1. Clinical Trials Explained and Explored
Presented By:
Jerry Call
March 11, 2013

2. What is a Clinical Trial?
Health-related research study
Requires ethics review (IRB)
Follows a pre-defined protocol
Requires informed consent
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Only 2-4% of cancer patients participate in clinical trials

3. 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,
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4. Risks Benefits May not be effective Side effects
Additional testing, time and travel (travel expenses)
Some costs may not be covered by insurance
Option to access treatment after standard treatments fail
Receive treatment at a major GIST trial center
Help future patients
Last bullet point is “Help future patients”

5. Pre-Clinical Evidence of Effect in GIST
Clinical Trial Phases
Effect
Regulatory
Approval
Further Study
Safety 1 2 3 4
Pre-Clinical Evidence of Effect in GIST
Effective in GIST
Compare
After Approval ?
GIST Targets
Drug Candidates
Sometimes Combined
Long Term
Effects
The overall picture:
In general cancer drugs have taken 7-9 years to travel this path
Gleevec did it in two years in GIST (but it had the benefit of CML preceding)
It can be done when efficacy is high (70 % benefit versus <10% typical) and side effects are minimal.
We are all looking for that next “Gleevec”
Phase I
First step in humans
Increasing doses (cohorts) determine safe dose
Evaluate route of administration
Side effects
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
Phase II
Further defines the safety and begins to evaluate effectiveness
Approx 10% of drugs that start get approved

6. FDA Procedures that look like trials
Compassionate access
Expanded access
Single patient IND
Treatment use
Example; Sutent Treatment Use protocol
There are several names for trials that provide access.
These do not have the same inclusion/exclusion criteria.
Because of potential bias, the study end points in these trials are limited.
We did see some data from nilotinib compassionate access at ASCO this month.

7. High Patient Interest in GIST Trials
Success of Gleevec

8. GIST Survival-Historical vs. Current Therapy*
*Lancet 2004;

9. High Patient Interest in GIST Trials
Success of Gleevec
Educated patient population
Internet-based support groups
Patients continue to join trials of new therapies for GIST
But at a declining rate?
Early success- high expectations
GIST patients spoiled by the initial success
Off-Label drug access

10. Factors Affecting Choice in Trials
Eligibility
Inclusion/exclusion
Insurance coverage
National health care issues
Placebo vs. non-placebo
Early perception
Efficacy, side effects, etc
Location
Travel
How far?
How often?
How long do you have to stay?
Phase
Mutation type
Last bullet is Mutation Type
Next slide talks about phase I dose, eligibility, logistic/financial issues
Some trials may have a placebo
Some placebo trials have a crossover provision to receive the treatment being evaluated
Some placebo trials (none in GIST or CML yet) have no provision for crossovers

11. 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?

12. Previous Treatment Exclusions
Participation in some trials may prevent entry into other trials
Examples
Treatment with an HSP90 inhibitor may exclude you from trials with a different HSP90 inhibitor
Treatment with a VEGFR inhibitor may prevent treatment with a second VEGFR/KIT inhibitor
May require some planning to “sequence” trials
May be good or bad. Need to balance the need for both patient and trial to have the maximum chance for success.
LRG example: Talks with the sponsor (Amgen) led to Amgen’s agreement to extend their phase I trial and allow entry of this patient population into that trial.

13. Treatment Phases Recently Diagnosed Stable Disease 2nd Line
3rd Line and beyond

14. Recently Diagnosed Neoadjuvant trials Adjuvant trials
Does drug therapy before surgery make surgery easier?
Adjuvant trials
Does Gleevec after surgery prevent or delay a recurrence of GIST
First Line Trials
Is another drug better than Gleevec when given to new patients?
Plasma levels?
Is another drug more tolerable?
By genotype

15. 1st line Trials Masitinib Crenolanib (D842V mutation only)
Phase III
USA
Florida
Ohio
Crenolanib (D842V mutation only)
Fox Chase
OHSU
Dasatinib (Sprycel)
Recently closed

16. Stable Disease Surgery for metastatic GIST that is stable?
Difficult to randomize patients to surgery

17. 2nd line means “After Failure of Gleevec”
2nd Line Trials
Sutent + TH-302
Masitinib vs Sutent
Phase 3 trial recently opened; 50 sites.
2nd line means “After Failure of Gleevec”

