|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2002 American Society for Clinical Oncology Phase I Clinical and Pharmacologic Trial of Intravenous Estramustine PhosphateByFrom the Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA; Active Biotech Research AB, Lund, Sweden; and Pharmacia Corporation, Peapack, NJ. Address reprint requests to Gary Hudes, MD, Department of Medical Oncology, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email: g_hudes{at}fccc.edu
PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP). PATIENTS AND METHODS: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m2. Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment.
RESULTS: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m2, and cumulative fatigue developed after multiple cycles at 2,500 mg/m2. Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 µmol/L after IV EMP doses CONCLUSION: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.
ESTRAMUSTINE PHOSPHATE (EMP), a nornitrogen mustard carbamate derivative of estradiol-17-beta-phosphate, is widely used for the treatment of advanced prostate cancer. An intravenous formulation of EMP (IV EMP) was initially produced for administration on a multiple-day, low-dose (300 to 450 mg) loading schedule (eg, daily for 7 to 10 days) by short infusion into a peripheral vein, a route that was associated with a high rate of superficial phlebitis.1 The apparent vesicant effect of peripheral IV administration, together with the convenience of an oral formulation for daily use, led to greater use of oral EMP in the clinic. Approved for the palliative treatment of metastatic prostate cancer in 1981, oral EMP is the only formulation of EMP presently available in the United States. Although oral EMP demonstrated modest single-agent activity in patients with hormone-refractory prostate cancer (HRPC), re-evaluation of its mechanism of action in a series of preclinical investigations predicted that the drug would be more effective if administered in combination with other antimitotic agents. These studies, undertaken because the structure and toxicity profile of the drug were atypical for an alkylating agent, established that estramustine (EaM) and its major metabolite estromustine (EoM) are devoid of alkylating activity.2 Instead, both possess antimitotic properties3,4 independent of hormonal effects that result from estrogenic metabolites.5 EaM binds directly to tubulin6-8 and to microtubule-associated proteins (MAPs).9-11 Binding of EaM (and presumably EoM) to these microtubule targets results in inhibition of microtubule dynamics,8 leading to anaphase arrest in a dose-dependent fashion.12 Pharmacokinetics of both IV EMP and oral EMP have been studied in small cohorts of patients.13,14 These limited data, together with other in vitro and clinical studies,15,16 indicated that EMP was rapidly dephosphorylated to metabolites EaM and EoM, the latter via oxidation of EaM at the C17 position of the estradiol (E2) moiety, with additional metabolism of EaM and EoM to E2 and estrone (E1), respectively (Fig 1). The interaction of orally administered EMP with calcium-containing foods leads to large intrapatient and interpatient variability in plasma levels of the active metabolites, which could affect antitumor activity.17
Nausea and fluid retention are common toxicities of oral EMP administered on a daily schedule.1 Less frequently, but with more serious consequences, cardiovascular toxicity (predominantly venous thrombosis) may occur during oral EMP therapy. In combination studies, particularly those using oral EMP and a taxane, thrombotic events complicate treatment in approximately 10% of patients.18-21 The cardiovascular effects of oral EMP have been attributed in part to first-pass hepatic metabolism that can lead to high intrahepatic concentrations of estrogenic metabolites and consequent hypercoagulability, for example, through reduction of antithrombin III levels.22 Like IV estrogen therapy, the IV administration of EMP may permit use of higher doses of the drug intermittently with reduced risk of thromboembolism compared with daily oral dosing of the drug.23 Although IV EMP doses of 300 to 900 mg per day for 7 to 10 consecutive days have been well tolerated,1,24 formal phase I evaluation of the presently available IV formulation has not been previously reported. Thus, dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD) for IV EMP have not been determined. The occurrence of hepatotoxicity in some patients treated with IV EMP and oral EMP1,24 suggested that hepatotoxicity might be dose limiting. Preliminary pharmacokinetic data (unpublished) indicated longer elimination half-lives for EoM and EaM than had been previously observed after IV EMP administration. We hypothesized that weekly administration of IV EMP would produce levels of active metabolites equivalent to or greater than those achieved by daily, oral EMP with reduced toxicity. We therefore initiated a phase I trial of IV EMP to determine the DLTs and MTD of IV EMP given by weekly infusion in male patients with refractory malignancies, describe the pharmacokinetic properties of IV EMP on a weekly schedule, and document antitumor effects. The results of this phase I trial support additional study of IV EMP in clinical trials of EMP-based combination therapies.
The institutional review board of the Fox Chase Cancer Center approved the protocol describing all treatment and procedures included in this study. Written informed consent was obtained from all patients before entering the study.
