Accelerated titration designs - National Institutes of … · 4 Accelerated titration designs Janet Dancey Investigational Drug Branch, CTEp, DCTD, NCI, Bethesda, Maryland, USA Boris

4

Accelerated titration designs

Janet DanceyInvestigational Drug Branch, CTEp, DCTD, NCI, Bethesda,Maryland, USA

Boris Freidlin and Larry RubinsteinBiometric Research Branch, DCTD, NCI, Bethesda, Maryland, USA

4.1 Introduction

A decade ago, investigators in oncology had a clear interest in modifications to thestandard phase I design to make it more effcient, to treat fewer patients at nontoxicdose levels (which may be less effcacious) and to increase the precision of phase IIdose recommendations. This was the conclusion of the 1996 Joint Meeting of theUS National Cancer Institute and the European Organization for the Research andTreatment of Cancer (1,2). At approximately the same time, a review of the recentphase I oncology literature revealed that few investigators were makng use of theinnovative phase I tral designs developed over the previous decade (3), which weremeant to accomplish these very objectives.

Approximately five years previous to this, Sheiner and coworkers published a se-ries of papers in which they argued for the use of dose-response models in the analysisof phase I trals (4-). Standard practice in oncology trals, among other fields, was to

analyze the dose-toxicity relationship only in terms of the population as a whole, andto analyze it separately for each dose. Rarely were attempts made to fit a dose-toxicitymodel to the phase I data that accounted for interpatient and intrapatient varabilty

Statistical Methods/or Dose-Finding Experiments Edited by s. Chevret(Q 2006 John Wiley & Sons, Ltd

91

92 ACCELERATED TITRATION DESIGNS

separately, acc0!l0dated the possibility of cumulative toxicity and allowed for theconstrction of dose-toxicity curves for the sensitive as well as the typical patients.In addition, Sheiner argued for the use of intrapatient dose escalation, to maximizethe possibilty of individual patients receiving effcacious doses and to increase theaccuracy of the analysis of the phase I data. This was not commonly practised inoncology phase I trals.

In response to the above, Simon et at. (7) developed a family of 'accelerated titra-tion designs' and proposed the use of an accompanying dose-toxicity model, basedon the work of Sheiner and coworkers (4, 5). The main distinguishing features ofthese designs are (a) a rapid initial escalation phase, (b) intrapatient dose escalationand (c) the ability to analyze tral results using a dose-toxicity model that incorporatesparameters for intrapatient and interpatient varation in toxicity and cumulative toxi-city. The distinguishing features of the model are its simplicity and the incorporationof separate varables for interpatient and intrapatient varability, as well as for thepossibility of cumulative toxicity.

4.2 Design

Simon et at. (7) proposed a family of accelerated titration dose-escalation designs.In their formulation all designs use 40 % dose-escalation steps. The dose-escalation!de-escalation rules are based on definitions of dose-limiting toxicity (DLT) and of'moderate' toxicity. These definitions may be protocol specific. For example, Simonet at. used any grade 2 toxicity that was considered to be treatment related as moderatetoxicity. For purposes of comparson, they designated the standard phase I design(with 40 % escalation steps in place of the standard modified Fibonacci escalation)as 'design 1'. They then introduced accelerated designs designated as 'design 2','design 3' or 'design 4' .

Design 1 dictates that patients are dose escalated in cohorts of three until DLT isobserved. One instace of DLT leads to treatment of three additional patients at thecurrent dose level (with escalation continuing if no additional DLT is observed). Twoinstances ofDLT, at a dose level, leads to a halt in dose escalation, with the prior doselevel declared the MTD so long as six patients have been treated at that level, withone instance of DLT (de-escalation continues until such a dose level is determned).

Design 2 stars with an accelerated phase that uses single-patient cohorts per doseleveL. When the first instance of first-course DLT is observed or the second instanceof first-course moderate toxicity is observed, the cohort for the current dose level isexpanded to thee patients and the tral reverts to use of design 1 for fuer cohorts.

Design 3 is similar to design 2 except that double-dose steps are used during theaccelerated phase. Two 40 % dose steps correspond to approximately a doubling ofthe actual dose. The accelerated phase ends, as with design 2, when the first instance offirst-course DLT or the second instance of first-course moderate toxicity is observed.After that, design 1 is used for fuher patients.

