Download Novel Trial Designs for Early Phase Drug Development

Novel Trial Designs for
Early Phase Drug Development
CNIO Frontiers Meeting
Molecular Cancer Therapeutics
March 8-10, 2010
Madrid
Elizabeth Garrett-Mayer, PhD
Associate Professor
Director of Biostatistics
Hollings Cancer Center
Medical University of South Carolina
Phase I trial goals
 Classic Phase I trials:
• Find the highest dose that is deemed safe: the
Maximum Tolerated Dose (MTD)
• DLT = dose limiting toxicity
• Goal is to find the highest dose that has a DLT rate of
x% or less (usually ranges from 20% to 40%)
 Newer Phase I trials:
• Find the dose that is considered to safe and have
optimal biologic/immunologic effect (OBD).
• Goal is to optimize “biomarker” response within safety
constraints.
Schematic of Classic Phase I Trial
% Toxicity
100
33
0
d1 d2
...
mtd
Dose
3
1.0
Based on Presumption:
Efficacy and toxicity both increase with dose
DLT =
doselimiting
toxicity
0.8
0.6
0.4
0.2
0.0
Probability of Outcome
Response
DLT
1
2
3
4
Dose Level
5
6
7
Classic Phase I approach: Algorithmic Designs
 “3+3” or “3 by 3”
 Prespecify a set of doses to consider, usually between
3 and 10 doses.
Treat 3 patients at dose K
1. If 0 patients experience DLT, escalate to dose K+1
2. If 2 or more patients experience DLT, de-escalate to level K-1
3. If 1 patient experiences DLT, treat 3 more patients at dose level K
A. If 1 of 6 experiences DLT, escalate to dose level K+1
B. If 2 or more of 6 experiences DLT, de-escalate to level K-1
 MTD is considered highest dose at which 1 or 0 out of
six patients experiences DLT.
 Confidence in MTD is usually poor.
Some properties of the “3+3”
What can you learn from 3 patients at a single
dose? What is the 95% exact c.i. for the
probability of toxicity at a given dose if you
observe




0/3 toxicities at that dose?
1/3 toxicities at that dose?
2/3 toxicities at that dose?
3/3 toxicities at that dose?
( 0, 0.64)
(0.09, 0.91)
(0.29, 0.99)
(0.36, 1.00)
Dose Level
Actual P(DLT)
Chance of being
highest tried dose
1
0.10
9%
2
0.15
17%
3
0.20
21%
4
0.25
21%
5
0.30
32%
Even if dose level 5 corresponds exactly to a DLT rate
of 0.30, the chance that this particular trial will ever
reach it is only 32%.
The chance of correctly concluding dose level 5 is the
MTD is 16%.
“Novel” Phase I approaches
 Continual reassessment method (CRM)
(O’Quigley et al., Biometrics 1990)
• Many changes and updates in 20 years
• Tends to be most preferred by statisticians
 Other Bayesian designs (e.g. EWOC) and
model-based designs (Cheng et al., JCO, 2004, v 22)
 Other improvements in algorithmic designs
• Accelerated titration design (Simon et al. 1999, JNCI)
• Up-down design (Storer, 1989, Biometrics)
CRM: Bayesian Adaptive Design
 Dose for next patient is determined based on
toxicity responses of patients previously treated in
the trial
 After each cohort of patients, posterior distribution
is updated to give model prediction of optimal dose
for a given level of toxicity (DLT rate)
 Find dose that is most consistent with desired DLT
rate
 Modifications have been both Bayesian and nonBayesian.
Examples: Candidate Models
CRM Designs
 Underlying mathematical model
 Doses can be continuous or discrete
 Compared to the ‘3+3’ the CRM is
• safer: fewer patients treated at toxic doses
• more accurate: selected MTD is closer to the true MTD
• more efficient: more patients are treated at doses near the MTD.
 Disadvantages:
• requires intensive involvement of statistician because future
doses depend on model prediction
• need more lead time: statisticians need time (weeks?) to select
the appropriate CRM design for a given trial
 simulations
 need to ensure that it will “behave” in a smart way
Long-term toxicities?
 CRMs and algorithmic designs take a long time to
accrue, even with rapid accrual.
 Investigators may be interested in toxicities over a span
of one to two years.
 For a study with only 15 patients with two year follow-up,
“three-at-a-time” designs require 10 years to complete,
even with perfect accrual.
 Need alternatives!
 Example scenario
• interested in the MTD as the 20%-tile of a toxicity
• requires 2 years followup (so we now have cohorts of 5, not 3).
Prorated Designs (Cheung & Chappell, 2000, Biometrics)
 Instead of collecting data on a group of 5 patients for 2
years each,
 Collect data on more than 5 patients for a total of 10
patient-years.
 One patient measured for one year counts (is “prorated”
as) 1/2 of a patient.
 A Bayesian version (TIme-To-Event Continual
Reassment Method, TITE-CRM, is available).
