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(2l) Application Number: KE/P/2003/ 000277   
   
(22) Filing Date: 15/0512003   
   
(30) Priority data: 60/380,850  17105/2002  us

(86)  PCT data    PCT/EP03/07443    15/0512003 W02003/097164    27/1112003

(73) Owner: Aventis Phanna S.A. of 20 Avenue Raymond A ron, 92160 Antony, France

(72) Inventor: CHAKROUN, Hichem 5, Pare Delattre de Tassigny F- 92400 Courbevoie, France

(74) AgenUaddress for correspondence: Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi

(54)    Title: USE OF DOCETAXELIDOXORUBICIN/CYCLOPHOSPHAMIDE IN ADJUVANT THERAPY OF BREAST AND OVARIAN CANCER

(57)    Abstract: The present invention relates to a new method of adjuvant therapy in the treatment of metastatic breast or  ovarian cancer, comprising administering six cycles of docetaxel, doxorubicin and cyclophosphamide to a patient in need thereof, wherein said dosages have a marked therapeutic effect when compared to other adjuvant therapies. USE  OF  DOCETAXEL/DOXORUBICIN/CYCLOPHOSPHAMIDE  IN  ADJUVANT  THERAPY  OF  BREAST AND  OVARIAN  CANCER

DESCRJl'TlON OF THE INVENTION

Field of the Invention

This invention relates to a novel therapeutic combination of taxotere with other antineoplastic agents which are useful in the adjuvant therapy of metastatic breast and ovarian cancer.

Background of the Invention

The present invention relates morl! specifically to the use of docetaxel in

10    combination with doxorubicin and cyclophosphamide as adjuvant therapy in the treatment of cancer after surgery or other first line therapy.

Selected tenn definitions used herein and in Tables 1-36 are as follows: "Adjuvant therapy" refers to chemotherapy started within but no greater than
60 days from surgery.

15    "AT" refers to Adriamycinri'axotere;

"docetaxcl" refers to the active ingredient ofTAXOTERE®  or TAXOTERE®

itself;

"doxorubicin"    refers  to  the  active  ingredient  of  ADRIAMYCIN®   or

ADRIAMYCIN®  itself.

20    "ER" refers to estrogen receptor;

"FAC"  refers  to  the  combination  of  5-fluorouracil,  doxorubicin  and

cyclophosphamide;

"HER211 refers to is a transmembrane receptor tyrosine kinase with partial homology with the epidennal growth factor 2 receptor, both of which receptors
25    belong to the type 1 tyrosine kinase receptor superfamily;

11KPS11 refers to Kamovsky Perfonnance Status which is an index of a patient's physical condition;

11 MF" refers to Methotrexate/5-Fluorouracil;
 
"MV" refers to Mitomycin!Vinblastin combination; "PR'' refers to progesterone receptor;
"TAC" refers to the combination of TAXOTERE© (docetaxel), ADRIAMYCIN (doxorubicin) and cyclophosphamide;

and

"drug" or "drugs" refers to the above-mentioned active ingredients or medicaments or phnrmaceutical preparations containing them.

Previous researchers have noted that docetaxel (TAXOTERE®) and its derivatives (such as TAXOL®, paclitaxel) are useful in the treabnent of malignant
10    neoplasms, such as solid tumors and other malignancies. European Patent EP 0 253 738 and International Patent Application WO 92/09589 describe a method of preparation of docetaxel. Generally, the doses, which vary depending on the patien~ comprise between 60 and 400 mg/m2 of docetax.el. Commonly, docetaxel is

administered via intravenous route at doses of 60 to 100 mg/m2 over 1 hour every 15 3 weeks (Textbook of Medical 0Jicology, Franco Cavelli et al., Martin Dunitz Ltd.,

p. 4623 (1997)).

Many clinical studies have confirmed the efficacy of docetaxel in treating many types of cancer, particularly breast, non-small cell lung, and ovarian cancer. Docetaxel's effects are shown in both first and second line therapies. The mechanism
20    of docctaxel's action is thought to be via enhancement of microtubule assembly and inhibition of the depolymcrization oftubulin at the cellular level.
However, all treatments based on taxoid derivatives, including docetaxel, can show serious and troubling toxicities, such ~ myelosuppression, neutropenia,

hypersensitivity, peripheral neuropathy, and fluid retention, among others (Fumoleau

25    et al., Bull. Cancer, (82)8: 629-636 (1995)). When such toxicities appear, dosages of the drugs must be limited with a resulting limitation on the efficacy of the treatment.
Consequently,  there  is  an  unmet  need  in  the  art  for  pharmaceutical

preparations and methods of treating cancer which enhance the activity of docetaxel without increasing the amount of the dosages administered and without increasing
30    adverse side effects.