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ACCELERATED TITRATION DESIGNS93

Design 4 is similar to design 3, except for the criterion that is used for trggeringthe end of the accelerated phase. With designs 2 and 3, the accelerated phase ends withthe first-course instance of DLT or second instance of first-course moderate toxicity.With design 4, the trgger is the first instance of any-course DLT or the second instanceof any-course intermediate toxicity. In addition, when the first instace of moderatetoxicity is observed, two additional patients must have been treated at that dose, or ahigher dose (during any course), without experiencing moderate or worse toxicity, inorder that the accelerated phase continues. This may require the treatment of one ortwo additional patients at that dose. Hence, design 4 may stop the accelerated phaseearlier than design 3.

Table 4.1 summarzes the characteristics of the four dose escalation designs.

Table 4.1 Summar of the four dose-escalation designs and the two intrapatientdose-escalation options.

Design Description

Cohorts of 3 new patients per dose leveL. If i of 3 patientsexperiences DLT in first course, expand to 6 patientsCohorts of i patient per dose leveL. When first instance offirst-course DLT is observed, or second instance of first-coursegrade 2 toxicity of any type, expand cohort for current doselevel and revert to use of design 1 for all furher cohortsSame as design 2, except that double-dose steps are usedduring initial accelerated stage of trial (both forbetween-patient and within-patient escalation)Cohort of 1 new patient per dose level and double-dose stepsare used durng the initial accelerated stage of the tral. Whenthe first instance of DLT is observed at any course, or thesecond instance of any-course grade 2 toxicity of any type,expand cohort for current dose level and revert to use of design1 for all further cohorts. When the first instance of moderatetoxicity is observed, two additional patients must have beentreated at that dose, or a higher dose (during any course),without experiencing moderate or worse toxicity, in order thatthe accelerated phase continues

Description

No withn-patient dose escalation. De-escalate if grade 3 orworse toxicity at previous courseEscalate if grade 0-1 toxicity at previous course. De-escalateif grade 3 or worse toxicity at previous course

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94 ACCELERATED TITRATION DESIGNS4.2.1 Intrapatient dose-escalation

In order to maximize each patient's chance to be treated at a potentially active dose,the accelerated titration design allows intrapatient dose-escalation for a patient whoremains on study and has no evidence of toxicity at the current dose. Specifically,the dose for the next course is escalated if less than moderate toxicity was observedfor the patient during the current course. If moderate toxicity occured, then the dosestays the same for the next course for that patient. If DLT occurred, then the patientgenerally goes off-study, but if not, then the dose is reduced. For design 2, single-dosesteps are used for intrapatient dose changes. For designs 3 and 4, double-dose stepsare used for intrapatient dose changes durng the accelerated stage, and single-dosesteps subsequently.

All four designs may be used with and without intrapatient dose-escalation. Simonet at. (7) compared the performance of the four designs, with and without intrapatientdose-escalation, in terms of toxicity, potential effcacy (reduction of treatment at dosesbelow the MTD) and tral length. Table 4.1 also summarzes the two intrapatient dose-escalation options.

4.3 Evaluation of performance

Simon et at. (7) fit the above model to data from 20 phase I trals (involving 9 distinctagents). Only thee ofthe trals showed any evidence of cumulative toxicity (a :: 0).The estimates of a for the other trals were zero or very close to zero. The trials varedsubstantially in the other parameters and thus provide a broad range of experience forevaluation of the accelerated titration designs.

Simon et at. (7) evaluated the performance of the accelerated titration designs bysimulating phase I data based on the 20 sets of parameters estimated from the 20 realtrals that they studied. For each of the 20 sets of parameters, they generated data for1000 phase I trals and applied each of their designs to the simulated data. Figure 4.1shows the average number of patients per tral utilzed by each of the designs. Foreach design, the average is taken over the same 20000 simulated datasets generatedfrom the sets of parameters derived from the 20 actual trals analyzed. Results foreight designs are shown. Designs 1 to 4 are as described above. The designs labeledwith B utilize intrapatient dose-escalation if the toxicity in the previous course is lessthan intermediate. Designs labeled with A do not permt intrapatient dose-escalation.

