Prostate carcinoma remains the most common malignancy in the. Docetaxel and Ketoconazole in Advanced Hormone- Refractory Prostate Carcinoma

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1 1855 Docetaxel and Ketoconazole in Advanced Hormone- Refractory Prostate Carcinoma A Phase I and Pharmacokinetic Study Peter J. Van Veldhuizen, M.D. 1 Gregory Reed, Ph.D. 2 Arvind Aggarwal, M.D. 1 Joaquina Baranda, M.D. 1 Muhammad Zulfiqar, M.D. 1 Stephen Williamson, M.D. 1 1 Department of Medicine, Section of Hematology/ Oncology, Kansas City Veterans Affairs Medical Center, University of Kansas Medical Center, Kansas City, Missouri. 2 Department of Pharmacology, the University of Kansas Medical Center, Kansas City, Kansas. Supported by a grant from Aventis Pharmaceuticals (Bridgewater, NJ). The current article is the result of work supported by resources and the use of facilities at the Kansas City Veterans Administration Medical Center (Kansas City, MO). Address for reprints: Peter J. Van Veldhuizen, M.D., Department of Medicine, Section of Hematology/Oncology, Veterans Affairs Medical Center/ University of Kansas Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128; Fax: (816) ; peter.vanveldhuizen@ med.va.gov The views expressed herein do not necessarily reflect the views of the Department of Veterans Affairs or the U.S. Government. Received May 5, 2003; revision received July 29, 2003; accepted July 29, *This article is a U.S. Government work and, as such, is in the public domain in the United States of America. BACKGROUND. Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction. METHODS. For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m 2 over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3 5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole). RESULTS. Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m 2. Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels. CONCLUSIONS. The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m 2 every 21 days. Cancer 2003;98: Published 2003 by the American Cancer Society.* KEYWORDS: docetaxel, ketoconazole, toxicity, prostate carcinoma, pharmacokinetics. Prostate carcinoma remains the most common malignancy in the United States male and will cause an estimated 28,900 deaths in For patients with advanced disease, response rates to hormonal therapy are 80 90%. Although this therapy frequently results in improvement of clinical symptoms with an average response duration of approximately 18 months, the majority of these patients eventually develop hormone-refractory disease. Treatment options that improve the overall survival of this patient population are limited, and improved therapies are needed desperately. Docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) is a semisynthetic taxane that inhibits mitotic activity via high-affinity binding to microtubules. Phase II single-agent studies in patients with advanced prostate carcinoma have demonstrated prostate-specific antigen (PSA) response rates of 38 46%. 2 4 Combinations of do- Published 2003 by the American Cancer Society* DOI /cncr.11733

2 1856 CANCER November 1, 2003 / Volume 98 / Number 9 cetaxel with other agents, such as estramustine, have demonstrated PSA responses of 63 82%, as defined by a PSA decline 50%, with 19% of patients achieving normalization of their PSA levels in one study. 5 7 Ketoconazole is a potent inhibitor of all adrenal steroid synthetic pathways. Its efficacy in prostate carcinoma is related in part to the suppression of testicular and adrenal androgen production. In previously untreated patients with prostate carcinoma, a daily dose of 1200 mg resulted in castrate levels of testosterone within a 24-hour period. 6 In addition, ketoconazole also appears to have a direct antiproliferative effect and, in vitro, has demonstrated synergy with some chemotherapeutic agents by enhancing the intracellular retention of the cytotoxic agent In patients with prostate carcinoma who are refractory to first-line hormonal therapy, single-agent PSA response rates as high as 62% have been demonstrated. 11 Trials evaluating ketoconazole in conjunction with chemotherapeutic agents have yielded promising results. Encouraging responses rates were seen in a Phase II study of doxorubicin plus ketoconazole that demonstrated a PSA response of at least 50% in 55% of study patients and soft tissue responses in 7 of 12 patients (58%). 12 Widespread utility of this regimen, however, has been limited by its toxicity, which includes stomatitis, neutropenia, and asthenia. Toxicity concerns also have been confirmed in a follow-up randomized Phase II study evaluating ketoconazole alone versus doxorubicin plus ketoconazole. 