- Email: [email protected]
A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer
A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer James M. McKiernan, LaMont J. Barlow,* Melissa A. Laudano, Mark J. Mann, Daniel P. Petrylak and Mitchell C. Benson From the Department of Urology (JMM, LJB, MAL, MJM, MCB) and Oncology (DPP), Columbia University Medical Center, New York, New York
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guérin CR ⫽ complete response DLT ⫽ dose limiting toxicity MDD ⫽ maximum deliverable dose nab-paclitaxel ⫽ nanoparticle albumin-bound paclitaxel NMIBC ⫽ nonmuscle invasive bladder cancer NR ⫽ no response NS ⫽ normal saline TUR ⫽ transurethral resection Submitted for publication January 13, 2011. Study received institutional review board approval. Supported by Abraxis Oncology and the Doris Duke Charitable Research Foundation. * Correspondence: Department of Urology, Herbert Irving Pavilion–11th Floor, 161 Fort Washington Ave., New York, New York 10032 (telephone: 617-538-2648; FAX: 212-305-6813; e-mail: [email protected]).
For another article on a related topic see page 702.
448
www.jurology.com
Purpose: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albuminbound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. Materials and Methods: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. Results: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. Conclusions: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen. Key Words: urinary bladder neoplasms; administration, intravesical; paclitaxel; nanotechnology IN 2009 more than 70,000 new cases of bladder cancer were diagnosed in the United States and more than 14,000 deaths occurred due to the disease.1 NMIBC, including carcinoma in situ (Tis) as well as stages Ta and T1, accounts for approximately 70% of
cases.2 While the primary method of nonmuscle invasive bladder tumor diagnosis and treatment continues to be TUR, intravesical therapy has become an integral component in the management of NMIBC.3 Intravesical BCG is considered the gold standard
0022-5347/11/1862-0448/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 448-451, August 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.03.129
AND
RESEARCH, INC.
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
for the first line treatment of high grade carcinoma in situ, and is used as prophylaxis and treatment in Ta and T1 disease as well.3,4 However, even after TUR and standard 6-week BCG induction treatment, 5-year recurrence rates range from 16% to 59%, predominantly depending on disease grade.4 – 8 Current second line intravesical treatments have even higher recurrence rates and cystectomy is the option most likely to improve survival of these high risk patients. Novel agents are necessary to improve outcomes for patients who refuse this life altering procedure or are unable to undergo the surgery due to medical comorbidities. A previously conducted phase I trial of intravesical docetaxel (Taxotere®), a microtubule depolymerization inhibitor with antitumor activity in a wide range of cancers,9 –11 established a MDD and safety profile for this intravesical therapy for patients with BCG refractory NMIBC with no systemic absorption and limited toxicity.12 Of the 18 patients in this previous study 56% had no evidence of disease at posttreatment cystoscopy and biopsy. nab-paclitaxel is a novel agent in the taxane family which has been modified with the addition of albumin particles to form nanoparticles to increase solubility and facilitate drug delivery to tumor cells via biological interactions with albumin receptors that mediate drug transport across epithelial cells.13,14 In a multicenter phase III trial nab-paclitaxel was shown to have greater efficacy and a favorable safety profile compared to standard paclitaxel in systemic therapy for women with breast cancer.14 This pivotal trial led to Food and Drug Administration approval of nab-paclitaxel as systemic therapy for metastatic breast cancer. Given the safety profile of the previous phase I trial with intravesical docetaxel, and the improved efficacy and safety profile of nab-paclitaxel in systemic therapy, this nanoparticle bound agent is an excellent candidate for investigation in the intravesical setting. In this study we determined the safety, toxicity and maximum tolerated or deliverable dose of intravesical nab-paclitaxel in a phase I trial of patients with refractory NMIBC.