There is also an urunet need in the art for treabnent of cancer which has spread beyond the initial tumor site. In metastatic breast and ovarian cancer
 
especia11y) there is a need for effective post-surgery adjuvant therapy, which will result in disease free survival or at least, an extension of the duration of progression free survival.

In recent studies, docetaxel containing regimens have shown superior activity over standard regimens in metastatic breast cancer. Anthracycline-based regimens, using e.g. doxorubicin, are standard adjuvant therapy in node positive breast cancer patients. Therefore, considering the efficacy of both docetaxeJ and doxorubicin in treating advanced breast cancer and their potential noncross-resistance, it was decided to combine them with cyclophosphamide as a possible design for a more effective

10    adjuvant therapy for metastatic breast cancer. The combination of the docetaxel, doxorubicin, and cyclophosphamide (fAG) was tested in a phase Ill trial in 20 countries by more than 112 investigators. The results which are elaborated below show that the combination used as adjuyant therapy enhances the effect of docetaxel without increasing its dosage and results in increased survival for metastatic breast

15    cancer patients.

SUMMARY OF THE INVENTfON

The present invention embodies methods for treating metastatic cancer, especially metastatic breast cancer and ovarian cancer, comprising adminiswring docetaxel, doxorubicin and cyclophosphamide (TAC) in amounts effective to reduce

20    or eliminate the presence of cancer. The efficacy of this combination has been demonstrated over a period ofthirty-three months in more than seven hundred human patients who demonstrated positive nodal invo1vement and were treated pns!-surgcry

withTAC.

Another  aspect  of the  invention  comprises  new  pharmaceutical  kits  and

25    medicaments comprising docetaxel in combination with doxoruhicin and cyclophosphamide for treating cancers.

Yet another aspect of the invention is concerned with schedules of administration of TAC for the adjuvant treatment of cancer wherein the individual drugs in the TAC combination are infused separately on the same day, once every
30    three weeks.  This cycle is repeated six times.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The inventors of the present invention have demonstrated via clinical trials, that TAC dosages in particular manifest an unexpected and strong therapeutic effect
on  the  treatment  of  neoplastic  diseases,  particularly  breast  cancers,  and  more

particularly,    in   metastatic  breast  cancers  in   which   ERIPR  and  HER2   are

overexpressed.  Generally, according to the invention, docetaxel is administered in a

dosage of 75 mgfm2,  doxorubicin in a dosage of 50 mg/m2 and cyclophosphamide in

a dosage of 500 mg/m2,  once every three weeks.  This cycle is generally repeated six

times.

10 Docetaxel alone, in several in-house proprietary studies, gave overall response rates of 40 to 43% (in second line therapy at a dose of I 00 mg/m2), 48% (in first line therapy at a dose of 75 mg/m2) and 61 °/a (in first line therapy at a dose of
!00mg/m2).

In comparison, in the example below, 75 mf!lm2 of docetaxel administered in

15    combination with 50 mg/m2 doxorubicin and 500 mg/m2 cyclophosphamide resulted in an 82% response rate.

According to the invention, the new use of docetaxel as a component ofTAC is very advantageoUs for treating cancers of the breast, ovary, and lung; still more

preferably, the new use of docetaxel is particularly suitable for treating metastatic 20 breast cancer.

The safety and the efficacy of the combination of docetaxel, doxorubicin and cyclophosphamide was tested in patients according to the following protocol:

Patients were eligible for the study if they had histologically proven breast cancer, defmitive surgery with axillary lymph node dissection (greater than or equal

25    to 6 lymph nodes), a period of 60 days or less between surgery and randomization, stage 1 to 3 cancer, at least one node that was positive for cancer, were 70 years old or less, had a KPS index greater than or to 80% and had normal bone marrow, liver,

renal and cardiac function.  See Table 4.

One thousand, four hundred and ninety-one patients were accepted into the

30    study. Seven hundred and forty-five received TAC as adjuvant therapy and seven hundred and forty-six received FAC. The TAC patients had a median age of 49
 
years, 51 % were premenopausal, and 60% percent had had a mastectomy. Sixty-eight % had had radiotherapy and 68% had taken tamoxifen. The patient characteristics for the FAC group were similar (See Table 6).

