Transcript Nab paclitaxel Development in Gynecologic Malignancies

Nab-paclitaxel in Ovarian Cancer
Nab paclitaxel in Gynecologic Malignancy Trials
Study Description
Principal
Investigator
Status
Nab paclitaxel in Platinum-Sensitive
Ovarian Cancer
M. Teneriello
47 pts
JCO 2009
Nab paclitaxel + Carboplatin in
Platinum-Sensitive Ovarian Cancer
B. B. Benigno
38 pts
ASCO 2010
Nab paclitaxel in Recurrent or
Persistent Platinum-Resistant
Ovarian Cancer
R. Coleman
51 pts
Gyn Oncol 2011
Nab paclitaxel + Avastin in
Recurrent Platinum-Resistant
Ovarian Cancer
T. Tillmanns
48 pts
ASCO 2010
Nab-paclitaxel with GM-CSF as
chemoimmunotherapy for PlatinumResistant epithelial Ovarian Cancer
R.E. Swensen
20 pts
ASCO 2011
Key Eligibility
•
•
•
Measurable disease by
RECIST or elevated CA125 ( > 70 U/mL)
Prior platinum-based
chemotherapy
Platinum treatment-free
interval >6 months
Nab paclitaxel 260 mg/m2
on Day 1 q Q3W
x 6 cycles or
8 cycles if patient
achieved CR
n=47
Primary endpoints: Response Rate
Secondary endpoints: Progression Free and Overall Survival, Quality of
Life, Safety
Teneriello
Patient Characteristics
Number of Patients Enrolled
47
66 (42 – 84)
Age, mean (Range)
n
%
ECOG Performance Status
0
1
38
9
81
19
Prior Therapy
Prior taxane
Prior Chemotherapy > 12 months
Prior Chemotherapy < 12 months
Surgery
42
43
4
44
90
92
9
94
Site of Primary Disease
Epithelial Ovarian
Fallopian Tube
Peritoneum
37
1
9
79
2
19
Stage at Baseline
IC/IIB/IIC
III/IIIA/IIIB
IIIC
IV
4
7
25
11
9
15
52
23
Teneriello
Efficacy Data
64% Response Rate with Nab paclitaxel
Monotherapy
Total Number of Eligible/Treated Subjects
Best Response
Complete Response
Partial Response
Stable Disease
SD > 6 months
SD < 6 months
Progressive Disease
Clinical Benefit (CR + PR + SD > 6 months)
Non-evaluable*
Time to Response, median (months)
Range
Duration of Response, median (months)
Range
Progression-free Survival, median (months)
44
n (%)
95% CI
15 (34%)
13 (30%)
14 (32%)
6
8
2 (5%)
34 (77%)
3
(20.1 – 48.1)
(16.1 – 43.0)
(18.1 – 45.6)
(0 – 10.7)
1.3
(0.5 – 4.8)
7.9
(2.7 – 17.6)
(6.7 –10.5)
8.5
Overall response rates were calculated using either Response Evaluation Criteria in Solid Tumors or CA-125 or both; the overall response rate (CR PR)
was 64%.
*Three patients were not assessable; two patients were found to be ineligible after start of treatment, and one other patient was never treated.
Teneriello
Safety Data: Adverse Events
Most Common Grade 3/4 AEs
All Grade
n (%)
Grade 3
n (%)
Grade 4
n (%)
Neutropenia
20 (47%)
6 (13%)
5 (11%)
Leukopenia
7 (15%)
6 (13%)
--
Neuropathy
6 (13%)
4 (9%)
--
Fatigue
10 (22%)
1 (2%)
--
Diarrhea
3 (7%)
1 (2%)
--
Abdominal pain
2 (4%)
1 (2%)
--
Pneumonia
2 (4%)
1 (2%)
--
Upper respiratory tract
infection
2 (4%)
1 (2%)
--
Generalized weakness
2 (4%)
1 (2%)
--
40 (87%)
--
--
Hematological
Non-hematological
Alopecia
Teneriello
Conclusions
Nab-paclitaxel is active in this group of patients with
recurrent ovarian, peritoneal, or fallopian tube
cancer. The ORR was 64%.
Toxicities were manageable. Further studies of nabpaclitaxel in combination with platinum are warranted.
Teneriello
Phase II Study of Nab paclitaxel® Plus Carboplatin in
Patients with Recurrent Platinum-Sensitive Ovarian or
Primary Peritoneal Cancer
Key Eligibility
•
•
•
Recurrent ovarian
or primary
peritoneal cancer
Platinum-sensitive
Measurable
disease
Nab paclitaxel® 100
mg/m2
Days 1, 8, 15 q 28 days
+
Carboplatin AUC 5 or 6
Day 1 q 28 days
x 6 cycles
Continue Nab
paclitaxel until
progressive
disease or
PI-PT
discretion
n = 40
Primary endpoints: Antitumor activity and safety
Secondary endpoints: Progression-free survival and overall survival
Benigno
Patient Characteristics
Number of Patients Enrolled
40 (38 evaluable)
Age, mean (Range)
62 (42 - 81)
n
%
ECOG Performance Status
0
1
35
5
87
13
Prior Therapy
Prior taxane / platinum
Prior chemotherapy > 12 months
Prior chemotherapy < 12 months
40
14
25
100
35
63
Site of Primary Disease
Epithelial Ovarian
Fallopian Tube
39
1
98
2
Stage at Baseline
IIB / IIC / IIIB
IIIC
IV
9
28
3
23
70
7
Benigno
Dosing Information
• Carboplatin dose AUC 6 administered to first 9 patients
• After Grade 4 neutropenia in 3 patients, reduced carboplatin to AUC 5
• 20 patients discontinued treatment for reasons other than toxicity or disease
progression
Treatment Cycles
Completed
>18 cycles
n (%)
13-17 cycles
n (%)
7-12 cycles
n (%)
6 cycles
n (%)
< 6 cycles
n (%)
Evaluable Patients
38 TOTAL
5
1 pt active
4
10
14
5
Phys or Pt discretion
2
2
6
10
0
Progressive disease
2
2
4
3
3
Toxicitiy
0
0
0
1
2
(G4
neurotoxity
cycle 6)
(G4 pneumonia
cycle 5,
G3 hem cycle 4)
Reason for Discontinuing
Type/ cycle
Benigno
Safety Data: Adverse Events
Most Common Grade 3/4 AEs
Grade 3
n (%)
Grade 4
n (%)
Neutropenia
14 (34%)
3 (7%)
Anemia
4 (10%)
--
Thrombocytopenia
2 (5%)
--
Fatigue
13 (32%)
--
Carboplatin reaction
7 (17%)
--
Nausea
2 (5%)
--
Constipation
1 (2%)
--
Fever
1 (2%)
--
Shortness of breath
1 (2%)
--
--
1 (2%)
Hematological
Non-hematological
Neuropathy
Benigno
Efficacy Data: Survival
Over 50% of patients alive at 1-year
Survival Rates
1-Year
56%
2-Year
39%
* Until 9/18/2009, there are 18 patients alive, 21 are dead and one is UNK due to lost of FU, one still active on cycle 44
Benigno
Conclusions
With a 97% disease control rate (CR + PR + SD), the
combination of nab-paclitaxel plus carboplatin had
significant antitumor activity and was reasonably tolerated
in patients with platinum-sensitive recurrent ovarian cancer.
Benigno
Key Eligibility
•
•
•
•
Recurrent or
persistent ovarian,
peritoneal, fallopian
tube carcinoma
Platinum-resistant or
refractory
Paclitaxel-resistant or
refractory
Measurable disease
Nab paclitaxel 100 mg/m2
on Days 1, 8, 15 q 28
Treatment until disease
progression or
unacceptable toxicity
n = 51
Primary endpoints: Antitumor activity and safety
Secondary endpoints: Progression Free and Overall Survival
Coleman
Patient Characteristics



