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© 2003 American Society for Clinical Oncology Multicenter Phase II Study of Oral Bexarotene for Patients With Metastatic Breast Cancer
From the University of Texas M.D. Anderson Cancer Center, and Baylor College of Medicine; Houston, TX; Dana-Farber Cancer Institute, Boston, MA; Georgetown University, Washington, DC; Hematology/Oncology Consultants, Columbus, OH; Ligand Pharmaceuticals Inc, San Diego; University of California Los Angeles, Los Angeles; University of California San Francisco, San Francisco, CA; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Arkansas for Medical Sciences, Little Rock, AR; University of Michigan, Ann Arbor, MI; University of Pennsylvania Cancer Center, Philadelphia, PA; and University of Virginia, Charlottesville, VA. Address reprint requests to Francisco J. Esteva, MD, PhD, Departments of Breast Medical Oncology, and Molecular and Cellular Oncology The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 424, Houston, TX 77030; email: festeva{at}mdanderson.org.
Purpose: Bexarotene is a retinoid X receptor–selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer. Patients and Methods: The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m2/d. Results: One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m2/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis. Conclusion: The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.
BREAST CANCER is the most common malignancy and the second most common cause of cancer-related death in women.1 The treatment of metastatic disease remains a challenge.2,3 Only 10% to 20% of patients with metastatic breast cancer achieve a durable complete remission, and long disease-free survival indicative of cure is rare.4 Unquestionably, there is a need to identify new treatment approaches for women with advanced disease. Retinoids play critical roles in normal development and physiology by modulating cell growth, division, reproduction, differentiation, and immune function. They are also capable of inhibiting cell growth, inducing differentiation, and inducing apoptosis (programmed cell death) in a variety of tumor cell lines.5–7 The effects that retinoids produce seem to result from changes in gene expression mediated through specific intracellular receptors.8,9 There are two subfamilies of intracellular receptors through which retinoids exert their action: the retinoic acid receptors and the retinoid X receptors.9,10 Evidence from in vitro studies, experiments in animal models, and clinical trials indicates that various retinoids have therapeutic effects on several types of neoplastic diseases, including carcinomas, acute promyelocytic leukemia, cutaneous T-cell lymphoma, AIDS-related Kaposi’s sarcoma, and multiple myeloma.11 Bexarotene (Targretin; Ligand Pharmaceuticals Inc, San Diego, CA) is a novel synthetic retinoid analog with potentially unique biologic properties. Bexarotene displays selective binding and activation of the three known retinoid X receptors (a "rexinoid"). These receptors play a role in the regulation of cell growth and differentiation via their ability to regulate transcription.12,13 The subclass specificity of bexarotene may provide therapeutic specificity and/or reduced toxicity. In vitro, bexarotene inhibits the growth of tumor cell lines of both hematopoietic and squamous cell origin and induces apoptosis in a number of tumor cell lines. Bexarotene potentiates the in vitro growth inhibition by antiestrogenic agents such as 4-OH-tamoxifen, indicating that the mechanisms of growth inhibition by antiestrogens and retinoids might be distinct and additive. In an N-nitroso-N-methylurea (NMU) model of mammary carcinogenesis, bexarotene administration caused regression in 72% of primary tumors compared with a 33% response with tamoxifen.14,15 Based on these results, Bischoff et al16 developed a tamoxifen-resistance NMU-induced mammary tumor model in rats to mimic the clinical situation. Once established tumors became resistant to tamoxifen, bexarotene was added to the treatment regimen, and the tumors in these animals were compared with tumors in a group of animals that remained on tamoxifen alone. Bexarotene in combination with tamoxifen for up to 20 weeks resulted in an overall objective response rate of 94% (95% confidence interval, 86% to 100%) in primary tumors compared with a rate of 33% (95% confidence interval, 11% to 56%) in primary tumors treated with tamoxifen alone. In addition, the bexarotene and tamoxifen combination was associated with a statistically significant decrease in total tumor burden (P = .03). These findings indicated that bexarotene therapy could offer a novel approach to the treatment of breast tumors that may have developed resistance to antihormonal therapies such as tamoxifen. A multicenter phase II study was launched to determine the efficacy and safety of bexarotene-based therapy for patients with progressive metastatic breast cancer. A secondary objective included determination of plasma tamoxifen concentrations with or without concomitant bexarotene in women with advanced breast cancer.
