Phase I Trials
S. Gail Eckhardt, M.D.
University of Colorado Cancer Center
Phase I Clinical Trials: Definitions
•
Toxicity: side effects. These are generally graded using a
standard (NCI) scale from 1 (mild)-4 (severe).
•
Maximum Tolerated Dose (MTD): this is the dose where
no more than 30% of patients treated will experience
dose-limiting toxicity (DLT).
•
Phase II trials are often conducted at or near the MTD.
•
Dose Limiting Toxicity: toxicity that is considered severe
enough to limit further dose escalation, such as severe
(grade 4) hematologic toxicity or moderate (grade 3)
non-hematologic toxicity.
Phase I Clinical Trials: Definitions
• Pharmacokinetics (PK): the testing of blood and urine in
Phase I trials to determine where and how the drug is
distributed in the body and eliminated.
• Pharmacodynamics (PD): the physiological/biological impact
of a drug on the patient such as lowering of blood counts or
effect on tumor tissue or biomarker.
• Recommended Phase II dose: the dose that has been
determined to be tolerable in > 70% of cancer patients and is
used for testing in Phase II efficacy trials.
• Expanded Cohort: Enrollment of patients at the end of a
Phase I trial of a particular tumor type and/or genetic
subtype.
What Is Needed To Do A Phase I Study?
Investigational New Drug Application (IND) to the FDA:
• A formal application to study an intervention in patients that
can be sponsored (submitted) by:
• Commercial-sponsor usually a pharmaceutical company
• Investigator
• Provides a regulatory framework for advancing from preclinical to clinical testing
• Required for products that are not approved/marketed
• Required for marketed products being tested in a new disease
(indication)
General Contents of an IND Application
• Chemistry, manufacturing, and control information
• Animal pharmacology (includes efficacy) and toxicology
• Genotoxicity
• Histopathology
• Non-clinical justification for proposed dose/schedule (using
toxicology data)
• Prior use in humans if applicable
• Clinical protocol and investigator information
• Note: Data supporting dose/schedule and drug product is
performed under Good Laboratory Practice (GLP) conditions
IND Application- cont’d
Once submitted, there is a 30-day review clock that starts
• If you hear nothing: You are good to go as long as you have IRB
approval!
• A day or so before, you may be contacted requesting further
information, then be granted approval, or
• You could be put on Clinical Hold, due to
• Safety concerns, inadequate drug information, etc.
• Clinical trial design that will not allow protocol objectives to
be met
This generally leads to teleconference between sponsor and FDA
medical reviewer about what is required to lift the hold
What are the Primary Endpoints of a
Phase I Trial?
• To characterize and quantify the toxicities of a
new agent.
• To determine the dose-limiting toxicities (DLTs)
and maximum tolerated dose (MTD).
• To characterize the pharmacology of the agent.
• To assess overall tolerability and feasibility.
Note that in oncology, cancer patients traditionally participate
in Phase I testing, not normal volunteers (although some drugs
are tested in both).
What are Some Examples of Secondary
Endpoints in Phase I Trials?
• To assess the extent of preliminary anti-tumor
activity.
• To determine if there are pharmacokinetic/
pharmacodynamic relationships (PK/PD).
• For targeted agents, to assess the feasibility and
utility of a biological correlative assay.
Increasingly phase I trials have numerous secondary
endpoints that sometimes are used as go/no-go decision
points for moving forward with a drug
What are the Key Elements Required in a Phase I
Protocol to Accomplish these Objectives?
• Justification of the starting dose and dose escalation
plan.
• Appropriate patient eligibility/ exclusion criteria.
• Definition of DLT, MTD, and recommended phase II
dose.
• Pharmacokinetic sampling schedule.
• A study calendar for safety assessments.
• Tumor assessment criteria and schedule.
• Reporting requirements for adverse events and serious
adverse events.
• Consent form and other regulatory items.
Justification of the Starting Dose in Humans
• The starting dose of a drug that has not been in a human is
based upon animal toxicology studies- usually in mice, rats,
dogs, non-human primates.
• In general, 1/10th of the dose that leads to deaths in 10%
(LD10) of the animals is used in man.
• This dose is usually in mg/kg, so it must be converted to
mg/m2 for man- and there are conversion tables for this.
• If toxicology is performed in several species, then the LD10 is
used from the most sensitive species.
• 1/3rd of the lowest toxic dose is used in larger animals
This is very rudimentary and traditional, a lot of work is going
into refining these rules, particularly with targeted agents
Example of Determination of Starting Dose:
DFM (difungal muctane): standard cytotoxic agent that you will
be using on an every 3 week (Q3W) schedule, toxicology
results:
•
•
•
•
LD10 in rats was 50 mg/kg as a single dose.
LD10 in mice was 10 mg/kg on a Q3W schedule.
TDL was 50 mg/kg in dogs on a weekly schedule.
TDL was 24 mg/kg in dogs on a Q3W schedule.
The only relevant results to use are those from the same
schedule, although the other schedules give you information
on schedule-dependent toxicity:
1/10 LD10= 1 mg/kg x conversion factor of 3= 3 mg/m2
1/3 TDL= 8 mg/kg x conversion factor of 20= 160 mg/m2
Dose Escalation Scheme and Schedule
Factors to be considered
•Are there significant inter-species differences in tolerance? (as in
prior example: how fast, how slow for dose escalation)
•Is the drug a typical cytotoxic agent or more targeted agent?