PATIENTS AND METHODS Study Design This study was a single center, institutional review board approved, Food and Drug Administration Investigational New Drug Application exempt, investigator initiated trial. For this phase I trial a modified Fibonacci dose escalation scheme was used with an initial dose of 150 mg in 30 ml NS given to the first 3 patients. If DLT (defined by the National Cancer Institute Common Toxicity Criteria version 3.0) did not develop in any patients the dose was increased by 75 mg for the subsequent 3 patients. Three patients were to be treated at each of 6 dose levels (150, 225, 300, 375, 450 and 500 mg) for a target enrollment of
449
18 patients. The nab-paclitaxel dose of 500 mg diluted in 100 ml NS was chosen as the target dose level because of the expected inability of patients to tolerate intravesical instillation volumes greater than 100 ml for the full 2-hour dwell time, and nab-paclitaxel has only been previously studied in a reconstituted suspension of 5 mg/ml. Therefore, 500 mg was deemed the MDD. The end point in phase I was when the maximum tolerated dose was achieved, defined as the dose at which DLT occurred or when a MDD was reached in the dose escalation scheme described without any DLT.
Eligibility Patients eligible for this study all had high grade transitional cell carcinoma of the bladder with cystoscopic biopsies consistent with stage T1, Ta or Tis NMIBC. Each patient had been treated with a minimum of 1 complete course of intravesical BCG, mitomycin C, interferon or any combination thereof, and had experienced recurrence after treatment. All patients were offered cystectomy and refused, or were considered poor surgical candidates due to medical comorbidities. Other study inclusion criteria were age 18 years old or older, Eastern Cooperative Oncology Group performance status 0 or 1, no previous intravesical therapy within 6 weeks of study entry, peripheral neuropathy grade 1 or less, no prior radiation to the pelvis, and adequate hematological, hepatic and renal parameters. Exclusion criteria were prior systemic docetaxel or paclitaxel therapy, any other malignancy diagnosed within 2 years of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix), concurrent treatment with any chemotherapeutic agent, history of vesicoureteral reflux or an indwelling urinary stent, or participation in any other research protocol involving administration of an investigational agent within 3 months before study entry. All patients underwent cystoscopy with TUR at the study center before treatment with nab-paclitaxel. All patients were required to undergo cross-sectional imaging before enrollment. The Columbia University institutional review board approved the study protocol and consent (institutional review board number AAAC-1114), and all patients gave written informed consent before enrollment.
Drug Preparation and Administration For each treatment nab-paclitaxel was reconstituted in 0.9% sodium chloride for a concentration of 5.00 mg/ml given weekly for 6 weeks. All patients were permitted to delay 1 treatment by up to 7 days due to grade 1 or 2 toxicities, or scheduling difficulties. On the day of each instillation an updated history and physical examination were performed, and urine pH was measured by dipstick to ensure that pH was within the range of nab-paclitaxel solubility (pH 5 to 7.5). The bladder was emptied by sterile urethral catheterization before instillation. The nab-paclitaxel solution was then instilled into the bladder during 1 to 2 minutes, and patients retained the drug for 2 hours before voiding. Blood was drawn 2 hours after voiding to check hematological, hepatic and renal parameters, and high-pressure liquid chromatography was used to measure systemic absorption (with an ability to detect serum concentrations greater than 10 ng/ml). Symptoms of local toxicity were
450
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
monitored throughout treatment. If a National Cancer Institute Common Toxicity Criteria grade 2 local toxicity developed, treatment was delayed for 1 week and resumed if the toxicity resolved to grade 1 or less. Any patient with evidence of grade 3 or 4 toxicity was considered to have experienced a DLT and was immediately removed from the trial.
Treatment Assessment and Evaluation The initial response after induction treatment was assessed via cystoscopy with biopsies of the urothelium and urine cytology 6 weeks after the final instillation of nabpaclitaxel. Cross-sectional imaging was also performed at the posttreatment cystoscopic evaluation. Patients were considered to have a complete response if they had a negative biopsy and negative cytology. All patients with positive biopsies or cytology were classified as having no response. Treatment efficacy was measured using complete response rate for the cohort treated.
