AU7179200A - Method of treatment of breast cancer - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Bristol-Myers Squibb Company Actual Inventor(s): Marcel Rozencsweig, Renzo Mauro Canetta, Elizabeth Eisenhauer Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHOD OF TREATMENT OF BREAST CANCER Our Ref: 631599 POF Code: 140109/1490 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- FIELD OF THE INVENTION This invention relates to a method of treatment of breast cancer.

Each year there are over 7000 newly diagnosed cases of breast cancer in Australia. About 7% of women develop breast cancer. The mortality rate of patients for breast cancer is about 28.6 per 100,000 woman years.

Four drugs, used either alone or in combination, have been the first line treatment for breast cancer for a number of years. These are cyclophosphamide methotrexate, 5-fluorouracil and prednisone. A treatment using the first three of these drugs, called the CMF regimen, is generally given orally.

There is a need for additional effective treatments for breast cancer.

SUMMARY OF THE INVENTION The invention provides a method of treatment of a patient suffering breast cancer comprising administering taxol to the patient by intravenous infusion wherein the taxol is administered at a dose of from 135 mg/m 2 to 175 mg/m 2 over a duration not exceeding 6 hours.

!0.0 Preferably the method comprises either administration of 135 mg/m 2 of taxol over a duration of about 3 hours or administration of 175 mg/m 2 taxol over a duration of about 3 hours.

These results are surprising in view of the reports that a bolus injection or short (1-3 hour infusions) will induce anaphylactic reactions or other hypersensitivity responses, and that only premedication coupled with extension of the infusion time to 6-24 hours would reduce or eliminate the most serious allergic reactions. In a preferred embodiment the invention accordingly provides a method 'of treatment of a patient suffering breast cancer comprising administering taxol to S0 the patient by intravenous infusion wherein the taxol is administered at a dose of from 135 mg/m 2 to 175 mg/m 2 over a duration of from 1 to 3 hours and the patient W:'eannie\species\704393div.doc has been treated with a premedication to reduce or eliminate hypersensitivity responses.

It is particularly preferred that patients to be infused with taxol are pretreated to alleviate or minimize hypersensitivity responses.

Preferably, patients are premedicated with steroids, antihistamines, and H 2 antagonists. The amount of the premedications is typically sufficient to at least prevent an anaphylactoid shock capable of causing patient death in greater than 95% of cancer patients treated, and avoid acute hypersensitivity reactions in greater than 90% of cancer patients treated.

To ameliorate myelosuppression associated with taxol administration, particularly associated with high dosages of taxol, granulocyte-colonystimulating factor (G-CSF) is typically given as a daily subcutaneous injection preferably started 24-hours after the completion of a taxol infusion. With the use of G-CSF, taxol dosages of up to 175 mg/m 2 can be safely administered using the methods of the present invention.

Other aspects of the present invention include a method of administering taxol to a patient suffering from breast cancer by monitoring certain clinical parameters, and temporarily halting taxol administration when infusion related toxicities exceed safe limits. After the parameters return to near baseline, therapy is restarted, preferably with 72 hours. In a preferred embodiment, premedication is given intravenously prior to restarting the infusion. For patients suffering severe HSRs near the end of, or after, a taxol infusion, the HSR is treated, and the patient is rechallenged during the next course by providing premedication intravenously, followed by using a modified 24-hour infusion, in which the infusion is initiated at about one fourth the planned infusion 24-hour rate; if there are no severe HSR symptoms after about six hours, the infusion is continued at the 24-hour rate.

Additional aspects include the administration of multiple courses of taxol over regular periods of time, such as at approximately 21-day intervals, or when adverse effects of a previous course or infusion substantially subside.

W:\jeannie\species\704393div.doc 4 Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude the use of other additives or components or integers.

DETAILED DESCRIPTION OF THE INVENTION Despite the conventional understanding that it is necessary to infuse patients over a 24-hour period with high dosages of taxol (greater than 170 mg/m 2 following premedication to minimize or eliminate hypersensitivity responses, while obtaining the desired anti-neoplastic effect, it has been surprisingly discovered that taxol can be safely administered to cancer patients via infusions lasting less than 6 hours at dosages of about 135 mg/m 2 to about 175 mg/m 2 In a preferred embodiment, taxol is administered via an infusion having a duration of about three hours, with a taxol dosage of about 135 mg/m 2 or about 175 mg/m 2 Of great significance is a surprising discovery that the short term infusion causes less myelosuppression, which leads to a lower incidence of infections and fever episodes febrile neutropenia).

The surprising, discovery that taxol could be safely administered via a short infusion less than six hours and preferably over about 3 hours) means that it will now be possible to administer taxol on an out-patient basis, saving patients the time and expense of yet another hospitalization while improving patient quality of life.

It has also been surprisingly discovered that lower taxol dosages, such as 25 about 135 mg/m 2 can be administered via infusions lasting about 3-hours to about 28-hours, and still be antineoplastically effective.

EXPERIMENTAL PROTOCOL A multi-center, randomized comparative study of taxol in patients suffering from ovarian carcinoma which had been pretreated with platinum was carried out. The high degree of success, greater than 10% objective response, to treatment by patients suffering from drug refractory ovarian carcinoma is truly astonishing, since responses to drug refractory ovarian carcinoma are extremely uncommon. While experimental data is provided herein for the successful treatment of ovarian W: jeannie\species\704393div.doc carcinoma with taxol using the present treatment protocol, it is to be understood that the treatment protocol can be used for the treatment of other forms of cancer with taxol, such as breast cancer, melanoma, renal cell carcinoma, and other cancers which are treatable with taxol. The present invention provides an improvement in the treatment of all types of cancer which can be treated with taxol, since by use of the administration protocol of the present invention, lower toxicities and/or less time is required than that associated with prior art protocols for administering antineoplastically effective amounts of taxol.

