September, 2006

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GIST Clinical Trials Life Fest 2006 Jerry Call

• September, 2006

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Novartis video

• GIST-Gleevec video

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Why do Patients Participate in Trials?

• 89-Obtaining possible benefit very important
• 17-Helping future cancer patients/treatments
• Other factors cited as very important
• 66-Trust in doctor
• 66-Being treated by the latest treatment
  available
• 61-Better standard of care and closer follow-up
• 71 stated that surviving for as long as
  possible was the most important thing for them
• Survey of 38 patients participating in phase I
  and phase II trials
• British Journal of Cancer (2005) 92, 1001-1005

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Trial phases

• Phase I
• First step in humans
• Increasing doses (cohorts) determine safe dose
• Evaluate route of administration
• Side effects
• Phase II
• Further defines the safety and begins to evaluate
  effectiveness
• Phase III
• Compare a new agent with the current standard
  treatment.
• Randomized to groups
• Phase IV
• Usually take place after the treatment is
  approved
• Further evaluate long-term safety and
  effectiveness

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High Patient Interest in GIST Trials

• Success of Glivec
• But also, an educated patient population
• Internet-based support groups
• Patients continue to join trials of new therapies
  for GIST
• SU11248, AMG706, RAD001, PKC412, BMS-354825,
  AMN107, BAY 43-9006
• Early success- high expectations. GIST patients
  spoiled by the initial success.

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Patients use clinical trials to survive

• Access to the latest drugs
• Medical team that is more familiar with GIST
• Medical treatment and monitoring are usually
  better
• Clinical trials move GIST research forward
• May be a last resort/last chance

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Factors Affecting Choice in Trials

• Location
• Travel
• How far?
• How often?
• How long do you have to say?
• Phase

• Eligibility
• Inclusion/exclusion
• Insurance coverage
• National health care issues
• Placebo vs. non-placebo
• Early perception
• Efficacy, side effects, etc

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Finding Clinical Trials

• http//www.liferaftgroup.org/treat_trials.html
• www.clinicaltrials.gov
• www.emergingmed.com
• http//www.gistsupport.org/

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Navigating Clinical Trials

• Phase l Starting at the right dosage level
• Determining Eligibility
• Logistic and Financial Issues
• Where is the trial site?
• Am I eligible to go there?
• How often to I have to go there?
• For how long?
• At what costs?

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Previous Treatment Exclusions

• Participation in some trials may prevent entry
  into other trials
• Example Phase II AMG706 does not allow previous
  inhibitors of c-Kit (except Glivec) or VEGF
  inhibitors (SU11248, PTK787, Avastin).
• How do we maximize the chance for success for
  both patients and trials?

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Failure to Inhibit KIT-secondary mutations

• Possible Solutions
• Different KIT inhibitor with activity against
  both the primary and secondary mutation.
  Possibilities include
• Sutent (approved in US)
• AMG706 (closed)
• BMS-354825
• BAY 43-9006
• Destroy KIT protein
• IPI-504
• Combinations Gleevec
• AMN107, PKC412, etc

Prior to treatment with Gleevec none of 112 GIST
samples had more than one activating mutation in
KIT or PDGFRA (Heinrich MC, et al. J Clin Oncol
2003. 214342-49)
Common initial mutations
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Surgery and Imatinib for GIST Clinical Trials
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KIT and downstream pathways are often targets in
clinical trials
KIT
PI3K - a central player But no drug yet!
PI3K
PKC-?
AKT/mTOR
MAPK
Jak/Stat 3
PLC gamma
Survive-grow
Survive
Proliferate
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Effects of signaling inhibition on proliferation
in GIST cell lines
Cell lines with secondary KIT mutations were
hyperactivated. KIT activation levels were 3 to 6
times higher than the cell line with a single KIT
mutation. Bauer et al, 2005 ASCO
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KIT Gleevec-SU11248-BMS354825-AMG706-AMN107 PKC412
-BAY 43-9006-HSP-90 inhibitors (indirect)
Src/Fyn/Lyn BMS-354825
PLC
PI3K
JAK2
DAG
PKC-?
AKT Perifosine
RAS R115777-SCH66336
PTEN
Ca2 CAI
STAT3
mTOR RAD001-CCI779 AP-23573-Rapamycin
RAF-1 BAY 43-9006
MEK
BAD
Survive-grow
STAT1
MAPK
BCL-XL
BCL-2 Gentasense
Proliferate
Survive
VEGF Avastin-Su11248-BAY 43-9006 PKC412-AMG706
New blood vessel growth
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Drugs in GIST trials

• Sutent
• BAY 43-9006
• BMS-354825
• IPI-504
• CCI-779 (complete)
• AMG706 (complete)

• AMN107 Gleevec
• RAD001 Gleevec
• PKC412 Gleevec
• Perifosine Gleevec
• Genasense Gleevec

• Future Trials?
• Avastin Gleevec
• OSI-930

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Sarcoma Trials that allow GIST

• Doxorubicin Flavopiridol
• Phase I-MSKCC
• Flavopiridol is an inhibitor of the cell cycle
  and an inhibitor of transcription
• FR901228
• Phase II
• Belongs to a new class of chemotherapy drugs
  called histone deacetylase inhibitors (HDAC
  inhibitors). This is a class of drugs that works
  at a higher level within the cell-acting on the
  genome, which is like the master control room for
  all of the genes in a cell.