RESULTS Enrollment began in January 2008 and reached 100% accrual as of November 1, 2009 (18 patients enrolled). All patients had recurrent nonmuscle invasive transitional cell carcinoma, including 9 with stage Tis, 3 with high grade Ta and 6 with high grade T1 disease (table 1). Median patient age was 71 years (range 56 to 84), and 13 men and 5 women were enrolled in the study. The median number of prior courses of intravesical induction therapy was 2. All 18 patients refused cystectomy after the most recent recurrence before trial enrollment. A total of 108 intravesical instillations were administered on the dose escalation scheme previously described, with a dose of 500 mg in 100 ml NS given as the MDD to the final cohort. One patient experienced detectable systemic absorption of nab-paclitaxel after a single instillation at the 450 mg dose (detected level 16 ng/ml). For this patient the following instillation was delayed by 1 week, after which serum levels returned to undetectable and remained so for the remainder of treatment. The patient went on to have a regularly scheduled posttreatment cystoscopy 6 weeks after the final instillation. No patients experienced grade 2 or greater local toxicity. Ten patients (56%) experienced grade 1 local Table 1. Patient characteristics No. clinical stage: Tis Ta T1 No. prior intravesical treatment: BCG BCG ⫹ interferon Mitomycin C Other agents Mean prior induction courses
9 3 6 18 12 3 3 2.8
Table 2. Grade 1 local toxicities
150 225 300 375 450 500
Mg Mg Mg Mg Mg Mg
No. Dysuria
No. Urinary Retention
No. Urinary Frequency
No. Hematuria
0 1 1 1 0 2
1 0 0 1 0 0
0 1 0 0 0 1
1 0 0 1 0 1
toxicities, with dysuria being the most commonly acquired (table 2). Only 1 patient was unable to achieve a successful 2-hour dwell time in 1 of 6 instillations due to preexisting urgency and an inability to refrain from voiding for the full 2 hours. There were 5 patients (28%) who demonstrated a complete response to therapy with intravesical nabpaclitaxel (table 3). The other 13 patients had positive biopsies and were considered nonresponders. Only 1 of the nonresponders had evidence of stage progression at the posttreatment evaluation.
DISCUSSION While most would agree that the presence of muscle invasive bladder cancer is an absolute indication for radical cystectomy, the treatment of high grade NMIBC has been a topic of interest and debate for decades. The rate of NMIBC recurrence and progression varies significantly based on histological tumor grade and history of recurrence, among other factors.15 First line treatment for NMIBC is typically limited to TUR plus intravesical BCG for treatment and prophylaxis for recurrence. However, in patients at increased risk for recurrence and stage progression after intraTable 3. Response to therapy with intravesical nab-paclitaxel Pt No.
Dose (mg)
Pretrial Stage
Response
1 4 5 6 10 2 3 7 8 9 11 12 13 14 15 16 17 18
150 225 225 225 375 150 150 300 300 300 375 375 450 450 450 500 500 500
T1 Tis T1 Ta T1 Tis Ta ⫹ Tis Ta ⫹ Tis Tis Ta ⫹ Tis Tis T1 T1 ⫹ Tis Tis Ta Ta T1 ⫹ Tis Tis
CR CR CR CR CR NR NR NR NR NR NR NR NR NR NR NR NR NR
*Results based on 6-week posttreatment biopsy and urine cytology.
