Phase II Trial of Intravesical Nanoparticle Albumin Bound for the Treatment of Nonmuscle Invasive Urothelial Carcinoma of the Bladder after bacillus Calmette-Guerin Treatment Failure

James M. McKiernan,* Dara D. Holder, Rashed A. Ghandour, LaMont J. Barlow, Jennifer J. Ahn,† Max Kates, Gina M. Badalato, Arindam Roychoudhury,‡ G. Joel Decastro and Mitchell C. Benson

From the Department of Urology, Herbert Irving Cancer Center (JMM, DDH, RAG, LJB, JJA, MK, GMB, GJD, MCB) and Department of Biostatistics, Mailman School of Public Health (AR), Columbia University Medical Center, New York, New York

Purpose: Response rates to current second line intravesical therapies for Abbreviations recurrent nonmuscle invasive range between 10% and 30%. and Acronyms Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower ¼  toxicity compared to other . Results of the phase I intravesical trial of this BCG bacillus Calmette-Guerin compound demonstrated minimal toxicity during dose escalation. We now report CFS ¼ cystectomy-free survival the results of a phase II trial to assess efficacy. CIS ¼ carcinoma in situ Materials and Methods: This study was an investigator initiated, single center, CR ¼ complete response single arm, phase II trial investigating the use of nab-paclitaxel in patients with MDD ¼ maximal deliverable dose recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen nab ¼ nanoparticle albumin  of intravesical bacillus Calmette-Guerin failed. Patients received 500 mg/100 ml bound nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was NMIBC ¼ nonmuscle invasive evaluated with cystoscopy, biopsy, cytology and imaging. If complete response bladder cancer was achieved, patients were treated with full dose monthly maintenance treat- RC ¼ radical cystectomy ments for 6 months. RFS ¼ recurrence-free survival Results: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of Accepted for publication June 25, 2014. these responses remained durable after maintenance therapy. At a mean fol- Study received institutional review board lowup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their approval. bladders without progression or distant metastases. A single patient had Supported by an investigator initiated grant from Celgene Pharmaceutical. No edits to the progression to muscle invasive disease at radical cystectomy. Treatment related manuscript were performed by the Celgene adverse events were noted in 9 of 28 (32.1%) patients and were limited to editorial office. grade 1 or 2. * Correspondence: Department of Urology, Columbia University Medical Center, 161 Fort Conclusions: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% Washington Ave., Herbert Irving Pavilion, 11th response rate in patients with nonmuscle invasive bladder cancer and previous Floor, New York, New York 10032 (telephone: 212-  305-5526; FAX: 212-305-6813; e-mail: jmm23@ bacillus Calmette-Guerin failure. Complete response remained durable at 1 year columbia.edu). followup in this heavily pretreated patient population. † Financial interest and/or other relationship with Celgene. ‡ Financial interest and/or other relationship Key Words: neoplasms; intravesical administration; with Novartis. therapies, investigational; paclitaxel; nanotechnology

IN 2013 the incidence of bladder can- Urothelial carcinoma constitutes more cer in the United States was 72,500 than 90% of cases and approximately with approximately 15,000 deaths.1 70% present initially with NMIBC.2

0022-5347/14/1926-1633/0 http://dx.doi.org/10.1016/j.juro.2014.06.084 THE JOURNAL OF UROLOGY® Vol. 192, 1633-1638, December 2014 www.jurology.com j 1633 © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Printed in U.S.A. 1634 NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER

In 1976 Morales reported the therapeutic efficacy MATERIALS AND METHODS 3 of BCG in high grade NMIBC. Subsequently BCG Study Design has become the gold standard treatment. This study was a single center, prospective, institutional Currently the American Urological Association review board approved (IRB-AAAC1114), investigator and European Association of Urology recommend initiated and industry sponsored phase II nonrandomized intravesical BCG as first line treatment after trans- trial. The MDD was 500 mg in 100 ml normal saline in the urethral resection of high grade NMIBC.4,5 Five- previously published phase I study.20 A Simon 2-stage year recurrence rates after BCG induction with design was used. There were 10 patients enrolled in the maintenance range from 30% to 60% depending on first stage, and only when 2 or more of those patients stage, grade, multiplicity and length of followup.3,6,7 responded, 18 additional patients were evaluated in the Recurrent NMIBC is a heterogeneous disease state, second stage. The probability of correctly concluding the therapy is worthy of further study was calculated to be and can be defined and characterized using terms 80% if the true underlying response rate was 30%. The such as refractory, resistant and relapsing. With a probability of incorrectly concluding the therapy is prom- progression risk of 20% to 30% in this setting, radical ising was 5% if the true response rate was approximately 4e8 cystectomy is currently the standard of care. 10%.21e23 The expected sample size for this study design Second line novel agents have been an area of was a minimum of 15 and a maximum of 28 patients. active investigation. To date, valrubicin is the only FDA (Food and Drug Administration) approved Patient Eligibility intravesical therapy for BCG refractory NMIBC and Patients eligible for this study all had high risk NMIBC has been associated with an 18% to 21% CR rate in with pathologically proven stage T1, Ta or Tis. Patients had high grade disease except 1 who had multifocal studies limited exclusively to patients with CIS.9,10 recurrent low grade stage Ta disease. All patients were Multiple other agents have been investigated, subject to a minimum of 1 prior intravesical BCG induction including BCG combined with alpha-interferon, course. Prior use of intravesical , interferon, mitomycin C with or without electromotive and hy- , or other experimental clinical perthermic techniques, gemcitabine, docetaxel and agents was allowed. If a patient was treated in a prior combination intravesical in preclini- , a minimum of 3 months after completion of cal studies.11e13 the prior protocol was required with documented disease In 2006 we reported the results of 18 patients in a recurrence before enrollment in this study. All patients phase I clinical trial of intravesical docetaxel for the had grossly visible disease fully resected with pathological treatment of recurrent NMIBC after BCG ther- confirmation of histology before enrollment. They were apy.14 Docetaxel showed no systemic absorption and offered RC as the gold standard option and refused, or were at unacceptable surgical risk. Patients underwent minimal toxicity, and a 56% CR at initial assess- pretreatment assessment including physical examination, ment in that trial, with a 4-year recurrence-free cystoscopy and cross-sectional imaging, as well as com- survival of 22%. In that phase I trial the maximal plete blood count, basic metabolic panel, hepatic function tolerated dose and safety profile were the primary panel and coagulation profile before study enrollment. 12,15 end points. Paclitaxel, another and Additional inclusion criteria were age 18 years or older, depolymerization inhibitor, is used for ability to provide informed consent, Eastern Cooperative systemic treatment of multiple cancers and, in its Oncology Group performance status 0 or 1, mild or no nanoparticle albumin bound (nab-) form, is peripheral neuropathy, no hematological disturbances as 3 currently an FDA approved systemic therapy for defined by neutrophil count 1,500/mm or less, hemoglo- 3 breast and pancreatic cancer.16,17 bin 9 gm/dl or less, or platelet count 100,000/mm or less, Nab-paclitaxel has a fivefold higher solubility in no hepatic dysfunction as defined by abnormal bilirubin or liver function tests 2.5 or greater than upper normal limit, aqueous environments compared to docetaxel and no renal dysfunction as defined by serum creatinine 2.0 a facilitated drug delivery mechanism into tumor mg/dl or greater, negative pregnancy test in women of cells via albumin receptor mediated transport childbearing age and no intravesical therapy within 6 17,18 across epithelial cells. A third mechanism of weeks before enrollment. Exclusion criteria were prior improved action is through the newly described systemic taxane therapy, any other malignancy diagnosed SPARC tumor interstitium protein, which mediates within 2 years of study entry (except nonmelanoma skin transcytosis into tumor cells.19 The first human cancer, chronic lymphocytic leukemia or noninvasive phase I trial of intravesical nab-paclitaxel was cervical cancer), concurrent treatment with any chemo- published in 2011, with an encouraging safety therapeutic agent, pregnant or lactating women, history profile and acceptable secondary end points of of vesicoureteral reflux or an indwelling urinary stent, or efficacy.20 The current phase II study used the administration of any investigational agent within 3 months before study. MDD of nab-paclitaxel to further explore the activity of this agent in the treatment of high risk Drug Preparation and Administration NMIBC that has relapsed or persisted after BCG The dose of nab-paclitaxel was the MDD of 500 mg/100 ml therapy. 0.9% NaCl. The dose was instilled intravesically on a NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER 1635

