Anthony Tolcher Director of Clinical Research Institute for Drug Development CTRC, San Antonio TX
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Phase I Drug Development:Early Indications of Antitumor Activity
for Sarcoma Patients and Opportunities for Progress
Anthony TolcherDirector of Clinical Research
Institute for Drug DevelopmentCTRC, San Antonio TX
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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
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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
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May 18 2004 Sep 15 2004
AP23573- Phase I
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AP23573 Phase I
34 yr old female with GIST Refractory to Gleevec, ET743 and others
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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
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Integrated Proliferation/Apoptosis Targets
Adapted from Johnstone et al. Cell. 2002.
DR4/5
TRAIL
TRM1ETR2
YM155Oblimersen
CCI 779AP23573
R115777
TNTC
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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
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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
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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
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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