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

Sample size: Approximately 460 patients

Arm 2:medroxy progesterone 200 mgor megestrol 160 mg (as per local practice) po dailyChemotherapy options

Survivalfollow-up

Diseaseprogression

Imagingq 8 weeks

Arm 1: ridaforolimus 40 mg po days 1-5 each week

RANDOMIZE

Women with recurrent or metastatic

endometrial cancer

1-2 Prior Chemotherapy

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

ROUTE DOSE 1st LINE ACTIVITY

2nd LINE ACTIVITY

temsirolimus IV 25 mg Q wk

(100/mo)

~25% RR

(60% SD)

7% RR

(2/27)

everolimus PO 10 mg QD

(56/mo*)

ND 0% RR

CBR 40%

ridaforolimus IV 12.5 QDx5 Q2 wk

(130/mo)

ND 9% RR

(4/45)

CBR 30%

ridaforolimus

PO 40 QDx5 Q wk

(160/mo*)

206I NCIC

RR endpoint

205 RP2

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

Agent Cycles (N) Dose Units/week Receiving

Median (Range) Intensity

Median (Range)

> 90% of Planned DI

ridaforolimus 2 (1-6) 200 mg112.5

(56.8-200) 11.1

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 sizetotal 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?