Patient Selection Patients with prostate cancer were required to have progressive disease after first-line hormonal therapy but may have received additional hormonal therapy or chemotherapy. Prior therapy with oral EMP was permitted but not within 3 months of registration. For patients who had not undergone orchiectomy, androgen ablation with luteinizing hormone–releasing hormone therapy was continued, whereas other hormonal therapies were not permitted within 2 weeks of registration. A minimum observation period of 4 weeks after discontinuing flutamide (6 weeks for nilutamide and bicalutamide), with evidence of progression, was required for patients treated with antiandrogens. Patients with prostate-specific antigen (PSA) elevation alone as the only evidence of recurrent disease were not eligible. Patients were required to have adequate bone marrow, renal, and hepatic functions, defined as WBC count of 4,000/µL or greater, platelet count of 100,000/µL or greater, serum creatinine 1.5 mg/dL or less, total bilirubin within the normal range, and AST/ALT two times the upper limit of normal or less. Patients with uncontrolled brain metastases and patients with history of deep venous thrombosis (DVT) or pulmonary embolism were ineligible. Patients with myocardial infarction or symptomatic cardiac ischemia within 6 months before registration were excluded. Known hypersensitivity to E2 or nitrogen mustard was also grounds for exclusion.
Drug Formulation and Treatment
Dose Escalation and Definitions of DLTs and MTD Toxicity was graded according to the United States National Cancer Institute Common Toxicity Criteria (Version 1.0). DLT was defined as any hematologic or nonhematologic toxicity grade 2 or higher that did not resolve within 1 week after dosage reduction or that recurred or any toxicity grade 3 or higher that occurred during cycle 1. Thus, dose reduction for 2 weeks or longer of the initial 4-week cycle was considered DLT. The MTD was defined as the starting dose level associated with zero, one, or two instances of DLT, with the next higher dose level having three or more instances of DLT. Because the chronicity of toxicities can also affect the tolerability of a new treatment, selection of a recommended phase II dose took this assessment into account.
Duration of Therapy and Dose Modification
Evaluations Patients were examined at a minimum of every 4 weeks, and toxicity was assessed weekly. Complete blood count and chemistries were repeated weekly for the duration of protocol therapy. PSA was repeated every 4 weeks. Bone scans were obtained every two cycles (2 months), and if initially positive, CT scans and other imaging studies were repeated every two cycles of treatment.
Pharmacokinetics Plasma concentrations of EMP were measured by a reverse-phase high-pressure liquid chromatography method with fluorescence detection, and the metabolites EaM, EoM, E2, and E1 were measured using gas chromatography with nitrogen-phosphorus and mass spectrometric detection techniques, as previously described.25 Limits of quantitation (LOQ) were 2.3 µmol/L plasma for EMP, 30 nmol/L for EaM and EoM, 12 nmol/L for E1, and 8 nmol/L for E2. Interassay variability was 2.7% to 7.3% for EMP, 5.9% to 9.1% for EoM, 4.8% to 9.7% for EaM, 5.8% to 21.1% for E1, and 9.6% to 10.7% for E2, respectively. WinNonlin Professional Version 2.0 (Pharsight, Mountain View, CA) was used for calculation of the noncompartmental pharmacokinetic parameters. The maximum concentration (Cmax) and time to maximum concentration (tmax) values were determined from the observed plasma concentration versus time curves. Only patients with 30-minute infusion times (see below) were included in the analysis of dose versus Cmax.
The elimination half-life, t1/2, was determined from the relationship t1/2 = ln2/
The AUC after three daily administrations was estimated as total AUCinf = AUC24h + (AUC24h + AUC48-72h)/2 + AUC 48h-t + Ct/
Statistical Analysis Time dependency was evaluated by analysis of variance assuming steady state after 4 weeks, with the logarithm of the parameter as the dependent variable, whereas subject and week of treatment were independent variables. The statistical analysis was performed assuming that the residuals in the analysis were normally distributed. The assumption was tested by the Shapiro-Wilk test.
Patient Demographics Patient characteristics are summarized in Table 1. A total of 31 patients were enrolled between January 1997 and July 1999. Although male patients with any solid tumor were eligible, all patients accrued to this trial had metastatic HRPC. All patients had undergone prior orchiectomy or received luteinizing hormone–releasing hormone therapy, either together with antiandrogen or with the antiandrogen delayed until progressive disease on monotherapy, and all had progressive disease after withdrawal of antiandrogen therapy. Twelve patients (39%) had received prior chemotherapy, including 10 patients (32%) who had received previous oral EMP treatment. A total of 70 cycles of treatment were administered over seven dose levels. The median number of cycles received was two (range, one to six).
