SARC 005:

Adjuvant treatment of high risk uterine LMS with

gemcitabine/docetaxel followed by doxorubicin: a phase II multi-

center trial

PI: Martee L. Hensley, MD

Objectives:

• Determine 2-year PFS among women with uterine LMS treated with gem-doce x 4, followed by doxorubicin x 4

• Determine tolerability/toxicity • Explore predictors of PFS: age, tumor size,

grade, serosal involvement, STS stage v. FIGO stage, mitotic rate, ER, PR, menopausal status at dx

SchemaGemcitabine 900 mg/m2 over 90 minutes days 1, 8

Docetaxel 75 mg/m2 day 8

q 3 wk x 4 cycles

Repeat CT scan

Doxorubicin 60 mg/m2 q 3 w x 4

Repeat CT scan within 6 weeks after

CT c/a/p every 3 mo for 2 y, then every 6 mo

Eligibility

• > 18 years• FIGO stage I or II, high grade

LMS s/p hysterectomy (serosal involvement IS eligible even though this is FIGO IIIA)

• <12 weeks from surgery• NED by CT within 3 weeks of

enrollment• Good marrow, kidneys, liver

• No other cancer within 5 years

• No prior gem, doce, or dox• No prior pelvic RT• No current HRT or anti-

hormone therapy• EF > 50%

Correlative studies

• Provide tumor details: size, serosal disease, mitotic rate

• Provide patient details: age, menopausal status at dx and at start of adjuvant therapy

• Send unstained slides to MSKCC-ER and PR

-institutions are paid $75 when slides are received

Statistical issues

• Target accrual 45 patients

• Bayesian model for continuous assessment of PFS and safety

• Accrue at least 15 patients per year

• Stop early if data suggest 2 year PFS will be no better than 30%

Calculating futility

• Event: death or evidence of progression

• Stop if number of events is too many for the total patient-disease-free-days-on study:

Number of events Minimum total time on test in days

1 0

2 0

3 408

4 920

5 1435

6 1955

7 2477

8 3003

Data capture and management

• On line SARC registration• On line data entry• On line CRFs—easy to use

- all grade 3 and 4- selected grade 2 (neuro, hypersensitivity,

pulmonary)• Data monitored by SARC• Some detail for management plan after recurrence• Vital status after recurrence every 6 months

Drug details

• Gemcitabine and docetaxel both supplied

• Drug distribution from SARC via Biologics to institutions

Open Sites

• MSKCC• Washington Cancer

Institute• U Michigan• Dana Farber• U Chicago

• Penn Onc/Hem• Moffitt• St. Vincent’s• Mass General• MedStar• MDACC

Results

First accrual: 2/13/06

• Accrual to date: 22 patients

• Recurrence/Death events = 0

• 9 patients have completed all planned therapy

• Progression-free days = 5211 (as of 28 Sep 07)

Results—are we on target?

• Target accrual goal 15 patients per year: in 19. months we have 22—seems okay

• Treatment is highly unlikely to be futile: up to 7 events could have happened in 2477 days and we have had 0 events in over 5700 days

Results: toxicity

Gr 3 G/T heme 4 pts (6 events)Gr 3 Dox heme 6 pts (11 events)Gr 4 Dox heme 3 pts (3 events)Gr 2 G/T hypersensitivity 3 pts (3 events)Gr 3 G/T hypersensitivity 1 patient (1

event)

No pulmonary toxicity1 patient off study treatment for abnl AST/ALT after C3 G/T—

proceeded on to doxorubicin. Remains on study for f/u purposes

For discussion:

• Clarify in next amendment that patients that must discontinue Gem-Doce for toxicity reasons may remain on study treatment to complete the doxorubicin

Discussion of next steps:

• Is a phase III trial with a no-chemotherapy control arm accruable?

• Scientifically reasonable control arm options are:– Pelvic RT (would likely appeal to Gyn Onc/GOG)– Observation (could be hard to accrue)

Phase III size considerations:

• Home run assumption: 50% PFS at 2 y for “no chemo” group (arm B) and 80% PFS at 2 y for “chemo” group (arm A).

-two sided 0.05 level calculation with continuity correctionsType I error    Power   N for arm A or arm B    Total N for two arms   

0.05    0.80    46      92     0.05    0.85    51      102    0.05    0.90    58      116    

Phase III size considerations:

• Chemo improves PFS by 30% assumption: 50% PFS at 2 y for “no chemo” group (arm B) and 65% PFS at 2 y for “chemo” group (arm A).

-two sided 0.05 level calculation with continuity correctionsType I error    Power   N for arm A or arm B    Total N for two arms   

0.05    0.80    183      366    0.05    0.85    297      414   0.05    0.90    240    480    

Are there other options?:

• Increase the sample size of SARC 005 in order to narrow the confidence interval?

• Open the eligibility to non-uterine LMS (which will of course increase heterogeneity)?

• Even if we put our hearts and time behind a phase III, funding for such large trial may be very challenging