Design lA corresponds to the standard design, although it does not use Fibonaccidose steps. Design lB is the standard design augmented to permt intrapatient dose-escalation. As can be seen in Figure 4.1, the average number of patients is much greaterfor the standard design lA or lB than for any of the accelerated titration designs. Theaverage number of patients is somewhat less for designs 3 and 4 that use double-dose steps compared to design 2. Although the average differences are not great, thedifferences for individual trals can be; i.e. for a tral in which the starng dose isvery low relative to the dose at which intermediate toxicity is expected, designs 2and 3 wil require substantially fewer patients.

ACCELERATED TITRATION DESIGNS

Patients and Cohorts Distribution for8 Designs

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Figure 4.1 Average number of patients and number of cohorts for the eight designs.

Figure 4.1 also shows the average number of patient cohorts utilized by eachdesign. The average is lowest for designs 3 and 4, which use double-dose steps.Although the difference in average number of cohorts is not large, the difference inaverage time to complete the trals wil be much shorter for designs 2 to 4 if patientsare not instantaneously available, since the accelerated phase of those designs requiresonly one patient per cohort.

Figure 4.2 shows the average number of patients experiencing each level of toxicityas their worst toxicity durg their treatment on the tral. With the standard design, anaverage of 23 patients experience less than intermediate toxicity (labeled 'no toxicity'in the figure). These patients are underteated. For design 2B the average number ofunderteated patients is about eight and for designs 3B and 4B the number is less thanfive. Ths major reduction in the number of underteated patients is achieved with verysmall increases in the average number of patients experiencing DLT or unacceptabletoxicity with the accelerated titration designs. Figure 4.3 shows the average percentageof patients experiencing each level of toxicity as their worst toxicity during theirtreatment on the tral.

The accelerated titration designs without intrapatient dose-escalation, 2A, 3A and4A, performed quite well with regard to reduction in average number of patients andreduction of number of underteated patients. However, they do not provide patientsaccrued early in the tral a full opportnity to be treated at a therapeutic dose. Theyare also less effective in situations where interpatient varabilty in susceptibility totoxicity is large.

These designs may be attactive, however, when there is concern about cumulativetoxicity. It is worth noting in ths regard that analysis of the 20 phase I trals used

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Toxicity Distribution for 8 Designs

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ACCELERATED TITRATION DESIGNS 97

Comparison of Design 1 A vs Design 48

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Figure 4.4 Diagram of the comparative performances of design 1A and design 4B,in terms of patients required to reach each dose level and to define the MID.

for evaluation of these designs revealed no evidence of il effects from intrapatientdose-escalation and lead the investigators to conclude that 'cumulative toxicity doesnot appear to be a valid reason to prohibit intra-patient dose escalation, as it occursrarely' (1).

To ilustràte furter the effciency of the accelerated designs in comparson withthe standard, we give in Figure 4.4 a simulated comparson of the performance of de-sign 4B versus design lA for a paricular dose-toxicity modeL. The accelerated designcompletes the tral with less than half the number of patients required by the stan-dard. More dramatically, due to the single-patient cohorts and two-step escalations,it requires only one patient for every six of the stadard design to escalate throughthe portion of the dose-toxicity curve where DLT is unlikely. Of course, if the initialdose of the tral is not defined so conservatively, the comparson is not so extreme.

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4.4 Model-based analysis

By using a model for the statistical distrbution of toxicity, based on current andprevious doses, a graded toxicity scale, based on the unobserved continuous varableassociated with toxicity and multi course treatment results, the accelerated titrationdesigns allow for an effcient approach to analysis of phase I data. The model used inSimon et at. (7) was based on measurng the worst toxicity experience for each patientdurng each course of treatment; i.e. the model does not consider separate toxicity foreach organ system, but takes the maximum over all organ systems' and records thatworst toxicity separately for each course of treatment for each patient. The modelwas designed to represent different levels of worst toxicity. The toxicity experiencedin a paricular course was determned by the curent dose administered and the total

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Table 4.2 Summar of the dose-toxicity modelfor both the unobserved continuous toxicityvarable and the observed toxicity grade leveL.

