WO2021259472A1

WO2021259472A1 - Micellar docetaxel for use in the treatment of cancer

Info

Publication number: WO2021259472A1
Application number: PCT/EP2020/067738
Authority: WO
Inventors: Dzianis BABROU
Original assignee: Oasmia Pharmaceutical Ab
Priority date: 2020-06-24
Filing date: 2020-06-24
Publication date: 2021-12-30

Abstract

A composition comprising docetaxel and monovalent cation salt(s) of methyl ester of N-all- trans-retinoyl cysteic acid, wherein the molar ratio of the docetaxel to the monovalent cation salt(s) of methyl ester of N-all-trans-retinoyl cysteic acid is in the range of 1:3.4 to 1:4.1. Uses in the treatment of a solid tumor disease and processes of manufacture thereof.

Description

MICELLAR DOCETAXEL FOR USE IN THE TREATMENT OF CANCER

TECHNICAL FIELD

The present invention relates to docetaxel formulations and their uses in the treatment of cancer.

BACKGROUND TO THE INVENTION

Docetaxel, a semisynthetic compound of the taxane group, has been widely used in the treatment of cancer for several decades. A fundamental issue with docetaxel is that the compound has extremely poor solubility in water yet needs to be administered via intravenous infusion.

The reference docetaxel formulation Taxotere^® utilizes a non-ionic detergent (polysorbate 80) and ethanol to render the docetaxel soluble. Both these excipients have undesirable properties. Administration of Taxotere™ mandates a premedication with dexamethasone (a corticosteroid) starting 1 day prior to infusion for a total of 3 days. Additional routine premedications include antihistamines and antiemetics.

W02004/009538 discloses retinol derivatives that may be used to manufacture formulations of poorly soluble pharmaceutical compounds, such as docetaxel, paclitaxel, as well as of water soluble doxorubicin and mitoxantrone. W02009/078802 discloses drug delivery systems for water insoluble compounds using sodium salt of N-(all-trans-retinoyl)-L- cysteic acid methyl ester and/or the sodium salt of N-(13-cis-retinoyl)-L-cysteic acid methyl ester to solubilize the compounds.

The above-cited prior art fails to disclose a docetaxel formulation that may be administered via intravenous infusion without the need of premedication.

An object of the present invention is the provision of an improved or alternative docetaxel formulation for use in the treatment of cancer via intravenous infusion, wherein the treatment does not comprise premedication with one or more of corticosteroids, antiemetics or antihistamines.

DEFINITIONS

The term premedication refers to a first medication administered prior to administering second medication for the purpose of preventing or alleviating adverse effects from the administration of the second medication. In the present context, the premedication preferably refers to corticosteroid medication given prior to docetaxel infusion for the purpose of preventing or alleviating hypersensitivity reactions from the docetaxel infusion.

Pharmacokinetic parameters used:

• Cm_ax - maximum plasma concentration observed after a single dose

• AUCo-_t - area under the plasma concentration curve from administration (0) to the last measurable concentration

• AUCo- - area under the plasma concentration curve from administration (0) to infinity

• K_ei - terminal elimination rate constant

• T 1/2 - terminal elimination half-life

• CL - total body clearance

• CLBSA - total body clearance adjusted to body surface area

• V_ss - volume of distribution at steady-state

• VSSBSA - volume of distribution at steady-state adjusted to body surface area

• MRT- mean residence time

BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Pharmacokinetics of Docetaxel micellar. Mean (± sd) plasma concentration-time curves for total docetaxel in the PK analysis set (N=28 each treatment) after 100 mg/m² intravenous infusion (duration 60 minutes) of Docetaxel micellar (solid lines, solid circles) and Taxotere^® (dashed lines, open squares) A) linear-linear scales, B) log-linear scales. LLOQ: 1.00 ng/mL.

Figure 2. Clinical study outline for comparison of Docetaxel micellar with Taxotere^®. Study population: locally advanced or metastatic breast cancer after failure with previous anthracycline-containing chemotherapy.

Figure 3. Progression free survival in Intention-to-treat population. Comparison of Docetaxel micellar (solid line) with Taxotere^® (dashed line) in locally advanced or metastatic breast cancer after failure with previous anthracycline-containing chemotherapy. Product- limit survival estimates with number of subjects at risk. Event: documented progression, study termination due to clinical progression or death from any cause.

The number of patients remaining at given time points are summarized as follows:

SUMMARY OF THE INVENTION

The present invention relates to the following items. The subject matter disclosed in the items below should be regarded disclosed in the same manner as if the subject matter were disclosed in patent claims.

1. A composition comprising docetaxel and monovalent cation salt(s) of methyl ester of N-all-trans-retinoyl cysteic acid, wherein the molar ratio of the docetaxel to the monovalent cation salt(s) of methyl ester of N-all-trans-retinoyl cysteic acid is in the range of 1:3.4 to 1:4.1.

2. The composition according to any of the preceding items, wherein the molar ratio is about 1:3.6 to 1:3.8.

3. The composition according to any of the preceding items, wherein the molar ratio is about 1:3.7.

4. The composition according to any of the preceding items, wherein the molar ratio is 1:3.73.

5. The composition according to any of the preceding items, wherein the composition comprises docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid at the indicated ratios.

6. The composition according to item 5, wherein the composition comprises no additional salts of methyl ester of N-all-trans-retinoyl cysteic acid.

7. The composition according to any of the preceding items, wherein the composition does not contain any sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid. 8. The composition according to any of the preceding items, wherein the composition does not contain any derivatives of retinoyl cysteic acids other than the methyl ester of N-all-trans-retinoyl cysteic acid.

9. The composition according to any of the preceding items, wherein the composition is a micellar formulation in a solvent suitable for infusion.

10. The composition according to item 9, wherein the solvent suitable for infusion is 9 mg/ml NaCI in water, Ringer lactate or Ringer acetate, preferably 9 mg/ml NaCI in water.

11. The composition according to any of items 9-10, wherein the micellar formulation contains docetaxel at a concentration in the range of 0.2-5 mg/ml, more preferably 0.4-2 mg/ml, even more preferably 0.4-1.1 mg/ml and most preferably about 0.5 mg/ml or about 1.0 mg/ml.

12. The composition according to any of items 9-11, wherein at least 90% of the micelles in the micellar formulation are in the size range of 13-17 nm (Z-average) when determined using dynamic light scattering.

13. The composition according to any of items 9-12, wherein at least 90% of the micelles in the micellar formulation are in the size range 13-17 nm (Z-average) when determined using dynamic light scattering, in 9 mg/ml NaCI water solution at 0.5 mg/ml docetaxel concentration.

14. The composition according to any of items 9-13, wherein the composition consists of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid in a solvent suitable for infusion.

15. The composition according to any of items 1-8, wherein the composition is a dried lyophilized composition.

16. The composition according to any of items 1-8, wherein the composition is a dried lyophilized composition essentially consisting of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid.

17. The composition according to any of items 1-16, for use in the treatment of a solid tumor disease by administration via intravenous infusion to a patient in need thereof.

18. The composition for use according to item 17, wherein the treatment does not comprise premedication with a corticosteroid prior to the infusion. 19. The composition for use according to any of items 17-18, wherein the treatment does not comprise administering a corticosteroid to the patient within the 48h preceding the infusion, preferably within 24h preceding the infusion.