• Require more patients than traditional designs, provide more
information at study’s conclusion; and
• Are much quicker than traditional designs (commensurate with
the number of extra patients).
TITE-CRM: Schematic Example
Accelerated Titration Design (Simon et al., 1999, JNCI)
 The main distinguishing features
(1) a rapid initial escalation phase
(2) intra-patient dose escalation
(3) analysis of results using a dose-toxicity model that incorporates
info regarding toxicity and cumulative toxicity.
 “Design 4:”
 Begin with single patient cohorts,
 double dose steps (i.e., 100% increment) per dose level.
 When the first DLT is observed or the second instance of
moderate toxicity is observed (in any course), the cohort for the
current dose level is expanded to three patients
 At that point, the trial reverts to use of the standard phase 1
design for further cohorts.
 dose steps are now 40% increments.
Accelerated Titration Design
 “Rapid intrapatient dose escalation … in order to
reduce the number of undertreated patients [in
the trials themselves] and provide a substantial
increase in the information obtained.”
 If a first dose does not induce toxicity, a patient
may be escalated to a higher subsequent dose.
 Obviously requires toxicities to be acute.
 If they are, trial can be shortened.
Accelerated Titration Design
 After MTD is determined, a final “confirmatory” cohort is
treated at a fixed dose.
 Jordan, et al. (2003) studied intrapatient escalation of
carboplatin in ovarian cancer patients and found “The
median MTD documented here using intrapatient dose
escalation ... is remarkably similar to that derived from
conventional phase I studies.”
I.e., accelerated titration seems to work. Also, since it
gives an MTD for each patient, it provides an idea about
how MTDs vary between patients.
New paradigm: Targeted Therapy
How do targeted therapies change the early phase
drug development paradigm?
 Not all targeted therapies have toxicity
• Toxicity may not occur at all
• Toxicity may not increase with dose
 Targeted therapies may not reach the target of
interest
Implications for Study Design
 Previous assumption may not hold
• Does efficacy increase with dose?
 Endpoint may no longer be appropriate
• Should we be looking for the MTD?
 What good is phase I if the agent does not hit the target?
0.2
0.4
0.6
0.8
Efficacy
Toxicity
0.0
Probability of Outcome
1.0
Possible Dose-Toxicity & Dose-Efficacy Relationships for
Targeted Agent
0
2
4
6
dose
8
10
12
Trinary outcome CRM
Y = 0 if no toxicity, no efficacy
= 1 if no toxicity, efficacy
= 2 if toxicity
Adding in a pre-phase I level? Phase 0 trials
•
•
•
•
“Human micro-dosing”
First in man
Not dose finding
Proof-of-principle
 Give small dose not expected to be therapeutic
 Test that target is modified
 Small N (10-15?)
• Short term: one dose
• Requires pre and post patient sampling. Usually PD
assay.
• Provides useful info for phase I (or if you should
simply abandon agent).
Phase 0: Example Parp-inhibitor
 ABT-888 administered as a single oral dose of 10, 25, or
50 mg
 Goals:
• determine dose range and time course over which
ABT-888 inhibits PARP activity
 in tumor samples
 in PBMCs
• To evaluate ABT-888 pharmacokinetics
 Blood samples and tumor biopsies obtained pre- and
postdrug for evaluation of PARP activity and PK
 If patients available, trials are quick.
 Exploratory Investigational New Drug (EIND)
Kummar S, Kinders R, Gutierrez ME, et al.. Phase 0 clinical trial of the poly (ADP-ribose) polymerase
inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 2009; 27.
Study Schema
Phase 0: Example Parp-inhibitor
 N = 13 patients with advanced malignancies
 N = 9 had paired tumor biopsies
Clin Cancer Res June 15, 2008 14
 Designing Phase 0 Cancer Clinical Trials
 Oncologic Phase 0 Trials Incorporating Clinical Pharmacodynamics:
from Concept to Patient
 A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and
IV Melanoma
 Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a
Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in
Tumor Biopsies of Mouse Xenografts
 Phase 0 Trials: An Industry Perspective
 The Ethics of Phase 0 Oncology Trials
 Patient Perspectives on Phase 0 Clinical Trials
 The Development of Phase I Cancer Trial Methodologies: the Use of
Pharmacokinetic and Pharmacodynamic End Points Sets the Scene
for Phase 0 Cancer Clinical Trials
 Phase 0 Trials: Are They Ethically Challenged?
Article Coming out March 15
In Clinical Cancer Research
Approaches to Phase 1 Clinical Trial Design
Focused on Safety, Efficiency, and Selected
Patient Populations: A Report from the Clinical
Trial Design Task Force of the National Cancer
Institute Investigational Drug Steering
Committee.
S. Percy Ivy, Lillian L. Siu, Elizabeth Garrett-Mayer,
and Larry Rubinstein
Questions and Comments?
[email protected]