Transcript Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in

Gemcitabine Plus nab-Paclitaxel Is
an Active Regimen in Patients With
Advanced Pancreatic Cancer (PDA)
A Phase I/II Trial
Daniel D. Von Hoff, Ramesh K. Ramanathan, Mitesh J. Borad, Daniel Laheru,
Lon S. Smith, Tina E. Wood, Ronald L. Korn, Neil Desai, Vuong Trieu, Jose L.
Iglesias, Hui Zhang, Patrick Soon-Shiong, Tao Shi, N.V. Rajeshkumar, Anirban
Maitra, and Manuel Hidalgo
J Clin Oncol 2011; online Oct 3rd
Objectives
• Identify the MTD of 1st-line Gemcitabine plus
nab-paclitaxel
• Provide efficacy and toxicity data
– PET scan response
– SPARC
– CA19-9 levels in relation to efficacy
– Subsequent preclinical studies investigated the
changes involving the pancreatic stroma and drug
uptake.
Patients / Eligibility criteria
•
•
•
•
•
18 years
Histologically or cytologically confirmed metastatic PDA
Measurable disease by CT-scan (RECIST 1.0)
No previous treatment for metastatic disease
Prior adjuvant treatment with fluorouracil or
gemcitabine administered as a radiation sensitizer
during and up to 4 weeks after radiation therapy was
allowed. If a patient received adjuvant therapy, tumor
recurrence must have occurred 6 months after the last
treatment.
• ECOG PS = 0 or 1
• Adequate hematologic, hepatic, and renal function
Study Design
• Phase I
– Identify MTD and DLT
– Standard 3 + 3 dose-escalation
• DLTs treatment-related toxicities during cycle 1 per NCI-CTCAE
v3.0
–
–
–
–
Any grade 4 hematologic toxicity
Grade 3 thrombocytopenia with hemorrhage;
Grade 3 nausea, vomiting, or diarrhea despite prophylaxis
Any grade3 treatment-related nonhematologic toxicity, excluding
alopecia and fatigue.
– Dose escalation stopped when 1 of 3 pts had DLTs, and
the dose below was declared the MTD
– Patients continued treatment until PD or unacceptable
toxicity
Treatment Dose Finding
Gemcitabine 1000 mg/m2 i.v.
nabPaclitaxel
Dose Levels
100 mg/m2 i.v.
125 mg/m2 i.v.
150 mg/m2 i.v.
1
Week 1
8
Week 2
15
Week 3
22
Days
Week 4
28
Assessments
• CT-scans baseline and every 4 weeks on day 1
of each cycle (RECIST v1)
– An initial response (CR or PR) had to be confirmed
at least 4 weeks later
• PET-scan at baseline and at 6 and 12 weeks on
the basis of the EORTC criteria
• Safety NCI-CTCAE v3
• CA19-9 levels at every cycle
• Archived tumor blocks collected for SPARC
Statistics
• 44 pts treated at the MTD
– ≥ 95% power of observing a SAE that had an incidence of ≥ 7%
• Percentage of patients (with 95% CI) who achieved an objective
response summarized
• SPARC immunohistochemistry was performed using a monoclonal
and a polyclonal antibody and proprietary methodology.
– Seven tissue components including tumor cells and stromal
components such as fibroblast and inflammatory cells were evaluated.
– For each tissue component and each antibody, three measures were
recorded by two board-certified pathologists at a Clinical Laboratory
Improvement Amendments laboratory: maximum intensity,
percentage of cells at the maximum intensity, and overall score,
providing 42 variables.
– All variables were standardized across patients via z-score
transformation and averaged between the two pathologists. For each
patient, an average z-score was calculated across variables. On the
basis of the average z-scores ≥ or less than 0, patients were classified
into a high- or low-SPARC group, respectively.
Preclinical Study
• Objective:
– Evaluate tumor progression, potential changes in the pancreatic
stroma, and intratumoral drug penetration
• Xenograft
– Fresh Pancreatic Cancer tissues from 11 pts subcutaneous tumors in 6week-old female athymic nude mice
• Mice with tumor size of 200 L were randomly assigned to 4
treatment groups:
– Control,
– Gemcitabine 100 mg/kg intraperitoneally (IP) on days 1 and 5 weekly
for 4 weeks,
– nab-paclitaxel 30 mg/kg/d IV for 5 consecutive days,
– Gemcitabine plus nab-paclitaxel in the preceding regimens for 4 weeks.