Dose Escalation, DLT, and MTD IV EMP was escalated from 500 to 1,000 mg/m2 without dose-limiting toxicity. Rectal burning was noted in five of eight patients treated at these dose levels, but it was fleeting, described by patients as a minor annoyance, and did not require interrupting or slowing the rate of infusion. At the 1,500-mg/m2 dose level, all patients experienced severe rectal and perianal burning commencing within the first minute of the initial infusion, increasing in intensity over the next 5 to 10 minutes, and then gradually diminishing over the remaining infusion time. Rectal discomfort required cessation of IV EMP followed by reduction of the infusion rate in several patients at this dose level. Consequently, the infusion time of IV EMP was increased to 60 minutes for subsequent patients treated at 1,500 mg/m2 and for patients treated at 2,000 mg/m2. Because prolonging the infusion time at the lower dose levels ameliorated rectal burning, the infusion time was additionally increased to 90 minutes for patients treated at 2,500 and 3,000 mg/m2. Three of the six patients treated at 2,500 mg/m2 and none of the four patients treated at 3,000 mg/m2 required additional slowing of the infusion rate for the first week of treatment because of rectal pain. Thus, rectal pain was related to the IV EMP dose rate rather than simply the dose alone. The cohort treated at 1,500 mg/m2 was expanded to six assessable patients because of one DLT (deep vein thrombosis, grade 3 bilateral lower leg edema) in the initial three patients treated at that level. A seventh patient began treatment at 1,500 mg/m2 but withdrew consent after experiencing rectal burning during the first infusion. Six patients were treated at 2,500 mg/m2 because of DLT (deep vein thrombosis) in one of the initial three patients. Four patients received an IV EMP starting dose of 3,000 mg/m2; two of four patients treated at this level experienced dose-limiting fatigue and malaise, and a third had grade 3 hypotension. All of these patients required dose reduction to 75% of the starting dose after the first infusion, indicating that the MTD had been exceeded and thus ending dose escalation. On the basis of these findings, the MTD was established as 2,500 mg/m2. Given the overall pattern of toxicities observed, 2,000 mg/m2 was determined to be the recommended phase II dose.
Toxicity
Hematologic toxicity. Myelosuppression was rarely observed. One patient treated at the 3,000-mg/m2 dose level had transient neutropenia associated with an unusual reaction to his first infusion (see below). No other patient experienced neutropenia, and thrombocytopenia was observed in only three patients. One heavily pretreated patient at the 1,000-mg/m2 dose level experienced grade 2 thrombocytopenia. This patient had received multiple courses of external radiation with cumulative exposure to approximately 50% of marrow-containing skeleton. In addition, he received two courses of strontium-89 and two chemotherapy regimens before treatment with IV EMP. Two other patients had grade 1 thrombocytopenia, one treated at 2,500 mg/m2 and the other on the loading schedule of 1,500 mg/m2 for 3 days in week 1 followed by 1,500 mg/m2 as a single weekly dose. Anemia of grade 1 or 2 was present at baseline in 25 and four of the patients, respectively. After initiation of treatment, anemia worsened by 1 grade in 14 patients, with one patient increasing from grade 2 to grade 3. In addition, one patient became anemic (grade 1) on study. Gastrointestinal toxicity. Nausea of grade 1 or 2 was experienced by 81% of patients over all dose levels throughout the duration of the trial and was associated with emesis in 58% of patients. Because of the predictable onset and duration of nausea and the increasing intensity after dose escalation to 1,500 mg/m2/wk, prophylactic prochlorperazine was instituted before and 4 hours after each IV EMP infusion for patients treated at the 2,000-mg/m2 and higher dose levels. This intervention was partially successful in ameliorating nausea and vomiting, but even with such premedication, grade 1 or 2 nausea and emesis remained a concern for several of the patients treated at doses higher than 2,000 mg/m2 and required use of other antiemetics. Eleven patients (36%) experienced mild to moderate (grade 1 or 2) diarrhea. There were no episodes of stomatitis. Rectal burning (proctalgia), as described above, was a transient effect temporally associated with the start of the first IV EMP infusion in 81% of patients. It was easily managed by stopping the infusion until resolution of the burning, usually for 10 to 20 minutes, followed by resuming treatment at a slower infusion rate, as described above. Rectal pain rarely recurred, and dose interruption or reduction was never required for this effect in any patient during the second and subsequent IV EMP infusions. Cardiovascular toxicity. Fluid retention manifest as lower-extremity edema was noted in 10 patients (32%) and was not dose-related. One patient at the 1,500-mg/m2 level developed congestive heart failure after his sixth cycle (24 weeks) of treatment. Two additional patients experienced cardiac toxicity. One patient experienced transient grade 2 bradycardia and hypotension, both occurring in association with rectal pain, and grade 1 paresthesias affecting the neck, thighs, and arms that developed at the start of his first IV EMP infusion at 1,500 mg/m2 (30-minute rate). The hypotension and bradycardia were believed to be part of a vasovagal response to proctalgia and resolved within 20 minutes of stopping the infusion. This patient was retreated uneventfully 24 hours later with the same dose of IV EMP but with an increased infusion time of 60 minutes. Another patient developed grade 3 hypotension associated with the onset of malaise, fever, chills, rigors, and hypotension within 2 hours of completing the first dose of