13 In a separate trial evaluating mitoxantrone 12 mg/m 2 every 3 weeks plus ketoconazole 400 mg 3 times daily, 73% of patients had a PSA decline of at least 50%, and an additional 9% of patients had a complete response. 14 Given the encouraging single-agent activity of docetaxel and the possible synergy with ketoconazole, this combination has the potential to have significant activity in patients with hormone-refractory prostate carcinoma. A potential for a drug-drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome P450 enzyme system (CYP3A4) In addition, an in vitro study suggested that ketoconazole may delay this hepatic metabolism by causing an inhibition of the hydroxylation of docetaxel. 18 Therefore, we designed a Phase I study and a pharmacokinetic study to evaluate this treatment regimen as well as this potential drugdrug interaction. MATERIALS AND METHODS Patient Selection Patients with histologically proven adenocarcinoma of the prostate, nonsmall cell lung carcinoma, breast carcinoma, or other solid tumor malignancies for which no effective alternative therapy exists were eligible to participate in this study. Other eligibility criteria for patients with prostate carcinoma included hormonerefractory disease, as evidenced by measurable soft tissue metastases; new bone scan abnormalities; or a rise in 3 consecutive PSA measurements at least 1 week apart. Patients with other solid tumor malignancies must have failed at least one previous chemotherapy regimen. Patients with prostate carcinoma must have failed antiandrogen withdrawal, as evidenced by the discontinuation of the antiandrogen of at least 28 days for flutamide or at least 42 days for bicalutamide. At least 8 weeks had to have passed since strontium-89 therapy, and at least 4 weeks had to have passed since any prior chemotherapy or radiotherapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 2. Patients with a preexisting peripheral neuropathy Grade 2 were ineligible. All patients must have had measurable or evaluable disease, and all measurable/evaluable lesions must have been assessed within 28 days prior to registration by physical examination, X-ray, computed tomography (CT) scan, or magnetic resonance image. Patients were ineligible if they had received prior therapy with docetaxel, although they could have received prior ketoconazole provided they had not received it for at least 90 days. Patients were required to have serum creatinine levels 2.0 mg/dl. Prior to receiving any dose of docetaxel, patients were required to have an absolute neutrophil count 1000/mm 3 and a platelet count 100,000/mm 3. Patients with a baseline bilirubin levels elevated above the institutional upper limit of normal (ULN) were excluded. Liver aspartate aminotransferase and alanine aminotransferase levels were required to be 2.5 times the institutional ULN. Patients who had both transaminase elevations 1.5 times the ULN and alkaline phosphatase elevations 2.5 ULN were not eligible for this study due to a potential for a decreased clearance of docetaxel and an increased risk of toxicity. Patients receiving concurrent warfarin were eligible but required monitoring of their International Normalized Ratio (INR) on a weekly basis. Patients were excluded from the study if they had any unstable, preexisting medical condition; and all patients with reproductive potential were required to use an effective contraceptive method if they were sexually active. All patients provided written informed consent according to federal and institutional guidelines. Study Design The current study was a single-center, dose-escalation Phase I trial in which all patients were accrued at either the Kansas City Veterans Affairs Medical Center

3 Docetaxel and Ketoconazole in Prostate/Van Veldhuizen et al or the University of Kansas Medical Center. For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m 2 over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3 5 new patients were enrolled to receive escalating doses of ketoconazole at the following dose levels; no ketoconazole, ketoconazole 200 mg twice daily, ketoconazole 400 mg twice daily, and ketoconazole 400 mg 3 times daily. Because of the toxicity observed in the initial 2 patients who were accrued at the ketoconazole 200 mg twice-daily dose (see Results, below), the study was amended to include a cohort of patients enrolled at a ketoconazole dose of 200 mg once daily. Because of the pharmacokinetic studies, the initiation of ketoconazole was delayed; however, after Day 8, all patients continued to receive it daily for the remainder of their time on study. Once the maximum tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Before proceeding with patient accrual at a new dose level, all patients at the previous