nab-paclitaxel development in gynecologic malignancies robert coleman, md, facog, facs director of...
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Nab-paclitaxel Development in Gynecologic Malignancies
Robert Coleman, MD, FACOG, FACSDirector of Clinical Research
Department of Gynecologic OncologyMD Anderson Cancer Center
Nab-paclitaxel Gynecologic Malignancy Trials with Enrollment Complete
Study Description Principal Investigator
Status
nab-paclitaxel in Platinum-Sensitive Ovarian Cancer
M. Teneriello 47 pts
Published JCO 2009
nab-paclitaxel + Carboplatin in Platinum-Sensitive Ovarian Cancer
B. Benigno 38 pts / 1 active
nab-paclitaxel in Recurrent or Persistent Platinum-Resistant Ovarian Cancer
R. Coleman 49 pts / 2 active
Final data analysis pending
Current data from 41 pts
nab-paclitaxel + Avastin in Recurrent Platinum-Resistant Ovarian Cancer
T. Tillmanns 48 pts / 2 active
Primary endpoints: Response Rate
Secondary endpoints: Progression Free and Overall Survival, Quality of Life, Safety
Phase II Evaluation of Nab-paclitaxel in Platinum-Sensitive Patients with Recurrent Ovarian, Peritoneal, or Fallopian
Tube Cancer
Teneriello, JCO 2009
Key Eligibility
• Measurable disease by RECIST or elevated CA-125 ( > 70 U/mL)
• Prior platinum-based chemotherapy
• Platinum treatment-free interval >6 months
n=47
nab-paclitaxel 260 mg/m2 on Day 1 q Q3W
x 6 cycles or
8 cycles if patient achieved CR
Patient Characteristics
Number of Patients Enrolled 47
Age, mean (Range) 66 (42 – 84)
n %
ECOG Performance Status01
389
8119
Prior TherapyPrior taxanePrior Chemotherapy > 12 monthsPrior Chemotherapy < 12 monthsSurgery
42434
44
90929
94
Site of Primary DiseaseEpithelial OvarianFallopian TubePeritoneum
3719
792
19
Stage at Baseline IC/IIB/IICIII/IIIA/IIIBIIICIV
47
2511
9155223
Teneriello JCO 2009
Efficacy Data64% Response Rate with Nab-paclitaxel
Monotherapy
Total Number of Eligible/Treated Subjects 44
n (%) 95% CI
Best ResponseComplete ResponsePartial ResponseStable Disease
SD > 6 monthsSD < 6 months
Progressive DiseaseClinical Benefit (CR + PR + SD > 6 months)Non-evaluable
15 (34%)13 (30%)14 (32%)6 (14%)8 (18%)2 (5%)
34 (77%)3
(20.1 – 48.1)(16.1 – 43.0)(18.1 – 45.6)
(0 – 10.7)
Time to Response, median (months) Range
1.3(0.5 – 4.8)
Duration of Response, median (months)Range
7.9(2.7 – 17.6) (6.7 –10.5)
Progression-free Survival, median (months) 8.5
Teneriello JCO 2009
Safety Data: Adverse Events
Most Common Grade 3/4 AEs
All Grade
n (%)
Grade 3
n (%)
Grade 4
n (%)
Hematological
Neutropenia 20 (47%) 6 (13%) 5 (11%)
Leukopenia 7 (15%) 6 (13%) --
Non-hematological
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%) --
Alopecia 40 (87%) -- --
Teneriello JCO 2009
Primary endpoints: Antitumor activity and safety
Secondary endpoints: Progression-free survival and overall survival
Phase II Study of nab-paclitaxel Plus Carboplatin in Patients with Recurrent Platinum-Sensitive Ovarian or Primary
Peritoneal Cancer
Benigno
Key Eligibility
• Recurrent ovarian or primary peritoneal cancer
• Platinum-sensitive• Measurable
disease
n = 41
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
Patient Characteristics
Number of Patients Enrolled 40 (38 evaluable)
Age, mean (Range) 62 (42 - 81)
n %
ECOG Performance Status01
355
8713
Prior TherapyPrior taxane / platinumPrior chemotherapy > 12 monthsPrior chemotherapy < 12 months
