1. Phase I Drug Development: Early Indications of Antitumor Activity for Sarcoma Patients and Opportunities for Progress
Anthony Tolcher
Director of Clinical Research
Institute for Drug Development
CTRC, San Antonio TX

2. Phase-1-ologist Pronounced: faez·won·ole·geest Definition:
1small curious creature that inhabits Texas, Ohio, California, and occasionally Arizona.
2Exhibits animated activity when exposed to novel chemical structures or mechanisms of action
3Becomes ecstatic if one patient in 40 has response

3. Conventional Wisdom Focus on main indications
Breast, lung, colon, maybe prostate
Smaller pharma- quickest route to NDA
unmet need, or accelerated approval
Serendipity versus screening
Apriori, cannot predict activity
If we fail to have sarcoma patients, it is hard for us to convince sponsors to explore sarcoma as an indication

4. AP Phase I
May
Sep

5. AP23573 Phase I
34 yr old female with GIST Refractory to Gleevec, ET743 and others

6. Activity in Phase I Meaningful for Some Agents
Regulatory Success from phase I activity
Iressa: NSCLC activity phase I
colon intended as indication
Contrast Tarceva
Irinotecan: persistent SD in colorectal
Gemcitabine: pancreas

7. Integrated Proliferation/Apoptosis Targets
TRAIL
TNTC
TRM1
ETR2
DR4/5
CCI 779
AP23573
R115777
YM155
Oblimersen
Adapted from Johnstone et al. Cell

8. Current Phase I Targets
Survivin
MFH
TRAIL R1
TRAIL R2
Durable SD
PDGFR
c-Met
Multi-targeted TKi
Integrins
mTOR
IGFR
Considerable literature
PARP
Kinesin 1 inhibitors
Aurora Kinase Inhibitors
Polo kinase inhibitors
C-myc

9. Opportunities for Strategic Collaborations
Sarcoma patients account for 10% or less of IDD phase I population (500 yr)
Serendipity or screening?
Can we increase “chance” to see activity
Known targets in sarcoma subtypes
Direct patients to studies
Early identification of activity, rapid dissemination to phase II through affiliation

10. Create a Relationship Activity seen in phase I (sarcoma pt)
Rapid access network of phase II sarcoma investigators to conduct study
Accrual remains a serious concern
Need to be “problem-free”
Quality of data remains the key

11. Referrals This is key Help from patient advocates
Early Screen / serendipity
40% of our patients come from southern USA
Good performance status, adequate organ function
Help from patient advocates
Opportunities for patients looking for expt options