Transcript Sviluppi futuri di nab-paclitaxel nel carcinoma metatatico

Sviluppi futuri di nabPaclitaxel nel carcinoma
metastatico del pancreas
Michele Milella
Istituto Nazionale Tumori Regina Elena
Roma
It’s not just the cancer cell: interaction with
the (micro)environment in PDAC
Hh inhibitors: targeting tumor-stroma
interactions in PDAC
Meccanismo d’azione
nab-paclitaxel è la prima nano-chemioterapia target1
Dissociazione in singoli
complessi di paclitaxel albumina
Legame recettoriale attivo e mirato tra paclitaxel
albumina e recettori gp60, con attivazione di
caveolina-1
Incremento della transcitosi attraverso le
membrane cellulari endoteliali
Incremento dell’accumulo a livello tumorale di
paclitaxel albumina attraverso il legame con la
proteina SPARC
A Phase II Trial of nab‐Paclitaxel in Patients With Advanced Pancreatic
Paclitaxel
albumin on
inGemcitabine‐Based
patients with Therapy
gemcitabineCancer
Who Have Progressed
refractory advanced pancreatic cancer:
Study Design/Eligibility Criteria
•
• Single-institution phase II openlabel trial
• Treatment: nab-P 100 mg/m2 IV
over 30 minutes on days 1, 8 and
15 of a 28-day cycle
• Contrast CT at baseline and every
2 cycles
•
•
•
•
Age > 18
Locally advanced, unresectable or
metastatic pancreatic ductal
carcinoma
ECOG PS 0-2
Good organ function
Progressed within 6 months of
gemcitabine
Endpoints
•
•
•
•
6-month overall survival rate
Response rate by RECIST criteria / Progression-free survival
Safety and tolerability
CA19-9 at baseline and every 2 cycles /SPARC immunohistochemistry (IHC)
on available pre-treatment tumor specimens performed at a reference lab
Hosein et al. Presented at ASCO Annual Meeting, 2010; Abstract #4120
Paclitaxel albumin in patients with gemcitabinerefractory advanced pancreatic cancer: safety
Event
Grade 1/2, n (%)
Grade 3/4, n (%)
Neutropenia
8 (42.1)
5 (26.3)
Anaemia
11 (57.9)
1 (10.5)
Thrombocytopenia
1 (5.2)
0
Neutropenic fever
0
2 (10.5)
Fatigue
12 (63.1)
0
Nausea
12 (63.1)
0
Alopecia
12 (63.1)
-
Anorexia
9 (47.4)
0
Hypocalcaemia
7 (36.8)
1 (5.2)
Vomitting
5 (26.3)
0
Neuropathy
3 (15.8)
0
Haematological
Paclitaxel albumin was well tolerated in this group of patients
Hosein, et al. ASCO 2010 (abstract 4120)
Non-haematological
Best response (RECIST)
n (%)
95% CI
PR
1 (5.3)
0.1-26
SD
6 (31.6)
12.6-56.6
Clinical benefit rate (PR+SD)
7 (36.8)
16.3-61.6
PD
12 (63.2)
38.4-83.7
Timepoint, mo
PFS, % (95% CI)
OS, % (95% CI)
3
31.6 (12.9-52.2)
73.7 (47.9-88.1)
6
15.8 (3.9-34.9)
57.9 (33.2-76.3)
9
5.3 (0.4-21.4)
47.4 (24.4-67.3)
12
5.3 (0.4-21.4)
36.8 (16.5-57.5)
Median
1.6 (1.5-3.4)
7.3 (2.8-15.8)
37% of patients derived clinical benefit and 21% remained on therapy for 6
months, suggesting paclitaxel albumin is active in this setting
Hosein, et al. ASCO 2010 (abstract 4120)
Paclitaxel albumin in patients with gemcitabinerefractory advanced pancreatic cancer: efficacy
nab-Paclitaxel has single-agent activity in
advanced PDAC: a clinical case
• D.C., 60 yr-old female, with locally advanced, inoperable PDAC
• Pretreated with single-agent Gem, Gem/Ox, Folfox (with very poor
tolerance) and RF ablation of the pancreatic lesion
• Subsequent therapy with Folfiri for peritoneal progression
• April 2011, further peritoneal and hepatic progression, symptomatic
ascites, ECOG PS 2, CA19.9: 1742  off-label nab-Paclitaxel started
(100 mg/m2 weekly 3/4)
• After 2 administrations: G4 neutropenia, with worsening of the ascites
and PS 3, hospitalization required; CA19.9: 1280  supportive care and
restarted on nab-Paclitaxel (dose -reduced to 75%) w G-CSF support
• July 2011: CT scan shows SD, PS improved to 1, no signs of ascites,
CA19.9: 880  continue nab-Paclitaxel w G-CSF support
• As of today, the patient has completed 5 cycles of nab-Paclitaxel with
good tolerance, her ECOG PS has returned to 0, she has gone back to
work; clinically there are no signs of ascites, CA19.9 has decreased to
278, CT scan is stable.