20. The composition for use according to any of items item 17-19, wherein the treatment does not comprise administration of dexamethasone to the patient.

21. A process for manufacturing a composition according to any of items 1-8 or 15-16, comprising the steps of: a. Dissolving docetaxel and a monovalent cation salt of methyl ester of N-all- trans-retinoyl cysteic acid in a first solvent at the appropriate molar ratio of the docetaxel to the monovalent cation salt of methyl ester of N-all-trans- retinoyl cysteic acid, said ratio being in the range of 1:3.4 to 1:4.1; b. Evaporating said solvent leaving an amorphous residue of the docetaxel and the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid; c. dissolving the amorphous residue in an aqueous solvent to form a micellar solution; d. sterilizing the micellar solution, preferably by sterile filtration; e. lyophilizing the filtered micellar solution to form a lyophilized composition according to any of items 1-8 or 15-16.

22. The process according to item 21, wherein the first solvent is an organic solvent.

23. The process according to item 22, wherein the first solvent is methanol.

24. The process according to any of items 21-23, wherein the aqueous solvent is water suitable for injection.

25. The process according to any of items 21-24, wherein the sterilized solution is distributed into vials prior to lyophilization.

26. The process according to any of items 21-25, wherein the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid is sodium salt of methyl ester of N- all-trans-retinoyl cysteic acid.

27. A method of treatment for a solid tumor disease comprising administering a composition according to any of items 1-16 via intravenous infusion to a patient in need thereof.

28. The method according to item 27, wherein the treatment does not comprise premedication with a corticosteroid prior to the infusion. 29. The method according to any of items 27-28, wherein the treatment does not comprise administering a corticosteroid to the patient within the 48h preceding the infusion, preferably the within 24h preceding the infusion.

30. The method according to any of items 27-29, wherein the treatment does not comprise administration of dexamethasone to the patient.

DETAILED DESCRIPTION

The present disclosure describes the development of a micellar formulation with improved stability utilizing a salt of the methyl ester of N-all-trans-retinoyl cysteic acid to solubilize the otherwise water insoluble docetaxel (Example 1). The micellar formulation does not suffer from occasional precipitation as the earlier versions of the formulation. The micellar docetaxel formulations were shown to be bioequivalent to the reference docetaxel formulation Taxotere^® (Examples 2-3).

Docetaxel is one of the most established cytostatic drugs, so the efficacy of the new formulation was tested with Taxotere^® as the comparator.

Importantly and unpredictably, it was shown that the micellar docetaxel formulation can be administered without the steroid premedication required by Taxotere^® (Example 4). This is a significant benefit, since corticosteroids have numerous well-known side-effects that are especially deleterious for cancer patients that often are already frail from the disease and the associated treatments. Unwanted effects of corticosteroids include neuropsychiatric (steroid psychosis, anxiety, depression), cardiovascular (fluid retention, hypertension), metabolic (lipodystrophy, muscle wasting), endocrine (hyperglycemia, insulin resistance, diabetes mellitus), skeletal (osteoporosis) and gastrointestinal (fulminant amebic colitis) side effects as well as increased vulnerability to infection. Avoiding the need of premedication also provides a convenience benefit by simplifying the treatment procedure.

Docetaxel formulations

In a first aspect, the present invention provides a composition comprising docetaxel and monovalent cation salt(s) of methyl ester of N-all-trans-retinoyl cysteic acid, wherein the molar ratio of the docetaxel to the monovalent cation salt(s) of methyl ester of N-all-trans- retinoyl cysteic acid is in the range of 1:3.4 to 1:4.1. The molar ratio is preferably about 1:3.5 to 1:4.0, more preferably 1:3.6 to 1:3.9, even more preferably 1:3.6 to 1:3.8, yet more preferably about 1:3.7, most preferably 1:3.73. Any range formed by the endpoints of the aforementioned ranges is also contemplated.

The composition preferably comprises docetaxel and sodium salt of methyl ester of N-all- trans-retinoyl cysteic acid at the indicated ratios, and most preferably comprises essentially no additional salts of methyl ester of N-all-trans-retinoyl cysteic acid in addition to the sodium salt. In this context, the word "essentially" means that other salts are present in trace amounts at most.

Preferably, the composition essentially does not contain any sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid. More preferably, the composition essentially does not contain any derivatives of retinoyl cysteic acids other than the methyl ester of N-all-trans-retinoyl cysteic acid.

The composition may be a micellar formulation in a solvent suitable for infusion. Many solutions suitable for infusion are known in the art. The solvent suitable for infusion may be 9 mg/ml NaCI in water, Ringer lactate or Ringer acetate, preferably 9 mg/ml NaCI in water.

The micellar formulation preferably contains docetaxel at a concentration in the range of about 0.2-5 mg/ml, more preferably about 0.4-2 mg/ml, even more preferably about 0.4-1.1 mg/ml and most preferably about 0.5 mg/ml or about 1.0 mg/ml.

Preferably at least 90% of the micelles in the micellar formulation in solution are in the size range of 13-17 nm (Z-average) when determined using dynamic light scattering (DLS). More preferably, at least 90% of the micelles in the micellar formulation are in the size range 13- 17 nm (Z-average) when determined using DLS, in 9 mg/ml NaCI water solution at 0.5 mg/ml concentration.

The composition may be a solution and consist essentially of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid in a solvent suitable for infusion, such as 9 mg/ml NaCI in water, Ringer lactate or Ringer acetate, preferably 9 mg/ml NaCI in water.

The composition may also be a dried lyophilized composition. Preferably, such dried lyophilized composition essentially consists of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid. In the context of a lyophilized composition the word "essentially" means that the composition may contain unavoidable trace amounts of water and other solvents and impurities.

Therapeutic uses

According to the second aspect of the present invention the composition of the first aspect is for use in the treatment of a solid tumor disease by administration via intravenous infusion to a patient in need thereof.

The second aspect also encompasses a method of treatment for a solid tumor disease comprising administering a composition according to the first aspect via intravenous infusion to a patient in need thereof.

Preferably and advantageously, the treatment does not comprise premedication with a corticosteroid prior to the infusion. Such corticosteroid premedication is standard for docetaxel but is clearly disadvantageous as it may result in detrimental side-effects.

More preferably, the treatment does not comprise administering a corticosteroid to the patient within the 48h preceding the infusion, preferably within 24h preceding the infusion. Most preferably the treatment does not comprise administration of dexamethasone to the patient.

Processes for manufacture

In a third aspect, the present invention provides a process for manufacturing a composition according to the first aspect, comprising the steps of: a. Dissolving docetaxel and a monovalent cation salt of methyl ester of N-all-trans- retinoyl cysteic acid in a first solvent at the appropriate molar ratio of the docetaxel to the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid, said ratio being in the range of 1:3.4 to 1:4.1; b. Evaporating said solvent leaving an amorphous residue of the docetaxel and the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid; c. dissolving the amorphous residue in an aqueous solvent to form a micellar solution; d. sterilizing the micellar solution, preferably by sterile filtration; e. lyophilizing the filtered micellar solution to form a lyophilized composition according to the first aspect.

The first solvent is preferably an organic solvent e.g. an aliphatic alcohol, most preferably methanol.

The docetaxel may be anhydrous or a hydrate, such as docetaxel trihydrate. Preferably, the docetaxel is anhydrous.