weekly basis for 6 weeks as induction and on a monthly chemotherapy (mitomycin C or other agents) sub- basis for 6 months as maintenance in case of response. On sequent to BCG with or without interferon (table 2). the day of each instillation an updated history and phys- Only 1 patient previously responded to BCG then ical examination were performed, and a urine pH was experienced relapse, yet he never received mainte- measured by dipstick to be in the range of 5 to 7.5 to nance. No other patient in this study previously ensure nab-paclitaxel solubility. Sterile urethral cathe- received BCG maintenance. Twenty patients terization was performed to empty the bladder and instill nab-paclitaxel solution into the bladder with a drug refused and 8 were medically unfit for cystectomy. retention time of 2 hours. Median followup was 21 months (range 5 to 47). Twenty-six patients completed the 6 intravesical Treatment Assessment and Evaluation induction instillations and the remaining 2 patients After induction treatment, initial response was assessed were still included in the analysis of efficacy. through urine cytology, cystoscopy with biopsy, directed On initial posttreatment assessment 6 weeks and random, 6 weeks after the last instillation of the after the last induction instillation, 10 of the 28 induction nab-paclitaxel course. Cross-sectional imaging was included in the posttreatment evaluation. CR was patients (35.7%) had a CR. The pretreatment stages defined by the absence of any residual carcinoma in stratified by response status and the posttreatment the biopsy specimen as well as in cytology following the stages and cytology are presented in table 3. Among combination of maximal transurethral resection and the 10 responders 8 received the entire induction nab-paclitaxel. The efficacy of this protocol was measured course followed by 6 months of maintenance ther- using the CR rate as the primary end point, and apy. The 2 who did not complete induction also recurrence-free and cystectomy-free survival as the sec- did not receive maintenance therapy. Of the 10 ondary end points. responders 2 elected to continue on maintenance Local toxicity symptoms were monitored throughout therapy off protocol following the conclusion of the treatment, and graded using the Common Terminology 6-month maintenance period. One of these patients Criteria for Adverse Events, version 3.0, published by the exhibited positive cytology 14 months after enroll- National Cancer Institute. Treatment was delayed by 1 week if grade 2 local toxicity developed, then resumed ment with normal cystoscopic examination until if symptoms improved. Grade 3 or 4 toxicity prompted 45 months of followup, and refused further biopsy. discontinuation of therapy. Two patients died of unrelated causes at 11 and 24 months of followup. The remaining 7 patients were disease-free at a median followup of 21 months. RESULTS All 18 nonresponders were recommended by the A total of 28 patients were enrolled in the study urologist to proceed to RC yet only 9 accepted and between 2010 and 2013. Median patient age was followed the recommendation. Of these 9 patients 7 76 years (range 33 to 91), and 22 men and 6 women are alive with no evidence of local or systemic dis- were enrolled. All patients had nonmuscle invasive ease. One died 9 weeks after RC due to periopera- urothelial carcinoma of the bladder, with disease tive complications with final pathology showing CIS stage and grade presented in table 1. Only 1 patient only. A single patient undergoing RC exhibited had unifocal T1 while all the remaining had stage progression to muscle invasive disease multifocal disease. The median number of prior (pT2N0M0) on surgical pathology, and eventually courses of intravesical therapy was 2, with 7 pa- died of metastatic urothelial cancer 18 months after tients who received 1 course and 9 who received 3 or treatment initiation. more courses, including enrollment in prior clinical Of the 18 patients who did not respond to nab- trials of intravesical chemotherapy. Of the 28 paclitaxel therapy 9 did not undergo cystectomy. patients 6 (21.4%) previously received intravesical Table 2. Intravesical treatment history of participants Table 1. Demographic and clinical characteristics of participants No. (%)

No. (%) BCG alone induction 27 (96) BCG alone reinduction 6 (21) Gender: BCG maintenance 0 F 6 (21) BCG þ interferon 13 (46) M 22 (79) Intravesical chemotherapy: 6 (21) Clinical stage: Mitomycin 1 (3.6) Ta 4 (14) Gemcitabine 3 (11) Ta þ Tis 2 (7) Mitomycinþgemcitabine 1 (3.6) T1 4 (14) Valrubicin 1 (3.6) T1 þ Tis 5 (18) No. cycles: Tis only 13 (46) 1 7 (25) Tumor grade: 2 12 (43) Low grade/multifocal Ta 1 (4) 3 8 (29) High grade 27 (96) 4 1 (3.6) 1636 NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER

Table 3. Assessment of patients before and after treatment discontinuation of therapy because of a drug related No. Complete No. Noncomplete event. One patient received only 3 of the planned Responders (%) Responders (%) 6 instillations due to unrelated pneumonia, while Before nab-paclitaxel treatment* another patient withdrew from the trial due to Stage: recurrent urinary tract infections after receiving Ta 3 (30) 1 (5.6) only 2 instillations. These infections were multidrug Ta þ Tis 0 (0) 2 (11) T1 2 (20) 2 (11) resistant, present for more than 2 years before T1 þ Tis 1 (10) 4 (22) enrollment and due to incomplete bladder emptying. Tis only 4 (40) 9 (50) No grade 3 or higher toxicity was noted. After nab-paclitaxel treatment Stage on biopsy: T0 10 0 Ta (þTis) 0 (0) 2 (2) T1 (þTis) 0 (0) 2 (3) DISCUSSION Tis 0 9 High risk NMIBC represents a challenging disease Cytology: state to manage. While intravesical BCG is a well Malignant 0 (0) 11 (61) Suspicious 4 (40) 3 (17) established first line treatment for patients with Benign 6 (60) 4 (22) NMIBC, patients with recurrence after the initial treatment have lower response rates to subsequent *p<0.001. courses.24 BCG was previously compared as an induction agent to adjuvant intravesical chemo- Two died of unrelated causes, both within 12 therapy. However, it was only compared to mitomycin, months of initiation of treatment. The remaining and .8,25 Alternative agents 7 patients all had residual high grade NMIBC, that have proven successful in the systemic ther- 4 have not received further intravesical therapy and apy of advanced urothelial carcinoma such as 3 went on to receive further intravesical therapy , gemcitabine and docetaxel have now (2 docetaxel and 1 valrubicin), with 1 completely been investigated intravesically with varying yet responding to docetaxel and 1 completely respond- promising results. ing to valrubicin. None of those 9 exhibited stage Intravesical gemcitabine in particular was sup- progression at a median followup of 21 months. In ported by multiple studies in patients with high this study 19 of 28 patients retained their bladders risk disease. In a study by Gunelli et al a group of without disease progression or metastasis. RFS was 40 patients without CIS had a CR rate of 95% at 35.7% at 1 year and 30.6% at 2 years of followup. 6 months and disease-free survival of 66% at 24 CFS at 12, 24 and 36 months was 74%, 74% and months.26 However, a separate study by Dalbagni 55%, respectively. RFS and CFS are presented in et al of 30 patients (which included 23 patients Kaplan-Meier survival analysis plots (see figure). with CIS) showed a 20% disease-free survival at Nine patients (32%) experienced adverse events 12 months without the use of maintenance therapy in this study. All events were grade 1 or 2, and for responders.27 The most recent trial of gemcita- included fatigue, urinary urgency and self-limiting bine was conducted by Skinner et al of the South- hematuria for grade 1 (4 of 28 patients, 14%). west Oncology Group and was reported in 2013.11 Grade 2 toxicities (5 of 28 patients, 18%) included They found a 47% complete initial response rate urinary tract infection, frequency and urgency, at 3 months and a RFS of 28% and 21% at 1 and gross hematuria. No patient underwent and 2 years, respectively. Of note, maintenance

Disease-free (A) and cystectomy-free (B) survival after intravesical nab-paclitaxel NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER 1637

