Transcript Document

Investigator Meeting
SOFT
GOCCHI August 16, 2007
B
I
G
Tailored Treatment Investigations
Premenopausal patients with endocrineresponsive disease (ER > 10% and/or PgR > 10%)
Open questions related to adjuvant
treatments:
1. Role of suppression of ovarian function
2. Role of AI
3. Role of chemotherapy in addition to endocrine
therapies
4. Duration of GnRH analogue when combined
with SERMS
STP
Tailored Treatment Investigations
Premenopausal patients with endocrine-responsive
disease (ER > 10% and/or PgR > 10%)
SOFT: Suppression of Ovarian Function Trial (IBCSG 24-02; BIG 2-02)
TEXT: Tamoxifen and Exemestane Trial (IBCSG 25-02; BIG 3-02)
North American Intergroup and Breast International Group (BIG) participation
Coordinating Group: International Breast Cancer Study Group (IBCSG)
Pharmaceutical Partner: Pfizer
SOFT
Suppression of Ovarian Function Trial
A Phase III Trial Evaluating the Role of Ovarian
Function Suppression and the Role of
Exemestane as Adjuvant Therapy for
Premenopausal Women with Endocrine
Responsive Breast Cancer
Gini Fleming and Prue Francis
SOFT: Background
• EBCTCG overview: Ovarian ablation
effective adjuvant therapy in women < 50
• EBCTCG overview: benefit of ovarian
ablation uncertain in women < 50 if also
receive chemotherapy
Does Overview underestimate
ovarian ablation efficacy?
• Some were hormone receptor negative
• Most women < 50 who receive adjuvant
chemotherapy become menopausal
• Need to test ovarian function suppression
in group who can benefit i.e. remain
premenopausal after chemo + receptor
positive cancer
Amenorrhea after Chemotherapy
• 80% of women > 40 yrs after CMF x 6
• < 50% women < 40 yrs after CMF
• Less amenorrhea with AC than CMF (34% vs
69%)
• Prognosis after CMF better in those who get
amenorrhea
Combining Tamoxifen plus
ovarian function suppression
• In advanced breast cancer there is a survival
advantage to combined endocrine treatment
(GnRH + Tam) vs. single hormonal treatment
in premenopausal women
Women < 35 yrs with hormone
receptor positive breast cancer
• Do poorly after adjuvant chemotherapy
alone
• Worse prognosis than premenopausal
women > 35
• Paradoxically have worse prognosis than
same age group with hormone receptor
negative cancer when treated with
adjuvant chemotherapy
SOFT [IBCSG 24-02, BIG 2-02]
Patients who remain premenopausal within 6 months after
CT, or receive tamoxifen alone as adequate treatment
Strata
Premeno.
ER  10% and/or
PgR  10%
Patients with
estradiol (E2) in the
premenopausal
range either after
CT or without CT
Any CT
No CT
P
r
e
m
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n
o
p
a
u
s
a
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*
R
A
N
D
O
M
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Z
E
T x 5y
OFS + T x 5y
OFS + E x 5y
* Randomization within a 8-month evaluation period after end of CT,
or within 12 weeks after definitive surgery for patients with no CT
CT=chemotherapy; T=tamoxifen; E=exemestane; OFS=ovarian function suppression
using triptorelin x 5 years or surgical oophorectomy or ovarian irradiation
Target sample size: 3000 patients
SOFT: Eligibility (the basics)
• Resected Breast Cancer
• ER and/or PgR positive
(10% IHC)
• Premenopausal
SOFT: Premenopausal
• Estradiol within institutional premenopausal
range
• Measured between 2 wks and 8 mos post
chemotherapy
• Transient amenorrhea which resolves is
acceptable (with premenopausal E2 level)
• Amenorrhea on tamoxifen acceptable if
estradiol level in premenopausal range
SOFT: Treatment
• CHEMOTHERAPY