IV EMP 3,000 mg/m2. Unlike the vasovagal reaction described above, this patient did not have severe proctalgia preceding the hypotensive episode. An ECG obtained during the hypotensive episode revealed a new left bundle branch block but no changes suggestive of acute myocardial ischemia. Laboratory studies during this event revealed grade 2 neutropenia, grade 2 hyperbilirubinemia, grade 3 transaminase elevations, and grade 2 creatinine elevation. Hypotension and malaise resolved quickly after modest fluid replacement, and other symptoms and laboratory abnormalities of this acute reaction reversed within 24 hours of onset. Repeat ECG 6 hours after the initial study and correction of hypotension showed resolution of the left bundle branch block. Multiple cultures were negative for bacterial infection, and other causes of hypotension, such as acute pulmonary embolism and myocardial infarction, were ruled out. This patient did not receive additional treatment with IV EMP. DVT has been observed with oral EMP, particularly in studies using continuous daily EMP in combination with taxanes, etoposide, and carboplatin.18-21 We observed three episodes of extremity DVT (9.7%) with IV EMP. One patient with bilateral pelvic adenopathy and locally advanced tumor invading the bladder base developed a lower-extremity DVT after his third week of treatment at 1,500 mg/m2. Two other patients developed upper-extremity thrombosis, both in association with a subclavian catheter. One of these patients developed superficial thrombosis in a brachial vein, distal to the subclavian catheter, after his third dose of IV EMP. The second patient developed subclavian DVT during the third cycle (10th week) of treatment. Neither of these patients had received prophylactic warfarin after insertion of the subclavian catheter. These two episodes of upper-extremity DVT were the only such events among the 31 patients, all of whom had subclavian venous access catheters, over a total of 70 courses of treatment. Hepatotoxicity. Elevations of hepatic transaminases in 14 patients (45%) and total bilirubin in nine patients (29%) were observed during the first 4 weeks of treatment. Transaminase elevations were grade 1 to 2 and did not recur with subsequent cycles of treatment even when doses were maintained. Bilirubin elevations were also transient, and with the exception of two patients at the highest dose levels, were restricted to the initial 4 weeks of treatment. Although hepatic transaminase elevations did not occur more frequently at the higher dose levels, all nine patients with bilirubin elevation were treated at 2,500 or 3,000 mg/m2 or received the loading schedule of 4,500 mg/m2 in the first week. Malaise and fatigue. Malaise or fatigue were reported during the first cycle in 13 (46%) of 28 patients receiving once weekly treatment, was more frequent and severe at doses of 2000 mg/m2 or greater, and was a DLT for three of four patients enrolled at 3,000 mg/m2 (Table 2). Although not dose limiting in the first 4 weeks of treatment at lower doses, fatigue considered to be drug related resulted in treatment breaks or discontinuation of therapy for six patients after receiving 8 to 24 consecutive weeks of IV EMP. Other toxicities. Several other treatment-related toxicities were observed, none of which seemed to be dose dependent. Reversible renal impairment occurred in three patients, one at the 1,500-mg/m2 x 3 level with grade one creatinine elevation and two at the 3,000-mg/m2 level, one with grade 1 and the other with grade 2 elevation of creatinine. Mild breast enlargement (grade 1) occurred in 12 patients (39%), and nipple sensitivity or nipple tenderness affected 16 patients (52%). Asymptomatic fever of grade 1 was detected in 13 patients (42%) during cycle one when vital signs were routinely obtained during hospitalization for pharmacokinetic studies after the first and fourth doses of IV EMP. There were two grade 2 infections, both bacterial pneumonia, and one grade 3 infection, an episode of catheter-related sepsis. None of these infections occurred in association with neutropenia. Grade 1 anorexia was reported by 15 patients (48%), and one patient experienced grade 3 anorexia (3%). Seven patients reported grade 1 to 2 dyspnea that was not associated with pneumonia or pulmonary congestion. Three patients described exacerbation of bone pain requiring additional doses of narcotic medication within 24 hours of IV EMP infusion.
Pharmacokinetics of EMP and Metabolites
EMP Pharmacokinetic parameters for EMP after the initial infusion and week 4 infusion are summarized in Table 4. The tmax for EMP varied according to infusion time, ranging from 0.5 to 2.2 hours as the infusion time was extended and as dose escalation proceeded.
Week 1 values of Cmax ranged from 288 to 1,370 µmol/L over the IV EMP dose range of 500 to 3,000 mg/m2. The corresponding week 4 values ranged from 244 to 1,130 µmol/L. There was no change in the volume of distribution, whereas the CL of EMP increased 37% (28% to 46% geometric mean and 90% CI) after the fourth week of treatment compared with the first week (P < .001, analysis of variance). Week 1 and week 4 mean values for total clearance (CL) of EMP were 3.7 ± 1.0 and 5.0 ± 1.0 L/h, respectively (Table 4). The interpatient variations in EMP CL for week 1 and week 4 were 26% and 21%, respectively. There was no correlation of EMP CL with dose, supporting the linearity of EMP pharmacokinetics. EMP AUC values ranged from 440 to 4,210 µmol/L/hr after 1 week of treatment, and from of 330 to 2,970 µmol/L/hr after 4 weeks of treatment. Mean elimination t1/2 for EMP was 3.7 hours. Consistent with this short t1/2, plasma EMP concentrations usually were below the limit of quantitation by 24 hours after dosing. No significant deviations (P > .05) from dose proportionality for AUC (Fig 4A) and Cmax were found after the week 1 and 4 infusions.
