Use of docetaxel for treating cancers

The present invention relates to a method of treating cancer, comprising administering a dose of docetaxel and a dose of rhuMAb HER2 to a patient in need thereof, wherein said dosages have a synergistic therapeutic effect when compared to the administration of docetaxel or rhuMAb HER2 alone.

FIELD OF THE INVENTION
 This present invention relates to a novel therapeutic and synergistic
 combination of antineoplastic agents which are useful in the treatment of
 cancer.
 BACKGROUND OF THE INVENTION
 The present invention relates more specifically to the use of docetaxel in
 combination with recombinant humanized anti-HER2 antibody, rhuMAb HER2,
 for the treatment of cancers.
 Selected term definitions are as follows:
 "docetaxel" refers to the active ingredient of TAXOTERE.RTM. or else
 TAXOTERE.RTM. itself;
 "rhuMAb HER2," or trastuzumab, refers to the active ingredient of
 HERCEPTIN.RTM. or else HERCEPTIN.RTM. itself;
 "HER2" refers to human epidermal growth factor 2, a 185 kD transmembrane
 glycoprotein receptor (p185.sup.HER2); and
 "drug" or "drugs" refers to the above-mentioned active ingredients or
 medicaments or pharmaceutical preparations containing them.
 Previous researchers have noted that docetaxel (TAXOTERE.RTM.) and its
 derivatives (such as TAXOL.RTM., paclitaxel) are useful in the treatment
 of the malignant neoplasms, such as solid tumors and other malignancies.
 European Patent EP 0 253 738 and International Patent Application WO
 92/09589 describe a method of preparation of docetaxel. Generally, the
 doses, which vary depending on the patient, comprise between 60 and 400
 mg/m.sup.2 of docetaxel. Commonly, docetaxel is administered via
 intravenous route at doses of 60 to 100 mg/m.sup.2 over 1 hour every 3
 weeks (Textbook of Medical Oncology, Franco Cavelli et al., Martin Dunitz
 Ltd., p. 4623 (1997)).
 Many clinical studies have confirmed the efficacy of docetaxel in treating
 many types of cancer, particularly breast cancer. Docetaxel's effects are
 shown in both first and second line therapies. The mechanism of
 docetaxel's action is thought to be via enhancement of microtubule
 assembly and inhibition of the depolymerization of tubulin at the cellular
 level.
 The humanized recombinant monoclonal antibody rhuMAb HER2 (Trastuzumab,
 HERCEPTIN.RTM., Genentech) has also been found to be active in treatment
 of cancers that express HER2. A gene known as neu, or c-erbB-2, encodes
 the human epidermal growth factor receptor 2, known as HER2. HER2 is a
 transmembrane receptor tyrosine kinase with partial homology with the
 epidermal growth factor receptor, both of which receptors belong to the
 type 1 tyrosine kinase receptor superfamily. About 30% of human breast
 tumors overexpress HER2. Such overexpression is associated with a poor
 prognosis. rhuMAb HER2 inhibits the growth of breast cancer cells
 overexpressing HER2 and has shown some clinical activity as a single
 agent.
 It has also been described that rhuMAb HER2 enhances the antitumor activity
 of chemotherapeutic agents against HER2/neu overexpressing human breast
 cancer xenografts (Baselga et al., Cancer Research, 58, 2825-2831, Jul. 1,
 1998), but this result was based solely on preclinical animal models.
 Further, both treatments, taxotere and rhuMAb HER2, used alone can have
 disturbing side effects. All treatments based on taxoid derivatives,
 including docetaxel, can show serious and troubling toxicities, such as
 myelosuppression, neutropenia, hypersensitivity, peripheral neuropathy,
 and fluid retention, among others (Fumoleau et al., Bull. Cancer, (82)8:
 629-636 (1995)). While neutropenia, alopecia and mucositis are rarely
 caused by treatment with rhuMAb HER2, that drug has been shown to be
 associated with cardiac dysfunction. When such toxicities appear, dosages
 of the drugs must be limited with a resulting limitation on the efficacy
 of the treatment.
