1. ABRAMYO Phase I-II study of weekly nab paclitaxel in combination with liposomal encapsulated doxorubicin in patients with HER2 negative MBC
Alessandra Fabi

2. Rationale of encapsulated liposomal doxorubicin plus nab-paclitaxel association
✪ The combination of anthracyclines and taxanes is among the most active in metastatic breast cancer treatment, to date independently by biological histotype.
✪ The use of this combination is limited by myelosuppression, emesis, stomatitis, allergic reactions and, above all, cumulative cardiotoxicity.
Activity as single agents of both drugs and weekly combination showed a better tolerability with a good activity.
Improving outcome of both single agent compared respectively to anthra and paclitaxel
A. Fabi

3. nano-particles regimen
SCHEDULE
nano-particles regimen
Max L-doxo 900 mg/mq
Primary endpoints
PHASE I:
-Identification of the appropriate dose level for the combination (MTD).
PHASE II:
-PFS
Secondary endpoints
ORR (CR and PR)
Safety and tolerability
Duration of Response
Clinical Benefit (CR+PR+SD> 6 mesi)
Overall survival (OS)
A. Fabi

4. Fase I Fase II ongoing Roma (Istituto Regina Elena - Roma)
Napoli (Universita` Federico II - Napoli)
Fase II
ongoing

5. Main inclusion criteria
Histologically or cytologically confirmed HER-2 negative, newly diagnosed breast cancer
Metastatic breast cancer with measurable disease (by RECIST criteria)
No prior chemotherapy for metastatic disease
≥12 months since adjuvant taxanes and/or anthracyclines therapy
Patients not candidates for endocrine therapy
Not more than 2 metastatic endocrine therapies
Previous anthracycline (adjuvant setting) maximum dose of doxorubicin 360 mg/mq and epirubicin 480 mg/mq
Absence of brain metastases
ECG and LVEF will be evaluated at baseline, then q 2 cycles during phase I and q 4 cycles during phase II.
A. Fabi

6. Statistical Analysis
The total patient sample size of Phase I: min 9 max 18 patients.
Total patient sample size for Phase II - This part of the study is designed as a phase II trial according to the design described by A’Hern . A sample size of 62 patients is considered sufficient to give an 80% probability of rejecting a baseline 6-months PFS rate of 60% with an exact 5% one-sided significance test when the true 6-months PFS rate was 75%).
The drug regimen will be considered for further studies if at least 44 patients are free from progression at 6 months.
A. Fabi

7. Patient Characteristics
STEP
Pts
Age
Diagnosis
DFS
yrs
CT neo/adj
HT adj
ER/PR
KI 67%
Line HT met
Metastatic Sites % PC 54
mag-08
5.5
E+T-> CMF
TAM
80/10 35 1 3 MM 72
apr-85 23 -
50/5 40 2
PNG 63
ago-90 4
CMF AI
70/80 25
SMD
mar-12
3.5
50/50 30
CCA 70
apr-12
EC-T
60/55 20 FA 46
dic-14
40/40 50
MMS
lug-13
1.5
90/60
ADE 43
AC-T NL 39
mag-15
80/30 55
SDB 37
0/0 80  - AA 52
lug-05 10
FAC
 10/20
10  SC 53
ott-05
10.2
FEC -> T
TAM-AI
 25/25
25  I II
III
I - Nab-pacltaxel 100 mg/mq + L-Doxo 20 mg/mq 1,8,15 q 28
II - Nab-pacltaxel 125 mg/mq + L-Doxo 20 mg/mq1,8,15 q 28
III - Nab-pacltaxel 125 mg/mq + L-Doxo 25 mg/mq 1,8,15 q 28
A. Fabi

8. FIRST CYCLE main toxicity for patient
Pts
STEP
Neutro
Anemia
Leuco
Asthenia
Nausea
Vomiting
Diarrhea
Mucositis
Neuropathy 3 I
G1-G1-G3
G1-G1
 G2-G1-G3
 G1-G1- - -   -
G2- 6 II
G3-G4*-G3-G4-G4
 G2-G3*-G3-G3-G3-G2
G1-G1-
G1-
III
G1-G1-G4 G1
G1-G2-G1
Afebrile
^1 patient reported G4 afebrile neutropenia lasting > 5 days = DLT
I Nab-pacltaxel 100 mg/mq + L-Doxo 20 mg/mq 1,8,15 q 28
II Nab-pacltaxel 125 mg/mq + L-Doxo 20 mg/mq1,8,15 q 28
III Nab-pacltaxel 125 mg/mq + L-Doxo 25 mg/mq 1,8,15 q 28

9. Main Toxicity for Patient by StepII
III
Patient PC MM
PNM
SMDR
CCA FA
MMS
SCDE NL
DBS AA SC
Neutropenia G3 G1
 G1
G4*^ G4
Febrile Neutropenia
Anemia G2
Leukopenia
 G2
G3 
Thrombocytopenia
Asthenia
Nausea
Vomiting
Diarrhea
Mucositis
Neurological toxicity
Hypertransaminasemia
Afebrile ^1 patient reported G4 afebrile neutropenia lasting > 5 days = DLT
Total alopecia in all patients
Total cycle 101

10. Main Toxicity for Patient HypertransaminasemiaG1 G2 G3 G4
neutropenia
1 (8.3)
5 (41.7)
5(41.7)
Anemia
3 (25.0)
leukopenia
2 (16.7)
thrombocytopenia
Asthenia
Nausea
Vomiting
Diarrhea
Mucositis
Neurological
4 (33.3)
Hypertransaminasemia
Use og G-CSF in 36% of pts

11. Nab-paclitaxel 125 mg/mq + L-Doxo 25 mg/mq
MTD
Nab-paclitaxel 125 mg/mq + L-Doxo 25 mg/mq
1,8,15 q 28
Phase II

12. Metastatic site Response
Activity Phase I (total pts:12)
Pts
STEP
N. of cycles
Best Response for pt
Metastatic site Response 3 I
SD-PR-CR
CR: visceral
PR: visceral 6 II
SD-PD-PR-PR-PR/PR
PR: 2 soft tissues
PR: 1 liver
PR: 1 lung
III
6-6-11
PR-PR-SD
PR: 1 liver/soft t
PR: liver
Total Cycles: 101
A. Fabi

13. Dominant Metastatic site
Ongoing Phase II (total pts to date: 9)
Median age
Subtype
DFI median
Dominant Metastatic site
Median n. cycles
Response 51
(32-62)
4 TN
3 LB
2 LA
21 months
Visceral: 7
No Visceral: 2
8 (8-12+)
1 CR
5 PR
3 SD
A. Fabi