Pilot Study Evaluating the Pharmacokinetics, Pharmacodynamics, and Safety of the Combination of Exemestane and Tamoxifen

Home , Anastrozole, Aromatase inhibitor, Tamoxifen, Toremifene

Vol. 10, 1943–1948, March 15, 2004 Clinical Cancer Research 1943

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

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 included adequate bone mar- texemestane monotherapy period and postcombination treat- row, liver and kidney function, respectively, defined as an ment period). absolute granulocyte count of Ն1,500/␮l and platelet count of All blood samples were drawn into chilled blood collection Ն100,000/␮l, a bilirubin concentration of Ͻ1.5 mg/dl and cre- tubes containing sodium heparin as anticoagulant and immedi- atinine Ͻ2.5 mg/dl. Exclusion criteria included a history of deep ately placed in ice-water before centrifugation (1000–1200 ϫ g venous thromboembolism, pulmonary embolism, or stroke. The for 10–15 min at 4°C) within 30 min of collection. The har- use of hormone replacement therapy or of over-the-counter vested plasma was transferred to screw-cap polypropylene stor- products or supplements considered to have estrogenic effects, age tubes and stored frozen at approximately Ϫ20°C until such as ginseng, ginkgo biloba, and black cohosh, was not analysis. allowed during the study. Also prohibited during the trial was Plasma concentrations of exemestane were measured using the use of raloxifene for osteoporosis. a validated, sensitive, and specific high-performance liquid The study was approved by the Institutional Review Board chromatography method with tandem mass spectrometric detec- of the University of Texas M. D. Anderson Cancer Center, and tion (15). The lower limit of quantitation (LLOQ) of this assay all patients provided written informed consent to participate. was 0.1 ng/ml using 0.50 ml of aliquots. Treatment Plan and Evaluation. Patients were given Pharmacodynamic samples were assayed for plasma con-

single-agent exemestane (provided by Pharmacia Corp.), 25-mg centrations of E1,E1S, and E2 using solid-phase extraction and once daily, starting on day 1. On day 15, tamoxifen, 20-mg once high-performance liquid chromatography purification followed daily, was added. Both drugs were taken orally with a light by highly sensitive radioimmunoassay, according to a procedure meal. described previously (16). The LLOQ of the assay were 1.8

Before study entry, patients underwent a complete history pg/ml for E1, 6 pg/ml for E1S, and 0.7 pg/ml for E2. Estrogen and physical examination, including evaluation of performance concentrations below the LLOQ were recorded as the value of status and weight and documentation of all prior anticancer that limit. treatments and their residual side effects, if any. Baseline im- Statistical Analyses. Because this was a pilot study orig- aging studies were obtained to define the extent of disease. inally planned to generate only descriptive statistics, no formal Baseline laboratory tests included a complete blood cell count sample-size calculations were performed. Retrospectively, mean

with differential and platelet counts and blood chemistry includ- plasma concentrations of E1,E1S, and E2 following the exemes-

tane monotherapy and the tamoxifen plus exemestane combination therapy periods were compared using the nonparametric Mann-Whitney U test. Ps Ͻ 0.05 were considered to be statistically significant.

