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© 2001 American Society for Clinical Oncology Phase I Study of Stealth Liposomal Doxorubicin in Combination With Gemcitabine in the Treatment of Patients With Metastatic Breast CancerFrom the Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Edgardo Rivera, MD, Department of Breast Medical Oncology, Box 424, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: erivera{at}notes.mdacc.tmc.edu
PURPOSE: We conducted a single-institution phase I clinical trial to determine the maximum-tolerated dose (MTD) and define the toxic effects of stealth liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients were eligible if they had disease progression with no limit on prior number of chemotherapy regimens. Prior treatment with liposomal doxorubicin and/or gemcitabine was not allowed. The starting dose of liposomal doxorubicin was 20 mg/m2 on day 1 only with a 20% dose escalation of the previous mg/m2 dose until MTD was reached. Gemcitabine was given as a fixed dose of 800 mg/m2 on days 1 and 8 every 3 weeks. RESULTS: We treated 27 patients of whom six had never received chemotherapy for their disease. Most had had visceral involvement as their dominant site of disease. The dose-limiting toxicity was myelosuppression, which included neutropenia and thrombocytopenia. However, neither neutropenic fever nor episodes of bleeding were major occurrences. Significant antitumor activity was also observed with a total of two complete and seven partial responses. The recommended phase II dose is liposomal doxorubicin 24 mg/m2 on day 1 and gemcitabine 800 mg/m2 on days 1 and 8 every 21 days. CONCLUSION: The combination of liposomal doxorubicin and gemcitabine is an active and well tolerated regimen when administered on a 21-day schedule. Myelosuppression limited further dose escalation, however, it did not increase the incidence of neutropenic fever. Significant antitumor activity seen in heavily and minimally pretreated patients warrants further evaluation of this combination.
The anthracycline antibiotic doxorubicin has a broad spectrum of antineoplastic action and a correspondingly widespread degree of clinical use. In addition to its role in the treatment of breast cancer, doxorubicin is indicated in the treatment of Hodgkin’s disease and non-Hodgkin’s lymphoma, hepatocellular and gastric carcinoma, small-cell cancer of the lung, soft tissue and bone sarcomas, as well as cancer of the ovary, bladder, and thyroid. Unfortunately, toxicity limits the therapeutic activity of doxorubicin and may preclude adequate dosing. Liposomal encapsulation of doxorubicin may reduce both the nonspecific drug delivery to normal tissues as well as the high peak plasma levels of free drug responsible for its toxicity. Stealth liposomal doxorubicin is a formulation in which the drug is encapsulated in liposomes that escape instant recognition and uptake by the mononuclear phagocyte system. As a result, the formulation has a long circulation time, and the liposomes can eventually become extravasated through the abnormally permeable vessels characteristic of many tumors. Once concentrated in tumors, the liposomes can deliver high levels of doxorubicin to malignant cells, without affecting normal tissue.1-4 A phase II dose-finding study of the drug conducted in minimally pretreated stage IV breast cancer patients demonstrated an overall response rate of 31%. Skin toxicity was the most commonly observed side effect at doses greater than 45 mg/m2. However, myelosuppression was minimal which led the authors to conclude that it would be worth evaluating the drug in a combination regimen.5 Gemcitabine is a nucleoside analog that exhibits antitumor activity. Gemcitabine is 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (ß-isomer). The drug exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S phase) and also blocking the progression of cells through the G1/S phase boundary.6-8 Gemcitabine has been evaluated in patients with breast cancer. Carmichael et al9 performed a phase II study in 44 patients with locally advanced or metastatic breast cancer. Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered once a week for 3 weeks followed by a 1-week rest every 4 weeks. There were three complete responses and seven partial responses, for an overall response rate of 25%. Other trials10-12 of gemcitabine as a single agent have confirmed the activity of this drug in breast cancer. The treatment of metastatic cancer remains a challenge despite the recent introduction of additional cytotoxic agents such as the taxanes. The need for new therapeutics is evident. Liposomal doxorubicin seems to be more than an alternative or substitute for conventional doxorubicin. Likewise, gemcitabine has been shown to have antitumor activity against many solid tumors, including breast cancer. Therefore, due to the antitumor activity of both agents and due to the fact that both agents have different toxicity profiles and different mechanisms of action, we decided to evaluate the combination of these two agents against advanced breast cancer.
