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Phase I Trial of Pegylated Liposomal Doxorubicin and Docetaxel in Advanced Breast Cancer

From the Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Bronx, NY, and Winship Cancer Center, Emory University School of Medicine, Atlanta, GA.

Address reprint requests to Joseph A. Sparano, MD, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Department of Oncology-2 South, Rm 47, 1825 Eastchester Rd, Bronx, NY 10461-2373.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To develop a combination of pegylated liposomal doxorubicin (Doxil; Alza Pharmaceuticals, Palo Alto, CA) and docetaxel (Taxotere; Aventis Pharmaceutical, Parsipanny, NJ) that can be safely used for the treatment of advanced breast cancer.

PATIENTS AND METHODS: Forty-one patients with locally advanced (n = 10) or metastatic (n = 31) breast cancer received Doxil (30-, 40-, or 45-mg/m² intravenous [IV] infusion over 30 to 60 minutes), followed 1 hour later by docetaxel (60 or 75 mg/m² by IV infusion over 1 hour) in cohorts of three to six patients. Dose-limiting toxicity (DLT) was defined as febrile neutropenia, prolonged neutropenia, or grade 3 to 4 nonhematologic toxicity that occurred during cycle 1.

RESULTS: In conjunction with docetaxel 75 mg/m² every 4 weeks, the MTD of Doxil was 30 mg/m² and required granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. Without G-CSF, the MTD was docetaxel 60 mg/m² and Doxil 30 mg/m² every 3 weeks; only 1 (7%) out of 15 patients treated at this dose level had cycle 1 DLT. Infusion reactions were common with Doxil with the recommended infusion schedule during the first cycle (55%) but were reduced with a modified schedule (7%). There was no clinically significant cardiac toxicity. Objective response occurred in eight of nine assessable patients with stage III disease and in 16 (52%) of 31 patients (95% confidence interval, 34% to 70%) with stage IV disease.

CONCLUSION: The recommended dose and schedule of this combination for further evaluation is Doxil 30 mg/m² and docetaxel 60 mg/m² given every 3 weeks without G-CSF. When used with G-CSF, it is Doxil 30 mg/m² and docetaxel 75 mg/m² every 4 weeks.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE ANTHRACYCLINES (ie, doxorubicin and epirubicin) and the taxanes (ie, paclitaxel and docetaxel) are the most active cytotoxic agents for the treatment of metastatic breast cancer.¹ A pooled analysis of randomized trials conducted in the pretaxane era demonstrated that doxorubicin-containing regimens resulted in a higher response rate and improved survival in patients with metastatic breast cancer.² Regarding early-stage disease, the Breast Cancer Trialists’ meta-analysis demonstrated a modest improvement in survival when doxorubicin was used as a component of adjuvant therapy.³

More recently, the taxanes have proved to be effective agents for patients with metastatic breast cancer who have failed doxorubicin-based therapy.^4,5 The taxanes induce cytotoxicity by binding to tubulin, promoting microtubule assembly and inhibiting microtubule depolymerization.⁶ In addition, they effect various other biologic processes that may contribute to their antineoplastic activity, such as inducing apoptosis⁷ and inhibiting angiogenesis,⁸ invasiveness,⁹ cell motility, and metalloproteinase production.¹⁰ Given their antitumor activity, differing mechanism of action, and partially nonoverlapping toxicity profiles, there has been considerable interest in combining anthracyclines with taxanes for the treatment of breast cancer and other neoplasms. For example, the addition of paclitaxel after doxorubicin-cyclophosphamide in early-stage breast cancer was shown to significantly reduce the risk of relapse and improve survival.¹¹ In addition, several phase III trials in metastatic breast cancer have demonstrated improved response rate and time to disease progression for doxorubicin-taxane combinations compared with doxorubicin-based regimens without taxanes.^12,13

