Study Of Letrozole Extension

Investigator Meeting

Dec 13, 2007, San Antonio

Study Of Letrozole Extension

Coordinating Group

IBCSG

IBCSG 35-07

BIG 1-07

A phase III trial evaluating the role of continuous letrozole versus intermittent letrozole following 4 to 6 years of prior adjuvant endocrine therapy for postmenopausal women with hormone-receptor positive, node-positive early stage breast cancer

BackgroundS LE

• Current standard duration of adjuvant endocrine therapy for breast cancer (either SERMs or AIs) is 5 years.

• Improved DFS observed for:– Patients who receive extended adjuvant

letrozole for 5 years following 5 years of tamoxifen compared with 5 years of tamoxifen alone. (MA.17)

– Switching from tamoxifen to an AI after 2 to 3 years of tamoxifen to complete five years of endocrine therapy. (EIS)

– 5 years of initial AI compared with 5 years initial tamoxifen. (ATAC, BIG 1-98)

0

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4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12

Years

Perc

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Adapted from Saphner et al, JCO 1996

N=2257Annualized Hazard of Recurrence For ER+

Patients in ECOG Trials

BackgroundS LE

BackgroundS LE

• Open Questions about AIs–Optimal duration–Best schedule of AIs in the extended

adjuvant setting.

S LEHypothesis

Introducing 3-month treatment-free intervals during the course of five years of extended adjuvant letrozole will improve disease-free survival.

Hypothesis is based on the theory that letrozolewithdrawal for 3 months will permit some estrogenic stimulation which will make residual resistant disease susceptible to letrozolereintroduction.

Patient PopulationS LE

• Postmenopausal• Disease-free after 4 and 6 years of

prior adjuvant endocrine therapy (SERM and/or AI)

• Endocrine-responsive breast cancer at diagnosis

• Node-positive breast cancer at diagnosis

S LERANDOMIZE

Continuous letrozole x 5 yrs

StratifyInstitutionPrior ET:SERMAIBoth

Intermittent letrozole over 5 yrs

9 mos. 9 mos. 9 mos. 9 mos. 12 mos.

0 6 12 18 24 30 36 42 48 54 60

Extended Adjuvant Endocrine TherapyA: Continuous letrozole 2.5 mg daily for 5 yearsB: Intermittent letrozole 2.5 mg daily for the first 9

months of years 1 through 4, followed by 12 months in year 5

End Points• Primary: Disease-free survival (DFS) • Time from randomization to first occurrence of:

– Local relapse (including invasive recurrence restricted to the breast after breast-conserving treatment)

– Regional relapse– Distant relapse– Contralateral breast cancer– Appearance of a second (non-breast)

malignancy – Death from any cause

S LE

End PointsS LE

• Secondary:–Overall survival (OS)–Distant disease-free survival (DDFS) –Breast cancer free interval (BCFI)–Sites of first failure–Second (non-breast) malignancies–Deaths without prior cancer events–Adverse events

Statistical ConsiderationsS LE

• Hypothesize 20% reduction in risk of a DFS event (HR = 0.80) with intermittent letrozolevs. continuous letrozole

• Assumes 4-year DFS = 90% for continuous letrozole (based on N+ cohort in MA.17)

• 2 interim and 1 final analysis at 647 DFS events

• 80% power; two-sided 0.05 level test of significance

• Target=4800 patients • 1600 patients per year for 3 years, 5 years of

additional follow-up; one year start-up time anticipated

Eligibility: Postmenopausal

Definitive confirmation of postmenopausal status is required. • Any age with bilateral oophorectomy (including

radiation castration AND amenorrheic for > 3 months)

• Age 56 or older: If the patient has any evidence of ovarian function, biochemical evidence of definite postmenopausal status (defined as estradiol, LH, and FSH in the postmenopausal range) is required

• Age 55 or younger must have biochemical evidenceof postmenopausal status

Note: Patients who have received prior LHRH analogue within the last year are eligible if they have biochemical evidence of postmenopausal status

S LE

Eligibility: Disease Characteristics

• At randomization: Patients must be clinically disease-free

• No previous or concomitant malignancy EXCEPT adequately treated: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, contra- or ipsilateral in situbreast carcinoma.

• No bilateral breast cancer• At diagnosis

– Operable, non-inflammatory breast cancer– Steroid hormone receptor positive tumor (ER

and/or PgR) determined by IHC– Node-positive (axillary or IM nodes)

S LE

Eligibility: Prior/Concurrent Treatment

• Proper local treatment including surgery with or without radiotherapy for primary breast cancer with no known clinical residual loco-regional disease.

• Completed 4 to 6 years of prior adjuvant endocrine therapy with SERMs, AIs, or a sequential combination of both.

• Stopped prior endocrine SERM/AI therapy• Randomized within 12 months of the last dose

of prior SERM/AI• No restriction on other prior adjuvant therapies• Stopped HRT, bisphosphonates (except for

treatment of bone loss), or any investigational agent at randomization.

S LE

Eligibility

S LE

• Pathology material from the primary tumor must be available for submission for central review as part of the quality control measures for this protocol

• No bone fractures due to osteoporosis at any time during the 4-6 years of prior endocrine SERM/AI therapy

• Adequate hepatic function• Trial and tissue informed consent

Patient Visit ScheduleS LE

• All patients will be followed every 6 months for years 1 to 5, and thereafter yearly for assessment of disease status and for survival data collection.

Patient Reported Symptoms and Quality of Life Substudy

QL Substudy Background• Information about concomitant and late

symptoms of adjuvant endocrine therapies is crucial when guiding the patients through treatment.

