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Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy

James M. McKiernan, Puneet Masson, Alana M. Murphy, Manlio Goetzl, Carl A. Olsson, Daniel P. Petrylak, Manisha Desai, Mitchell C. Benson

From the Columbia University Medical Center, New York, NY

Address reprint requests to Puneet Masson, MD, Columbia University Medical Center, 161 Fort Washington Ave, 11th Floor, Department of Urology, New York, NY 10032; e-mail: pm2016{at}columbia.edu

	ABSTRACT

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PURPOSE: Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent.

PATIENTS AND METHODS: This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging.

RESULTS: Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression.

CONCLUSION: Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

	INTRODUCTION

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In 2005, an estimated 63,210 new cases of bladder cancer will be diagnosed in the United States and approximately 13,180 people will die from the disease.¹ Superficial transitional-cell carcinoma (TCC) accounts for 70% to 80% of these cases; in individual cases with high-risk clinical and pathologic features (Ta, T1, and Tis), intravesical therapy has become the standard of care.² Unfortunately, up to 50% of patients treated with intravesical therapies for high-risk superficial transitional cell carcinoma will recur.³ Previously studied second-line and salvage intravesical therapies have response rates of 20% to 40%, respectively.^4,5 When currently available intravesical agents fail to control disease, the option most likely to improve patient survival is radical cystectomy with urinary diversion. Not all patients are candidates for radical cystectomy; multiple trials have demonstrated that radical cystectomy is associated with significant short-term and long-term morbidities, and many patients refuse or are medically unfit to undergo this operation.^6-9 For this subgroup of patients, there are limited alternatives, so there is an active need to investigate other intravesical options.

Docetaxel (Taxotere; sanofi-aventis, Bridgewater, NJ; [(2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester,13-ester with 5ß, 20-epoxy-1, 2, 4, 7ß, 10ß, 13 –hexahydroxytax-11-en-9-one 4-acetate2 benzoate, trihydrate]) is a cytotoxic chemotherapeutic agent derived from the needles of Taxus baccata.¹⁰ Docetaxel exerts its chemotherapeutic effect through promotion of the intracellular bundling of microtubules; the subsequent inhibition of microtubule depolymerization results in M-phase cell cycle arrest and cell death.¹¹ In clinical trials, systemic docetaxel has demonstrated antitumor activity in a wide range of cancers.^12-16 DeWit et al¹⁷ observed an overall response rate of 31% using intravenous docetaxel in a phase II study among 30 patients with metastatic urothelial cancer; 14% of patients had a complete response. In a similar phase II study of combined docetaxel and cisplatin, Dimopoulos et al¹⁸ achieved an objective response rate of 52% in 66 patients with advanced urothelial cancer. Further studies of docetaxel combined with other chemotherapeutic agents have shown response rates ranging from 33.3% to 66.7%.^19-22

Both docetaxel and its close molecular relative, paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ), have been extensively studied in vitro and proven effective in TCC cytotoxicity assays. Docetaxel has been proven effective in inhibiting growth of human bladder tumor cell lines at concentrations as low as 0.1 µmol.²³ In a study involving beagle dogs, Song et al²⁴ instilled paclitaxel 500 µg in 20 mL water into the bladder of each dog and found that the plasma concentration of paclitaxel after intravesical instillation was less than 0.05% of the maximally tolerated plasma concentration of paclitaxel in humans (1 µg/mL). Song et al²⁴ also found that intravesical paclitaxel produces a substantial chemotherapeutic targeting advantage, with a 6,000-fold greater average bladder tissue concentration of the drug compared with its intravenously administered steady-state plasma concentration. The systemic efficacy of docetaxel, its relatively high molecular weight of 861.9 da, and the preclinical safety data available for its close molecular relative, paclitaxel, in the animal model make it a logical candidate for a phase I trial in patients with refractory superficial bladder carcinoma.

The primary objectives of this study were to determine the safety and toxicity profile of intravesical docetaxel and to define the maximum-tolerated dose (MTD) of docetaxel by an intravesical route.