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Drug Targets
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Sutent

• Pfizer Oncology
• Other names
• SU11248 (sometimes appears as SU011248)
• Sugen
• Sunitinib malate (the generic name)
• TKI-KIT, PDGFR, FLT-3, VEGF
• Only drug with proven ability against Gleevec
  resistant GIST
• Approved in the United States, Canada and the
  U.K.
• Europe?
• Available in other countries via a Treatment use
  protocol administered by EmergingMed
  (1-800-620-6104)
• Phase II continuous use trial is closed
• New phase IIIb trial will test 800 mg Gleevec vs.
  continuous use Sutent (37.5 mg) in GIST that is
  resistant to 400 mg Gleevec.

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Sutent-2

• Gleevec-resistant GIST highly sensitive to
  SU11248
• KIT
• Exon 9
• Wild-type for KIT PDGFRA
• Secondary exon 13 or 14
• Gleevec-resistant GIST less sensitive to SU11248
• KIT exon 11
• KIT secondary exon 17, exon 18 mutations

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Sutent concerns

• Increased activity/growth during the off cycle?
• Side effects
• Heart toxicity? Is this concern overrated?
• Hypertension
• Increased fatigue

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AMN107 ( Gleevec)

• Phase I/II GIST trials underway
• US
• Boston
• Philadelphia
• Europe
• Leuven, Belgium
• Lyon, France
• Berlin, Germany
• Milan, Italy
• AMN107 targets Bcr/Abl, KIT and PDGFRA (the same
  targets as Gleevec)
• The combination of AMN107 and Gleevec may provide
  a broad spectrum of activity against different
  primary and secondary mutations
• Compassionate use
• Registration trial-Fall of 2006?

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mTOR as a target

• mTOR is a downstream protein in the KIT and PDGFR
  pathways
• Three mechanisms of anti-tumor activity
• Tumor cell shrinkage
• Cell cycle arrest at late G1
• Anti-angiogenesis

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mTOR inhibitors

• RAD001
• In phase I trials in combination with Gleevec.
  RAD001 is approved for transplant patients in
  many European countries
• AP23573
• Ongoing sarcoma trials. GIST?
• CCI-779
• Ongoing phase II GIST trial as a single agent
• Rapamycin (Rapamune)
• Earliest mTOR inhibitor (least advanced?)
• Approved for transplant patients in many
  countries

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BMS-354825

• TKI inhibitor of Bcr-Abl, KIT, PDGFRA, Src
• Activity against both the inactive and active
  kinase conformations of Bcr-Abl (and also KIT?)
• Effective against 14 of 15 Gleevec resistant CML
  mutations
• Not effected by p-glycoprotein MDR efflux pump
• 300 to 650 times more potent than Gleevec against
  Gleevec resistant CML lines
• Less effective for KIT? For GIST, may need to be
  dosed near the MTD

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Perifosine and Genasense

• Perifosine
• Small molecule inhibitor of AKT.
• AKT is an anti-apoptosis protein. Inhibition of
  AKT may enhance therapy.
• Phase II trial combining Gleevec Perifosine at
  MDACC.
• Genasense
• An antisense drug that inhibits bcl-2, an
  anti-apoptosis protein. Inhibition of bcl-2 may
  enhance therapy.
• Phase II trial at MDACC is accruing patients. The
  trial combines Gleevec Genasense. Four more
  trial sites are pending activation.

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BAY 43-9006

• Known as a RAF kinase inhibitor, but also a
  powerful KIT inhibitor, as well as VEGFR2
• RAF is part of the MAPK downstream pathway in KIT
  and PDGFR
• Inhibition of multiple kinases may be more
  effective (KIT, RAF, VEGF)
• Inhibits PDGFRß, but not PDGFRa
• Several responses in Imatinib-resistant GIST have
  been reported
• FDA approved for advanced kidney cancer
• Phase II GIST trials at Univ. of Chicago and
  other centers

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IPI-504

• HSP90 inhibitors
• 17AAG (poor drug-like qualities)
• Would participation in a trial of 17AAG preclude
  entry into a trial with one of the newer drugs?
• 17DMAG
• IPI-504 Infinity Pharmaceuticals phase I trial is
  open at Dana-Farber (no results yet)
• Next generation may include oral drugs
• CNF20204 (Conforma)
• The stronger KIT activation, the better the drug
  works

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HSP90

• The HSP90 protein helps to fold proteins into
  their proper conformation and protects client
  proteins
• Improperly folded proteins are not functional and
  are destroyed within the cell
• HSP90 inhibitors degrade KIT and other proteins
  in GIST
• Will the lack of specificity contribute to side
  effects?
• OR
• Will the broad-activity contribute to anti-tumor
  effects?
• In theory works against KIT regardless of
  secondary mutations

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PKC-412 ( Gleevec)

• TKI inhibitor of several PKC isoforms
• but perhaps not the most relevant one for GIST
  (PKC theta)? Also inhibits KIT, PDGFR, VEGF, and
  FLT3
• PK interactions with Gleevec, resulting in the
  need for very high doses of Gleevec
• Phase I trials proceeding at a slow pace
• Germany and US
• Not currently recruiting patients
• In vitro activity against many secondary KIT
  mutations and PDGFRA mutations

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AMG706

• AMGEN
• Inhibits KIT, PDGFR, RET, and all VEGF receptors
• Phase II trials closed.
• Less side effects than SU11248?
• Continuous dosing schedule
• Efficacy does not support a FDA filing
• Results to be presented in late 2006, will not
  move forward in Gleevec-resistant GIST