Baseline patient demographics
Characteristic
nab-Paclitaxel mg/m2
100
125
155
(n=20)
(n=44)
(n=3)
No.
%
No. %
No. %
Age, years
Median
Range
62
30-86
Female sex
9
45
25
57
1
33
ECOG
0
1
9
11
45
55
22
22
50
50
2
1
67
33
61
28-78
69
53-72
Baseline patient characteristics
Characteristic
nab-Paclitaxel mg/m2
100
125
155
(n=20)
(n=44)
(n=3)
No.
%
No. %
No. %
Site of metastatic disease
Abdomen/
peritoneal
16
Liver
11
Liver only
1
Lung
5
Lung only
1
Other
10
80
55
5
25
5
50
38
34
2
18
5
12
86
77
5
41
11
27
2
2
1
1
1
1
67
67
33
33
33
33
Baseline patient characteristics
Characteristic
nab-Paclitaxel mg/m2
100
125
155
(n=20)
(n=44)
(n=3)
No.
%
No. %
No. %
No. of metastatic sites
1
6
30
2
8
40
≥3
6
30
CA19-9
baseline levels, n
15
Normal
2
13
Elevated
13
87
CA19-9 baseline,
m /mL Median
1,148
Range
14-180,062
8
18
18
37
6
31
18
41
41
1
2
0
16
84
2
1
1
881
1-96,990
181
23-339
33
67
50
50
Baseline patient characteristics
Characteristic
nab-Paclitaxel mg/m2
100
125
155
(n=20)
(n=44)
(n=3)
No.
%
No. %
No. %
Previous treatment
Prior chemo.
3
15
10
Prior adjuvant
3
15
10
Gemcitabine
1
5
5
Capecitabine 1
5
4
5-FU
2
10
1
Docetaxel
0
2
Erlotinib
0
0
Time since adjuvant therapy, months
Median
64
12
Range
9-81
1-23
23
23
11
9
2
5
1
1
0
0
0
0
1
5
33
33
33
Reason for discontinuation
%
Disease Progression
48
Unacceptable toxicity
18
Patient discretion
17
Investigator discretion
8
AE*
8
Other
2
AE*: neuropathy and fatigue
MTD and DLT
nabPaclitaxel Dose Levels
100 mg/m2 i.v.
First 6 pts:
2 pts day 8 dose hold 850 Neutr, 60 000 Plat
3 responders
Protocol amendment to allow 20 pts
125 mg/m2 i.v.
150 mg/m2 i.v.
1 pt died due to neutropenia (biliary stent) cycle 1
2 pts reversible Grade 3 Aes (Fatigue, Neutropenia)
MTD and DLT
nabPaclitaxel Dose Levels
Protocol amendment to allow 20 pts
125 mg/m2 i.v.
MTD
150 mg/m2 i.v.
1 pt died due to neutropenia (biliary stent) cycle 1
2 pts reversible Grade 3 Aes (Fatigue, Neutropenia)
44 pts
recruited
Efficacy Results
N=44
125
mg
Median
months
CI 95%
PFS
7.9
5.8 to 11
OS
12.2
8.9 to 17.9
N=67
Any
dose
Median
months
CI 95%
PFS
7.1
5.7 to 8
OS
10.3
8.4 to 13.6
Response Rate
Dose level 125 mg
N=44
CR
PR
SD
≥16weeks
PD
Disease
Control
No.
0
21
9
7
30
%
All dose levels
N=67
48
20
No.
