1. EFFECT: A randomized phase II study to evaluate the EFficacy and impact on Function of two different doses of nab-paclitaxEl in elderly patients with advanCed breasT cancer
Laura Biganzoli
Oncologia Medica
Nuovo Ospedale di Prato
Istituto Toscano Tumori

2. EFFECT: A randomized phase II study to evaluate the EFficacy and impact on Function of two different doses of nab-paclitaxEl in elderly patients with advanCed breasT cancer
Age ≥ 65
Locally recurrent or metastatic HER2-neg breast cancer or HER2-
positive but considered not eligible for anti-HER2 therapy
No prior CT for advanced breast cancer
Measurable or evaluable disease
N=156
nab-paclitaxel 100mg/m2
day 1, 8, 15 q 28
nab-paclitaxel 125mg/m2 R
till disease progression or toxicity A B
Stratification factors:
Age vs ≥ 75 yrs
Diabetes yes, no  
G3-4 CIRS-G yes, no
IADL deficient yes, no
Prior adj taxanes yes, no

3. Study endpoints Primary endpoint:
Event-free survival (EFS) where an event is either disease progression or death or decline in functional status
Functional status will be measured using ADL and IADL at baseline, prior to each treatment cycle, at treatment discontinuation and at 4 weeks after the last cycle of chemotherapy
An ‘event’ is defined as a decrease in at least 1 point with respect to values observed at the baseline on the ADL and/or IADL scales, considered by the investigator to be treatment related, and confirmed at the subsequent cycle
ADL, Activity of daily living; IADL, Instrumental ADL

4. Secondary endpoints Objective response rate (ORR)
Clinical benefit rate (CBR)
Progression free survival (PFS)
Overall survival (OS)
Incidence of Adverse events (defined by CTCAE v4.0)

5. Statistical considerations
This study is not designed to provide adequate power for a two arm comparison.
The evaluation of the best appropriate dose will be based on clinical/general conditions.
In each treatment arm, the null hypothesis to be tested is that the median of the EFS time is equal to or less than 7 months. The alternative hypothesis is that the median of the EFS time is equal or greater than 12 months.
The protocol will aim to accrue up to 156 patients with 78 patients randomized to Arm A, and 78 patients to Arm B.
The cut-off date for primary analysis will be 12 months after the enrollment of the last study patients

6. Patient disposition Accrual completed (22 Sept 2016)
Randomized patients =160 (80/arm)
Modified ITT = 79 patients/arm*
Safety = 79 patients/arm
* 1 patient/arm never started treatment

7. Patient characteristics° (modified ITT population)
100 mg/m2
N=76
125 mg/m2
N=77
Median age, y (range)
72 (65-84)
73 (65-88)
Median ECOG performance status (range)
0 (0-2)
Marital status n(%)
- single/married
- separate or divorced/widowed
6 (8)/ 56 (74)
-/ 14 (18)
8 (10)/ 51 (66)
2 (3)/ 16 (21)
Education n(%)
- illitterate/elementary school/middle school
- high school/university
1(1)/ 35 (46) /26 (34)
10 (13)/ 4 (5)
-/ 46 (60)/ 20 (26)
10 (13)/1 (1)
Caregiver presence n(%)
34 (45)
30 (39)
ADL impaired n(%)
14 (18)*
20 (26)
IADL impaired n(%)
21 (28)*
° patients who received ≥ 1 dose of nab-paclitaxel and have documented interruption of study treatment
Data cleaning is ongoing
* missing value (n=2)

8. Patient and tumor characteristics
100 mg/m2
N=76
125 mg/m2
N=77
Hormone receptor status*
- ER and PgR negative n(%)
- ER and/or PgR positive n(%)
8 (11)
66 (87)
8 (10)
65 (84)
HER2 positive**
2 (3) -
Prior neo/adjuvant chemotherapy
- anthracycline +/- taxane based
- taxane-based
37 (49)
22 (29)
11 (14)
45 (58)
9 (12)
Anti-HER2 adjuvant therapy
Site of metastatic disease
- non visceral only
- visceral only
- visceral+non visceral
21 (28)
5 (7)
50 (66)
24 (31)
44 (57)
*missing value n=2 (arm A) n=4 (arm B); ** missing value n=5 (arm A) n=10 (arm B);

9. Treatment administration and compliance
100 mg/m2
N=76
125 mg/m2
N=77
Delivered cycles n
544
412
Median number of cycles (range)
6 (1-28)
6 (1-11)
Patients with dose reductions n(%)
54 (71)
61 (79)

10. Haematological adverse events (AEs)
100 mg/m2
n=76
125mg/m2
n=77
Grade 2
n(%) 3 4 5
Anemia
25 (33)
2(3) -
29(38)
Leucopenia
18 (24)
7(9)
23(30)
13(17)
1(1)
Neutropenia
12(16)
3(4)
Incidence of ≥10% for G2 or any G3-5 in either arm

11. Non-haematological AEs
100 mg/m2
n=76
125mg/m2
n=77
Grade 2
n(%) 3 4 5
Fatigue
23(30)
7(9)
2(3) -
35(45)
4(5)
Peripheral neuropathy
10(13)
3(4)
21(27)
8(10)
Nausea/vomiting
8(11)
1(1)
12(16)
Diarrhoea
5(6)
Fever
Febrile neutropenia NA
Infection
Dyspnoea
Hepatotoxicity
Renal toxicity

12. Planned final analysis
At present 17 patients without events have a follow-up time <1 year
3 patients are still on treatment
Planned submission to SABCS

13. Accrual by center CENTER N . patients Opedale A.Perrino Brindisi 30*
AO Ospedali Riuniti Ancona 23
Spedali Civili Brescia 18
AO  S.Maria della Misericordia Udine 16
AO Papa Giovanni XXIII Bergamo 15
CRO di Aviano 14
AUSL centro-Prato 13
ASL Frosinone 8
IOV Padova 5
Ospedale Vito Fazzi Lecce 4
Fondazione S.Maugeri Pavia 5*
IEO 3
AUSL 12 Viareggio
Universita’di Napoli Federico II 2
AOU Integrata Verona 1
TOTAL
160
*1 pt never started per protocol therapy

14. Back up

15. The Breast 2011

16. Sopravvivenza libera da progressione
Valutazione dello sperimentatore
Valutazione indipendente
PFS mediana (mesi)
A nab q3
11,0 mesi
B nab 100
12,8 mesi
C nab 150
12,9 mesi
D docetaxel
7,5 mesi
PFS media
Totale vs. D
0,0498
B vs. C NS
C vs. D
0,0065
Sopravvivenza libera da progressione
Mesi
Gradishar JCO 2009 16

17. Background and rationale
Elderly patients are at higher risk of chemotherapy related side effects
Weekly taxanes are generally recommended treatment options in older metastatic breast cancer
Fatigue and neurotoxicity are dose-limiting toxicity for docetaxel and standard paclitaxel with a possible negative impact on function
Nab-paclitaxel compares favorably with paclitaxel and docetaxel both in terms of safety and efficacy
Median time to resolution to G<3 neurotoxicity is shorter with nab-paclitaxel than with conventional taxanes

18. Background and rationale (I)
Limited amount of data available on activity and safety of nab-paclitaxel in older patients
Aapro et al. The Breast 2011