 Consequently, there is an unmet need in the art for pharmaceutical
 preparations and methods of treating cancer which enhance the activity of
 docetaxel and rhuMAb HER2 without increasing the amount of the dosages
 administered and without increasing adverse side effects.
 SUMMARY OF THE INVENTION
 The present invention embodies methods for treating cancer, comprising
 administering docetaxel and rhuMAb HER2 in amounts effective to produce a
 synergistic effect in a patient in need thereof. Among the preferred
 features of the invention are compositions wherein the ratios of docetaxel
 and rhuMAb HER2 provide therapeutic synergistic activity. The improved
 efficacy of this combination has been demonstrated by the determination of
 resulting therapeutic synergy. Such therapeutic synergy is demonstrated by
 the showing that the combination is therapeutically superior to one or
 other of the constituents used as its optimum dose (T. H. Corbett et al.,
 Cancer Treatments Reports, 66: 1187 (1982)). To demonstrate the efficacy
 of a combination, it may be necessary to compare the maximum tolerated
 dose of each of the separate constituents in question.
 It has also been discovered that the combination of docetaxel and rhuMAb
 HER2 significantly reduces the development of tumor volume over what would
 be predicted from administration to tumor-infected mammals of each
 compound alone.
 Another aspect of the invention comprises new pharmaceutical kits and
 medicaments comprising docetaxel in combination with rhuMAb HER2 for
 treating cancers.
 Yet another aspect of the invention is concerned with new schedules of
 administration of docetaxel and rhuMAb HER2 for the treatment of cancers
 wherein rhuMAb HER2 is administered weekly and docetaxel is either
 administered weekly or triweekly.
 DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The inventors of the present invention have demonstrated via clinical
 trials, that the combination of docetaxel and rhuMAb HER2 in particular
 dosages manifests an unexpected and strong synergistic, therapeutic effect
 on the treatment of neoplastic diseases, particularly breast cancers, and
 more particularly, in metastatic breast cancers in which the
 HER2/protooncogene is overexpressed. Generally, according to the
 invention, docetaxel is administered in a dosage of approximately 20 to
 100 mg/m.sup.2, and rhuMab HER2 is administered in a dosage of 2 to 10
 mg/kg. In a specific embodiment of the invention, docetaxel is
 administered at a dosage of approximately 75 mg/m.sup.2 once every three
 weeks, and rhuMAb HER2 is administered initially at a dosage of 4 mg/kg
 and thereafter weekly at a dosage of 2 mg/kg. In another embodiment of the
 invention, docetaxel is administered in a dosage of 35 mg/m.sup.2 weekly
 and rhuMab HER2 is administered at an initial dosage of approximately 4
 mg/kg, followed by 2 mg/kg weekly. In both of these specific embodiments,
 the combination exhibits therapeutic synergy.
 Therapeutic synergy is demonstrated by the showing that the combination is
 therapeutically superior to one or other of the constituents used as its
 optimum dose (T. H. Corbett et al., Cancer Treatments Reports, 66: 1187
 (1982)). Therefore, the response rates obtained from the individual
 components must be considered first.
 rhuMAb HER2 administered alone, in two recently published clinical studies,
 gave complete remission and partial remission data, from which the
 resulting objective response rates were calculated. The first study
 reported an overall objective response rate of 11.6% (J. Baselga et al.,
 Oncology, March 1997, Supplement 2: 43-48). The second study, which was
 multinational, reported two large clinical trials in which the anitbody
 was administered to patients with a loading dose of 4 mg/kg, followed by
 weekly administration of 2 mg/kg, which is the dosage and administration
 used in the instant examples. In this large study, there were eight
 complete responses (4%) and 26 partial responses (11%) for an objective
 overall response rate of 15% (M. A. Cobleigh, C. L. Vogel, et al., J.
 Clin. Oncology, 17: 2639-2648 (1999)).
