2098 Vol. 9, 2098–2107, June 2003 Clinical Cancer Research Dose Escalation Study of Intravenous Estramustine Phosphate in Combination with Paclitaxel and Carboplatin in Patients with Advanced Prostate Cancer1 William Kevin Kelly,2 Andrew X. Zhu, timated. Pharmacokinetic evaluation was performed in cy- Howard Scher, Tracey Curley, Mary Fallon, cles 1 and 2 during the first week of therapy. Results: Nineteen patients were entered on the initial three Susan Slovin, Lawrence Schwartz, Steve Larson, dose levels (cohorts 1–3). Dose-limiting transient hepatic toxic- mg/m2). An 1500 ؍ William Tong, Beryl Hartley-Asp, ity was encountered in cohort 3 (EMP Cinzia Pellizzoni, and Maurizio Rocchetti additional 13 patients were treated with paclitaxel (100 mg/m2) Genitourinary Oncology Service, Division of Solid Tumor, first, followed by i.v. EMP at 1000 mg/m2 (cohort 4), and 1500 Department of Medicine [W. K. K., H. S., S. S.], Department of mg/m2 (cohort 5). No dose-limiting toxicities were seen, and Nursing [T. C.], Department of Radiology [L. S.], Division of cohort 5 was determined safe for Phase II studies. Thrombo- Epidemiology and Biostatistics [M. F.], Department of Pharmacology embolic events were observed in 9% of patients (no prophy- [W. T.], and Department of Nuclear Medicine [S. L.], Memorial Sloan Kettering Cancer Center, New York, New York 10021; Department lactic coumadin was used). Plasma concentrations of EMP and of Medicine, Joan and Sanford Weill Medical College of Cornell metabolites increased proportionally with dose. In all cohorts, University, New York, New York [W. K. K., S. S.]; Hematology- there was a slight decrease in EMP and estramustine plasma Oncology, Massachusetts General Hospital, Dana-Farber/Partners concentrations between cycles 1 and 2. Although not signifi- Cancer, Boston, Massachusetts [A. X. Z.]; and Pharmacia cant, higher levels of estromustine at cycle 2 were observed in Corporation, Peapack, New Jersey [B. H-A., C. P., M. R.] comparison to cycle 1. Decreased clearance of paclitaxel lead- ing to higher than expected paclitaxel plasma concentrations ABSTRACT was observed during the first cycle of therapy. Paclitaxel Purpose: The purpose is to determine a safe weekly dose plasma concentrations were lower during cycle 2. In 17 pa- > of i.v. estramustine phosphate (EMP) to combine with tients with androgen-independent disease, 59% had 50% weekly paclitaxel and monthly carboplatin in patients with posttherapy decline in PSA and 22% showed measurable dis- advanced prostate cancer. ease regression. Experimental Design: Patients with advanced prostate Conclusions: The regimen of weekly i.v. EMP in com- cancer (castrate and noncastrate) were administered esca- bination with paclitaxel and carboplatin can be safely lating doses of weekly 1-h infusion of i.v. EMP (500–1000- administered with hepatic toxicity being transient and re- 1500 mg/m2) in combination with weekly paclitaxel (100 versible. Pharmacokinetic results suggest that EMP com- mg/m2 over 1 h) and i.v. carboplatin (area under the curve petitively inhibits the biotransformation of paclitaxel after 6 mg/ml-min every 4 weeks). Four weeks of therapy were the first administration. This effect is counterbalanced, after considered one cycle. In the first three cohorts, EMP was repeated administrations, by a possible induction of the given i.v. 3 h before paclitaxel. Cohorts 4 and 5 reversed the metabolic system caused by EMP. Phase II testing is ongoing administration order: EMP (doses 1000–1500 mg/m2) was to evaluate the efficacy of this combination. given immediately after the end of paclitaxel infusion. Plasma levels of EMP and its metabolites, estramustine and INTRODUCTION estromustine, were monitored at time 0, at 120 min, and Over the preceding 5 years, we have seen the development approximately at 20, 21, and 168 h from the start of EMP of more effective treatment regimens for patients with meta- infusion. Paclitaxel concentrations were determined at basal static prostate cancer; however, the morbidity of the therapy can (0), 30, 60, 90, and 120 min and 18 h after the start of deter many physicians and patients from treatment. We have paclitaxel infusion, and a concentration-time curve was es- previously explored the use of weekly paclitaxel combined with oral EMP3 and i.v. carboplatin (TEC; Ref. 1). The rationale was based on: (a) the single agent activity profile of carboplatin (2); (b) the observation that weekly paclitaxel and carboplatin are synergistic and platelet sparing (3–5); (c) the known synergy of Received 11/1/02; revised 1/16/03; accepted 1/30/03. estramustine and paclitaxel (6); and (d) work suggesting that The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by CaPCURE, Bristol-Myers Squibb, Pharmacia Corpora- tion, American Cancer Society, Career Training Grant 97-118-01-CCE, 3 The abbreviations used are: EMP, estramustine phosphate; PSA, pros- and PepsiCo Foundation Grant CA 05826. tate-specific antigen; CT, computed tomography; MRI, magnetic reso- 2 To whom requests for reprints should be addressed, at Memorial Sloan nance imaging; DLT, dose-limiting toxicity; KPS, Karnofsky perform- Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. ance status; BSI, bone scan index; AUC, area under the curve; MTD, Phone: (646) 422-4473; Fax: (212) 988-0701; E-mail: [email protected]. maximum-tolerated dose; CYP, cytochrome P-450. Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 2099 estramustine may increase the intracellular concentration of tion of progressive disease after the discontinuation of an anti- concomitantly administered drugs by inhibiting p-glycoprotein- androgen, castrate levels of testosterone (Ͻ30 ng/ml), a life catalyzed drug efflux from tumor cells (7). In previous work expectancy of Ͼ3 months, and no more than one prior course of with the combination of oral EMP with paclitaxel and carbo- chemotherapy (patients could have had one previous EMP- or platin, we showed that 36 of 54 castrate metastatic prostate taxane-based regimen), palliative radiotherapy, or radioisotope cancer patients (67%) had Ն50% posttherapy decline in PSA, therapy. Disease progression was defined as the presence of at 45% showing measurable disease regression, and a palliative least one of the following events: (a) a rising PSA of Ն50% benefit in the majority of patients who presented with pain (1). from baseline on three successive occasions; (b) new metastatic Mild to moderate nausea and thromboembolic events, known lesions on bone scan; or (c)aϾ25% increase in a bidimension- side effects of EMP, complicated the therapy. ally measurable tumor mass. Patients who had not undergone Despite the convenience of the oral formulation of EMP, surgical castration were continued on luteinizing hormone- gastrointestinal and cardiovascular toxicity limit its use in the releasing hormone agonists. clinic. After oral dosing, no EMP is present in the systemic circu- All patients had a KPS Ն 70%, WBC Ն 3500 cells/mm3, lation, and only the dephosphorylated species of estramustine with granulocytes Ն 1500 cells/mm3, platelet count Ն 120,000 cells/ the oxidized metabolite, estromustine, and the corresponding hy- mm3, hemoglobin Ն 8.0 g/dl, serum creatinine Յ 2.0 mg/dl, and drolysis products (estradiol, estrone) can be measured in plasma a baseline serum glutamic-oxaloacetic transaminase Ͻ 1.5ϫ the (8). This first-pass formation of metabolites is thought to account, institutional normal. Patients must not have undergone major to a considerable extent, for these DLTs. To improve on oral EMP surgery, radiation therapy, chemotherapy, or immunotherapy toxicity profile, Hudes et al. (9) performed a Phase I study in which within 4 weeks before entry. Patients could not have radioiso- high i.v. doses of EMP were administered weekly. They demon- tope therapy within 8 weeks before entry. Individuals were strated that a high dose of i.v. EMP can be administered safely with excluded if they had New York Heart Association class III or IV a decrease in the gastrointestinal and cardiovascular adverse effects heart disease, history of ventricular arrhythmias, history of when compared with the oral EMP. In addition, high peak concen- bleeding disorder, peripheral neuropathy (grade 3 or 4), central trations of active metabolites after i.v. EMP were supposed to nervous system disease, active infection, insulin-dependent di- provide an advantage over oral EMP in antimicrotubule drug abetes mellitus, or the presence of brain metastases. The Insti- combinations (9). tutional Review Board approved the protocol and written in- On the basis of these results and to improve on the safety formed consent was required for all patients. profile of the TEC regimen, we investigated the use of i.v. The pretreatment evaluation included a complete history weekly EMP in combination with paclitaxel and carboplatin in and physical examination with a baseline KPS. Laboratory patients with advanced prostate cancer. The study was con- studies included an automated blood and platelet count, serum ducted in two parts. The first was a dose escalation study to electrolytes, comprehensive screening profile (alkaline phospha- establish a safe dose of i.v. EMP to combine with paclitaxel and tase, lactate dehydrogenase, aspartate transglutaminase, blood carboplatin. This portion of the study included patients with urea nitrogen, creatinine, calcium, phosphorus, uric acid, total castrate and noncastrate prostate cancer, and the objective was protein, albumin, total bilirubin, and electrolytes), testosterone not to see if there was a beneficial effect from the chemotherapy level, serum acid phosphatase, and PSA. Imaging studies in- but rather to establish a safe regimen that is feasible in multiple cluded an abdominal and pelvic CT or MRI scan, bone scan, and prostate cancer disease states. Once a safe dose was established, chest radiograph.