	PATIENTS AND METHODS

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Eligibility Criteria
All patients had a histologically confirmed diagnosis of superficial transitional cell carcinoma of the urinary bladder (Ta, T1, or Tis) at Columbia University Medical Center and were deemed medically unable to undergo radical cystectomy or had refused cystectomy. Demonstrated evidence of recurrent superficial bladder cancer refractory to standard intravesical therapy, including Bacillus Calmette-Guerin (BCG), mitomycin, interferon, or any combination thereof, was required. All grossly visible disease was fully resected before the study. Other eligibility criteria included the following: age 18 years; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; no previous intravesical therapy for 6 weeks; no history of prior radiation to the pelvis; peripheral neuropathy grade 1; and adequate hematopoietic and hepatic parameters. Specific exclusion criteria included muscle-invasive disease (T2-T4), prior treatment with docetaxel, concomitant treatment with any chemotherapeutic agent, history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80, history of vesicoureteral reflux or an indwelling urinary stent, any other malignancy diagnosed within 2 years of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix), participation in any other research protocol involving administration of an investigational agent within 3 months before study entry, and any contraindication to prescribed immunosuppressive medications because of a confounding medical condition. Female patients who were pregnant or lactating also were excluded. Columbia University Medical Center's Herbert Irving Comprehensive Cancer Center and institutional review board approved the study protocol and consent, and all patients gave written informed consent before enrollment.

All patients were screened by the principle investigator (J.M.M.) to ensure eligibility requirements were met. Weight, vital signs, and ECOG performance status were also evaluated. Adequate hematopoietic (absolute neutrophil count 1,500/µL, hemoglobin 8.0 g/dL, platelet count 100 x 10⁹/L) and hepatic (serum total bilirubin within the normal institutional ranges and serum AST and ALT 2.5x the institutional upper limit of normal [ULN] if alkaline phosphatase is the institutional ULN, or alkaline phosphatase 4x the institutional ULN if AST and ALT are both the institutional ULN) parameters were confirmed before study entry. Pretreatment studies also included a chest x-ray, abdominal and pelvic computed tomography (CT) scan with and without oral and intravenous contrast, and ECG.

Study Drug and Preparation
An investigational new drug application for docetaxel was filed, and exemption was granted by the US Food and Drug Administration in January 2003. Docetaxel was reconstituted with polysorbate 80 by the medical center's research pharmacy and was then diluted in 0.9% sodium chloride and stored in glass vacucontainer bottles.

Drug Administration
One week before each treatment day, all patients had a CBC fulfilling the hematopoietic inclusion criteria. Additionally, three doses of dexamethasone 4 mg tablets were administered; patients took one tablet 12 hours before, 1 hour before, and 8 hours after each treatment cycle.

During each treatment, all patients had an updated history performed by the principle investigator. Patients were screened to evaluate local bladder toxicity using the National Cancer Institute Common Toxicity Criteria version 2.0 (NCICTC 2.0). A physical examination and assessment of ECOG status were performed, and urine was evaluated for pH by dipstick. If the urine pH was outside the range of docetaxel solubility (pH 5 to 7), the treatment was withheld.

The phase I trial was begun with an initial dose of docetaxel 5 mg in 40 mL normal saline (NS). The final solution of the medication was infused by a Bardex All-Silicone 18-F Foley catheter. Before instillation, the bladder was emptied by sterile urethral catheterization. Patients then received the docetaxel solution intravesically over a 5-minute infusion, weekly for 6 weeks. Patients retained the drug in the bladder for 2 hours before voiding. Two hours after voiding, high-pressure liquid chromatography (HPLC) serum docetaxel levels and a CBC were checked for the determination of systemic toxicity. Evidence of systemic absorption of docetaxel was measured weekly by HPLC as described by Rouini et al²⁵ and Ardiet et al.²⁶ On even-numbered treatment cycles (treatments 2, 4, and 6), patients also had basic metabolic panel, hepatic function panel, and coagulation studies checked for evidence of electrolyte abnormalities, renal dysfunction, coagulopathy, or hepatic dysfunction. If any evidence of grade 2, 3, or 4 systemic toxicity was found in these laboratory values, then the patient was immediately removed from the trial and was deemed to have systemic dose-limiting toxicity (DLT).

