A Phase I Study of Estramustine, Weekly Docetaxel, and Carboplatin Chemotherapy in Patients with Hormone-Refractory Prostate Cancer

284 Vol. 11, 284–289, January 1, 2005 Clinical Cancer Research

William K. Oh,1 Elizabeth Hagmann,1 docetaxel is 43 mg/m2 combined with estramustine and Judith Manola,2 Daniel J. George,1 carboplatin. PSA declines were seen at every dose level. Timothy D. Gilligan,1 Joseph O. Jacobson,4 Matthew R. Smith,3 Donald S. Kaufman,3 and INTRODUCTION Philip W. Kantoff 1 Prostate cancer remains the second leading cause of cancer 1Lank Center for Genitourinary Oncology, Department of Medical death in men in the United States (1). Although initially Oncology and 2Department of Biostatistical Science, Dana-Farber responsive to androgen deprivation therapy, prostate cancer Cancer Institute; 3Department of Medical Oncology, Massachusetts almost always becomes refractory to hormonal manipulation (2) 4 General Hospital Cancer Center, Boston, Massachusetts; and North Mitoxantrone chemotherapy combined with corticosteroids Shore Cancer Center, Peabody, Massachusetts provides palliative benefit in the management of symptomatic disease, but no improvement in survival (3, 4). Phase I and II ABSTRACT trials have shown that the combination of docetaxel and Purpose: To define the maximal tolerated dose, safety, estramustine is effective and well tolerated in patients with and efficacy of docetaxel, carboplatin, and estramustine in hormone refractory prostate cancer (HRPC; refs. 5–9). Two patients with hormone-refractory prostate cancer (HRPC). recently reported large phase III trials showed that docetaxel Methods: Patients with HRPC received docetaxel for 3 combined with either prednisone or estramustine was associated weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or with a survival benefit compared with mitoxantrone and 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. prednisone in the treatment of HRPC (10, 11). Platinum compounds have been studied both as single Patients also received estramustine (140 mg p.o. three times agents and in combination regimens in the treatment of daily on days 1-5, 8-12, and 15-19) and carboplatin [area hormone refractory prostate cancer (12–22). Yagoda et al. under the curve, AUC (5) or (6) on day 2]. (12) reported a 12% partial remission and 24% stable disease Results: Thirty patients were treated. Five patients rate in 25 patients with measurable HRPC treated with cisplatin. received carboplatin [AUC (6)] but experienced delayed Merrin (13) noted partial or complete responses in 17 of 54 thrombocytopenia. After a protocol amendment, 25 subse- (31%) patients treated with weekly cisplatin, whereas Moore quent patients received carboplatin [AUC (5)]. Median age et al. (14) found a 10% response rate in 29 patients treated with was 64 years. Median prostate-specific antigen (PSA) was a similar regimen. Carboplatin has a distinct toxicity profile from 117 ng/mL. Fifty-three percent received prior ketoconazole cisplatin that allows for potentially equivalent antitumor effect with less toxicity (15). Miglietta et al. (16) treated 35 patients and 10% had mitoxantrone. No dose-limiting toxicities were 2 noted. Although maximal tolerated dose was not reached, with weekly carboplatin at a dose of 150 mg/m . Prostate- z docetaxel dose escalation was stopped at 43 mg/m2. specific antigen (PSA) declines of 50% were seen in 28%, with a mean duration of about 6 months. Also, 27% with Significant myelosuppression was not seen until the highest measurable disease had a partial response. Jungi et al. (17) dose level, when seven and four patients experienced grade treated 27 patients with carboplatin 400 mg/m2 every 28 days 3 and 4 toxicities, respectively. Among all patients, PSA and noted decreased pain and/or an improved performance declines of z50% occurred in 63%. At the recommended status in 48%. phase II dose, PSA declines of z50% occurred in 75% (95% Platinum compounds also have been studied in combina- confidence interval, 43-95). Four of 14 (29%) patients with tion regimens. Cisplatin or carboplatin was combined with measurable disease had partial responses. Median survival etoposide and estramustine in men with poorly differentiated was 14.6 months. HRPC (18). Fifteen of 30 patients experienced tumor response Conclusions: Estramustine, docetaxel, and carboplatin by PSA declines or decrease in measurable disease. Several are well tolerated and active in HRPC. Myelosuppression is trials have evaluated the efficacy of estramustine, paclitaxel, and the primary toxicity. The recommended phase II dose of carboplatin (19–21). In one multicenter trial, 56 patients were treated with estramustine, weekly paclitaxel, and carboplatin every 4 weeks. PSA declines of z50% were seen in 67%, and Received 7/28/04; revised 9/24/04; accepted 10/21/04. measurable responses were noted in 15 of 33 patients (45%; ref. Grant support: Aventis Pharmaceuticals. 19). The Cancer and Leukemia Group B completed a phase II The costs of publication of this article were defrayed in part by the triall of estramustine, docetaxel and carboplatin given on an payment of page charges. This article must therefore be hereby marked every 3 week schedule and showed PSA declines >50% in 68% advertisement in accordance with 18 U.S.C. Section 1734 solely to of patients and measurable responses in 52% (22). indicate this fact. Requests for reprints: William K. Oh, Lank Center for Genitourinary In summary, platinum compounds have modest but distinct Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA single agent activity in HRPC. However, combined with taxanes 02115; E-mail: [email protected]. and estramustine, carboplatin may offer the greatest potential for D2005 American Association for Cancer Research. benefit. In addition, since weekly docetaxel chemotherapy is

