Download Anthony Tolcher, MD

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
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
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
AP23573- Phase I
May 18 2004
Sep 15 2004
AP23573 Phase I
34 yr old female with GIST Refractory to Gleevec, ET743 and others
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
Integrated Proliferation/Apoptosis Targets
TRAIL
TRM1
ETR2
DR4/5
TNTC
CCI 779
AP23573
R115777
YM155
Oblimersen
Adapted from Johnstone et al. Cell. 2002.
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
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
Create a Relationship
1. Activity seen in phase I (sarcoma pt)
2. 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
Referrals
• This is key
– 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