Patients with platinum pretreated recurrent ovarian cancer were randomized to a 135 or 175 mg/m 2 dose arm, administered as a 3-hour or 24-hour IV infusion, which was repeated every three weeks. Responses were evaluated every two cycles. All four treatment groups were matched for age, performance status, previous treatments, and time from last platinum therapy. If a patient showed a complete response, CR, taxol infusions were continued for four cycles post-CR; patients showing a partial response, PR, had taxol infusions continued until relapse, or treatment was stopped after four cycles post PR stabilization. For a stable disease, taxol infusions were stopped after a maximum of 10 cycles or earlier if unacceptable toxicity was present; if disease progressed, PD, patients 20 were taken off the study.

.i The study included four arms as indicated below: ooo i ARM INFUSION DURATION DOSAGE A 24hours 175 mg/m 2 B 3 hours 175 mg/m 2 C 24 hours 135 mg/m 2 D 3 hours 135 mg/m 2 Patients with ovarian carcinoma included in the study had been treated with and were unresponsive to a minimum of one but no more than two platinum-containing chemotherapy regimens, and were required to have shown progression during or relapse after their last regimen of chemotherapy. Patients were treated every 21 days if allowed by toxicity. Granulocyte count and platelet count were monitored; W:\eannie~species\704393div.doc provided granulocyte count was at least 1500 cells/cmm and platelet count was at least 100,000 cells/cmm, taxol was administered.

ADMINISTRATION OF TAXOL Prior to initiating an infusion, a resuscitation/emergency cart was placed outside the infusion room and remained there during the first hour of infusion. An emergency drug tray having all the necessary drugs, etc. was set up in the room in the event of an acute hypersensitivity reaction. Oxygen and suction equipment are provided at the bedside of each patient along with a 3-hour or 24-hour observation sheet (depending on the arm), and a fluid balance sheet.

Nitroglycerin tubing is required for the IV equipment because the polyethoxylated castor oil (available under the brand name "Cremophor EL" from BASF) leaches plasticizer from regular IV tubing made of polyvinylchloride. Glass or polyolefin containers were used for storing all Cremophor containing solutions.

All taxol-containing solutions were infused with in-line filtration using a microporous filter, preferably having a pore size not greater than 0.22 microns.

In order to minimize acute hypersensitivity reactions, patients were premedicated according to the protocol with dexamethasone or an equivalent mg taken OS at home, 12 hours and 6 hours prior to taxol infusion).

Diphenhydramine (or equivalent antihistamine), 50 mg IV; and ranitidine equivalent H-2 receptor blocker), 50 mg IV, were provided minutes prior to the taxol infusion, taxol was supplied by BRISTOL-MYERS SQUIBB as a concentrated sterile solution for IV administration. Each 5 ml vial contained 6 mg/ml taxol in polyethoxylated castor oil (Cremophor EL) 50% in dehydrated alcohol, USP 50%. While an emulsion of taxol in polyethoxylated caster oil in dehydrated alcohol is utilized as a vehicle in a preferred embodiment, it is contemplated that other pharmaceutically acceptable vehicles for taxol may be used.

Taxol was administered, after dilution in dextrose or saline solution, as a continuous infusion in two 500 mL glass bottle of 5% dextrose (D5W) or normal saline (NS) over 3 hours, or in two 500 mL glass bottles over 12 hours each for the W:jeanniespecies\704393div.doc 24-hour infusion. The first 18 mL of IV solution were infused at a fast rate (300 ml/hour) via the previously primed line to ensure that the taxol had reached the end of the IV tubing. This procedure enables the accurate assessment of the patient receiving the taxol.

A nurse remained with each patient for the first hour of each infusion.

Temperature, pulse, blood pressure, and respiration were taken preinfusion, every minutes for the first hour, every thirty minutes for the next 2 hours, hourly for the next 4 hours, and every other hour until the end of the infusion (for patients receiving the 24-hour infusion). Other observations were also documented, such as rash/redness of the skin, hives, vomiting, nausea, and any other symptoms including neuropathy and skin rashes.

Another aspect of the present invention is that patients suffering from hypersensitivity reactions to taxol infusions can be retreated with taxol following management of the hypersensitivity reaction. In a preferred embodiment, patients experiencing hypersensitivity reactions were taken off taxol. Hypersensitivity reactions were treated by administration of diphenhydramine (50 mg IV) with administration of epinephrine 0.35-0.5 cc s.c. every 15-20 minutes until reaction 20 subsided or until a total of six dosages of epinephrine were given. IV fluids were administered when hypotension did not respond to epinephrine. Likewise, if wheezing did not stop in response to epinephrine, 0.35 cc of nebulized albuterol solution was administered.

To prevent recurrent or ongoing allergy manifestation, 125 mg methylprednisolone was administered via IV.

