WO1993021938A1

WO1993021938A1 - Methods for treating cancer using high-dose epirubicin

Info

Publication number: WO1993021938A1
Application number: PCT/US1992/003451
Authority: WO
Inventors: Richard A. Gams; Ralph D. Reynolds; George W. Sledge
Original assignee: Adria Laboratories
Priority date: 1992-05-04
Filing date: 1992-05-04
Publication date: 1993-11-11
Also published as: AU1875292A

Abstract

The invention relates to methods for treatment of cancer in humans comprising the administration of high-dose epirubicin, preferably in amounts exceeding 120 mg/m2, together with the administration of an anti-myelosuppressive agent, such as G-CSF or GM-CSF. The invention further includes the administration of a cardioprotective agent in order to prevent or reduce the cardiotoxicity usually associated with administration of epirubicin. The preferred cardioprotective agent is dexrazoxane. The invention is particularly well suited for the treatment of breast cancer.

Description

METHODS FOR TREATING CANCER USING HIGH-DOSE EPIRUBICIN

TECHNICAL FIELD OF THE INVENTION

The invention relates to methods for treating cancer in humans using high-dose epirubicin alone or in combi¬ nation with cardioprotective and anti-myelosuppressive agents.

BACKGROUND

Epirubicin (.'-epidoxorubicin or ^Λ-epiadriamycin) is an anthracycline antibiotic closely related to the anthracycline antineoplastic drug, doxorubicin. Epirubicin differs from doxorubicin by the epimerization of the hydroxyl group in position of the aminosugar moiety. While the antitumor activity of epirubicin is comparable to doxorubicin, the therapeutic index for epirubicin is more favorable, resulting in less hematological and cardiac toxicity at equivalent dosage levels.

Doxorubicin is one of the most widely prescribed antitumor agents, and it possesses a broad spectrum of activity. However, the hematological and cardiac toxicity of doxorubicin limit its use. For example, the permitted cumulative dosage level of doxorubicin is only 550 mg/m² due to toxic effects on the heart, and for many patients, the tolerable cumulative dosage level is even lower. Doxorubicin is commonly administered at a dosage schedule of 60-75 mg/m² every three weeks, and is usually part of a regimen or combination therapy with other chemotherape βic agents, such as cyclophosphamide and 5-fluorouracil. Even at these dosage levels, doxorubicin exhibits a substantial degree of toxicity causing some cardiac failure and a relatively high incidence of bone marrow depression.

Epirubicin was developed with the hope of overcoming some of the toxic side effects associated with doxorubicin and has been the subject of considerable clinical study in recent years. In most cases, epirubicin demonstrated a comparable level of antineoplastic efficacy with doxorubicin, but showed a lower degree of toxicity, particularly at low dosage levels. At higher dosage levels, however, both the hematological and cardiac toxicities of epirubicin can also be dose limiting. A recent study of epirubicin cardiotoxicity in patients with advanced breast cancer concludes that cumulative doses of epirubicin above 1000 mg/m² pose a considerable risk of cardiotoxicity and death due to congestive heart failure. Nielsen et al.. Journal of Clinical Oncology. Vol. 8, No. 11, pp. 1806-10, (November 1990).

Epirubicin is a cytotoxic anthracycline antibiotic consisting of a naphthaceneguinone nucleus linked through a glycosidic bond to an aminosugar. The structural formula and methods for making epirubicin are disclosed in U.S. Patent No. 4,058,519, the disclosure of which is incorporated herein by reference.

Epirubicin's mechanism of action is believed to be similar to that of doxorubicin in binding to DNA and inhibiting nucleic acid synthesis. Thus, epirubicin is most lethal against the fast growing cells in the body, such as the tumor cells as well as the heart, bone marrow, the gastrointestinal tract and the skin.

While at the time of filing this application, epirubicin is not yet approved for general use in the United States, epirubicin has been the subject of numerous clinical trials. Phase II and Phase III studies have shown epirubicin to have antitumor activity against several tumor types. These include carcinoma of the breast, lymphoma, carcinoma of the lung, leukemia, multiple myeloma, ovarian carcinoma, head and neck cancer, malignant melanoma, sarcoma, endometrial carcinoma, cervical carcinoma, urinary bladder cancer, prostatic carcinoma, testicular cancer, esophageal carcinoma, gastric carcinoma, hepatocellular carcinoma, pancreatic carcinoma, and colorectal carcinoma.

Acute toxicity and clinical studies have demonstrated the dose-limiting toxicity to be primarily due to myelotoxicity. Neutropenia is the most common manifestation of myelotoxicity, and infection is the complication that leads to life-threatening clinical experiences. Anemia and thrombocytopenia are less significant manifestations of myelotoxicity. Mucositis, nausea and vomiting are other serious toxicities related to the acute toxicity syndromes. Other severe acute toxicities include allergic reactions and extravasation injuries. Moreover, with increasing cumulative doses of epirubicin, cardiotoxicity becomes significant.

Various Phase I trials have reported the maximum tolerated dose (WTO) of epirubicin to be over a wide range of dosages. When doses of less than 50 mg/m² are given at three week intervals, very few patients experience significant toxicity. Many Phase II trials have used doses between 60 and 80- mg/m² and report the MTD to be in this range because of dose-limiting toxicity attributed to myelosuppression. Subsequent Phase I trials have focused on higher dosage levels and, based on the lack of significant degrees of myelotoxicity, have concluded that the MTD is actually somewhere between 120 and 180 mg/m². At these dosage levels, mucositis and life-threatening infections are significant. Perhaps the most commonly used dosage level in Phase II trials on epirubicin has been 90 mg/m², although doses of 120 mg/m² and higher have also been investigated.

One high-dose study by Walde et al. on a limited number of previously untreated patients with advanced metastatic cancer shows that epirubicin is active against advanced solid tumors and is tolerated at a recommended dose of 135 mg/m² every three weeks. Although dosage levels of 165 and 180 mg/m² were tried in the study, at these levels, myelosuppression was reported to be severe resulting in low median nadirs for granulocytes and platelets. D. Walde et al. "High-dose Epirubicin in Previously Untreated Patients With Advanced Metastatic Cancer: A Phase I Study", ASCO Proceedings, Vol. 7, p»73, (March 1988) . Other Phase I studies have agreed with these results. Karp et al. conducted a Phase I trial and concluded that the maximum tolerated dose of epirubicin was 150 mg/m² every three weeks. At this dose level, however, the patients developed severe leukopenia and sepsis. Three of the ten patients receiving 150 mg/m² died. Karp et al., "A Phase I Trial of High-Dose Epirubicin in Advanced Cancer", ASCO Proceedings. 8:A 325 (1989). In a study by Blackstein et al. , the results again showed a maximum tolerated dosage of 150 mg/m², but at this dosage level, febrile neutropenia occurred in half of the patients. Blackstein et al. , "Phase I Study of Epirubicin in Metastatic Breast Cancer", ASCO Proceedings, 7:A 87 (1988) . The results of these and other studies show the potential anti-tumor benefit of higher doses of epirubicin, but the problems of cardiac and hematological toxicity still remain. In order for high-dose epirubicin to be clinically useful, the toxicity concerns must be adequately addressed. The present invention addresses both the hematological and cardiac toxicities associated with epirubicin and allows the use of high-dose epirubicin to achieve remarkable results in cancer treatment.

SUMMARY OF THE INVENTION

The invention relates to methods of treating cancer in humans using relatively high doses of epirubicin preferably in combination with cardioprotective and/or anti-myelosuppressive agents. In practicing the invention, it is preferred that the dosage level of epirubicin be at least about 120 mg/m², more preferably at least 150 mg/m², and most preferably at least about 180 mg/m². This high-dose epirubicin treatment is preferably administered once in a cycle that is repeated on a schedule depending on the tolerance and state of the patient but typically is about every three weeks. A preferred use of the claimed invention, and one for which it has shown remarkable results, is in the treatment of breast cancer.

