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33 Cards in this Set

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