The aqueous solvent is preferably water suitable for injection. Advantageously, the sterilized solution is distributed into vials prior to lyophilization. The monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid is preferably the sodium salt of methyl ester of N-all- trans-retinoyl cysteic acid.

The process may further comprise reconstituting the lyophilized composition in a solvent suitable for infusion, such as such as 9 mg/ml NaCI in water, Ringer lactate or Ringer acetate, preferably 9 mg/ml NaCI in water. The volume for reconstitution is preferably selected such that the reconstituted formulation contains docetaxel at a concentration in the range of about 0.2-5 mg/ml, more preferably about 0.4-2 mg/ml, even more preferably about 0.4-1.1 mg/ml and most preferably about 0.5 mg/ml or about 1.0 mg/ml.

General aspects relating to the present disclosure

The term "comprising" is to be interpreted as including, but not being limited to. All references are hereby incorporated by reference. The arrangement of the present disclosure into sections with headings and subheadings is merely to improve legibility and is not to be interpreted limiting in any way, in particular, the division does not in any way preclude or limit combining features under different headings and subheadings with each other.

EXAMPLES

The following examples are not to be regarded as limiting the scope of the invention. Example 1: Manufacture of docetaxel micellar formulations Material

Table 1. Material.

Method

The micellar size and polydispersity index was determined using Dynamic Light Scattering (DLS) technique. The mean size determined, the z-average size, is an intensity mean value. In this technique, the brownian motion of the particles is determined by illuminating the sample with laser light and measuring the intensity fluctuations of the backscattered light. Assuming a spherical shape, the Stoke Einstein equation relates this motion to the size of the particles in the solution.

The Stoke Einstein equation:

where D is the diffusion constant, ke is the Boltzmann constant, Tis the temperature, h is the viscosity and R the radius of the sphere.

The following instrumental settings were used:

Number of replicate measurements: S

Material: Rl 1.590 Material absorption: 0.01

Temperature: 25 °C Sample Viscosity: 0.8872 cP Dispersant Rl: 1.330 Analysis model: Normal Resolution Cell: Disposable sizing cuvette

Docetaxel (anhydrous) was dissolved in methanol. Sodium salt of N-(all-trans-retinoyl)-L- cysteic acid methyl ester was separately dissolved in methanol.

The above solutions were combined at a ratio corresponding to 1.5:1 weight ratio (2.49:1 molar ratio) of the sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl esterdocetaxel.

The resulting methanol bulk solution was evaporated leaving an amorphous film. The film was dissolved in water for injection, sterile filtered, distributed into vials and lyophilised to form a powder.

It was subsequently discovered that the formulation with the 1.5:1 ratio was not satisfactory in terms of stability (precipitation/crystallization was occasionally observed after reconstitution).

In a further development program, it was discovered that increasing the relative amount of the sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester overcame the stability issues.

Based on the results from the further development, subsequent batches were made at 2.25:1 weight ratio (3.73:1 molar ratio) of the sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl esterdocetaxel using the same procedure described above.

Lyophilized batches made using the 2.25:1 weight ratio demonstrated stability for at least 24h after reconstitution in phosphate buffered saline. No visible precipitation or crystallization occurred and the micellar size as measured by DLS was stable over time. A monomodal particle size distribution pattern was observed for Docetaxel micellar samples reconstituted in 9 mg/ml NaCI solution at 0.5 mg/ml. Table 2. Particle size measurements or reconstituted solutions of Docetaxel micellar at 0.5 mg/ml concentration, reconstitution media 9 mg/ml NaCI water solution.

Example 2: Bioequivalent pharmacokinetics of docetaxel micellar formulation compared to reference formulation

Pharmacokinetics of total and unbound docetaxel after administration of docetaxel micellar formulation or Taxotere™ were compared in an open, randomized, cross-over study in patients with metastatic breast cancer.

Primary objective:

• To compare the plasma concentration curves of total and unbound docetaxel after single dose of docetaxel micellar or Taxotere.

Secondary objectives:

• To assess the safety of docetaxel micellar.

• To characterize the pharmacokinetic (PK) profile of docetaxel micellar after a single intravenous dose.

• To assess infusion site reactions during treatment.

Methodology:

This was a two-cycle, cross-over study with patients randomized to either the administration sequence Docetaxel micellar followed by Taxotere^® or Taxotere^® followed by Docetaxel micellar. Blood samples for PK were assessed at 0 min (pre-infusion), after 15 min (during infusion), 30 min (during infusion), 55 min (5 min before end of infusion) and at 2 h, 4 h, 7, h, 12 h and 24 h post end of infusion.

All patients in this study received dexamethasone as premedication as routinely prescribed for Taxotere. Number of patients (planned and analysed):

The planned and analysed number of patients in the pharmacokinetic analysis set was 28 patients. 30 patients were included in the safety analysis set.

Diagnosis and main criteria for inclusion:

Inclusion criteria:

1. Signed informed consent form prior to start of any study related procedures.

2. Female patients with histologically or cytological confirmed metastatic breast cancer, who have previously failed treatment with anthracyclines or for whom anthracycline treatment is contraindicated.

3. Life expectancy of at least four months.

4. Age > 18 years.

5. Body mass index >18 and <34 kg/m²

6. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.

Exclusion criteria:

1. Impaired liver, renal, and bone marrow functions including the following: a. Bilirubin > 1.5 times upper limit of normal (ULN), b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times ULN, c. Alkaline phosphatase > 2.5 ULN, d. Serum creatinine >1.5 times ULN, e. Absolute neutrophil count (ANC) < 1.5 x 10⁹/l (or <1500 cells/mm). f. Platelet count <100 x 10⁹/l (or < 100000 cells/mm3).

2. Any uncontrolled medical problem that in the opinion of the investigator would preclude safe administration of the study drugs.

3. Treatment with investigational agents within the last 30 days prior to enrolment including

4. patients previously randomized and subsequently withdrawn from this study.

5. Prior anticancer therapy within one month.

6. Pre-existing peripheral neuropathy of CTCAE grade 2 or higher.

7. Body surface area > 2.0 m2.

8. Known brain metastases/leptomeningeal involvement.

9. Severe infectious diseases.

10. History of significant neurological or psychiatric disorders, including dementia or seizures.

11. Uncontrolled concomitant diseases, including but not limited to symptomatic congestive heart failure, unstable angina pectoris, and heart arrhythmias.

Test products, dose and mode of administration:

Docetaxel (Docetaxel micellar and Taxotere) were administered as an intravenous infusion over 60 minutes at a dose of 100 mg/m². The docetaxel dose used in the study was the approved dose for Taxotere^® for the indication of metastatic breast cancer. The duration of the infusion was as specified in Taxotere^'s Summary of Product Characteristics. The infusion was performed on Day 1 of each of the two cycles. The body surface area (m²) was calculated by the same formula at both treatments using e.g. the Mosteller formula.

The intravenous lines were flushed prior and after use. The time of the docetaxel administration was considered the infusion start time and the flushing of lines prior to administration was not a part of the 60 minutes. In contrast, the flushing of lines after docetaxel administration to ascertain that all docetaxel was given to the patient was included in the 60 minutes.

Patients were pre-treated with oral dexamethasone (16 mg/day) for three consecutive days at both cycles, starting the day before each study drug administration.