Model relating toxicity to dose

Yij = log(dij + aDi) + ßi + êijdij = dose for the ith patient in course ja = cumulative toxicity parameter

Dij = cumulative dose up to course jßi = interpatient random effect, N (0, aÐêij = intrapatient random effect, N(Q, a;)

Yij -: K 1 grade 0-1 toxicityKi -: Yij -: K2 grade 2 toxicityK 2 -: Yij -: K 3 grade 3 toxicity

Yij ~ K3 grade 4 toxicity

dose administered in the previous courses. The model incorporated parameters forboth intrapatient and interpatient varabilty, and for cumulative toxicity.

Suppose that the ith patient receives dose dij during dose j and received a totaldose Dij for courses prior to j. Let a represent the effect of cumulative toxicity

(a = 0 indicates no effect of cumulative toxicity). The random varable ßi representsinterpatient varability in the toxic effects; ßi is taken to be normally distrbutedwith mean zero and varance aJ. The random varable Bij represents intrapatientvarabilty in the toxic response; B¡j is taen to be normally distrbuted with meanzero and varance a;. These terms and random varables determne the unobservedmagnitude Yij of the worst toxicity for patient i in course j, according to the formula

Yij = log(d¡j + aDij) + ßi + Bij.

In addition to the thee parameters a, aJ and a;, there are also several parameters

for converting value Yij into a graded level of toxicity. Values of Yij less than K 1

correspond to less then moderate toxicity values between K 1 and K2 correspond tomoderate toxicity, values between K2 and K3 correspond to dose-limiting toxicity andvalues greater than K3 correspond to life-theatening toxicity: If one does not wishto distinguish DLT from life-theatening toxicity, then only K 1 and K2 are needed.

Therefore there are five or six parameters to be estimated from the data. Table 4.2summarzes the characteristics of the modeL. Ths model is a generalization of the K maxmodel of Sheiner, Beal and Sambol (5) and of the model of Chou and Talalay (8,9).

Given the data of the grade of toxicity (worst over organ systems) for eachcourse of each patient, the method of maxmum likelihood is used to estimatethe model parameters. Splus software for fitting the parameters is available athttp://inus.nci.nih.govlbrb. That website also contains an Excel macro for managing

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Probabilties of Grade 3+ Toxicity

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Figure 4.5 Probabilities of grade 3+ toxicity at varous dose levels for the meanpatient and the patients one standard deviation above and below the mean.

dose assignments to patients durng accelerated titration design trals. The macroassists investigators in quality controlling the dose assignment and provides a conve-nient way of recording dose assignments in a systematic manner that makes the dataavailable for subsequent analysis.

Figure 4.5 ilustrates the power of the model-based analysis to constrct a dose-toxicity curve, not only for the typical patient (50th percentile) but also for the patientwho falls one standard deviation below the typical in terms of increased susceptibilityto toxicity (16th percentile). The standard approach to defining the MID is based onthe probabilty of toxicity at a given dose for the population as a whole, which oftenroughly corresponds to the probabilty of toxicity for the typical patient. With thisapproach, the initial phase II dose would be set, for Figure 4.5, at dose level 16 or17, to keep the probabilty of DLT below 30 %. However, the model-based analysisreveals that such a dose level results in at least a 40-0 % likelihood of DLT for anontrvial subgroup of the patient population (those at the 16th percentile or below).This might suggest that a more prudent approach would be to define a lower initialphase II dose, to accommodate the susceptibilty of this subgroup.

Figure 4.6 ilustrates the power of the model-based analysis to constrct com-parative dose-toxicity cures for the different levels of toxicity. For example, theanalysis suggests that the dose-toxicity cures for grade 2 versus grade 3 toxicity areseparated by approximately four dose levels. This indicates that for a given patient,as well as for the population as a whole, DLT is likely to occur approximately fourdose levels beyond moderate toxicity, suggesting that accelerated dose-escalation islikely to be safe, both for the population and for a given individual. Even though thedose-toxicity curve for DLT is relatively steep, it is well separated from the curve formoderate toxicity.