Paclitaxel albumin + vandetanib in patients with
advanced pancreatic cancer
• Treatment
–
Cohort A: paclitaxel albumin 100 mg/m2 QW 3/4 + V 100, 200 or 300 mg po QD
–
Cohort B: paclitaxel albumin 260 mg/m2 Q3W + V 100, 200 or 300 mg po QD
• Results
–
MTD of V was the maximum planned dose in each cohort (300 mg QD)
–
DLTs
• Cohort A: 3 DLTs (1 at each dose level)
–
2 patients with grade 3 rash and 1 patient with grade 4 neutropenia,
grade 3 mucositis, prolonged QTc
• Cohort B: No DLTs at any dose level
–
Preliminary efficacy results of all evaluable patients (n=22)
• PR: 6 (27%), SD: 10 (45%), PD: 6 (27%)
• Median PFS: 5.3 months (95% CI 3.7- 7.3)
• Median OS: 8.2 months (95% CI: 6.2-11.5)
• Conclusions
–
Both schedules were well tolerated with promising preliminary efficacy indicated
El-Khoueiry et al. ASCO 2011 (abstract 4124)
Paclitaxel albumin + gemcitabine in patients with
metastatic pancreatic cancer: Phase I/II study design
Open label phase I/II study in chemotherapy-naive patients with
metastatic adenocarcinoma of the pancreas
Phase I:
Gemcitabine 1000 mg/m2 QW 3/4
+
Dose escalation of paclitaxel albumin
according to a standard 3+3 design
Phase II:
Accrual expanded to 42 patients
Treatment at the MTD
• Study objective: To evaluate the safety and efficacy of paclitaxel albumin +
gemcitabine and the correlation of clinical response with tumoural SPARC and serum
CA19-9 levels in patients with metastatic pancreatic cancer
• Study endpoints
 Safety: MTD and DLTs (Phase I); safety (incidence of treatment-related AEs and
SAEs)
 Efficacy: RR, PFS, OS, PET scan response, CA 19-9 and SPARC levels in relation
to efficacy
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: eligibility criteria
Inclusion criteria
• Age 18 years
• Histologically and cytologically confirmed
metastatic pancreatic ductal
adenocarcinoma
Exclusion criteria
• Prior chemotherapy for metastatic disease
 Prior adjuvant 5-FU or gemcitabine as a
radiation sensitizer during and up to 4
weeks after radiation therapy was
permitted
• Measurable disease by CT according to
RECIST
• Islet cell neoplasms
• ECOG PS 0 or 1
• Locally advanced disease
• Adequate haematological, hepatic and
renal function
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Dose Finding Scheme
Gemcitabine 1000 mg/m2 i.v.
Dose Levels
nab-Paclitaxel
100 mg/m2 i.v.
125 mg/m2 i.v.
150 mg/m2 i.v.
1
Week 1
8
Week 2
15
22
Week 3
Days
28
Week 4
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
MTD and DLT
nab-Paclitaxel Dose Levels
100
mg/m2
i.v.
First 6 pts:
2 pts d8 dose held for neutropenia (G3) and
thrombocytopenia (G2)
3 responders
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
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: baseline demographics
Paclitaxel albumin (mg/m2)
Characteristics
100
(n=20)
125
(n=44)
150
(n=3)
62 (30–86)
61 (28–78)
69 (53–72)
Female, n (%)
9 (45)
25 (57)
1 (33)
ECOG PS, n (%)
0
1
9 (45)
11 (55)
22 (50)
22 (50)
2 (67)
1 (33)
Site of metastatic disease, n (%)
Lung
Liver
Abdomen/peritoneal
Other
5 (25)
11 (55)
16 (80)
10 (50)
18 (41)
34 (77)
38 (86)
12 (27)
1 (33)
2 (67)
2 (67)
1 (33)
No of metastatic sites, n (%)
1
2
3
6 (30)
8 (40)
6 (30)
8 (18)
18 (41)
18 (41)
1 (33)
2 (67)
0
Baseline CA 19-9 levels, n (%)
Normal*
Elevated
(n=15)
2 (13)
13 (87)
(n=37)
6 (16)
31 (84)
(n=2)
1 (50)
1 (50)
Median age (range), years
* cut-off for normal range: <37 u/mL
Von
Hoff 2011
et al. (published
J Clin Oncol
2011.
