Randomized, optimal dose finding, Phase II Study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer（ABROAD）#1070

Fumikata Hara1, Masahiro Kitada2, Masato Takahashi3, Yuichiro Kikawa4, Hiroaki Kato5, Eiko Sakata6, Yoichi Naito7, Yoshie Hasegawa8, Tsuyoshi Saito9,
Tsutomu Iwasa10, Junji Tsurutani11, Naruto Taira12, Tsutomu Takashima13, Kosuke Kashiwabara14, Tomohiko Aihara15, Hirofumi Mukai7
1Cancer Institute Hospital of JFCR, Koto, Tokyo, Japan; 2Asahikawa Medical University Hospital, Asahikawa, Japan; 3NHO Hokkaido Cancer Center, Sapporo, Japan; 4Kobe City Medical Center General Hospital, Kobe, Japan; 5Teine Keijinkai Hospital, Sapporo, Japan; 6Niigata City General Hospital, Niigata, Japan;
7Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan; 8Department of Breast Surgery, Hirosaki Municipal Hospital, Hirosaki, Japan; 9Japanese Red Cross Saitama Hospital, Saitama, Japan; 10Kindai University Faculty of Medicine, Osaka-Sayama, Japan;
11Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan; 12Okayama University Hospital, Okayama, Japan; 13Osaka City University Graduate School of Medicine, Osaka, Japan; 14Department of Biostatistics, School of Public Health, the University of Tokyo, Tokyo, Japan; 15Aihara Hospital, Minoh, Japan

BackgroundStatistics

 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-PTX.
 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 higherCIPN.
 Herein, we conducted multicenter randomized controlled study to evaluate optimal doseof nab-PTX comparing lower dose (LD or MD) to standard dose (SD).

Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 ormore 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.

Enrolled (n=141)

Study design
SD260 (standard dose) arm:
Nab-Paclitaxel: 260 mg/m2, q3w IVMulticenter rP2 study

Patients with
HER2-negative MBC
in 1st or 2nd line
Chemotherapy
for MBC (N = 138)
Stratification factors• Hormone receptor• DFI• Institution• Prior chemotherapy• Prior taxane

RMD220 (Medium dose) arm
Nab-Paclitaxel: 220 mg/m2, q3w IV

SD260 (n=47)

MD220 (n=46)

FAS (n=47)

FAS (n=45)
No initiation of
nab-paclitaxel (n=1)

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=4)• Death (N=0)• Others (n=2)

LD180 (n=48)
FAS (n=47)

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

 Primary endpoints
Progression-Free Survival (PFS), Incidence of Grade 3/4 peripheral neuropathy
 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-QoLSNPs associated with CIPN (Translational research) Key eligibility criteria
Female and aged between 20 and 75 years,
PS 0 or 1 (ECOG scale)
Never received or 1 regimen of cytotoxic chemotherapy for MBC.
Adequate organ function
Peripheral neuropathy ≤ grade 1

SD260(n=47)

MD220(n=45)61.0 (34–74)

LD180(n=48)
58.5 (35–74)

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
Chemotherapy for MBC
Yes
No
Prior taxane therapy
Yes
No

0.82

0.88
0.53

11 (22.9%)
27 (56.3%)
10 (20.8%)
0.96

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%)

nSD260 (n=47)

6.66

4.82-8.82

41

No. Pts

39

MD220 (n=45)

7.34

4.59-8.92

38

Response

19LD180 (n=48)

6.82

4.43-9.15

43

 Dose reduction

17 (35.4%)
31 (64.6%)%

95% CIn%

LD180

95% CI

3448.7(32.4, 65.2)

15n%

95% CI

37.8(22.5, 55.2)

3744.1(27.2, 62.1)

14

Treatment Arm
SD260 (n=47)

20

Dose reduction

nYes%

MD220 (n=45)

95% CIn19 40.4(26.4, 55.7)

1

14 29.82

5

By 1st course%

LD180 (n=48)

95% CIn%

95% CI

11 24.4(12.9, 39.5)

