Transcript S. S. Sridhar, C. M. Canil et al. ASCO 2010

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
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
Treatment
◆ Nab paclitaxel 260 mg/m2 IV over 30 minutes every 21 days
◆ Premedication not require but permitted
◆ 2 dose reductions permitted
Dose Level
Nab paclitaxel dose
(m2)
0
260
-1
200
-2
160
◆ 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
Sridhar, 2011
Baseline Characteristics
Number of patients
48*
Age (years): mean (range)
68 (39-88)
Gender: M / F
40 / 8
ECOG PS: 0 / 1 / 2
Histology
Median time from last chemotherapy
15 / 24 / 8
TCC = 43; Mixed = 2; Missing = 3
5.2 mo (range 0.69-49 months)
Prior platinum response
Yes
No
53%
47%
* 1 patient inevaluable and 2 patients received only 1 treatment cycle
Sridhar, 2011
Treatment Exposure & Dose Reductions
Median number of cycles administered (range)
Patients with at least one dose reduction*
5.5 (1 – 15)
17 / 48 (35%)
* Most commonly due to fatigue or neuropathy
Sridhar, 2011
Response
N=40*
Objective Response
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
Toxicities – Grade 3 & 4
Toxicity
%
N=48
Grade 3&4
Pain
45%
Fatigue
8%
Weakness
4%
Neuropathy
4%
Joint stiffness
5%
Hypertension
14%
No grade 3/4 neutropenia and no febrile neutropenia
Sridhar, 2011
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
Trial
Regimen
Phase
N
Response
Rate
TTP Months
Median
Survival
Lorusso 1998
Gemcitabine
II
35
23%
3.8
5
Albers 2002
Gemcitabine
II
30
11%
4.9
8.7
Vaughn 2002
Paclitaxel
II
31
10%
2.2
7.2
Pronzato 1997
Ifosfamide
II
20
5%
NR
NR
Witte 1997
Ifosfamide
II
56
20%
2.5
5.5
McCaffrey 1997
Docetaxel
II
20
13%
NR
9
Sweeney 2006
Pemetrexed
II
47
28%
2.9
9.6
Dreicer 2007
Epothilone B
II
45
12%
2.7*
8
Bellmunt 2009
Vinflunine
III
370
9%
3.0*
6.9
Sridhar 2011
Nab paclitaxel
II
47
33%
6.0*
10.8
*PFS
Combination 2nd Line Trials
Trial
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
Gemcitabine/Paclitaxel
27
44%
13
Vaishampayan 2005
Paclitaxel/Carboplatin
44
16%
6
Pagliaro 2002
Ifosfamide/Gem/Cisplatin
49
41%
NR
Chen 2004
Gem/Docetaxel/Carboplatin
20
45%
NR
Tu 1995
Paclitaxel/Cisplatin/MTX
25
40%
NR
Sridhar 2011
nab-Paclitaxel
47
33%
10.8