dose level must have received at least two cycles of docetaxel. There was no intrapatient dosage escalation. All patients received oral dexamethasone 8 mg twice daily for 3 days starting 24 hours prior to docetaxel infusion. Except for the initial 5 patients who received decadron 4 mg daily, all other patients received hydrocortisone 20 mg each a.m. and 10 mg each p.m. as their adrenal replacement steroid beginning on Day 8, concurrent with starting ketoconazole. Previous studies have suggested that the nonhematologic toxicity and treatment-related mortality is negligible for docetaxel administered at a dose of 60 mg/m 2 every 3 weeks. Dosing schedules as high as 100 mg/m 2 have been used, although with an increased risk of toxicity. A starting dose of 55 mg/m 2, which should be tolerated well with minimal toxicity, was chosen because of the potential that ketoconazole may interfere with the hepatic metabolism of docetaxel. Pharmacokinetic Studies Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (before patients received ketoconazole) and on Day 22 (14 days after patients started ketoconazole) on 19 of the initial 20 patients. The initial cohort of 3 patients did not receive ketoconazole in an effort to evaluate the reproducibility pharmacokinetics of docetaxel on Day 1 (first docetaxel dose) compared with Day 22 (second docetaxel dose). In all treatments that included pharmacokinetic sampling, docetaxel infusions were given at a steady rate over 60 minutes, recording both the starting and ending infusion times. Pharmacokinetic samples were drawn peripherally from the arm opposite the arm used for docetaxel infusion. Samples were obtained at time 0 and at 0.5 hours, 1.0 hour, 2.0 hours, 3.0 hours, 4.0 hours, 5.0 hours, 6.0 hours, 8.0 hours, 18.0 hours, and 24.0 hours after docetaxel infusion. A 15-mL blood sample was obtained for each pharmacokinetic time point. Each sample was labeled immediately with the exact time of collection as well as the docetaxel infusion start and stop times. The plasma was collected immediately after samples were centrifuged (7000 rpm 10 minutes). Samples were then stored in a 70 C freezer in nonpolyvinyl chloride vials until the completion of the analysis of docetaxel levels. Samples were completed with separate runs of 9 patients and 10 patients, respectively. Analytic procedures were based on the reports of Bissett et al. 19 and Burris et al. 20 Aliquots of plasma (1.0 ml) were thawed, 200 ng of paclitaxel were added as an internal standard, and the sample was applied to a BondElut HF C2 extraction column (Varian Analytical Instruments, San Fernando, CA). The column then was washed with 1 ml water and 1 ml water:methanol (1:1) before analytes were eluted with 1 ml 90% methanol in water. The eluted samples were evaporated under vacuum and reconstituted in 100 L 90% methanol. A 50- L aliquot was injected onto a Supelco Discovery C18 column (4.6 mm 250 mm; 5 ul; Sigma- Aldrich, St. Louis, MO) eluted with 70% methanol:30% 0.3% phosphoric acid in water at 1.0 ml per minute 1 with monitoring by absorbance at 228 nm. Paclitaxel was eluted at 9.0 minutes, and docetaxel was eluted at 10.8 minutes. This assay reportedly has a linear response range of from 10 ng to 500 ng taxotere per ml plasma when 1-mL plasma samples were employed. This range should span comfortably the expected range of plasma concentrations achieved during the first 2 4 hours after infusion. To achieve higher sensitivity for later time points, the plasma sample size was increased to 5 ml. Definition of Study Endpoints Dose-limiting toxicities (DLTs) from the first two cycles were considered in calculating the MTD. DLTs were defined as follows: Grade 3 or 4 neutropenia associated with fever 38.0 C; Grade 4 neutropenia or thrombocytopenia lasting at least 7 days; Grade 3 or 4 nonhematologic toxicity, including refractory nausea/emesis, fatigue/weakness, diarrhea not responsive to treatment, and neuropathy; and any toxicity resulting in a treatment delay 3 weeks. If one patient at a dose level experienced a DLT, then at least three more patients were accrued at that dose level. Toxicity was