Of the seven  hundred  and  forty-five  TAC  patients,  62%  had  1-3  cancer-

S    positive nodes, 30% had 4 to 10 positive nodes and 8% had more than 10 positive nodes. In 40% of the patients, the size of the tumor was 2 em or less, in 53%, the size of the tumor was more than 2 em but equal to or less than 5 em., and in 7 % of the patients, the tumor was larger than 5 em. Sixty-nine per cent of the patients had overexpressing ER or PR tumors and 19% had overexpressing HER2 + (FISH)

10    tumors. Again, the tumor characteristics of the FAC group were comparable. See Table 7.

The primary endpoint of this Phase III study was to facilitate disease free survival while secondary endpoints were overall survival, toxicity, quality of life and monitoring pathological and molecular markers.

15 Post-TAC and post-FAC treatment included 1) radiation therapy for all patients with breast conserving surgery and 2) tamoxifen (20 mgiday for 5 years) for those patients withER or PR positive tumors. See Table 3.

The Example below illustrates the new use of docctaxcl according to the invention without limiting it.

20    EXAMPLE:

Dexamethasone, 8 mg BID was given as a premedication for 3 days. The combination adjuvant therapy was then administered on Day 4. One group of patients received docetaxel, doxorubicin and cyclophosphamide (TAC) administered intravenously in that order. Another group of patients received 5-FU, doxorubicin,

25    and cyclophosphamide (FAQ administered intravenously in that order. Prophylactic Cipro was then given to both groups on days 5-14 in a dose of 500 mg BID. This course of drugs was repeated every three weeks for six cycles. See Table 2.

Six hundred and seventy-nine patients (91 %) completed six cycles of TAC adjuvant therapy followed by the postchemical therapy regimens described above.
 
The median total dose per patient over the six cycles was 446 mgfm2  of docetaxel,

297 mglm2 of doxorubicin, and 2978 mglm2 of cyclophosphamide. See Table 8. Seven hundred and eleven patients (96%) completed six cycles of FAC

adjuvant tlierapy followed  by the postchemical therapy regimens described above.

The median total dose per patient over the six cycles was 2985 mgfm2 of 5-FU, 298

mglm2 of doxorubicin, and 2985 mglm2 of cyclophosphamide. ,hl.

Thirty-three months after adjuvant therapy, 82% ofthe TAC group vs. 74% of the FAC group were alive and disease free (Table 10). At the same time, the overall survival oftheTAC group was 92% vs. 87% for the FAC group (Table 13).

10    Results by Nodal Status

If disease free survival  of the TAC  and FAC groups is compared by nodal

status, 90% of patients with 1-3 positive nodes who received TAC were alive and disease free at 33 months after therapy vs. 79% of the FAC group. There was no statistical difference between the two adjuvant therapies in patients with 4 nodes,

15    although 69% of patents receiving TAC therapy were alive and disease free at 36 months compared to 67% who received FAC. See Table 15.

The overall survival rate for patients with 1-3  positive nodes was 96%  for

TAC and 89% for FAC. Again, there was no statistical difference between the two therapies in patients with 4 or more positive nodes, although again more TAC
20    patients (86%) survived than FAC patients (84%).  See Tables 16 and 32.

Results by Hormonal Status

In patients with negative ERIPR tumors, the disease free survival rate was about 70% in those who had received TAC adjuvant therapy and about 62% in those receiving FAC. In patients with positive ER/PR nodes, the disease free survival rate

25    among those who received TAC was about 88% vs. 82% in those who received FAC.

See Tables 17 and 33.

If one calculates overall survival by hormonal status, about 83% of TAC recipients with negative ERIPR tumors survived vs. about 72% of FAC recipients.

Among patients with positive  tumors,  about 90% of TAC recipients  survived vs.

30    about 88% ofFAC recipients.  See Tables 18 and 35.
 
Results by HER2 Status

In patients with negative HER2 tumors, the disease free survival rate at 33 months was about 86% in those who had received TAC adjuvant therapy and about 80% in those receiving FAC. In patients with positive HER2 tumors, the disease free survival rate among those who received TAC was about 75% vs. 60% in those who received FAC. See Table 19.

