Randomized, optimal dose finding, Phase II Study oftri-weekly nab-paclitaxel in patients with metastatic
breast cancer（ABROAD）
Masato Takahashi1, Fumikata Hara2, Masahiro Kitada3, Yuichiro Kikawa4, Hiroaki Kato5,
Eiko Sakata6, Yoichi Naito7, Yoshie Hasegawa8, Tsuyoshi Saito9, Tsutomu Iwasa10, Junji
Tsurutani11, Naruto Taira12, Tsutomu Takashima13, Kosuke Kashiwabara14, TomohikoAihara15, Hirofumi Mukai7;
1NHO Hokkaido Cancer Center, Sapporo, Japan; 2Cancer Institute Hospital of JFCR, Koto, Tokyo, Japan; 3Asahikawa Medical UniversityHospital, Asahikawa, Japan; 4 Kobe City Medical Center General Hospital, Kobe, Japan an; 5Teine Keijinkai Hospital, Sapporo, Japan;
6Niigata City General Hospital, Niigata, Japan; 7 National Cancer Center Hospital East, Kashiwa, Japan; 8 Hirosaki Municipal Hospital,Hirosaki, Japan; 9Japanese Red Cross Saitama Hospital, Saitama, Japan; 10 Kindai University Faculty of Medicine, Sayama, Japan ; 11
Advanced Cancer Translational Research Institute Showa University, Shinagawa, Japan; 12Okayama University Hospital, Okayama, Japan;
13Osaka City University Graduate School of Medicine, Osaka, Japan; 14 The University of Tokyo Hospital, Bunkyou, Japan ; 15Aihara
Hospital, Minoh, Japan

Conflict of Interest disclosure slide for representative speakers or investigators
Research fundName of lead presenter□scientific research fund □contract □donation

Sponsor■other （ CSPOR-BC ） □N/A

Masato Takahashi

Institution or company/position
No

employee or adviser of company and/or profit-making organization■

profit of stock■

patent fee■

lecturer fee□manuscript fee■

research expenses from company■

contributions or endowed chair■fees of testimony, judgment, comment, etc.

■

presents or other payment■

representative of organization for clinical study receiving research expenses from company■

Name of principal investigator

Taiho co ltd.

Fumikata Hara

If yes, please specify the name of company, organization, your status.

Astra Zeneca, Eisai, Eli Lilly, pfizer

Institution or company/position
No

employee or adviser of company and/or profit-making organization■

profit of stock■

patent fee■

lecturer fee□manuscript fee■

research expenses from company■

contributions or endowed chair■fees of testimony, judgment, comment, etc.

■

presents or other payment■

representative of organization for clinical study receiving research expenses from company■NHO Hokkaido Cancer Center / Deputy DirectorCancer Institute Hospital of JFCR / Chief, Breast
Medical Oncology

If yes, please specify the name of company, organization, your status.

Kyowa-Kirin, pfizer

Background Although nab-paclitaxel (nab-PTX) has shown superior efficacy
compared to conventional paclitaxel in metastatic breast cancer (MBC),
chemotherapy induced peripheral neuropathy (CIPN) was more
frequently observed in nab-PTX1).

 In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2)
every 3 weeks (q3w) demonstrated a good objective response rate
(39.5%) without grade 3 or higher CIPN2).
 Herein, we conducted multicenter randomized controlled study toevaluate optimal dose of nab-PTX comparing lower dose (Low dose: LDor Medium dose: MD) to standard dose (SD).

Study design
Multicenter rP2 study

Patients withHER2-negative MBC
in 1st or 2nd line
Chemotherapy
for MBC (N = 138)
Stratification factors• Hormone receptor• DFI• Institution• Prior chemotherapy• Prior taxane
MBC: metastatic breast cancer, PD: progressive disease
DFI: Disease-free interval

SD260 (standard dose) arm:
Nab-Paclitaxel: 260 mg/m2, q3w IVR

MD220 (Medium dose) arm
Nab-Paclitaxel: 220 mg/m2, q3w IV
LD180 (Low dose) arm
Nab-Paclitaxel: 180 mg/m2, q3w IV

These treatments were repeated until PD or unacceptable toxicity

Study Objectives• To evaluate non-inferiority of low dose nab-PTX compared tocurrent standard dose 260mg/m2 of nab-PTX in 1st or 2nd line
chemotherapy for metastatic breast cancer.
• To compare adverse events including chemotherapy-induced
peripheral neuropathy (CIPN), health-related QOL (HRQOL), andPatient Reported Outcomes (PROs) between the three different
doses of nab-PTX.

