Phase I Trial

Question 1

in phase I trials it is the first time that a ?

Answer 1

drug is introduced into human subjects

Question 2

primary objective of phase I trial is?

Answer 2

identify safe dose to be tested in phase II studies (target dose)

Question 3

what is target dose?

Answer 3

the safe dose to be tested in phase II studies

Question 4

whats the primary concern in phaseI?

Answer 4

safety of study subjects

Question 5

who meets criteria to participate in phase I studies?

Answer 5

patients with advanced disease resistant to standard therapies
good functional status
all tumor types

Question 6

what are the different types of phase 1 studies?

Answer 6

• single drugs

- combinations of licensed drugs with new agents

Question 7

what dose do you start with?

Answer 7

1/10 LD in mice likely to be safe

Question 8

cohorts

Answer 8

groups of patients where all get same dose treatment and the size is determined by progression model

Question 9

progression models

Answer 9

1) Fibonacci - to identify the MTD. prior 2 doses to next level. If one patient suffers from grade 3 or 4 toxicity, enter another 3. if only 1/6 have grade 3/4 toxicity go on to next level. If 2/6 have 3/4 grade toxicity, that level is DLT level (dose limiting toxicity). The level before DLT would be MTD and you go back to enter 10 patients = target dose
2) continual reassessment method (CRM) - aims to find the maximum tolerated dose (MTD) of a new therapy
Shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3. design,
3) Bayesian approach - model for relationship between probability of toxicity and the dose to be observed before expressing an opinion concerning unknown parameters of model. Used to update the probability for a hypothesis as more evidence or information becomes available.

Question 10

all progression models..

Answer 10

re evaluate toxicity with prior doses prior to escalation

Question 11

pharmacokinetics

Answer 11

what your body does to the drug
behavior of drug in patients
drug concentration
half life
distribution
area under curve
concentraion of drug in blood in system

Question 12

pharmacodynamics

Answer 12

what drug does to body

Question 13

1/10 mouse LD sometimes?

Answer 13

exceeds MTD and you have to de-escalate doses or use more sensitive species which are higher order mammals

Question 14

dose escalation methods?

Answer 14

Fibonacci 3+3 design

Question 15

problems with traditional dose escalation method?

Answer 15

• too long to escalate, wasting cost and time
• MTD may exceed acceptably high rate of toxicity
• high % of patients found to have toxicity
• no clear definition of MTD
• too many pts at low ineffective doses

Question 16

in crm, the probabiloity of toxicity prior to a dose is estimated from prior data =

Answer 16

prior probability of toxicity

Question 17

in CRM, the estimated probabilty of toxicity is updated after each patient using toxicity assessment from the patient=

Answer 17

posterior probability of toxicity

Question 18

CRM risk?

Answer 18

risk of entering patient first patient on too high a dose and assigning patients to higher more dangerous doses than the target dose

Question 19

bayesian decision approach

Answer 19

estimate whole dose response curve while giving attention on target dose

Question 20

in phase 1 MTD is?

Answer 20

associated with greatest chance of efficacy

Question 21

toxicity is not an appropriate end point in?

Answer 21

• phase 1 studies of drugs with dose response curve that reaches a plateau at non toxic doses
• phase 1 studies of agents with bell shaped dose response curve and dose toxicity curve that rises after maximal therapeutic dose

Question 22

obd

Answer 22

optimum biological dose is the lowest dose associated with biological efficacy in early-phase trials

Question 23

molecular targets for cancer therapy

Answer 23

• proliferation
• migration
• metastases
• angiogenesis
• motility

Question 24

how do you see eficacy in drugs that target signal pathways and receptors?

Answer 24

• pharmacokinetics or pharmacodynamics endpoints
• molecular target endpoints
• off target effects
• look at responses

Question 25

phase I clinical trials targeted therapy

Answer 25

paradigms are different
DLT not always reached
biologically effective dose or inhibiotin of target molecule
substantial inter-patient variability of drug plasma levels
off target effects may contribute to clinical efficacy but may not be reached until higher doses
administration with or without food important

Question 26

acneiform rash of CI-1040 MEK inhibitor in phase I trial is?

Answer 26

positive indicator of how well drug is doing against cancer

Question 27

if toxicity is not our endpoint what is?

Answer 27

whether the drug is working