 Docetaxel alone, in several in-house proprietary studies, gave overall
 response rates of 40 to 43% (in second line therapy at a dose of 100
 mg/m.sup.2), 48% (in first line therapy at a dose of 75 mg/m.sup.2) and
 61% (in first line therapy at a dose of 100 mg/m.sup.2).
 In comparison, in Examples 1 and 2 below, a lower, and therefore less
 toxic, dose of docetaxel administered in combination with rhuMab HER2 gave
 an unexpectedly better overall response rate compared to either component
 alone. Specifically, in these second line studies, rhuMab HER2 was
 administered at an initial loading dose of 4 mg/kg, followed by weekly
 administration at 2 mg/kg, while docetaxel was administered at a dose of
 75 mg/m.sup.2 every twentyone days. The overall response rate obtained so
 far in this preliminary study was 44%, which in fact is superior to the
 rate for second-line docetaxel alone (40 to 43%) obtained previously,
 because the dosage of docetaxel required in the combination was 25
 mg/m.sup.2 less than the 100 mg/m.sup.2 in monotherapy. Further, an
 overall response rate of 44% is also markedly superior to the overall
 response rate of 15% when rhuMab HER2 is used alone. Thus, this result
 demonstrates therapeutic synergy.
 Likewise, in Example 3, a lower dose of docetaxel administered in
 combination with rhuMab HER2 gave an unexpectedly better overall response
 rate compared to either component alone. Specifically, weekly docetaxel at
 a dose of 35 mg/m.sup.2 and weekly rhuMab HER2 at a dose of 2 mg/kg after
 an initial 4 mg/kg loading dose were administered in the treatment of
 first line metastatic breast cancer patients with HER2 overexpression. The
 overall response rate was 54%. This is superior to a response rate of 48%
 for docetaxel alone in first line therapy with a dosage of 75 mg/m.sup.2,
 and to a response rate of 15% for rhuMab HER2 alone with identical amounts
 and mode of administration. In other words, a lesser dose of docetaxel and
 the same amount of rhuMab HER2, when utilized as a combination therapy,
 gave an overall response rate of 54%, better than either drug alone.
 Hence, this docetaxel/rhuMab HER2 combination was therapeutically
 synergistic.
 The new use of docetaxel is not limited to combinations administered
 separately, but also includes the compositions obtained by physical
 association of docetaxel and rhuMAb HER2, but in either case a synergistic
 therapeutic effect is obtained.
 It has also been found that this new use of docetaxel according to the
 invention may enable the phenomena of pleiotropic resistance or
 "multi-drug resistance", or other resistance mechanisms, to be avoided or
 delayed. As described in the Examples 1 and 2 below, many of the clinical
 patients, who were successfully treated with the combination of the
 invention as a second line therapy, had already failed to respond to other
 forms of chemotherapy, suggesting that this novel combination is effective
 in combating multi-drug resistant or other resistant forms of cancer.
 Docetaxel may be administered once every week or once every three weeks. It
 may be administered over a one-hour period; or over a shorter period such
 as 30 minutes, or any period of time in between 30 minutes and an hour.
 The dose of docetaxel will vary according to the nature of the cancer to
 be treated, the interval in which the drug is given and the manner of
 administration. A preferred dose is usually 100 mg/m.sup.2 or 75
 mg/m.sup.2 every three weeks. Optionally, the dose may be less than 100
 mg/m.sup.2, or comprise dosages between 20 mg/m.sup.2 and 100 mg/m.sup.2.
 For instance, suitable doses are between 20 and 50 mg/m.sup.2,
 preferentially 40 mg/m.sup.2 on a weekly basis.
 The monocolonal antibody, rhuMAb HER2, is usually administered once weekly.
 rhuMAb HER2 may appropriately be administered over a period of
 approximately 30 to 120 minute periods; preferably, over 90 minutes. Each
 dose of rhuMAb HER2 may be in the range of 2 to 20 mg/kg. In the most
 preferred embodiment, the monoclonal antibody is initially administered at
 a dose of 4 mg/kg, followed by doses of approximately 2 mg/kg weekly.