intravesical gemcitabine was given to complete additional maintenance treatments beyond those responders. allowed by our protocol. Prospective, randomized Intravesical taxane therapy has been a topic of studies are required to determine the ideal treat- interest at our institution since initiating our initial ment schedule and the true effect of maintenance phase I trial of intravesical docetaxel in 2003. The intravesical nab-paclitaxel. results of this trial were published in 2006, and Although CFS is not a widely studied or a widely demonstrated acceptable safety and efficacy pro- accepted outcome in bladder cancer literature, it files.14 However, no phase II trial of efficacy was provides a method to describe the likelihood of conducted.15 Paclitaxel, another taxane, recently bladder preservation in this population facing RC became available in an albumin bound formulation, as the standard of care, particularly in studies of improving its and safety profile, similar design and objective. The relatively short and theoretically its efficacy in targeting cancerous followup and limited sample size of this phase II trial cells. In our prospective phase II trial of efficacy in a limit any broad conclusions regarding the future heavily pretreated high risk population of patients role of nab-paclitaxel in patients with recurrent high with NMIBC, a CR rate of 35.7% was achieved. risk NMIBC after BCG. To resolve the role of novel More importantly, all patients who responded agents in this setting, a definitive randomized phase remained disease-free at 1 year, and RFS at 2 years III trial comparing a novel therapeutic agent with and at last followup was 30.6%, with a median fol- BCG or a similar standard intervention will be lowup of 21 months. These results demonstrate a required. durability of response to intravesical nab-paclitaxel induction plus maintenance not seen in any previ- ous taxane based clinical trial. CONCLUSIONS All patients were compliant with the induction This phase II study of intravesical nab-paclitaxel and maintenance therapy schedules and specified demonstrated significant activity in high risk followup except for 2 patients as described earlier. patients with recurrent NMIBC after treatment However, these 2 patients were included in the with BCG with or without other chemotherapeutic final analysis of therapy outcomes. Since this was agents. In a heavily pretreated population the a single arm study in which all complete initial limited toxicity profile in conjunction with a CR of responders were offered monthly maintenance 35.7% warrants further investigation. Furthermore, therapy throughout the duration of recurrence-free the addition of maintenance therapy resulted in a status for up to 6 additional treatments, the effect durability of response not frequently seen in such of maintenance therapy on durability could not be populations. Either alone or in combination with assessed. With a favorable safety profile, minimal other agents, nab-paclitaxel is a viable candidate absorption and a 6,000-fold greater bladder tissue for further study in this high risk population. concentration for intravesical therapy over systemic therapy,28 maintenance seems to be justified and ACKNOWLEDGMENTS practical. It is even possible that the durability Jiibril Palmer and Matthew Danzig provided seen in the current study could be improved with assistance.

REFERENCES 1. National Cancer Institute: SEER Stat Fact 5. Babjuk M, Burger M, Zigeuner R et al: EAU of non-muscle-invasive bladder cancer. Eur Urol Sheets: Bladder Cancer, Statistics at a Glance, guidelines on non-muscle-invasive urothelial 2010; 57: 410. November 2013. Available at http://seer.cancer. carcinoma of the bladder: update 2013. Eur Urol gov/statfacts/html/urinb.html. 2013; 64: 639. 9. Dinney CP, Greenberg RE and Steinberg GD: Intravesical valrubicin in patients with bladder 2. Jones JS: Non-muscle-invasive bladder cancer 6. Lamm DL, Blumenstein BA, Crissman JD et al: carcinoma in situ and contraindication to or (Ta, T1, and CIS). In: Campbell-Walsh Urology, Maintenance bacillus Calmette-Guerin immuno- failure after bacillus Calmette-Guerin. Urol Oncol 10th ed. Edited by L Kavoussi, A Partin, A Novick therapy for recurrent TA, T1 and carcinoma in 2013; 31: 1635. et al. Philadelphia: Saunders 2012; vol 3, p 2335. situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. 10. Steinberg G, Bahnson R, Brosman S et al: 163: 3. Morales A: Long-term results and complications J Urol 2000; 1124. Efficacy and safety of valrubicin for the treatment of intracavitary bacillus Calmette-Guerin therapy 7. Herr HW, Wartinger DD, Fair WR et al: Bacillus of bacillus Calmette-Guerin refractory carcinoma 132: 163: for bladder cancer. J Urol 1984; 457. Calmette-Guerin therapy for superficial bladder in situ of the bladder. J Urol 2000; 761. cancer: a 10-year followup. J Urol 1992; 147: 4. Hall MC, Chang SS, Dalbagni G et al: Guideline 1020. 11. Skinner EC, Goldman B, Sakr WA et al: SWOG for the management of nonmuscle invasive S0353: phase II trial of intravesical gemcitabine bladder cancer (stages Ta, T1, and Tis): 2007 8. Gontero P, Bohle A, Malmstrom PU et al: The in patients with nonmuscle invasive bladder update. J Urol 2007; 178: 2314. role of bacillus Calmette-Guerin in the treatment cancer and recurrence after 2 prior courses of 1638 NAB-PACLITAXEL FOR BACILLUS CALMETTE-GUERIN REFRACTORY BLADDER CANCER