•What is the PK half-life? (short vs. long)
•Does the therapeutic index appear narrow? (slower dose
escalation)
•Is cumulative toxicity an issue? (may need to assess longer than
30 days for dose limiting toxicity)
•Is there schedule-dependent toxicity or efficacy? (continuous vs.
intermittent)
•What is the formulation? (can’t give daily IV)
Frequently Used Dose Escalation Schemes
• Modified Fibonacci: sequentially smaller increments of dose
escalation- 100%, 67%, 50%, 40%, 33%, etc.
• Doubling method: doubling of the dose until any grade 2
drug-related toxicity, then reversion to modified Fibonacci or
fixed (25-40%) dose escalation.
• Pharmacologically guided: use of real-time PK data to guide
escalation with intent to achieve target AUC.
• Continual Reassessment Method (CRM): statistically-guided
dose escalation that uses real-time toxicity data to predict the
dose closest to the MTD.
• Accelerated Titration Design: a constellation of designs that
utilize single-patient toxicity-guided escalations (intra-patient
dose escalation allowed).
Phase I “Standard” 3 + 3 Design
Bottom line is that there are many ways to do this and a lot of
flexibility as long as it is safe for patients!
Patient Eligibility Criteria: Inclusion
The purpose of inclusion criteria are to define the minimum
requirements of the phase I population under study:
• Regulatory: Signed consent, age > 18.
• Disease: Failed standard therapy (or no standard therapy
exists), histologically confirmed.
• Constitutional: Performance status 0-2 (out of bed > 50%)
• Organ function: ANC > 1500/uL; plts > 100 K/uL; hgb > 9 g/dL;
creatinine < 1.5 g/dL, SGPT/SGOT 2-5 X ULN, total bilirubin <
ULN.
• Mental: Able to comprehend and comply with study
requirements.
Patient Eligibility Criteria: Exclusion
The purpose of exclusion criteria are to minimize the risks of
drug-related toxicity, thus some are agent-specific:
• Constitutional: Almost all phase I studies exclude pregnancy
due to the lack of information on fetal effects, as well as other
serious underlying medical diseases.
• Prior therapy: For myelosuppressive compounds, patients with
extensive prior therapy are excluded.
• Cardiac: Patients may be excluded with known underlying
diseases, or may require a MUGA, EKG, etc.
• Gastrointestinal: Studies of oral drugs exclude patients with
refractory N/V or extensive bowel surgery.
Typical Definitions of DLT
Dose escalation proceeds, as planned, with 1-3 patients
until DLT occurs, as typically defined by:
• Grade 4 neutropenia for > 5 days, or complicated by
fever requiring antibiotics.
• Platelets < 25, 000/uL.
• Non-hematologic toxicity > grade 3 (tailored for
agent).
• Chronic > grade 2 toxicity.
Once DLT occurs, up to 6 patients are treated to assess
the frequency.
Definition of the MTD
• The MTD is generally defined as the dose in which
less than 2 of 6 new patients develop DLT in the first
cycle.
• In some places, the MTD is the dose level where >
2/6 patients develop DLT.
• In any event, DLT is generally allowed in up to 30% of
the population.
• The MTD is not always the recommended dose for
phase II testing.
• In general, at least 10-12 patients should be treated
at the MTD.
Why the MTD ≠ Dose to be used in Phase II
• DLT and MTD are used for the purposes of making
decisions about dose escalation.
• The occurrence of DLT in the first course of therapy is
what limits dose escalation.
• The phase II dose should incorporate multiple-cycle
toxicity (including DLT), tolerability, dose reductions,
and dose delays.
• This distinction should be clarified in the protocol.
Biological Correlative Studies:
Why are They Important?
In early clinical trials of targeted agents:
• Normal tissue may not be used as a surrogate for effects, as is
the case with standard cytotoxic agents
• The relative lack of toxicity to normal tissue often means that
deriving the MTD, or optimal biological dose may be difficult.
• Therefore, biological correlative studies may be used to derive
the best dose and schedule of an agent, and
• To determine whether the drug is inducing a biological effect
in the patient before advancing to phase II.
Biomarker Definitions:
Pharmacodynamic (PD) biomarker: Associated with drug
exposure- commonly used in Phase I trials.
Example: Reduction in p-ERK in PBMCs post-MEK inhibitor
Predictive biomarker: Predicts outcome to therapy- most
common in Phase II trials.
Example: KRAS/BRAF mutation, Her2/Neu, ER/PR
Prognostic biomarker: Associated with outcome, independent
of therapy- often discovered retrospectively in Phase III trials.
Example: Ki67 index
PD Biomarker: Decrease in Ki67 (top) and pERK1/2 (bottom) in skin biopsies
following PF299804 (pan-EGFR TKI) treatment.
Jänne P A et al. Clin Cancer Res 2011;17:1131-1139
©2011 by American Association for Cancer Research
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How To Become
Famous in Phase I:
Expanded Cohorts using Predictive Biomarkers!!!
Vemurafenib/BRAF MU melanoma
Crizotinib/ALK+ NSCLC
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