RESULTS Patient Characteristics. Between September 2001 and April 2002, 18 eligible patients were recruited; Table 1 lists their characteristics. Most patients were in late middle age, had bone as their dominant disease site, and were treated previously. Six patients had experienced progressive disease on single-agent tamoxifen, and two patients on single-agent exemestane. All patients received therapy for at least the planned 8 weeks, except one individual who withdrew from the study for personal reasons after 2 weeks of combination treatment. Thir- teen of the 17 remaining patients took all study medication prescribed per protocol, and an additional three missed only 2 days of dosing each because of surgeries. Pharmacokinetic Measurements. For exemestane pharmacokinetic measurements, blood samples were available from at least one collection occasion (i.e., the end of the exemestane monotherapy period and/or after ϳ4 weeks of combination Fig. 1 Mean (ϮSE) plasma concentration-time profiles of exemestane treatment) for all 18 patients. Samples were available for all given as monotherapy or in combination with tamoxifen. time points during both collection occasions for seven patients. Two of the 18 patients did not have any specimens collected during the combination treatment period and nine patients had a Estrogen Measurements. Estrogen specimens were re- specimen for at least one time point missing or with labels that ceived at the laboratory for 16 patients during the monotherapy became detached during shipping to the laboratory. Four pa- period and for 15 patients during the combination treatment tients had concentrations at 24 h after dosing that were much period. E1 concentrations could not be determined for one higher than at earlier time points, and these findings were patient, and E1S concentrations could not be quantified for three attributed to specimen collection after the patients had taken patients because of insufficient volume available for reanalysis their next morning dose. These four 24-h specimens were not of the samples; no reportable result had been obtained during included in subsequent analysis. initial analysis. E2 concentrations were determined for all Mean plasma concentration-time profiles of exemestane patients. when exemestane was administered alone were similar to those In this study, baseline estrogen levels were not measured. observed when exemestane was combined with tamoxifen (Fig. However, in a similar population of breast cancer patients, and 1). This suggests that tamoxifen does not alter the pharmacoki- using the same assay methodology, mean pretreatment levels of netics of exemestane. 40.8, 349.8, and 10.3 pg/ml were reported for E1,E1S, and E2, respectively (2). A profound suppression of all plasma estrogens after 2 weeks of exemestane monotherapy was confirmed in the present study, with mean concentrations of 2.3, 25.4, and 0.7 Table 1 Patient characteristics pg/ml for E1,E1S, and E2, respectively (Table 2). The E1 and Characteristic No. of patients/value E1S suppression that was achieved after 2 weeks of exemestane Total patients 18 monotherapy was maintained after ϳ4 additional weeks of Age combination therapy (Table 2). Mean E levels were suppressed Median (range) 62 yrs (46–84 yrs) 2 Performance status below the LLOQ in all but one evaluable patient after 2 weeks 118of exemestane monotherapy and were suppressed below the Dominant metastatic site LLOQ in all evaluable patients after an additional ϳ4 weeks of Viscera 2 combination therapy (Table 2). In a retrospective analysis, no Bone 15 statistically significant differences were noted between plasma Soft tissue 6 Prior therapy concentrations of any measured hormone after the monotherapy Chemotherapy 15 period versus after ϳ4 weeks of combination therapy (Table 2). Hormones 16 Toxicity. All 18 patients were evaluable for toxicity. Prior hormonal therapy After a median follow-up of 9 months (range, 2.5 to 19 months), SERM 8 AI 6 both single-agent exemestane and combination therapy with Progestins 2 exemestane and tamoxifen were very well tolerated. All drug- Androgens 2 related adverse events were classified as mild or moderate AI, aromatase inhibitor; SERM, selective estrogen receptor mod- (Table 3), and no patient withdrew from the study because of ulator. toxicity. No unexpected toxicities were reported. Three of six