In order to counteract the myelosuppression associated with the administration of high-dose epirubicin, the invention includes the administration of an anti-myelosuppressive agent at some point during the treatment cycle. These anti-myelosuppressive agents stimulate or protect hematopoietic cells thereby reducing the toxic effects and quickening the systemic recovery after each treatment of high-dose epirubicin. The pre erred anti-myelosuppressive agents include granulocyte colony stimulating factor (G-CSF) and granulocyte- macrophage colony stimulating factor (GM-CSF) and such similar acting agents. The preferred dose of G-CSF or GM-CSF is 1 - 15 μg/kg/day, and more preferably 5 - 10 μg/kg/day. The administration of G-CSF or GM-CSF is commenced preferably no earlier than 24 hours after the administration of high-dose epirubicin and is given each day thereafter until the desired hematological recovery is obtained. A suggested treatment cycle is the administration of high-dose epirubicin on day l and the administration of the anti-myelosuppressive agent on days 2-12, or longer if necessary until the absolute granulocyte count is above a certain minimum level such as 1500/μl. This cycle can then be repeated every three weeks or as soon as the patient can again tolerate the epirubicin treatment.

In order to overcome the cumulative toxicities associated with the administration of high-dose epirubicin, the invention further comprises the administration of effective amounts of cardioprotective agents at some point during the treatment cycle. The use of cardioprotective agents permits the extended administration of high-dose epirubicin so as to fully exploit the antitumor properties of epirubicin without being limited by the cumulative dosage level. The preferred cardioprotectors are chelating agents of the bis-piperazinedione family with the particularly preferred agents being two compounds identified as razoxane (also known as ICRF 159) and dexrazoxane (also known as ADR-529 and as ICRF 187) with the use of dexrazoxane being especially preferred. These compounds have demonstrated an ability to block the destruction of heart tissue caused by epirubicin. When dexrazoxane is used, the preferred dosage level is about 1 - 15 times, and most preferably, about 5 - 10 times the amount of epirubicinon on a weight basis. The preferred treatment schedule is to administer dexrazoxane within thirty (30) minutes prior to the initiation of epirubicin administration.

The use of the cardioprotective and anti- myelosuppressive agents, in conjunction with high-dose epirubicin, provides a superior response rate while minimizing the toxicities associated with the administration of high-dose epirubicin. DETAILED DESCRIPTION

It has been discovered that the use of high-dose epirubicin provides surprising response rates in the treatment of cancer. It is believed that, as compared to doxorubicin, the high individual dose, as well as the extended treatment program, contribute to the increased level of response. The use of high-dose epirubicin in combination with an anti-myelosuppressive agent and with a cardioprotective agent is the preferred practice of the invention.

Epirubicin differs from doxorubicin by the inversion or epimerization of the hydroxyl group at the 4'-position of the amino sugar moiety. This inversion gives the hydroxyl group an equatorial orientation, rather than the axial orientation present in doxorubicin. Recent studies have di fered as to why this change in orientation would result in different properties, including less toxicity for epirubicin. One reliable study concludes that epirubicin is metabolized by an additional pathway as compared with doxorubicin resulting in a more efficient and faster elimination of epirubicin and suspected toxic derivatives from the plasma. As described by Camaggi et al.. Cancer Chemother. Pharmacol.. Vol 21(3): 221-28 (1988) , the hydroxyl group in the 4' position of the aminosugar conjugates with glucuronic acid, and the glucuronide of epirubicin is the major metabolite found in the plasma. The lower toxicity of epirubicin compared with doxorubicin is due to this additional metabolic pathway. Initially, epirubicin was studied at the same dosage levels as used for doxorubicin, i.e., about 30 - 80 mg/m². The initial Phase I studies, which have the purpose of defining a maximum tolerated dose (MTD) , concluded that the MTD was at various levels, with the highest being about 90 - 100 mg/m² administered every three weeks. As interest in the possibility of using higher doses of epirubicin increased, new Phase I studies were performed that concluded the MTD was higher than previously thought. Each subsequent study produced different results depending upon the factors used to determine the MTD. Generally, the studies concluded that the recommended dosage level be limited to about 120 - 135 mg/m² because of the increasing hematological toxicities found at the higher levels.