EaM and EoM. Pharmacokinetic parameters for EaM and EoM are summarized in Table 5. EoM was the main metabolite in plasma after IV EMP administration. Mean tmax values for EoM ranged from 2.0 to 2.8 hours, and for EaM, 1.2 to 2.5 hours, again reflecting the longer infusion duration at the higher dose levels. As the initial dose of IV EMP increased from 500 to 3,000 mg/m2, the EoM Cmax values increased from 2.0 to 30.2 µmol/L and the EaM Cmax values increased from 1.22 to 25.1 µmol/L. Corresponding values of AUCinf ranged from 46.1 to 682 µmol/L/hr for EoM and 16.1 to 166 µmol/L/hr for EaM (Table 5).
Elimination t1/2 of EoM and EaM was longer than previously reported.12-14 Mean terminal t1/2 was estimated to be 110 hours for EoM and 64 hours for EaM. Consequently, significant concentrations of both metabolites were present at the end of the dosing interval (C168h). For example, the C168h of EoM at steady state measured 7 days after a 2,000-mg/m2 IV EMP dose was 1.4 µmol/L, or 40% of the EoM plasma concentration measured 24 hours after dosing. Thus, accumulation of this metabolite after weekly dosing could account for the observed increase of EoM AUC168h after the fourth week of IV EMP (Table 5). The accumulation ratio of AUC168h was 1.4. However, the accumulated exposure to EoM over time was not greater than expected, as shown by the similarity of the EoM AUCinf values at week 1 and the AUC168h values at week 4. There was no significant time dependency in EaM exposure, and EaM Cmax and AUC168h after the first and fourth doses of IV EMP were similar. Values of AUC168h for both metabolites were proportional to dose after weeks 1 and 4 of IV EMP (Figs 4B and 4C). Week 1 and week 4 interpatient variability of AUC per dose values for EoM and EaM ranged from 28% to 33%. E2 and E1. Noncompartmental pharmacokinetic parameters for the estrogenic metabolites E2 and E1 for weeks 1 and 4 are summarized in Table 6. tmax for E2 and E1 ranged from 1.0 to 7.5 hours and 1.0 to 5.5 hours, respectively, varying with the infusion duration. The overall mean terminal t1/2 for E2 and E1 was 67 hours and 120 hours, respectively, the E2 t1/2 similar to that of EaM and the E1 t1/2 paralleling the elimination of EoM. Cmax levels of E2 and E1 increased with IV EMP dose, and, like EMP and the other metabolites, the Cmax values were also influenced by infusion duration. Cmax increased from 0.047 to 0.797 µmol/L for E2 and 0.36 to 5.11 µmol/L for E1. First-dose AUC168h values for E2 and E1 increased from 1.23 to 14.6 µmol/L/hr and 7.9 to 118 µmol/L/hr, respectively, without significant deviation from dose proportionality.
After 4 weeks of treatment, the corresponding AUC values for E2 were approximately twice the week 1 values. The week 4 AUC168h values for E1 were approximately 2.5 times those observed after week 1 IV EMP. These increases were approximately 40% greater than the expected accumulation of these metabolites based on terminal t1/2. These data reveal that E1 is the predominant estrogen in plasma after the administration of IV EMP, with Cmax and AUC values eight- to ten-fold higher than those of E2. Pharmacokinetics after the 4,500-mg/m2 loading dose. As shown in Tables 4 through 6, the noncompartmental pharmacokinetic parameters determined after three consecutive daily IV EMP doses of 1,500 mg/m2 received over the first week of treatment by three patients confirm that the pharmacokinetics of EMP and metabolites are linear and dose proportional over the dose range of 500 to 4,500 mg/m2. For EMP, values of CL, Vss, and t1/2 were similar to those observed after single-dose treatment. Body surface area and pharmacokinetics. The routine use of estimated body surface area (BSA) for individualized dose calculation has been questioned, because pharmacokinetic parameters do not correlate with BSA for most anticancer agents.26,27 Although the week 1 EMP CL values were weakly correlated with estimated BSA (r = .40, P = .05), there was no correlation of week 4 EMP CL with BSA (r = .27, P = .24). Moreover, there were no significant correlations of EMP Vss (r = .22 week 1, r = .07 week 4) or Vz (r = .21 week 1, r = .08 week 4) with BSA. Lack of correlation with BSA was also found for dose-normalized values of AUC for EaM (r = -.24 and .01 for weeks 1 and 4), EoM (-.21 and -.08), E1 (-.18 and -.27), and E2 (.02 and -.07).