Based on this data, the combination of docetaxel, doxorubicin and cyclophosphamide as adjuvant therapy is well-tolerated and results in a significant advantage over 5FU, doxorubicin and cyclophosphamide as adjuvant therapy. If one

10    measures disease free survival, at 33 months, TAC provided over FAC a 32% reduction in deaths overall, a 50% reduction in deaths where the patients had 1-3 positive nodes, a 38% reduction in deaths where the honnonal status of the tumor was negative and a 32% reduction where the hormonal status was positive. See Table 22.

If one measures overall survival, there was a 24% reduction in deaths of those

15    receiving TAC adjuvant therapy and a 54% reduction in those patients with 1 to 3 positive nodes. !4:.

The difference bet\veen TAC and FAC is the presence ofdocetaxel rather than 5-FU. These statistics prove conclusively that the observed benefit of docetaxel in

combination with doxorubicin and cyclophophamide is large enough to be of clinical 20 value in the adjuvant treatment of node positive breast cancer patients.

The described embodiments are to be considered in all respects as illustrative only and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within

25    their scope.
 
I. Use of docetaxel in the manufacture of a medicine for treating nade~positive, Mo breast cancer by adjuvant therapy following surgery in combination with doxorubicin and cyclophosphamide only and which provides an increased survival rate.

2.    Use according to claim 1 wherein docetaxel, doxorubicin and cyclophosphamide are administered separately.

3.    Use according to claim 1 wherein the said breast cancer ER, PR and/or HER2 are overexpressed.

10    4. Use according to claim 2 wherein docetaxel, doxorubicin and cyclophosphamide are administered once every 3 weeks.

5.    Use according to claim 2 wherein doceta.xel is administered at a dose of approximately 7S mgfm2 per cycle.

6.    Use according to claim 2 wherein doxorubin is administered at a dose of
IS    approximately 50 mgfm2 per cycle.

7. Use according to claim 2 wherein cyclophosphamide is administered at a dose of approximately 500 mg/m2 per cycle.

1/18

Study Rationale

D    Anthracycline-based regimens are standard adjuvant treatments in node positive breast cancer patients

D    Docetaxel containing regimens have shown superior activity over standard regimens in MBC

D Anthracycline failure

D Docetaxel versus MV, Nabholtz et al, JC0'99 D Docetaxel versus MF, Sjostrom et al, EJC '99

D CMFfailure

D Docetaxel versus Doxorubicin, Chan et al, JCO '99

D First-line

D AT versus AC,    Nabholtz et al, ASCO 2000

D TAG versus FAG, Nabholtz et al, ASCO 2001 Mackey et al, ASCO 2002

Table 1

DESIGN

        F  5-FU    500 mg/m2   
        A  Doxorubicin    50 mg/m2   
        C  Cyclophosphamide    500 mg/m2   
        Every 3 weeks x 6 cycles       
        T  Taxotere    75 mg/m2   
        A  Doxorubicin    50 mg/m2   
Stratification :    C  Cyclophosphamide    500 mg/m2   
•    Nodes           
    1-3    Dexamethasone premedication, 8 mg BID, 3 days   
    4+       
•    Center    Prophylactic Cipro 500 mg bid, day 5-14       
               
 




2/18

Post Chemotherapy Treatment

F
cA}Tamoxifen 20 mg/day for 5 years
• Patients with ER and/or PR positive tumors

Radiation Therapy
T    • All pis with breast conserving surgery
A    • Per each center'sguidelines after mastectomy

c


Table 3


Major Eligibility Criteria

o    Histologically proven breast cancer

o Definitive surgery with axillary LN dissection (<: 6 LNs) o 60 days between surgery and randomisation

o    Stage T 1-3, N1, MO

o    Age~ 70 years, KPS <: 80%

o Normal bone marrow, liver, renal and cardiac function o Informed consent

Table 4
 

3/18


Endpoints

Primary

o  Disease-free survival

Secondary

o Overall survival o Toxicity

o Quality of Life, Socioeconomic analyses o Pathologic & Molecular markers

Source verification : 1DO % data for all patients

Table 5



Patient Characteristics

Randomized    TAC    FAC
(n=1,491)    n=745    n=746
           
Median Age    49    49
Median KPS    100%    100%
Premenopausal    51%    50%
Mastectomy    60%    59%
Radiotherapy    68%    71%
Tamoxifen    68%    69%
           