 Both the docetaxel and rhuMAb HER2 may be administered parenterally, but
 are preferably given via the intravenous route (IV). The drugs may also be
 administered intraperitoneally in the case of localized regional therapy.
 Both drugs may be administered simultaneously, separately, or spaced out
 over a period of time so as to obtain the maximum efficacy of the
 combination. It is possible for each administration to vary in duration
 from a rapid total administration to a continuous infusion.
 Drugs for intravenous administration are generally pharmaceutically
 acceptable, sterile solutions or suspensions which may optionally be
 prepared as required at the time of use or just prior to the time of use.
 For the preparation of nonaqueous solutions or suspensions, natural
 vegetable oils, such as olive oil or sesame oil, liquid petrolatum, or
 injectable organic esters, such as ethyl oleate, may be used. The sterile
 aqueous solutions can consist of a solution of the product in water.
 Aqueous solutions are suitable for intravenous administration provided the
 pH is appropriately adjusted and the solution is made isotonic, for
 example, with a sufficient amount of sodium chloride or glucose.
 Sterilization may be carried out by heating or by any other means which
 does not adversely affect the composition. The drugs may also take the
 form of liposomes, or the form of an association with cyclodextrins,
 polyethylene glycols, or polysorbates. Compositions for oral and
 intraperitoneal administration are preferably aqueous suspensions or
 solutions.
 The compositions using docetaxel according to the invention comprise the
 drugs and one or more suitable pharmaceutically acceptable excipients. A
 suitable pharmaceutical formulation of docetaxel may be supplied in 20 mg
 or 80 mg vials containing 0.59 ml or 2.36 ml of a 40 mg/ml solution of
 docetaxel in polysorbate. This vial is then diluted with a corresponding
 additionally supplied solvent vial containing 1.83 ml or 7.33 ml of a 13%
 ethanol solution diluted in water. The docetaxel concentration of the
 resulting solution obtained is 10 mg/ml.
 The antibody rhuMAb HER2 is supplied for use as a freeze dried preparation
 with a nominal content of 400 mg per vial for parenteral administration.
 It may be formulated in any one or a combination of histidine, trehalose,
 and polysorbate 20. Each vial is reconstituted with 20 ml of
 bacteriostatic water for injection, USP (containing 1.1% benzyl alcohol),
 which is supplied with each vial. The reconstitued solution contains 22
 mg/ml rhuMAb HER2 and may be added to 250 ml of 0.9 sodium chloride
 injection USP. This formulation may be designed for multiple usage but
 must be used within 28 days after reconstitution.
 According to the invention, it is advantageous that the amount of docetaxel
 represents approximately 10 to 90% by weight of the combination. This
 content may vary in accordance with the nature of the associated
 substance, the efficacy sought, and the nature of the cancer to be
 treated, and may be determined by the practitioner.
 According to the invention, the new use of docetaxel is very advantageous
 for treating all types of cancers, and more preferably cancers of the
 breast, ovary, lung, head and neck, prostate, gastric cancers, or Kaposi's
 sarcoma; still more preferably, the new use of docetaxel is particularly
 suitable for treating breast cancers.

The Examples below illustrate the new use of docetaxel according to the
 invention without limiting it.
 EXAMPLE 1
 The safety and the efficacy of the combination of docetaxel and
 rhuMabHER2was tested in patients according to the following protocol:
 Patients were eligible for the study if they had metastatic breast cancer,
 2+ or 3+ HER2 overexpression, had failed up to one prior nontaxane
 containing regimen for metastatic breast cancer or may have received
 additionally any adjuvant chemotherapy regimen or hormonal therapy in the
 adjuvant or metastatic setting. Patients must have had either
 bidimensionally measurable or evaluable disease.
 The combination therapy was administered intravenously in an outpatient
 setting, with rhuMAb HER2 administered first, followed on the same day by
 docetaxel. Acute rhuMAb HER2 toxicities were resolved prior to docetaxel
 administration.