intravesical bacillus Calmette-Guerin. J Urol 17. Gradishar WJ, Tjulandin S, Davidson N et al: 23. Herr HW: Transurethral resection and intra- 2013; 190: 1200. Phase III trial of nanoparticle albumin-bound vesical therapy of superficial bladder tumors. paclitaxel compared with polyethylated castor Urol Clin North Am 1991; 18: 525. 12. Laudano MA, Barlow LJ, Murphy AM et al: oil-based paclitaxel in women with breast Long-term clinical outcomes of a phase I trial cancer. J Clin Oncol 2005; 23: 7794. 24. Catalona WJ, Hudson MA, Gillen DP et al: Risks of intravesical docetaxel in the management of and benefits of repeated courses of intravesical non-muscle-invasive bladder cancer refractory 18. Sparreboom A, Scripture CD, Trieu V et al: bacillus Calmette-Guerin therapy for superficial to standard intravesical therapy. Urology 2010; Comparative preclinical and clinical pharmaco- bladder cancer. J Urol 1987; 137: 220. 75: 134. kinetics of a cremophor-free, nanoparticle 25. Sylvester RJ, Oosterlinck W and Van der Meijden 13. Delto JC, Kobayashi T, Benson M et al: Preclin- albumin-bound paclitaxel (ABI-007) and pacli- taxel formulated in Cremophor (Taxol). Clin AP: A single immediate postoperative instillation ical analyses of intravesical chemotherapy 11: of chemotherapy decreases the risk of for prevention of bladder cancer progression. Cancer Res 2005; 4136. recurrence in patients with stage Ta T1 4: Oncotarget 2013; 269. 19. Elsadek B and Kratz F: Impact of albumin on bladder cancer: a meta-analysis of published 14. McKiernan JM, Masson P, Murphy AM et al: drug deliveryenew applications on the horizon. results of randomized clinical trials. J Urol 2004; Phase I trial of intravesical docetaxel in the J Control Release 2012; 157: 4. 171: 2186. management of superficial bladder cancer 20. McKiernan JM, Barlow LJ, Laudano MA et al: A 26. Gunelli R, Bercovich E, Nanni O et al: Activity refractory to standard intravesical therapy. J Clin Oncol 2006; 24: 3075. phase I trial of intravesical nanoparticle albumin- of endovesical gemcitabine in BCG-refractory bound paclitaxel in the treatment of bacillus bladder cancer patients: a translational study. 15. Barlow L, McKiernan JM and Benson MC: Calmette-Guerin refractory nonmuscle invasive Br J Cancer 2007; 97: 1499. Long-term survival outcomes with intravesical bladder cancer. J Urol 2011; 186: 448. docetaxel for recurrent nonmuscle invasive 27. Dalbagni G, Russo P, Bochner B et al: Phase II bladder cancer after previous bacillus Calmette- 21. Bartoletti R, Cai T, Gacci M et al: Intravesical trial of intravesical gemcitabine in bacille  Guerin therapy. J Urol 2013; 189: 834. gemcitabine therapy for superficial transitional Calmette-Guerin-refractory transitional cell car- cell carcinoma: results of a phase II prospective cinoma of the bladder. J Clin Oncol 2006; 24: 16. Saif MW: U.S. Food and Drug Administration multicenter study. Urology 2005; 66: 726. 2729. approves paclitaxel protein-bound particles (AbraxaneÒ) in combination with gemcitabine as 22. Melekos MD and Moutzouris GD: Intravesical 28. Song D, Wientjes MG and Au JL: Bladder tissue first-line treatment of patients with metastatic therapy of superficial bladder cancer. Curr Pharm pharmacokinetics of intravesical taxol. Cancer pancreatic cancer. JOP 2013; 14: 686. Des 2000; 6: 345. Chemother Pharmacol 1997; 40: 285.