Docetaxel micellar was a greenish-yellow to yellow sterile, lyophilized powder of docetaxel and sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester in the proportion of 1:2.25 (molar ratio 1:3.73), prepared as described in Example 1. Each vial of sterile non- pyrogenic powder contains 100 mg docetaxel and 225 mg sodium salt of N-(all-t rans- retinoyl)-L-cysteic acid methyl ester. Docetaxel micellar was reconstituted with physiological saline (sodium chloride 9 mg/mL [0.9%]) before use to a concentration of 0.5 mg docetaxel/mL. Docetaxel micellar was stored refrigerated (2-8°C). Docetaxel micellar was shipped and stored at refrigerated conditions and protected from bright or direct light.

Taxotere^® was a pale yellow to brownish-yellow solution for infusion with the concentration of 20 mg docetaxel/mL. The concentrate also contained polysorbate 80, ethanol anhydrous, and citric acid. Taxotere^® was not reconstituted before added to the infusion for solution. Taxotere^® was stored in room temperature. Commercially available Taxotere^® (Sanofi- Aventis) was used as comparator in the study.

Criteria for evaluation:

Pharmacokinetics:

The following PK parameters were planned to be determined for total and unbound docetaxel after administration of Docetaxel micellar and Taxotere: area under the plasma concentration-time curve (AUC)o-iast, C_max, AUCo-inf, residual area, clearance, l_z, fraction unbound, t_max, ti/2, volume of distribution. However, AUCo-iast, AUCo-25h, AUCo-inf, residual area, clearance, l_z, fraction unbound, ti/2, and volume of distribution could not be determined for unbound docetaxel since most unbound docetaxel concentrations at time points later than 30 minutes post end of infusion were below limit of quantification. The Linear Up/Log Down method was used for the AUC calculations. PK parameters were calculated by non-compartmental methods using Phoenix WinNonlin version 7.0.

Safety:

Physical examination, clinical chemistry, haematology, electrocardiography (ECG), and vital signs were assessed and summarized by study drug. All clinically significant abnormalities were reported as adverse events. Adverse events were summarized by frequency and severity during the two study drug cycles. Infusion site reactions were assessed by visual inspection of the infusion site during infusion and summarized by frequency and severity during administration of Docetaxel micellar and Taxotere.

Statistical methods:

Data were presented by study drug. Numerical data were presented in summary tables by number of patients, arithmetic mean, median, standard deviation, minimum and maximum. Categorical data were presented by number and percent of patients and number of events.

Bioequivalence between the two formulations (Docetaxel micellar and Taxotere) was addressed in a hierarchical order (first total docetaxel and, if confirmed, unbound docetaxel). AUCo-iast were log transformed and analysed using an analysis of variance model with fixed effect terms for period, formulation, sequence and patient (sequence). Bioequivalence was concluded if the backtransformed 90% 2-sided confidence interval for the ratio (Docetaxel micellar/Taxotere) for both AUCo-iast and C_max was within the interval 0.80-1.25.

SUMMARY - CONCLUSION

EFFICACY RESULTS:

Bioequivalence of AUCo-iast and C_max for total docetaxel was demonstrated between Docetaxel micellar (DM) and Taxotere^® following 60 minutes intravenous infusion of 100 mg docetaxel/m². Table 3. Summary of PK parameters for total docetaxel after intravenous infusion of 100 mg/m² Docetaxel micellar (DM) or Taxotere^® for 60 minutes

Geometric means of AUCo-i_astand C_max for Docetaxel micellar/Taxotere^® were 0.89 (90% Cl: 0.81-0.98) and 1.03 (90% Cl: 0.98-1.09), respectively. All AUCo-iast covered more than 80% of

AUCo-inf and was thus a reliable estimate of the extent of exposure (AUCo-inf). A 3-phasic pharmacokinetic profile was observed with the terminal elimination phase starting at 4-7 hours post end of infusion. The unbound fraction of docetaxel (C_Unbound/C_totai) was low for both Docetaxel micellar and Taxotere^® (approximately 0.1-0.2%) during the intravenous infusion and most patients had unbound docetaxel concentrations below lower limit of quantification after 30 minutes post end of infusion.

Bioequivalence of AUCo-iast for unbound docetaxel could not be assessed as there were not enough data points to calculate a reliable AUCo-iast. However, bioequivalence regarding C_max of unbound docetaxel between Docetaxel micellar and Taxotere^® could not be shown and a lower C_max for unbound docetaxel was observed for Docetaxel micellar compared to Taxotere; 4.5 ng/mL (95% Cl: 3.8-5.2) vs 9.3 ng/mL(95% 0:7.9-10.8), respectively.

The slightly higher concentration of unbound docetaxel after the Taxotere^® compared to Docetaxel micellar administration may be explained by that its excipient Polysorbate 80 has been shown to moderately increase the fraction of unbound at clinically relevant concentrations. The observed difference of unbound docetaxel concentrations was small and is unlikely to be of clinical significance. Given the very low unbound concentrations, the estimates of f_u may also be less reliable than the total concentrations in this study. It should be noted that the unbound docetaxel concentrations measured in this study were lower than in previously published studies where the fraction unbound for docetaxel was reported in the range of 4-7% (Baker et al. Clinical Pharmacology & Therapeutics 2005;77(l):43-53; Minami et al. Cancer Sci 2006; 97: 235-241; , Loos et al. Clinical Pharmacology & Therapeutics 2003; 74(4):364-371). The reason for this discrepancy is unknown but possible explanations could be use of other filter materials or sample work up before the ultrafiltration step.

SAFETY RESULTS:

All 30 patients exposed to Docetaxel micellar and/or Taxotere^® experienced an adverse event at any of the two treatment cycles; 97% of the patients after Docetaxel micellar treatment and 100% of the patients after Taxotere^® treatment. The three most common adverse events were within the SOC Blood and lymphatic system disorders; neutropenia, followed by leukopenia and febrile neutropenia.

No fatal events occurred during the study. Serious adverse events were reported in 23% of the patients after Docetaxel micellar treatment (8 events) and in 34% of the patients after Taxotere^® treatment (14events). All serious adverse reactions but one (enterocolitis infectious after Taxotere^® administration) were myelosuppression. Neutropenia was reported in 20% of the patients, leukopenia in 3% and febrile neutropenia in none after Docetaxel micellar treatment. The corresponding numbers after treatment with Taxotere^® were 31%, 10% and 3%.

The clinical chemistry, haematology, vital signs, ECG assessment and physical findings following Docetaxel micellar administration were similar to that after Taxotere^® administration, indicating that there is no specific safety issue following Docetaxel micellar.

The infusion site was visually inspected during the infusion and most infusions did not seem to cause any infusion site reactions. However, grade 1 pain was reported during the Docetaxel micellar infusion for 4 patients.

CONCLUSION:

Docetaxel micellar is bioequivalent to Taxotere^® regarding AUCo-iast and C_max for total docetaxel in plasma. The observed safety profile following administration of Docetaxel micellar was similar to the one observed after Taxotere^® administration and corresponded to what can be expected when treated with docetaxel.

If anything, fewer patients seemed to experience a serious myelosuppression after Docetaxel micellar administration than after Taxotere^® administration.

Example 3: Exploratory PK study

Docetaxel micellar used in this study was a greenish-yellow to yellow sterile, lyophilized powder of docetaxel and sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester in the weight proportion of 1:2.25 (molar ratio 1:3.73), prepared as described in Example 1.

