% to about 10% by weight.
- Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
- the filler and/or diluent e.g., may be present in an amount from about 0% to about 80% by weight of the composition.
- each of the therapeutic agents employed in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
- the dosage regimen of the COMBINATION OF THE INVENTION is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
- a clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single therapeutic agents required to alleviate, counter or arrest the progress of the condition.
- the optimum ratios, individual and combined dosages, and concentrations of the therapeutic agents (a) and (b) and optionally (c) of the COMBINATION OF THE INVENTION that yield efficacy without toxicity are based on the kinetics of the therapeutic agents' availability to target sites, and are determined using methods known to those of skill in the art.
- packaged pharmaceutical products may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the combination of compounds, but not the other compound(s) of the combination.
- the optimal dosage of each therapeutic agents for treatment or prevention of a proliferative disease can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
- each therapeutic agent of the COMBINATION OF THE INVENTION that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
- the unit dosage forms containing the combination of agents as described herein will contain the amounts of each therapeutic agent of the combination that are typically administered when the therapeutic agents are administered alone.
- Frequency of dosage may vary depending on the therapeutic agent used and the particular condition to be treated or prevented. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the treatment or prevention of a cancer of the head and neck.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the treatment or prevention of a cancer of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the treatment or prevention of a squamous cell carcinoma of the head and neck.
- the present invention pertains to the use of the pharmaceutical combination comprising COMPOUND A or a pharmaceutically acceptable salt thereof and paclitaxel or a pharmaceutically acceptable salt thereof for the treatment or prevention of a squamous cell carcinoma of the head and neck.
- the squamous cell carcinoma of the head and neck is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment or prevention of a cancer of the head and neck.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment or prevention of a cancer of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment or prevention of a squamous cell carcinoma of the head and neck.
- the present invention pertains to the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment or prevention of a squamous cell carcinoma of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention pertains to the use of the pharmaceutical combination comprising COMPOUND A or a pharmaceutically acceptable salt thereof and paclitaxel or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a squamous cell carcinoma of the head and neck.
- the squamous cell carcinoma of the head and neck is resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- the present invention provides a commercial package comprising as active ingredients of COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the treatment or prevention of a cancer of the head and neck.
- the present invention provides a commercial package comprising as active ingredients of COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential administration thereof for use in the treatment or prevention of a cancer of the head and neck resistant to prior treatment with paclitaxel, fluorouracil (5-FU), platinum-based therapies, or a combination thereof.
- FaDu xenograft Hypopharynx squamous cell carcinoma
- Compound A at 30 mg daily (equivalent to 100 mg daily in patients) shows inhibition of pAKT in tumor tissue confirming down-regulation of the PI3K pathway upon treatment.
- Treatment with Paclitaxel and Compound A in head and neck cancer cell lines displays combination effect with potential for synergy in some cases.
- Cells were plated in 24-well plates at a density of 5 ⁇ 104 to 1 ⁇ 105 cells per well and grown in DMEM with 10% FBS and 1% PSF. The day after plating (day 1), Compound A—1 pmol/L was serially diluted 10-fold over 6 concentrations, and drug was added alone or in combination with a single concentration of paclitaxel 1 ng/mL. Data was compared with untreated controls. Cells were counted on the day drug was added and 5 days later and these 2 counts were compared. Cells were harvested by trypsinization and counted immediately using a Coulter Z2 particle counter (Beckman Coulter Inc., Fullerton, Calif., USA).
- Percentage of growth inhibition defined as 100 ⁇ [1 ⁇ (generations in treated wells/generations in untreated controls)] was determined, as previously published (Finn, et al, 2009). Experiments were carried out in duplicate. The table below details the results.
- a multi-center, randomized, double-blind, placebo-controlled phase II trial of the combination comprising (a) COMPOUND A or its hydrochloride salt and (b) paclitaxel is conducted in patients with recurrent or metastatic HNSCC cancer that has progressed after prior platinum based treatment regimen.
- Patients with histologically/cytologically-confirmed HNSCC, recurrent or metastatic disease progressing after prior platinum-based first-line treatment will be randomized in a 1:1 ratio to 2 different clinical group arms to receive in a blinded manner one of two treatments: (a) COMPOUND A or its hydrochloride salt in combination with paclitaxel, or (b) placebo in combination with paclitaxel.
- Approximately 150 will be enrolled in the study, but the effectiveness of the combination treatment may be assessed with results from fewer total patients. Patients may be stratified according to the number of prior lines of treatment (1 vs. 2) and the region of the investigator's site. Patients are continuing to receive study treatment according to randomization until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new neoplastic therapy or at the discretion of the investigator). Efficacy and safety monitoring will continue as per visit schedule. Tumor assessments will be performed 4 weeks after study treatment start and afterwards every 6 weeks until radiological progression.