Eligibility Criteria Patients were eligible for the study if they had histologic proof of metastatic breast carcinoma with evidence of progression of their disease. There was no limit on the prior number of chemotherapy regimens. Patients could have either measurable or assessable disease but bone marrow metastases, pleural effusions, or ascites could not be the only sites of disease. Patients were required to have a life expectancy of at least 12 weeks, to have a performance status of  2 on the Zubrod scale,13 and to be at least 18 years of age. Patients were not eligible for this study if they had received prior therapy with liposomal doxorubicin and/or gemcitabine. Other eligibility criteria included adequate bone marrow function, defined as an absolute granulocyte count of  1,500/µL and a platelet count of 100,000/µL; adequate liver and renal function, defined as a bilirubin concentration less than 1.2 mg/dL and serum creatinine concentration less than 2.0 mg/dL; and a cardiac ejection fraction 50% without evidence of congestive heart failure. All participants signed an informed consent form. The simultaneous administration of other chemotherapy, hormone therapy, immunotherapy, or radiotherapy was not allowed. Patients must have been off all previous systemic therapy, except hormone therapy, for 3 weeks before entering this study and must have recovered from the toxic effects of prior therapy. Patients were not eligible for the study if they had evidence of uncontrolled brain metastases or depletion of bone marrow reserves secondary to tumor involvement, irradiation or high dose chemotherapy followed by bone marrow transplant. Patients were not allowed to enter the study if they had evidence of other serious uncontrolled illnesses or if the control of an illness may have been jeopardized by the complications of this therapy.
Treatment Plan and Evaluation All patients deemed to be eligible signed a written informed consent form before being registered with the M.D. Anderson Cancer Center data management office. The study was conducted using a standard phase I design, with sequential cohorts of patients receiving liposomal doxorubicin at escalated doses as listed in Table 1. Patients received a fixed dose of 800 mg/m2 of gemcitabine infused intravenously over 30 minutes on days 1 and 8 via a peripheral vein or central line. Stealth liposomal doxorubicin was given at a starting dose of 20 mg/m2 infused intravenously via peripheral vein or central line every 21 days on day 1 of each cycle. The dose of liposomal doxorubicin was calculated as a 20% escalation of the previous mg/m2 dose until the maximum-tolerated dose was reached and it was infused before the dose of gemcitabine. Stealth liposomal doxorubicin was provided free of charge to the patients by Alza Pharmaceuticals (Mountain View, CA). The cost of gemcitabine was reimbursed by Eli Lilly Company (Indianapolis, IN) in those patients in whom the drug was not covered by medical insurance.
Stealth liposomal doxorubicin is normally infused intravenously over 1 hour. However, ongoing studies in our institution with liposomal doxorubicin had reported a number of cases in which infusion reactions had developed. This was discussed with the pharmaceutical company (Alza Pharmaceuticals) which in turn recommended to lengthen the infusion to 2.5 hours. Twenty five percent of the drug was administered over 1 hour with the remaining of the drug being administered over the duration of the infusion.
The patients were treated until there was unacceptable toxicity or evidence of progression of their disease. The patients were also allowed to go off treatment at the investigator’s discretion. Unacceptable toxicity was defined as (1) grade A minimum of three assessable patients were entered at each dose level. At least three patients were observed for acute toxicity for a minimum of three weeks before doses were escalated to the next dose level. Patients were entered onto the next group if dose-limiting toxicity was not observed during the first course of treatment. The dose was escalated until unacceptable toxicity was observed in one of three patients entered at a given dose level. Intrapatient dose escalation was not allowed. Once unacceptable toxicity was observed, no patients could be entered at the next dose level until all patients had been evaluated at the previous level. Dose escalation was continued if less than two of six patients at the same dose level exhibited unacceptable toxicity. Enrollment of patients was stopped as soon as unacceptable toxicity was observed in two patients at a given level. Once the MTD was reached it was ascertained in patients who had never received chemotherapy for their metastatic disease. Six previously untreated patients for their metastatic disease were entered at the dose level above the first MTD. Dose escalation for this group of patients was to continue until two of six patients at the same dose level exhibited unacceptable toxicity.