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Figure 4.6 Probabilities of grade 2+, grade 3+ and grade 4+ toxicity at varous

dose levels for the mean patient.

Sheiner and coworkers (4,5) proposed the use of dose-toxicity models for phase Itrals a decade ago. They are stil rarely used, despite their potential for facilitatingthe definition of a phase II staring dose.

4.5 Clinical applications

First-in-man phase I tral designs of oncology agents share the following charac-

teristics: selection of a 'safe' starng dose, sequential dose-escalation in cohorts ofpatients and determnation of a recommended dose based on a prespecified primarendpoint, usually the occurrence of unacceptable toxicity in a defined number of pa-tients treated at a given dose leveL. Optimal phase I designs result in the identificationof a dose for furer evaluation in a manner that is both safe and effcient. Higher

staring doses, fewer patients per dose level and large escalation steps require fewer

patients overall. However, safety is enhanced by lower staing doses, more patientsper dose level to ensure safety of the dose and smaller dosing increments. Phase Idesigns must strke a balance between these elements. Accelerated titration designsproposed by Simon et aI. (7) use the following modifications to enhance effciency:as few as one patient per level are enrolled and initial dose-escalation steps are larger

(e.g. 100 % increments in the absence of toxicity). The number of patients per doselevel increases to thee, once toxicity of a minimum degree (e.g. second instace of

grade 2; first instance of DLT) has been seen in at least one patient. Thereafter aminimum of thee patients in each cohort are recruited, expanding to six in the eventthat one of thee has a DLT in the protocol prescribed observation period (usuallyone cycle or 4-8 weeks of chronic therapy) and the dose-escalation increments arereduced.

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To assess the use and utilty of the accelerated titration designs in the evaluationof novel oncology therapeutics, we conducted a literature search using the ISI Webof Knowledge Database (Thomson ISI, Thomson Corporation, Philadelphia, Penn-sylvania) in May and August 2005. All aricles in the database that cited the originalpaper by Simon et at. (7) were retreved and reviewed. In tota, 106 publications wereidentified. Aricles that focused on statistical methodology of phase I studies (10),were not of phase I studies (4), that evaluated combinations of agents (12), werereview aricles (34), or of phase I studies that did not use the Simon et at. (7) acceler-ated titration designs (10), were not included in our review. In total, 36 publicationsof phase I trals of novel cancer therapeutics were identified. From the tral publi-

cations, the following details were abstracted: agent/class, schedule, type of design,study-specific modifications to the design (e.g. patients/cohort and dose-escalationincrements during the accelerated phase, rules for termnating the accelerated phase,dose-escalation increments following termnation of the accelerated phase, dose lev-els evaluated and the number of dose levels evaluated during the accelerated phaseand subsequently). A summar of these trals are provided in Tables 4.3 and 4.4.

From the results of our review a number of observations can be made regarding theutilzation of the designs. Firstly, the classes of agents selected for evaluation using anaccelerated titration design favor agents that belong to chemical classes that have beenpreviously studied or to biological agents not associated with significant risk of severe,irreversible organ toxicity. This is not surprising, as agents with these characteristicswould engender a level of comfort regarding the safety of using an accelerated titrationdesign. Secondly, designs 3 and 4, which utilize single-patient cohorts and 100 % dose-escalations, are the most commonly used. Thirdly, almost half of the studies do notutilze intrapatient dose-escalation. Fourtly, the most common modifications to thedesigns are those determning the dose-escalation increments following termnationof the accelerated phase and/or modifications to rules for termnating the acceleratedphase. Most trals with modifications in the dose increments following termnationof the accelerated phase stipulated dose increments of 15-30 % rather than 40 %.A few utilzed higher-dose increments (50-67 %) and a few reverted to a modifiedFibonacci escalation schema. Rules for termnating the accelerated phase included

the first occurrence of any toxicity, or the achievement of a prespecified dose (e.g.mouse equivalent MTD). Given the frequency and nature of these modifications,it appears that investigators retain concerns regarding the safety of the acceleratedtitration design dose-escalation increments and termnation rules.