- Screening is conducted within 1 to 35 days prior to treatment start (except for radiological tumor assessments which are done within 1 to 28 days prior to treatment start). Rescreening is permitted only once per patient if the patient was not registered as entering treatment phase. Repeat laboratory evaluations within the screening window is permitted for screening results out of the defined range.
- the primary objective is to estimate treatment effect of the combination of once-daily Compound A or its hydrochloride salt and paclitaxel on progression-free survival (PFS) (based on local radiological assessment) in these above-identified patients.
- PFS progression-free survival
- a primary efficacy variable is progression free survival as assessed by local radiological reviewed as per RECIST v 1.1.
- PFS is defined as the time from the randomization date until objective tumor progression or death from any cause. The date of progression is the earlier time when any RECIST progression event (i.e, radiological progression or death) is observed with no more than one prior missing assessment.
- Tumor evaluations are made based on RECIST criteria.
- measurability is defined as the presence of at least one measurable nodal or non-nodal lesion and, if restricted to a solitary lesion, its neoplastic nature sure be confirmed by cytology/histology.
- Secondary objectives include assessment of overall survival (time from randomization to date of death due to any cause), overall response rate (the ortion of patients with a best overall response of complete response (CR) or partial response (PR) based on investigator assessment); disease control rate (the proportion of patients with a best overall response of CR, PR or stable disease (SD), based on investigator assessment, and duration of response (defined only for the responder subset, i.e., patients with confirmed CR or PR based on investigator assessment. This is the elapsed time between the date of first documented response and the following date of event defined as the first documented progression or death due to underlying cancer).
- COMPOUND A or its hydrochloride salt is administered orally once daily on a continuous dosing schedule starting on day 1 in combination with once weekly paclitaxel at a dose of 80 mg/m 2 (days 1, 8, 15, and 22) on a 28-day cycle.
- COMPOUND A or its hydrochloride salt is administered at a dose of 100 mg Compound A free-base.
- Paclitaxel is administered by intravenous infusion. Paclitaxel is supplied as multi-dose vials for injection. Paclitaxel is diluted using 0.9% sodium chloride injection, USP; 5% dextrose injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP, or 5% dextrone in Ringer's injection to a final concentration of 0.3 to 1.2 mg/mL. Paclitaxel is administered every week as 1-hour ( ⁇ 15 minutes) IV infusion after standard premedication on Day 1 of every cycle. Prior to administration of paclitaxel, patients are pre-medicated according to the standard institutional practice or the product label to prevent severe hypersensitivity reactions. Anti-hypersensitivity therapy may be administered prior to the ECG of each cycle.
- Options include: Dexamethasone: 20 mg orally administered 12 and 6 hours prior to start of paclitaxel administration, or diphenhydramine (or equivalent): 50 mg IV administered by IV approximately 30-60 minutes prior to start of paclitaxel administration, or ranitidine: 50 mg IV administered approximately 30-60 minutes prior to the start of paclitaxel administration, or cimetidine: 300 mg IV administered approximately 30-60 minutes prior to start of paclitaxel administration.
- Cimetidine should be administered as a single dose and only if no alternative can be found. If hypersensitivity occurs during the administration of paclitaxel, the following treatment guidelines may be followed:
- COMPOUND A-matching placebo will be administered orally once daily on a continuous dosing schedule starting on day 1.
- a complete treatment cycle is defined as 28 calendar days during which COMPOUND A or its hydrochloride salt or its placebo is given once daily and paclitaxel is given once weekly. The last day of complete treatment cycle is day 29. Day 1 of the next cycle starts on day 29. Efficacy and safety monitoring are conducted regularly. Tumor assessments are performed 4 weeks after study treatment start and afterwards every 6 weeks until radiological progression.
- Efficacy and tumor response is determined according to specific guidelines on the Response Evaluation Criteria in Solid Tumors (RECIST), based on RECIST version 1.1.
- Safety is monitored by physical examination, vital signs, weight, performance status evaluation, ECG, cardiac imaging, laboratory evaluations including glucose monitoring and assessments of patient rated mood scales as well as adverse events (serious and non-serious).