In a preferred embodiment for rechallenging with taxol patients who had experienced a hypersensitivity reaction (other than hypotension requiring pressor therapy, angioedema respiratory distress requiring bronchodilation therapy, and generalized urticaria), the following protocol was followed. All rechallenge patients S"received a prolonged 24-hour infusion, even if the hypersensitivity reaction occurred during a 3-hour infusion. Dosage reductions in subsequent treatment courses were mandated for all patients having a granulocyte count of less than W:\eannie\species\704393div.doc 8 500 cells/cmm, a platelet count of less than 50,000 cells/cmm for seven days or more, febrile neutropenia, infection, hemmorage, mucositis with vesiculation and/or ulcers, or vomiting appearing despite anti-emetic premedication. taxol treatment was discontinued in patients having intolerable paresthesias and/or marked motor loss (neurological toxicity of World Health Organization, WHO, grade greater than symptomatic bradycardia or heart block of any degree or other arrhythmias; and other major organ toxicity of WHO grade greater than 2.

If less than 75% of a total taxol dose was infused prior to a hypersensitivity reaction, retreatment preferably occurs within 72 hours of cessation of taxol infusion, and the amount of taxol used for retreatment equals the originally planned taxol dose less the amount infused before the taxol infusion was stopped due to the hypersensitivity reaction. A non-limiting embodiment of a preferred rechallenge procedure follows: A. A steroid is given preferably at least 6 hours prior to administration of taxol. For example, 8 mg dexamethasone is given intravenously 24, 18, 12, and 6 hours prior to taxol administration.

B. An antihistamine is given 30 minutes prior to taxol, for example, 50 mg IV diphenhydramine.

C. An H2 receptor antagonist is given 30 minutes prior to taxol infusion, for example, ranitidine 50 mg IV.

D. Taxol is administered in the 24-hour infusion volume, but at one quarter the planned rate for a 24-hour IV infusion during the first 6 hours. If no reaction is noted, the rate is increased to normal infusion speed. Thus, the entire infusion time is somewhat longer than 24 hours because of the slow infusion during the first 6 hours. Thus, by way of non-limiting example, total infusion time would be approximately 28.5 hours.

E. If a hypersensitivity reaction sufficient to discontinue the taxol infusion recurs during the rechallenge procedure, the patient is taken off taxol.

However, if a patient is successfully rechallenged without recurrence of a hypersensitivity reaction severe enough to require discontinuation of the infusion, the rechallenge procedure is continued.

W.\eannie\species\704393div doc 9 EFFICACY AND SAFETY In order to confirm the efficacy and safety of the taxol administration method of the present invention, patients with histologically confirmed ovarian carcinoma, who had shown progression during or relapse after platinum-containing therapy, were administered taxol according to one of the four previously described Arms.

Patients ranged between 18 and 75 years in age with an Eastern Cooperative Oncology Group, ECOG, performance status of 0, 1, or 2, and had to have recovered from all toxicities of previous treatment. Further, no prior chemotherapy or radiotherapy were allowed within four weeks prior to entry into the study (patients were also not entered into the study if there had been less than six weeks since prior mitomycin, nitrosureas, or high-dose carboplatin therapy). An adequate baseline bone marrow function was required, which was defined as a granulocyte count 2 2,000 cells/cmm and a platelet count 2 100,000 cells/cmm.

Adequate hepatic and renal functions were required with normal hepatic function defined as total billirubin 1.5 times upper normal value and normal renal function defined as serum creatinine <1.5 times upper normal value. Patients with abdominal adenocarcinoma, a previous history of atrial or ventricular arrhythmias, congestive heart failure, myocardial infarction within six months preceding S. 20 randomization, complete bowel obstruction, a pre-existing neuropathy WHO grade 2, active infection, prior allergic reaction to drugs containing Cremophor, or other serious medical condition were excluded from the study.

Eligible patients were randomized according to a computerized randomization 25 log. During therapy, hematology data (hemoglobin, white blood cell count, granulocytes and platelets) were collected, and toxicity assessments were continuously made. After each cycle, a physical history update was recorded, as well as tumor measurement, performance status (ECOG), hematology, chemistry (serum creatinine, billirubin, alkaline phosphatase, SGOT (AST), CA125) and a toxicity assessment. A quality of life assessment was also made after each cycle, and every two months until six months after treatment stopped.

The efficacy and safety of the improved method for administration of taxol of the present invention was based on 159 patients randomized into the four W:\jeannie\species\704393div.doc treatment Arms previously described. Of the 159 patients, 157 patients received at least one dose of taxol and were evaluated for both safety and efficacy.

528 courses of taxol were given to 157 patients distributed over the 4 treatment Arms. The median number of courses received was 3 (range 1 which is equivalent to a median of 9 weeks on study. Overall 27 of 157 patients required a dose reduction, mainly for neutropenia with less than 500 cells/cmm for more than 7 days duration. Taxol administration was discontinued for 2 patients during the second course. One of the 27 patients was retreated at a reduced dose level, and dosage was re-escalated after one course at a reduced dose level.

Overall, 11% of the taxol courses were administered at reduced dosage.

Dose reduction was required in the 2 Arms using long term infusion more frequently than in Arms using the short term infusion. This is surprising considering that a more concentrated dosage of taxol is given during the short infusion than during the long infusion.