Although there is considerable information regarding the combination of doxorubicin and taxanes, there is little information regarding the use of liposomal anthracyclines and taxanes. Liposomes are closed vesicular structures that are capable of enveloping water-soluble molecules and were initially described in the 1960s.¹⁴ They may serve as a vehicle for delivering cytotoxic agents more specifically to tumor and for limiting exposure of normal tissues to the drug. Doxil (Alza Pharmaceuticals, Palo Alto, CA) is a pegylated form of liposomal doxorubicin that is 85 nm in size. Its liposome consists of cholesterol, fully hydrogenated soy phosphatidylcholine, and the polyethylene glycol preparation N-[carbamoyl]- methoxypolyethylene glycol 2000-1,2-dis-tearoylsn-glycero-3-phosphoethanolamine sodium salt. Relative to conventional doxorubicin, Doxil has a very limited volume of distribution (2.5 to 3 L/m² v 240 to 690 L/m²) because of its confinement to the vascular space, slower clearance from the circulation (0.04 L/h/m² v 27.5 to 59.6 L/h/m²), prolonged beta half-life (55 hours v 0.43 to 2.0 hours), and approximately three-fold greater area under the curve.¹⁵ Preclinical data suggest that this preparation may preferentially localize to tumorous tissue in a variety of animal models, including a mouse mammary carcinoma¹⁶ and lymphoma model,¹⁷ a brain tumor model,¹⁸ a colon carcinoma xenograft,¹⁹ and human xenografts of prostate,²⁰ ovarian,²¹ and lung carcinoma.²² Some clinical studies in humans have shown better tumor localization and penetration in solid tumors,²³ Kaposi’s sarcoma,²⁴ malignant effusions,²⁵ and metastatic bone lesions from breast cancer²⁶ (as reviewed in²⁷). Phase III studies in patients with Kaposi’s sarcoma have indicated that Doxil produces less nausea, vomiting, alopecia, and stomatitis than conventional doxorubicin-containing regimens,^28,29 and other studies have demonstrated that Doxil is less cardiotoxic than conventional doxorubicin.^30,31 Several studies have evaluated Doxil for the treatment of metastatic breast cancer by using a variety of doses and schedules, with objective response reported in 38% in one series with 42 patients³² and 31% in another series with 71 patients.³³

In the trial that forms the basis for this article, we sought to determine the maximum-tolerated dose (MTD) of Doxil that could be safely used in combination with docetaxel (Taxotere; Aventis Pharmaceutical, Parsipanny, NJ) and to determine the efficacy of this combination in patients with locally advanced and metastatic breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients were required to have histologically confirmed adenocarcinoma of the breast with manifestations of progressive regional or metastatic disease that was measurable or assessable. Other requirements included an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; normal organ function (ie, normal total bilirubin and AST 2.5-fold the upper limits of normal, neutrophil count 1,500/µL, and platelet count 100,000/µL); a normal left ventricular ejection fraction (LVEF) as measured by radionuclide angiography; and no symptomatic or untreated brain metastases. Patients were allowed to receive up to one prior regimen for metastatic disease as long as it did not contain an anthracycline or taxane. Prior adjuvant doxorubicin (up to 400 mg/m²) or taxane therapy was permitted, as was prior hormonal therapy. All patients were required to provide written informed consent, and the protocol was approved by the institutional review boards at each participating institution. Doxil was provided by Alza Corporation at no cost to patients participating in this study.

Treatment Plan
Groups of three to six patients received Doxil (30 mg/m² at the first dose level, 40 mg/m² at the second dose level, and 45 mg/m² at the third dose level) by intravenous (IV) infusion over 60 minutes during the first cycle, then 30 minutes for subsequent cycles, followed 1 hour later by Taxotere (75 mg/m²) given by IV infusion over 1 hour. Doxil was diluted in either 250 mL (for doses < 90 mg) or 500 mL (for doses at least 90 mg) of 5% dextrose and infused via a catheter that had been flushed or was infusing 5% dextrose. Dexamethasone (8 mg orally bid) was given for 3 days beginning 1 day before each treatment cycle, and diphenhydramine (25 mg) was given IV before the Doxil. Patients received the combination every 3 or 4 weeks (see below) if the neutrophil count was 1,500/µL, the platelet count was 100,000/µL, and the patient had recovered from nonhematologic toxicity to grade 1. Granulocyte colony-stimulating factor (G-CSF), when used (see below), was given as a subcutaneous daily dose of 5 µg/kg/d beginning on day 5 and continuing until the postnadir neutrophil count was 10,000/µL. Complete blood counts were obtained twice weekly, beginning on day 8 of each cycle. The dose of both drugs was reduced by 25% if the patient met the criteria for dose-limiting toxicity (DLT; see below) in any cycle. Patients continued treatment until administration of the maximum cumulative doxorubicin dose (500 to 550 mg/m², including prior doxorubicin and Doxil), prohibitive toxicity, progressive disease, or achievement of maximal response. Patients with responding disease were permitted to continue docetaxel alone (100 mg/m² every 3 weeks) at the discretion of the treating physician.

