1. Nab paclitaxel in Bladder Cancer

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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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 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

11. 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

12. 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

13. 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

14. 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

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

16. 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

17. 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

18. 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

19. 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 months)
Prior platinum response
Yes 53%
No 47%
* 1 patient inevaluable and 2 patients received only 1 treatment cycle
Sridhar, 2011

20. 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

21. 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

22. 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

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

24. 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

25. 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