Table 6
 




4/18


Tumor Characteristics

                        TAC    FAC   
                        n=745    n-746   
                    Nodal Status    %    %   
                           
    1-3    62    62   
    4-10    30    31   
    >10    8    7   
    Tumor Size (em)           
               
        $2    40    43   
                    >2 and::; 5    53    51   
    >5    7    6   
            ER and/or PR +    69    69   
                       
            HER2 +(FISH)    19    20   
                               

Table 7

Exposure to Treatment

            TAC    FAC   
            n-745    n-746   
Completed 6 cvcles    679791 %)    711 (96 %)   
                   
Relative dose intensity    0.98    0.97   
    median           
>0.90    89%    84%   
Median total dose mg/m2    446    -   
Docetaxel           
Doxorubicin    297    298   
Cyclophosphamide    2978    2985   
5FU    -    2985   

Table 8
 




5/18


Protocol Defined Statistical Analyses

Disease Free Survival and Overall Survival

o  First planned analysis : 3 years

o  Cohort : Intent to treat

o Main Analysis

o Log rank test stratified by nodal status o p-value not adjusted for interim analysis

o Confirmatory analyses o Unadjusted

o Multivariate (Cox model)

Table 9

Disease Free Survival (ITI)

Median follow-up : 33 months

100                           
                           
90                           
ao                           
70            # Events   RR    P-Va(ue   
                   
60        TAC    119    0.001       
            0.68           
        FAC  ...!Z9._           
so        Total    289           
                           

12    \B    24    30    36    42    48

Months
NumberalR!sk
TAC    7<15    736    710    67a        373    152    23
FAC    745    725    csg    6S6    605    JJ..;    ~50    31
                    "'           
Table 10
 




6/18

Confirmatory Analyses : DFS

    Analysis    Cohort    RR    p   
                               
                               
Stratify on    ITT    0.68    0.001   
Nodes        (0.54-0.86)_       
                   
                           
Unadjusted    ITT    0.67    0.0008   
                    (0.53-0.85)       
                               
                           
Cox Model*    ITT    0.64    0.0002   
                    (0.50-0.81)       
                               
                               

•    Controls for nodes, age, tumor size, histology, ERIPR, HER2

Table 11




Sites of First Events

            TAC(N)    FAC(N)
           
Distant    80    119
Local/Regional    23    31
Contralateral    3    6
Other 2"0  Primary    6    10
Death NED    7    4
            119    170
               

Table 12
 




7/18

Overall Survival (ITT)

Median follow-up : 33 months

100

90

m BO                                                    FAC           
.2                                                                   
<i'                                                               
"$.  70                                                               
                            #Events   RR    P-Value                                   
60            TAC    57        0.76    0.11                                   
                                                               
                        FAC_7_6 __                                       
50            Total    133                                               
                                                               
                                    12    18    24    30    36    42    48   
                                        Months                           
Number at Risk    741        732    718    700    393    171    24           
            TAC    745                                           
            FAG    746    738        72S    713    678    375    171    33           
                                        Table 13                           
                Confirmatory Analyses of Overall Survival           
                                                           
            Analysis            Cohort            RR            p           
                                                                           
Stratify on Nodes        ITT            0.76            0.11           
                                                    (0.54-1.07)                       
                                                           
Unadjusted                ITT            0.75            0.10           
                                                    (0.53-1.06)                       
                                                                           
                                                           
Cox Model•                ITT            0.71            0.049           
                                                    (0.50-1.00)                       
                                                                           

•    Controls for nodes, age, tumor size, histology, ERIPR, HER2

Table14
 




8/18

Disease Free Survival by Nodal Status
 

100

•    90
.t
~
~ 80
6

m  70
~
~    60

50
 

_,~~ -        TAC

'--.._"'- -~-  1..,
FAG~~\, ___ ~ lEtic

RR    P-Value    ••••\_~•=:.-:=-:

1•3Nodes    0.50    0.0002

4+ Nodes   0.85    0.33

\2    18    24    30    36    42    48
 

Months

Number a\ Risk    462    452    43'    427    250    103    '6"   
1-3  ~~g :~~                               
    '"274    438    "7    393    2:24    .,       
4+  ~~g ~:~        256    241    227    123    49       
    275    2G1    239    212    110    52       