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
vesical treatment failure, definitive surgical treatment is usually considered if not preferred.2,8 Undergoing cystectomy can be a life altering experience with significant long-term morbidity, and many patients are unwilling or unable to undergo such an extensive procedure.16 Any effort to find alternative medical treatments for BCG refractory NMIBC could impact thousands of lives each year. Our previous phase I trial of intravesical docetaxel was the first human trial of intravesical taxane therapy.12 The results from that trial demonstrated that docetaxel could be given intravesically with minimal toxicity, and the initial response rate of 56% suggested that intravesical taxane therapy might be a promising new treatment for NMIBC refractory to BCG therapy. Our current trial of nabpaclitaxel uses another drug in the taxane family that acts via the same mechanism as docetaxel by inhibiting microtubule depolymerization and disrupting the mitotic spindle, thereby blocking cell division and inducing apoptosis.13,14 The combination of albumin and paclitaxel molecules to create nanoparticles makes nab-paclitaxel more soluble than traditional unbound taxanes, allowing higher concentrations to be administered intravesically. There is also greater uptake of the drug via albumin receptor mediated transport into epithelial cells which may be enhanced in tumor cells. These factors made nab-paclitaxel an ideal candidate for intravesical administration. Grade 1 local toxicities were observed in 10 of the 18 patients who received intravesical nab-pacli-
451
taxel. The distribution of toxicities does not appear to be dose dependent. Of note, no patients experienced grade 2 or higher toxicities after 108 intravesical instillations, and only 1 had detectable systemic absorption of nab-paclitaxel as measured by highpressure liquid chromatography assays. However, the level detected in this patient (16 ng/ml) was more than 1,000-fold lower than the normal range seen after standard intravenous therapy (mean detected level 19,556 ng/ml).17 While the primary objective of this phase I trial was to determine the safety and tolerability of 6 weekly instillations of nab-paclitaxel, the complete response rate of 28% in the 18 patients evaluated 6 weeks after the final instillation suggests that this drug may be a valuable agent for the future treatment of high risk NMIBC. Future followup of these patients will help to characterize the durability of this initial response. The currently accruing phase II trial treating 29 patients at the MDD of 500 mg will be designed and powered to formally assess the anticancer activity of this regimen.
CONCLUSIONS nab-Paclitaxel appears to be a well tolerated novel intravesical agent for the treatment of BCG refractory nonmuscle invasive bladder cancer. Because of the findings of this study, a larger phase II trial using the MDD of 500 mg/100 ml is currently under way.
REFERENCES 1. Jemal A, Siegel R, Ward E et al: Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71. 2. Malkowicz SB: Management of superficial bladder cancer. In: Campbell’s Urology, 8th ed. Edited by PC Walsh, AB Retik, ED Vaughan et al. Philadelphia: WB Saunders 2002; vol 4, p 2785. 3. Crawford ED: Intravesical therapy for superficial cancer: need for more options. J Clin Oncol 2002; 20: 3185. 4. Morales A: Long-term results and complications of intracavitary bacillus Calmette-Guerin therapy for bladder cancer. J Urol 1984; 132: 457. 5. Lamm DL, Blumenstein BA, Crissman JD et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163: 1124. 6. Herr HW, Wartinger DD, Fair WR et al: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 1992; 147: 1020.
7. Pansadoro V, Emiliozzi P, Defidio L et al: Bacillus Calmette-Guerin in the treatment of stage T1 grade 3 transitional cell carcinoma of the bladder: long-term results. J Urol 1995; 154: 2054. 8. Kim JC and Steinberg GD: Medical management of patients with refractory carcinoma in situ of the bladder. Drugs Aging 2001; 18: 335. 9. de Wit R, Kruit WH, Stoter G et al: Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in nonchemotherapy-pretreated patients. Br J Cancer 1998; 78: 1342. 10. Chan S, Friedrichs K, Noel D et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 2341. 11. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502. 12. McKiernan JM, Masson P, Murphy AM et al: Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory
to standard intravesical therapy. J Clin Oncol 2006; 24: 3075. 13. Sparreboom A, Scripture CD, Trieu V et al: Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res 2005; 11: 4136. 14. Gradishar WJ, Tjulandin S, Davidson N et al: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oilbased paclitaxel in women with breast cancer. J Clin Oncol 2005; 23: 7794. 15. Heney NM, Ahmed S, Flanagan MJ et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083. 16. Skinner DG, Crawford ED and Kaufman JJ: Complications of radical cystectomy for carcinoma of the bladder. J Urol 1980; 123: 640. 17. Gardner ER, Dahut WL, Scripture CD et al: Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res 2008; 14: 4200.