EQ-5D (EuroQol 5 Dimension), EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer QLQ-C30),
PNQ (Patient Neurotoxicity Questionnaire), PHRF-SCL(Public Health Research Foundation- Stress Check List), CES-D (The Center
for Epidemiologic Studies Depression Scale)Endpoints
 Primary endpoints••

Progression-free Survival (PFS)
Incidence of Grade 3/4 chemotherapy induced
peripheral neuropathy (CIPN) Secondary endpoints•
•
•
••
•

Time to treatment failure (TTF)
Overall survival (OS)Overall response rate (ORR)
Disease control rate (DCR)
Adverse events (AEs)
Health-related quality of life (HR-QoL)- FACT-G, FACT-Taxane, EQ-5D, PNQ, CFS, BCSS
(Detailed results of HR-QoL will be planed to present at SABCS this year.)•

SNPs associated with CIPN (Translational research)

Key patient eligibility criteria• Female and aged between 20 and 75 years• PS 0 or 1 (ECOG scale)• Histologically confirmed breast cancer• Metastatic/ advanced breast cancer• Never received or 1 regimen of cytotoxic chemotherapy for MBC• Adequate organ functions• Peripheral neuropathy ≤ grade 1

Statistics Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for
PFS was less than 0.75 or more than 1.33, the inferior dose was dropped.
Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%
estimated by the logistic regression, that dose was also dropped.
 The study was planned to ensure to select MD220 with a probability of 70%,
when the one-year PFSs of the three doses are all 30% and the grade 3
neurotoxicity rates of SD260, MD220 and LD180 are 15%, 8% and 0.1%,
respectively, which requires 42 patients per group with expected registration
period of two years and mean follow-up period of two years, and finally 46
patients per group was chosen.

CONSORT diagram
Enrolled (n=141)
Randomized (n=141)
SD260 (n=47)

MD220 (n=46)

LD180 (n=48)

FAS (n=47)

FAS (n=45)
No initiation ofnab-paclitaxel (n=1)

FAS (n=48)

Treatment
discontinuation• Progression (n=35)• AEs (n=5)• Patients’ will (n=6)• Death (N=0)• Others (n=2)

Treatment
discontinuation• Progression (n=28)• AEs (n=4)• Patients’ will (n=13)• Death (N=0)• Others (n=0)

Treatment
discontinuation• Progression (n=34)• AEs (n=3)• Patients’ will (n=9)• Death (N=0)• Others (n=2)

FAS: Full analysis set

Patients characteristics (FAS: Full analysis set)
SD260
(n=47)

MD220(n=45)

LD180(n=48)

P-value

59.0 (36–75)

61.0 (34–74)

58.5 (35–74)

0.82

PS (ECOG)
0138 (80.9%)9 (19.1%)

34 (75.6%)
10 (22.2%)

31 (64.6%)
17 (35.4%)

ER-positive
PgR-positive

38 (80.9%)
29 (61.7%)

34 (75.6%)
22 (48.9%)

37 (77.1%)
27 (56.3%)

Disease-free interval
De novo≥ 2 years< 2 years

13 (27.7%)
27 (57.4%)
7 (14.9%)

12 (26.7%)
24 (53.3%)
9 (20.0%)

11 (22.9%)
27 (56.3%)
10 (20.8%)

Median age, yrs (range)

Chemotherapy for MBC
Yes
No
Prior taxane therapy
Yes
No

0.22

0.88
0.53
0.930.96
12 (25.5%)
35 (74.5%)

11 (24.4%)
34 (75.6%)

13 (27.1%)
35 (72.9%)
0.88

19 (40.4%)
28 (59.6%)

17 (37.8%)
28 (62.2%)

17 (35.4%)
31 (64.6%)

Progression-free Survival (FAS)MedianPFS(mon)95% CI(mon)No.
eventsSD260 (n=47)

6.66

4.82-8.82

41

MD220 (n=45)

7.34

4.59-8.92

38

LD180 (n=48)

6.82

4.43-9.15

43

Progression-free survival (%)

10080

60
Stratified log-rank test: 0.429

4020006121824

Incidence of G3/4 neuropathy (FAS)

Incidence of G3/4 neuropathy (%)

100806040
200036912Time from randomization (months)

15

18

Incidence of G2/3/4 neuropathy (FAS)100

Incidence of G2/3/4 neuropathy (%)

80

60

40
20003

69

Time from randomization (months)

12

Selection of optimal dose

First selection (equivalence)

Cox regression

Selection1)

Hazard ratio (HR)
Estimate

95% CI

MD220 vs SD260

0.73(0.42, 1.28)

Drop SD260 due to HR<0.75

LD180 vs SD260

0.77(0.47, 1.28)

Equivalent

LD180 vs MD220

0.96(0.56, 1.66)

Equivalent1) If HR <0.75 or >1.33, the inferior one will be dropped.