3
28
12
%
4
42
18
16
68
15
43
22
64
Overall Survival
nabPaclitaxel 125 mg/m2
+
Gemcitabine
1.00
Probablity
0.75
0.50
Median = 12.2 months
0.25
0.00
0
3
6
9
12
15
18
Months
21
24
27
30
Treatment Exposure
125 mg
cohort
All cohorts
% nabPaclitaxel planned dose administered
81%
% gemcitabine planned dose administered
85%
Median number of cycles
Dose Reduction
nabPaclitaxel
gemcitabine
Dose Delay
nabPaclitaxel
gemcitabine
6 (range 1 to 24)
20%
43%
25%
31%
70%
72%
73%
Safety (n=44 Dose Level 125 mg)
9%
83 %
2%
49%
89 %
91%
98%
37%
20%
63 %
48 %
27%
76 %
32%
Patient Number
DLTs: sepsis and neutropenia
SPARC (n=36)
• High SPARC (average z-score ≥0) = 19 pts
• Low SPARC (average z-score <0) = 17 pts
• SPARC was a significant prognostic variable
– Univariate p < 0.001
– Multivariate p = 0.041 after adjusting for sex, race,
age, treatment, and baseline CA19-9 level (Cox
regression model)
– Stromal SPARC was significantly correlated with OS
(p=0.013), but not SPARC in tumor cells (p=0.15)
Overall Survival & SPARC
1.00
Probablity
0.75
0.50
0.25
P .001
0.00
0
3
6
9
12
15
18
Months
21
24
27
30
CA 19-9 Levels
• % decrease level in the 125 mg/m2 cohort
– 92% (34 of 37) had a ≥ 20%
– 78% (29 of 37) had a ≥ 50%
– 70% (26 of 37) had a ≥ 70%
• Median maximum % change = 91%
• Median time to maximum decrease = 89 days
• Prognostic correlations:
≥ 50% decrease
< 50% decrease
P value
ORR
62%
33%
.1
PFS
8 months
3,6 months
<.001
OS
13.6 months
6.5 months
.004
Maximum % change in CA 19-9 levels
300
PR
SD
200
100
0
-100
Every bar represents % change in a single patient
Overall Survival & PET
1.00
Probablity
0.75
0.50
0.25
0.00
0
3
6
9
12
15
18
Months
21
24
27
30
Preclinical Study Results
N=11 patient derived xenografts
Tumor Regression
Gemcitabine
2 (18%)
nabPaclitaxel
4 (36%)
nabPaclitaxel + gemcitabine
7 (64%)
Aggregate tumor regression response in individual xenografts
22 of 90
(24%)
34 of 95
(36%)
53 of 96
(55%)
Effects in Tumor Stroma
Collagen Type I Immuno-staining
Treatment group
Control
Profuse
Desmoplastic
Stroma
Gemcitabine
Persisting
Stroma
nabPaclitaxel
Desmoplastic
Stroma
Depletion
GEM + nabPtx
Dilated blood vessels
x3 increase in mNestin
Intratumor concentration of GEM
7500
2.8 fold
increase
5000
Mean
Gemcitabine
concentration
ng/g
2500
Gemcitabine
alone
0
nabPaclitaxel
+
Gemcitabine
Maximum Tolerated Dose
Recommended Dose for Phase II
Gemcitabine 1000 mg/m2 iv
nabPaclitaxel 125 mg/m2 iv
1
Week 1
8
Week 2
15
Week 3
22
Days
Week 4
28
Conclusions: antitumor activity
• The 48% ORR, 12.2 months of OS, and 1-year survival
of 48% at the MTD is among the highest reported for a
phase II study in patients with PDA
• SPARC in the stoma is associated with poor survival, so
a unique MoA of GEM+nabPaclitaxel play a role in
reversing this outcome
– SPARC expression in stroma may be a predictive marker
• In addition to intrinsic antitumor effects against the
cancer cell, nabPaclitaxel may target stromal SPARC
and facilitate delivery of chemotherapy
• Hypothesis: “Reducing the dense tumor stroma may
allow the chemotherapeutics to reach the tumor tissue
more efficiently”
Back-up Slides
SPARC & Prognosis
Title:
Authors:
Reference:
• Peritumoral Fibroblast SPARC
Expression and Patient Outcome With
Resectable Pancreatic Adenocarcinoma
• Jeffrey R. Infante, Hiroyuki Matsubayashi, Norihiro Sato, James
Tonascia, Alison P. Klein, Taylor A. Riall,Charles Yeo, Christine
Iacobuzio-Donahue, and Michael Goggins
• J Clin Oncol 2007; 25:319-325.