To assess the effciency and safety of the accelerated designs, the numbers ofpatients and dose levels, overall and during the accelerated phase, were evaluatedacross the 36 studies. Patients treated above the ultimately recommended phase IIdose (RP2D) were identified. If a patient was treated at a dose level prescribed bythe accelerated phase dose increase and that dose exceeded the RP2D, then the doselevel was considered to have exceeded the recommended dose due to the acceleratedphase rules. Similarly, patients that died on the study due to obvious or suspectedtreatment-related toxicity were identified. Those fatalities which occured at dosesprescribed during the accelerated phase of the study were classified as deaths during

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m2/

d w

ithou

tm 0

et a

t. (2

1)m

etal

lopr

otei

nase

sunb

lock

din

hibi

tor

i-Sy

edC

OL-

3, m

atrix

Ora

lly d

aily

2AN

o50

mg/

m2/

day

~et

at.

(22)

met

allo

prot

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se¡. 0

inhi

bito

rZ

Rus

tinC

ombr

etas

tatin

A4

iv x 5 for 2 weeks every

Mod

ifie

d 4B

Yes

52-6

8 m

g/m

2 x

5 fo

r0 tr

et a

t. (2

3)phosphate, ubulin

3 w

eeks

2 w

eeks

eve

ry 3

wee

ksen ¡.

targ

etin

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ent

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hatte

rjee

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F-10

42, c

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aily

x 5

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Mod

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d 3B

Yes

80 m

g/m

2 x

5 fo

r 2

wee

ksen

et a

t. (2

4)an

alog

2 w

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eve

ryev

ery

3 w

eeks

3 w

eeks

Vila

lona

-E

ctei

nasc

idin

-743

,iv daily x 5 every

Mod

ified

3A

No

325

g/m

2/da

y da

ily x

5C

aler

ote

trah

ydro

isoq

uino

line

3 w

eeks

et a

t. (2

5)al

kalo

idK

o et

at.

(26)

EM

D 2

7306

6 (h

uKS-

IL2)

iv daily x 3 every

Mod

ifie

d 4A

No

6.4

mg/

m2/

day

x 3

ever

yim

mun

ocyt

okin

e4

wee

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wee

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oel

GE

M23

1

, olig

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ide

to3

day

(1 p

atie

nt)

or a

Mod

ifie

d 4A

No

120

mg/

m2/

day

x 5

days

et a

t. (2

7)ty

pe i

regu

lato

ry s

ubun

it5 day continuous iv

of p

rote

in k

inas

e A

infu

sion

Che

nG

EM

23

1 , o

ligon

ucle

otid

e to

2 hour iv infusions

Mod

ifie

d 4A

No

240

mg/

m2

twic

e w

eekl

yet

at.

(28)

type

I r

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ator

y su

buni

ttw

ice

wee

kly

of p

rote

in k

inas

e A

..(

Con

tinue

d)0 U

J

i

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. -"

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le 4

.3(

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0 .t

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a pa

tient

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hor/

dose

-R

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ded

refe

renc

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gent

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dule

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ign

esca

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ndo

se

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ann

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4BY

es80

mg/

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per

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e

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647-21 days

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ove

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r 3

days

et a

t. (3

1)co

njug

ate

ofev

ery

4 w

eeks

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ance

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ry 3

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ifie

d 4A

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m2

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kly

6 ho

ur~

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l. (3

3)an

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the

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3 w

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i-

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t. (3

4)en

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ted

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de J

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1595

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2 IV

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ry~

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l. (3

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stu

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)3

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j

106ACCELERATED TITRATION DESIGNS

Table 4.4 Summar of phase I studies using accelerated titration design.