The time between courses ranged from 17 to 49 days, with the median number of days between courses being 21. The following table lists the various 20 premedications used in the various treatment Arms: *TABLE 1 EXAMPLES OF PREMEDICATIONS

USED

H-2 Receptor Blocker: Steroid: Antihistimine: Ranitidine Dexamethasone Diphenhydramine Famotidine Hydrocortisone Clemastine Cimetidine Prednisone Chlorpheniramine Chlorphenamine Dimethindene maleate Promethazine W:\jeannie\species\704393div.doc 11 In a preferred embodiment, at least one of each of the H-2 receptor blockers, steroids and antihistimines is utilized. By way of non-limiting examples, a combination of prednisone and hydrocortisone, or dexamethasone and hydrocortisone could be used in combination with at least one of the antihistamines and least one of the H-2 receptor blockers.

22 patients achieved an objective response (CR or PR). Thus, the overall objective response rate is 14% (22/157) for this study. However, 17 patients were not evaluated and another five patients were unavailable. If these latter patients are excluded, the objective response rate is 16% (22/135). Further, 51 patients with stable disease were continued on taxol and may later meet the criteria for an objective response (note that an average of only three courses of taxol yielded the present results). Thus, use of the present method for administration of taxol produces at least a 14% overall objective response rate for 157 patients. This is an astonishing result, since all of the patients were considered drug refractory. It is also remarkable that 3 out of 46 of these patients who had progressed on previous platinum containing chemotherapy responded to taxol. Overall, responses to taxol occurred in 13% of patients (14/114) who were considered resistant to platinum therapy progression on therapy or relapse within six 20 months). Further, 52% of patients (24/46) with disease truly refractory to platinum, and 53% of patients (16-36) with an early relapse after platinum, achieved a stabilization of their disease.

15% of the platinum resistant patients who had received one previous regimen of platinum responded to taxol, versus 10% of the platinum resistant patients who had received two previous regimens of platinum, corresponding to 19 and 23%, respectively.

0:000 Of 159 patients, only one died of taxol related toxicity (less than HEMATOLOGIC TOXICITY Another aspect of the present invention is the reduction in hematologic toxicity associated with the treatment of cancer with taxol. The 157 patients who received taxol had blood counts performed weekly. White blood cell (WBC) W: jeannieLspecies\704393div.doc 12 counts, absolute neutrophil count (ANC), platelet counts, and hemoglobin (Hb) concentration were the primary variables used to evaluate treatment related myelosuppression. The World Health Origination, WHO, grades of nadir for the entire study population of 157 patients during course 1 are presented in the table below. Leukopenia and neutropenia were the most frequent and severe hemotologic adverse effects observed during the first cause of treatment. 53% (83/156) of the patients had Grade III or IV neutropenia, while 39% (61/157) had Grade III or IV leukopenia. Severe thrombocytopenia was observed in only two patients during course 1.

Of particular significance is that Grade IV neutropenia was reported almost five times more frequently in the patients treated with the 24-hour taxol infusion than the patients treated with a 3-hour taxol infusion.

TABLE 2 Myelotoxicity Course 1 WHO Grade Per Treatment Arm 175/24 175/3 135/24 135/3 TOTAL (n=45) (n=29) (n=44) (n=39) (n=157) n n n n n WBC Count 0 1 11 (38) 4 15 (38) 31 25 I 5 (11) 6 (21) 5 (11) 13 (33) 29 (18) II 11 (25) 7 (24) 11 (25) 7 (18) 36 (23) III 22 (49) 5 (17) 20 (46) 3 50 (32) IV 6 (13) 0 4 1 11 (7) ANC Count 0 2 11 (38) 6 (14) 18 (46) 37 (24) I 1 2 2 (15) 8 (21) 13 (8) II 5 (11) 3 (10) 7 (16) 8 (21) 23 III 8 (18) 6 (21) 6 (14) 4 (10) 24 IV 28 (63) 7 (24) 23 (52) 1 59 (38) Platelet Count 0 39 (87) 29 (100) 43 (98) 36 (92) 147 (94) I 3 0 1 2 6 (4) II 1 0 0 1 2 (1) III 1 0 0 0 1 (1) IV 1 0 0 0 1 (1) o *o oeooo o• oo W.\jeannie\species\704393div.doc 13 As is clear from Table 2, grade 4 neutropenia was reported almost 5 times more frequently in patients treated with the 24-hour taxol infusion compared to patients treated by a 3-hour infusion. 58% (51/88) of the patients treated with the 24-hour taxol infusion had grade 4 neutropenia in comparison to 12% (8/68) of the patients treated by a 3-hour infusion. When the incidence of grade 3 and grade 4 are pooled, it is clear that severe leukopenia occurs more frequently in patients treated with a 24-hour taxol infusion than with a 3-hour infusion.

In a preferred embodiment the invention provides a method of reducing hemalological toxicity in patients undergoing taxol therapy comprising parenterally administering to patients experiencing hematologic toxicity upon taxol administration, an infusion of taxol of about 135 mg/m 2 over a duration not exceeding six hours.

With reference to Table 3 below, analysis of median values for nadir count confirms the severity of taxol induced neutropenia, especially in the two 24-hour treatment Arms.

TABLE 3 Myelotoxicity Course 1 Nadir Counts, Per Treatment Arm 175/24 175/3 135/24 135/3 TOTAL (n=45) (n=29) (n=44) (n=39) (n=157) (1) WBC Count Median 1,600 3,300 1,900 3,700 2,400 Range 300-7,300 1,400-13,900 500-7,800 980-6,850 300-13,900 ANC Count 30 Median 330 1,390 470 1,930 840 Range 0-664 210-11,770 0.555 360-6,290 0-11,770 Platelet Count Median 168,000 285,000 236,500 298,000 226,000 -Range 11,000 144,000 87,000 65,000 11,000 -345,000 -688,000 -710,000 -749,000 -749,000 Cell counts expressed in number of cells/cmm.