- Thrombocytopenia Grade 1 (PLT ⁇ LLN ⁇ 75 ⁇ 10 9 /L) Maintain dose level Grade 2 (PLT ⁇ 75 ⁇ 50 ⁇ 10 9 /L) Grade 3 (PLT ⁇ 50 ⁇ 25 ⁇ 10 9 /L) Omit dose until resolved to ⁇ Grade 1, then: If resolved in ⁇ 7 days, then maintain dose level If resolved in >7 days, then ⁇ 1 dose level Grade 4 (PLT ⁇ 25 ⁇ 10 9 /L) Omit dose until resolved to ⁇ Grade 1, then ⁇ 1 dose level RENAL Serum creatinine Grade 1 ( ⁇ 2 ⁇ ULN) Maintain dose level Grade 2 (2 ⁇ 3 ⁇ ULN) Omit dose until resolved to ⁇ grade 1, then: If resolved in ⁇ 7 days, then maintain dose level If resolved in >7 days, then ⁇ 1 dose level Grade 3 (>3.0 ⁇ 6.0 ⁇ ULN) Permanently discontinue patient from COMPOUND A
- ENDOCRINE/METABOLIC Fasting Plasma Glucose (FPG) Grade 1 (>ULN ⁇ 160 mg/dL) Maintain dose level, check FPG every week [>ULN ⁇ 8.9 mmol/L] initiate or intensify medication with appropriate anti- diabetic treatment as per investigator's discretion instruct patient to follow dietary guidelines according to local and/or institutional standards for management of diabetes mellitus (such as those provided by the American Diabetes Association) during the study consider use of oral anti-hyperglycemic therapy such as metformin (or intensify existing medications) check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks Grade 2 (>160 ⁇ 250 mg/dL) If asymptomatic, maintain dose and re-check FPG [>8.9 ⁇ 13.9 mmol/L] within 24 hours.
- FPG remains at Grade 2: maintain dose level and monitor FPG at least weekly until FPG resolves to ⁇ Grade 1 initiate or intensify medication with appropriate anti-diabetic treatment such as metformin; consider adding a second oral agent if no improvement after several days instruct patient to follow dietary guidelines according to local and/or institutional standards for management of diabetes mellitus (such as those provided by the American Diabetes Association) during the study If FPG does not resolve to ⁇ Grade 1 within 14 days after institution of appropriate anti-diabetic treatment reduce COMPOUND A/placebo by 1 dose level Continue with anti-diabetic treatment and check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks Grade 3 (>250 ⁇ 500 mg/dL) Omit COMPOUND A/placebo, initiate or intensify [>13.9 ⁇ 27.8 mmol/L] medication with appropriate anti-diabetic treatment, re-check FPG within 24 hours.
- appropriate anti-diabetic treatment such as metformin
- FPG is at Grade 3: administer intravenous hydration and intervention for electrolyte/ketoacidosis/hyperosmolar disturbances as clinically appropriate continue to omit COMPOUND A/placebo monitor FPG at least twice weekly until FPG resolves to ⁇ Grade 1 If FPG resolves to ⁇ Grade 1 in 7 days or less, then re-start COMPOUND A/placebo and ⁇ 1 dose level If FPG remains greater than Grade 1 severity for more than 7 days, then discontinue patient from COMPOUND A/placebo initiate or continue anti-diabetic treatment as appropriate instruct patient to follow dietary guidelines according to local and/or institutional standards for management of diabetes mellitus (such as those provided by the American Diabetes Association) during the study consider use of oral anti-hyperglycemic therapy such as metformin check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks For non-fasting plasma glucose >250-500 mg/dL (>13.9
- FPG fasting plasma glucose
- Grade 4 administer intravenous hydration and intervention for electrolyte/ketoacidosis/hyperosmolar disturbances as clinically appropriate discontinue patient from Comopund A/placebo instruct patient to follow dietary guidelines according to local and/or institutional standards for management of diabetes mellitus (such as those provided by the American Diabetes Association) during the study consider use of oral anti-hyperglycemic therapy such as metformin check FPG at least weekly for 8 weeks, then continue checking at least every 2 weeks if clinically indicated For non-fasting plasma glucose >500 mg/dL (>27.8 mmol/L) accompanied by signs/symptoms of hyperglycemia (for example, mental status changes, excessive thirst, polyuria), or presence of blood or urine ketones, discontinue Compound A and following guidance for management of Grade 4 fasting plasma glucose (FPG).
- non-fasting plasma glucose >500 mg/dL (>27.8 mmol/L) accompanied by signs/symptoms of hyperglycemia
- Concomitant medication usage must be reviewed. Perform a repeat ECG within one hour of the first QTcF of >500 ms or >60 ms from baseline If QTcF remains >500 ms or >60 ms from baseline, repeat ECG as clinically indicated, but at least once a day until the QTcF returns to ⁇ 480 ms. Seek cardiologist input.
- COMPOUND A/placebo may be restarted at a one lower dose level Second Occurrence: Permanently discontinue patient from COMPOUND A/placebo Other Cardiac Events Grade 1 or 2 Maintain dose level Grade 3 Omit dose until resolved to ⁇ Grade 1, then ⁇ 1 dose level Grade 4 Permanently discontinue patient from COMPOUND A/placebo OTHER Mood alteration *Note: For all grades, if question 9 on the PHQ-9 has a positive response (as indicated by selecting “1”, “2”, or “3”), omit study drug and refer patient for psychiatric consult regardless of the total questionnaire score or CTCAE grading to confirm if study drug should be interrupted or permanently discontinued.