• Randomized trials in postmenopausal women revealed a differential impact on QL domains by different endocrine agents.

• An extension of treatment implies a continuation of endocrine symptoms, which may be a burden to the patient.

S LE

S LEQL Substudy Hypotheses

• Introducing 3-month treatment-free intervals during the course of 5 years of extended letrozole will reduce both the number and the bother of symptoms.

• However, starting and stopping treatment repeatedly over 5 years may be more burdensome on a global QL level than undergoing continuous treatment for 5 years.

S LERANDOMIZE

Continuous letrozole x 5 yrs

StratifyInstitutionPrior ET:SERMAIBoth

Intermittent letrozole over 5 yrs

9 mos. 9 mos. 9 mos. 9 mos. 12 mos.

0 6 12 18 24 30 36 42 48 54 60

QL assessment time points

S LEQL Substudy Forms

• Form 35-PRS: Patient reported endocrine symptoms (1 page)

• Form 35-QL: Selected IBCSG QoLindicators (1 page)

• Form 35-AC: Assessment Checklist(1 page)

S LEQL Substudy Sample Size

• To achieve 90% statistical power to detect an effect size of 0.25 between the two groups

• 338 patients in each randomized treatment arm (676 total)

• 744 patients are needed to allow for a 10% non-compliance rate

S LEQL Substudy Participation

• selected centers

• with a history of high recruitment rates and

• good QL compliance in other IBCSG trials

Logistics and Activation

Distribution / activationS LE

• Distributed to IBCSG membersNovember 8, 2007

• First patient in Dec 5, 2007 (earlyactivation in selected countries and centers)

• Activation in sites ongoing

Activation stepsS LE

1. IBCSG CC distributes protocol/appendices/CRFs2. Center/group and IBCSG CC agree on activation

procedure3. Center/group and IBCSG CC develop necessary

documents4. IBCSG CC provides insurance policy5. Center/group applies for regulatory/EC approval6. Center/group submits all requested docs to

IBCSG CC7. IBCSG CC activates center

Activation stepsS LE

1. IBCSG CC distributes– Protocol– Appendices– CRFsto all IBCSG centers and to interested groups

The distribution letter contains detailedinstructions

Activation stepsS LE

2. Center/group and IBCSG CC agree on activation procedure

- center/group contacts IBCSG CC- Initial contact with all involved- Establish list of involved persons- explain all necessary steps- Agree on communication lines- Agree on timelinesIBCSG CC is prepared to help as much as

possible

Activation stepsS LE

3. Center/group and IBCSG CC developnecessary documents

- IBCSG CC provides translated PIS/IC and trial summary (if not already available)and QL forms (if center participates in QL)

- Center/group adapts PIS/IC and trialsummary to local/national needs

- IBCSG CC provides CTA (for EU countries)- Both develop group specific appendix

including drug supply details- Both work on subcontract

Activation stepsS LE

4. Insurance policy- IBCSG CC needs realistic accrual estimate- Contracts insurance with appropriate

insurance company- Supplies insurance policy to center/group- Center/group submits to regulatory

authorities and EC

Activation stepsS LE

5. Center/group applies for regulatoryapproval

- Submission to central/local ethicscommittee / IRB

- Submission to regulatory authorities

… according to local/national regulation

EC fee covered by IBCSG

Activation stepsS LE

6. Center/group submits all requesteddocs to IBCSG CC

As specified in the distribution letter,especially (but not only):- EC/IRB approval- Regulatory authorities approval- Locally approved PIS/IC- Protocol signature page- Signed subcontract- Authorization log

Activation stepsS LE

7. IBCSG CC activates center

- Drug Supply organized and shipment to siteconfirmed

- Activation e-mail

- Authorization to randomize patients throughthe web-based randomization system

Drug supplyS LE

Letrozole will be supplied by Novartis freeof charge for both arms

Commercial batches of Letrozole (Femara®2.5 mg) will be used overlabelled as clinical trial medication

Femara packs containing 30 tablets will bedispensed to patientsfor entire trial duration:60 packs for continuous Arm 48 packs for intermittent Arm

Drug supplyS LE

For Initiation of Drug Supply by IBCSG:All regulatory documents (country

specific authorizations → HealthAuthority/EC approvals) must be in place

Drug supplyS LE

Initial supply: will be ordered by IBCSG CC prior to activation of site

Local Novartis Country Office orSubcontractor (eg warehouse) will distribute the drug to sites

Drug supplyS LE

Resupply: site to order resupply directly from

Novartis or distributor (country-specific procedure, detailsdescribed in Logistics App.V)

Important: monitoring of stocks, accurate drug accountability, order re-supplies timely

SAE ReportingS LE

Collect, record, assess and report SAEs• during and up to 4 weeks after trial

treatment stop→ all adverse events qualifying as serious

• ≥ 4 weeks after trial treatment stop→ all deaths and other SAEs at least possibly related to trial treatment→ all 2nd non-breast malignancies→ all congenital abnormalities

How to report SAEsS LE

Submit (datafax) initial SAE-reportwithin 24 hours after occurrence of the event, Follow-up report uponresolution of the event or within15 days

use Forms 35 SAE-A & 35 SAE-B

Processing & Handling of SAE Reports by IBCSG

S LE

• Medical review• Assessment of expectedness• Distribution of the SAE-reports to

Novartis Central Clinical Trial Safety Office and other parties concerned

• Notification of investigators and regulatory authorities if expeditedreporting is required (unexpectedserious adverse reactions)

• Preparation of periodic reports(monthly, annual)