Patients were accrued at 28 institutions and enrolled between November 16, 1998, and November 9, 2000. All patients signed an institutional review board–approved informed consent form. Patients were required to have pathologic confirmation of breast cancer and clinical evidence of metastatic disease, a life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Furthermore, they were required to have acceptable organ function defined as follows: adequate hematologic function, defined as WBC  3,000/µL, absolute neutrophil count 1,500/µL, and platelet count 100,000/µL; normal coagulation parameters; bilirubin  1.5 times the upper limit of normal (ULN); AST/ALT 2.5 x ULN; and serum creatinine 2.5 x ULN (or creatinine clearance > 40 mL/min). In addition, only patients who had a normal baseline fasting triglyceride (FTG) level were allowed to enter the study; triglycerides could be normalized before study entry with use of an antilipemic agent. At least one bidimensionally measurable lesion was required for entry onto the study. Patients with bone metastases only were allowed if the bone metastases were predominantly or mainly lytic and they measured at least 1 centimeter in diameter. If a patient was of childbearing potential, she had to have a negative serum pregnancy test within 7 days before study entry and had to have used an effective means of contraception or have been sexually abstinent for at least 4 weeks before the negative serum pregnancy test and through to study entry. All patients agreed to practice an effective method of birth control during the entire study and for at least 3 months after their last treatment on protocol. Patients with breast cancer metastatic to the CNS were not eligible. Other exclusion criteria included the inability to comply with protocol requirements for oral administration of bexarotene capsules, pregnant or lactating women, and serious intercurrent medical illnesses that would interfere with the ability of the patient to carry out the treatment program. Prior treatment with retinoids for breast cancer and prior therapeutic retinoids or investigational agents for any indication during the past 3 months were not allowed. Patients with a history of pancreatitis or with clinically significant risk factors for developing pancreatitis were excluded from study participation. Systemic treatment with more than 15,000 IU of vitamin A daily while on this treatment protocol was prohibited.
Treatment Plan
Antitumor response was categorized as complete response (disappearance of all clinical and laboratory signs and symptoms of disease for a minimum of 4 weeks during which time no new lesions may appear) or partial response (a minimum reduction of at least 50% in the sum of the products of the longest perpendicular diameters of all indicator lesions; there could be no new lesions, and the response had to last for at least 4 weeks). Patients who failed to qualify for complete or partial response or progressive disease were categorized as having stable disease. The appearance of a new lesion or an increase of at least 25% in the sum of the products of the longest perpendicular diameters of measurable lesions was defined as progressive disease. If at least one response (complete or partial) was seen in the initial 14 patients treated in a given group, at least 30 assessable patients were enrolled to obtain an estimate of the true response rate. The decision to enroll patients to the second stage of the study was made independently for each specific dose for each of the groups. If a response was seen in the initial 14 assessable patients in the low- or high-dose arm of a specific group before a response was seen in the other dose arm, further enrollment of patients in the responding-dose group proceeded forward. If a response was then seen in the other dose arm of that specific group, further enrollment of patients to that group was to occur through randomization (low dose v high dose). It was established that bexarotene would be clinically useful and worthy of further evaluation if the response rate in any of the six groups was at least 20%.
Instructions for dose modification of bexarotene capsules were included in the protocol and were dependent on the nature and the grade level of the toxicity reported. Patients who had FTG levels greater than 800 mg/dL during study drug therapy had the dose of bexarotene capsules reduced to the next lower dose level as indicated in Table 2
Pharmacokinetics Patients from selected institutions were asked to participate, as an optional, voluntary procedure, in bexarotene serum level monitoring. Plasma samples were obtained predose, and at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, and (if possible) 9.0, 12.0, and 24 hours after dosing on day 1 and at 4-week intervals while patients remained on study. For tamoxifen-resistant patients, it was mandatory to determine the effect of concomitant administration of bexarotene capsules on plasma tamoxifen concentrations. Single time-point plasma samples were obtained on day 1 and at 4-week intervals during the study. Plasma samples were forwarded to Ligand Pharmaceuticals for determination of the tamoxifen concentrations using a validated high-performance liquid chromatography procedure.
