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in Exploratory Drug Development

An ICON White Paper

Executive Summary

The determination of the maximum tolerated dose (MTD)

level is a critical step in oncology drug development.

High doses are needed to improve the efficacy of the

drug, but can result in an increased number and severity

of undesired drug limiting toxic (DLT) reactions. Phase

I oncology trials aim to determine the MTD using dose

escalation strategies, resulting in the recommendation

of a dose or drug combination for Phase II efficacy

testing. The selection of the dose escalation strategy

has an impact on the recommended dose level and

inadequate dose escalation schemes may put the

whole drug development program at risk.

Oncology Phase I trials differ from most general Phase

I trials in that the medication is examined in the target

population of diseased patients. Patients included into

these trials often suffer from advanced cancer, and

have often exhausted the standard treatment options.

Therefore in addition to the appropriate detection of the

MTD, dose escalation designs should enroll the majority

of patients to therapeutic levels of the drug,

while controlling the numbers of DLT events. These

competing objectives for dose escalation designs

make it unlikely that one design will be the best in

all circumstances.

Although the determination of the MTD is of such

critical importance in oncology, in the vast majority

of dose escalation trials a simple common method

has been used. The 3+3 design is a simple rule-based

escalation scheme, and has been used in approximately

95% of the published Phase I oncology trials over the

last two decades.1 During the same period, a number

of innovative rule-based and model-based dose

escalation designs have been developed and studied,

for example the Continual Reassessment Method (CRM)

or interval-based escalation schemes. These innovative

approaches allow tailored escalation towards the dose

level providing the specified maximal tolerable rate of

toxic events.

software ADDPLAN DF for designing, simulating and

analysing dose-finding trials. The methodology

underpinning these innovative dose escalation

approaches are described in this paper and their

performance is illustrated in a simulation study.

The overall scope is to provide insight into the capability

of ADDPLAN DF to design, simulate and analyse dose

escalation trials. Future versions of ADDPLAN DF will

expand the set of available dose escalation methods,

and will include approaches targeting efficacy and

safety simultaneously, time to event data, and more.

The process of defining the dose and dosing regimen

has been identified by regulatory authorities and industry

as a major factor impacting late-phase attrition.

Improved dose selection in both Phase I and Phase II

trials is generally considered to increase R&D efficiency

and effectiveness. Many groups of methodologists

in the pharmaceutical industry and in academia have

developed innovative statistical methods for designing

and analysing dose-finding trials. The acceptance of

innovative dose-finding methodologies was supported

this year by the European Medicines Agency (EMA)

qualification opinion on the Multiple Comparison

Procedure and Modeling (MCP-Mod) approach

developed by Novartis for dose-finding under

model-uncertainty.3

The list of innovative design and analysis methods

applied in drug development is increasing. Considerable

effort is being spent on the development and

implementation of innovative approaches for early

phase drug development. Particular examples for

these novel methodologies are toxicity interval-based

dose escalation such as the Novartis version of the

CRM4 and the modified toxicity probability interval

(mTPI) approach, which has been utilized by Merck

in a number of Phase I oncology trials.5

ICON has implemented a selection of these

standard toolbox of design and analysis techniques will

lead to improved decision making in drug development.

The consequences of improved dose selection in early

phase drug development can amount to billions of

dollars of additional value across a product portfolio.

The MTD is defined as the maximum dose for which

less than a given proportion of the population suffer a

DLT. In oncology studies the proportion is often taken

to be between 20% and 35%. Dose escalation designs

approach this MTD via an adaptive allocation procedure,

which either increases or decreases the dose-level

for the next cohort of patients based on observed

outcomes. As a limited measure of overdose control,

many dose escalation algorithms adjust the dose levels

to approach the MTD from below.

3+3 Design

Approximately 95% of all published Phase I oncology

dose escalation trials have used a 3+3 design.

The 3+3 design (Figure 1) can be described as follows.

no patients have a DLT, then the dose will be escalated

to the next dose level, i+1. If 2 or more patients have a

DLT then the previous dose level, i-1, will be considered

as MTD. If 1 patient has a DLT an additional 3 patients

will be treated at this dose level, i. If no further patients

suffer a DLT then the dose level will be escalated to i+1

and if any further patients have a DLT then the previous

dose level, i-1, will be considered the MTD. In other

words, the MTD level will be the maximum dose level

with an observed toxicity rate of 0% or 17%. Depending

upon the maximum tolerable toxicity rate for the trial

and the numbers of dose levels in the trial, the resulting

estimate of the MTD may be much too conservative: the

algorithm will reject doses with 20% DLT-rate in at least

29% of the cases. The probability of underestimating

the MTD increases with increasing numbers of dose

levels below the true but unknown MTD, while additional

patients will be treated at sub-therapeutic dose-levels.