Criteria for Dose Escalation and Definition of DLT
Patients were treated in cohorts of three to six per group by using a standard phase I design. If none of three patients had DLT during cycle 1, the Doxil dose was escalated. If one of three had cycle 1 DLT, then three additional patients were treated at the same dose level, and further escalation was permitted if one of six had cycle 1 DLT. The MTD was considered one dose level below which two of three or two of six patients had cycle 1 DLT. DLT was defined as febrile neutropenia (fever 100.4°F plus neutrophil count < 1,000/µL), prolonged neutropenia (< 500/µL for > 7 days), severe thrombocytopenia (< 25,000/µL), or grade 3 nonhematologic toxicity.

Dose escalation of Doxil occurred initially with a fixed dose of docetaxel (75 mg/m²) by using the every-4-week schedule without G-CSF (group A), then with G-CSF when neutropenia was found to be dose limiting (group B). After achieving the MTD, 12 additional patients (group C) were treated at the MTD identified in group B (Doxil 40 mg/m² and docetaxel 75 mg/m² plus G-CSF every 4 weeks). Despite observing no DLTs among three patients treated at this dose level in group B, six of 12 patients treated at the same dose level in group C had cycle 1 DLTs. For this reason, the protocol was subsequently modified to include 15 additional patients (group D) treated with Doxil (30 mg/m²) plus docetaxel (60 mg/m²) without G-CSF every 3 weeks.

Schedule for Tumor Evaluation and Criteria for Response
All patients had all sites of measurable or assessable disease recorded within 2 weeks of registration, after cycles 4 and 8 of the combination, and then every 3 months thereafter until disease progression. Computed tomography of the chest and abdomen, bone scan, and skeletal radiographs (if the bone scan was abnormal) were required at baseline in all patients. All studies were repeated at the indicated times if the baseline study demonstrated measurable or assessable disease. The Eastern Cooperative Oncology Group response criteria were used to define response.³⁴ Response duration, time to treatment failure, and survival were estimated with the Kaplan-Meier method.³⁵ Response duration was measured from the day the patient was first documented to have at least 50% tumor volume reduction until the time of disease progression. Time to progression was defined as time from registration to tumor progression. Patients who died while on study without progression or shortly after going off study without progression were considered treatment failures. Patients without progression were censored at the last time known to be in remission or stable. Patients unassessable for response were censored at zero.

Monitoring for Cardiac Toxicity
All patients had an ECG, chest x-ray, and assessment of the LVEF (by radionuclide angiography or ECG) within 6 weeks before therapy and after receiving a cumulative Doxil dose of 300 mg/m² and/or after completing Doxil therapy.

Statistical Considerations
A standard phase I trial design was used with three to six patients per cohort³⁶; this permitted only a 17% likelihood of escalating to the next dose level if the true rate of underlying DLT was 50%. The number of patients treated at the MTD was expanded to 12 to 15 patients to more accurately characterize the incidence of grade 3 to 4 toxicities.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Forty-one patients were enrolled between August 1997 and May 2000 at either the Albert Einstein Comprehensive Cancer Center (n = 37) or the Winship Cancer Center (n = 4). The characteristics of these patients are listed in Table 1. The median age was 52 years (range, 32 to 83 years). Ten had stage IIIA (n = 1) or IIIB (n = 9) disease, and 31 had metastatic disease. Fourteen patients (34%) had prior adjuvant chemotherapy, nine patients (22%) had prior adjuvant doxorubicin, and four patients (10%) had prior chemotherapy for metastatic disease.

Because of unacceptably high rate of toxicity in group C, the protocol was modified to permit treatment of 15 additional patients with Doxil (30 mg/m²) and docetaxel (60 mg/m²), a dose and schedule that we thought would be tolerable without adjunctive G-CSF (group D). Of the 15 patients treated at this dose level, only one patient experienced a cycle 1 DLT that consisted of grade 3 mucositis.

Overall Toxicity
A total of 222 assessable treatment cycles were administered on protocol, including 213 cycles of the combination and nine cycles of single-agent docetaxel. Patients received a median of six cycles of the combination (range, one to 12 cycles). Of the 213 cycles of the combination, 138 were given at full dose and 75 were given at a reduced dose from that initially assigned. Reasons for discontinuing the combination included achievement of maximum response (n = 18), progressive disease (n = 9), no response (n = 4), toxicity (n = 6), patient refusal (n = 2), or death unrelated to treatment (n = 2). One patient died 15 days after registration because of unsuspected brain metastases that produced cerebral herniation, and another patient with a history of phlebitis died suddenly 21 days after treatment because of a presumed pulmonary embolus. The six patients who discontinued treatment with the combination because of toxicity did so after a median of four cycles (range, one to six cycles) because of mucositis, skin toxicity (n = 4), a severe infusion reaction (n = 1), or an asymptomatic decrease in the LVEF (from 80% to 65%) associated with an asymptomatic pericardial effusion detected on computed tomography (Doxil was discontinued, not according to the protocol guidelines but rather at the discretion of the treating physician in this patient, who had received no prior adjuvant doxorubicin).