Age:
– 50-59
15 (36.6%)
-- 30-39
1(2.1%)
– 60-69
14 (34.1%)
– 30-49
7 (17 %)
– 70-79
5 (12.2%)
Performance Status:
– 0
31 (66.0%)
– 1
15 (31.9%)
– 2
1 (2.1%)
Prior Therapy
– 1 Reg.
47 (100%)
– Immunoth 2
– Hormonal 2




Race:
– White
– African American
– Hispanic
– Am Indian
Site of Disease
– Ovary
– Fallopian Tube
– Other
Grade
– 1
– 2
– 3
Cell Type:
– Serous Adeno
35 (74.5%)
9 (19.1%)
2 ( 4.3%)
1 ( 2.1%)
41 (87.2%)
1 (2.1%)
5 (10.6%)
7 (14.9%)
2 (4.3%)
33 (80.9%)
34 (72.3%)
Coleman
Efficacy Data
23% Response Rate with Nab paclitaxel
Monotherapy
Responses reported in 47 of 51 patients:
N
%
CR+PR (1CR&10PR)
11
23
Stable Disease
17
36
Progressive Disease
17
36
Responses
Coleman
Efficacy Data: Overall Survival and Progressionfree Survival


Progression-free Survival, median: 4.5 months
Overall survival, median: 17.5 months
Coleman
Safety Data: Adverse Events