Doxorubicin is sold with the warning that "serious irreversible yocardial toxicity with delayed congestive failure often unresponsive to any cardiac supportive therapy may be encountered as total dosage approaches 550 mg/m²." In fact, the total cumulative dose administered to patients usually does not exceed 400 mg/m² because of the cardiac toxicity concerns. This limits the number of treatments and the duration of the therapy. While the definitive cumulative dosage level of epirubicin has not been determined, it is believed to be upwards of 1,000 mg/m². Thus, the lower toxicity of epirubicin provides for nearly double the number of treatments as compared with doxorubicin.

As an example of the superior results obtained by practicing the present invention, high-dose epirubicin at a dose of 180 mg/m² was administered as first-line therapy to patients having advanced breast cancer. The patients received, on average, seven courses of the high-dose epirubicin, with each course administered every three weeks, but allowing additional time, if necessary, for the patient to sufficiently recover from the hematological effects of the previous treatment. The overall response rate from 20 patients was 85%, including six complete responses and eleven partial responses. However, one patient who received a cumulative epirubicin dose of 1150 mg/m² suffered clinical congestive heart failure. Further, myelosuppression was severe, as seven patients required hospitalization due to fevers. The median absolute granulocyte nadir was 300 and the median maximum platelet nadir was 74,000.

In order to minimize these toxicities, the invention further comprises the use of a cardioprotective agent and an anti-myelosuppressive agent. The use of these agents, in conjunction with high-dose epirubicin, over the course of a series of treatments, provides a high response rate, while minimizing the toxic side effects on the patient. Numerous compounds have been studied as potential cardioprotective agents, but the only compounds that have demonstrated any level of success are dexrazoxane and razoxane. These compounds are chelating agents of the bispiperazinedione family that chemically resemble ethylenediaminetetraacetic acid (EDTA) . The preparation of dexrazoxane and razoxane is described in U.S. Patent No. 3,941,790, the disclosure of which is incorporated herein by reference. Razoxane has the formula (±)-(S)- 4,4'-propylenedi-2,6-piperazinedione. Dexrazoxane is the (+) enantiomer of razoxane, and since dexrazoxane is more water soluble than razoxane, dexrazoxane is the preferred isomer for use in parenteral injections. If razoxane is used, it should be administered orally. In Phase I trials, dexrazoxane exhibited a maximum tolerated dose of about 4000 mg/m² with the limiting toxic effect being leukopenia.

Early animal studies using dexrazoxane in combination with doxorubicin resulted in reduced cardiomyopathy in various types of animals. The other toxic effects of doxorubicin, however, such as alopecia, mucositis, and myelosuppression, were not reduced. From these studies, it was determined that dexrazoxane could be used as a cardioprotective agent with doxorubicin without increasing the systemic toxicities if the drugs were administered to the subject within a short period of time of each other. _ Dexrazoxane has demonstrated a remarkable ability to reduce the cardiac toxicity in humans associated with the administration of anthracyclines. Speyer and Green et al. tested the cardioprotective effect of dexrazoxane (identified as ICRF 187) when used in conjunction with a combination regimen of fluorouracil, doxorubicin and cyclophospha ide (FDC) . Speyer et al., N. Engl. J. Med.. 319:745-52 (September 1988). The results showed that those patients receiving FDC and dexrazoxane received a mean cumulative dose of doxorubicin of 466.3 mg, with eleven of those patients receiving cumulative doses of doxorubicin doses above 600 mg/m². In contrast, the mean cumulative dose for those patients receiving only FDC was 397.2 mg/m² and only one patient was able to receive FDC beyond a dose of 600 mg/m² of doxorubicin. The antitumor response rates between the two groups were almost identical and the indications of noncardiac toxicity were not significantly different between the two groups. Importantly, dexrazoxane demonstrated the ability to provide cardioprotection. Eight of the patients receiving FDC had a resting left ventricle ejection fraction (LVEF) that fell below the normal range, while only one patient in the FDC + dexrazoxane group had a lowering of the LVEF. Other indications of cardiac toxicity also demonstrated the ability of derazoxane to protect the heart during administration of doxorubicin.