4 1858 CANCER November 1, 2003 / Volume 98 / Number 9 considered to be dose limiting if DLTs occurred in two or more patients at one dose level. Granulocyte-colony stimulating factor administration was not allowed. Docetaxel infusions were stopped for any symptoms related to a potential allergic reaction, including generalized pruritis, flushing, dyspnea, hypotension with systolic blood pressure 90, or angioedema. Patients were treated with diphenhydramine 50 mg intravenously (IV) and/or dexamethasone 10 mg IV. Depending on the severity of the reaction, the infusion was resumed at a decreased rate and slowly increased to the baseline infusion rate. Edema and fluid retention edema were managed at the early stages. Weight gain that was not explained by other factors was managed by the early institution of a mild diuretic treatment. Suggested treatment included the following: oral furosemide 40 mg daily or oral hydrochlorothiazide 50 mg daily. Potassium supplementation was given as needed. If, after a trial of 2 weeks, this was ineffective, then treatment with oral furosemide 20 mg daily plus oral metolazone 2.5 mg daily with potassium supplementation was recommended. Patients who experienced a DLT were allowed to continue on protocol with a one-level dose reduction at the discretion of the treating physician. Responding or stable patients continued on study until tumor progression. If the treatment was discontinued due to any toxicity, then patients were followed to monitor duration of toxicity, response, and time to progression. Docetaxel was supplied by Aventis Pharmaceuticals in 80 mg vials. Ketoconazole was commercially available (Janssen, Titusville, NJ) in 200 mg tablets. Pretreatment and Follow-up Evaluation Before starting treatment, each patient had his medical history recorded and underwent physical examination and laboratory evaluations, including a complete blood count (CBC) and electrolyte, blood urea nitrogen, creatinine, glucose, liver function, total protein, albumin, calcium, and phosphate assays. In addition, all patients had a 12-lead electrocardiogram, a chest radiograph, and assessment of performance status. History, physical examination, and all laboratory tests were completed on Day 1 of each 21-day treatment cycle. A CBC was performed on a weekly basis. All radiographs required for tumor measurements were completed within 28 days prior to study enrollment and were repeated after every 2 cycles of therapy. All patients with prostate carcinoma had a bone scan prior to study enrollment, and this was repeated after every four cycles of therapy. All patients with prostate carcinoma also had a PSA assessment prior to each treatment cycle. Toxicity assessment using the TABLE 1 Patient Characteristics Characteristic No. of patients (%) Patients enrolled 26 (100) Male gender 26 (100) Age (yrs) Median 72 ( ) Range ( ) Performance status 0 8 (31) 1 17 (65) 2 1 (4) Prior therapy Chemotherapy a 6 (23) Local irradiation 10 (38) Palliative irradiation 3 (12) Strontium-89 2 (8) Ketoconazole 6 (23) Diagnosis Prostate carcinoma 24 (96) Bone metastases 4 7 (29) 4 17 (71) Visceral metastasis 2 (8) Lung carcinoma 2 (8) a Both patients with lung carcinoma received prior chemotherapy but no prior radiotherapy. National Cancer Institute Common Toxicity Criteria also was performed before each treatment cycle. A complete response (CR) was defined as the complete disappearance of all measurable and evaluable disease maintained on 2 consecutive measurements at least 6 weeks apart. Patients with prostate carcinoma must have maintained a PSA serum level 1.0 ng/ml correlating with a negative bone scan and CT scan of the abdomen/pelvis. A partial response (PR) was defined as a reduction 50% in tumor size of all measurable lesions lasting at least 6 weeks along with the appearance of no new lesions. Patients with prostate carcinoma also had to have had a decrease 50% in PSA levels. Progressive disease was defined as a 50% increase in the sum of products of all measurable disease, clear worsening of any evaluable disease, or the appearance/reappearance of any new lesion. PSA response was defined as a decrease 50% in baseline serum PSA levels that was sustained for at least 2 treatment cycles. PSA progression was defined as two consecutive increases in serum levels from baseline. Stable disease (SD) was any disease that did not qualify as CR, PR, or disease progression. RESULTS The characteristics of the 26 patients enrolled in this study are listed in Table 1. Two of the initial patients

5 Docetaxel and Ketoconazole in Prostate/Van Veldhuizen et al TABLE 2 Common Toxicity during Cycle 1 (without Ketoconazole) and Cycle 2 (with Ketoconazole) No. of patients with toxicity of specified grade Dose level Ketoconazole/ docetaxel dose No. of patients Cycle Edema Fatigue Diarrhea Neutropenia Nausea Hyperglycemia / / / / / / a Total daily ketoconazole dose in mg; total docetaxel dose in mg/m 2. accrued to the study had lung carcinoma, including small cell carcinoma in one patient and nonsmall cell carcinoma in the other patient. All of the remaining patients had metastatic prostate carcinoma with bone as one of their disease sites. Four of the patients with prostate carcinoma previously had received chemotherapy, and six patients previously had received ketoconazole therapy. The