No grade 4 toxicities
Only 1 patient grade 3 neurosensory toxicity
Toxicity / Adverse Events
Maximum grade, no. of patients
1
2
3
4
Hematological
anemia
neutropenia
19
5
20
6
3
6
0 (0%)
0 (0%)
leukopenia
thrombocytopenia
15
4
11
0
1
0
0 (0%)
0 (0%)
14
20
5
15
1
0
0 (0%)
0 (0%)
gastrointestinal
metabolic
19
8
8
2
2
2
0 (0%)
0 (0%)
pain
10
3
2
0 (0%)
Non-hematological
neurosensory
constitutional
AE, adverse event
Coleman
Conclusion
The authors conclude that this data support the contention
that weekly nab-paclitaxel is associated with significant
clinical efficacy in highhly resistant ovarian cancer patients,
and compared to weekly paclitaxel in this setting, may have
a more favorable side effect profile.
Coleman
Phase II Study of Nab paclitaxel® with Bevacizumab in
Patients with Recurrent Platinum-Resistant Primary
Epithelial Ovarian or Primary Peritoneal Cancer
Key Eligibility
•
•
•
Recurrent or
persistent ovarian,
peritoneal cancer
Platinum-resistant
within 6 months
Measurable disease
n = 48
Nab paclitaxel 100 mg/m2
on Days 1, 8, 15
+
Bevacizumab 10 mg/kg
Days 1, 15
Q 28 d
Treatment until disease
progression or
unacceptable toxicity
Primary endpoints: Duration of objective response, safety
Secondary endpoints: Duration of progression-free survival, overall
survival, quality of life
Tillmanns
Efficacy Data
48% response rate with Nab paclitaxel +
Bevacizumab
 Response rate: 48%
 Stable Disease: 25%
Best Overall Response
Not Done
Treatment Cycle
n
%
4
16
7
PD
n
PR
%
SD
n
%
n
%
33.3
19
39.6
13
27.1
16
33.3
21
43.8
11
22.9
10
16
33.3
22
45.8
10
20.8
13
16
33.3
22
45.8
10
20.8
16
16
33.3
22
45.8
10
20.8
19
16
33.3
22
45.8
10
20.8
22
16
33.3
22
45.8
10
20.8
25
16
33.3
22
45.8
10
20.8
28
16
33.3
22
45.8
10
20.8
EOS All Pts
5
10.4
8
16.7
23
47.9
12
25.0
EOS Pts off study
1
26
8
20.5
18
46.1
12
30.8
Tillmanns
Efficacy: Progression-free Survival

Median Progression-free Survival: 8.26 months
Tillmanns
Safety Data: Grade 3 / 4 Adverse Events*
Most Common Grade 3/4 AEs*
All Grade
n (%)
Grade 3
n (%)
Grade 4
n (%)
Neutropenia
13 (27%)
5 (10%)
--
Anemia
11 (23%)
1 (2%)
--
Abdominal pain
17 (35%)
3 (6%)
--
Bowel obstruction
17 (35%)
4 (8%)
2 (4%)
Cardiac disorder
11 (23%)
--
1 (2%)
Fatigue
35 (73%)
2 (4%)
--
GU / renal
7 (15%)
1 (2%)
1 (2%)
Infections
8 (17%)
4 (8%)
--
Metabolism disorders
18 (38%)
2 (4%)
--
Other blood / lymphatic system disorders
16 (33%)
2 (4%)
--
Other gastrointestinal disorders
29 (60%)
6 (13%)
--
Vascular disorders
12 (25%)
3 (6%)
--
Neuropathy
14 (29%)
--
--
Hematological
Non-hematological
* One Death, NOS
Tillmanns
Conclusions
Nab-Paclitaxel 100 mg/m2 IV on days 1, 8, 15 in combination
with bevacizumab 10 mg/kg IV on days 1 and 15 every 28 days
appears to be highly active with impressive PFS and
OS combined with low G3/G4 toxicity.
Further prospective trials should be explored in this population.
Tillmanns
A phase 2 trial of weekly nanoparticle paclitaxel with
GM-CSF as chemoimmunotherapy for platinumresistant epithelial ovarian cancer
 Phase II study to evaluate wkly nab-paclitaxel followed by GM-CSF in
patients (n=30) with platinum-resistant ovarian cancer, primary peritoneal or
fallopian tube cancer and elevated CA-125
 Endpoints:
ORR
TTP on current study
TTP on the prior platinum
regimen
Swensen
Treatment
Nab-paclitaxel 100 mg/m² d 1,8,15 followed by Leukine 250
mcg/day d 16-26 of 28 day cycle until progression or 6
cycles.
Responding patients received up to 6 more cycles of
Leukine d 14-28
Swensen
Results
 20 patients received at least 1 dose study medication; 16 have
completed the study:
 CR: 13% (2/16); PR: 50% (8/16)
 TTP (median): 110 days overall; 140 days for responders ; 269
days on prior platinum regimens
Toxicities:
Gr 3 lymphopenia: 3; Gr 3 neutropenia: 3; Gr 3 fatigue: 1; Gr 3
hypokalemia: 1; Gr 3 anemia: 1; One pt hospitalized for bowel
obstruction, another with bowel obstruction, esophagitis and hypoxia due
to pleural effusion. 2 pts went off study due to progressive sensory
neuropathy. 2 pts died while on study
Swensen
Conclusions
Weekly nab-paclitaxel with GM-CSF induces a high
response rate in platinum-resistant ovarian cancer with
manageable toxicity. Current regimen did not prolong TTP
vs. TTP on prior platinum regimen.
Swensen