Transcript Diapositiva 1

#Abst1097#
wALT trial (Phase I-II): Weekly non-pegylated
liposomal anthracycline and taxane
combination in first-line breast cancer
chemotherapy
Authors: M. S. Rosati 1, C. Raimondi 1, S. Quadrini 1, R. De Sanctis 1,L. Stumbo 1,
B. Gori 1, E. Del Signore 1, M. P. Poleggi 2, M. Di Seri 1
2Oncology
DH, Tarquinia (VT); 1 University of Rome “Sapienza”, Dpt of ONCOLOGY A,
Policlinico “Umberto I”; Rome, ITALY
Why metastatic breast cancer is incurable?
Absolute or relative resistance?
•Gompertzian growth-model
•log-kill in Gompertzian like tumor
•dose-dense sequential regimen
ABSTRACT #1097#
Background: Weekly administration of proved efficacy agents, through different
pharmacodynamic-kinetic interactions, overcomes resistance with lower toxicities and
greater benefits and preservation of quality of life. Based on this assumption we designed
wALT (weekly liposomal-anthracycline and taxane) trial. Methods: Patients (pts) with
previously untreated metastatic breast cancer were eligible. Prior adjuvant anthracycline or
taxane exposure was permitted. We designed a phase I multicenter, open lable dosefinding study to examine the safety and efficacy of weekly combination (d 1,8,15 q4w) of
paclitaxel (n=28 pts) or docetaxel (n=20 pts) with non-pegylated liposomal anthracycline;
a phase II trial followed and a total of 48 patients was enrolled from January 2002. All
Her2(+) pts received trastuzumab after 6 cycles until progression. Primary endpoint of
phase I study was dose limiting toxicity (DLT) and safety assessment; phase II trial primary
endpoint was overall response rate (ORR) while secondary endpoints were time to
progression (TTP) and 2-years survival (2yOS). Patients characteristics were as follows:
median age 56 years old (range 45-65), n=31 were PS 0, n=40 ER (+), n=29 (Her2+),
n=32 had > 2 metastases sites, n=29 showed liver and n=34 bone metastases. Results:
DLT was 50 mg/m2 for paclitaxel or 30 mg/m2 docetaxel combined with 25 mg/m2 of nonpegylated liposomal anthracycline. We recorded 5.4 median cycle/pt. The 12.5% and
60.41% pts achieved complete and partial response respectively with a clinical benefit of
85.41%. Median TTP was 10.68 months and median 2y OS was 21.60 (65.6% pts). No
survival differences were recorded between groups (paclitaxel vs docetaxel). WHO G3-4
toxicities included neutropenia (68.75%) and complete alopecia (60.41%). Mucositis
(12.53% vs 8.3%), onycholysis (22.91% vs 10.41%) and peripheral sensory neuropathy
(25% vs 14.58%) were significantly higher for docetaxel than paclitaxel. A total of 29.3%
pts showed left ventricular ejection fraction (LVEF) reduction but none > 10% with recover
after treatment completion. Conclusions: Weekly administration of taxane and nonpegylated liposomal anthracycline is well tolerated and clinical benefit data encourage a
phase III study design.
INTRODUCTION
In an attempt to improve the efficacy of chemotherapy in breast cancer and to suppress cancer regrowth of resistant cells during and between each cycles, dose intensification has been extensively
evaluated over the past decade. Tumor re-growth after subcurative therapy could be quite rapid
after each cycle of treatment that eradication of disease is difficult, even when all of the cells are
"sensitive" to the drugs used. Considering the Gompertzian kinetic growth curve in which cell
doubling time increases with tumour size, the Norton–Simon model predicts that the best way to
destroy an heterogeneous mix of cancer cells is to eradicate the numerically dominant, fastergrowing cells first, followed by eradication of the more slow-growing, resistant clone through a dose
intensification [1]. Dose-dense treatments increase dose-intensity not by increasing the dose, as
with dose escalation, but by decreasing the time, evoiding regrowth of the resistant, slow-growing
clones [2]. Moreover, metastatic disease is often incurable for the presence of multiple resistant
clones [3]. Combined use of liposomal non-pegylated anthracycline and dose-dense regimen is
supposed to overcame multidrug resistance.
Although Metastatic breast cancer (MBC) treatment is extensively changing with biologic drugs
development and gene profiling, anthracyclines remain the backbone of therapy for advanced
breast cancer. Unfortunately, their extensive use as a detrimental part of adjuvant treatment,
strongly limits rechallenge with conventional formulations for cumulative cardiotoxicity. Moreover,
MBC patients who are likely to receive first line chemotherapy, are often good performance status
(PS). To preserve acceptable QoL and obtain disease control, first line chemotherapy tolerability
profile has not to exceed grade 2 toxicity (G2). Based on these assumptions, to preserve good QoL
and overcame cancer resistance, in 2002 we designed the phase I-II of wALT trial (weekly nonpegylated Liposomal Anthracyclines and Taxane), a multicenter institution study, to establish the
safety and efficacy of the combined non-pegylated liposomal anthracycline/taxane weekly
administration in metastatic breast cancer (MBC).
PATIENTS PROFILE
Patients profile
Tot
N (%)
48
Age
Median
55.8 years
Range
45-65
(ECOG) PS
Previous CHT
Anthracycline
48
Taxane
12
Hormonotherapy
40
Adjuvant
Trastuzumab
6
0
31
Metastases (n°)
1
12
1
16
2
5
≥2
32
Type of cancer
Sites of
metastases
Ductal
32
Lobular
7
Soft tissue
Mixed
9
Nodes
10
Liver
29
Receptor status
5
ER(+)
40
Lung
4
PgR(+)
39
Brain
2
HER2(FISH +)
29
Bone
34
STUDY DESIGN (from 2002 to 2007)
Standard ALT
Non pegylated Liposomal Anthracycline (AL) 35 mg/m2 q3w
Paclitaxel 135 mg/m2 q3w or Docetaxel 75 mg/m2 q3w
wALT TRIAL
6 cycles
(on study)
AL 25 mg/m2 d1,8,15 q4w
Paclitaxel 50 mg/m2 d1,8,15 q4w or Docetaxel 30 mg/m2 d1,8,15 q4w
END-POINTS
 Phase I (dose-finding):