The 3+3 design is used for its simplicity and the very

limited number of patients which are needed to get a

decision on the MTD.

The obvious limitations of the 3+3 design have led to

numerous improved dose escalation approaches.

An alternative class of dose escalation algorithms is

given by the model-based approach known as the

continual reassessment method (CRM). The basic

procedure is described in the flow chart (Figure 2).

Model-based analysis allows the utilisation of all

available data for predicting the probability of toxic

events at any dose level. Bayesian modelling allows the

inclusion of uncertainty in the model-parameters into

the analysis. However, the administration of a dose

level to patients based on a set of modelling

assumptions may result in doses that are too toxic,

if the wrong dose-toxicity curve was selected or if

inappropriate parameters were specied. Overdose

control options may be adjusted to prevent the CRM

from administering these doses.

Control (BLOC) 4

Overestimating the dose-toxicity curve may lead to

suboptimal allocation of patients to sub-therapeutic

doses, whereas underestimating the curve may

recommend toxic doses. An alternative approach for

the estimation of an appropriate dose was proposed

by Neuenschwander (2008). The basic idea is very

similar to the CRM approach. The toxicity data

are analysed using Bayesian modelling on a exible

two-parameter dose-toxicity model. However, instead of

targeting the MTD rate, the authors recommend that the

target dose is selected based on a classication of the

drug-limiting toxicity probabilities into four regions:

In the design phase of the CRM, a dose-toxicity

model, stopping rules and overdose control options

need to be dened. Given the toxicity data, a Bayesian

dose-toxicity model is tted to the data and the dose

with a posterior expected toxicity probability closest

to the maximum tolerable toxicity rate is determined.

is dose will be administered to the next cohort,

unless a stopping rule is met or the dose level is not

admissible due to overdose control options. The CRM

design stops allocation, if a stopping criterion is met

or if the maximum number of patients have been

analysed in the trial. The dose with posterior expected

toxicity rate closest to the maximum tolerable toxicity

rate will be declared the MTD. The estimation is

based on the assumed dose-response model and

the toxicity data of all dose-levels.

Under-dosing:

Target toxicity:

Excessive toxicity

Unacceptable toxicity

(0,0.2]

(0.2,0.35]

(0.35,0.6]

(0.6,1.00]

within each of the four toxicity regions can be calculated

for each dose level based on Bayesian modelling.

A dose may then be recommended based on the

observed posterior distribution and some specied

considerations on the risks and benets of the dose

categories. This Bayesian logistic approach provides a

mechanism to control both under- and over-dosing.

5

(mTPI) Approach 7

Analyse Innovative Dose Escalation Studies

dose escalation methods is given by the modied

toxicity probability interval approach (mTPI). Similar to

Neuenschwanders BLOC approach, mTPI provides a

recommendation to escalate, de-escalate or stay at the

current dose level, based on the posterior probability

of toxicity regions. The equivalence interval species a

range of toxicity probabilities, close to the maximum

tolerable toxicity, which is equivalent to the target toxicity

range of Neuenschwander. One difference compared

to CRM is that there is no formal dose-toxicity model

linking responses at the various doses tested. For each

dose level, a Beta-prior on the probability of toxic events

is used to model the uncertainty on the true toxicity

probability. Given observations at this dose level, the

posterior probabilities of under-dosing, target-dosing or

over-dosing are calculated. The dose-level to be used

at the next stage is determined from the unit posterior

probability mass of the toxicity ranges. The resulting

dose escalation scheme can easily be specied for

a range of toxicity outcomes as described in Ji and

Wang.5 Additionally, Bayesian modelling allows the

inclusion of an overdose control into the mTPI based

on the posterior probability of the toxicity rate.

be studied using the simulation engine of ADDPLAN

DF, which provides four different dose escalation

methods and allows the specication of additional

options.

this approach using isotonic regression based on

the posterior mean toxicity probabilities at each

acceptable dose level. The resulting estimate of the

MTD is therefore based on a monotonic non-parametric

estimation of the dose-toxicity curve and may be

regarded as robust.

The fully validated dose escalation functionality

of ADDPLAN DF allows the design and analyses

of innovative Phase I oncology trials. Operating

characteristics of 3+3 designs, the classical CRM,

BLOC and the mTPI approach may be studied under

different dose-toxicity proles. is allows the selection

of an appropriate dose escalation design.

reliable insight into the characteristics of the approach.