SPARC as Prognostic Factor
• Evaluation of the prognostic significance of
SPARC expression in patients with pancreatic
adenocarcinoma
• The expression patterns of SPARC
– Characterized by immunohistochemistry
– 299 primary pancreatic ductal adenocarcinoma
resection specimens from patients who
underwent pancreaticoduodenectomy at Johns
Hopkins Hospital (Baltimore, MD) between 1998
and 2003
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC: IMH
• The monoclonal anti-SPARC antibody (clone ON1-1) was
from Zymed Laboratories Inc (San Francisco, CA)
• Immunolabeling of the markers was scored by authors
blinded to the outcome
– Negative = intensity was absent to weak (+) and the extent was
less than 10%
– Positive = intensity was moderate (++), to strong (+++), and the
extent was > 10%
• SPARC was categorized as positive or negative for both the
carcinoma and the normal juxta-tumoral pancreas tissue:
–
–
–
–
Tumor negative/stroma negative
Tumor positive/stroma negative
Tumor negative/stroma positive
Tumor positive/stroma positive
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC: IMH Results
• SPARC expression most clearly seen in the cytoplasm
of peritumoral fibroblasts
– Extracellular matrix and local inflammatory cells (macrophages and
lymphocytes) did not show SPARC expression
– Fibroblast SPARC expression most prominent in cells immediately
adjacent to infiltrating cancer cells and usually weak to absent in the
stroma distant to the malignant epithelium
• SPARC expression
–
–
–
–
Tumor negative/stroma negative
Tumor positive/stroma negative
Tumor negative/stroma positive
Tumor positive/stroma positive
17%
17%
52%
15%
• Patients with poorly differentiated tumors were
significantly more likely to have peritumoral stromal
SPARC expression: 55% vs 32%
Infante JR et. J Clin Oncol 2007; 25:319-325
OS & SPARC expression
Infante JR et. J Clin Oncol 2007; 25:319-325
OS, Grade & SPARC
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC &Prognosis, Univariate analysis
• SPARC expression in peritumoral
fibroblasts associated with worst
prognosis
– Median survival: 15 months for pts whose stroma
expressed SPARC vs 30 months for pts whose stroma
did not express SPARC, log-rank P<.001
– Univariate Cox proportional hazards regression for
stromal SPARC expression independent of tumor
SPARC staining was 2.36 (95% CI, 1.67 to 3.34)
– Prognostic significance in the adjuvant therapy
subgroup was similar (hazard ratio, 2.47; 95% CI, 1.41
to 4.33) to that of the entire cohort
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC &Prognosis, Multivariate Analysis
• Multivariate regression model based on all 299
patients, the adjusted Cox proportional hazards
regression for patients whose cancer stroma
expressed SPARC was 1.89 (95% CI, 1.31 to 2.74)
compared with patients whose stroma did not
express SPARC
• Increased tumor size, positive lymph nodes,
positive margins, increased tumor grade, and
older age all independently and significantly
increased mortality
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC & Histologic Grade
• Patients whose pancreatic cancers were well or
moderately differentiated and whose peritumoral
fibroblasts lacked SPARC had significantly better
survival than other groups (P .0001)
• However, patients with tumors with poor
differentiation (regardless of SPARC) and tumors that
were well or moderately differentiated with stromal
SPARC expression had a significantly worse prognosis
(hazard ratios, 2.59, 3.25 and 4.56, respectively; all
with P.0001) compared with the patients with SPARCnegative stroma and well or moderately
differentiated tumors
Infante JR et. J Clin Oncol 2007; 25:319-325
SPARC Prognostic Meaning
• Stromal SPARC expression is a marker of poor
prognosis, independent of common clinical
parameters including tumor size, margin status,
and lymph node metastasis.
• The mechanism by which stromal SPARC
expression portends a worse prognosis is not
known
– Most likely explanation is that peritumoral fibroblast
SPARC expression is a marker of activated fibroblasts
– Activated peritumoral fibroblasts portend a
significantly poor patient prognosis, by mechanisms
not yet understood
Infante JR et. J Clin Oncol 2007; 25:319-325
Title:
• SPARC mRNA expression as a
prognostic marker for pancreatic
adenocarcinoma patients
Authors:
• Kei Miyoshi, Norihito Sato, Kenoki Ohuchida, Kazuhiro
Mizumoto, Masao Tanaka
Reference:
• Anticancer Res 2010; 30:867-872
Methods
• 104 pts with resected pancreatic cancer at a
single institution between 1992 to 2007
• Analysis of total mRNA extracted from
formalin-fixed paraffin-embebed tissue
samples
• qRT-PCR, with designed specific primers
• SPARC expression was split into high and low
as per recursive descent partition analysis
Miyoshi K et. Anticancer Res. 2010; 30:867-72
Results
• No significant association between SPARC
expression and prognostic factors
– Non-significant trend for grade:
G0=0%, G1=11%, G3=18%
• SPARC level associated with OS (p = 0.0001)
– Low level = 22.5% survival probability at 5 years
– High level = 0% survival probability at 5 years
• Univariate and multivariate analysis confirmed
the adverse prognostic impact of high SPARC level
Miyoshi K et. Anticancer Res. 2010; 30:867-72