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Investigator Meeting SOFT

Investigator Meeting SOFT. GOCCHI August 16, 2007. BIG. Tailored Treatment Investigations Premenopausal patients with endocrine-responsive disease (ER > 10% and/or PgR > 10%). Open questions related to adjuvant treatments: Role of suppression of ovarian function Role of AI

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Investigator Meeting SOFT

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  1. Investigator MeetingSOFT GOCCHI August 16, 2007 BIG

  2. Tailored Treatment InvestigationsPremenopausal patients with endocrine-responsive disease (ER > 10% and/or PgR > 10%) Open questions related to adjuvant treatments: • Role of suppression of ovarian function • Role of AI • Role of chemotherapy in addition to endocrine therapies • Duration of GnRH analogue when combined with SERMS

  3. STP Tailored Treatment InvestigationsPremenopausal 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. SOFT [IBCSG 24-02, BIG 2-02]Patients who remain premenopausal within 6 months after CT, or receive tamoxifen alone as adequate treatment Strata * P r e m e n o p a u s a l Premeno. ER  10% and/or PgR  10% Patients with estradiol (E2) in the premenopausal range either after CT or without CT R ANDOMIZE Any CT T x 5y OFS+ T x 5y OFS + Ex 5y No CT * 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

  11. SOFT: Eligibility (the basics) • Resected Breast Cancer • ER and/or PgR positive (10% IHC) • Premenopausal

  12. 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

  13. 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

  14. SOFT: Primary Objectives • Compare OFS + T vs T • Compare OFS + E vs T • Compare OFS + E vs OFS + T • Primary endpoint: Disease-free survival

  15. 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

  16. 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

  17. 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

  18. 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

  19. Exemestane • Irreversible inactivator of aromatase • Steroidal structure

  20. 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

  21. 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** R ANDOMIZE GnRH + Tamoxifen* x 5y +/- CT** GnRH +Exemestane* x 5yy +/- CT** Any CT No 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

  22. 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.

  23. 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

  24. 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

  25. STP: Quality of Life Study LASA scale example Likert scale example

  26. STP Target and Actual Accrual(through July 31, 2007)

  27. STP Information • STP@ibcsg.org • www.ibcsg.org

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