Von Hoff et al. J Clin
Oncol
online
Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: prior therapy
Paclitaxel albumin (mg/m2)
Previous treatment, n (%)
Chemotherapy
Adjuvant therapy
Adjuvant gemcitabine
Adjuvant capecitabine
Adjuvant 5-FU
Adjuvant docetaxel
Adjuvant erlotinib
Median (range) time since adjuvant
therapy, mo
100
(n=20)
125
(n=44)
150
(n=3)
3 (15)
3 (15)
1 (5)
1 (5)
2 (10)
0
0
10 (23)
10 (23)
5 (11)
4 (9)
1 (2)
2 (5)
0
1 (33)
1 (33)
0
0
0
0
1 (33)
64 (9-81)
12 (1-23)
5*
*data are for 1 patient
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: safety
Selected Grade 3/4 AEs, n (%)
Paclitaxel albumin (mg/m2)
100 (n=20)
125 (n=44)
150 (n=3)
Diarrhoea
3 (15)
1 (2)
0
Fatigue
1 (5)
12 (27)
1 (33)
Nausea
0
1 (2)
0
1 (5)
9 (20)
0
0
3 (7)
0
Anaemia
1 (5)
6 (14)
0
Leukopenia
4 (20)
24 (55)
1 (33)
Neutropenia
10 (50)
32 (73)
2 (67)
Febrile neutropenia
2 (10)
1 (2)
0
Thrombocytopenia
3 (15)
12 (27)
0
Non-haematological
Sensory neuropathy
Vomiting
Haematological
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: Treatment exposure
Dose admin./planned
Median number of Cycles
nab-paclitaxel
Gemcitabine
81%
85%
6 (1-24)
Dose reduction (% pts)
25%
(20% - Cohort 125 mg/m²)
31%
(43% - Cohort 125 mg/m²)
73%
Dose delay (% pts)
72%
(70% - Cohort 125 mg/m²)
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: efficacy
Paclitaxel albumin (mg/m2)
125 (n=44)
All dose levels (n=67)
21 (48)
31 (46)
CR
0
3 (4)
PR
21 (48)
28 (42)
SD
9 (20)
12 (18)
PD
7 (16)
15 (22)
DCR
30 (68)
43 (64)
PFS*
7.9 (5.8–11.0)
7.1 (5.7–8.0)
OS*
12.2 (8.9–17.9)
10.3 (8.4–13.6)
n, %
ORR
1-yr OS, %
48
* Median, months (95% CI)
Von
Hoff 2011
et al. (published
J Clin Oncol
2011.
Von Hoff et al. J Clin
Oncol
online
Oct 3rd)
Paclitaxel albumin + gemcitabine in patients with
metastatic pancreatic cancer: survival
Probability of survival (%)
100
Paclitaxel albumin 125 mg/m2 (n=44)
75
12.2 months
50
25
0
0
3
6
9
12
15
18
21
Time (months)
24
27
30
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in metastatic
pancreatic cancer: rapid response on PET scans
Baseline
6 weeks
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in patients with
metastatic pancreatic cancer: FDG PET
• FDG PET scans were available
for 55 patients
Incomplete metabolic
responses (n=38)
100
• Median decrease in metabolic
activity at 12 weeks:
– 79% (all patients)
• Patients with a metabolic
response (defined by EORTC as
absence of FDG uptake) had a
significantly improved OS:
– Median OS: 20.1 vs 10.3
mo, p=0.01
Probability of survival (%)
Complete metabolic
responses (n=17)
75
p=0.01
20.1 months
50
10.2 months
25
Complete
Censored
0
0
3
6
9 12 15 18 21 24 27 30
Time (months)
Von Hoff et al. J Clin Oncol 2011 (published online Oct 3rd)
Paclitaxel albumin + gemcitabine in patients
with metastatic pancreatic cancer: CA19-9
•
Rapid CA19-9 decreases after treatment
initiation
•
CA19-9 decrease ≥50% was observed in
(78%) of patients with available CA19-9 levels
•
Median max % change in 54 patients was 91%
CA19-9 levels strongly correlated with RR, PFS, OS
CA19-9
Classification
RR, n
(%)
Median
PFS, mo
Median
OS, mo
≥50% Decrease
(n = 42)
24 (57)
8.7
12.3
<50% Decrease
(n = 12)
2 (17)
3.6
6.2
P-values
0.021
0.004
<0.001
D. von Hoff et al. ASCO 2009 (Poster 4525).
Paclitaxel albumin + gemcitabine in patients with
metastatic pancreatic cancer: SPARC
• SPARC status was evaluated in 36
patients
– Median OS: 17.8 vs 8.1 mo,
p=0.0431
• SPARC level remained a significant
predictor for OS after adjusting for
clinical covariates (eg age, sex, race,
baseline CA 19-9) (p=0.041)
• Stromal SPARC correlated with OS
(p=0.013) but SPARC in tumour cells
did not (p=0.15)
Probability of survival (%)
• A significantly longer OS was reported
in the high SPARC vs low SPARC
group
Average z score ≥0,
high SPARC (n=19)
100
Average z score <0,
low SPARC (n=17)
75
p=0.0431
17.8 months
50
8.1 months
25
0
0
3
6
9 12 15 18 21 24 27 30
Time (months)
Von Hoff et al. J Clin Oncol 2011.