Every effort was made to administer the full dose regimen. In case of unacceptable toxicity, treatment was interrupted until the patient recovered to grade 0 or baseline and was restarted at the next lower dose level. If grade 2 thrombocytopenia and/or grade 3 neutropenia occurred on day 8 then the patient received only 50% of the total gemcitabine dose. If grade
Patients were followed with complete blood cell counts, differential counts, and platelet counts before each dose of liposomal doxorubicin and each dose of gemcitabine. Blood chemistry studies were repeated before each course or as frequently as needed to define drug toxicity. Serum tumor markers were repeated every three courses if levels were initially elevated. Radiologic assessments were performed after every three courses unless the clinical situation required it sooner. An isotope cardiac scan was performed every 100 mg/m2 increments of liposomal doxorubicin if the patient had received Although the major thrust of a phase I study is to evaluate dose-ranging experience and the toxicity observed, an attempt was made to evaluate the efficacy of this drug combination in this patient population. The size of measurable lesions was reported as the product of the longest diameter and its perpendicular. Standard response criteria were applied.14
Statistical Analysis
Patient Characteristics Between September 1997 and May 1999, 27 eligible patients were registered in this study. Demographic and clinical characteristics of all patients are listed in Table 2. The median age was 53 years and the median Zubrod performance status was 1. The median number of metastatic sites was two (range, one to four sites). Most patients had visceral involvement as their dominant site of disease. Fourteen patients had received three prior chemotherapeutic regimens, and 24 had received three chemotherapeutic agents. Two patients had never received chemotherapy, neither in the adjuvant nor in the metastatic setting. A total of six patients was treated for the first time for their metastatic disease. Nineteen patients had received prior hormonal therapy, 17 had prior radiation therapy, and 24 had prior surgery.
Responses Evaluation of response was not considered the primary end point of this study. However, significant antitumor activity was observed in those patients who were previously treated and those who had never been treated for their metastatic disease. There was a total of two complete, seven partial, and two minor response. Eight patients had evidence of stable disease. The remaining patients had evidence of progression of their disease. Responses were observed in cohorts 2, 3, 5, and 6. Three of the partial responses were observed in the minimally pretreated group or cohort 6. Patients had evidence of response in soft tissue, bone, and visceral sites. Skin was the only site of disease in the two patients who were reported to have a complete response.
Toxicity The dose-limiting side effects observed were neutropenia and thrombocytopenia, as listed in Table 3. Patients in cohort 1 and 2 were scheduled to receive gemcitabine 1,000 mg/m2 and 800 mg/m2, respectively, on day 15. However, two patients in cohort 1 and two patients in cohort 2 required omission of the day 15 dose during their first cycle due to neutropenia and thrombocytopenia. Of note is the fact that one of the patients in cohort 1 had previously received high-dose chemotherapy followed by a bone marrow transplant. The study was amended and the day 15 dose of gemcitabine was deleted. Patients in subsequent cohorts were given their chemotherapy on a 21-day schedule with gemcitabine administered on days 1 and 8. Seven of 21 heavily pretreated patients and none of six minimally pretreated patients required a dose variation during their first cycle of chemotherapy because of neutropenia and/or thrombocytopenia. The nadir granulocyte and platelet count for all first courses was 800 and 158,000 and occurred on day 15 in most patients. Hematologic toxicity, in this case neutropenia and thrombocytopenia, continued to be the most commonly observed toxicity during all subsequent courses for all the cohorts ( Table 4). However, the drug combination was found to be very safe when it came to neutropenic complications. There were a total of nine hospitalizations in eight patients, all of which were non neutropenic. One patient in cohort 2 developed an episode of neutropenic fever during course 1 of chemotherapy. This patient was found to have a Gram-positive bacteremia but was successfully treated as an outpatient with oral antibiotic therapy.