 On day zero, patients received a 4 mg/kg loading dose of rhuMAb HER2
 administered IV, followed by 2 mg/kg weekly until disease progression or
 unacceptable side effects occurred.
 The initial dose of rhuMAb HER2 was administered over a 90 minute period.
 If this first dose was well-tolerated, subsequent infusion periods were
 sometimes shortened to 30 minutes. If the initial or subsequent doses were
 not well-tolerated (e.g., the patient experienced fever or chills),
 subsequent infusions were shortened only after a dose was well-tolerated.
 Patients remained under medical supervision for 1 hour following completion
 of the initial dose of rhuMAb HER2. If no adverse events occurred with the
 first infusion, the postinfusion observation period for the second
 infusion was optionally shortened to 30 minutes, or optionally eliminated
 entirely with subsequent infusions.
 Docetaxel was administered in an outpatient setting following the
 completion of the initial rhuMAb HER2 dose and an appropriate observation
 period. Patients who received docetaxel were given a premedication (such
 as dexamethasone, 8 mg by mouth every 12 hours, starting 24 hours prior to
 each infusion of docetaxel and continuing for a total of 3 days). The
 patient was expected to be discharged after the IV infusion was completed
 and after a sufficient duration of observation to ensure that vital signs
 were stable.
 Three weeks after the initial dose of rhuMAb HER2, docetaxel was given at a
 dose of 75 mg/m.sup.2 as a one-hour IV infusion. This dose of docetaxel
 was given every 21 days for a total of 6 doses or until either progressive
 disease or unacceptable side effects occurred.
 If G-CSF (Granulocyte Colony Stimulating Factor) was required as a
 secondary prophylaxis for patients, G-CSF was administered at the dose and
 schedule recommended by the manufacturer as a subcutaneous injection
 starting on day 2-5 of the treatment of the cycle.
 Primary endpoints included response rate, response duration, time to
 treatment failure, safety, and tolerability.
 Radiographic studies of evaluable lesions were performed at weeks 9, 18,
 27, then every 3 months thereafter until disease progression. Patients
 were treated for a maximum of one year on this trial. Patients were
 promptly removed from the study and offered other therapeutic options if
 there was objective disease progression by radiographic or clinical
 assessment. All patients who developed disease progression were followed
 for survival information every 2 months until termination of statistical
 analysis of the study.
 Reponse criteria were as follows:
 Complete Response (CR): disappearance of all radiographically and/or
 visually apparent tumor for a minimum period of 4 weeks;
 Partial Response (PR): a reduction of at least 50% in the sum of the
 products of the perpendicular diameters of all measurable lesions for a
 minimum period of 4 weeks;
 Minor Response (MR): a reduction of 25% to 49% in the sum of the products
 of the perpendicular diameters of all measurable lesions;
 Stable Disease: no change greater than 25% in the size of measurable
 lesions;
 Progressive Disease: objective evidence of an increase of 25% or more in
 any measurable lesion; and
 time to disease progression, progression-free, time to treatment failure,
 and survival.
 Thirteen eligible patients received therapy according to the above
 protocol. There were 2 confirmed partial responses, 3 minor responses, and
 no patient was removed for progressive disease. There were no reports of
 serious toxicities. Thus, the addition of rhuMabHER2 to chemotherapy in
 patients with HER2 overexpressing breast cancers was shown to improve not
 only response rate and time to tumor progression, but also survival.
 EXAMPLE 2
 The initial phase II trial of Example 1 was continued to confirm the
 efficacy as well as the safety profile of the combination of rhuMAb HER2
 and docetaxel in patients with measurable metastatic breast cancer.
 In this trial, rhuMAb HER2 was given on day 1 as a 4 mg/kg loading dose,
 followed by 2 mg/kg weekly until disease progression. Docetaxel at 75
 mg/m.sup.2 every 3 weeks was administered on day 1 of each cycle after
 rhuMAb HER2. One cycle represents three weeks of treatment, with docetaxel
 administered on days 1 and 22.