401425
1003563
Site of Primary DiseaseEpithelial OvarianFallopian Tube
391
982
Stage at Baseline IIB / IIC / IIIBIIICIV
9283
23707
Benigno
Dosing Information
Treatment Cycles Completed
>18 cyclesn (%)
13-17 cyclesn (%)
7-12 cyclesn (%)
6 cyclesn (%)
< 6 cyclesn (%)
Evaluable Patients38 TOTAL
51 pt active
4 10 14 5
Reason for Discontinuing
Phys or Pt discretion
Progressive disease
Toxicitiy
Type/ cycle
2
2
0
2
2
0
6
4
0
10
3
1
(G4 neurotoxity
cycle 6)
0
3
2
(G4 pneumonia cycle 5,
G3 hem cycle 4)
Benigno
• 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
Safety Data: Adverse Events
Most Common Grade 3/4 AEs
Grade 3
n (%)
Grade 4
n (%)
Hematological
Neutropenia 14 (34%) 3 (7%)
Anemia 4 (10%) --
Thrombocytopenia 2 (5%) --
Non-hematological
Fatigue 13 (32%) --
Carboplatin reaction 7 (17%) --
Nausea 2 (5%) --
Constipation 1 (2%) --
Fever 1 (2%) --
Shortness of breath 1 (2%) --
Neuropathy -- 1 (2%)
Benigno
Efficacy Data: SurvivalOver 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
Primary endpoints: Antitumor activity and safety
Secondary endpoints: Progression Free and Overall Survival
Phase II Evaluation of nab-paclitaxel in Recurrent or Persistent Platinum-Resistant Ovarian, Fallopian Tube, or
Primary Peritoneal Cancer
Key Eligibility
• Recurrent or persistent ovarian, peritoneal, fallopian tube carcinoma
• Platinum-resistant or refractory
• Paclitaxel-resistant or refractory
• Measurable disease
n = 49
nab-paclitaxel 100 mg/m2 on Days 1, 8, 15 q 28
Treatment until disease progression or
unacceptable toxicity
R.Coleman
Patient Characteristics
Age:
– 50-59 15 (36.6%)
– 60-69 14 (34.1%)
– 30-49 7 (17 %)
– 70-79 5 (12.2%) Performance Status:
– 0 28 (68.3%)
– 1 12 (29.3%)
– 2 1 ( 2.4%) Prior Therapy
– 1 Reg. 41 (100%)
– Immunoth 1
– Hormonal 2
Race:
– White 30 (73.2%)
– African American 8 (19.5%)
– Hispanic 2 ( 4.9%)
– Am Indian 1 ( 2.4%)
Site of Disease
– Ovary 35 (85.4%)
– Fallopian Tube 1 ( 2.4%)
– Peritoneum 5 (12.2%) Grade
– 1 5 (12.2%)
– 2 2 ( 4.9%)
– 3 34 (82.9%)
Cell Type:
– Serous Adeno 29 (72%)
R.Coleman
Efficacy Data23% Response Rate with nab-paclitaxel
Monotherapy
Responses reported in 41 of 49 patients: 8 patients still to be evaluated
N %
Responses
Partial Response 11 23.4
Stable Disease 17 36.2
Progressive Disease 17 36.1
Indeterminate 2 4.3
PFS > 6mo
No 30 63.8
Yes 16 34.0
Pending 1 2.1
R.Coleman
Status of Patients by Cycles Completed55% of patients received more than 3 cycles
# of Cycles Received n %
R.Coleman
Efficacy Data: Overall Survival and Progression-free Survival
R.Coleman
Progression-free Survival, median: 4.5 months Overall survival, median: 18.5 months
Safety Data: Adverse Events
No grade 4 toxicities Only 1 patient grade 3 neurosensory toxicity
AE, adverse event
Toxicity / Adverse Events
41 of 49 pts
Maximum grade, no. of patients
1 2 3 4
Hematological
anemia 20 (49%) 17 (41%) 1 (2%) 0 (0%)
neutropenia 4 (10%) 5 (12%) 5 (12%) 0 (0%)
leukopenia 16 (39%) 8 (20%) 1 (2%) 0 (0%)
thrombocytopenia 3 (7%) 0 (0%) 0 (0%) 0 (0%)
Non-hematological
neurosensory 11 (27%) 3 (7%) 1 (2%) 0 (0%)
constitutional 20 (49%) 10 (24%) 0 (0%) 0 (0%)
gastrointestinal 18 (44%) 7 (17%) 2 (5%) 0 (0%)
metabolic 7 (17%) 2 (5%) 2 (5%) 0 (0%)
pain 10 (24%) 0 (0%) 2 (5%) 0 (0%)
R.Coleman
GOG Phase II Trials in Platinum-Resistant Ovarian Cancer: Active Agents (126 Queue)