One hundred forty-six patients were randomly assigned and dispensed bexarotene. One patient withdrew consent after receiving study medication. A total of 145 patients were treated on this phase II study. Baseline demographic characteristics are listed in Table 3  . The patients had a median age of 56 years and were predominantly white (88%). Most patients had hormone receptor–positive tumors (89%). In the hormone-refractory group, 33 patients were randomly assigned to 200 mg/m2/d, and 15 patients were assigned to 500 mg/m2/d. In the chemotherapy-refractory group, 32 patients were randomly assigned to 200 mg/m2/d, and 15 patients were assigned to 500 mg/m2/d. In the tamoxifen-resistant group, 36 patients were randomly assigned to 200 mg/m2/d, and 15 patients were assigned to 500 mg/m2/d. There were no patients in the hormone-refractory or chemotherapy-refractory groups with bone metastases only. There were 13 patients in the tamoxifen-resistant group with bone metastases only. Nine of these patients were randomly assigned to the 200-mg/m2/d dose group, and four were randomly assigned to the 500-mg/m2/d dose group.
All 146 patients were assessable for response using intent-to-treat analysis. Two patients (6%) responded in the hormone-refractory group, and two patients (6%) responded in the chemotherapy-refractory group. Only one tamoxifen-resistant patient (3%) responded to continuation of tamoxifen plus bexarotene therapy. This patient had lung and bone metastases, and a partial response was noted after 48 days of therapy. The duration of response was 345 days. All the responses were observed in patients treated with bexarotene 200 mg/m2/d. No patients treated at 500 mg/m2/d had objective responses (Table 4 ). The overall response rate was 3%. Eighteen percent of patients (27 of 146 patients) achieved clinical benefit (complete response, partial response, and stable disease 6 months). In the hormone-refractory group, the clinical benefit rate was 24% (eight of 33 patients) for patients treated with low-dose bexarotene and 13% (two of 15 patients) for patients receiving high-dose bexarotene. In the chemotherapy-refractory group, the clinical benefit rate was 16% (five of 32 patients) for patients treated with low-dose bexarotene and 7% (one of 15 patients) for patients receiving high-dose bexarotene. In the tamoxifen-resistant group, the clinical benefit rate was 22% (eight of 36 patients) for patients treated with low-dose bexarotene and 20% (three of 15 patients) for patients receiving high-dose bexarotene. The stabilization of disease rates are listed in Table 5.
The data collection for survival analysis was completed in December, 2000. The Kaplan-Meier projected median time to progression ranged from 8.3 to 9.6 weeks (Fig 1 ). The median time to treatment failure was defined as the time elapsed from day 1 on study to the time of withdrawal from study for any primary reason for withdrawal except partial response or complete response. The median projected time to treatment failure ranged from 8.7 to 10.4 weeks. At the time of this analysis, 38 patients (26%) had died. The cause of death was progressive breast cancer in all except for three patients; for one patient, the cause of death was sepsis, and for two patients, the cause was unknown.
Most patients assigned to the low-dose cohort did not require dose adjustments, whereas most patients assigned to the high-dose cohort required dose reductions (Fig 2 ). Compared with the patients treated with low-dose bexarotene, all high-dose groups had 97% more patients with dose reduction/suspension; 73% higher time-averaged exposure (mg/m2/d); 82% higher overall exposure (mg/m2); higher incidence of drug-related adverse events, except for hyperlipemia; more severe hypertriglyceridemia; more dose-limiting toxicities; but fewer withdrawals for drug-related adverse events. The mean total exposure was 10.9 g/m2 for the low-dose cohort and 19.8 g/m2 for the high-dose cohort.
There were no treatment-related deaths and no episodes of pancreatitis. One hundred fifteen patients (79%) withdrew from the study because of progressive disease. Seven patients (5%) were taken off study because of drug-related adverse events. Eleven patients withdrew from the study because of adverse events (Table 6 ).