As part of the present invention, the use of derazoxane, or such similar cardioprotective agent allows the administration of epirubicin to cumulative approaching, and even exceeding, 1000 mg/m² while minimizing the associated cardiotoxicity. Dose levels of dexrazoxane are between 500-4000 mg/m² by intravenous administration (i.v.) repeated every three weeks. Dexrazoxane is available in a lyophilized form which must be reconstituted prior to administration. Dexrazoxane does exhibit a modest myelosuppressive effect, and in that sense, its effect is additive to that of epirubicin.

The invention further comprises the administration of anti-myelosuppressive agents. Again, many compounds have been studied for this effect, but the preferred compounds are the granulocyte colony stimulating factor (G-CSF) and the granulocyte macrophage colony stimulating factor (GM-CSF) . The use of one or both of these compounds with high-dose epirubicin provides a significant reduction in the hematological toxicity associated with high-dose epirubicin.

One form of G-CSF, also known as filgrastim, is marketed under the trademark NEUPOGEN^® by Amgen Inc. and is sold as a sterile, colorless, preservative-free liquid that can be administered intravenously or subcutaneously. G-CSF is produced through use of recombinant DNA technology from Eschrichia coli bacteria into which has been inserted the gene for human granulocyte colony stimulating factor. G-CSF produced in this manner, has the same amino acid sequence as G-CFS isolated from a human cell, but is non-glycosylated.

While the mode of anti-myelosuppressive action is not critical to the invention, it is believed that colony stimulating factors act on hematopoietic cells by binding to specific cell receptors, stimulating proliferation of the cell and promoting other cell activity. G-CSF is selective for the neutrophil lineage and has been shown to affect neutrophil progenitor proliferation, differen¬ tiation and selected end-cell functions and activation. In humans, administration of G-CSF at doses within the range of 1 - 40 μg/kg/day produces an increase in the number of peripheral blood neutrophils by up to tenfold with no significant change in hemoglobin or lymphocyte and platelet counts. Moreover, it has been reported that administration of G-CSF following.doxorubicin injections resulted in the return of the absolute neutrophil count to normal or above normal levels within 12 - 14 days, thereby shortening the time periods between treatments.

The package insert for NEUPOGEN^® recites that NEUPOGEN^® has been shown to be safe and effective in accelerating the recovery of neutrophil counts following the administration of a variety of chemotherapy regimens, and it cites several Phase I and Phase II studies using NEUPOGEN^®. Some of these regimens included doxorubicin at a relatively low dosage level, and one included doxorubicin as the sole chemotherapy agent. The latter doxorubicin study was performed by Bronchud et al. , who administered doxorubicin at dosages of 75, 100, 125 and 150 mg/m² every two weeks. Except for those patients receiving 150 mg/m², all the patients received three cycles, while those receiving 150 mg/m² received only two. Thus, the treatment lasted, at most, for only six weeks, with a maximum cumulative dosage of 375 mg/m². The dosage level for NEUPOGEN^® was 11.5 μg/kg/day for days 2-9 and 5.75 μg/kg/day for days 10-11. Bronchud et al., British Journal of Cancer. 60:121-28 (1989). Bronchud's results showed that the absolute neutrophil counts rose to normal ' or above normal levels by days 12-14 at all dose levels of doxorubicin, while an absolute neutrophil count greater than 2.5 x 10⁹/1 was not reached until day 19-21 for those patients who received 75 mg/m² of doxorubicin without G- CSF. Further, the nadir occurred most typically on day 7 after chemotherapy with the administration of G-CSF, and on days 12-13 when G-CSF.was not given. Bronchud's study was limited and does not provide any suggestion of success in using G-CSF with epirubicin at the doses contemplated in the present invention. Specifically, the invention contemplates providing treatment with epirubicin for a cumulative dosage much higher than 375 mg/m². For doxorubicin, this amount is approaching the cumulative limit due to cardiac toxicity, and undoubtedly, that is why Bronchud only performed two or three cycles of treatment. In contrast, in practice of the present invention, epirubicin can be administered at higher doses for more than three cycles, thereby increasing the concentration and the duration of the treatment.