The classical CRM is implemented for two different

one-parameter probability models and a range of prior

distributions. There are different options to enable the

selection of the next stage dose which are based on

a range of estimates of the probability of toxicity. The

inuence of three dierent stopping rules, which may be

combined, can be studied using the CRM simulations.

The Bayesian logistic regression with overdose control

(BLOC) follows the approach to dose escalation

proposed by Neuenschwander. The toxicity probabilities

may be changed and an overdose control option

may be used to prevent excessive toxicity. The mTPI

approach can be simulated for dierent selections of

the Beta-prior and equivalence interval.

Active dose escalation may be analysed using the

dose escalation functionality in the analysis engine

of ADDPLAN DF. The analysis functionality provides

recommendations of the dose-level for the next cohort

of patients and the nal target dose. Additionally,

information on the posterior distribution is provided

when using any of the CRM approaches. The posterior

probability of the toxicity ranges and the posterior

probability for the doses being the MTD is displayed

after clicking the compute button. ADDPLAN DF

supports the implementation of innovative dose

escalation trials, from design to analysis in a fully

validated dose finding software suite.

The continual reassessment method (CRM) was used

in 20098 to identify the MTD of an agent, intravenously

administered to subjects with solid tumours. The study

was separated into two parts. The first part aimed at

escalating to the MTD with about 50 subjects, whereas

the second part of the study aimed at confirming this

estimated MTD and to assess safety, tolerability and

preliminary efficacy in a group of 20 subjects. The CRM

design was used, since the targeted MTD dose range

was not well dened, implying that the application of the

standard 3+3 approach might result in an inefficient

dose escalation strategy.

The dose range considered during the planning stage

of the trial consisted of 20 doses, ranging from 10mg

to 319mg in increments of 20%. The target toxicity

range for the new compound was set at 18% to 33%

with a target toxicity of 25% being used for simulating

the operating characteristics of the CRM design. In

designing the dose escalation trial, a set of six different

dose-toxicity scenarios was considered. In the current

discussion, we focus on three scenarios, representing

target toxicity either at the low end, in the middle or at

the high end of the dose range (Figure 3).

parameters of the logistic model were used in the

simulation of the BLOC. The toxicity regions were

specied with a target toxicity range of 18% to 33%.

The next stage cohort will generally be allocated to

the dose level having the highest posterior probability

of the DLT rate to be located within the target toxicity

range. A safety rule will additionally limit the number of

allocations to toxic doses. Cohorts will not be allocated

to dose levels with posterior probabilities of the DLT

rate exceeding the target toxicity range above some

safety boundary. The maximum acceptable posterior

probability of overdosing is set in the simulations at

25%. Increasing the overdose threshold would increase

the number of DLTs per patient, as the probability of

allocating cohorts to toxic doses will be increased.

The DLT probabilities using the CRM dose escalation

design were modelled using a one-parametric logistic

dose-toxicity model with normal prior on the logarithm

of the slope parameter. The probability of observing

DLTs is, in the CRM settings, assumed to follow a

straight line from 10% DLT probability at the minimum

dose to 70% DLT probability at the maximum dose.

If the posterior probability that a dose is the MTD

exceeds 70% after a run-in phase of 5 cohorts, the

corresponding dose will be claimed as the MTD.

Alternative prior distributions and stopping rules may

be studied using ADDPLAN DF.

Figure 4 displays the simulated probability of selecting

appropriate dose-levels for the MTD in the considered

scenarios. Throughout all three scenarios, the tendency

of the 3+3 designs to underestimate the target dose

is evident. In the first scenario with a target toxicity

range at the very beginning of the dose range, the

3+3 designs lead in about 70% of the simulations to

an under-estimated MTD. About 60% of the patients

are treated with doses, which may be regarded as

sub-therapeutic. Similar relations resulted for mTPI.

However, the estimates of the MTD were more reliable

in scenario 1 using mTPI. In about 50% of the cases,

the target toxicity region was reached, compared to

30% when using the 3+3 design. The mTPI provided

the minimum number of DLTs per patient throughout

all methods.

demonstrated the most promising results in terms of

accurately estimating the MTD. Both CRM and BLOC

allocated fewer patients to sub-therapeutic dose levels

and identified the MTD in the target toxicity range

in scenario 1 and 2 in more than 50% of the cases.