median age was 72 years (range, years). All patients completed at least the first 2 cycles of therapy, with only 2 patients requiring a 1-week delay prior to receiving Cycle 2. Three patients died while on study treatment. The initial study design called for a starting dose of ketoconazole 200 mg twice daily. The first patient who was treated this dose level died unexpectedly at home of an unknown cause 14 days after his third cycle of docetaxel. He had had a physical and laboratory examination 5 days prior to his death, at which time he was doing well except for the presence of peripheral edema. The second patient who was treated at this dose level died after presenting with neutropenia and urosepsis 8 days after receiving Cycle 2 of docetaxel. Study enrollment was halted temporarily, and the study was amended using a starting ketoconazole dose of 200 mg daily. The next six patients were treated at this dose level with no doselimiting toxicities. A third patient died unexpectedly at home after recovering from a respiratory infection. He had received 10 cycles of therapy. The most commonly observed toxicities for Cycle 1, before the administration of ketoconazole, and Cycle 2, after the start of ketoconazole administration, are listed in Table 2. Other frequent toxicities included taste alterations, alopecia, and Grade 1 or 2 anemia. There were no episodes of hepatic toxicity. Peripheral edema was a common toxicity for initial patients but improved with a change in the replacement steroid from decadron to hydrocortisone and a more stringent adherence to the recommended diuretic regimen. The severity of fatigue and weakness increased with the escalating ketoconazole dose and was more common after the second treatment cycle. There were no DLTs seen with ketoconazole 800 mg daily and docetaxel 55 mg/m 2. The 5 patients who were treated with this as the initial starting dose level tolerated repeat treatment cycles, receiving an average of 8 cycles (range, 4 19 cycles). One of those patients still was on the study 18 months after enrollment. Two patients who received the dose level of ketoconazole 1200 mg daily and docetaxel 55 mg/m 2 developed DLTs of both febrile neutropenia and prolonged fatigue after the second cycle of treatment. The third patient who was treated at this level had a prolonged treatment response and has received a total of 13 cycles. After the MTD of 800 mg ketoconazole was reached, the docetaxel dose was escalated to 65 mg/ m 2. Four patients have been treated at this dose level. One patient developed a DLT of Grade 3 weakness/ fatigue after treatment Cycle 2 and required hospitalization. An additional patient developed Grade 4 neutropenia along with Grade 3 fatigue after treatment Cycle 2. For the remaining 2 patients at this dose level, cumulative toxicity was seen with subsequent dose reductions at Cycle 3 and 6, respectively. Table 3 lists the number of total treatment cycles delivered at each

6 1860 CANCER November 1, 2003 / Volume 98 / Number 9 TABLE 3 Dose Levels and Number of Cycles Dose level No. of patients Docetaxel (mg/m 2 ) Ketoconazole (mg/day) No. of cycles dose level. Patients who were treated at Dose Levels 5 and 6 were allowed to continue on treatment at Dose Level 4. Based on the absence of DLTs in Cycles 1 and 2 and the ability to administer repeated treatment cycles without dose modification or delay, we recommend the dose of ketoconazole of 800 mg daily and docetaxel of 55 mg/m 2 every 3 weeks for further evaluation in Phase II studies. Table 4 presents the results of the analyses of docetaxel pharmacokinetics. At all dose levels, we observed significant interpatient variability in both maximum plasma concentration (C max ) and area under the curve (AUC). This issue was addressed by converting the data to ratios of Cycle 1 values (no ketoconazole) to Cycle 2 values (after the indicated administrations of ketoconazole) for each patient. Intrapatient variability in those parameters also was noted in the 3 patients in the first treatment group, who received 2 identical doses of docetaxel without ketoconazole, but the extent of this variability was relatively minor, with a mean C max ratio of Cycle 1 to Cycle 2 for these patients of , and a mean AUC ratio of The mean (Cycle 2:Cycle 1) C max and AUC ratios for the 200-mg, 400-mg, and 800-mg ketoconazole treatment groups all were increased; however, at each dose, the interpatient variability in the ratios prevented the changes from being statistically significant. In addition, there was no consistent change with ketoconazole dose for Cmax values. A final argument against any significance of the observed changes in docetaxel pharmacokinetics caused by ketoconazole is the lack of a