GM-CSF is a granulocyte-macrophage colony stimulating factor and is also known by the name sargramostim. This product is manufactured by Immunex Corporation of Seattle, Washington, and is distributed by Hoechst-Roussel under the tradename PROKINE™. Like G-CSF, GM-CSF is produced by recombinant DNA technology in a yeast expression system. GM-CSF is also a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. While not critical to the practice of the invention, it is believed that GM-CSF induces division and differentiation of cells in the granulocyte-macrophage pathways, as well as activating matured granulocytes and macrophages.

Prokine™ is available as a sterile, white preservative-free lyophilized powder and is reconstituted with sterile water for injection prior to administration. The recommended dosage for Prokine™ is 250 μg/m²/day for 21 days as a two-hour infusion, beginning not less than 24 hours after the last dose of chemotherapy.

Several clinical studies have shown that GM-CSF is effective in reducing hematological toxicity associated with the administration of anthracyclines. In a study by O'Shaughnessy et al., GM-CSF was given in combination with a regimen of fluorouracil, leucovorin, doxorubicin and cyclophosphamide. The dosage level of doxorubicin was only 15 mg/m²/day for days 1-3, repeated every three weeks. The patients were treated with 10 μg/kg/day of GM-CSF on days 4-17. The preliminary results showed that GM-CSF was effective in ameliorating the hematological toxicities. ASCO Proceedings. 9:A180 (1990)

In another study by Speyer et al. , the regimen of doxorubicin administration was combined with ICRF 187 and GM-CSF. ICRF 187 was administered at a 20:1 ratio of doxorubicin, while GM-CSF was given at a dosage of 15 μg/kg. Speyer et al., ASCO Proceedings. 9:A161 (1990). The results were negative in that eight of the nine patients had fevers and exhibited other forms of significant toxicities, some of which were attributed to the GM-CSF. Again, these studies do not suggest the use of high-dose epirubicin, and the successes to be gained by such use, in combination with a proper dose of dexrazoxane and anti-myelosuppressive agents such as G-CSF and GM-CSF. In the practice of the present invention, epirubicin may be used alone as a single chemotherapeutic agent or as part of combination chemotherapy with other agents such as cyclophosphamide and/or fluorouracil. The manner of administration for epirubicin parallels that practiced for doxorubicin except for the difference' in dosage levels. The present invention contemplates the use of high doses of epirubicin, meaning the. administration of about 120 - 180 mg/m², or higher, up to levels as high as 250 or 300 mg/m², and most preferably 180 mg/m² or higher. This treatment is preferably repeated every three weeks or upon such conditions as the patient may tolerate the administration of high-dose epirubicin.

According to the present invention, a preferred treatment plan for treating cancer in humans includes the administration through intravenous infusion of high-dose epirubicin, at a dose of about 120 - 180 mg/m² _f and most preferably at 180 mg/m². Preferably, this infusion is accomplished within 30-60 minutes. In a preferred embodiment, the epirubicin administration should follow immediately after administration of the cardio-protective agent, preferably dexrazoxane, has been completed. Initiation of the dexrazoxane administration should not begin more than thirty minutes prior to the initiation of the treatment with epirubicin. Dexrazoxane can be administered in an amount equal to about 1 - 15, preferably 1 - 10 and more preferably about 5 - 10, times the amount of epirubicin on a weight basis. Thus, if epirubicin is administered at a dose of 180 mg/m², then the more preferred range of doses for dexrazoxane is 900- 1800 mg/m². The most preferred amount of dexrazoxane is equal to about 5 times the amount of epirubicin on a weight basis. The dexrazoxane administration can be by either slow push i.v. or rapid-drip infusion.