Primary end points:
 maximum tolerated dose (MTD)
 dose limiting toxicity (DLT)
 Phase II:

Primary end-points:
 Overall response rate (ORR)
 Paclitaxel arm vs Docetaxel arm RR

Secondary end-points:
 Toxicity
 Time to progression (TTP)
 2-years overall survival (2y-OS)
PHASE I: RESULTS
•
•
Dose limiting toxicity (DLT) was defined as grade 4
neutropenia, febrile neutropenia, grades 3 or 4
non-haematological toxicity or treatment delay due to
unresolved toxicity during each cycle. The DLT were
G4 neutropenia (febrile, non-febrile) and sensory
neuropathy in docetaxel arm. There was no case with
more than a 10% LVEF decrease after a median of 15
administration/patients.
The maximum tolerated dose (MTD) was reached at
the dose of non-pegylated liposomal doxorubicin of 25
mg/m2/week and paclitaxel of 50 mg/m2/week or
docetaxel 30 mg/m2/week d 1,8,15 every 4 weeks.
TOXICITY (PHASE I – II)
Pts (n=48)
Grade
(WHO)
Administration (n=762)
1-2 (%)
3-4 (%)
1-2 (%)
3-4 (%)
Leucopenia
39 (81.25)
36 (75)
251 (32.93)
169 (22.17)
Neutropenia
34 (70.80)
33 (68.75)
202 (26.50)
158 (20.73)
7 (14.51)
-
102 (13.38)
60 (7.87)
28 (58.33)
24 (50)
154 (20.20)
94 (12.33)
Trombocitopenia
Anemia
Pz (n=48)
Grade (WHO)
Mucositis
Non-febrile neutropenia
Sensory neuropathy
Administration (n=762)
1-2 (%)
3-4 (%)
1-2 (%)
3-4 (%)
17 (35.41)
10 (20.83)
153 (20.07)
67 (8.7)
3 (6.25)
-
19 (39.58)
2 (4.16)
114 (14.96)
154 (20.20)
Hair loss
29 (60.41)
-
Fatigue
27 (56.25)
4 (8.3)
154 (20.20)
42 (5.5)
Nausea/Vomititing
17 (35.41)
-
40 (5.2)
-
Onicholysis
16 (33.33)
-
Edema
15 (31.25)
-
6 (12.5)
-
Allergic reaction
Docetaxel vs Paclitaxel
Docetaxel arm
Paclitaxel arm
p
G1/2
G3/4
G1/2
G3/4
Onicholysis
-
11
(22.91%)
-
5
(10.41%)
< .0001
Mucositis
9
(18.75%)
6
(12.53%)
8
(16.6%)
4
(8.3%)
< .0001
12
(25%)
5
(10.41%)
7
(14.58%)
5
(10.41%)
< . 001
Peripheral
sensory
neuropathy
CARDIOTOXICITY (PHASE I – II)
75
70
65
60
55
50
45
40
LVEF before
LVEF after
Graph 1: Median % of pts who presented LVEF decline: 29.16%
10%
never >
PHASE II: RESULTS
Pz
(n=48)
Paclitaxel arm
(n=28)
Docetaxel arm
(n=20)
CR
12.5%
14.2%
10%
PR
60.41%
67.85%
50%
SD
12.5%
3.5%
25%
PD
14.59%
14.2%
15%
Clinical benefit
85.41%
85.71%
85%
p=0,04
p=0,06
TTP
10.68 months
10.60 months
10.80
OS (2y)
21.60 months
21.71 months
21.45 months
(intent to treat)
TTP
event
100
80
60
40
20
0
0
5
10
15
20
25
Time
Graph 2: Kaplan-Meier TTP curve (median TTP: 10.68 months)
OS
eventOS
100
90
80
70
60
50
0
5
10
15
20
25
Time
Graph 3: Kaplan-Meier OS curve (median 21,60 months). The 2-years OS is 65.6%
wALT TRIAL: PRO E CONTRA
PRO
 Significative clinical benefit
(85,41%)