consistent correlation with either therapeutic or toxic endpoints in the patients. For example, Patient 9 had a marked increase in AUC with Cycle 2 that was associated with increased toxicity and a prolonged treatment response. Patient 17 also had a marked increase in the AUC but no increased toxicity. Patients 11 and 19, in contrast, had a decreased AUC with Cycle 2 but an increase in toxicity. This apparent disconnection between the effects of ketoconazole on docetaxel pharmacokinetics and changes in either therapeutic or toxic endpoints argues against a pharmacokinetic basis for those changes. Although assessment of tumor response was not a primary objective of this study, tumor responses were seen at all dose levels. Of the 12 patients who received the recommended Phase II dose of ketoconazole of 800 mg daily/docetaxel 55 mg/m 2 or higher (with subsequent dose reduction to this dose level), 7 patients sustained PSA responses of at least 50%, with 3 patients maintaining a PSA level 1. DISCUSSION Previous clinical trials have investigated the efficacy of combining oral ketoconazole with doxorubicin. Although response rates were encouraging, the widespread utilization of this combination has been limited because of toxicity. 12,13 A more recent trial showed improved tolerability when ketoconazole was given in combination with mitoxantrone. 14 We evaluated the combination of ketoconazole with docetaxel, which has better single-agent activity in prostate carcinoma than either doxorubicin or mitoxantrone. Phase I and pharmacokinetic studies were performed, because both drugs are metabolized by CYP3A4, and there is a potential risk of a significant drug interaction. We found that the MTD of this combination was ketoconazole 400 mg twice daily and docetaxel 55 mg/m 2 given every 21 days. This dose level was tolerated well and allowed for the administration of repetitive cycles without any significant dose reduction or delay. Patients who were treated at this level received an average of 8 cycles of docetaxel, with 1 patient receiving 19 cycles of therapy. There have been multiple reports evaluating ketoconazole as a single agent in patients with hormonerefractory prostate carcinoma The standard dose used in those studies was 400 mg 3 times per day, and the most common toxicities observed were gastrointestinal intolerance, fatigue, and liver function abnormalities. These single-agent toxicities can be significant, however, with as many as 32% of patients discontinuing treatment. 23 There are limited data available for evaluating the efficacy of ketoconazole at doses lower than 1200 mg per day. In a recent study, 28 patients with androgen independent prostate carcinoma were treated at a dose of 200 mg 3 times per day. At that dose, there was improved tolerability while antitumor activity was maintained, as evidenced by a decrease 50% in the PSA level in 13 patients (46%). 24 Docetaxel at doses as high as 100 mg/m 2 has been administered as a single agent every 3 weeks in some patient populations. However, in a Phase I study evaluating docetaxel in combination with estramustine in patients with hormone-refractory prostate car-

7 Docetaxel and Ketoconazole in Prostate/Van Veldhuizen et al TABLE 4 Docetaxel Pharmacokinetic Data Patient no. Dose a Cycle C max T max AUC C max ratio b AUC ratio b Response c Toxicity d 1 0/ SD No ( ) ( ) 2 0/ PD Yes / PSAR No / SD No ( ) ( ) 5 200/ PD No / PD No / SD No / SD No / PSAR Yes ( ) ( ) / PD No / SD Yes / NA Yes / SD No / PD No ( ) ( ) / PSAR No / SD No / PSAR No / SD Yes / PSAR Yes C max (ng/ml): maximum concentration; T max (ng/ml): time to maximum concentration; AUC: area under the time-concentration curve; SD: stable disease; PD: progressive disease; PSAR: prostate-specific antigen response of at least 50%; NA: not evaluable. a Total daily ketoconazole dose (in mg)/total daily docetaxel dose (in mg/m 2 ). b Values in parentheses indicate mean standard deviation for each dose level. c Best treatment response. d Assessment of any increased Grade 3 or Grade 4 toxicity on treatment Cycle 2 (with ketoconazole) compared with Cycle 1 (without ketoconazole). cinoma, the recommended dose was 60 mg/m 2 for extensively pretreated patients and 70 mg/m 2 for minimally pretreated patients. 6 Our findings regarding the limited tolerability of 1200 mg daily of ketoconazole, as stated above, are not inconsistent with the findings from single-agent studies. In addition, some additional fatigue could be expected with the docetaxel combination. Neutropenia also was a limiting factor in escalating the dose of docetaxel, with an MTD of 55 mg/m 2, which was lower than what might be expected when docetaxel is given in combination with a nonmyelosuppressive agent. With this finding, we cannot exclude a potential interaction; although, pharmacokinetically, no consistent effect on docetaxel levels was seen with the addition of ketoconazole. However, we did find significant interpatient and intrapatient variability in docetaxel pharmacokinetics. One other study has evaluated the pharmacokinetics of ketoconazole in the combination with a taxane. 