associated with less myelotoxicity than every 3 week docetaxel, pelvis, bone scans, and chest X-ray s. Treatment toxicity was particularly in older patients who may have received prior graded according to the National Cancer Institute Common radiotherapy, we undertook this phase I trial to determine the Toxicity Criteria. All patients with evidence of measurable maximum tolerated dose as well as the safety and efficacy of disease underwent tumor response evaluated by the Response weekly docetaxel in combination with estramustine and Evaluation Criteria in Solid Tumors (26). PSA response was carboplatin. defined according to the PSA Working Group and required a z50% reduction in PSA sustained for at least 4 weeks (23). PATIENTS AND METHODS Statistical Methods. Descriptive statistics were used to Eligibility. Patients had histologically confirmed prostate characterize patients at baseline. Exact binomial confidence cancer and showed progression despite androgen deprivation intervals were provided for response rates. The method of therapy. Progression was defined as either an increase in the Kaplan-Meier (27) was used to estimate overall survival. product of bidimensional diameters of one or more radiograph- ically documented sites of measurable disease or by PSA progression according to the PSA Working Group criteria (23). RESULTS Patients had Eastern Cooperative Oncology Group performance Thirty-two patients were registered for this trial. Two statuses of 0 to 2. Required laboratory values included a WBC patients withdrew prior to starting therapy; one who was count z3,000/mL, platelet count z100,000/mL, serum creatinine ineligible before treatment because of a deep venous thrombosis V2.0 mg/dL, bilirubin less than or equal the upper limit of normal, diagnosed within 1 year and a second who began treatment for AST V1.5 times the upper limit of normal, and testosterone levels brain metastases. Therefore, 30 patients are included in this V50 ng/mL. Prior chemotherapy was allowed if it did not include analysis. Baseline patient characteristics are listed in Table 1. taxanes or platinum derivatives. Patients with significant Most patients had received prior secondary hormonal therapies peripheral neuropathy and current congestive heart failure (New (53% ketoconazole, 33% PC-SPES) and 10% of patients had York Heart Association Class 2 or higher) were excluded. At least received prior chemotherapy with mitoxantrone. All patients had 4 weeks must have elapsed from radiation or antiandrogen a performance status of 0 or 1. therapies. No patients were allowed with myocardial infarction or This study was initiated with a carboplatin dose of AUC deep venous thrombosis within 1 year or significant change in (6). Five patients were treated at this dose of carboplatin, three anginal pattern within 6 months of study entry. All patients signed at the first dose level, and two at the second dose level. Two of an informed consent form approved by the institutional review three patients in the first dose level experienced significant dose board of the Dana-Farber/Partners Cancer Care before partici- pating in this trial. Treatment Plan. Patients were treated with one of five escalating doses of docetaxel for three consecutive weeks Table 1 Baseline patient characteristics followed by a rest week. Docetaxel was given i.v. on days 2, Characteristic % 9, and 16 of a 28-day cycle. Patients received the same dose of Age Median 64 treatment to which they were assigned for each cycle of Range 46–82 chemotherapy, unless a dose-reduction was instituted secondary Performance status 0 10 33 to toxicity. Dexamethasone was given orally at a dose of 8 mg, 12067 f Time since diagnosis Median (y) 6 12 hours and 1 hour prior to and again 12 hours after Range (y) 0.5–10.5 docetaxel. Carboplatin was given i.v. at a dose AUC (6) or (5), Unknown 7 over 60 minutes, on day 2 of each cycle (24). Creatinine PSA at study entry Median 117.5 clearance was estimated using the Cockcroft-Gault formula (25). Range 5.9–6,290.0 Testosterone at study Median 20 Estramustine was given orally at a dose of 140 mg three times entry daily on days 1 to 5, 8 to 12, and 15 to 19 of each cycle. Range 4–37 Treatment was discontinued at any time if patients had Acid phosphatase Median 7.2 unacceptable toxicity, evidence of progressive disease, occur- at study entry rence of dose-limiting toxicity, or withdraw consent. Range 0.8–113.0 Unknown 5 Maximum tolerated dose was defined as one dose level Gleason score at diagnosis 5–6 3 14 below that at which two or more patients experienced dose- 7419 limiting toxicity. Dose-limiting toxicity was defined as an 8–10 14 67 absolute neutrophil count of <500 mm3, a platelet count of Unknown 9 3 Prior treatment Radical Prostatectomy 13 43 <100,000 mm for >7 days, or nonrecovery of absolute Prostate Radiotherapy 16 53 3 3 neutrophil count to >1,500 mm or platelets to >100,000 mm LHRH Agonists 27 93 within 14 days of a given dose of docetaxel. Dose-limiting Anti-Androgens 21 70 toxicity also included any irreversible grade 3 or 4 non- Ketoconazole 16 53 PC-SPES 10 33 hematologic toxicity, excluding nausea, vomiting, alopecia, and Mitoxantrone 3 10 hypersensitivity reactions. Megace 3 10 Toxicity and Response Evaluation. Patients were DES 3 10 followed weekly. Patients were restaged every 2 months, Steroids 2 7 including computed tomography scans of the abdomen and Radiopharmaceutical 1 3