7

14.6

(6.1, 27.8)(17.3, 44.9)

8

17.8

(8, 32.1)

6

12.5(4.7, 25.2)

10.6(3.5, 23.1)

36.7(1.4, 18.3)

12.1(0.1, 11.1)

00.0(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

58.5(2.4, 20.4)

24.4(0.5, 15.1)00.0(0, 7.4)

No. of dose reduction

06100

1218
Time from randomization (months)

8060
40
2003691224100

 CIPN G3/4

1518

Time from randomization (months)

 CIPN G2/3/4

60

 Adverse events

40

Events20003

69

Time from randomization (months)

Hazard ratio (HR)

Selection1)

95% CI

MD220 vs SD260

0.73(0.42, 1.28)

Drop SD260 due to HR<0.75

LD180 vs SD260

0.77(0.42, 1.28)

Equivalent

LD180 vs MD220
0.96(0.42, 1.28)
1) If HR <0.75 or >1.33, the inferior one will be dropped.

Equivalent

Logistic regression Incidence (%)

12

No. of pts
Leukopenia
Neutropenia
Hemoglobin
ALT elevation
Fatigue
Sensory
neuropathy
Arthralgia
Myalgia
RashAnorexia

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)

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)

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)

43 (91.5) 15 (31.9) 38 (84.4)

4 (8.9)39 (81.3)

4 (8.3)35 (74.5)
34 (72.3)
16 (34.1)
24 (51.1)

5 (11.1)
3 (6.7)0 (0.0)0 (0.0)27 (56.3)
19 (39.6)
12 (25.0)
20 (41.7)

0 (0.0)0 (0.0)0 (0.0)1 (2.1)4 (8.5)6 (12.8)
0 (0.0)1 (2.1)30 (66.7)
26 (57.8)
14 (31.1)
23 (51.1)

Conclusions

 Second selection (peripheral sensory neuropathy)
Selection2)

Estimate

95% CI

SD260

29.5

(18.7, 43.2)

Not candidate for 2nd selection

MD220

14.0

(8.8, 21.6)

Drop MD220 due to estimatedincidence 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 dose

By treatment course

80

Estimate

P-value

0.93
12 (26.7%)
24 (53.3%)
9 (20.0%)

Measurable

MD220

Stratified log-rank test: 0.429

Cox regression

0.22

13 (27.7%)
27 (57.4%)
13 (27.7%)

No.
events First selection (equivalence)Median age, yrs (range)
59.0 (36–75)

95% CI(mon)

400

LD180 (Low dose) arm
Nab-Paclitaxel: 180 mg/m2, q3w IV
These treatments were repeated until PD or unacceptable toxicity

600Patients characteristics

MBC: metastatic breast cancer, PD: progressive disease, DFI: Disease free interval•••••

Randomized (n=141)

Incidence of G3/4 neuropathy (%)

 To evaluate non-inferiority of low dose nab-PTX compared to current 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), and Patient Reported Outcomes(PROs) between the three different doses of nab-PTX.

80SD260MedianPFS(mon)Incidence of G2/3/4 neuropathy (%)

CONSORT diagramTreatment Arm PFS

100

The study was planned to ensure to select MD220 with a probability of 70%, when the one-year PFSs ofthe 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 40 patients per group with expected registration period of twoyears and mean follow-up period of two years, and finally 42 patients per group was chosen.

Study objectives

 Overall response rateResults
Progression-free survival (%)

Comprehensive SupportProject For OncologicalResearch of Breast CancerLD180Fumikata Hara, M.D., Ph.D., email: fumikatahara@gmail.com Clinical trial Registration Information: UMIN (http://www.umin.ac.jp/) Study ID: C000012429

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

Acknowledgement
To all of the patients who participated in ABROAD and their families
To the investigators and research coordinators at the 41 institutions and CSPOR-BC.
This study was funded by Comprehensive Support Project for Oncology Research of Breast Cancer (CSPOR-BC). All decisions
concerning the planning, implementation and publication of this study were made by the executive committee of this study.
Printed by