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Printable Handouts
Navigable Slide Index
- Introduction
- Three trials
- First trial - introduction
- Scientific background
- Scientific background: test doses
- Choice of design
- Dose-escalation trial designs
- TITE-CRM: general approach
- TITE-CRM: prior and target rate
- TITE-CRM: dose-toxicity model
- TITE-CRM: rescaled doses
- TITE-CRM: prior distribution of alpha
- TITE-CRM: dose-escalation constraints
- Operating characteristics of dose-escalation trials
- Operating characteristics
- Operating characteristics: estimation
- Simulations of percentiles of target dose
- Simulations of percentiles of # of DLTs
- Mean # treated per dose per trial
- Mean # DLTs per dose per trial
- Operating characteristics: learnings
- Implementation
- Results: observed results
- Estimating P(DLT) and selecting the RP2D
- Results (trial 1)
- Acknowledgments (trial 1)
- Second trial - introduction
- Scientific background: intrahepatic cancer
- Low-dose chemo-RT for intrahepatic cancer
- Radiation-induced liver disease (RILD)
- SBRT for intrahepatic cancer
- Trial design: individualized SBRT strategy
- Trial design: indocyanine green
- Trial design
- Trial design: treatment plan
- Trial design: biological rationale
- Trial design: summary
- Trial design: approximate model
- Trial design: Bayesian framework
- Trial design: dosing scenario 1
- Trial design: dosing scenario 2
- Trial design: dosing scenario 3
- Operating characteristics: sample size and power
- Operating characteristics
- Operating characteristics: example
- Operating characteristics: simulated
- Estimation of p2
- Estimation of gamma
- Results (trial 2)
- Acknowledgments (trial 2)
- Third trial - introduction
- Long-term reduction of PGE2
- Eicosapentaenoic acid and arachidonic acid
- Developmental program: bench studies
- Developmental program
- Known things when the trial was designed
- Developmental program: revised study design
- Personalized treatment: practical constraints
- Personalized treatment: general approach
- Determine the target EPA:AA ratio
- Determine the individual response to fish oil
- Personalized treatment: treatment and final data
- Adaptation
- Adaptation: Bayesian linear regression
- Operating characteristics
- Assumptions for simulated clinical trials
- Simulated clinical trial example
- How design addressed the critique
- Results (trial 3)
- Acknowledgments (trial 3)
- Summary
Topics Covered
- A model-based dose-escalation trial
- Bayesian modeling for personalized therapy
- Translation from animal to human dose-response models in a trial with a biomarker endpoint
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Normolle, D. (2016, December 29). Case studies of adaptive early phase trials [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 14, 2024, from https://doi.org/10.69645/FCXS4703.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Daniel Normolle has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: Adaptive Clinical Trial Design
Transcript
Please wait while the transcript is being prepared...
0:00
My name is Daniel Normolle,
and I am the Director of Biostatistics
at the University of Pittsburgh
Cancer Institute.
I'm going to be discussing
three case studies
of adaptive early phase
clinical trials today.
0:11
The first trial involves
the use of gemcitabine,
oxaliplatin, and radiation therapy
in pancreatic cancer.
This is a dose-escalation trial
of oxaliplatin.
The second trial is an example
of stereotactic beam radiotherapy
for intrahepatic cancer using an assay
to predict
radiation-induced liver disease.
And the third trial will be
a discussion of fish oil
as a colon cancer chemopreventitive.
0:36
These are the topics I'm going
to address in the first trial.
Basically, this is a TITE-CRM trial,
and we're going to look at first
the scientific background
of the use of oxaliplatin along
with gemcitabine and radiation therapy.
I'm going to talk about
the operating characteristics
of the TITE-CRM trial.
Why we chose it.
How it gets implemented,
and the results.
0:56
So in the vast majority of patients,
pancreatic cancer remains incurable.
It's a fatal disease.
Even patients
with potentially curative resection
may benefit from chemoradiotherapy.
When this trial was conceived in 2003,
radiation treatment of 54 Gy
over six weeks
with concurrent gemcitabine
was the standard
at the University of Michigan.
However, oxaliplatin,
approved by the FDA in 2002,
was of great interest.
The recommended phase
2 dose of oxaliplatin,
when administered concurrently
with radiation therapy
and gemcitabine, was to be determined.
1:28
We were going to test
six levels of this treatment.
Level -1 was a fallback level
we did not intend to visit.
We were going to escalate oxaliplatin.
And if oxaliplatin was successfully
escalated to 85 mg/m2,
we would then increase
the dose of gemcitabine.
The levels are not scaled
but they are ordered
in terms of intensity.