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33 Cards in this Set
- Front
- Back
common causes for drug failure?
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commercial interest, toxicology, effficacy, not so much phamacokinetics
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phase I study goals? Biologicals?
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MTD, DLT, pharacokinetics, anti-tumor activity is drug safe?; OBD, factors effective variability, drug marker
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MTD in US?
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1 dose lower than DLT
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fibonacci dose escalation?
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3 pateints per cohort, dose escalate until 2 people reach MTD
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problems of fibonacci dose escalation?
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lots of patients, long time, many exposed to ineffective doses
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accelerated titration design?
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single person, 40% escalation, until 1 @ DLT or 2 at grade 3 toxicity, then start enrolling 3 patients at a time; intrapatient dose escalation allowed
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problems w/ accelerated titration design?
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less experience, more high toxicity, harder to measure
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ktrans?
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vascular permeability, should decrease when given an anti-angiogenic like VEGF Trap
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ethical issues w/ phase I studies?
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not trying to fix a problem-response rate is 7-10%
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pateients eligible for phase I trials?
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no effective therapy exists, are not "sick"
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in which phase do most clinical drugs fail?
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phase II
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goals of phase II studies?
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anti tumor activity in a particular disease type: how well the drug works, safety, dosing, supportive meazures, late-onset or cumulative toxicities
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key design considerations for phase II trials?
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homogenous pt population, efficient sample size (inimum exposure via early stopping rules)
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what is evaluability?
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does the patient count
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standar 2-stage design?
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defined patient group-> defined intervention -> stoping rule check response rate -> continue only if response is as anticipated and enrol more patients
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what is RECIST?
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Response Criteria in Solid Tumors: how does total diameter of lesions decrease
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Criteria for Response in Recist?
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complete, parial= down 30%, progressive= up 20%, stable= between partial and progressive
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how do you pick what disease you want your drug to work in?
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usually know in the animal studies before phase I
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randomized phase II?
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2 different interventions; pick a winner and go to phase 3
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advantages of randomized phase II?
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controls for selection bias/changing standards of practice; assumes threshold of activity has been identified
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disadvantages of randomized phase II?
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misused/interpreted; requires more patients than single arm phase II
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randomized discontinuation phase II? Good for what?
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give all patients a new agent; take the patients with steady disease and take 1/2 of them off the agent, see if it gets worse when they get off; good for cytostatic drugs
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goal of phase 3 study?
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define the standard of care-is this drug clinically significant
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design of phase 3 study?
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large, muti centered (100s-1000s); comparative, very defined patient population; defined primary endpoint (overall survival)
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3 common endpoints for phase III studies?
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survival, time to tumor progression, qualityo of life
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disadvantages of survival as endpoint?
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takes a long time (people have to dies), may not correlate w/ clinically meaningful-what about quality of life?
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disadvantages of progression free survival or time to tumor progression?
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doesn't corellate w/ overall survival, quality of life may suffer, too many criteria, subject to frequency/intensitiy of evaluation
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advantages of Progression free survival or time to tumor progression?
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tracks w/ survival, earlier endpoint, less patients, not influenced by salvage Rx
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disadvantages of quality of life endpoint?
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subjective, labor/personel intensive
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advantages of QOL input?
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clinically meaningful, there are valid ways to measure, has worked before
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potential pitfalls in phase III studies?
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unvalidated surrogate endpoins (rare), underpowered studies (common), clinically-irrelevant studies
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rule of surrogate endpoints?
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must be associated w/ clinically-relevant endpoint
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most common problem of phase III studies?
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underpowered= too few patients to detect difference in outcome between treatment arms
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