Otherwise, the study was performed analogously to Example 2. Briefly, complete PK profiles were determined after the first infusion of study drugs in a subset of 12 evaluable patients (6 per treatment group) randomized to receive either Docetaxel micellar or Taxotere. Both treatment groups were well balanced with respect to baseline characteristics of patients participating in the PK sub-study. All patients received planned dose during the 60 minutes intravenous infusion and the mean doses were similar in both treatment groups.

Blood samples were to be taken during first cycle of chemotherapy at the following time points: before infusion, 30 min after the start of infusion, immediately before the end of infusion, at 10, 30 min after the end of infusion, and 1, 2, 3, 4, 6, 8, 12, 24 and 48 h after the end of infusion (a total of 14 blood samples). Patients were hospitalised during Days 1-3. After completion of all procedures scheduled on Day 3, the patient continued participation in the study described below (Example 4) on an outpatient basis.

The PK data from the subset of 12 patients (6 per treatment group) was used to perform noncompartmental PK analysis. Plasma docetaxel concentration-time profiles were determined after administration of the first dose of study drugs. PK parameters using actual sampling times after administration of study drugs were calculated and summarized descriptively for each product (Table 4).

Table 4: Summary of the Pharmacokinetic Parameters by Treatment (PK-P set). Group 1

(Test Drug) - 100 mg/m² ; Group 2 (Reference Drug) - Taxotere^®, 100 mg/m²

G AUC AUC Ratio Cmax, Tmax, Kel, T y₂, h CL, CL_B MRT, Vss, L Vss_B

R o-t, 0-¥, AUCt- ng/ml h 1/h L/h SA, h SA,

O ng*h/ ng*h/ , % L/h/m² L/m²

U ml ml

P

1 Mean 5095.9 5396.0 5.45 5105.0 .936 .030 23.71 36.69 20.16 8.13 296.75 162.29

5 9 0 n 6 6 6 6 6 6 6 6 6 6 6 6

Std. 1545.5 1661.3 1.182 1615.6 .2257 .0048 3.599 11 .531 6.401 1.206 105.57 54.234

Deviation 46 17 95 3 CV, % 30.3 30.8 21.7 31.6 24.1 16.0 15.2 31.4 31.8 14.8 35.6 33.4 Median 5153.9 5437.4 5.813 5190.0 .9917 .029 23.90 35.60 18.98 8.42 265.57 139.20

4 0 0

Minimum 3405.7 3583.6 3.35 3250.0 .50 .024 18.24 22.63 13.85 6.13 203.78 108.55

3 0 0

Maximum 6830.9 7222.2 6.52 6690.0 1.17 .038 28.88 51.71 27.90 9.22 476.81 248.34

8 7 0

Geometric 4893.6 5175.9 5.32 4883.8 .906 .030 23.48 35.15 19.32 8.05 282.78 155.45

Mean 1 0 1

Geometric 32.4 32.8 33.9 CV, %

2 Mean 3350.9 3585.2 6.44 3370.0 .944 .028 24.95 52.33 28.54 9.38 487.70 266.04

5 1 0 n 6 6 6 6 6 6 6 6 6 6 6 6

Std. 538.12 601 .30 .717 734.46 .2277 .0045 3.722 9.689 4.711 .560 71 .501 33.284

Deviation 7 0 6 CV, % 16.1 16.8 11.1 21.8 24.1 16.1 14.9 18.5 16.5 6.0 14.7 12.5 Median 3306.9 3546.5 6.49 3340.0 1.000 .027 25.81 50.63 28.21 9.21 466.43 259.89

0 9 0

Minimum 2609.8 2764.2 5.58 2230.0 .50 .024 19.80 40.01 21.74 8.91 418.56 227.48

9 7 0

Maximum 4254.6 4599.0 7.49 4160.0 1.17 .035 28.88 68.73 36.18 10.46 622.09 327.42

7 3 0

Geometric 3315.7 3544.1 6.41 3297.8 .914 .028 24.71 51.62 28.22 9.37 483.71 264.41

Mean 1 8 2

Geometric 15.9 16.5 23.8 CV, %

PK-P: PK parameter analysis set The geometric means of C_max and AUCo- were 4883.81 ng/mL and 5175.90 ng*h/mL in the Docetaxel micellar group and 3297.82 ng/mL and 3544.18 ng*h/mL in the Taxotere^® group. In both treatment groups, docetaxel was widely distributed in tissues with a mean steady- state volume of distribution of 162.29 L/m² and 266.04 L/m² in the Docetaxel micellar and Taxotere^® group, respectively. Docetaxel was rapidly eliminated from plasma, with the mean total body clearance and half-life of 20.16 L/h/m² and 23.71 h in the Docetaxel micellar group and 28.54 L/h/m2 and 24.95 h in the Taxotere^® group. Overall, these results should be considered exploratory in nature due to small sample size of the PK sub-study.

In combination with the results from Example 2, it could be concluded that Docetaxel micellar is bioequivalent to Taxotere^®.

Example 4: Docetaxel micellar formulation does not require premedication Methodology: This was a prospective, multi-country, multicenter, open-label, third-party blinded, randomized, parallel group, active-controlled study to compare the antitumor activity and safety of Docetaxel micellar (docetaxel and sodium salt of N-(all-trans-retinoyl)- L-cysteic acid methyl ester in the proportion of 1:2.25) and Taxotere^® (docetaxel + polysorbate 80) both given as 100 mg/m² 1-hour intravenous infusion every 21 days (1 cycle) for a total of 6 cycles. The possibility of administering the Docetaxel micellar formulation without the corticosteroid premedication that is mandated for Taxotere^® was also evaluated.

Upon confirmation of eligibility, a total of 200 patients were randomly allocated to one of the two treatment groups:

Group 1 (Test drug) - 100 patients were planned and received Docetaxel micellar, 100 mg/m² 1-hour intravenous infusion every 21 days for a total of 6 cycles. No dexamethasone premedication was administered to this group, except for a single patient that was mistakenly given one dose.

Group 2 (Reference drug) - 100 patients were planned and received Taxotere^®, 100 mg/m² 1-hour intravenous infusion every 21 days for a total of 6 cycles. Patients of this group received the dexamethasone premedication.

Twelve patients participated in the exploratory PK study (Example 3) but were otherwise treated similar to the rest of the group. The study consisted of a screening period (up to 21 days before first dose) and a treatment period of 126 days / 18 weeks (6 cycles of chemotherapy, each of 21 days). Final procedures were done at the end of chemotherapy visit, scheduled within 3-4 weeks after the last administration of study drug (study day 127+7). Thus, each patient's participation in the study was up to 155 days.

The total number of visits was sixteen (16): Screening visit (Visit 1), 14 visits of treatment period (Visits 2-15) and end of chemotherapy visit (Visit 16). Hospitalisation of patients was not planned, except for the patients participating in the exploratory PK sub-study as described above.

Diagnosis and Main Criteria for Inclusion: Women 18 years or older with histologically confirmed adenocarcinoma of the breast and (a) disease progression after one prior anthracycline chemotherapy regimen for locally advanced or metastatic breast cancer, or (b) with locally advanced or metastatic disease during or within 12 months of completing an adjuvant or neoadjuvant anthracycline chemotherapy regimen. Prior chemotherapy was to be completed at least 3 weeks before randomization (with the exception of oral cyclophosphamide [2 weeks] and nitrosureas or mitomycin [6 weeks]).