Abbreviations and Acronyms BCG ⫽ bacillus Calmette-Guérin CR ⫽ complete response DLT ⫽ dose limiting toxicity MDD ⫽ maximum deliverable dose nab-paclitaxel ⫽ nanoparticle albumin-bound paclitaxel NMIBC ⫽ nonmuscle invasive bladder cancer NR ⫽ no response NS ⫽ normal saline TUR ⫽ transurethral resection Submitted for publication January 13, 2011. Study received institutional review board approval. Supported by Abraxis Oncology and the Doris Duke Charitable Research Foundation. * Correspondence: Department of Urology, Herbert Irving Pavilion–11th Floor, 161 Fort Washington Ave., New York, New York 10032 (telephone: 617-538-2648; FAX: 212-305-6813; e-mail: [email protected]).
For another article on a related topic see page 702.
448
www.jurology.com
Purpose: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albuminbound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. Materials and Methods: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. Results: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. Conclusions: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen. Key Words: urinary bladder neoplasms; administration, intravesical; paclitaxel; nanotechnology IN 2009 more than 70,000 new cases of bladder cancer were diagnosed in the United States and more than 14,000 deaths occurred due to the disease.1 NMIBC, including carcinoma in situ (Tis) as well as stages Ta and T1, accounts for approximately 70% of
cases.2 While the primary method of nonmuscle invasive bladder tumor diagnosis and treatment continues to be TUR, intravesical therapy has become an integral component in the management of NMIBC.3 Intravesical BCG is considered the gold standard
0022-5347/11/1862-0448/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 448-451, August 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.03.129
AND
RESEARCH, INC.
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
for the first line treatment of high grade carcinoma in situ, and is used as prophylaxis and treatment in Ta and T1 disease as well.3,4 However, even after TUR and standard 6-week BCG induction treatment, 5-year recurrence rates range from 16% to 59%, predominantly depending on disease grade.4 – 8 Current second line intravesical treatments have even higher recurrence rates and cystectomy is the option most likely to improve survival of these high risk patients. Novel agents are necessary to improve outcomes for patients who refuse this life altering procedure or are unable to undergo the surgery due to medical comorbidities. A previously conducted phase I trial of intravesical docetaxel (Taxotere®), a microtubule depolymerization inhibitor with antitumor activity in a wide range of cancers,9 –11 established a MDD and safety profile for this intravesical therapy for patients with BCG refractory NMIBC with no systemic absorption and limited toxicity.12 Of the 18 patients in this previous study 56% had no evidence of disease at posttreatment cystoscopy and biopsy. nab-paclitaxel is a novel agent in the taxane family which has been modified with the addition of albumin particles to form nanoparticles to increase solubility and facilitate drug delivery to tumor cells via biological interactions with albumin receptors that mediate drug transport across epithelial cells.13,14 In a multicenter phase III trial nab-paclitaxel was shown to have greater efficacy and a favorable safety profile compared to standard paclitaxel in systemic therapy for women with breast cancer.14 This pivotal trial led to Food and Drug Administration approval of nab-paclitaxel as systemic therapy for metastatic breast cancer. Given the safety profile of the previous phase I trial with intravesical docetaxel, and the improved efficacy and safety profile of nab-paclitaxel in systemic therapy, this nanoparticle bound agent is an excellent candidate for investigation in the intravesical setting. In this study we determined the safety, toxicity and maximum tolerated or deliverable dose of intravesical nab-paclitaxel in a phase I trial of patients with refractory NMIBC.
