HCC-MUSC
Phase I Program
Development
Melanie B. Thomas, M.D.
Associate Director of Clinical Investigations
Hollings Cancer Center
Associate Professor of Medicine
Division of Hematology-Oncology
Clinicians Perspective:
Why do we need BIOMARKERS in Clinical Trials?
 90% of drugs that enter Phase II clinical trials will fail.
 21% of all drugs that enter Phase I testing ever reach the market.
 2-4% of newly-diagnosed adult cancer patients enroll in clinical trials.
 Of over 700,000 physicians in the US, only 4% of them have participated in
clinical trials since 1988.
 Tumor shrinkage (RR), the primary endpoint of most Phase II trials, is a
poor biologic signal
 The likelihood of new anti-cancer agent that enter Phase 1 trials reaching
the commercial market?
 1993 - 14%
 2008 - 8%
 The failure rate of Phase III cancer trials:
 1998 - 20% 2008 - 50%
Example of anti-tumor activity, but not
“response” by RECIST Criteria
CT abdomen, 63
year old woman
with hypervascular
hepatocellular
carcinoma, right
lobe.
Decreased tumor vascularity,
increased necrosis after 8, 16
weeks treatment with targeted
agents bevacizumab and
erlotinib.
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Linking Targeted Agents to Molecular Targets:
What is the Evidence:
Agent
Target
Tumor type
Effect
Target Validation
HER2 receptor
Her2overexpressing
breast cancer
Improves survival
Decreases recurrence
as adjuvant therapy
yes
Bevacizumab
Serum VEGF A ligand
Metastatic
colorectal, lung,
breast cancers
Improves survival, TTP
in metastatic colon,
lung, breast cancers
no
EGFR mAb
Extra-cellular domain
EGFR
Colorectal
in irintecanrefractory
Improves survival, TTP
in metastatic colon
Kras mutants do
not benefit from
EGFR inhibitors
Improves survival
NSCLA, 2nd line
Improves PFS in
pancreatic ca by <2 wks
EGFR
mutations in
minority of
patients
predict for
benefit
Trastuzumab
EGFR TKI
Intracellular
phosphorylation site
NSCLCa
pancreatic
Sorafenib
Raf-ras pathway
VEGF
GIST
RCC
no
Sunitinib
Raf-ras pathway
VEGF
GIST
RCC
no
Bortezomib
mtor
Myeloma
no
C-kit
GIST
yes
Drug Clinical Development - Overview
BLA/
NDA/
MA
IND
Drug
Discovery
Development
Preclinical
Phase 1
Phase 2
GLP
R&D
Genomics
Proteomics
High-thru
screening
DNA Arrays
Proof of Concept
Animal Toxicology
Animal Metabolism
studies
Production
Purification
Preparation for cGMP
Phase 3
GMP
cGMPs initiated
QA / QC
Safety, Dose
Production
Purification
Formulation
Characterization,
Stability
Safety
PK
QA / QC
Effectiveness
Production
Purification
Formulation
Stability
Full cGMP
QA / QC
Efficacy Safety
Production
Formulation
Stability
Release Tests
Validation
Clinical Trials - Phases
Length
Phase
Purpose
Subjects
Size
I
Safety, tolerabiltity,
bioactivity,
drug-drug
interaction
Healthy
volunteers or
subj. w/
indications
20-80
6-12 mos
II
Short-term side
effects & efficacy
Subjects
with
indications
Several
hundred
1-2 yrs
III
Safety & efficacy
Basis for labeling,
new formulations
Subjects
with
indications
Hundredsthousands
2-3 yrs
IV
New indications,
QoL, surveillance
Subjects
with
indications
Hundredsthousands
1-5 yrs
(per phase)
Phase I
 First time in human subjects
 Small number of healthy volunteers or advanced
disease patients who have no other options.
 Establish safety profile and dosage range
 Single and multi-dose studies
 Pharmacokinetics / pharmacodynamics
 Open label, often single center
 Commonly performed ex-U.S.
Phase II
 Safety, side effects
 Efficacy
 Tumor shrinkage (RR),
 Progression-free survical, overall survival
 Symptom palliation, QOL
 Single arm with historical controls
 Randomized PII
 Phase IIa – proof of concept, pilot, feasibility, usually
healthy volunteers
 Phase IIb – well-controlled in target population
 Seek to identify a “signal” of benefit to pave the way
for “pivotal trials”
Phase III
 2 or 3 studies are pivotal (critical) studies
 To prove safety and efficacy of primary endpoints
 Double-blind, positive or placebo control, multi-center
 Study population resembles the intended population
 Support package labeling
 New Drug Application (NDA)
 Special population, concomitant medications, multiple illnesses, etc.
 IIIb studies – post NDA-submission trial looking at additional
indications
 Pre-NDA meeting with the FDA near conclusion of Phase III
 Phase III trials can change standard of care without formal FDA
approval
Phase IV
 Post-licensure studies to confirm the safety in large
population (after NDA is filed)
 Phase IV commitments
 Possible types of studies
 Compared versus competition
 Post-marketing surveillance
 Special population
 Rare event incidences
 Additional long-term usage safety data
 Pharmacoecomonic and Quality of Life (QoL)
21 CFR 312.85
There Are Many Types of Phase I Trials
Study Type
Comments
First in human subjects
Combinations of approved +
new agents
Detailed study design based on
preclinical large animal toxicity.
Slow dose escalation.
Extensive subject monitoring
Fix dose of approved drug,
dose-escalate new agent
Combination of alreadyapproved single agents
Overlapping toxicity, expected,
unexpected
New agents in special
populations
Renal, hepatic dysfunction
Children, elderly, poor PS
Re-evaluate established dose(s)
when late toxicity has emerged
Cumulative neuropathy, other
neurologic effects.
Current Phase I Trials
13
Upcoming Phase I Trials
Investigator Initiated Trials
15
Investigator Initiated Trials
HCC-MUSC Phase I Clinical Research Support Services
 HCC Phase I portfolio:
 2007 7 - trials
 2011 – 13 trials
 HCC Clinical Trials Office
 Review and process Confidentiality Agreements
 Assist investigators with reviewing industry trials
 Coordinate all Regulatory submissions
 PRC, IRB, INDs, ongoing Compliance monitoring
 Negotiate, resolve COI issues
 Coordinate study-specific training, forms, data management
 Management multi-site studies
 Seasoned staff to screen, evaluate, enroll patients
HCC-MUSC Phase I Clinical Research Support Services
 Clinical & Translational Research Center
 Outpatient unit for early-phase trials (exam, treatment rooms, lab
draws, ECG etc).
 Priority inpatient bed assignment, dedicated unit
 Nursing support services on study-specific basis.
 Specialized services
 Sample procurement, processing, banking, shipping (PK, PD,
biomarkers) for in-house or external analysis
 Clean Room Facility: human cell isolation, processing, vaccine
development.
 Developing Phase I “capacity” within HCC Infusion Center
 Regular weekly Phase I meeting
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