– Completed prior to randomization or not given
• ADJUVANT ENDOCRINE THERAPY
– OFS by randomization (investigator choice of
method: Triptorelin 3.75mg IM q 28 days x 5 y
OR oophorectomy OR ovarian irradiation)
– Tamoxifen/Exemestane by randomization
• RADIOTHERAPY
– Optional after mastectomy
– Required after breast-conservation
SOFT: Primary Objectives
• Compare OFS + T vs T
• Compare OFS + E vs T
• Compare OFS + E vs OFS + T
• Primary endpoint: Disease-free
survival
SOFT:
Statistical Considerations
• 3 pairwise comparisons, each
tested at the 2-sided alpha level
0.0167
• Target: 25% reduction in hazard
• 80% power
• Sample Size: 3000 patients
STP: Secondary Endpoints
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Overall survival
Systemic disease-free survival
Quality of life
Sites of first treatment failure
Late side effects of early menopause
Incidence of second (non-breast) cancers
Causes of death without cancer event
SOFT: OFS
• Triptorelin: 3.75 mg IM q28 days for
5 years from randomization unless:
– relapse or intolerance
• Triptorelin supplied
• Zoladex allowed but not supplied
• Irreversible OFS allowed
Adjuvant Endocrine Therapy
• Exemestane 25 mg po daily for 5 years
Tamoxifen 20 mg po daily for 5 years
• Exemestane/Tamoxifen should start after
adjuvant chemotherapy has been completed
or at least 6 weeks after the initiation of
GnRH analogue, whichever is later
• NB if patient ceases GnRH, exemestane
ineffective
Exemestane
• Irreversible inactivator of aromatase
• Steroidal structure
TEXT
Tamoxifen and Exemestane Trial
A Phase III Trial Evaluating the Role of
Exemestane Plus GnRH Analogue as
Adjuvant Therapy for Premenopausal
Women with Endocrine Responsive
Breast Cancer
Olivia Pagani and Barbara Walley
TEXT [IBCSG 25-02, BIG 3-02]
Patients who should receive OFS from the start
Premeno.
ER  10%
and/or
PgR  10%
Candidates
to begin
GnRH
analogue
(triptorelin)
from the
start of
adjuvant
therapy
Strata**
Any CT
No CT
R
A
N
D
O
M
I
Z
E
GnRH + Tamoxifen* x 5y
+/- CT**
GnRH + Exemestane* x 5yy
+/- CT**
* to begin at least 6 weeks after start of
triptorelin or after CT, whichever is later.
** choice of +/- CT may be made by previous
randomization in the PERCHE trial.
CT=chemotherapy; GnRH analogue=triptorelin x 5 yrs,
but oophorectomy or radiation is allowed after 6 months
Target sample size: 1845 patients
TEXT + SOFT
• It is prospectively planned to combine
data from the arms comparing
exemestane plus ovarian function
suppression (OFS) versus tamoxifen plus
OFS in the SOFT trial with the data from
the TEXT trial.
STP: Quality of Life Study
• The Quality of Life (QL) component is an integral part
of the current protocols
• Includes core QL indices (e.g., physical well-being,
mood, coping) and focus on impact of menopausal
symptoms (e.g., hot flushes, loss of sexual interest)
• Baseline assessment prior to randomization
• Every 6 months for first two years
• Annually in years 3 to 6 (total 9 times thru 6 yrs)
See protocol section 10.0 and Appendix V
STP: Quality of Life Study
QL Forms
• One-page QL Core Form (QLC) – [LASA scales]
• One-page QL Module Form (QLM) – [LASA scales]
• For English-speaking centers: Two-page QL
Supplement Form (QLS) – [Likert scales]
• Missing QL Form (MQL) – for patients who do not
participate or whenever an assessment is missed
See protocol section 10.0 and Appendix V
STP: Quality of Life Study
LASA scale example
Likert scale example
STP Target and Actual Accrual
(through July 31, 2007)
3000
2500
2000
Target
Actual
1500
1000
500
0
SOFT
TEXT
STP Information
• [email protected]
• www.ibcsg.org