PATIENTS AND METHODS Study Design This study was a single center, institutional review board approved, Food and Drug Administration Investigational New Drug Application exempt, investigator initiated trial. For this phase I trial a modified Fibonacci dose escalation scheme was used with an initial dose of 150 mg in 30 ml NS given to the first 3 patients. If DLT (defined by the National Cancer Institute Common Toxicity Criteria version 3.0) did not develop in any patients the dose was increased by 75 mg for the subsequent 3 patients. Three patients were to be treated at each of 6 dose levels (150, 225, 300, 375, 450 and 500 mg) for a target enrollment of
449
18 patients. The nab-paclitaxel dose of 500 mg diluted in 100 ml NS was chosen as the target dose level because of the expected inability of patients to tolerate intravesical instillation volumes greater than 100 ml for the full 2-hour dwell time, and nab-paclitaxel has only been previously studied in a reconstituted suspension of 5 mg/ml. Therefore, 500 mg was deemed the MDD. The end point in phase I was when the maximum tolerated dose was achieved, defined as the dose at which DLT occurred or when a MDD was reached in the dose escalation scheme described without any DLT.
Eligibility Patients eligible for this study all had high grade transitional cell carcinoma of the bladder with cystoscopic biopsies consistent with stage T1, Ta or Tis NMIBC. Each patient had been treated with a minimum of 1 complete course of intravesical BCG, mitomycin C, interferon or any combination thereof, and had experienced recurrence after treatment. All patients were offered cystectomy and refused, or were considered poor surgical candidates due to medical comorbidities. Other study inclusion criteria were age 18 years old or older, Eastern Cooperative Oncology Group performance status 0 or 1, no previous intravesical therapy within 6 weeks of study entry, peripheral neuropathy grade 1 or less, no prior radiation to the pelvis, and adequate hematological, hepatic and renal parameters. Exclusion criteria were prior systemic docetaxel or paclitaxel therapy, any other malignancy diagnosed within 2 years of study entry (except basal or squamous cell skin cancers or noninvasive cancer of the cervix), concurrent treatment with any chemotherapeutic agent, history of vesicoureteral reflux or an indwelling urinary stent, or participation in any other research protocol involving administration of an investigational agent within 3 months before study entry. All patients underwent cystoscopy with TUR at the study center before treatment with nab-paclitaxel. All patients were required to undergo cross-sectional imaging before enrollment. The Columbia University institutional review board approved the study protocol and consent (institutional review board number AAAC-1114), and all patients gave written informed consent before enrollment.
Drug Preparation and Administration For each treatment nab-paclitaxel was reconstituted in 0.9% sodium chloride for a concentration of 5.00 mg/ml given weekly for 6 weeks. All patients were permitted to delay 1 treatment by up to 7 days due to grade 1 or 2 toxicities, or scheduling difficulties. On the day of each instillation an updated history and physical examination were performed, and urine pH was measured by dipstick to ensure that pH was within the range of nab-paclitaxel solubility (pH 5 to 7.5). The bladder was emptied by sterile urethral catheterization before instillation. The nab-paclitaxel solution was then instilled into the bladder during 1 to 2 minutes, and patients retained the drug for 2 hours before voiding. Blood was drawn 2 hours after voiding to check hematological, hepatic and renal parameters, and high-pressure liquid chromatography was used to measure systemic absorption (with an ability to detect serum concentrations greater than 10 ng/ml). Symptoms of local toxicity were
450
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
monitored throughout treatment. If a National Cancer Institute Common Toxicity Criteria grade 2 local toxicity developed, treatment was delayed for 1 week and resumed if the toxicity resolved to grade 1 or less. Any patient with evidence of grade 3 or 4 toxicity was considered to have experienced a DLT and was immediately removed from the trial.
Treatment Assessment and Evaluation The initial response after induction treatment was assessed via cystoscopy with biopsies of the urothelium and urine cytology 6 weeks after the final instillation of nabpaclitaxel. Cross-sectional imaging was also performed at the posttreatment cystoscopic evaluation. Patients were considered to have a complete response if they had a negative biopsy and negative cytology. All patients with positive biopsies or cytology were classified as having no response. Treatment efficacy was measured using complete response rate for the cohort treated.