Table 15

Overall Survival by Nodal Status

100                                                           
    90                                                           
..•    80                                                           
"<fl.    70                                                           
                            RR    P-Value                   
    60]        1•3Nodes    0.45    0.006                           
    so        4+ Nodes    1.08    0.75                           
                        12        \8    24        30    36    42    48   
                                                               
Number at Risk                Months                   
    462    459        453    <49    261    112    \4       
    ~~g    :~;                                       
1-3            45i    453        444    422    2'3    107    ,.       
    ;~g    ~:~    279    273        265    251        \32    59    10       
4+            261    275        2~9    256    132    64    5       

Table 16
 




9/18

Disease Free Survival by Hormonal Status

                                Negative                                                Positive                           
    10                                                        10                                                                       
                                                                                                                                   
ii:.. 90                                                    90                                                                   
                                                                                                                       
                                                                                                                               
.1l  ao                                                80                                            G                   
                                                                                                                       
D• 70                                                70        ~'   
                                                           
~                                                        60                                                                   
:I' 60        RR ~ 0.62                                    RR ~ 0.68                                       
                                                                                                       
    so        p ~ 0.005                            50        p ~ 0.02                                       
                                                                                                                       
                            12            24    36        46                                12        24        36    46   
                                    Months                Na!RL$1<                Months                           
    Na!Rosll        '"'ZGZ    '"    "                    "'                                       
                                TAC  514                        IC~                   
    TAC  231                                                                       
                                FAC  512.            l>:.~    J•;                   
    F'"AC 22<!                                                               
                                                                "'                           
                                            '" "        Table 17        "'                                       
                                                                                                               
                            Overall Survival by Hormonal Status                           
                            Negative                                            Positive                           
1    :~~TAG80            10~                   
                                   
        ,o                                                    ~c   
                                                                    FAG   
0        80                                                                           
"                                                                                                                                       
"    7                                            FAG    70                                                                           
*    °                                                                                                                           
    60 j RR = 0.57                            60            RR    = 1.00                                           
                                                                                           
        p = 0.02                            50            p ~.0.99                                       
    $o                                                                                                                           
                            12    24        36                                        12            2~        36        46   
                                Monlhs                NatR,slt                Momhs                           
NatRosk            2(6                sa                                                               
    TAC  :O.ll                                    TAC  51~                                                       
    FAC  22~            2:0                "            FAC  ~~e        s::~                Ill                   
                                                                                        "'                "'           
Table 18
 




10/18

Disease Free Survival by HER2 status

Negative (FISH)    Positive (FISH)

~ 70    FAC    ]~,
~                                       
"'  60                                    ~c   
"'so  RR = 0.74                    soj. RR = o.sg               
    p =0.06                    p = 0.02               
40                        40   ~~~~~~~~   
12    24    35    48    12    24    36    48   
        Months                    Months           
 

Na\Ris.k
TAC  485    ~e7
FAC  413    455
 
"'
"'
 

    NatR•IA
102    TAC    135
\CO    FAC    14S

Table 19
 
"'  "'  "
"'    1::1:"    2,)
 


•Hematological Toxicity

    Treated (n-1480\    TAC (n  744)    FAC(n-736)   
        %        %   
ANC < 1000oo    65.1.        49.0   
Febrile Neutr,openia§    23.9.        2.4   
Infection (Gr 3/4)    3.1        1.5   
Seotic Death    0        0   
               
Anemia (Gr 3/4)    4.8•        2.2   
               
Thrombocvtooenia (Gr 3/4)    2.4        1.8   
                   

oo  Prolocol reqwred blood counts every 3 weeks

§ Gr 4 neutropenia at time of grade;, 21ever and i.v. antibiotics p!>0.05

Table 20
 




11/18

Non-Hematological Toxicity Grade 3/4

Incidence > 1 %

    TAG    FAG
    n=744    n=736
    %    %
Nausea    5.1.    9.5*
Vomiting    4.3    7.3*
Diarrhea    3.4*    1.0
Stomatitis    7.1*    2.0
Asthenia    11.2*    5.3
CHF    1.6    0.7
Premenopausal pts    n=383    n=375
Amenorrhea    51.4*    32.8
•p,;;Q.05       