Second selection (peripheral sensory neuropathy)

Logistic regressionSelection2)

Incidence (%)
Estimate95% CI

SD260

29.5(18.7, 43.2)

Not candidate for 2nd selection

MD220

14.0(8.8, 21.6)

Drop MD220 due to estimated incidence rate
exceeding 10%LD180

5.9(2.3, 14.6)

Retain LD1802) The dose with its estimated incidence rate exceeding 10% will be dropped.

Finally selected doseLD180

Incidence of G3/4 neuropathy (%)

Second selection (Incidence of CIPN)
Estimated incidence rate of grade 3/4 neurotoxicity
by the logistic regression: cut off 10%

Logistic regressionestimation
1486LD180MD220HD260
15

Overall Response Rate (FAS)
Treatment
SD260Measurable

nNo. Pts

39Response

19%95% CI

MD220n%95% CI

3448.7(32.4, 65.2)

15LD180n%95% CI

37.8(22.5, 55.2)

3744.1(27.2, 62.1)

14

Dose reduction (FAS)

Treatment Arm
SD260 (n=47)

MD220 (n=45)

LD180 (n=48)

Dose reduction

n%95% CI

n%95% CI

n%95% CI

Yes

1940.4(26.4, 55.7)

1124.4(12.9, 39.5)

714.6(6.1, 27.8)

11429.8(17.3, 44.9)

817.8(8, 32.1)

612.5(4.7, 25.2)

25

10.6

(3.5, 23.1)

3

6.7(1.4, 18.3)

12.1(0.1, 11.1)

By 1st course00.0(0, 7.5)00.0(0, 7.9)

00.0(0, 7.4)

By 2nd course

36.4(1.3, 17.5)

12.2(0.1, 11.8)

00.0(0, 7.4)

By 3rd course

48.5(2.4, 20.4)

24.4(0.5, 15.1)

00.0(0, 7.4)

No. of dose reduction

By treatment course

Adverse Events (FAS)
EventsNo. of pts
Leukopenia
Neutropenia
Hemoglobin
ALT elevation
Fatigue
Sensory neuropathy
Arthralgia
Myalgia
Rash
Anorexia

SD260: n, (%)
Any
Grade≥3n =47
31 (66.0)
9 (19.1)
27 (57.4)
12 (25.4)
27 (57.4)
1 (2.1)26 (55.3)
1 (2.1)38 (80.9)
1 (2.1)43 (91.5)
15 (31.9)
35 (74.5)
4 (8.5)34 (72.3)
6 (12.8)
16 (34.1)
0 (0.0)24 (51.1)
1 (2.1)

MD220: n, (%)
Any
Grade≥3n =45
35 (77.8)
12 (26.6)
33 (73.3)
17 (37.7)
22 (48.9)
1 (2.2)20 (44.4)
2 (4.4)35 (77.8)
0 (0.0)38 (84.4)
4 (8.9)30 (66.7)
5 (11.1)
26 (57.8)
3 (6.7)14 (31.1)
0 (0.0)23 (51.1)
0 (0.0)LD180: n, (%)
Any
Grade≥3n =48
29 (60.4)
7 (14.6)
24 (50.0)
7 (14.6)
28 (58.3)
2 (4.2)18 (37.5)
0 (0.0)34 (70.8)
0 (0.0)39 (81.3)
4 (8.3)27 (56.3)
0 (0.0)19 (39.6)
0 (0.0)12 (25.0)
0 (0.0)20 (41.7)
1 (2.1)

Conclusions

 Low dose nab-PTX at 180 mg/m2/3 weeks could
be an optimal dose with good clinical efficacy andtolerability for patients with MBC.

Acknowledgement
To all of the patients who participated in ABROAD andtheir families
To the investigators and research coordinators at the 41
institutions and CSPOR-BC.
The research fund was provided to CSPOR-BC by Taiho
Pharmaceutical Co., Ltd under the study contract. All decisions
concerning the planning, implementation and publication of thisstudy were made by the executive committee of this study.