The toxicity observed for patients treated at the recommended schedule (group D) is listed in Table 3. At the recommended dose, the most common grade 3 to 4 toxicities included neutropenia (60%), hyperglycemia (20%), mucositis (13%), palmar plantar erythrodysesthesia (PPE; 13%), and anemia (13%). Although only one patient had DLT during cycle 1 (mucositis), three other patients had DLT during subsequent cycles for febrile neutropenia (n = 1) during cycle 2 or grade 3 mucositis during cycle 2 or 3 (n = 2). Ten patients (67%) tolerated at least four cycles of therapy without modification (range, four to eight cycles).

Cardiac Toxicity
The median cumulative Doxil dose given was 150 mg/m² (range, 30 to 282 mg/m²) for all patients. Nine patients had received prior adjuvant doxorubicin (median cumulative dose, 240 mg/m²). No patients developed clinical evidence of congestive heart failure (CHF). Only two patients had an absolute 10% or greater decrease in the LVEF. In one patient, the LVEF remained above normal (80% to 65%; cumulative Doxil dose, 120 mg/m²), but Doxil was discontinued because of the development of a asymptomatic pericardial effusion incidentally noted on computed tomography. In a second patient, there was an asymptomatic decrease in the LVEF from 63% to 47% after a cumulative Doxil dose of 190 mg/m² given over six cycles; this patient had previously received adjuvant doxorubicin (240 mg/m²).

Response and Survival Data
The response data are listed in Table 4. One patient with stage IIIB disease was not assessable for response because of a severe Doxil-associated infusion reaction that precluded therapy. Among nine assessable patients with stage IIIA (n = 1) or IIIB (n = 8) disease, partial response occurred in eight patients (88%; 95% confidence interval [CI], 67% to 100%). Patients received a median of four cycles (range, three to four cycles) of the combination before mastectomy. After mastectomy, additional chemotherapy consisted of two more cycles of the combination (in five patients) or six cycles of cyclophosphamide, methotrexate, and fluorouracil (in two patients). After chemotherapy, all stage IIIB patients received chest wall irradiation and tamoxifen (for those with hormone receptor–positive disease). Three patients have relapsed, and the remaining six are alive and disease free after a median of 18 months after presentation (range, 10 to 26 months).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We performed a phase I trial of Doxil (30, 40, or 45 mg/m²) and docetaxel (60 or 75 mg/m²) in 41 patients with advanced breast cancer, with the regimen administered either every 4 weeks or every 3 weeks. In previous studies that combined docetaxel with conventional doxorubicin, two schedules were recommended for phase II testing, including 75 mg/m² of docetaxel and 50 mg/m² of doxorubicin every 3 weeks, or 60 mg/m² of each drug every 3 weeks.³⁷ We initially chose the 75-mg/m² docetaxel dose for this trial because it was an intermediate dose in the approved dose range (60 to 100 mg/m²). We chose an every-4-week schedule because previous studies had suggested that administering Doxil at a dose rate of more than 10 mg/m²/wk (eg, 30 mg/m² every 3 weeks, 40 mg/m² every 4 weeks, and so on) produced prohibitive PPE.³³ We performed the dose escalation in the absence and in the presence of adjunctive G-CSF. G-CSF was initiated 5 days after therapy because of the prolonged half-life of liposomal doxorubicin and the recommendation that it not be administered concurrently with systemic chemotherapy (or at a time when there would be a significant plasma concentration of the cytotoxic agent).³⁸

With 75 mg/m² of docetaxel every 4 weeks, dose escalation of Doxil was limited by severe mucositis and febrile neutropenia at 45 mg/m² and by febrile neutropenia despite adjunctive G-CSF at 40 mg/m². The 30-mg/m² Doxil dose level was well tolerated with this dose and schedule of docetaxel, but it required adjunctive G-CSF to prevent febrile neutropenia. To identify a dose and schedule that did not require adjunctive G-CSF, we modified the protocol to evaluate 30 mg/m² of Doxil and 60 mg/m² of docetaxel every 3 weeks in 15 patients. We found that this dose and schedule were well tolerated. Although 60% of patients treated at this dose level developed grade 3 or 4 neutropenia, febrile neutropenia was uncommon (13%). Other grade 3 to 4 toxicities included mucositis (13%), PPE (13%), and anemia (13%). Overall, four patients (27%) required dose modification for toxicity after a median of two cycles (range, one to three cycles), and 10 patients (67%) tolerated at least four cycles of therapy without modification.

