Nab paclitaxel in Bladder Cancer

Summary of select novel intravesical agents Urologic Oncology: Seminars and Original Investigations 28 (2010) 108–111

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 albumin-bound paclitaxel (nab-paclitaxel, 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. J Urol, 2011

Study Design (1) 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. J Urol, 2011

Study Design (2) 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 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. J Urol, 2011

Patient Characteristics 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. J Urol, 2011

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 post-treatment evaluation. J Urol, 2011

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. J Urol, 2011

A phase II trial of neoadjuvant ABI-007, carboplatin, and gemcitabine (ACG) in patients with locally advanced carcinoma of the bladder. Neoadjuvant cisplatin-based chemotherapy benefits patients with bladder cancer, particularly in the 30% with pathologic complete response (pCR) at cystectomy. Many patients with bladder cancer are not candidates for cisplatin. Taxane-based regimens have activity in urothelial cancer. ABI-007 is an albumin-bound paclitaxel with increased activity and decreased toxicity compared to standard paclitaxel preparations. Smith, 2011

Methods Eligible pts have T2-4,N0,M0 or T any, N1- 3, M0 bladder cancer with ECOG PS 0-1, and adequate marrow (granulocyte count > 1,500/mm3, platelet > 100,000/mm3, and hemoglobin > 9.0 g/dl), hepatic (transaminases < 2.5 X upper limit of normal, alkaline phosphatase < 2.5 X upper limit of normal, and bilirubin < 1.5 mg/dl) and renal function (serum creatinine < 2.0 mg/dl and/or creatinine clearance > 40 ml/min). Treatment intravenous ABI-007 260 mg/m2 and carboplatin (target area under the curve=5) on day 1 with gemcitabine 800 mg/m2 on days 1 and 8, followed by radical cystectomy after three cycles of therapy. The primary study endpoint is the proportion of patients with pCR at cystectomy. Smith, 2011

Results 27 patients have been enrolled By clinical staging, 20 had T2 disease, 5 had T3, 2 had T4, and 2 had nodal enlargement. All are evaluable for toxicity with 22 evaluable for response (exclusions-3 for change in dose schedule, 1 each for refusal of cystectomy and withdrawal from study). 25/27 patients received all three cycles (78 total cycles) with doses reduced in 26 cycles for toxicity. Smith, 2011

Toxicities All patients had transient grade 3-4 neutropenia and 17 received filgrastim, but only two had febrile neutropenia. Six pts had pCR with an additional 5 having residual carcinoma in situ (CIS) and 1 with T1 disease at cystectomy. 54% of evaluable patients had no muscle invasive disease at cystectomy. Smith, 2011

Conclusions Neoadjuvant ACG is active in bladder cancer with pCR rate nearing 30% and nearly as many patients with CIS but no residual invasive disease. Marrow toxicity is significant but manageable. Smith, 2011

Phase II Study of Nab paclitaxel as 2nd Therapy in Patients with Metastatic Urothelial Carcinoma Study Design Open-label, single arm, multi-institutional phase II study Two-step enrollment design: Stage 1: If > 1/21 respond then proceed to Stage 2: Accrue 20 additional patients – If the total number of responses is  4  the drug is not effective Assuming 10-15% drop out rate, sample size = 48 total patients 90% power to detect a RR>20% Sridhar, 2011

Study Objectives Primary: to determine the overall response rate using RECIST Secondary: Time to disease progression Safety Overall survival Sridhar, 2011

Main Incl. & Excl. Eligibility Criteria TCC of the urothelium (including renal pelvis, ureter and bladder) Mixed histology (with squamous or adeno) allowed if TCC >50% of specimen Only one prior chemo regimen with platinum (≥ 1 cycle) for metastatic/recurrent disease Neoadjuvant/adjuvant chemo will be considered to be first line if progression < 12mths from last dose Age ≥18 years of age, ECOG PS ≤ 2, Hgb >90, and Adequate end organ function Prior taxane for metastatic disease (or ≤ 12mths since taxane containing neoadjuvant/adjuvant therapy) Pre-existing neuropathy ≥ grade 1 Uncontrolled brain metastasis (treated, stable disease is acceptable) Other investigational or XRT within 30 days before registration Sridhar, 2011 16