Table 2 Selected toxicities at carboplatin dose AUC (6) experienced prolonged thrombocytopenia after his second cycle Toxicity type Dose level 1 Dose level 2 and was removed from study. Table 2 shows the toxicity seen in (n =3) (n =2) these five patients. In general, few grade 3 or 4 nonhematologic Grade Grade Grade Grade toxicities were seen. In addition, only one patient experienced 1or2 3or4 1or2 3or4 grade 3 or 4 neutropenia and thrombocytopenia. Hemoglobin 1 Because of concerns regarding significant dose delays and Neutrophils 2 need for dose reductions using the carboplatin dose of AUC (6), Platelets 2 1 1 the trial was reinitiated with a carboplatin dose of AUC (5). Transfusion: 1 Table 3 shows the toxicities seen for 25 patients treated with five pRBCs Edema 3 dose levels of docetaxel with carboplatin AUC (5). The decision Thrombosis/ 1 was made to stop escalation at dose level 5 (docetaxel dose embolism 43 mg/m2), as evidence from other studies suggested that the Fatigue 2 1 maximum tolerated dose of single agent docetaxel was 36 to 40 Fever/ 11 2 chills mg/m and because of the significant activity seen at this dose Anorexia 1 1 level (28, 29). Therefore, an additional nine patients were Nausea/ 111accrued at dose level 5 to acquire more data about toxicity at this vomiting dose level. No dose-limiting toxicities were seen at all dose Hematuria 1 1 levels tested. No grade 3 or 4 myelosuppression was seen until Infection without 1 neutropenia dose level 5, when one patient each was noted to have grade 3 Neuropathy: 1 anemia, neutropenia, and thrombocytopenia. One patient devel- sensory oped grade 4 thrombocytopenia and two patients developed Abdominal/ 3 grade 4 neutropenia. Of 12 patients treated at dose level 5, four pelvic pain Pain: 12patients had a maximum grade 4 toxicity and seven patients had other a maximum grade 3 toxicity. Dysuria 1 Table 4 shows the antitumor efficacy noted among 30 Urinary 1 treated patients. Among all patients, a PSA decline of z50% was frequency/urgency seen in 63.3% [95% confidence interval (95% CI), 43.9-80.1]. Urinary 1 retention At the recommended phase II dose (dose level 5), PSA declines Injection 1 of z50% were seen in 75.0% (95% CI, 42.8-94.5). Of 17 site reaction patients with measurable disease, four (23.5%; 95% CI, 6.8- Worst degree 2 1 1 1 49.9%) had at least a partial response, whereas 10 (58.8%) had a z50% reduction in PSA after treatment. delays and were removed from study after two and four cycles of Five patients were not evaluable for objective response, treatment, respectively, because of delayed thrombocytopenia. four because of progression prior to a second cycle of treat- One of two patients at the second dose level similarly ment, and one because toxicity. In addition, two patients were