Acute infusion reactions were reported to occur with Doxil in approximately 7% of patients with Kaposi’s sarcoma and human immunodeficiency virus (HIV)³⁹ and in approximately 11% of heavily pretreated patients with a variety of cancers treated in two phase I trials.⁴⁰ The reaction is characterized by flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest and throat, and, in some cases, hypotension. The recommended method of administration of the drug (at a dose of 20 mg/m²) is for it to be diluted in 250 mL of 5% dextrose (for doses up to 90 mg) and infused over 30 minutes. In this trial, the initial infusion was given over 60 minutes. We observed a high rate (55%) of infusion reactions among the first 11 patients during the first infusion, a finding that is consistent with other reports regarding the higher incidence of infusion reactions in patients without HIV infection.⁴¹ We eliminated this problem by reducing the initial infusion rate to 10 mL/h and doubling the rate every 5 to 10 minutes until a maximum rate of 250 mL/h was achieved (Table 5). Although it is possible that IV diphenhydramine (25 mg) and oral dexamethasone as used in our study also contributed to the lower infusion reactions rate with the modified schedule, this premedication regimen was obviously insufficient to prevent infusion reactions with the conventional administration schedule. Our findings suggest that the incidence of Doxil-associated infusion reactions is higher in patients without HIV infection and that such patients should be given the drug by the modified infusion schedule outlined in Table 5.

The recommended dose and schedule of the Doxil-docetaxel regimen used in this study was associated with an acceptable toxicity profile. In addition, it does not require adjunctive G-CSF and is associated with a lower rate of febrile neutropenia than conventional doxorubicin-docetaxel combinations. However, there is somewhat more severe mucositis (13%) with Doxil-docetaxel compared with doxorubicin-docetaxel (8%), as well as a higher incidence of PPE. Nevertheless, these findings may provide sufficient justification for selecting Doxil-based combinations in selected patients with risk factors for doxorubicin-induced cardiomyopathy⁴⁶ and may provide sufficient justification for comparing Doxil-docetaxel with conventional doxorubicin-docetaxel in early-stage disease should the latter combination emerge as the preferred regimen on the basis of ongoing trials.⁴⁷

Perhaps the most immediate application of the results from this study apply to exploring the possibility of combining the Doxil-docetaxel combination with trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) in patients with Her2/neu overexpressing breast cancer. The pivotal trial that led to the approval of trastuzumab included 469 women with Her2/neu-positive metastatic breast cancer who had received no prior chemotherapy for metastatic disease; the addition of trastuzumab to standard chemotherapy consisting of doxorubicin (or epirubicin)-cyclophosphamide or paclitaxel produced a significant improvement in response rate, time to progression, and survival.⁴⁸ An unexpected side effect of trastuzumab that was observed in that trial was cardiac dysfunction.⁴⁸ The incidence of CHF was significantly greater for patients treated with trastuzumab plus either paclitaxel (4% v 1%) or doxorubicin-cyclophosphamide (19% v 3%). The basis for the enhanced cardiac toxicity of doxorubicin is unknown but clearly precludes administering conventional doxorubicin concurrently with trastuzumab.⁴⁸ To exploit the potential for enhancing the antitumor effects of the doxorubicin-trastuzumab combination without compromising safety, the Eastern Cooperative Oncology Group is currently performing a pilot study of Doxil-docetaxel alone (for Her2/neu-negative disease) or in combination with trastuzumab (for Her2/neu-positive disease) in 92 patients with metastatic breast cancer (E3198). The primary end point of the trial is cardiac safety. Should the trastuzumab-Doxil-docetaxel combination be found safe and effective, then further studies comparing trastuzumab-Doxil-docetaxel with either trastuzumab-paclitaxel or trastuzumab-docetaxel would be logical.

In conclusion, we have identified a dose and schedule of the Doxil-docetaxel combination that has an acceptable toxicity profile and that has efficacy comparable to combinations containing docetaxel and nonliposomal doxorubicin in patients with metastatic breast cancer. Further study of this combination alone or in combination with trastuzumab is warranted.

	ACKNOWLEDGMENTS

 
Supported by grants from Aventis, Inc, and Alza Pharmaceuticals and by National Institutes of Health Cancer Center core grant no. P30-CA113330.

We thank Yun Gu for her assistance with the statistical analysis.

	NOTES

 
Presented in part at the Twenty-First Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 15, 1998.

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Submitted September 29, 2000; accepted March 7, 2001.

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