Transcript GIST clinical trials - The Life Raft Group

GIST Clinical Trials
Life Fest 2006
Jerry Call
September, 2006
Novartis video
 GIST-Gleevec
video
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
Trial phases

Phase I





Phase II


Further defines the safety and begins to evaluate effectiveness
Phase III



First step in humans
Increasing doses (cohorts) determine safe dose
Evaluate route of administration
Side effects
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
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, BMS354825, AMN107, BAY 43-9006
Early success- high expectations. GIST
patients spoiled by the initial success.
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
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. nonplacebo
 Early perception

Efficacy, side effects,
etc
Finding Clinical Trials
 http://www.liferaftgroup.org/treat_trials.html
 www.clinicaltrials.gov
 www.emergingmed.com
 http://www.gistsupport.org/
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?
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?
Failure to Inhibit KIT-secondary
mutations
Initial and secondary KIT mutations
Ligand binding domain
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. 21:4342-49)
Common initial mutations
Cell membrane
Possible Solutions:
•Different KIT inhibitor with
activity against both the
primary and secondary
mutation. Possibilities include:
•Sutent (approved in US)
Exon 9-Extracellular domain
•AMG706 (closed)
Exon 11-Juxtamembrane domain
•BMS-354825
•BAY 43-9006
Exon 13-Tyrosine kinase domain 1
In addition to the initial
mutation, secondary
mutations that
promote resistance
to Gleevec can occur.
Kinase insert
•Destroy KIT protein
•IPI-504
•Combinations; Gleevec +
Exon 17-Tyrosine kinase domain 2
•AMN107, PKC412, etc
Surgery and Imatinib for GIST:
Clinical Trials
Trial
Description
Phase II Study of Adjuvant Imatinib Mesylate in
Patients With Completely Resected High-Risk
Primary GIST (ACOSOG-Z9000)
End points: survival, 2- and 5-year recurrence rates, toxicity;
imatinib therapy initiated within 84 days of surgical
resection, continuing for 1 year; enrollment complete (N =
110)
Phase III Randomized Study of Adjuvant Imatinib
Mesylate in Patients With Resected Primary GIST
(ACOSOG-Z9001)
End points: overall, recurrence-free survival; imatinib or placebo
administered postoperatively for 1 year, with crossover to
imatinib if recurrence; projected enrollment = 380
EORTC Soft Tissue and Bone Sarcoma Group
End points: overall, recurrence-free survival; risk
stratification/randomization after complete GIST resection to
imatinib or no treatment for 2 years; projected enrollment =
400
Scandinavian Sarcoma Group Trial SSGXVIII
End points: recurrence-free survival, safety, overall survival;
imatinib administered postoperatively for 12 or 36 months;
projected enrollment = 80
Phase II Study of Neoadjuvant and Adjuvant Imatinib
Mesylate in Patients With Primary or Recurrent
Potentially Resectable Malignant GIST (RTOGS0132
End points: progression-free survival, objective response rate,
safety; 8 weeks of imatinib therapy, then surgical debulking
of all gross tumor and reinstitution of imatinib for 2 years;
projected enrollment = 63
GIST indicates gastrointestinal stromal tumor; ACOSOG, American College of Surgeons Oncology Group; EORTC,
European Organization for Research and Treatment of Cancer; RTOG, Radiation Therapy Oncology Group.
KIT and downstream pathways
are often targets in clinical trials
KIT
PKC-θ
AKT/mTOR
MAPK
PLC gamma
Jak/Stat 3
Survive-grow
PI3K - a central player –
But no drug yet!
PI3K
Survive
Proliferate
Effects of signaling inhibition on
proliferation in GIST cell lines*
Inhibition target
GIST882
Exon 13
(k642E)
GIST430
Exon 11
(V560D)+
Exon 13
(V654A)
GIST48
Exon 11+
Exon 17
(D820A)
PI3-K
45
38
28
MEK/MAPK
48
67
74
mTOR
79
62
80
PLC-gamma
90
89
99
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
KIT
Gleevec-SU11248-BMS354825-AMG706-AMN107
PKC412-BAY 43-9006-HSP-90 inhibitors (indirect)
Src/Fyn/Lyn
BMS-354825
PLC
JAK2
PI3K
DAG
AKT
PKC-θ
PTEN
Perifosine
Ca2
RAS
R115777-SCH66336
CAI
STAT3
mTOR
RAF-1
RAD001-CCI779
AP-23573-Rapamycin
BAY 43-9006
MEK
Survive-grow
BAD
STAT1
BCL-2
BCL-XL
Gentasense
VEGF
Avastin-Su11248-BAY 43-9006
PKC412-AMG706
Survive
New blood
vessel growth
MAPK
Proliferate
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
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.
Drug Targets
Gleevec
KIT
PDGFRα
PDGFRß
Bcr/abl
Sutent
KIT
PDGFRα
PDGFRß
VEGFR
FLT3
AMG706
KIT
PDGFRα
PDGFRß
VEGFR
RET
BAY439006
KIT
PDGFRß
VEGFR
FLT3
AMN107
KIT
PDGFRα
PDGFRß
Bcr/abl
BMS354825
KIT
PDGFRα
?
Bcr/abl
SCR
PKC412
KIT
PDGFRα
PDGFRß
VEGFR
PKC
FLT3
RAD001
mTOR
CCI-779
mTOR
AP23573
mTOR
Rapamycin
mTOR
Perifosine
AKT
Genasense
Bcl-2
IPI-504
HSP90
KIT
AKT
VEGF
?
17DMAG
HSP90
KIT
AKT
VEGF
?
OSI930
KIT
RET
?
VEGFR
?
Sutent


Pfizer Oncology
Other names






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.




SU11248 (sometimes appears as SU011248)
Sugen
Sunitinib malate (the generic name)
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.
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
Sutent concerns
 Increased
activity/growth during the “off
cycle”?
 Side effects



Heart toxicity? Is this concern overrated?
Hypertension
Increased fatigue
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?
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
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
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
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.
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 PDGFRα
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
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?



Next generation may include oral drugs


17DMAG
IPI-504 Infinity Pharmaceuticals phase I trial is open at
Dana-Farber (no results yet)
CNF20204 (Conforma)
The stronger KIT activation, the better the drug
works
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
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
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