Patients had to have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension, Eastern Cooperative Oncology Group (ECOG) performance status < 2, adequate haematological, hepatic and renal function, negative urine pregnancy test (for female patients of childbearing potential), ability and willingness to follow all requirements of the study protocol.

Women of childbearing potential were required to use adequate method of contraception for the duration of study treatment and for 6 months after the last dose of study drug.

Test Product, Dose and Mode of Administration: Docetaxel micellar (docetaxel and sodium salt of N-(all-trans-retinoyl)-L-cysteic acid methyl ester in the weight proportion of 1:2.25, i.e. molar ratio 1:3.73), lyophilisate for solution for infusion. Each vial contained 80 or 100 mg docetaxel. Docetaxel micellar was given as 100 mg/m² 1-hour intravenous infusion.

Reference Therapy, Dose and Mode of Administration: Taxotere^® (docetaxel in polysorbate 80), concentrate for solution for infusion, 20 mg/0.5 mL, 20 mg/1 mL, 80 mg/2 mL, 80 mg/4 mL, 160 mg/8 mL. Taxotere^® was given as 100 mg/m² 1-hour intravenous infusion. Duration of Treatment with the Test and Reference Products: Six (6) cycles of chemotherapy each of 21 days unless an investigator-determined disease progression or unacceptable toxicity.

Criteria for Evaluation:

Efficacy: The primary efficacy endpoint was overall response rate (partial and complete response) after 6 cycles of chemotherapy, based on the assessments of the Independent Imaging Review Facility (IRF) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (2009).

Secondary efficacy endpoints were disease control rate (DCR), time to response (TTR), duration of response, progression free survival (PFS), time to progression (TTP), quality of life (QOL) using the Functional assessment of cancer therapy measurement system for breast cancer (FACT-B).

Safety: Safety endpoints were incidence and nature of adverse events, incidence of events considered to be hypersensitivity reactions and interpreted as fluid retention, changes in physical examination, vital signs (body temperature, pulse rate, systolic and diastolic blood pressure), electrocardiogram (ECG), laboratory tests (haematology, biochemistry, urinalysis) and ECOG status.

Statistical Methods: Statistical report was prepared using SAS 9.4. PK outputs were produced using SPSS 17.0.

The primary efficacy endpoint was analysed in the Intention to treat (ITT) population as the primary analysis. For the supportive analysis, the primary efficacy model was applied to the Assessable population. The secondary efficacy endpoints were analysed in the ITT population. Time-to-event analyses for progression free survival and time to progression, were done using Kaplan-Meier curves for estimation of the "survival functions" from time- to-event data and the log-rank test for comparison of "survival functions". Time to response and duration of response were assessed non-comparatively using Kaplan-Meier curves for patients with best objective tumor response either complete (CR) or partial response (PR).

Other categorical data were compared using the Chi-square (or Fisher's exact) test. Global QOL was assessed using the FACT-B questionnaire. Higher scores reflect a better QOL. Assessable questionnaires were to contain responses to at least 80% of the questions. The change from baseline in the global QOL scores at the end of cycle 3, and at the end of study was analysed using analysis of covariance (ANCOVA) including baseline value as the continuous covariate. For those patients who withdrew from the study before cycle 3, the end of study QOL assessment was used for comparison.

All secondary statistical analyses were carried out at a two-sided 5% significance level. Safety endpoints were analysed in Safety population.

Number of patients reporting adverse events was summarized by system organ class and preferred term: all adverse events, adverse events related to study drug, adverse events by severity grade, serious adverse events,

All laboratory values were normalized using National Cancer Institute (NCI) standard values. A subject experiencing adverse events (AEs) with the same system organ class (SOC) and preferred term (PT) more than once was counted only once in the number of subjects with AEs in the corresponding SOC / PT. In tables counting AEs by severity or relationship, only the most severe or most related AE were counted for each subject within the corresponding SOC / PT. The frequencies of adverse events of particular interest (hypersensitivity reactions, fluid retention, febrile neutropenia, and neurotoxicity) were compared between two treatment groups using a two-sided Fisher's exact test.

Premedication

Dexamethasone premedication

No premedication was required for patients of the Docetaxel micellar treatment group. However, if the patient experienced either hypersensitivity reaction or fluid retention, dexamethasone premedication could be administered for subsequent cycles, if judged necessary by the investigator. Ultimately, no patient required such premedication in the Docetaxel micellar group, but a single patient was administered dexamethasone mistakenly.

Patients of the Taxotere^® treatment group received dexamethasone premedication starting from the first cycle of chemotherapy. Dexamethasone was given at a dose of 16 mg/day (8 mg twice per day) for 3 days starting 1 day prior docetaxel administration. Route of administration (oral, intramuscular or intravenous) was defined in accordance with routine practice of investigational site.

No Hi- and H2-histamine blockers were required to prevent hypersensitivity reactions and/or fluid retention; monotherapy with dexamethasone was considered sufficient premedication approach.

Prophylactic treatment with recombinant granulocyte colony stimulating factor (G-CSF)

The use of G-CSF was permitted only:

• As curative treatment in case of absolute neutrophil count < 0.1 x 10⁹/L, febrile neutropenia, or infection

• As treatment for delayed recovery of absolute neutrophil count at cycle day 21

• As secondary prophylactic treatment in patients with a prior episode of febrile neutropenia or a neutrophil count of < 0.5 x 10⁹/L for more than 7 days or infections

Primary prophylaxis with G-CSF could be used to individual patients at the discretion of the investigator.

Prophylactic administration of G-CSF was to be performed in accordance with the American Society of Clinical Oncology (ASCO) guideline.

Prophylactic treatment with anti-emetic drugs

A prophylactic anti-emetic treatment was recommended in both arms starting at the first cycle. The type of treatment was at the discretion of the investigator.

Prophylactic treatment with anti-diarrheal drugs

No prophylactic treatment for diarrhoea was recommended. However, in case of Grade 2 to 3 diarrhoea, the patient was given treatment in accordance with the ASCO recommendations.

SUMMARY AND CONCLUSIONS

EFFICACY RESULTS

• In the Docetaxel micellar group, there was one complete response (1%) and 30 partial responses (30%) giving an ORR of 31.0%. In the Taxotere^® group, there were three complete responses (3.0%) and 42 partial responses (42.0%) giving an ORR of 45.0%. The difference in ORR between the treatment groups (Docetaxel micellar-Taxotere) was -14.0% and the lower limit of the one-sided 97.36% Cl for the difference in ORR was -27.0%. The pre-defined non inferiority margin was set to -23.0%.

• The DCR was 84% in the Docetaxel micellar group and 87% in the Taxotere^® group (p=0.5735, Barnard's exact test).

• The median time to response was 9.1 weeks in both treatment groups and the median response duration was 9.5 weeks in the Docetaxel micellar group and 9.9 weeks in the Taxotere^® group.

• Nine (9.0%) patients in each treatment group had progressive disease as the best response. The median TTP was 18.6 weeks in the Docetaxel micellar group and 18.9 weeks in the Taxotere^® group (p=0.4229, log-rank test). The median PFS was 18.6 weeks in the Docetaxel micellar group and 18.9 weeks in the Taxotere^® group (p=0.6207, log-rank test).