Regimen n RR PFS Median OS Number of Cycles
Toxicity
Paclitaxel Weekly
80mg/m2
49 21% 3.6 mo 13 mo Up to 13 cycles
5 patients discontinued for toxicity
Docetaxel 100mg/m2
q3w
58 22.4% 2.5 mo NR ANC: 75% Gr IV
Febrile: 30%
Dose reduction: 36%
Neuro: 3 grade III
Pemetrexed
900mg/m2 q3w
51 21% 2.9 mo 11.4 mo Grade 3/4
neutropenia 42%
leukopenia 25%
nab-paclitaxel 100 mg/m2
weekly
D1, 8, 15 of q4w
48
7 not yet
reported
2 active
23.4% 4.5 mo 18.5 mo 2 Patients are still being treated Cycle 21
No Grade 4 toxicity
No treatment related deaths
Primary endpoints: Duration of objective response, safety
Secondary endpoints: Duration of progression-free survival, overall survival, quality of life
Phase II Study of Nab-paclitaxel with Bevacizumab in Patients with Recurrent Platinum-Resistant Primary Epithelial
Ovarian or Primary Peritoneal Cancer
Tillmans
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 10mg/kg
Days 1, 15 Q28d
Treatment until disease progression or
unacceptable toxicity
Efficacy Data48% response rate with
Nab-paclitaxel + Bevacizumab
Best Overall Response
Not Done PD PR SD
Treatment Cycle n % n % n % n %
4 16 33.3 19 39.6 13 27.1
7 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
Response rate: 48% Stable Disease: 25%
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 (%)
Hematological
Neutropenia 13 (27%) 5 (10%) --
Anemia 11 (23%) 1 (2%) --
Non-hematological
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%) -- --
* One Death, NOS Tillmanns
Phase II Single Agent Bevacizumab Efficacy and Safety
GOG 170-DBurger et al
N = 62
Cannistra et al*N = 44
ORR 13 (21%) 7 (15.9%)
6 Month PFS 40.3% 27.8%
≥ Grade 3 Toxicity
GI Perforation - 5 (11.4%)
Thrombosis / Embolism1 (1.6%)
(Venous)
4 (9.0%)
(3 Arterial 1 VTE)
HTN 6 (9.7%) 6 (13.6%)
Cerebral ischemia - 1 (2.3%)
Proteinuria 1 (1.6%) -
Death Suspected as Related to Bevacizumab
- 3 (6.8%)
*Trial terminated prematurely due to incidence of GI perforation.*Trial terminated prematurely due to incidence of GI perforation.
Burger RA, et al. Burger RA, et al. J Clin OncolJ Clin Oncol. 2007;25(33):5165-5167; Cannistra SA, et al. . 2007;25(33):5165-5167; Cannistra SA, et al. J Clin Oncol.J Clin Oncol. 2007;25(33):5180-5186. 2007;25(33):5180-5186.
Nab-paclitaxel Gynecologic Malignancy Trials Ongoing
Study Description Principal Investigator
Status
nab-paclitaxel + GM-CSF in Platinum-resistant ovarian cancer
R. Swensen 8 of 30 patients enrolled
Phase I Trial of Intraperitoneal nab-paclitaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity
M. Cristea 2 of 20 patients enrolled
nab-paclitaxel in Recurrent or Persistent Cervical Cancer
D. Alberts GOG 2-stage trial
1st stage (24 pts) met RR to advance to 2nd stage
Ovarian Cancer Treatment Paradigm
Where does nab-paclitaxel fit into this treatment paradigm?
SurgeryFront-line
Platinum-based regimen
Non-platinum-based regimen
1st relapsed Platinum-based
regimen
Platinum-sensitive
Platinum-resistant
Platinum-sensitive = >6 months before recurrence after front-line platinum-based chemo
#3
#1
#3
#2
Platinum-resistant = <6 months before recurrence after platinum-based chemo
• Carbo + Taxol ± Avastin
Non-platinum-based
regimens
•Carbo + Taxol ± Avastin•Carbo + Gemzar ± Avastin•Carbo + Doxil•Doxil + Trabectedin
•Doxil•Hycamtin
•Doxil•Hycamtin