25 In that study of patients with ovarian carcinoma, ketoconazole was administered orally as a single dose 3 hours before an infusion of paclitaxel. Ketoconazole had no significant effect on paclitaxel levels; however, there was significant interpatient and inpatient variability in serum levels of ketoconazole. In addition, this variability was correlated with CYP3A4 activity, as measured by the erythromycin breath test. There are multiple polymorphisms of cy-

8 1862 CANCER November 1, 2003 / Volume 98 / Number 9 tochrome P450 that may explain this variability in CYP3A activity. 26 A Phase II study evaluating docetaxel 55 mg/m 2 every 21 days and ketoconazole 400 mg twice daily is being planned to further define the tolerability and antitumor activity of this regimen in patients with advanced prostate carcinoma. That study also will evaluate a potential docetaxel dose escalation in minimally pretreated patients. Given the significant interpatient variability in docetaxel levels, future studies should include an evaluation of individual CYP3A4 activity to define further its effect on treatment response, serum drug levels, and toxicity. REFERENCES 1. Jemal A, Thomas A, Murray T, et al. Cancer statistics, CA Cancer J Clin. 2003;53: Friedland D, Cohen J, Miller R, et al. A Phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorlylation of Bcl-2. Semin Oncol. 1999;26(5 Suppl 17): Beer TM, Pierce WC, Lowe BA, Henner WD. Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol. 2001;12: Berry W, Dakhil S, Gregurich MA, Amar L. Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol. 2001;28(4 Suppl 15): Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB Cancer and Leukemia Group B. J Clin Oncol. 2001;19: Petrylak DP, Macarthur RB, O Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol. 1999;17: Kreis W, Budman DR, Fetten J, Gonzales AL, Barile B, Vinciguerra V. Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma. Ann Oncol. 1999;10: Rochlitz CF, Damon LE, Russi MD, et al. Cytotoxicity of ketoconazole in malignant cell lines. Cancer Chemother Pharmacol. 1998;21: Eichenberger T, Trachtenberg J, Chronis P, Keating A. Synergistic effect of ketoconazole and antineoplastic agents on hormone-independent prostatic cancer cells. Clin Invest Med. 1989;12: Kreis W, Budman DR, Calabro A. Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol. 1997;79: Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol. 1997;157: Sella A, Kilbourn R, Amato R, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol. 1994;12: Millikan R, Baez L, Banerjee T, et al. Randomized Phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol Oncol. 200l;6: Kozloff M, Vlamakis J, Ferdman E, et al. Phase II trial of mitoxantrone and ketoconazole for hormone refractory prostate cancer [abstract]. Proc Am Soc Clin Oncol. 2002;21: 195a. 15. Clarke SJ, Rivory LP. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet. 1999;36: Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet. 1988;14: Marre F, Sanderink GJ, de Sousa G. Hepatic biotransformation of docetaxel (Taxotere) in vitro: involvement of the CYP3A subfamily in humans. Cancer Res. 1996;56: Royer I, Monsarrat B, Sonnier M, et al. Metabolism of docetaxel by human cytochrome P450: interactions with paclitaxel and other antineoplastic drugs. Cancer Res. 1996;56: Bissett D, Setanoians A, Cassidy J, et al. Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion. Cancer Res. 1993;53: Burris H, Irvin I, Kuhn J, et al. Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion. J Clin Oncol. 1993;11: Trump DL, Havlin KH, Messing EM, et al. High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects. J Clin Oncol. 1989;7: Johnson DE, Babaian RJ, von Eshenbach AC, et al. Ketoconazole therapy for hormonally refractive metastatic prostate cancer. Urology. 1988;31: Vanuytsel L, Ang KK, Vantongelen K, et al. Ketoconazole therapy for advanced prostatic cancer: feasibility and treatment results. J Urol. 1987;137: Harris KA, Weinberg V, Bok RA, et al. Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol. 2002;168: Jamis-Dow CA, Pearl ML, Watkins PB, et al. Predicting drug interactions in vivo from experiments in vitro. Human studies with paclitaxel and ketoconazole. Am J Clin Oncol. 1997; 20: Ingelman-Sundberg M. Polymorphism of cytochrome P450 and xenobiotic toxicity. Toxicology. 2002; :