Treatment Assessment
After the third treatment, all patients had cystoscopy performed to monitor for local bladder toxicity, including mucosal ulceration or erythema. Evidence of severe local toxicity would prompt discontinuation from the study. Patients also returned 1 week after concluding the 6-week treatment cycle to have an updated history, physical examination, and blood/urine studies performed. Four weeks after completing the treatment, the patients returned for the same serum studies and additional cystoscopy with bladder biopsies under anesthesia to evaluate safety and efficacy. Post-treatment studies also included an ECG, chest x-ray, and abdominal and pelvic CT scan with and without oral and intravenous contrast.

Toxicity Evaluation
All toxicities were graded according to the NCICTC 2.0. Systemic DLT was defined as plasma docetaxel values greater than 10 ng/mL or any grade 2, 3, or 4 systemic toxicity. Localized DLT was defined as any grade 3 or 4 hematuria, dysuria, urinary retention, urinary frequency/urgency, or bladder spasm. In the event of grade 2 hematuria, dysuria, urinary retention, urinary frequency/urgency, or bladder spasm, docetaxel instillation was postponed 1 week, provided that resolution of symptoms to a maximum of grade 1 occurred. Any patient who missed more than one dose of docetaxel had local DLT. Any patient who exhibited evidence of either systemic or local DLT was removed from the trial and treated according to the standard of care.

Dose Escalation and Statistical Analysis
The primary objectives of this phase I trial were to define the DLT and MTD of the intravesical infusion of docetaxel. The secondary objective was to obtain preliminary efficacy data. The Fibonacci dose-escalation design was utilized for the trial. If zero of three consecutive patients at a dose level experienced a DLT, three subsequent patients were enrolled at the next dose level. If one of three patients at a dose level experienced a DLT, an additional three patients would be enrolled at that dose level for an expanded cohort of six patients. If none of the three additional patients experienced a DLT, the next group of three patients was started on the next higher dose level for 6 weeks. If, at any dose level, two or more of six patients experienced a DLT, the previous dose level was defined as the MTD. A total of six patients were then treated at this MTD. Thus, establishment of an MTD was defined as that dose in which less than two of six patients experienced a DLT. All patients being treated at the dose level which defined an MTD would complete treatment at the lower dose. The docetaxel dose of 75 mg diluted in 100 mL NS was chosen as the target dose level, because of the expected inability to infuse higher delivery volumes for a 2-hour dwell time.

Response was based on each patient's 10-week post-treatment cystoscopy, including a biopsy of the urothelium and cytology, which occurred after the initial resection of tumor tissue and at 4 weeks after the six weekly infusions of intravesical docetaxel. Therefore, disease-free status (DFS) was defined as a negative post-treatment cystoscopy, including a biopsy of the urothelium and a negative cytology. A partial response (PR) was defined as a negative bladder biopsy with persistent positive cytology. No response (NR) was defined as a positive bladder biopsy.

	RESULTS

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Patient Characteristics
Eighteen patients were enrolled onto the study (Table 1 ). The median age was 75 years (range, 39 to 89 years). Sixteen males and two females were enrolled, for a male-female ratio of 8:1. Sixteen patients had refused surgery, and two patients were deemed medically ineligible for radical cystectomy. All eighteen patients had an ECOG performance score of 0. Every patient had refractory TCC; seven patients had disease stage Ta, six had stage Tis, and five had stage T1. All patients received prior intravesical treatment with BCG, including BCG (nine of 18) and BCG/interferon (nine of 18), with a mean of three prior treatments. Four patients received prior intravesical chemotherapeutic treatments with mitomycin, valrubicin, or thiotepa.