Table 2 Mean (ϮSD) plasma concentrations of estrogen markers bination was very well tolerated, with only mild or moderate after exemestane drug-related toxicity and no unexpected adverse events ob- Monotherapy and exemestane ϩ tamoxifen combination therapy. served during a median follow-up of 9 months. We did not Treatment period measure markers of the effects of combination therapy on the Estrogen marker, bone or on hepatic metabolism of lipids or lipoproteins; it will pg/ml Exemestane monotherapy Combination therapy be of interest to do so in future studies. a Estrone 2.3 Ϯ 1.1 (n ϭ 16) 2.5 Ϯ 0.8 (n ϭ 14) Although efficacy was not an end point of this pilot study, Estrone sulfate 25.4 Ϯ 24.0 (n ϭ 13) 21.7 Ϯ 17.7a (n ϭ 12) Estradiol 0.7b (n ϭ 16) 0.7a,c (n ϭ 14) over a 9-month median follow-up, we noted encouraging antitumor activity of the combination. Clinical benefit (i.e., partial a Ͼ Not significant (P 0.05, nonparametric Mann-Whitney U test); response or stable disease lasting Ͼ6 months) was seen in 5 of retrospective comparison of mean value, after exemestane ϩ tamoxifen combination therapy vs. after exemestane monotherapy. 17 patients evaluable for efficacy. It is noteworthy that both b All values but one below the lower limit of quantification. partial responders in our trial previously had disease progression c All values below the lower limit of quantification. despite adjuvant therapy with single-agent tamoxifen and that two of four patients with stable disease, including two of three with stable disease for Ͼ6 months, had received prior treatment with a single-agent AI. patients with bone pain and one of nine with hot flashes during Our findings of no effect of SERM coadministration on the study had reported these symptoms at baseline. Although a pharmacokinetics or pharmacodynamics of a steroidal AI agree comparison of toxicity during exemestane monotherapy versus with preliminary results from two clinical studies reported be- during combination therapy was not a formal study objective, cause we conducted our trial. A German pharmacokinetic study our clinical impression was that toxicity was similar during both noted no effect of the SERM, toremifene, on the mean area periods. under the curve or Cmax of the steroidal AI, atamestane, in 12 Efficacy. Response-related data were not end points of evaluable patients (17). In an initial 14-patient cohort, a Uni- this study. However, response was evaluable in all 17 patients versity of Wisconsin pharmacokinetic and pharmacodynamic who received the planned duration of therapy. After a median study (18) in postmenopausal women receiving adjuvant treat- follow-up of 9 months (range, 2.5 to 19 months) from study ment for early-stage breast cancer observed a mean area under entry, we observed antitumor activity of the combination of the curve of exemestane after 8 weeks of coadministration with exemestane and tamoxifen, with two partial responses and four tamoxifen that was similar to the published mean area under the cases of stable disease in the 17 patients. The two partial curve of single-agent exemestane in healthy postmenopausal responders previously had disease progression despite adjuvant women. Also in the Wisconsin study, after 8 weeks of combi- therapy with single-agent tamoxifen. Neither one of these two nation therapy, plasma E1 and E2 were suppressed to undetect- patients had previously received AIs. In the current trial, their ability in 8 of 12 and in all 14 patients, respectively. The time to response was 3 and 2 months, and their time-to-tumor Wisconsin study design differed from ours in preceding combi- ϩ progression was 7 and 19 months. In the patients with stable nation therapy with tamoxifen rather than exemestane mono- ϩ ϩ disease, time-to-tumor-progression was 8, 19 ,15 , and 5 therapy. Also, the Wisconsin trial took measurements after 8 months. Three of the four patients with stable disease, including rather than 4 weeks of combination therapy and 12 rather than Ͼ two of the three patients with stable disease for 6 months, had ϳ6 weeks of therapy in general. However, both studies used the received a prior single-agent AI. same doses for tamoxifen and exemestane, 20- and 25-mg once daily, respectively. DISCUSSION Of interest, although our trial did not address this question, This pilot study provides preliminary evidence suggesting that coadministration of tamoxifen does not affect the pharmacokinetics or pharmacodynamics of exemestane in postmenopausal women with metastatic breast cancer. Mean plasma con- Table 3 Drug-related adverse eventsa (N ϭ 18) centration-time profiles of exemestane were virtually identical No. of patients after 2 weeks of exemestane monotherapy and ϳ4 weeks of Toxicity Grade 1b Grade 2b coadministration with tamoxifen. Plasma E1,E1S, and E2 concentrations were rapidly and markedly suppressed by exemes- Nausea 6 0 tane monotherapy. In a retrospective analysis, these pharmaco- Alopecia 1 0 dynamic effects were found to be maintained without Bone pain 0 6 ϳ Hot flashes 5 4 statistically significant changes after 4 weeks of combination Myalgias 2 1 therapy. Although most patients had received prior hormonal Nail changes 1 0 therapy, the study protocol precluded such therapy during a Vaginal bleeding 2 0 3-week “washout period” before study entry, and in practice, Diarrhea 2 0 Constipation 2 0 none was received within 30 days of study entry. Therefore, our Edema 1 0 pharmacokinetic and pharmacodynamic results are unlikely to Fatigue 5 1 have been influenced by prior hormonal therapy. a Median follow-up of 9 months (range, 2.5–19 months). This pilot study also provides preliminary evidence of the b Toxicities were graded according to the National Cancer Institute safety of exemestane and tamoxifen coadministration. The com- Common Toxicity Criteria; no grade 3 or 4 events were observed.

the German and Wisconsin studies observed no effects of the AI. These properties might include the mild androgenic effects steroidal AI on SERM pharmacokinetics, including, in the case of this class of drug on breast tumor tissue (4); indeed, a recent of the Wisconsin study, those of the tamoxifen metabolites, animal study (23) suggests that androgens inhibit mammary 4-hydroxy-tamoxifen and N-desmethyl tamoxifen. A similar epithelial proliferation. lack of altered SERM pharmacokinetics has been observed in Whether clinical results differ when a steroidal instead of a studies of tamoxifen plus letrozole (9) or anastrozole (10). nonsteroidal AI is given in combination with a SERM will be The body of the evidence thus far, then, would suggest that determined by a recently developed multicenter phase III North when a SERM and an AI are coadministered, the type of AI that Central Cancer Treatment Group study. This trial will compare is given (i.e., steroidal versus nonsteroidal) affects the pharma- the efficacy and safety of exemestane and tamoxifen as single cokinetics of the AI but not the SERM. It is possible that the agents and in combination, in postmenopausal women with observation of reduced plasma levels of nonsteroidal but not metastatic breast cancer. steroidal AIs in combination with SERMs is an artifact of the duration of follow-up of the studies in question, which tended to ACKNOWLEDGMENTS be longer (12 weeks to 8 months) in the nonsteroidal AI than in We gratefully acknowledge the efforts of the nursing and labora- the steroidal AI trials (Յ12 weeks; 9, 10, 17, 18). However, the tory staff, the cooperation of the study participants, the valuable advice consistency of this observation across several studies suggests of Enrico di Salle, and the editorial assistance of Robert J. Marlowe. that an artifactual explanation is unlikely. 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Edgardo Rivera, Vicente Valero, Deborah Francis, et al.

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