Table 3 Selected toxicities at carboplatin dose AUC (5) Toxicity type Dose level 1 (n = 3) Dose level 2 (n = 3) Dose level 3 (n = 3) Dose level 4 (n = 4) Dose level 5 (n = 12) Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade 1or2 3or4 1or2 3or4 1or2 3or4 1or2 3or4 1or2 3or4 Hemoglobin 1 1 1 5 1 Neutrophils 243 Platelets 1 1 2 5 2 Transfusion: pRBCs 1 3 Hyperglycemia 1 LFTs 115 Creatinine 111 Edema 1 1 1 4 1 Thrombosis/embolism 4 Fatigue 1 1 3 1 1 9 1 Anorexia/weight loss 3 2 1 4 Nausea/vomiting 2 1 3 2 1 1 8 2 Diarrhea 1 1 4 1 Infection without neutropenia 1 1 2 Neuropathy: sensory 12 Pain 3 2 2 5 Urinary retention 1 1 1 Injection site reaction/rash 1 1 Hot flash 1 1 1 Dyspnea 1 1 1 1 Fainting/lightheadedness 112 Worst degree 1 2 2 1 0 3 0 4 1 11

Table 4 Overall response Carboplatin dose AUC (6) AUC (5) Total Docetaxel dose level 1 2 1 2 3 4 5 No. patients 3 2 3 3 3 4 12 30 Patients with measurable disease 3 0 2 3 1 3 5 17 Measurable disease responses 0 — 0 0 1 2 4 PSA declines of z50% among patients 1—2211310 with measurable disease Nonmeasurable disease 0 2 1 0 2 1 7 13 PSA declines of z50% among patients —10—116 9 with nonmeasurable disease % Patients with PSA declines of z50% 33 50 67 67 67 50 75 63.3 among all patients