Antitumor Effects
Although EMP has been in clinical use for longer than three decades, this phase I trial is the first reported dose-escalation and pharmacokinetic study of this agent. This trial was prompted by continued interest in EMP as a component of prostate cancer therapy, particularly in combination with other tubulin-binding agents in the treatment of HRPC. These EMP-based combinations consistently demonstrate clinical benefit in terms of regression of measurable tumor, delay in time to progression, pain relief, and decrease in serum PSA.18-21 However, each of these combinations has been associated with gastrointestinal and cardiovascular toxicity, a portion of which can be attributed to oral EMP. Earlier experience suggested that IV EMP administered as multiple daily doses produced less nausea and cardiovascular toxicity than the oral formulation.1 The MTD of IV EMP administered on a weekly short infusion schedule was 2,500 mg/m2. DLTs were fatigue, malaise, and reversible hepatotoxicity. Repeated weekly dosing of IV EMP was feasible, although fatigue was cumulative and became dose limiting after 12 weeks of continuous treatment at 2,500 mg/m2. On the basis of this experience, the IV EMP dose and schedule recommended for phase II single agent evaluation is 2,000 mg/m2 by 60- to 90-minute infusion weekly for 3 weeks and repeated every 4 weeks. Because there was a general lack of correlation of pharmacokinetic data with BSA, a fixed phase II dose of 4,000 mg (based on an average BSA of 2 m2) may be a simpler alternative to 2,000 mg/m2, recognizing that this approach may not be optimal for extremes of body size outside the range included in this clinical trial. Rectal and perineal discomfort was common and occasionally intolerable at the start of the IV EMP infusions. Reducing the infusion rate during the initial treatment averted this effect. A tachyphylaxis seemed to develop in all patients who received more than one dose of treatment, so that dose-rate adjustments were not required after the first week of treatment. The cause of this adverse effect is unknown, but it is similar to the perineal discomfort that was described with lower doses of IV EMP1 and with rapid infusion of corticosteriods.28,29 Nausea was experienced by 81% of patients, seemed to be more prolonged at levels higher than 1,000 mg/m2, and prompted the use of prophylactic antiemetic premedication for patients treated at doses higher than 1,500 mg/m2. On the basis of this experience, we recommend antiemetics before and after IV EMP dosing to minimize nausea and emesis. Because of the limited number of patients in this phase I trial, it is not possible to fully assess the impact of IV EMP on cardiovascular toxicity. However, we are encouraged by the lack of severe peripheral edema and by the occurrence of only one lower-extremity DVT in the 31 patients treated. The single episode of grade 3 hypotension was peculiar in being associated with a constellation of findings more typical of a hypersensitivity reaction. Similar to oral EMP, we observed gynecomastia in several patients receiving IV EMP, attributable to the estrogenic metabolites and antigonadotrophic effect. Prior clinical experience with IV EMP has been limited to multiple daily doses ranging from 300 to 900 mg/d, usually for a period of 7 to 10 days as a loading course before oral EMP therapy in patients with advanced prostate cancer. Although the active metabolites EoM and EaM were known to have long elimination half-lives, intermittent dosing schedules and higher doses of IV EMP have not been investigated previously. We have confirmed the persistence of EoM and EaM in plasma with half-lives in the range of 110 and 60 hours, respectively, and have demonstrated the feasibility of weekly IV EMP dosing. In human studies, distribution of EoM and EaM to adipose tissue and liver was shown after single and multiple oral doses of radiolabeled EMP, with tissue concentrations exceeding plasma concentrations by 10- to 40-fold for both metabolites.30 In addition, a protein that binds both EaM and EoM is present in normal prostate and in prostatic carcinoma. The uptake of EaM and EoM in human prostate tumor tissue after IV EMP administration has been correlated with the concentration of this so-called EaM binding protein in tumors. This could explain the substantially higher levels of EaM and EoM found in tumor compared with plasma from the same patient, with ratios of 13:1 and 5:1, respectively.31 Thus, the long elimination half-lives of EoM and EaM may be in part attributable to extensive tissue distribution followed by slow release back into the plasma compartment. The slow disappearance of these metabolites from plasma supports intermittent dosing of EMP at weekly intervals for future studies. Because of the long t1/2 values for EoM and EaM, studies evaluating new agents (eg, microtubule inhibitors) in patients previously treated with EMP therapy may require more than the conventional 4-week washout period to distinguish single-agent therapeutic and toxic effects from combined effects of the new agent plus EMP. We observed dose-proportional increases in AUCinf for EMP and the metabolites EaM, EoM, E2, and E1 after single-dose weekly treatment, and EMP CL was unrelated to dose, indicating linear pharmacokinetics over