Nonhematologic. Grade 3 or 4 nonhematologic toxicity was not a significant problem during any of the first courses for patients in any of the cohorts (Table 3). Grade 3 vomiting was reported by one patient, and grade 3 fatigue was reported by four other patients. Other grade 3/4 toxicity experienced by patients during the trial included constipation in two patients, diarrhea in one, fatigue in 12, hand-foot syndrome in two, stomatitis in three, and nausea in five patients. Grade 3/4 elevation of total bilirubin and SGPT was observed in one patient in each case. Toxicity observed with all subsequent courses was generally mild (Table 4).
Dose Modifications The maximum-tolerated dose of the combination was deemed to be 24 mg/m2 of liposomal doxorubicin and 800 mg/m2 of gemcitabine on day 1 and 8. At this dose level, the regimen was well tolerated. Grade 3/4 hematologic and nonhematologic toxicity was not reported during the first course at this dose level for any of the patients. Only in a few subsequent courses was grade 3/4 toxicity reported at this dose level. Dose-limiting toxicity, which included grade 3/4 granulocytopenia and thrombocytopenia, was observed in three patients at a higher dose level of 29 mg/m2 of liposomal doxorubicin and 800 mg/m2 of gemcitabine. An attempt was made to escalate the dose of liposomal doxorubicin in a minimally pretreated patient population. Six patients who had never received chemotherapy for metastatic disease were treated at a dose level of 29 mg/m2 of liposomal doxorubicin and 800 mg/m2 of gemcitabine. However, there were five patients who developed grade 3/4 neutropenia and one patient who developed grade 3 thrombocytopenia for which further dose escalation was not attempted.
Cardiac Toxicity
Stealth liposomal doxorubicin has been reported to have significantly less cardiac toxicity compared to standard doxorubicin. It has also been associated with less nausea and no alopecia. The improved toxicity profile and the antitumor activity associated with the drug led us to the evaluation of this agent in combination with other known active drugs. Gemcitabine was chose to be evaluated in combination with liposomal doxorubicin due to its already known anti tumor activity and its minimal toxicity profile. The most commonly observed toxicity during the study was hematologic in nature with neutropenia and thrombocytopenia being the most common. In most patients, the nadir granulocyte and platelet count occurred on day 15, which would explain the inability to administer the day 15 dose of gemcitabine with this regimen. The late drop in granulocyte and platelet count could have been caused in part by the long half-life of liposomal doxorubicin leading to a more significant delayed myelosuppression especially when combined with other agents. This was apparent when we initially evaluated this combination on an every 28-day cycle with gemcitabine being administered on days 1, 8, and 15. Patients were not able to tolerate the day 15 dose, which resulted in delayed hematologic recovery. Modifying the regimen to a 21-day schedule allowed enough time for patients to recover and continue treatment as planned. Perhaps the most important aspect of this combination is the fact that neutropenic fever and/or events were not commonly observed with this regimen. This finding will impact the safe use of this combination in breast cancer patients but it will also affect the cost that comes with active or prophylactic treatment of neutropenic events. Hospitalizations during the study were very infrequent and none of the patients required the use of colony-stimulating growth factors. Nonhematologic toxicity was not predominant during the study. Discontinuation of treatment was not usually related to this type of toxicity. Hand-foot syndrome, a toxicity commonly observed with the use of higher doses of liposomal doxorubicin, was mild, infrequent, and did not cause patients to stop their treatment. This can be explained in part by the fact that we used lower doses of the drug than what we would normally expect to produce this particular toxicity. Our previous experience with this drug from an unpublished study suggests that the use of liposomal doxorubicin in doses as high as 50 to 60 mg/m2 on a 28-day cycle could create a significant problem with non hematologic toxicity, in this case in the form of hand-foot syndrome. A dose lower than 50 mg/m2 is recommended to be used either as a single agent or in combination, especially if administered on a 21-day schedule. The combination of these two drugs is currently being evaluated in