unevaluable for PSA response, both because of progression. The transition of prostate cancer from a hormone Eight patients are known to have died, all of prostate cancer. sensitive to hormone refractory state is associated with Median survival is 14.6 months. Figure. 1 shows overall survival increased neuroendocrine differentiation (31). Markers of and 95% CI on the survival estimate, calculated using the neuroendocrine differentiation, such as chromogranin A and Kaplan-Meier method. neuron-specific enolase, are seen more frequently as cancers progress (32, 33). Since platinum compounds have activity DISCUSSION against cancers with neuroendocrine differentiation, their In this phase I dose escalation trial, estramustine, weekly incorporation into regimens for HRPC may represent an docetaxel, and monthly carboplatin showed significant activity additional option for some patients. and an acceptable toxicity profile. Weekly docetaxel has been Recent data presented at the 2004 Annual Meeting of the noted to be less myelosuppressive than every 3-week dosing (28, American Society of Clinical Oncology showed a survival benefit 29). In addition, estramustine may have a myeloprotective effect for docetaxel plus prednisone compared with mitoxantrone plus when combined with cytotoxic chemotherapy such as vinblastine prednisone (11). In this trial, 1,006 patients were randomized to docetaxel 75 mg/m2 every 3 weeks, docetaxel 30 mg/m2 weekly (30). On the other hand, carboplatin given every 4 weeks can 2 clearly cause neutropenia and thrombocytopenia. Indeed, in for 5 of 6 weeks, and mitoxantrone 12 mg/m every 3 weeks. All this trial, we found excessive delayed myelosuppression with a patients received prednisone 5 mg p.o. twice daily. Median carboplatin dose of AUC (6), which required a dose adjust- survival was 18.9, 17.4, and 16.5 months, respectively. The ment of carboplatin to continue this study. However, when the hazard ratio was 0.76 (95% CI, 0.62-0.94; P = 0.0009) in the carboplatin dose was decreased to AUC (5), the regimen was every 3-week docetaxel arm compared with the mitoxantrone better tolerated and a maximum tolerated dose was not reached, arm. The weekly docetaxel arm did not show a statistically although myelosuppression represented the most common grade significant improvement in survival compared with mitoxan- 3 and 4 toxicities. Nonetheless, it is also important to note that, trone. As a result of this trial, docetaxel every 3 weeks plus although this regimen had an acceptable toxicity profile, the prednisone has been approved by the Food and Drug Adminis- median age of patients on trial was 64 years and the performance tration for the treatment of hormone refractory prostate cancer. In status was either 0 or 1. Proper patient selection remains an important consideration for clinicians considering the use of such regimens. Although this was a phase I trial, data across all dose levels showed that the combination was active even at the lower doses of docetaxel, when combined with estramustine and carboplatin. At the recommended phase II dose, 9 of 12 (75%) of patients experienced a PSA decline of at least 50% and 2 of 5 (40%) patients with measurable disease showed at least a partial response. The degree to which carboplatin enhances clinical response and survival in patients with HRPC treated with estramustine plus docetaxel is uncertain. Five recent phase I or II trials involving 183 patients, including this report, have been published using estramustine, carboplatin and a taxane (19–22; Table 5). PSA declines of z50% have been seen in 60% to 100% of patients enrolled on these trials. Measurable responses were seen in 24% to 65% of patients with measurable disease, although if only patients who received the recommended phase II dose are included, the range is 40% to 65% across these trials. Fig. 1 Kaplan-Meier plot of overall survival. Dotted lines, 95% CIs.

Table 5 Recent trials of estramustine, carboplatin plus taxane chemotherapy Author Year Taxane n PSA declines >50% Measurable response rate Kelly et al. (19) 2001 Paclitaxel 56 67% 45% Urakami et al. (21) 2002 Paclitaxel 32 100% 61% Solit et al. (20) 2003 Paclitaxel 30 60% 65% Oh et al. (22) 2003 Docetaxel 40 68% 52% Current report: overall 2004 Docetaxel 30 63% 24%

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William K. Oh, Elizabeth Hagmann, Judith Manola, et al.

Clin Cancer Res 2005;11:284-289.

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