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Phase 0 Trials Role in Radiation Mitigation Agent Development?
Anthony J. Murgo, M.D., M.S.Office of Oncology Drug Products
Center for Drug Evaluation and ResearchFood and Drug Administration
Jan 25, 2010
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Outline• Description of Phase 0 trials• Phase 0 vs. traditional first-in-human
Phase 1 trials• Types of agents appropriate for Phase 0
testing• Ways Phase 0 may improve efficiency of
drug development
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Disclosure
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What is a Phase 0 trial?
A what???
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What is a Phase 0 trial?
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Basic Features of Phase 0 trials• First-in-human trial conducted prior to
traditional Phase 1 study• Small number of subjects (≈10-15)• Limited drug exposure
– Low, non-toxic doses– Short duration (≈ ≤7 days)– One course only
• No therapeutic intent• Phase 0 trials are not definitive studies
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Phase 0 trials can start earlier than Phase 1
Conceived under FDA’s “Critical Path” initiative to help sponsors identify promising candidate drugs more quickly
Toxicology evaluation less extensive than for traditional IND because of reduced dosing and limited exposure.
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How do Phase 0 Trials Differ from Traditional First-In-Human Phase 1 Trials?
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Phase 0 vs. FIH Phase 1 Oncology Trials
Variable Phase 1 Trial Phase 0 Trial
Preclinical tox Full IND-directed Less required; sufficient to support ExpIND
Pre-clinical target/biomarker validation studies
Not consistently performed; assays rarely validated in preclinical models
Target/biomarker analytical assays validated in preclinical models
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Phase 0 vs. FIH Phase 1 Oncology TrialsVariable Phase 1 Trial Phase 0 Trial
Primary objective & dose-escalation scheme
Establish dose-limiting toxicities and MTD
Establish a dose-range that modulates target, for use in subsequent Phase 1 (or 2 trials)
Duration of dosing
Repetitive; multiple cycles until disease progression or unacceptable toxicity
Limited dosing (e.g., 1-7 days); one cycle only
Evaluation for therapeutic benefit
Tumor response routinely evaluated None
Tumor BiopsiesAlmost always optional
Required (pre- and post) to evaluate drug effect
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Phase 0 vs. FIH Phase 1 Oncology Trials (cont.)Variable Phase 1 Trial Phase 0 Trial
PD/target effect assays
Not consistently performed; commonly use assay methods that are not validated or standardized
Integrated into the trial to establish MOA and target/biomarker analytical assay validation in subject tissue samples
SOP’s for tissue acquisition, handling, and processing
Generally not validated or standardized
SOP’s validated first in in vivo preclinical models and applied to Phase 0 human samples
PK/PD analysis
Samples usually batched and analyzed at a later time point, generally after completion of the trial
Performed in “real-time”
12Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
Phase 0 Trials
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Types of Phase 0/Expl IND trials
• Pharmacologically relevant doses
• Micro-dose studies
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Various Goals of Phase 0/Expl IND trialsPharmacologically relevant doses• Explore mechanism of action in humans
– MOA defined in non-clinical models can be observed in humans
– Agent binds to or inhibits its alleged target
• Refine a biomarker assay using human tumor tissue and/or surrogate tissue
• Provide human PK-PD relationship data prior to definitive single-agent or combination Phase 1 testing
• Select most promising candidate for further development– Evaluate human PD of two or more analogs directed at same
target and possessing practically the same preclinical properties
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Various Goals of Phase 0/Expl IND trials(2)
Micro-dose studies • Less than 1/100th of the dose calculated (based on
animal data) to yield a pharmacologic effect (max dose of <100 micrograms (≤30 nanomoles, protein products)
• Evaluate in humans an agent’s biodistribution, binding characteristics and target effects
• Develop novel imaging probes
• Evaluate human PK (e.g., bioavailability) to select most promising candidate for further development
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Phase 0 – Small Sample Size
• Demonstration target modulation requires:– Precise and reproducible assay methods– Robust drug effect– Limited intra-patient variability– Limited inter-patient variability– Innovative, rational statistical designs
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Why conduct Phase 0 trials?
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Kola & Landis; Nat Rev Drug Disc 2004Ma & Zemmel; Nat Rev Drug Disc 2002
• Unfavorable PK currently plays less of a role compared to early 1990’s• Lack of efficacy continues to play a major role• Lack of predictive animal models
Why drugs fail
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Phase 0 trials Can Improve Efficiency and Success of Subsequent Trials
Informing subsequent trials– Establishing MOA and drug hits its target in human subjects– Refining target/biomarker PD analytical assay with human
biopsy samples– Developing reliable SOP for human tissue acquisition, handling,
and processing– Determining dose and time-course that yields desired target
effect– Exploring PK-PD relationships
• Approximation of safe, efficacious starting dose for studies in different populations and settings:
– Use in otherwise healthy subjects– In combination with other drugs or radiation
• Support limited sampling in subsequent trials
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Phase 0 trials Can Improve Efficiency and Success of Subsequent Trials (cont.)
• Selecting a candidate agent with most favorable properties for further clinical testing
• Eliminating “bad” agents early in clinical development because of poor PD or PK properties
e.g., lack of target effect, poor bioavail., very rapid clearance
“Fail fast, fail early”
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What Makes an Agent a Good Candidate for a Phase 0 PD Trial
• Credentialed target (modulation yields desired effect)• Wide therapeutic window (e.g., biomodulators)
• PD modulation expected at low doses and short duration of exposure (e.g. ≤7 days)
• Drug target effect evaluable with a relatively small sample size (≤10-15 patients)– Robust drug effect– Precise analytical assay– Target expressed in majority of study subjects
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• Kummar, S., et al. Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies. J Clin Oncol; 27:2705-11, 2009
• Kinders, R., et al. Phase 0 trials in cancer drug development. Mol Interventions; 7:327-34, 2007
• Jacobson-Kram D, Mills G. Leveraging exploratory investigational new drug studies to accelerate drug development. Clin Cancer Res;14:3670–4, 2008
• Murgo AJ, et al. Designing phase 0 cancer clinical trials. Clin Cancer Res; 14:3675-82, 2008
• Doroshow, JH, Parchment, RE. Oncologic Phase 0 Trials: Incorporating Clinical Pharmacodynamics from Concept to Patient. Clin Cancer Res 14:3658-63, 2008
• Gutierrez, M, Collyar, D. Patient perspectives on phase 0 clinical trials. Clin Cancer Res 14:3689–91, 2008
• Abdoler E, et. al. The ethics of phase 0 oncology trials. Clin Cancer Res 2008;14:3692–7
• Kummar, S, et al. Compressing drug development timelines in oncology using phase ‘0’ trials. Nature Reviews Cancer 7:131-9, 2007
• Rubinstein, LV, et al. The Statistics of Phase 0 Trials. Statistics in Med; in press.
Suggested Reading
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Back-up Slides
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Phase 0 – Patient Recruitment and Ethical ConsiderationsChallenging, but not insurmountable• Potential barriers to patient enrollment
– No therapeutic intent or chance of benefit– Pre- and post-treatment tissue biopsies– Delay or exclusion from other trials or therapies
External concerns about ethics and availability of patients for study
• Institutional Ethics committee review and input• IRB approval• Informed Consent Process
– Clearly explain the rationale for the study– Clearly describe the limited treatment and follow up period– Clearly state that there is absolutely no anticipated clinical benefit to
the participant– More straightforward than Phase 1
– but low risk– avoid if possible
– washout period for phase 0 shorter
26Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
Statistical Methodology for Phase 0 Trials
27Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682