- Grade 1* Maintain dose level Consider psychiatric consultation at the investigator's discretion and introduce optimal management Grade 2* Omit dose until resolved to ⁇ Grade 1, or baseline status
- First event if the condition resolved to Grade ⁇ 1 or to baseline status, continue to co-medicate and then maintain dose level Second and further events: if the condition resolved to Grade ⁇ 1 or to baseline status, continue to co-medicate and then ⁇ 1 dose level Grade 3* Omit dose until resolved to ⁇ Grade 1, or baseline status Psychiatric consultation is required and introduce optimal management If the condition resolved to Grade ⁇ 1 or to baseline status, continue to co-medicate and then then ⁇ 1 dose level Grade 4* Permanently discontinue patient from COMPOUND A/placebo Psychiatric consultation is required and introduce optimal management Rash Grade 1 Maintain dose level.
- Second Occurrence permanently discontinue patient from COMPOUND A/placebo
- a paired skin biopsy could be obtained (from both an affected and an unaffected skin area for local histopathology assessment) if clinical appropriate.
- Grade 4 Permanently discontinue patient from COMPOUND A/placebo According to the investigators discretion, a paired skin biopsy could be obtained (from both an affected and an unaffected skin area for local histopathology assessment) if clinical appropriate.
- Grade 2 Reduce COMPOUND A/placebo by 1 dose level until recovery to ⁇ Grade 1.
- Study treatment may be interrupted. Patients will discontinue if they fail to recover to ⁇ Grade 1 within 3 weeks.
- Grade 3 Hold treatment with COMPOUND A/placebo until recovery to ⁇ Grade 1. May restart study treatment within 3 weeks at a reduced dose level (by one level) if evidence of clinical benefit.
- Grade 4 Discontinue treatment with COMPOUND A/ placebo. Stomatitis/Oral mucositis Grade 1/Tolerable Grade 2 Maintain dose level.
- Non alcoholic or salt water mouth wash First occurrence: hold until ⁇ G1 and ⁇ 1 dose level (if stomatitis is Intolerable Grade 2 or Grade 3 readily manageable with optimal management, re- introduction at the same level might be considered at the discretion of the investigator). Second occurrence: hold until ⁇ G1 and ⁇ 1 dose level.
- Grade 4 Permanently discontinue patient from COMPOUND A/placebo. Other non- hematological adverse events Grade 1 or 2 Maintain dose level Grade 3 Omit dose until resolved to ⁇ Grade 1, then ⁇ 1 dose level Grade 4 Permanently discontinue patient from COMPOUND A/placebo Note: Omit dose for ⁇ Grade 3 vomiting or Grade 3 nausea only if the vomiting or nausea cannot be controlled with optimal antiemetic
- Patients may be withdrawn from the study if any of the following occur: adverse event, lost to follow-up, non-compliance with study treatment, physician decision, pregnancy, progressive disease, protocol deviation, study terminated by sponsor, technical problems, subject/guardian decision, death. Patients must be discontinued if any of the following occur: adjustment to study treatment that results in discontinuation, use of prohibited medication, interruption of study treatment for >28 days from intended day of next scheduled dose.
- tumor assessments are performed every 6 weeks until the start of new anti-cancer therapy, disease progression, death, lost to follow-up or withdrawn consent to efficacy follow-up.
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US9913846B2 (en) | 2018-03-13 |
EP2994126B1 (en) | 2018-06-20 |
MX2015015475A (es) | 2016-03-21 |
ES2688464T3 (es) | 2018-11-02 |
KR102356393B1 (ko) | 2022-01-26 |
CN105228611A (zh) | 2016-01-06 |
KR20160005702A (ko) | 2016-01-15 |
CY1120693T1 (el) | 2019-12-11 |
DK2994126T3 (en) | 2018-09-24 |
LT2994126T (lt) | 2018-09-25 |
CN105228611B (zh) | 2018-01-26 |
CA2909448C (en) | 2021-10-26 |
WO2014181252A1 (en) | 2014-11-13 |
AU2014264318B2 (en) | 2017-03-16 |
JP2019131559A (ja) | 2019-08-08 |
CA2909448A1 (en) | 2014-11-13 |
US20170173032A1 (en) | 2017-06-22 |
HRP20181489T1 (hr) | 2018-11-16 |
PL2994126T3 (pl) | 2018-11-30 |
JP6643978B2 (ja) | 2020-02-12 |
RU2672555C2 (ru) | 2018-11-16 |
EP2994126A1 (en) | 2016-03-16 |
BR112015027047A2 (pt) | 2017-07-25 |
RU2015152032A (ru) | 2017-06-13 |
SI2994126T1 (sl) | 2018-10-30 |
AU2014264318A1 (en) | 2015-10-22 |
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