*r a W:\ieannie\species\704393div.doc Further, anemia of any grade occurred in 47% (26/55) of patients with normal baseline Hb values who had been treated with a taxol long-term infusion, and anemia occurred in only 28% of patients treated with the short-term infusion.

In summary, neutropenia and leukopenia were the most frequent and severe hematologic adverse effects during the study period, with 63% of the patients displaying severe neutropenia (WHO Grade III and IV) during at least one cause.

The incidence of severe neutropenia in the long-term infusion versus the shortterm infusion Arms was 85% versus 32%. The incidents of severe neutropenia in the high dose Arms was 74% (55/74) versus 52% (43/83) in the low dose Arms.

Thus, it is clear that both reducing the dosage and the infusion time will lower hematologic toxicity; however, reducing the infusion to 3 hours from 24 hours appears to have a greater impact on reducing toxicity than reducing the taxol dosage from about 175 mg/m 2 to 135 mg/m 2 Those patients suffering from myelotoxicity can be treated with colony stimulating factors, CSFs. In a preferred embodiment, patients are given granulocyte colony stimulating factors in an amount sufficient to be effective in either reducing myelotoxicity or increasing the rate of recovery from myelotoxicity.

Preferably, the CSFs are provided in accordance with the method taught by Sarosy et al. in "Phase I Study of Taxol and Granulocyte Colony-Stimulating Factor In Patients With Refractory Ovarian Cancer," Journal of Clinical Oncoloav, Vol. 10, No. 7, (July, 1992) pp. 1165-1170. In a preferred embodiment, G-CSF (available from Amgen, Inc. of Thousand Oaks, CA) can be self-administered subcutaniously on a daily basis (thus allowing for treatment on an outpatient basis), with injections beginning 24 hours after the completion of a taxol infusion.

Preferably a G-CSF dose of about 10 pg/kg/d is used, and G-CSF injection continues until there is convincing evidence of bone marrow recovery from taxolinduced nadir. Convincing evidence of bone marrow recovery includes a white blood cell count of 10,000 cells/mm 3 and a platelet count of more than 50,000/mm 3 The use of G-CSF enables higher doses of taxol to be used, and allows for certain patients suffering severe myelosuppression to be continued on taxol treatment whereas, in the past, such patients may not have been allowed to continue on taxol.

W:\jeannie\species\704393div.doc HYPERSENSITIVITY REACTIONS (57/157) of the patients exhibited some type of hypersensitivity reaction. Only two hypersensitivity reactions (2 of 157 patients or were reported which required acute therapeutic intervention.

Table 4 below lists the number and percentage of patients demonstrating hypersensitivity reactions per treatment Arm and also provides the type of HSR per course.

TABLE 4 Hypersensitivity Reactions (HSR) Per Treatment Arm 175/24 1 75/3 135/24 135/3 TOTAL n n n n n Per Patient Number of patients analyzed 45 29 44 39 157 Patients reporting a HSR 6(36) 12(41) 18(41) 11 (28) 57(36) Per Course Number of courses 30 analyzed 163 92 141 132 528 Courses with a reported HSR 46(28) 23(25) 44 (31) 23 (17) 136 (26) Type of HSR Per Course (1 Flushing 32 16 40 15 103 -Rash 3 6 6 6 21 40 -Hypotension 10 1 1 1 13 Dyspnea 3 2 Edema face 1 1 2 Eye Disorder -2 2 Pruritis -2 2 45 -Headache -1 1 Arrhythmia 1 1 Hypertension 1 1 Tachychardia 1 1 NauseaNomiting -1 1 Chest pain -1 1 More than 1 sign and symptom may be experienced in each course.

W:\jeannielspecies\704393divdoc The most frequent symptoms were flushing, mainly confined to the face, following by skin rash, hypotension, and dyspnea.

Of the two patients suffering severe hypersensitivity reactions, one patient was not rechallenged with taxol. The other patient suffering a severe hypersensitivity reaction received a 135 mg/m 2 24-hour infusion first course of taxol without experiencing a severe hypersensitivity reaction. Due to WHO Grade IV neutropenia for more than 7 days, the scheduled dose for course 2 was reduced by 20%. During the second course, the delivery of less than 1 ml of taxol infusion induced tachychardia and shortness of breath, requiring the infusion to be stopped. The patient developed an extreme general flush, with a heart rate of 150 per minute (regular) and the blood pressure was 150/100. The allergic reaction resolved completely after the administration of 56 mg benadryl IV and 35 mg adrenalin S.C. The infusion of taxol was restarted after an interruption of minutes at the regular infusion rate without further problems.

Another patient encountered a hypersensitivity reaction, which prompted the investigator to interrupt the infusion. However, this incident did not qualify as a significant HSR. During a first course, the patient received 135 mg/m 2 during a 24hour infusion. Course 1 was administered uneventfully. Taxol infusion during course 2 was interrupted after 1 minute (less than 1 mg of taxol) due to dyspnea, flushing, and nausea, which was treated with 5 mg of chlorphenamine. The patient received another 250 mg hydrocortisone, and the taxol infusion was recommenced 70 minutes after. The total infusion time was 28 hours, 15 minutes with no further occurrence of hypersensitivity reaction. Course 3 was administered uneventfully with normal premedication.