TTP: 10.68 months

Very well tolerated combination
treatment
CONTRA
• Not powered to investigate
the role of combined
Trastuzumab
• Small number of series (48
pts)
 Overexpression of
Topoisomerase-2α need to
be investigated
 Not powered to investigate
the role of continuig treatment
after 6 cycles.
 Not powered to investigate
differences between HER2(+)
and HER2(-)
CONCLUSIONS
To the best of our kwnowledge, this is the first study with combined
weekly non-pegylated liposomal anthracycline and taxane in MBC which
seemed to be feasible and to improve clinical benefit. Considering the
direct dose-response relationship in improvement of outcomes as one of
the most important tools in chemotherapy, weekly dose-dense regimen
has to be preferred. Weekly combined liposomal anthracycline and taxane
showed acceptable toxicity profile with neutropenia as the major G4
toxicity but no primary prophylaxis with G-CSF needed[4]. These findings
are extremely encouraging and are consistent with the hypothesis of that
by shortening the time interval between each chemotherapy treatment
could result in more effective eradication of malignant cells and thus
resulting in improved survival. Use of non-pegylated liposomal formulation
permits anthracycline rechallenge even in those pts who have previously
received conventional epirubicin or doxorubicin whose cardiac toxicity
limits the total dose. This is particularly important for that anthracyclines
still represents the cornerstone of MBC.
Our phase II results encourage phase III trial (trial will open to enrollment
June 2008*) to establish if dose-dense scheduling with non-pegylated
liposomal anthracycline and paclitaxel (the lower toxicity arm) is superior
to conventional scheduling of chemotherapy in larger size of patients.
REFERENCES and CONTACT
1. Goldie J, Coldman A: Application of theoretical models to chemotherapy protocol design.
Cancer Treat Rep 70:127-131, 1986
2. Norton L: A Gompertzian model of human breast cancer growth. Cancer Res 1988,
48:7067-7071.
3. Seidman AD, Berry D, Cirrincione C, et al. CALGB 9840: Phase II study of weekly (W)
paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3 h infusion every third week in
the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive
MBC and randomized for T in HER2 normal MBC [Abstract 512]. Proc Am Soc Clin Oncol
2004; 23: 6s.
4. Nisticò C, Bria E, Cuppone F et al Weekly epirubicin and paclitaxel with granulocyte
colony-stimulating factor support in previously untreated metastatic breast cancer patients:
a phase II study. Anticancer Drugs. 2007 Jul;18(6):687-92.
* To learn more about wALT phase III trial enrollment, please feel free to contact Dr MS Rosati:
mail: [email protected], tel: +39 06 4441675; fax: +39 06 4941035