Vol. 10, 1943–1948, March 15, 2004 Clinical Cancer Research 1943 Pilot Study Evaluating the Pharmacokinetics, Pharmacodynamics, and Safety of the Combination of Exemestane and Tamoxifen Edgardo Rivera,1 Vicente Valero,1 pharmacokinetics or pharmacodynamics and that the com- Deborah Francis,1 Aviva G. Asnis,2 bination is well-tolerated and active. Further clinical inves- Larry J. Schaaf,2 Barbara Duncan,2 and tigation is warranted. Gabriel N. Hortobagyi1 1Department of Breast Medical Oncology, The University of Texas INTRODUCTION 2 M. D. Anderson Cancer Center, Houston, Texas, and Pharmacia Breast cancer growth frequently is promoted by estrogen, Corporation, Peapack, New Jersey and approximately one-third of tumors respond to estrogen deprivation therapy (1). In current clinical practice, two main ABSTRACT single-agent strategies are used to deprive breast cancer cells of Purpose: We conducted a pilot study assessing the ef- estrogen. A selective estrogen receptor modulator (SERM), such fects of the selective estrogen receptor modulator, tamox- as tamoxifen, is given to block binding of the hormone to the ifen, on the pharmacokinetics, pharmacodynamics, and cancer cells. Alternately, in postmenopausal women, an inhib- safety of the steroidal, irreversible aromatase inhibitor (AI), itor of the enzyme, aromatase, is administered to suppress their exemestane, when the two were coadministered in post- main source of estrogen synthesis, conversion of androgens by menopausal women with metastatic breast cancer. this enzyme. Experimental Design: Patients with documented or un- One aromatase inhibitor (AI) that has been studied exten- known hormone receptor sensitivity were eligible. Patients sively and shown activity as a single agent in postmenopausal received oral exemestane at 25-mg once daily. Starting day women with breast cancer is exemestane (Aromasin, Pharmacia 15, oral tamoxifen at 20-mg once daily, was added. We Corp., Peapack, NJ; Ref. 2–4). In contrast to other currently measured plasma concentrations of exemestane, estrone, es- approved AIs, which are nonsteroidal (type II) agents that tem- trone sulfate, and estradiol after 14 days of exemestane porarily inhibit aromatase activity, exemestane is a steroidal monotherapy and after ϳ4 weeks of combination therapy. (type I) agent that permanently inactivates the enzyme (5–7). As The incidence and severity of adverse events were assessed an androstenedione derivative, exemestane serves as a false by physical examination and patient reporting. substrate for aromatase. The drug is processed through the Results: We treated 18 patients. All had received prior normal catalytic mechanism to a transformed product, which chemotherapy and/or hormonal therapy, eight and six, re- binds covalently and irreversibly to the catalytic site of the spectively, with single-agent selective estrogen receptor enzyme (“suicide inhibition”). Resumption of estrogen produc- modulators or irreversible aromatase inhibitors; no hormo- tion depends on the synthesis of new aromatase molecules. nal therapy was given within 30 days of study entry. Plasma The separate and potentially complementary mechanisms exemestane concentrations and estrone, estrone sulfate, and of action of SERMs and AIs have prompted study of combina- estradiol suppression were unchanged after ϳ4 weeks of tion therapy of breast cancer with tamoxifen plus individual AIs. tamoxifen coadministration. All drug-related adverse events Initial investigation in a nude mouse model of breast carcinoma were grades 1 or 2; none was unexpected. Although not a suggested that coadministration of tamoxifen and either of the formal study end point, antitumor activity was noted, with nonsteroidal AIs, letrozole or anastrozole, provided no added two partial responses and four cases of stable disease among activity compared with single-agent use of these AIs (8). A pair 17 evaluable patients after a 9-month median follow-up of early pharmacokinetic and pharmacodynamic clinical studies (range, 2.5–19 months). showed that the combination of tamoxifen plus a nonsteroidal Conclusions: This pilot study provides evidence that AI at clinically recommended doses decreased mean plasma coadministration of tamoxifen does not affect exemestane concentrations of the AI relative to levels attained with single- agent therapy; for example, there was a decrease by 37.6% in the case of letrozole (9) and 27% in the case of anastrozole (10). However, both studies showed no effect of the addition of tamoxifen on the reduction in plasma estrogens effected by the Received 7/8/03; revised 11/10/03; accepted 12/5/03. nonsteroidal AIs. Grant support: Pharmacia Corporation, Peapack, NJ research grants. In contrast to the preclinical experience with tamoxifen The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked plus a nonsteroidal AI, an early study in rats with 7,12-dimeth- advertisement in accordance with 18 U.S.C. Section 1734 solely to ylbenzanthracene-induced mammary tumors showed that the indicate this fact. combination of exemestane plus tamoxifen had greater activity Requests for reprints: Edgardo Rivera, Department of Breast Medical than did either agent alone (11). On the basis of these results and Oncology, Unit 424, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: on the demonstrated clinical efficacy of single-agent exemes- (713) 792-2817; Fax: (713) 794-4385; E-mail:erivera@mdanderson. tane (2–4) and tamoxifen (12) in this setting, we conducted a org. pilot study in postmenopausal women with metastatic breast Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2004 American Association for Cancer Research. 1944 Exemestane in Combination with Tamoxifen cancer to evaluate the pharmacokinetics, pharmacodynamics, ing tumor marker studies (cancer antigens 27–29 and carcino- and safety of exemestane when administered in combination embryonic antigen). Physical examination and all laboratory with tamoxifen. We now report the results of this trial. assessments were repeated every 8–12 weeks. Patients were told to report toxicities as any arose and were queried about adverse events during all follow-up visits. Toxicities were graded using PATIENTS AND METHODS the National Cancer Institute Common Toxicity Criteria, version Study End Points. To assess the pharmacokinetics of 2.0. Follow-up radiological evaluations were performed as re- exemestane when administered in combination with tamoxifen, quested by the primary physician. To verify compliance, pa- we measured plasma concentrations of exemestane after an tients were asked to bring their bottles of exemestane and initial period of single-agent administration and a subsequent tamoxifen on each follow-up visit and to document any missed period of combination therapy. To assess the pharmacodynam- doses. ics of exemestane in this setting, we performed similar meas- Patients continued on treatment until they had disease urements for plasma estrone (E1), estrone sulfate (E1S), and progression, became unable to tolerate or were noncompliant estradiol (E2). Additional endpoints were the incidence rate and with therapy, or withdrew consent. Patients were evaluated 4 grade of observed toxicities during the study, assessed by phys- weeks after their last dose of the combination and assessed for ical examination and patient reporting. any toxicities. We retrospectively plotted plasma exemestane concentra- Pharmacokinetic and Pharmacodynamic Measure- tion-time profiles after both the exemestane monotherapy and ments. Collection, storage, and processing of blood speci- exemestane plus tamoxifen combination therapy periods. In mens for pharmacokinetic and pharmacodynamic (i.e., estrogen) addition, we performed a retrospective statistical comparison of measurements were carried out according to specified proce- mean plasma estrogen values between these periods, with the dures. Briefly, blood samples were collected via venipuncture or study population serving as its own control. Compliance with an indwelling i.v. cannula on two occasions: at the end (day 14) and clinical response to therapy were not formal study end of the 2-week single-agent exemestane treatment period, and points but were recorded. after ϳ4 weeks of combination treatment (i.e., ϳ6 weeks after Eligibility Criteria and Ethical Considerations. Pa- the first dose of exemestane). These collection times were tients were eligible for the study if they had stage IV breast chosen in light of the published times to attain steady-state cancer with documented or unknown hormone receptor sensi- serum concentrations of 7 days for exemestane and 3–4 weeks tivity, were postmenopausal, and were candidates for hormonal for tamoxifen given as single agents at the doses used in our therapy. Patients who had received single-agent tamoxifen or study (7, 14). For exemestane pharmacokinetic measurements, AIs in the adjuvant or metastatic setting were eligible, as long as ϳ5 ml of venous whole blood was obtained before (0 h) and 1, these drugs had not been given within 21 days of study entry. 2, 4, 6, 8, and 24 h after dosing. For pharmacodynamic meas- Patients were required to have measurable or evaluable disease, urements, a single 16-ml venous whole blood specimen was a life expectancy Ն12 weeks and a Zubrod performance status obtained on the mornings of the two collection occasions (pos- (13) Յ1. Other eligibility criteria