It is well known, that overdosing might be an issue

when using the CRM approach. The relative number

of DLTs per patient was in all considered scenarios

at the maximum when using the CRM approach. An

alternative implementation using escalation designs with

overdose control may minimise these shortcomings of

CRM, as displayed by the promising simulation results

for BLOC.

The total number of observations is at minimum when

using the 3+3 design and the trial will stop early when

using 3+3 designs, if there is a high probability of

observing toxicities at low doses, as given in scenario

1. For scenarios 2 and 3, the sample size among all

procedures was similar.

Using the ADDPLAN DF simulation results, the dose

escalation design options may be adjusted to obtain

a design, which fits well in all scenarios. Different

assumptions on the dose-toxicity model and prior

distributions, additional stopping rules and options

limiting the probability of overdosing may be verified

to further optimise the trial design.

Conclusion

The accurate estimation of the MTD is of critical

importance in the drug development process. This white

paper discusses innovative dose escalation designs and

their implementation in ADDPLAN DF.

The aim of the software is to support the process of

decision making in the design and analysis of dose

Finding trials using these innovative methods.

Uncertainty in the true underlying dose-toxicity profile

needs to be taken into account when designing efficient

and effective dose escalation trials.

ADDPLAN DF enables drug developers to study the

operating characteristics of standard and innovative

dose escalation methods under different scenarios,

allowing the selection of the appropriate methods for

successful Phase I dose escalation trials.

and industrial dose-finding methodology specialists to

further enhance and extend adaptive and innovative

approaches to dose-finding. Future versions of

ADDPLAN DF will include additional sets of innovative

dose escalation designs, targeting both safety and

efficacy endpoints. Adaptive components for Phase

II studies using multiple comparison procedures,

dose-response modelling and MCP-Mod1 are in

development for future software releases.

References

adaptive clinical trials. We are the only CRO that offers

the knowledge, software, systems and global footprint

to make global adaptive trials a reality.

Escalation Methods in Phase I Cancer Clinical Trials.

Journal of the National Cancer Institute, 101, 708-720.

planning and managing nearly 200 adaptive clinical

trials for over 30 sponsors

Experts with direct involvement in regulatory agency

adoption of adaptive design trials and subsequent

agency guidance

Operational teams and technologies to apply the

power of adaptive techniques to drug and medical

device trials

Additionally, you have access to the ICON Adaptive Trial

Innovation Centre, a group of world leading experts in

adaptive design and execution, providing leadership in

these key areas:

Design, simulation and execution of adaptive trials

across all phases of development

Development of innovative trial methodologies

Customized training in adaptive trial statistical

methodology

Advice and guidance on the logistical and operational

requirements for successful adaptive trial execution

Selection in Exploratory Drug Development. An Aptiv

Solutions White Paper.http://www.aptivsolutions.com/

addplan-df-landing-page/

3. EMA-CHMP (2014) Qualification Opinion of

MCP-Mod as an efficient statistical methodology for

model-based design and analysis of Phase II dose

finding studies under model uncertainty. EMA/CHMP/

SAWP/757052/2013.

4. Neuenschwander, B., Branson, M., Gsponer, T. (2008)

Critical Aspects of the Bayesian Approach to Phase I

Cancer Trials. Statistics in Medicine, 27, 2420-2439.

5. Ji, Y., Wang, S.-J. (2013) Modified Toxicity Probability

Interval Design: A Safer and More Reliable Method Than

the 3+3 Design for Practical Phase I Trials. Journal of

Clinical Oncology 31, 1785-1791.

6. OQuigley, H., Pepe, M., Fisher, L. (1990) Continual

Reassessment Method: A Practical Design for Phase 1

Clinical Trials in Cancer, Biometrics, 46, 33-48.

7. Ji, Y., Liu, P., Li, Y., Bekele, B.N. (2010) A Modified

Toxicity Probability Interval Method for Dose-Finding

Trials, Clinical Trials, 7, 653-663.

8. Perevozskaya, I., Han, L., Pierce, K. (2014) Continual

Reassessment Method For First-in-Human Trial: From

Design to Trial Implementation. KOL lecture series on

adaptive designs; Friday, March 14, 2014.

Using Surrogates for Decision Making in Confirmatory

Adaptive Clinical Trials

Using Adaptive Design to Optimize Product

Development at the Program and Portfolio Level

ADDPLAN PE: Population Enrichment Designs for

Adaptive Clinical Trials

South Country Business Park

Leopardstown, Dublin 18

Ireland

T: +353 1 291 2000

F: +353 1 291 2700

info@iconplc.com

ICONplc.com

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