RESULTS Enrollment began in January 2008 and reached 100% accrual as of November 1, 2009 (18 patients enrolled). All patients had recurrent nonmuscle invasive transitional cell carcinoma, including 9 with stage Tis, 3 with high grade Ta and 6 with high grade T1 disease (table 1). Median patient age was 71 years (range 56 to 84), and 13 men and 5 women were enrolled in the study. The median number of prior courses of intravesical induction therapy was 2. All 18 patients refused cystectomy after the most recent recurrence before trial enrollment. A total of 108 intravesical instillations were administered on the dose escalation scheme previously described, with a dose of 500 mg in 100 ml NS given as the MDD to the final cohort. One patient experienced detectable systemic absorption of nab-paclitaxel after a single instillation at the 450 mg dose (detected level 16 ng/ml). For this patient the following instillation was delayed by 1 week, after which serum levels returned to undetectable and remained so for the remainder of treatment. The patient went on to have a regularly scheduled posttreatment cystoscopy 6 weeks after the final instillation. No patients experienced grade 2 or greater local toxicity. Ten patients (56%) experienced grade 1 local Table 1. Patient characteristics No. clinical stage: Tis Ta T1 No. prior intravesical treatment: BCG BCG ⫹ interferon Mitomycin C Other agents Mean prior induction courses
9 3 6 18 12 3 3 2.8
Table 2. Grade 1 local toxicities
150 225 300 375 450 500
Mg Mg Mg Mg Mg Mg
No. Dysuria
No. Urinary Retention
No. Urinary Frequency
No. Hematuria
0 1 1 1 0 2
1 0 0 1 0 0
0 1 0 0 0 1
1 0 0 1 0 1
toxicities, with dysuria being the most commonly acquired (table 2). Only 1 patient was unable to achieve a successful 2-hour dwell time in 1 of 6 instillations due to preexisting urgency and an inability to refrain from voiding for the full 2 hours. There were 5 patients (28%) who demonstrated a complete response to therapy with intravesical nabpaclitaxel (table 3). The other 13 patients had positive biopsies and were considered nonresponders. Only 1 of the nonresponders had evidence of stage progression at the posttreatment evaluation.
DISCUSSION While most would agree that the presence of muscle invasive bladder cancer is an absolute indication for radical cystectomy, the treatment of high grade NMIBC has been a topic of interest and debate for decades. The rate of NMIBC recurrence and progression varies significantly based on histological tumor grade and history of recurrence, among other factors.15 First line treatment for NMIBC is typically limited to TUR plus intravesical BCG for treatment and prophylaxis for recurrence. However, in patients at increased risk for recurrence and stage progression after intraTable 3. Response to therapy with intravesical nab-paclitaxel Pt No.
Dose (mg)
Pretrial Stage
Response
1 4 5 6 10 2 3 7 8 9 11 12 13 14 15 16 17 18
150 225 225 225 375 150 150 300 300 300 375 375 450 450 450 500 500 500
T1 Tis T1 Ta T1 Tis Ta ⫹ Tis Ta ⫹ Tis Tis Ta ⫹ Tis Tis T1 T1 ⫹ Tis Tis Ta Ta T1 ⫹ Tis Tis
CR CR CR CR CR NR NR NR NR NR NR NR NR NR NR NR NR NR
*Results based on 6-week posttreatment biopsy and urine cytology.
