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Investigator Meeting
SOFT
GOCCHI August 16, 2007BIG
Tailored Treatment Investigations Premenopausal patients with endocrine-
responsive 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
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
STP Tailored Treatment Investigations
Premenopausal patients with endocrine-responsive disease (ER > 10% and/or PgR > 10%)
SOFTSuppression 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
Premeno.
ER 10% and/orPgR 10%
Patients with estradiol (E2) in the premenopausal range either after CT or without CT
CT=chemotherapy; T=tamoxifen; E=exemestane; OFS=ovarian function suppression using triptorelin x 5 years or surgical oophorectomy or ovarian irradiation
RANDOMIZE
T x 5y
OFS + T x 5y
OFS + E x 5y
Any CT
Premenopausal
No CT
Strata
Target sample size: 3000 patients
*
* Randomization within a 8-month evaluation period after end of CT,or within 12 weeks after definitive surgery for patients with no CT
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
• 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
TEXTTamoxifen 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/orPgR 10%
Candidatesto beginGnRHanalogue(triptorelin)from thestart of adjuvant therapy
Strata**
Any CT
No CT
CT=chemotherapy; GnRH analogue=triptorelin x 5 yrs, but oophorectomy or radiation is allowed after 6 months
RANDOMIZE
GnRH + Tamoxifen* x 5y+/- CT**
GnRH + Exemestane* x 5yy+/- CT**
* to begin at least 6 weeks after start oftriptorelin or after CT, whichever is later.
** choice of +/- CT may be made by previousrandomization in the PERCHE trial.
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.
• 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
STP: Quality of Life Study
LASA scale example
Likert scale example
STP Target and Actual Accrual(through July 31, 2007)
0
500
1000
1500
2000
2500
3000
SOFT TEXT
Target
Actual