 Twenty-one patients received 108+ cycles of docetaxel and 300+ doses of
 rhuMAb HER2. Of these patients, the median age was 54, within a range of
 36-72. All patients'0 tumor specimens were sent to a central laboratory
 for determination of HER2 expression by the DAKO kit
 (immunohistochemistry). Fourteen patients showed 3+ overexpression, 7
 patients showed 2+ overexpression; 16 had been treated with prior
 chemotherapy. A median of 6 cycles per patient were given and the median
 time on the study was approximately 200 days.
 Toxicity was minimal with 1 episode of febrile neutropenia, and 3 patients
 with .gtoreq.grade 2 dermatitis. No clinically significant cardiotoxicity
 has been observed (no left ventricular ejection fraction, LVEF, decline in
 .ltoreq.40%, no LVEF decline .gtoreq.20%, and no symptoms).
 Of 16 patients evaluable for response (3 patients were too early to
 evaluate, and 2 patients were inevaluable for response), 1 CR, 6 PRs, and
 3 MRs have been observed, for an overall response rate of 44%. Six of the
 seven major responses were observed in 3+ overexpressing patients. Only 1
 patient had progressive disease as her best responses. Median time to
 progression exceeded 6 months.
 This combination regimen generated efficacious antitumor activity as
 demonstrated by both objective tumor responses and time to progression, as
 well as minimal toxicity.
 EXAMPLE 3
 In this example, weekly docetaxel was combined with weekly rhuMAb HER2 as a
 first line treatment in HER2 overexpressing (2+ or 3+) metastatic breast
 cancer ("MBC"). Patients with MBC who had received no more than 1 prior
 chemotherapy regimen and no prior taxane therapy were eligible.
 The treatment regimen was as follows. Docetaxel, at 35 mg/m.sup.2 IV 6 of 8
 weeks, was combined with same day administration of weekly rhuMAb HER2 at
 2 mg/kg IV after an initial 4 mg/kg loading dose. Preliminary toxicity and
 response data on 14 eligible patients and 26 cycles of therapy have been
 completed. All tumors were reviewed centrally and determined to
 overexpress HER2 (10 patients-HER2 3+; 4 patients-HER2 2+). The median
 patient age was 53, within a range of 36-73. The median number of disease
 sites was 2, within a range of 1-4. The clinical results were as follows.
 One patient experienced grade 3 nausea, grade 4 neutropenia, and
 neutropenic fever with cycle one. No other grade 3 or 4 toxicities were
 observed in any other patient. The most frequently reported
 non-hematologic toxicities were fatigue (3 patients-G2, 8 patients-G1),
 dyspepsia (2 patients-G2, 4 patients-G1), diarrhea (1 patient-G2, 5
 patients-G1), and nausea (1 patient-G3, 2 patients-G2, 3 patients-G1).
 MUGA scans were performed at baseline and after every 8 weeks. Cardiac
 dysfunction was measured by a decline in ejection fraction (EF). No
 symptomatic decline in EF was experienced by any patient. Only one patient
 experienced an asymptomatic decline in EF from 68% at baseline to 52%
 after 2 cycles of therapy, and the EF returned to baseline (65%) without
 medical intervention.
 One CR and 6 PR's have been observed in 13 assessable patients for an
 overall response rate of 54%. Although preliminary, this response rate is
 significantly higher that the rate reported for either rhuMab HER2 or
 docetaxel alone as noted above. Based on these preliminary data, the
 combination of weekly docetaxel and rhuMAb HER2 is well-tolerated and
 results in significant antitumor activity.
 The present invention may be embodied in other specific forms without
 departing from its spirit or essential characteristics. The described
 embodiments are to be considered in all respects as illustrative only and
 not restrictive. The scope of the invention is, therefore, indicated by
 the appended claims rather than by the foregoing description. All changes
 which come within the meaning and range of equivalency of the claims are
 to be embraced within their scope.