INTRAVESICAL nAB-PACLITAXEL FOR NONMUSCLE INVASIVE BLADDER CANCER
vesical treatment failure, definitive surgical treatment is usually considered if not preferred.2,8 Undergoing cystectomy can be a life altering experience with significant long-term morbidity, and many patients are unwilling or unable to undergo such an extensive procedure.16 Any effort to find alternative medical treatments for BCG refractory NMIBC could impact thousands of lives each year. Our previous phase I trial of intravesical docetaxel was the first human trial of intravesical taxane therapy.12 The results from that trial demonstrated that docetaxel could be given intravesically with minimal toxicity, and the initial response rate of 56% suggested that intravesical taxane therapy might be a promising new treatment for NMIBC refractory to BCG therapy. Our current trial of nabpaclitaxel uses another drug in the taxane family that acts via the same mechanism as docetaxel by inhibiting microtubule depolymerization and disrupting the mitotic spindle, thereby blocking cell division and inducing apoptosis.13,14 The combination of albumin and paclitaxel molecules to create nanoparticles makes nab-paclitaxel more soluble than traditional unbound taxanes, allowing higher concentrations to be administered intravesically. There is also greater uptake of the drug via albumin receptor mediated transport into epithelial cells which may be enhanced in tumor cells. These factors made nab-paclitaxel an ideal candidate for intravesical administration. Grade 1 local toxicities were observed in 10 of the 18 patients who received intravesical nab-pacli-
451
taxel. The distribution of toxicities does not appear to be dose dependent. Of note, no patients experienced grade 2 or higher toxicities after 108 intravesical instillations, and only 1 had detectable systemic absorption of nab-paclitaxel as measured by highpressure liquid chromatography assays. However, the level detected in this patient (16 ng/ml) was more than 1,000-fold lower than the normal range seen after standard intravenous therapy (mean detected level 19,556 ng/ml).17 While the primary objective of this phase I trial was to determine the safety and tolerability of 6 weekly instillations of nab-paclitaxel, the complete response rate of 28% in the 18 patients evaluated 6 weeks after the final instillation suggests that this drug may be a valuable agent for the future treatment of high risk NMIBC. Future followup of these patients will help to characterize the durability of this initial response. The currently accruing phase II trial treating 29 patients at the MDD of 500 mg will be designed and powered to formally assess the anticancer activity of this regimen.
CONCLUSIONS nab-Paclitaxel appears to be a well tolerated novel intravesical agent for the treatment of BCG refractory nonmuscle invasive bladder cancer. Because of the findings of this study, a larger phase II trial using the MDD of 500 mg/100 ml is currently under way.
REFERENCES 1. Jemal A, Siegel R, Ward E et al: Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71. 2. Malkowicz SB: Management of superficial bladder cancer. In: Campbell’s Urology, 8th ed. Edited by PC Walsh, AB Retik, ED Vaughan et al. Philadelphia: WB Saunders 2002; vol 4, p 2785. 3. Crawford ED: Intravesical therapy for superficial cancer: need for more options. J Clin Oncol 2002; 20: 3185. 4. Morales A: Long-term results and complications of intracavitary bacillus Calmette-Guerin therapy for bladder cancer. J Urol 1984; 132: 457. 5. Lamm DL, Blumenstein BA, Crissman JD et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163: 1124. 6. Herr HW, Wartinger DD, Fair WR et al: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 1992; 147: 1020.
7. Pansadoro V, Emiliozzi P, Defidio L et al: Bacillus Calmette-Guerin in the treatment of stage T1 grade 3 transitional cell carcinoma of the bladder: long-term results. J Urol 1995; 154: 2054. 8. Kim JC and Steinberg GD: Medical management of patients with refractory carcinoma in situ of the bladder. Drugs Aging 2001; 18: 335. 9. de Wit R, Kruit WH, Stoter G et al: Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in nonchemotherapy-pretreated patients. Br J Cancer 1998; 78: 1342. 10. Chan S, Friedrichs K, Noel D et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 2341. 11. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502. 12. McKiernan JM, Masson P, Murphy AM et al: Phase I trial of intravesical docetaxel in the management of superficial bladder cancer refractory
to standard intravesical therapy. J Clin Oncol 2006; 24: 3075. 13. Sparreboom A, Scripture CD, Trieu V et al: Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol). Clin Cancer Res 2005; 11: 4136. 14. Gradishar WJ, Tjulandin S, Davidson N et al: Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oilbased paclitaxel in women with breast cancer. J Clin Oncol 2005; 23: 7794. 15. Heney NM, Ahmed S, Flanagan MJ et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130: 1083. 16. Skinner DG, Crawford ED and Kaufman JJ: Complications of radical cystectomy for carcinoma of the bladder. J Urol 1980; 123: 640. 17. Gardner ER, Dahut WL, Scripture CD et al: Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res 2008; 14: 4200.