Two patients experienced three serious adverse events. One patient with bilateral obstructive uropathy treated at 200 mg/m2/d developed acute renal failure and hypercalcemia. Both adverse events were severe and attributed to bexarotene therapy. These complications resolved after drug discontinuation and bilateral ureteral stent placement. One patient treated at 500 mg/m2/d developed severe granulocytopenia (435 cells/mL) on day 19, which was attributed to bexarotene therapy. Bexarotene was discontinued. The patient required no treatment, and this event promptly resolved with no sequelae. The patient was able to resume bexarotene therapy at a lower dose (250 mg/m2/d) without recurrence of granulocytopenia.
The most common toxicity observed was hypertriglyceridemia, recorded as an adverse event for 84% of patients. Grade 3 hypertriglyceridemia occurred in 13% of patients. No grade 4 hypertriglyceridemia was observed. Thirty-six percent of patients required a dose-reduction or brief suspension because of hyperlipemia. Seventy percent of patients required antilipid therapy with fenofibrate. Other common drug-related adverse events (affecting
Pharmacokinetics Baseline (n = 27) and on-study (n = 93) plasma samples from 33 patients with breast cancer in the tamoxifen-resistant group were available for assessment. Of the 33 patients with tamoxifen concentration data, 19 patients were considered assessable based on complete data collection set and no potentially confounding medications. Baseline tamoxifen concentrations for the assessable patient data set ranged from 61.3 ng/mL to 189 ng/mL with a mean of 111 ng/mL (n = 19), similar to reported literature values. Of the 16 assessable patients with a week 4 sample, 14 patients experienced a reduction in plasma tamoxifen concentrations by study week 4, at which time the mean tamoxifen concentration was 67.8 ng/mL (n = 16). Overall, the mean reduction in plasma tamoxifen concentrations during concomitant bexarotene dosing relative to baseline values was 38%. There was no apparent relationship between initial bexarotene dose and the reduction in tamoxifen concentrations. The mean percent reduction in on-study tamoxifen concentrations relative to baseline values in the 200-mg/m2/d and 500-mg/m2/d bexarotene dose groups was 41% and 33%, respectively. Also, there was no identifiable relationship between the reduction in tamoxifen concentrations and tamoxifen dosing or administration of other concomitant medications.
In this study, oral bexarotene at 200 mg/m2/d or 500 mg/m2/d resulted in limited clinical activity for patients with progressive metastatic breast cancer refractory to chemotherapy and/or hormone therapy. In patients treated at a dose of 200 mg/m2/d, the objective response rate ranged from 3% to 6%. If the proportion of patients who remained stable for at least 6 months is included, approximately 20% of patients derived clinical benefit from oral bexarotene capsules. There were no major responses in patients treated at the high-dose level in any of the three groups. The response rate to bexarotene capsules was lower than the response rates reported for other hormone therapies commonly used for patients who progress on tamoxifen, such as megestrol acetate or aromatase inhibitors.17 Approximately 20% of patients remained stable for 6 months or longer while receiving bexarotene capsules. However, it is unknown how this would compare to either a placebo or no treatment. The median time to progression was similar among all strata dose groups. The range of 8.3 to 9.6 weeks for median time to progression for all strata-dose groups seems inferior to the range of 16 to 20 weeks for megestrol acetate,18–22 18 to 23 weeks for anastrozole,18–21 20 weeks for exemestane,22 and 22 weeks for letrozole23 in patients with advanced breast cancer refractory to tamoxifen. The doses of bexarotene chosen for this trial were based on previous phase I trials and pharmacologic data in rats. Two phase I trials of bexarotene established two different maximum-tolerated doses for treatment with bexarotene capsules, 300 mg/m2/d and 650 mg/m2/d.24 Patients with cutaneous T-cell lymphoma, however, when dosed at the 650-mg/m2/d level, were unable to tolerate this dose over longer periods of time primarily because of hypertriglyceridemia. In subsequent protocol modifications for studies in cutaneous T-cell lymphoma, doses were reduced to 500 mg/m2/d. The 200-mg/m2/d dose used in this study was based on available clinical data and preclinical studies of human breast cancer in rats.25,26 The biologic effects of a lower dose in breast cancer patients are not known. It is possible that dosing based on body-surface area produced doses that were too high for human compared with mice.