	DISCUSSION

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Intravesical treatment with BCG is the most common therapy for high-grade, superficial TCC²⁷ and has been highly effective in delaying time to recurrence in this disease.^28-30 In patients with Tis alone, BCG has been the most effective agent, with two-thirds of patients responding to BCG.³¹ Unfortunately, recurrence after BCG therapy is associated with poor health outcomes, and a significant number of patients have lifelong risk for disease progression.^32,33 Our study population was comprised of individuals with highly resistant disease and increased risk for recurrence; they had previously failed an average of three treatments with the most effective intravesical agents currently available. Although efficacy was not the primary objective in this phase I trial, the presence of activity in 12 (67%) of our 18 heavily pretreated patients suggests that docetaxel may be of value to patients failing treatment with BCG.

Safety and tolerability were the primary objectives of this study, so the systemic absorption of docetaxel was an important concern. Although docetaxel is routinely given intravenously for carcinoma of the breast, prostate, and lung, it has never been administered intravesically in humans. Its close molecular relative, paclitaxel, has shown minimal systemic absorption in intravesical animal models. Used previously as intravesical therapy in beagle dogs, paclitaxel has an almost identical molecular weight (853.9 da) to docetaxel (861.9 da).²⁴ Systemic absorption of chemotherapeutic drugs through the bladder wall is highly unlikely for compounds with a molecular weight greater than 300 da.⁹ Current intravesical chemotherapeutic agents, such as mitomycin C and doxorubicin, have molecular weights of 334 and 580 da, respectively.³⁴ Despite the low risk of absorption, we had several safeguards in our study design: First, all patients were pretreated with dexamethasone, as it has been shown to reduce the incidence and severity of fluid retention and hypersensitivity reaction.³⁵ Second, we measured serum docetaxel levels weekly with HPLC analysis to evaluate systemic absorption. With these two conservative precautions in place, we ensured that no patients experienced any systemic absorption of docetaxel.

Intravesical docetaxel given weekly for 6 weeks demonstrated excellent tolerability in this phase I clinical trial. Treatment was safe and tolerable at doses up to 75 mg/100 mL NS per instillation, and there was no evidence of systemic absorption or DLT. Only 44% of patients experienced grade 1 and 2 toxicities, including grade 1 dysuria, grade 1 and 2 hematuria, and grade 1 frequency; all of these symptoms were defined by the NCICTC 2.0 as resolving without any clinical intervention. Although efficacy was not a primary end point of our study, the preliminary response data in this patient population merits further investigation in a phase II trial.

In a cohort of three patients at every dose level, no observable correlation occurred between dose and toxicity or between dose and response. Grade 1 and 2 toxicities were experienced at every dose level, except for at the maximum administered dose of docetaxel 75 mg. Activity, based on response, was demonstrated at each dose level. The response remained unpredictable as the dose was increased. Because only three patients were treated at each dose level, it is impossible to determine whether a dose-response relationship would exist.

Based on the need for intravesical chemotherapeutic alternatives for localized bladder cancer and on the preliminary efficacy data in our heavily resistant population, intravesical docetaxel merits further investigation. Because of the positive findings of this study, we plan to evaluate the docetaxel 75 mg/100 mL NS weekly for 6 weeks in a larger phase II trial.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other James M. McKiernan sanofi-aventis (B) sanofi-aventis (B) Mitchell C. Benson sanofi-aventis (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: James M. McKiernan, Manlio Goetzl, Carl A. Olsson, Daniel P. Petrylak, Manisha Desai, Mitchell C. Benson Administrative support: Puneet Masson, Alana M. Murphy, Manlio Goetzl, Mitchell C. Benson Provision of study materials or patients: James M. McKiernan, Puneet Masson, Alana M. Murphy, Manlio Goetzl, Carl A. Olsson, Daniel P. Petrylak, Mitchell C. Benson Collection and assembly of data: James M. McKiernan, Puneet Masson, Alana M. Murphy Data analysis and interpretation: James M. McKiernan, Puneet Masson Manuscript writing: James M. McKiernan, Puneet Masson Final approval of manuscript: James M. McKiernan, Puneet Masson, Manisha Desai, Mitchell C. Benson

 

	NOTES

 
Supported in part by the sanofi-aventis Corp.

Presented at the 100th Annual Meeting of the American Urological Association National Convention, San Antonio, TX, May 21-26, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted June 20, 2005; accepted April 6, 2006.

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