18. Resistant to Gleevec 1st Line 2nd Line 3rd Line 4th Line & beyond
Surgery, RFA, Ablation for limited progression
400 mg 800 mg
2nd Line
Sutent
3rd Line
Stivarga (regorafenib)
4th Line & beyond
Clinical trials
Off-label
Treatment Use Trials (expanded access)
Discusses what normally happens when you are resistant to Gleevec,
1st line
2nd line
3rd line
4th line & beyond (trials & off label)

19. Mutation Characteristics Possible Solutions
Target KIT and secondary mutations
Secondary mutations are frequent
Exon 11
Less sensitive to imatinib
Less secondary mutations?
Exon 9
Insensitive to imatinib
Insensitive to sunitinib
Primary resistance
PDGFRA
Imatinib poor WT-KIT inhibitor
KIT may remain activated
2/3 overexpress IGF1R
Some driven by SDH mutations
Wild-Type
KIT exon 13
KIT exon 17
PDGFRA exon 12
PDGFRA exon 18, non D842V
Rare Mutations
Higher dose IM or Sutent
Much not known
CP-868,596 (ph II trial)
Dasatinib?
HSP90 or PI3K inhibitor
Potent WT KIT inhibitors
IGF-1R
SDH ?
Little clinical data
Some in-vitro data

20. Failure to Inhibit KIT-secondary mutations
Initial and secondary KIT mutations
Ligand binding domain
Exon 9-Extracellular domain
Exon 11-Juxtamembrane domain
Exon 13-Tyrosine kinase domain 1
Exon 17-Tyrosine kinase domain 2
Kinase insert
Cell membrane
Possible Solutions:
Different KIT inhibitor with activity against both the primary and secondary mutation. Possibilities include:
Sutent (approved in US)
Stivarga (approved in US)
Dovitinib
DCC-2618 (Deciphera)
Destroy KIT protein
STA-9090, AUY922
Combinations; Gleevec +
AT13387, BKM120, 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 : )
Common initial mutations
In addition to the initial mutation, secondary mutations that promote resistance to Gleevec can occur.

21. Drugs and Names
IND INN Brand Name Manufacturer
STI-571 Imatinib Gleevec/Glivec Novartis
SU Sunitinib Sutent Pfizer
AMN107 Nilotinib Tasigna Novartis
Bay Sorafenib Nexavar Bayer
BMS Dasatinib Sprycel Bristol-Myers Squibb
Bay Regorafenib Stivarga Bayer
GW786034B Pazopanib Votrient GlaxoSmithKline
STA Ganetespib Synta
AB1010 Masitinib AB Science
OSI 906 Linsitinib OSI Pharmaceuticals
LBH589 Panobinostat Novartis
RAD001 Everolimus Afinitor Novartis
L Vorinostat Zolinza Merck
IND – Investigational New Drug INN – International Non-proprietary Name

22. Drugs and Names (Cont.) Stem Meaning
-tinib = Tyrosine Kinase Inhibitor (imatinib, sunitinib, regorafenib)
-mab = Monoclonal Antibody (ipilimumab)
-rolimus = Rapamycin Derivatives (mTOR inhibitors) (everolimus)
-inostat = Histone Deacetylase (HDAC) Inhibitors (vorinostat)
World Health Organization (WHO) International Nonproprietary Names (INN) for pharmaceutical substances, Stem Book 2009
United States Adopted Names (USAN) are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA). As a general rule, the application for a USAN should be forwarded to the USAN Council after the Investigational New Drug (IND) has been approved by the FDA and clinical trials have begun.
Reference

23. NCCN Clinical Practice Guidelines for GIST
SARC-E: Systemic agents and regimens with activity in Soft Tissue Sarcoma: GIST
Imatinib
Sunitinib
Disease progression after Imatinib & Sunitinib
Sorafenib
Nilotinib
Dasatinib
NCCN Guidelines Version /24/ Soft Tissue Sarcoma - Discussion - Gastrointestinal Stromal Tumors - Progressive Disease: Page MS-30 "Any patients who has progression of GIST despite prior therapy or who has a recurrence, regardless of presentation, should be considered a candidate for enrollment in a clinical trial, if an appropriate trial is available."
Reference

24. Trials Drug Category Action Stage STA9090 (I.V.) HSP90i
Wide-Spectrum KIT inhibitor
Phase 2
Multiple drugs
(most oral)
PI3Ki
Downstream
Phase 1
Linsitinib (OSI-906)
(I.V. & oral)
IGF1Ri
Alternate Pathway
Deciphera
(oral?)
KIT/PDGFRA
Preclinical
Imatinib + ipilimumab
KIT inhibitor
First-line phase 3
Masitinib
Gleevec
First-line Plasma level trial