Bexarotene was generally well tolerated. As expected, the most common side effect was hypertriglyceridemia. Although the incidence was similar to other studies in patients with cutaneous lymphoma and lung cancer,25 hypertriglyceridemia27 was generally easily managed with fenofibrate therapy. Eight patients (6%) developed hypothyroidism that required initiation of thyroid hormone replacement therapy. Six of these patients (75%) received bexarotene at 200 mg/m2/d and two (25%) received bexarotene at 500 mg/m2/d. It should be noted that, in previous studies, hypothyroidism was noted in patients treated with bexarotene at doses The preliminary pharmacokinetic data indicate that concomitant administration of bexarotene capsules during tamoxifen therapy is associated with a reduction in plasma tamoxifen concentrations. The major tamoxifen metabolites are primarily formed by the cytochrome P450 isozyme family.29 The primary tamoxifen metabolite, N-desmethyltamoxifen, is formed via CYP 3A4. Tamoxifen has a long elimination half-life in humans of approximately 5 to 7 days, and plasma tamoxifen concentrations are relatively stable at steady-state. Therefore, an alteration in plasma tamoxifen concentrations during concomitant therapy may occur as the result of induction or inhibition of CYP 3A4. The mean degree of reduction in tamoxifen levels with concomitant bexarotene (38%) is less than that reported in the literature for other enzyme-inducing drugs such as rifampin, aminoglutethimide, or phenytoin (60% to 86%). Concomitant therapies were examined for those patients in the assessable data set for whom concomitant therapy data were available. A review of the data indicated that a reduction in plasma tamoxifen concentrations was observed in patients receiving concomitant bexarotene irrespective of concomitant antilipemic therapy (none, atorvastatin, simvastatin, or fenofibrate). The mechanism of this bexarotene/tamoxifen interaction has not been determined. However, the reduction in tamoxifen concentrations is consistent with an induction of CYP 3A4, the cytochrome P450 enzyme primarily responsible for the metabolism of both tamoxifen and bexarotene.
In conclusion, although the preclinical data from the NMU rat model are compelling, in this study bexarotene produced limited antitumor activity for patients with progressive, hormone- and/or chemotherapy-refractory metastatic breast cancer. However, approximately 20% of patients derived clinical benefit (partial response and stable disease
In addition to the coauthor investigators, the following investigators contributed patients to this study: Jonathan Polikoff, MD, Kaiser Permanente (San Diego, CA); Richard Elledge, MD, University of Texas Health Sciences at San Antonio (San Antonio, TX); William Gradishar, MD, Northwestern University (Chicago, IL); Tanya Repka, MD, University of Minnesota (Minneapolis, MN); Nikolay Dimitrov, MD, Michigan State University (Ann Arbor, MI); Steven Come, MD, Beth Israel Deaconess Medical Center (Boston, MA); Barbara Burtness, MD, Yale University School of Medicine (New Haven, CT); Chris Theodossiou, MD, LSU School of Medicine (New Orleans, LA); Christy Ann Russell, MD, USC/Norris Cancer Center (Los Angeles, CA); Lisle Nabell, MD, University of Alabama at Birmingham (Birmingham, AL); Edith Perez, MD, Mayo Clinic Jacksonville (Jacksonville, FL); Przemyslaw Twardowski, MD, City of Hope National Medical Center (Duarte, CA); Jose Leis, MD, Oregon Health Sciences University (Portland, OR); Victoria Seewaldt, MD, and Charles Shapiro, MD, Ohio State University (Columbus, OH); Charles L. Vogel, MD, Columbia Cancer Research Network of Florida, Inc. (Plantation, FL); Charles Taylor, MD, University of Arizona Cancer Center (Tucson, AZ); F. Anthony Greco, MD, Sarah Cannon Cancer Center (Nashville, TN); Edgardo Rivera, MD, Vicente Valero, MD, Daniel Booser, MD, Richard Theriault, DO, Lajos Pusztai, MD, PhD, and James L. Murray, MD, The University of Texas M.D. Anderson Cancer Center (Houston, TX). We would like to thank research nurses and data managers involved in this study at all 28 sites.
This study was supported in part by Ligand Pharmaceuticals Inc, San Diego, CA. F.J.E. is a recipient of Career Development Award no. K23-CA82119 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