• FACT-B subscale and total scores decreased from baseline during the study for both treatment groups, but the FACT-B total score decreased significantly more in the Docetaxel micellar group. The change from baseline to end of study (LS mean) was -9.06 (95%CI: - 11.96; -6.16) in the Docetaxel micellar group and -3.64 (95%CI: -6.49; -0.78) in the Taxotere^® group; the LS means difference between treatment groups was -5.42 (95%CI: -9.50; -1.35, p=0.0094, ANCOVA).

• A post-hoc analysis was performed investigating the ORR based on the tumour assessment at the end of chemotherapy visit (Visit 16/Day 127+7), both in the ITT and Assessable populations. Noninferiority of Docetaxel micellar as compared to Taxotere^® was shown for both populations in this analysis. In the ITT population, the ORR was 27.0% in the Docetaxel micellar group and 35.0% in the Taxotere^® group, the difference between the treatment groups was -8.0%, and the lower limit of the one-sided 97.36% Cl for the difference in ORR was -20.4%. In the Assessable population, the ORR was 29.0% in the Docetaxel micellar group and 36.5% in the Taxotere^® group, the difference between the treatment groups was -7.4%, and the lower limit of the one-sided 97.36% Cl for the difference in ORR was -20.4%. No superiority was found in either the ITT or the Assessable population. SAFETY RESULTS:

• All patients in each treatment group reported at least one AE during the study. Predominant AEs were neutropenia (Docetaxel micellar, 92.9%; Taxotere^®, 100.0%), leukopenia (Docetaxel micellar, 82.7%; Taxotere^®, 99.0%), asthenia (Docetaxel micellar, 44.9%; Taxotere^®, 50.0%) and alopecia (Docetaxel micellar, 39.8%; Taxotere^®, 60.0%). Overall, the incidence of AEs was higher in the Taxotere^® group than in the Docetaxel micellar group for the majority of SOCs and PTs, with the exception of injections site reactions, oedema peripheral, nausea, vomiting, and phlebitis that occurred more frequently in the Docetaxel micellar group.

• There were 9 patients with AEs leading to study discontinuation: 3 patients in the Docetaxel micellar group and 6 patients in the Taxotere^® group. The events leading to study discontinuation were blood bilirubin increased, asthma and death in the Docetaxel micellar group and blood bilirubin increased (3 patients) and death (3 patients) in the Taxotere^® group.

• A total of 10 patients in each group had AEs that led to dose delay during the study. The most common reason for treatment delay was upper respiratory tract infection and hepatic impairment in the Docetaxel micellar group and thrombocytopenia in the Taxotere^® group.

• Twelve (12.2%) patients in the Docetaxel micellar group and 24 (24.0%) patients in the Taxotere^® group needed at least one dose reduction due to AE. Febrile neutropenia was the main reason for dose reduction in both treatment groups. Overall, there were more reductions due to haematologic toxicity in the Taxotere^® group than in the Docetaxel micellar group.

• Grade 4 (life-threatening) was more frequently in the Taxotere^® group (Docetaxel micellar, 56.1%; Taxotere^®, 82.0%). Overall, Grade 3 or 4 AEs were reported for 82.7% of patients from Docetaxel micellar group and 99.0% of patients from Taxotere^® group. The most frequently reported Grade 3/4 AEs were neutropenia, leukopenia and febrile neutropenia with higher incidence of these events reported for the Taxotere^® group.

• All patients experienced at least one study drug-related AE during the study. In both treatment groups the most commonly reported treatment-related AEs were haematological AEs (neutropenia, leukopenia, febrile neutropenia), asthenia and alopecia. • Hypersensitivity reactions (adverse reactions occurring within seconds or minutes of drug administration with features of an anaphylactic or anaphylactoid reaction) were reported for 2 patients, one patient in each of the treatment groups. Both patients experienced hypersensitivity reaction of Grade 1 (mild) in intensity at the beginning of chemotherapy (Day 1/Cycle 1). In addition, there were 6 patients (3 patients in each group) who had other hypersensitivity manifestations that occurred during or after the drug infusion. Those were pruritus, vascular pain, and hypersensitivity in the Docetaxel micellar group, and allergic dermatitis, erythema, and hypertension in the Taxotere^® group.

• Fluid retention was reported for 39.8% of patients from Docetaxel micellar group and 37.0% of patients from Taxotere^® group (p=0.7703, Fisher exact test). The majority of events were classified as mild in intensity and occurred at Cycle 4 or Cycle 5. There were more patients with oedema peripheral in the Docetaxel micellar group than in the Taxotere^® group (28.6% vs 18.0%). Other reported oedema events were face oedema (Docetaxel micellar, 21.4%; Taxotere^®, 21.0%), peripheral swelling (Docetaxel micellar, 1.0%; Taxotere^®, 4.0%), oedema (2.0% in each group), localised oedema (Docetaxel micellar, 1.0%; Taxotere^®, 2.0%), eyelid oedema (Docetaxel micellar, 2.0%; Taxotere^® , 1.0%), and breast oedema (Docetaxel micellar, 1.0%; Taxotere^®, 0.0%).

• Febrile neutropenia occurred in 15.3% of patients in the Docetaxel micellar group and 23.0% of patients in the Taxotere^® group (p=0.2072, Fisher exact test). One case in the Docetaxel micellar group was non-serious, all other cases in both groups were reported as SAEs. In both treatment groups, the majority of cases were classified as Grade 4 (Docetaxel micellar, 10.2%; Taxotere^®, 16.0%). Febrile neutropenia events were considered definitely (Docetaxel micellar, 11.2%; Taxotere^®, 14.0%) or probably (Docetaxel micellar, 4.1%; Taxotere^®, 9.0%) related to study drug.

• Nervous system AEs were reported more frequently in the Taxotere^® group than in the Docetaxel micellar group (49.0% of patients vs 33.7% of patients), the difference between treatment groups was statistically significant (p=0.0313, Fisher exact test). In both treatment groups, the most common events were peripheral sensory neuropathy (Docetaxel micellar, 11.2%; Taxotere^®, 25.0%), dysgeusia (Docetaxel micellar, 8.2%; Taxotere^®, 11.0%) and hypoaesthesia (Docetaxel micellar, 4.1%; Taxotere^®, 7.0%). The majority of nervous system AEs were mild in severity (Docetaxel micellar, 26.5%; Taxotere^®, 40.0%) and were classified as definitely related to study drug (Docetaxel micellar, 14.3%; Taxotere^®, 26.0%).

• Injection site reactions were reported for 27.6% of patients in the Docetaxel micellar group. No events were reported in the Taxotere^® group. In the Docetaxel micellar group, these AEs mainly included injection site phlebitis (13.3%) and injection site thrombosis (9.2%). The majority of injections site reactions were considered definitely related to study drug and were mild or moderate in intensity. One patient experienced severe injection site dermatitis.

• Four deaths occurred during the study: one in the Docetaxel micellar group (as a result of pulmonary embolism) and three in the Taxotere^® group (one with the unknown cause, one death due to coronary artery insufficiency and one death due to erysipelas). All deaths were considered unrelated to study drug.

• SAEs were reported more frequently in the Taxotere^® group (87.0%) than in the Docetaxel micellar group (58.2%). In both treatment groups, the most common SAEs reported were neutropenia (Docetaxel micellar, 52.0%; Taxotere^®, 83.0%), leukopenia (Docetaxel micellar, 15.3%; Taxotere^®, 27.0%), febrile neutropenia (Docetaxel micellar, 14.3%; Taxotere^®,

23.0%). Other SAEs included thrombocytopenia, pneumonia, central pain syndrome, headache, asthma, pulmonary embolism, tumour haemorrhage in the Docetaxel micellar group and anaemia, abscess soft tissue, erysipelas, coronary artery insufficiency, death, hypersensitivity in the Taxotere^® group. The majority of SAEs were considered study drug- related.

