EN.8 - A PHASE III STUDY OF STANDARD
THERAPY VERSUS RIDAFOROLIMUS IN
WOMEN WITH RECURRENT OR
METASTATIC ENDOMETRIAL CANCER
WHO HAVE PREVIOUS HAD
CHEMOTHERAPY
Proposed Design Change
• Accrual to the phase 2 studies has
been slower than expected.
• Reasons: start up for centres,
increasing use of prior chemotherapy
in preference to hormonal agent.
• Consider allowing either hormonal OR
chemotherapy as the control arm for
this study.
Schema
R
A
Women with
N
recurrent or
D
metastatic
O
endometrial
M
cancer
I
1-2 Prior
Z
Chemotherapy
E
Arm 1: ridaforolimus 40 mg
po days 1-5 each week
Imaging
Disease
Survival
q8
progression follow-up
weeks
Arm 2:
medroxy progesterone 200 mg
or
megestrol 160 mg (as per local
practice) po daily
Chemotherapy options
Sample size: Approximately 460 patients
Eligibility
•
•
•
•
•
Metastatic or recurrent endometrial cancer, not
curable by other means
Patient with endometrial carcinoma for whom a
hormonal therapy or chemotherapy would be
considered an acceptable treatment option.
At least one prior chemotherapy and up to two
prior chemotherapy regimens (chemotherapy
may have been administered in the adjuvant OR
for metastatic disease settings).
Measurable or non-measurable disease (per
RECIST) site of disease
ECOG Performance status 0-2
mTOR in Endometrial Ca
temsirolimus
everolimus
ROUTE
DOSE
1st LINE
ACTIVITY
2nd LINE
ACTIVITY
IV
25 mg Q wk
~25% RR
7% RR
(100/mo)
(60% SD)
(2/27)
10 mg QD
ND
0% RR
PO
(56/mo*)
ridaforolimus
IV
12.5 QDx5 Q2 wk
CBR 40%
ND
(130/mo)
9% RR
(4/45)
CBR 30%
ridaforolimu
s
PO
40 QDx5 Q wk
206I NCIC
205 RP2
(160/mo*)
RR
endpoint
PFS
endpoint
NCIC CTG IND.192
Phase II Trial Update
• Patients enrolled = 13
• 8 on study, 4 off study
• 1 confirmed PR to date
• (no prior chemo patient)
• Toxicity: ALT, Diarrhea,
Granulocytopenia,
Mucositis/Stomatitis (grade 1, 2)
Dose Intensity
(n = 9 patients)
Planned
Actual
Cycles (N)
Dose
Units/week Receiving
Median
Median
> 90% of
(Range) Intensity
(Range) Planned DI
112.5
ridaforolimus 2 (1-6)
200 mg (56.8-200)
11.1
Agent
Stratification
• Patients will be stratified by:
– Cooperative group
– Performance status
– Prior chemotherapy
– Hormone receptor (ER/PR) status
– Tumour grade
– Proposed treatment (chemo versus
hormones)
Endpoints
• Primary Endpoint:
– Overall survival
• Secondary Endpoints:
– Response rates
– Duration of response
– Time to progression
– Toxicity
– Quality of Life
– Economic Analysis
• Correlative Studies:
– To explore potential prognostic and predictive factors in
correlative studies of archival endometrial tissue.
Statistics
• The primary endpoint of the study is overall survival.
• We assume that the median overall survival for patients with
prior chemotherapy treated with hormones is 8 months and
the hazard ratio of ridaforolimus to hormones will be 0.75 (an
improvement of 2.7 months in median survival); a two-sided
alpha 0.05; and 80% power, then 380 deaths will be
required.
• Sample Size and Duration of Study
• Accrual rate duration of follow-up
sample size
total
duration
• 150 per year 12 months
450
4.0
years
• 200 per year 12 months
460
3.3
years
Translational Research
•
Formalin-fixed paraffin embedded blocks and one plasma blood sample will
be obtained from patients entered into EN.8 phase 3 trials.
•
These samples will be analyzed for genetic abnormalities likely to correlate
with benefit/resistance to mTOR inhibitor. The genetic profile will be
determined through translational research studies undertaken concurrent
with the proposed phase 3 trials.
•
The studies will evaluate the following:
–
–
–
One hundred snap frozen endometrial carcinoma specimens with associated
blood samples will be obtained from the Ontario Tumour Bank. DNA will be
extracted and assessed for amplifications and deletions. 100 samples will identify
genetic events occurring at > 3%.
DNA from formalin fixed paraffin embedded samples obtained from NCIC CTG
phase 2 studies of mTOR inhibitors will be extracted and analyzed for deletions
and amplifcations identified from study 1. DNA results will be correlated with
clinical outcomes of patients entered into the phase 2 trials to determine the
genetic abnormalities that correlate with patient outcome.
The genetic profile will be tested on tumour samples and germline DNA obtained
from patients enrolled on EN.8 study.
Status
• Company and NCIC CTG phase II trials underway
– Accrual slower than expected; both protocols amended to
allow 1 prior chemotherapy
– Company trial – RP2 - amended to allow
chemotherapy OR hormonal agent in control arm
– Projected completion of accrual April 2010 and analysis
around ASCO
• Potential to look at accrual rate and efficacy patients versus
hormone or dealers choice control
• Concept updated for potential international group
collaborators
• First draft of protocol completed – internal review
prior to distribution to company and collaborators
Questions
• Design acceptable?
• Chemotherapy Control Options?
– Proposed:
• Platinums – carboplatin, cisplatin
• Taxanes – paclitaxel, docetaxel
• Doxorubin or doxil
• Single agent or combination
• Groups that are interested?
• Expected accrual?