Statistical Hypothesis Two-stage design to test the null hypothesis P<=0.05 vs alternate P>=0.20 Stage 1: Enroll 21 pts. If > 2 responses proceed Stage 2: Accrue to total of 48 evaluable pts Design has a 90% power to detect a true RR of 20% or greater assuming a 15% drop out rate Sridhar, 2011

Nab paclitaxel dose (m2) Treatment Nab paclitaxel 260 mg/m2 IV over 30 minutes every 21 days Premedication not require but permitted 2 dose reductions permitted Standard anti-emetics as per institution for Nab paclitaxel Grade 2 neurotoxicity should lead to holding dose until ≤ grade 1 then one dose reduction Growth factor support permitted Dose Level Nab paclitaxel dose (m2) 260 -1 200 -2 160 Sridhar, 2011 18

Baseline Characteristics Number of patients 48* Age (years): mean (range) 68 (39-88) Gender: M / F 40 / 8 ECOG PS: 0 / 1 / 2 15 / 24 / 8 Histology TCC = 43; Mixed = 2; Missing = 3 Median time from last chemotherapy 5.2 mo (range 0.69-49 months) Prior platinum response Yes 53% No 47% * 1 patient inevaluable and 2 patients received only 1 treatment cycle Sridhar, 2011

Treatment Exposure & Dose Reductions Median number of cycles administered (range) 5.5 (1 – 15) Patients with at least one dose reduction* 17 / 48 (35%) * Most commonly due to fatigue or neuropathy Sridhar, 2011

Response Objective Response N=40* Number (%) Complete Response 1 (2.5%) Partial Response 11 (28%) Stable Disease 9 (23%) PD 20 (49%) *One patient was inevaluable for response, 7 patients are too early for evaluation. Sridhar, 2011 21

Toxicities – Grade 3 & 4 Toxicity % N=48 Grade 3&4 Pain Fatigue 45% Fatigue 8% Weakness 4% Neuropathy Joint stiffness 5% Hypertension 14% No grade 3/4 neutropenia and no febrile neutropenia Sridhar, 2011 23

Conclusions Single-agent ABI-007 was well tolerated with a Response Rate (CR+PR) of 33% (12/36) and a Clinical Benefit Rate (CR+PR+SD) of 58% (21/36), representing one of the highest reported response rates to date in the second-line UC setting. These results suggest further study of ABI-007 in urothelial carcinoma is warranted. Sridhar, 2011

Single Agent 2nd Line Trials Regimen Phase N Response Rate TTP Months Median Survival Lorusso 1998 Gemcitabine II 35 23% 3.8 5 Albers 2002 30 11% 4.9 8.7 Vaughn 2002 Paclitaxel 31 10% 2.2 7.2 Pronzato 1997 Ifosfamide 20 5% NR Witte 1997 56 20% 2.5 5.5 McCaffrey 1997 Docetaxel 13% 9 Sweeney 2006 Pemetrexed 47 28% 2.9 9.6 Dreicer 2007 Epothilone B 45 12% 2.7* 8 Bellmunt 2009 Vinflunine III 370 9% 3.0* 6.9 Sridhar 2011 Nab paclitaxel 33% 6.0* 10.8 *PFS

Combination 2nd Line Trials Regimen N RR Median Survival Krege 2001 Docetaxel/Ifosfamide 22 25% 4 Lin 2007 Gemcitabine/Ifosfamide 23 22% 4.8 Bellmunt 2002 MTX/Paclitaxel 20 32% 5 Sternberg 2001 Gemcitabine/Paclitaxel 41 60% 14.4 Fechner 2006 27 44% 13 Vaishampayan 2005 Paclitaxel/Carboplatin 44 16% 6 Pagliaro 2002 Ifosfamide/Gem/Cisplatin 49 41% NR Chen 2004 Gem/Docetaxel/Carboplatin 45% Tu 1995 Paclitaxel/Cisplatin/MTX 25 40% Sridhar 2011 nab-Paclitaxel 47 33% 10.8