On the day following the administration of epirubicin and dexrazoxane, the anti-myelosuppressive agents can be administered subcutaneously or by intravenous infusion, preferably no sooner than 24 hours after the completion or epirubicin administration. The administration should be repeated preferably for the next eleven days or longer, if necessary, to raise the absolute granulocyte count above a certain desired minimum level such as 1500/μl. The amount of anti-myelosuppressive agent to be administered may vary, but when using G-CSF or GM-CSF, the preferred amount is 1 - 15 μg/kg/day, and more preferably 5 - 10 μg/kg/day. The actual dosage levels and treatment schedules will vary depending upon the severity and type of cancer, as well as the age, weight, health and fitness of the patient. The courses are preferably repeated every three weeks or sooner, provided that recovery from toxicity has occurred. Patients can remain on the therapy for as many as nine courses or more, or until a toxicity develops that precludes further therapy. As with all chemotherapy treatments, the patient should be monitored and dose reductions or delays in treatment be made if any severe level of toxicity is demonstrated. While the invention may be applied to various forms of cancer in humans, breast cancer is a particular cancer for which the invention is well suited. The preferred dosage levels for treatment of breast cancer are 180 mg/m² of epirubicin, 900 mg/m² of dexrazoxane, and 5 μg/kg/day of G-CSF. This course may be given every three weeks for as many as nine courses or more. The patient should be carefully monitored for toxicities throughout the treatment and particularly so as cumulative doses of epirubicin approach and exceed 1000 mg/m². Applying the methods of the invention, response rates to the cancer treatment can be as high as 85% or higher as seen in a sampling of patients having breast cancer.

Claims

WHAT XS CLAIMED:

1. A method for treating cancer in a human, comprising: administering epirubicin to said human at dose levels of at least about 120 mg/m²; and administering an effective amount of an anti- myelosuppressive agent.

2. The method of Claim 1 wherein the dose level of epirubicin is at least about 150 mg/m².

3. The method of Claim 1 wherein the dose level of epirubicin is about 150 - 180 mg/m².

4. The method of Claim 1 wherein the anti- myelosuppressive agent is G-CSF or GM-CSF.

5. The method of Claim 1 wherein the anti- myelosuppressive agent is G-CSF and is administered in an amount of about 1 - 15 μg/kg/day.

6. The method of Claim 5 wherein the amount of G- CSF is about 5 μg/kg/day.

7. A method for treating cancer in a human, comprising: administering epirubicin in an amount of at least about 120 mg/m²; administering an effective amount of anti- myelosuppressive agent; and administering an effective amount of a cardioprotective agent.

.

8. The method of Claim 7 wherein the dose level of epirubicin is at least about 150 mg/m².

9. The method of Claim 7 in which the anti- myelosuppressive agent is G-CSF or GM-CSF.

10. The method of Claim 7 wherein the anti- myelosuppressive agent is G-CSF and is administered in an amount of about 1 - 15 μg/kg/day.

11. The method of Claim 10 in which the amount of G- CSF is about 5 μg/kg/day.

12. The method of Claim 7 wherein the cardio¬ protective agent is dexrazoxane or razoxane.

13. The method of Claim 12 wherein the effective amount of the cardioprotective agent is equal to about 1 - 10 times the amount of epirubicin administered on a weight basis.

14. The method of Claim 7 wherein the cardioprotective agent is dexrazoxane and is administered in an amount equal to about 5 times the amount of epirubicin administered on a weight basis.

15. A method for treating breast cancer in a human, comprising: administering epirubicin at dosage levels of at least about 120 mg/m²; administering effective amounts of an anti- myelosuppressive agent selected from the group consisting of G-CSF and GM-CSF; and administering an effective amount of dexrazoxane.

16. The method of Claim 15 wherein the epirubicin is administered at a dosage level of about 180 mg/m².

17. The method of- Claim 15 wherein the dexrazoxane is administered in an amount equal to about 5 - 10 times the amount of epirubicin administered on a weight basis.

18. The method of Claim 15 wherein the anti- myelosuppressive agent is administered in an amount of about 5 - 10 μg/kg/day.

19. The method of Claim 18 wherein dexrazoxane is administered in an amount equal to about 5 - 10 times the amount of epirubicin administered on a weight basis

20. The method of Claim 15 wherein the dexrazoxane is administered first followed by the administration of epirubicin and then the antimyelo-suppressive agent.