Table21


Conclusions

At 33 months median follow-up, TAG provides over FAG :

o    Primary endpoint : Disease-Free Survival   
    "    Overall :        32 "'o reduction (p=0.001)   
    "    By nodal status:    1-3:    50 "'o reduction (p=0.0002)   
            4+ :    No difference   
    "    By hormonal    HR- :    38 % reduction (p=O.OOS)   
        status:    HR+:       
                32 % reduction (p=0.02)   
o    Secondary endpoint : Overall Survival    24 % reduction (p=0.11)   
    "    Overall:           
    "    By nodal status    1-3:    54 % reduction (p=0.006)   
            4+:    No difference   


Table22
 

12/18

Conclusions

o    Febrile neutropenia was more frequent on TAC, without increased incidence of infection and no septic deaths

0    Other toxicities were acceptable and manageable in both arms

•    The observed benefit of T AC is large enough to be of clinical value in the adjuvant treatment of node positive breast cancer patients

•    Additional follow-up is necessary to confirm the integration of TAC in this patient population

Table 23



Design

F r•-;r-i!i:';l~~~"J~.q    5-FU    500 mg/m2
A ~UIIIl'lll•l    Doxorubicin    50    mg/m2
c • • •    Cyclophosphamide    500    mg/m2
        q. 3 wks x 6
~~~~~~~ b~~~~~~icin    7~0~~~2
c    Cyclophosphamide    500 mgfm2

Standard dexamethasone premed

Prophylactic Cipro SOOmg bid, d~y 5-14

Stratification  • Nodes: 1-3, 4+

• Center

Table 24
 




13/18


Protocol defined statistical analyses (II)

o    Analysis by Nodal Status o Prospectively defined

o Closed testing procedure to prevent multiplicity (Periormed only if main analysis statistically significant)

o    1-3 nodes (70 % of patients/events)

-a 0.05, power 91 % to detect DFS improvement of 38 %

o    4+ nodes (30 % of patients/events)

-a 0.05, power 81 %to detect DFS improvement of 40 %

Table 25




DFS and OS

Absolute difference at 3 Years

            TAG    FAG   
Intent to Treat    DFS    82%        74%   
    Survival    92%        87%   
                   
                       
1-3 nodes    DFS    90%        79%   
    Survival    96%        89%   
                   
<: 4 nodes    DFS    69%        67%   
    Survival    86%        84%   

Table 26
 




14/18

Disease Free Survival (ITT)

Median follow-up : 33 months








&o    TAC    745    119
0.68    0.001
FAC    746   12.Q_

Total    289

Months

Table 27

Survival (ITT)

Median follow-up : 33 months
~~~-~:TAC92%     I

~

FAC

    N    #Events   RR    P.~Vatue   
TAC    745    57    0.11   
FAC    746    0.76       
        76       
Total        133       


Table 28
 




                            15/18                   
            Disease Free Survival by Nod~l Status   
100                                               
                                               
•    90                                               
J:.                                                   
m so                                        1-3   
iS                                               
•    70                                               
.~                                                   
"~ 60                                               
            1-3 Nodes    o.so    0.0002                       
                                               
    so                                               
                                                   
                    12    1a    24        30    JG    "       
                    Time to BCR, SPM or Death (months)           
Number at Risk                                   
    452        427        250               
    462        437                103           
1-J    ~~g :~~  454        <17    393        22'    ga    25       
                    '"                        "       
                                                   
Table 29


DFS 4+ Nodes

100

90

BO

70

60
 

so
 

4+ Nodes   0.86   0.33

12    18    24    30    36    42
Time to BCR, SPM or Deuth (months)
 

4    ..  TAC    282    274    2SB    241    227    123    49
    FAC    285    2i5    2!il    ,,    212    110    52
Table 30
 




16/18

Disease Free Survival by Nodal Status









1-3 Nodes    0.0002

4+ Nodes    0.86   0.33

Mnnths

Table 31

Ove~all Survival by Nodal Status






RR    P-Value

1-3 Nodes    0.46   0.005

4+ Nodes    1.08   0.75



~~    -ffC,I~:JWodsll  -Frrt.,4•11o:da     -Trrt.,l-3~   -Trrt.,4•11odoroo

Table 32
 



17/18


Disease Free Survival by Hormonal Status












Months

Table 33


Patient Characteristics

    Randomized (n=1 !491)    TAG    FAG       
        n=745    n-746       
                   
    Median Age    49    49       
                   
    Median KPS    100%    100%       
                   
    Premenopausal    51%    50%       
                   
    Mastectomy    60%    59%    '   
                   
    Radiotherapy    68%    71%       
                   
    Tamoxifen    68%    69%       
                   

Table 34

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