Further examples of adverse reactions are discussed later.

S* PERIPHERAL NEUROPATHY 80 of 157 patients experienced some sign or symptom of peripheral neurotoxicity. The incidents in the high dose arms was 66% (49/74), while the incidents in the low dose arms was 37% (31/83). The incidents of peripheral neuropathy in the long-term (24-hour) infusion was 48% (43/89), while the W:\jeanniespecies\704393div.doc incidents of peripheral neuropathy in the short-term infusion arms was 54% (37/68).

Prior to taxol treatment, 75% (118/157) of patients were asymptomatic; of these, 44 patients developed some peripheral neuropathy symptoms.

Overall, 54 of 157 patients developed, or had worse peripheral neuropathy symptoms, as can be seen by Table 5 below.

The substantial reduction in peripheral neurotoxicity symptoms (PNS) in patients receiving lower dosages of taxol allows for more flexibility in treating patients, since lower taxol dosages over longer infusion periods can be used for patients suffering from PNS while higher doses and/or shorter infusion periods can be used for patients not suffering from PNS.

Table Peripheral Neuropathy Symptoms (PNS) and Taxol Dosing By Treatment Arm 175/24 175/3 135/24 135/3 TOTAL (n=29) (n=44) (n=39) (n=157) n n n n n 0@

SO

0 *566 0S

S.

Number of Patients Who Developed or Worsened PNS First Occurrence/ Worsening of PNS By Courses Course 1 Course 2 Course 3 Course 4 and more By Cumulative Dose of Taxol 20 (44) 9 8 1 2 18(62) 7 (16) 8(21) 54 (34) o 0 @0 55 5 0 S S 00 23/157 19/143 (13) 4/95 (4) 7/69(10) 200 mg/m 2 201-400 mg/m 2 401-600 mg/m 2 600 mg/m 2 W: eannie\spees\704393di.doc 18 It is clear that peripheral neuropathy symptoms (PNS) are reduced when a dosage of about 135 mg/m 2 taxol is provided rather than a dosage of about 175 mg/m 2 Further examples of adverse drug reactions, and the procedures used to continue treatment follow.

Patient BB-2 was allocated to the 135 mg/m 2 3 hour arm. Shortly after beginning her second cycle of treatment, she developed asymptomatic bradyarrhythmia characterized by short periods of AV block or sinus pauses accompanied by some ventricular extrasystoles. She had some extrasystoles in cycle 1 as well. There was no prior cardiac history and subsequent investigations were normal. She had a pacemaker inserted and was retreated with a third cycle.

The bradyarrhythmia appeared to have a definite relation to taxol, and the patient recovered with treatment.

Patient BB-3 was allocated to the 175 mg/m 2 3 hour arm. Shortly after beginning cycle 2, she developed a hypersensitivity reaction, characterized by 20 generalized urticaria, diaphoresis, and dyspnea. The infusion was interrupted and she recovered quickly after treatment with epinephrine and antihistamine. She was retreated using the re-challenge amendment discussed above. The HSR appeared to be definitely related to taxol, and the patient recovered with treatment.

25 Patient DF-1 was randomized to the 135 mg/m 2 24 hour arm. During her first treatment, she had 2 episodes of asymptomatic bradycardia, during which the infusion was interrupted for durations lasting 3 and 5 minutes, respectively. She also developed a mild skin rash. However, the infusion was completed. The bradycardia appeared related to taxol, and the patient recovered.

Patient IM-7 was allocated to the 135 mg/m 2 24 hour infusion, and experienced a non-significant HSR during cycle 2. Her first cycle of treatment had been uneventful; however, 5 minutes after the 2nd treatment began, she became flushed and dyspneic, with nausea (no vomiting). The infusion was stopped, 5 mg chlorpheniramine was given and symptoms rapidly resolved. The patient was re- W:\jeannie\species\704393div.doc 19 treated according to the retreatment protocol discussed earlier with no problem, aside from minor facial rash. The HSR appeared to be related to taxol.

Patient MP-7 was allocated to the 135 mg/m 2 24 hour infusion. About minutes after cycle 1 began, she became hot, flushed, and slightly dyspneic (BP 114/80, pulse 112). Taxol was stopped, she was given diphenhydramine, and the reaction resolved immediately. The patient was re-treated according to the retreatment protocol without event. Thus, the HSR appears related to taxol.

Patient VA-30 was randomized to the 135 mg/m 2 24 hour arm. During her second treatment, she developed flushing and a sense of tightness in her throat.

The infusion was stopped for a short while, and repeat doses of steroid, antihistamine and ranitidine were given. Taxol was restarted with no further problems; this indicates that the HSR was caused by taxol.

The success of the use of the new taxol infusion protocoTbf the present invention in the treatment of ovarian cancer makes it readily apparent that antineoplastically effective dosages of taxol can be infused over much shorter time periods than was previously believed possible, without inducing severe 20 hypersensitivity reactions or inducing fatal anaphylactic shock. Thus, it is contemplated that the infusion protocol of the present invention may be utilized to treat solid tumors and leukemias, such as but not limited to lung cancer, breast cancers, and ovarian cancers. It is to be understood that treatment of different forms of cancer may require the adjustment of the taxol dosage to have optimal 25 efficacy.

