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