Transcript SARC 005

SARC 005:
Adjuvant treatment of high risk
uterine LMS with
gemcitabine/docetaxel followed
by doxorubicin: a phase II multicenter 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
Schema
Gemcitabine 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 antihormone 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
Gr 3
Gr 4
Gr 2
Gr 3
G/T
Dox
Dox
G/T
G/T
heme
heme
heme
hypersensitivity
hypersensitivity
4 pts (6 events)
6 pts (11 events)
3 pts (3 events)
3 pts (3 events)
1 patient (1 event)
No pulmonary toxicity
1 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 corrections
Type I error
0.05
0.05
0.05
Power
0.80
0.85
0.90
N for arm A or arm B
46
51
58
Total N for two arms
92
102
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 corrections
Type I error
0.05
0.05
0.05
Power
0.80
0.85
0.90
N for arm A or arm B
183
297
240
Total N for two arms
366
414
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