The foregoing clearly establishes that taxol is both safe and effective in the treatment of cancer, such as ovarian cancer, when administered according to the protocol of the present invention. In particular, by use of a 3-hour infusion of about 30 135 w/m 2 Taxol, following premedication, a substantial reduction results in the frequency of myelotoxicity and neuropathy associated with the administration of taxol to patients suffering from cancer. Further, patients who exhibit severe hypersensitivity reactions can be rechallenged with taxol after treating the HSR symptoms by use of an infusion of about 24 hours or greater, preferably using a W:'jeannie\species\704393div.doc dosage of about 135 mg/m 2 to about 175 mg/m 2 Preferably, colony stimulation factors are administered to assist in ameliorating myelosuppression.

The use of lower dosages. of taxol to achieve antineoplastic results will allow for more patients to be treated with the present limited supply of taxol. Further, depending upon the toxicities noted in a patient during treatment with taxol according to the present protocol, the duration of infusion can be extended or shortened, or the taxol dosage can be reduced or increased, thus providing more flexibility in treating cancer with taxol. Further, patients capable of handling higher doses of taxol can be administered up to about 275 mg/m 2 should the patient encounter severe toxicity, such as a severe neuropathy, the protocol of the present invention allows for reducing the dosage.

The preferred infusion schedule of the invention which does not exceed six hours of a taxol infusion generally allows recipients to be treated on an out-patient basis. This avoids expense involved in monitoring the patients for an entire 6 to 24-hour infusion duration; which generally requires that patients spend at least one night in a hospital or treatment clinic. The taxol infusions is preceded by premedication, and post-infusion monitoring and record keeping is recommended.

20 The invention allows the infusion direction to not exceed 6 hours, yet the infusion dosage provides the patient with sufficient taxol to have an anti-neoplastic effect, while not exceeding dose-limiting toxicities. It is also desirable to minimize premedication since this increases patient discomfort and increases the expense and duration of treatment.

The invention also avoids the high dosages of taxol presently believed necessary to have an anti-neoplastic effect, which induce a variety of adverse side-effects, including respiratory distress, cardiovascular irregularities, flu-like symptoms, gastrointestinal distress, hematologic complications, genitourinary 30 effects, neuropathy, alopecia, and skin rashes.

The invention also enable the effective use of reduced taxol dosages thereby extending the supply of taxol and reducing the toxic side effects of taxol.

The invention therefore improves the usage of the extremely limited supply of W:jeannie\speces\704393div.doc 21 taxol. This is particularly important as the demand for taxol greatly exceeds the supply.

Example relating to Treatment of Breast Cancer The invention was used in treatment of metastatic breast cancer (MBC) in a multcentre randomised trial.

A total of 471 patients with MBC were randomised and received an intravenous taxol dose of 175 or 135 mg/m 2 over a duration of three hours, every 3 weeks in accordance with the general procedure described above.

The overall response rate of the 175 mg/m 2 arm of the study was 29% compared with 22% 108) in the 135mg/m 2 arm. The complete response rate was 5% compared with 2% (P=0.088). Full details of the multicentre trial are given in the paper by Nabholtz et al, J. of Clin. Oncol., Vol. 14, No. 6 (1996) pp.

1858-1867.

Example of Treatment of Breast Carcinoma by Adjuvant therapy using Taxol This example refers to Figures 1 to 6 of the attached drawings.

*o 20 Phase 3 intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with taxol no further chemotherapy following four courses of doxorubicin and cyclophosphamide 0* 25 This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of three different dose levels of doxorubicin and to evaluate the effect of the addition of taxol administered following the completion of AC therapy. After S. 30 stratification for the number of positive lymph nodes 4-9, or patients were randomized to receive cyclophosphamide at a dose of 600 mg/m 2 and doxorubicin at doses of either 60 mg/m 2 (on day 75 mg/m 2 (in two divided doses on days 1 and or 90 mg/m 2 (in two divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for four courses and W:'jeanniespecies\704393div.doc 22 either taxol 175 mg/m 2 as a 3-hour infusion every 3 weeks for four additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.

At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen.

The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included taxol administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by taxol had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR] 0.78, 95% Cl 0.67-0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR 0.74, 95% CI 0.60-0.92, p=0.0065). For disease-free survival and overall survival, p values were not adjusted for interim analyses. Kaplan-Meier curves are shown in Figures 1 and 2. Increasing the dose of doxorubicin higher than 60 mg/m 2 had no effect on either disease-free survival or overall survival.

Subset analyses Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma were examined, including number of positive lymph nodes, 25 tumor size, hormone receptor status, and menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall study result. In general, a reduction in hazard similar to the overall reduction was seen with taxol (paclitaxel) for both disease-free and overall survival in all of the larger subsets Swith one exception; patients with receptor-positive tumors had a smaller reduction 30 in hazard (HR 0.92) for disease-free survival with taxol than other groups.

Results of subset analyses are shown in Table 6.