• There was no obvious difference between both treatment groups in the results of monitoring of vital signs before and after the drug infusion.

• Incidence of ECG-related AEs was slightly higher in the Taxotere^® group than in the Docetaxel micellar group. The following AEs were reported: ECG abnormal (Docetaxel micellar, 1.0%; Taxotere^®, 3.0%), ECG repolarisation abnormality (Docetaxel micellar, no AEs; Taxotere^®, 3.0%), ECG QT prolonged (Docetaxel micellar, no AEs; Taxotere^®, 1.0%), ECG ST segment abnormal (Docetaxel micellar, no AEs; Taxotere^®, 1.0%). All these AES were mild in severity. The majority of them were considered probably related to study drug. • For haematology laboratory values, shifts from baseline normal/abnormal not clinically significant to abnormal clinically significant assessment were observed for neutrophils, leukocytes, platelets, haemoglobin, erythrocytes and erythrocyte volume fraction. There were more shifts in the Taxotere^® group as compared to the Docetaxel micellar group for neutrophils and leukocytes. In both treatment groups, following chemotherapy white blood cell count decreased from baseline values on Day 8 of each cycle and returned to baseline values before the next chemotherapy cycle. For biochemistry laboratory values most shifts were observed for alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase and blood glucose, particularly in the Taxotere^® group. No clinically significant abnormalities in urinalysis were reported.

CONCLUSION

The pre-defined non-inferiority criteria for the primary efficacy endpoint was not met. However, the observed best overall response for Docetaxel micellar was consistent with data from three out of six previously conducted phase III studies of single-agent docetaxel (100 mg/m² every three weeks) in metastatic breast cancer. Non-inferiority of Docetaxel micellar as compared to Taxotere^® was shown for both the ITT and the Assessable population in a post-hoc analysis investigating the ORR based on the tumour assessment at the end of chemotherapy visit. No significant difference between the two treatment groups was found for secondary efficacy endpoints. Despite the absence of dexamethasone premedication prior to Docetaxel micellar, the incidence of hypersensitivity reactions and fluid retention was similar to that reported for Taxotere^®. Thus, Docetaxel micellar provides a docetaxel formulation that spares the patients corticosteroid premedication.

Overall, Docetaxel micellar showed a more favourable safety profile than Taxotere^® with less SAEs and neurotoxicity. Higher incidence of infusion site reactions was however seen in the Docetaxel micellar group.

Claims

2. The composition according to any of the preceding claims, wherein the molar ratio is about 1:3.6 to 1:3.8.

3. The composition according to any of the preceding claims, wherein the molar ratio is about 1:3.7.

4. The composition according to any of the preceding claims, wherein the molar ratio is 1:3.73.

5. The composition according to any of the preceding claims, wherein the composition comprises docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid at the indicated ratios.

6. The composition according to claim 5, wherein the composition comprises no additional salts of methyl ester of N-all-trans-retinoyl cysteic acid.

7. The composition according to any of the preceding claims, wherein the composition does not contain any sodium salt of methyl ester of N-13-cis-retinoyl cysteic acid.

8. The composition according to any of the preceding claims, wherein the composition does not contain any derivatives of retinoyl cysteic acids other than the methyl ester of N-all-trans-retinoyl cysteic acid.

9. The composition according to any of the preceding claims, wherein the composition is a micellar formulation in a solvent suitable for infusion.

10. The composition according to claim 9, wherein the solvent suitable for infusion is 9 mg/ml NaCI in water, Ringer lactate or Ringer acetate, preferably 9 mg/ml NaCI in water.

11. The composition according to any of claims 9-10, wherein the micellar formulation contains docetaxel at a concentration in the range of 0.2-5 mg/ml, more preferably 0.4-2 mg/ml, even more preferably 0.4-1.1 mg/ml and most preferably about 0.5 mg/ml or about 1.0 mg/ml.

12. The composition according to any of claims 9-11, wherein at least 90% of the micelles in the micellar formulation are in the size range of 13-17 nm (Z-average) when determined using dynamic light scattering.

13. The composition according to any of claims 9-12, wherein at least 90% of the micelles in the micellar formulation are in the size range 13-17 nm (Z-average) when determined using dynamic light scattering, in 9 mg/ml NaCI water solution at 0.5 mg/ml docetaxel concentration.

14. The composition according to any of claims 9-13, wherein the composition consists of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid in a solvent suitable for infusion.

15. The composition according to any of claims 1-8, wherein the composition is a dried lyophilized composition.

16. The composition according to any of claims 1-8, wherein the composition is a dried lyophilized composition essentially consisting of docetaxel and sodium salt of methyl ester of N-all-trans-retinoyl cysteic acid.

17. The composition according to any of claims 1-16, for use in the treatment of a solid tumor disease by administration via intravenous infusion to a patient in need thereof.

18. The composition for use according to claim 17, wherein the treatment does not comprise premedication with a corticosteroid prior to the infusion.

19. The composition for use according to any of claims 17-18, wherein the treatment does not comprise administering a corticosteroid to the patient within the 48h preceding the infusion, preferably within 24h preceding the infusion.

20. The composition for use according to any of claims claim 17-19, wherein the treatment does not comprise administration of dexamethasone to the patient.

21. A process for manufacturing a composition according to any of claims 1-8 or 15-16, comprising the steps of: a. Dissolving docetaxel and a monovalent cation salt of methyl ester of N-all- trans-retinoyl cysteic acid in a first solvent at the appropriate molar ratio of the docetaxel to the monovalent cation salt of methyl ester of N-all-trans- retinoyl cysteic acid, said ratio being in the range of 1:3.4 to 1:4.1; b. Evaporating said solvent leaving an amorphous residue of the docetaxel and the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid; c. dissolving the amorphous residue in an aqueous solvent to form a micellar solution; d. sterilizing the micellar solution, preferably by sterile filtration; e. lyophilizing the filtered micellar solution to form a lyophilized composition according to any of claims 1-8 or 15-16.

22. The process according to claim 21, wherein the first solvent is an organic solvent.

23. The process according to claim 22, wherein the first solvent is methanol.

24. The process according to any of claims 21-23, wherein the aqueous solvent is water suitable for injection.

25. The process according to any of claims 21-24, wherein the sterilized solution is distributed into vials prior to lyophilization.

26. The process according to any of claims 21-25, wherein the monovalent cation salt of methyl ester of N-all-trans-retinoyl cysteic acid is sodium salt of methyl ester of N- all-trans-retinoyl cysteic acid.

27. A method of treatment for a solid tumor disease comprising administering a composition according to any of claims 1-16 via intravenous infusion to a patient in need thereof.

28. The method according to claim 27, wherein the treatment does not comprise premedication with a corticosteroid prior to the infusion.

29. The method according to any of claims 27-28, wherein the treatment does not comprise administering a corticosteroid to the patient within the 48h preceding the infusion, preferably the within 24h preceding the infusion.

30. The method according to any of claims 27-29, wherein the treatment does not comprise administration of dexamethasone to the patient.