25. Immunotherapy
Dasatinib + ipilimumab (Yervoy) (Memorial Sloan-Kettering (New York)
Imatinib + ipilimumab – MD Anderson (Houston)
Ipilimumab is approved for melanoma
Blocks CTLA-4 receptor on T-cells (enhances T-cell activity)
Imatinib positive effect on immunotherapy via inhibition of IDO. IDO inhibits cd8+ T-cells
Phase I plus expansion (MSKCC)
Phase I open to all stages
Expansion open to resistant GIST
Serious side effects
Some long-term responses seen in melanoma

26. Pediatric-type GIST Sutent Linitinib (OSI-906) Phase 1/2
6 years to 21 years old
6 yrs to <18 years 15 mg/m2 daily for 4 wks on/2 wks off
18 yrs to <21 yrs, 50 mg daily on 4/2 schedule
Multiple trial sites (as needed)
Linitinib (OSI-906)
IGF1R inhibitor
IGF1R overexpressed in pediatric-type GIST
Phase II trial opened March, 2012
Seven sites planned
SARC sponsored

27. GIST Stages Gleevec/Sutent resistance (3rd line and beyond)
Adjuvant Gleevec trials
First-line trials
Neo-adjuvant Gleevec
Second-line trials
Other
Resistant to 400 mg Gleevec
Palliative
Surgery (stable mets)

28. Trials by Genotype Pediatric-type GIST PDGFRA Exon 9
IGF1R - Linsitinib
SDH – no trials yet
PDGFRA
D842V - Crenolanib
IMC-3G3 – monoclonal antibody
PDGFRA mutation arm
No PDGFRA mutation arm (KIT mutation & wildtype GIST)
Exon 9
Korean Study – 400 mg IM for 4 wks, 600 mg for 4 wks, then 800 mg IM

29. KIT and downstream Pathways are often targets in clinical trials
PI3K – Drugs in phase 1 trials
PKC-θ
PI3K
Jak/Stat 3
PLC gamma
AKT/mTOR
MAPK
Survive-grow
Survive
Proliferate

30. KIT Src/Fyn/Lyn PKC-θ PI3K AKT RAS PTEN mTOR RAF-1 MEK BAD MAPK BCL-2
Imatinib-sunitinib-regorafenib-nilotinib-sorafenib
pazopanib -masitinib-HSP-90 inhibitors (indirect)
Src/Fyn/Lyn
dasatinib
PKC-θ
PI3K
AKT
Perifosine
RAS
R SCH66336
PTEN
mTOR
RAD001-CCI779
AP Rapamycin
RAF-1
regorafenib
MEK
PKC-theta may not be correctly located in this diagram.
RAS may be a potential target for NF-1 type GISTs?
BAD
MAPK
BCL-XL
BCL-2
Gentasense
Proliferate
Survive
VEGF
Avastin-sunitinib-regorafenib
sorafenib-pazopanib
New blood vessel growth

31. General Trial Issues Right now there are limited Phase 3 Options
Off Label use not formally reported outside clinical trial setting
Personalized GIST Treatment
“GIST may be 10 diseases” Jaap Verweij, MD ASCO 2011
Volunteer pool more critical with multiple smaller ‘groups’
Clinician awareness
Patients need to ask what trials are available
Trials without mutant KIT/PDGFRA Coverage
Washout periods

32. Ask Questions How does the new treatment work differently for you?
Which trial offers the best chance of survival?
What are the chances it will benefit you?
What are the options if the trial does not work for you?
Will this trial limit future options?
How much time do you have to decide?
If phase 1, will the dose be therapeutic?
Read

33. High Stakes Decision Making*
Allow yourself the time to decide.
Get emotional support.
Make sense of controversies.
Manage your decision like you manage other complex projects.
Give yourself permission to experiment.
Recognize your preferences.
Remain vigilant about ignorance. Seek those who will teach and learn with you.
Delegate.
Keep records.
Keep your sense of humor.
This seems like really good advice.
I remember that my daughter did many of these things.
*Top Ten Decision Lessons from the Community Breast Health Project (CBHP) in Palo Alto, CA By Jeff Belkora, September

35. Finding Clinical Trials
GIST centers, trial coordinators, doctors, websites

36. Help Understanding Trials
Jim Hughes – LRG Clinical Trials Coordinator
Jerry Call – LRG Science Director