the dose range of 500 to 3,000 mg/m2. Because infusion duration was lengthened at the higher dose levels, dose proportionality for Cmax was not uniformly observed at doses exceeding 1,500 mg/m2. Consistent with the pharmacokinetics obtained for the patients who received only a single dose of IV EMP during week 1, the three patients who received 1,500 mg/m2 daily for 3 days for the initial week of treatment had cumulative week 1 AUC values of EMP and metabolites that increased in proportion to their 4,500 mg/m2 total week 1 dose of IV EMP. However, administration of a daily loading dose of IV EMP provided no apparent advantage. All three of these patients required subsequent weekly doses of 1,500 mg/m2 or less because of fatigue and bilirubin elevations after the initial 4,500-mg/m2 cumulative dose. Although there was no significant time-dependent change in the volume of distribution of EMP after 4 weeks of treatment, week 4 clearance of EMP was 37% higher than in week 1 and was reflected in reduced EMP AUC for week 4 compared with week 1 of treatment. The observed plasma concentrations of EaM and EoM were consistent with the expected levels after 4 weeks, whereas the concentrations of E2 and E1 were somewhat higher than expected. It is unknown if time-dependent effects may be more pronounced after longer periods of treatment. At IV EMP doses of 2,000 mg/m2 and higher, the sum of C168h values for EoM and EaM approached 1 µmol/L after week 1 and exceeded this level after week 4 of treatment. These trough plasma EoM and EaM concentrations at the end of the IV EMP dosing interval are comparable to steady-state levels that result from administration of oral EMP doses of 560 to 840 mg per day14,28,29 and suggest that exposure to the active metabolites is similar with daily oral EMP or weekly IV EMP. Two differences in the pharmacokinetics of IV EMP and oral EMP are potentially important. First, high concentrations of the parent drug, EMP (approximately 0.5 mmol/L), are attained after IV EMP administration. Dephosphorylation, with conversion to EaM, most likely occurs at the tissue level, such as through hepatic metabolism, because it has been shown that EMP is stable in plasma.14 In contrast, oral administration of EMP does not produce measurable plasma concentrations of EMP, because rapid dephosphorylation occurs in the gastrointestinal tract and during the first pass through the liver.15,16 A second difference in the pharmacokinetics of IV and oral EMP is the magnitude of Cmax for EaM and EoM. After a 60-minute infusion, peak values for both EAM and EOM are 10- to 15-fold greater than those observed after conventional doses of oral EMP.13,14 Preclinical studies of EaM in combination with paclitaxel and vinblastine have shown enhanced antitumor and antimicrotubule effects with higher concentrations of EaM.8,32 Higher Cmax values for both of these microtubule-binding metabolites could thus be exploited for greater inhibition of microtubule function in combination therapy. Scheduling of IV EMP such that peak EaM and EoM concentrations occur at or near the Cmax of other tubulin-binding drugs, such as paclitaxel and docetaxel, may increase synergistic interactions with these agents. Because higher concentration of IV EMP metabolites may also affect drug metabolism or toxicity in such combinations, pharmacokinetic studies should be an integral component of future IV EMP combination trials. On the basis of the preliminary safety, favorable pharmacokinetics, and effects on serum PSA observed in this phase I trial, additional studies of IV EMP alone and in combination with other microtubule inhibitors have been initiated.33,34
We thank the Nursing Staff of the Mary S. Schinagl Pharmacology Unit of Fox Chase Cancer Center, Kerstin Heander, Karin Edman, Bengt Olofsson, Jean Winston, and Margie Bruns.
1. Jonsson G, Hogberg B: Treatment of advanced prostatic carcinoma with estracyt. Scand J Urol Nephrol 5: 103-107, 1971[Medline] 2. Tew KD, Erickson LC, White G, et al: Cytotoxicity of estramustine, a steroid-nitrogen mustard derivative, through non-DNA targets. Mol Pharmacol 24: 324-328, 1983[Abstract] 3. Hartley-Asp B: Estramustine-induced mitotic arrest in two human prostatic carcinoma cell lines DU 145 and PC-3. Prostate 5: 93-100, 1984[Medline] 4. Eklov S, Nilsson S, Larson A, et al: Evidence for a nonestrogenic cytostatic effect of estramustine on human prostatic carcinoma cells in vivo. Prostate 20: 43-50, 1992[Medline] 5. Tew KD, Stearns ME: Hormone-independent, non-alkylating mechanism of cytotoxicity for estramustine. Urol Res 15: 155-160, 1987[Medline]
6.
Dahllof B, Billstrom A, Cabral F, et al: Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res 53: 4573-4581, 1993 7. Laing N, Hartley-Asp B, Ranganathan S, et al: The interaction of estramustine with microtubule proteins and with beta-tubulin isotypes. Biochemistry 36: 871-878, 1997[CrossRef][Medline]
8.
Panda D, Miller HP, Islam K, et al: Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: A possible mechanistic basis for its antitumor action. Proc Natl Acad Sci U S A 94: 10560-10564, 1997
9.
Stearns ME, Wang M, Tew KD, et al: Estramustine binds a MAP-1 like protein to inhibit microtubule assembly in vitro and disrupt microtubule organization in DU 145 cells. J Cell Biol 107: 2647-2656, 1988
10.