two additional phase I studies. The preliminary results of a phase II study of the combination have also been reported. Tobias et al15 recently reported the results of a similar phase I study that was conducted in recurrent epithelial ovarian cancer patients. In this study, all patients were previously treated with a median number of 2.5 prior regimens. Hematologic toxicity was the observed dose-limiting toxicity. However, even more important is the fact that the investigators reported the maximum-tolerated dose to be at 650 mg/m2 of gemcitabine on days 1 and 8 and 25 mg/m2 of doxorubicin on day 1 of a 28-day cycle. Significant antitumor activity was also reported. The results of this study are very similar to ours, which confirms the safety of the regimen with the significant antitumor activity in previously treated cancer patients. The second phase I study was reported by Tan et al16 at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology. In this study, patients with refractory solid malignancies were treated with gemcitabine on days 1 and 15 and doxorubicin on day 1 of a 28-day cycle. In this particular study, the combination was evaluated at doses as high as 2000 mg/m2 of gemcitabine and 25 mg/m2 of liposomal doxorubicin. We were unable to escalate the doses of gemcitabine as in that study. This in part could be explained by the fact that were no previously treated breast cancer patients included in Tan’s study. In general, that specific patient population tends to be more sensitive when it comes to chemotherapy tolerance. Another possible explanation is the fact that high doses of gemcitabine seem to be better tolerated when given less frequently on an every other week schedule as opposed to every week. Grade 3/4 granulocytopenia and thrombocytopenia as well as grade 3 hand-foot syndrome were observed at different dose levels. However, the study had not been completed at the time it was reported. No data was available regarding antitumor activity. A similar schedule to the one evaluated in our study was reported by Ginopoulos et al17 at the Ninth International Congress on Anti-Cancer Treatment in 1999. This is the only phase II study reported on such drug combination. In this study, patients with gastrointestinal cancer received treatment if they had a poor performance status and/or were receiving second-line therapy. The patients received 1,000 mg/m2 of gemcitabine on day 1 and 8 and doxorubicin 25 mg/m2 on day 1 every 21 days. The fact that no serious toxicities were observed with an objective response rate of 58% at a very similar schedule confirms the results of our study. The evaluation of gemcitabine has not been limited only to the combination of liposomal doxorubicin. In 1997, Garcia-Conde et al18 reported the results of a phase II study evaluating the combination of gemcitabine and nonencapsulated doxorubicin. Gemcitabine was given at doses of either 1,000 mg/m2 or 800 mg/m2 on days 1, 8, and 15; doxorubicin was given at a dose of 25 mg/m2 on the same days as gemcitabine. These were patients who had only received adjuvant treatment and no prior treatment for their metastatic disease. Significant antitumor activity was observed with an overall response rate of 60%. However, there seemed to be greater toxicity observed with this regimen when compared with the combination of gemcitabine and doxorubicin. There was a 19% grade 3/4 neutropenia and 4% grade 3 thrombocytopenia with two deaths associated with myelosuppression. A third patient died suddenly after a hypertensive crisis. No cardiac toxicity was observed. In summary, our study demonstrated that the combination of stealth liposomal doxorubicin and gemcitabine is an active and well-tolerated regimen. The combination seems to be even better tolerated than the combination of gemcitabine with free doxorubicin. Cardiac toxicity was not observed, however, we did not reach a high enough cumulative dose level of total (free and liposomal) doxorubicin as to expect any cardiac toxicity. Breast cancer patients previously exposed to multiple chemotherapy regimens tend to become quite sensitive to the side effects related to additional treatment and response to treatment tends to be low. Therefore, it would be worth evaluating this regimen in this patient population as a way to achieve adequate responses with very minimal toxicity. A phase II study in breast cancer patients is currently being planned.
Supported by research grants from Alza Pharmaceuticals (Mountain View, CA) and by Eli Lilly Company (Indianapolis, IN).
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