W:jeannie\speces\704393div.doc TABLE 6 SUBSET ANALYSES ADJUVANT BREAST CARCINOMA STUDY Disease-Free Survival Overall Survival Patient Subset No. of No. of Hazard Ratio No. of Hazard Ratio Patients Recurrences (95% CI) Deaths (95% CI) No of Positive Nodes 1-3 1449 4-9 1310 360 Tumor Size (cm) 2 1096 >2 and 5 1611 0.72 (0.55-0.94) 0.78 (0.61-0.99) 0.93 (0.66-1.31) 0.79 (0.57-1.08) 0.79 (0.64-0.97) 0.75 (0.51-1.08) 0.83 (0.67-1.01) 0.73 (0.57-0.93) 0.92 (0.73-1.16) 0.68 (0.55-0.85) 107 148 87 0.76 (0.52-1.12) 0.66 (0.47-0.91) 0.90 (0.59-1.36) 0.73 (0.45-1.18) 0.74 (0.56-0.98) 0.73 (0.46-1.16) 0.72 (0.54-0.97) 0.77 (0.56-1.06) 0.83 (0.59-1.18) 0.71 (0.54-0.93) Menopausal Status Pre 1929 Post 1183 Receptor Status Positivea 2066 Negative/ Unknownb 1055 a Positive for either estrogen or progesterone receptors b Negative or missing for both estrogen and progesterone receptors (both missing: These retrospective subgroup analyses suggest that the beneficial effect of taxol is clearly established in the receptor-negative subgroup, but the benefit in W:\eannie\spedes\704393div.doc 24 receptor-positive patients is not yet clear. With respect to menopausal status, the benefit of taxol is consistent (see Table 2 and Figures 3-6).

Example of treatment of Breast Cancer in Patients after Failure of Initial Chemotherapy Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with one or two regimens of chemotherapy. Patients were randomized to receive taxol (paclitaxel) at a dose of either 175 mg/ m 2 or 135 mg/ m 2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting the metastatic setting or both Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% Cl: 22 to with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4- 18.1+ months). Overall for the 471 patients, the median time to progression was 20 3.5 months (range: 0.03-17.1 months). Median survival was 11.7 months (range: 0-18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table.

•e* W:\jeannie\species\704393div.doc TABLE 7 EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY 175/3 135/3 (n=235) (n=236) -Response -rate (percent) 28 22 -p-value 0.135 Time to Progression -median (months) 4.2 -p-value 0.027 Survival -median (months) 11.7 10.5 -p-value 0.321 W:\jeannie\species\704393div.doc

Claims (19)

1. A method of treatment of a patient suffering breast cancer comprising administering taxol to the patient by intravenous infusion wherein the taxol is administered at a dose of from 135 mg/m 2 to 175 mg/m 2 over a duration not exceeding 6 hours.

2. A method of treatment according to claim 1 wherein taxol is administered in a dose of 135 mg/m 2

3. A method of treatment according to claim 2 wherein the dose of 135 mg/m 2 is administered over a duration of from 1 to 3 hours.

4. A method of treatment according to claim 2 wherein the dose of 135 mg/m 2 is administered over a duration of about 3 hours.

A method of treatment according to claim 1 wherein taxol is administered in a dose of 175 mg/m 2 20

6. A method of treatment of breast cancer comprising according to claim wherein the dose of 175 mg/m 2 is administered over a duration of from 1 to 3 hours.

7. A method of treatment according to claim 5 wherein the dose of 175 25 mg/m 2 is administered over a duration of about 3 hours.

8. A method of treatment of a patient suffering breast cancer comprising Sadministering taxol to the patient by intravenous infusion wherein the taxol is administered at a dose of from 135 mg/m 2 to 175 mg/m 2 over a 30 duration of from 1 to 3 hours and the patient has been treated with a premedication to reduce or eliminate hypersensitivity responses.

9. A method of treatment of a patient suffering breast cancer comprising administering taxol to the patient by intravenous infusion wherein the W:\eannie\species\704393div.doc r 27 taxol is administered at a dose of either about 135 mg/m 2 or about 175 mg/m 2 over a duration of about 3 hours and the patient has been treated with premedication to eliminate hypersensitivity responses.

10. A method according to claim 9 wherein taxol is administrated in a dose of 135 mg/m 2

11. A method according to claim 9 wherein taxol is administered in a dose of 175 mg/m 2

12. A method according to any one of claims 8 to 11 wherein the pre- treatment to alleviate hypersensitivity response is selected from one or more medications selected from the group consisting of steroids, antihistamines and H-2 receptor antagonists.

13. A method according to any one of claims 8 to 12 wherein the pre- treatment to alleviate hypersensitivity responses includes an H-2 receptor blocker selected from ranitidine, famotidine and cimetidine; a steroid selected from dexamethasone, hydrocortisone and prednisone; 20 and an antihistamine selected from diphenhydramine, clemastine and chloropheniramine.

14. A method according to claim 12 wherein the pre-treatment to alleviate hypersensitivity is selected from a combination of prednisone and 25 hydrocortisone, or dexemethisone and hydrocertisone in combination with at least one antihistamine and at least one H-2 receptor blocker.

15. A method according to any one of claims 9 to 13 wherein granulocyte colony stimulating factor is administered to patients after completion of 30 the taxol infusion.

16. A method according to claim 15 wherein the granulocyte colony stimulating factor is administered to the patient in a dose of 10Lpg per kilogram of bodyweight per day. W:ieannie\species\704393div.doc t- 28

17. A method according to claim 16 wherein the granulocyte colony stimulating factor is administered daily until bone marrow recovery produces a white blood cell count of at least 10,000 cells/mm 3 and a platelet count of more than 50,000/mm 3

18. A method according to any one of claims 9 to 18 wherein the taxol is administered in a vehicle which comprises polyethoxylated castor oil.

19. A method according to claim 18 wherein the vehicle comprises a mixture of dehydrated alcohol and polyethoxylated castor oil. DATED: 23 November, 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: BRISTOL-MYERS SQUIBB COMPANY 6* 0 0 *oe See *so e S *o W:\jeannie\species\704393div.doc