Stearns ME, Tew KD: Estramustine binds MAP-2 to inhibit microtubule assembly in vitro. J Cell Sci 89: 331-342, 1988 11. Burns RG: Stoichiometry of estramustine phosphate binding to MAP2 measured by the disassembly of chick brain MAP2: Tubulin microtubules. Cell Motil Cytoskeleton 17: 167-173, 1990[CrossRef][Medline] 12. Sheridan VR, Speicher LA, Tew KD: The effects of estramustine on metaphase and anaphase in DU145 prostatic carcinoma cells. Eur J Cell Biol 54: 268-276, 1991[Medline] 13. Dixon R, Brooks M, Gill G: Estramustine phosphate: Plasma concentrations of its metabolites following oral administration to man, rat, and dog. Res Commun Chem Pathol Pharmacol 27: 17-29, 1980[Medline] 14. Gunnarsson PO, Andersson S-B, Johansson S-A, et al: Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancer patients. Eur J Clin Pharmacol 26: 113-119, 1984[CrossRef][Medline] 15. Gunnarsson PO, Andersson S-B, Johansson S-A: The hydrolysis of estramustine phosphate: In vitro studies. Eur J Drug Metab Pharmacokinet 8: 395-402, 1983[Medline] 16. Plym Forshell G, Muntzing J, Anders EK, et al: The absorption, metabolism, and excretion of estracyt (NSC 89199) in patients with prostatic cancer. Invest Urol 14: 128-131, 1976[Medline] 17. Gunnarsson PO, Davidsson T, Andersson S-B, et al: Impairment of estramustine phosphate absorption by concurrent intake of milk and food. Eur J Clin Pharmacol 38: 189-193, 1990[CrossRef][Medline] 18. Hudes GR, Nathan F, Khater C, et al: Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 15: 3156-1761, 1997[Abstract]
19.
Kreis W, Budman DR, Fetten J, et al: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone-refractory prostate carcinoma. Ann Oncol 10: 33-38, 1999
20.
Petrylak DP, Macarthur RB, O’Connor J, et al: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17: 958-967, 1999
21.
Smith DC, Esper P, Strawderman M, et al: Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer. J Clin Oncol 17: 1664-1671, 1999 22. Von Schoultz B, Carlström K, Collste L, et al: Estrogen therapy and liver function-metabolic effects of oral and parenteral administration. Prostate 14: 389-395, 1989[Medline] 23. Daehlin L, Damber J-E, von Schoultz B, et al: The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma: A comparative study of oestrogen sensitive liver proteins, gonadotrophins and protein. Br J Urol 58: 412-416, 1986[Medline] 24. Maier U, Hienert G, Simak R: Estramustine phosphate in secondary hormone-resistant carcinoma of the prostate. Eur Urol 17: 216-218, 1990[Medline] 25. Edman K, Svensson L, Eriksson B, et al: Determination of estramustine phosphate and its metabolites estromustine, estramustine, estrone, and estradiol in human plasma by liquid chromatography with fluorescence detection and gas chromatography with nitrogen-phosphorus and mass spectrometric detection. J Chromatogr 738: 267-279, 2000 26. Gurney H: Dose calculation of anticancer drugs: A review of the current practice and introduction of an alternative. J Clin Oncol 14: 2590-2611, 1996[Abstract] 27. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19: 171-177, 2001[CrossRef][Medline] 28. Thomas VL: More on dexamethasone-induced perineal irritation. N Engl J Med 314: 1643-1644, 1986 (letter)[Medline] 29. Allan SG, Leonard RCF: Dexamethasone antiemesis and side-effects. Lancet 1: 1035, 1986 (letter) 30. Gunnarsson PO, Andersson SB, Sandberg AA, et al: Accumulation of estramustine and estromustine in adipose tissue of rats and humans. Cancer Chemother Pharmacol 28: 361-364, 1991[CrossRef][Medline] 31. Walz PH, Bjork P, Gunnarsson P-O, et al: Differential uptake of estramustine phosphate metabolites and its correlation with levels of EMBP in prostate tumor tissue. Clin Cancer Res 4: 2079-2084, 1998[Abstract]
32.
Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and Taxol in human prostatic carcinoma cell lines. Cancer Res 52: 4433, 1992 33. Hovey E, Monroe J, Nanus DM, et al: Phase I safety and pharmacokinetic study of weekly intravenous (IV) estramustine phosphate (EMP) and docetaxel (D) in patients with solid tumors. Proc Am Soc Clin Oncol 20: 168b, 2001 (abstr 2424) 34. Hartley-Asp B, Natale RB, Dreicer R, et al: A phase II evaluation of intravenous estramustine phosphate in patients with advanced prostate cancer. Proc Am Soc Clin Oncol 20: 183a, 2001 (abstr 731) Submitted June 12, 2001; accepted November 1, 2001.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2,000 mg/m2. 
, where the elimination rate constant (
ij, where 