Companion Preclinical Studies
N=11 patient derived xenografts
Tumor Regression
Gemcitabine
2 (18%)
nab-Paclitaxel
4 (36%)
nab-Paclitaxel + 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
nab-Paclitaxel
Desmoplastic
Stroma
Depletion
GEM + nab-Ptx
Dilated blood vessels
x3 increase in Nestin
Mean Gem concentration (ng/g)
Intratumor concentration of GEM
7500
2.8 fold
increase
5000
2500
Gemcitabine
alone
0
nab-Paclitaxel
+
Gemcitabine
Ongoing studies with nab-Paclitaxel in
pancreatic cancer
Study Title
Phase
Current status
Nab-paclitaxel (nab-paclitaxel), Gemcitabine, and Capecitabine
(Xeloda) for Pancreatic Adenocarcinoma
I
Recruiting
PD
Recruiting
Study of Gemcitabine and nab-paclitaxel to Treat Potentially
Operable Pancreatic Cancer
II
Recruiting
Efficacy & Safety of ODSH (2-0, 3-0 Desulfated Heparin) in
Patients With Metastatic Pancreatic Cancer Treated With
Gemcitabine & nab-paclitaxel
II
Not yet recruiting
Erlotinib, Gemcitabine and Nab-Paclitaxel in Advanced
Pancreatic Cancer
I
Active, not recruiting
Hedgehog Inhibitors for Metastatic Adenocarcinoma of the
Pancreas (Gemcitabine, nab-Paclitaxel, GDC-0449)
II
Recruiting
Safety and Tolerability Study of GSK1120212, a MEK Inhibitor,
in Combination With Docetaxel, Erlotinib, Pemetrexed,
Pemetrexed + Carboplatin, or Nab-Paclitaxel
I
Recruiting
Assessment Of Stromal Response To Nab-Paclitaxel In
Combination With Gemcitabine In Pancreatic Cancer
Randomized Phase III Study of Weekly nab-Paclitaxel plus
Gemcitabine versus Gemcitabine Alone in Patients with
Metastatic Adenocarcinoma of the Pancreas (CA046)
• Primary Objective
– To evaluate efficacy of the combination of nab-paclitaxel and gemcitabine
versus gemcitabine alone in improving overall survival in patients with
metastatic adenocarcinoma of the pancreas
• Secondary Objectives
– To evaluate the following:
• Objective tumor response and progression-free survival (PFS) according to
RECIST criteria
• Safety and tolerability
• Functional tumor response according to EORTC criteria
• Change in serum CA19-9 and plasma SPARC levels
• SPARC in tumor tissue and peripheral blood and determine its possible
correlation with efficacy outcomes
Study Design
R
A
N
D
O
M
I
Z
E
nab-Paclitaxel 125 mg/m2
(No Premedication)
+
Gemcitabine 1000 mg/m2
Weekly, 3 of 4 Weeks
Gemcitabine 1000 mg/m2
Weekly, 7 of 8 Weeks (Cycle 1) then
Weekly, 3 of 4 Weeks (Cycle 2 Onward)
(1:1)
Planned accrual
N = 842 Intent-To-Treat (ITT) Patients
We left here just one year ago…
Results: OS
Results: OS
RCTs (pts)
HR (95% CI)
P-value
Het. (p)
1-yr AD (%)
NNT
CIS
3 (702)
0.94 (0.76-1.17)
0.610
0.19
-
-
L-OHP
2 (868)
0.86 (0.74-0.99)
0.041
0.65
2.6
38-39
CAP
2 (852)
0.86 (0.75-0.99)
0.039
0.94
3.0
33-34
7 (2,422)
0.89 (0.81-0.97)
0.009
0.41
2.3
43-44
Legend – OS: overall survival; CAP: capecitabine; DDP: cisplatin; LOHP: oxaliplatin; HR: hazard ratio;
CI: confidence interval; Gem: gemcitabine.
Overall
Interaction according to Combo: p=0.45
Sperduti, ASCO 2010
Legend – RCTs: randomized clinical trial; HR: hazard ratio; CI: confidence interval; Het:
heterogeneity; AD: absolute difference; NNT: number needed to treat; CAP: capecitabine; DDP:
cisplatin; LOHP: oxaliplatin
…and we got here in just one year!!!!
50
Gem/Gem-based combos
45
Folfirinox
Gem/nab-Ptx
40
35
30
25
20
15
10
5
0
ORR
1-yr OS
OS (median, mo)
…with great hope for a bright future!!!