Trials (n)

Patients (n)t

¡

1i

I

I

r!

il

i

Il

Design

Intrapatientdose-escalation

Modifications

Types of

modifications

Patients/study(n)

Dose levels (n)Fold dose rangePatients treatedAbove RP2DDose levelsAbove RP2D

Deaths due totoxicity

Type1

23

4Unknown

YesNoYesNo

Dose-escalation duringthe accelerated phase

Patients/cohort duringthe accelerated phase

Rules for terminationof accelerated phase

Dose-escalationfollowingaccelerated phase

During accelerated phase

Median5

Range0-15

36911

Trials (n)1

610

18

1

2016

15

11

3

2

8

19

For study

Median Range

22 7-74

6 3-15

16 2-320

6 0-28

1 0-3

o

(13 patients acrossall studies dieddue to toxicities)

0-3

3 0-12

o 0-

o 0-1

(4 of 36 studies had adose level thatexceeded the RP2Ddurng the ATD)

0-1(1 patient across all

studies died due totoxicities)

o,I'

"

.,1-i

I

1i

" '.~;.-,'".-

d


the accelerated phase. As summarzed in Table 4.4, the accelerated titration designs,as used in these studies, rarely resulted in dose escalation beyond the recommendedphase II dose. Only 4 of 36 exceeded the recommended phase II dose during theaccelerated titration phase and only 1 death from toxicity occurred during the accel-erated titration phase, among the 91 I patients enrolled in these studies. (It should benoted, however, that the use of acceleration may have contrbuted, in some trials, toexceeding the RP2D by a greater number of doses, or for a greater number of patients,than would otherwise have happened. Thus, the use of acceleration in these trials mayhave increased the overall number of patients treated above the RP2D, even beyondthe acceleration phase itself, and thus contrbuted to a greater death rate from toxic-ity.) Based on its utilization in these selected studies, the accelerated titration designappears to provide an enhanced effciency with acceptable safety. However, thereare a number of issues investigators might consider prior to selecting an acceleratedtitration design to evaluate a novel agent in a first-in-man phase I clinical tral.

The use of minimum one-patient cohorts and larger dose-escalation steps may beadvantageous under the following circumstances: (a) the agent is of a chemical classthat has been widely studied; (b) tle agent is predicted to have minimal interpatientvarability in pharacokinetics; (c) the agent's anticipated toxicity is unlikely to besevere or ireversible and is amenable to close monitoring and supportive interven-tions. Examples of agents most amenable to evaluation using a phase I acceleratedtitration design might be the following: a new formulation of a previously studiedagent (e.g.liposomal formulation ofpaclitaxel), a biological agent with minimal tox-icity based on animal models (e.g. antibody or small molecule inhibitor of a receptortyrosine kinase inhbitor) or an agent for which significant interspecies varabilty in

preclinical toxicology has led to a very conservative staring dose in a human phase Istudy. Under these circu:Qstances, the increased effciency and presumed safety of anaccelerated design might make it preferable.

Conversely, there are situations where an accelerated titration design may notprovide the optimal balance between safety and effciency as either larger numbersof patients/dose cohort and/or smaller dose increments would be preferable. Agentsassociated with steep dose-response curves for toxicity, severe ireversible toxicity,unexplained mortalty in anmal toxicology studies or large varabilty in doses orplasma drg levels eliciting effects may require alternative designs to balance safetyand effciency optimally. For example, larger patient numbers/dose cohorts may bepreferred if there is anticipated wide interpatient varabilty in toxic effects due topharacokinetic or pharacogenomic differences between patients. For this circum-stance, larger patient numbers per dose level is appropriate since decisions about thesafety of a given dose may require more than a single patient's experience. Similarly,when a pharacokinetic or a pharacodynamc endpoint, rather than toxicity, is theprimar endpoint, larger numbers of patients per dose level are recommended due toanticipated interpatient varability in these endpoints. With either situation, the useof an accelerated titration design with single-patient cohorts may not be optimal.

There are also situations where small dose-escalation increments may be advis-able. For example, if the agent is predicted to have severe, ireversible or potentially

-

l~:r~:f!

108ACCELERATED TITRATION DESIGNS

"".,".~.;

fatal organ toxicity based on animal toxicology, paricularly if associated with a steepdose-response curve for toxicity, relatively small changes in dose/concentration maylead from minimal toxicity to severe toxicity, and thus smaller dose-escalation incre-ments are preferable to ensure safety.

Approaches to enhancing the proportion of patients in a phase I tral receiving'therapeutic' dose levels includes not only limiting enrolment on lower dose levels butalso allowing dose-escalation within individual patients. Intrapatient dose-escalationprovides two advantages: it improves the lielihood of benefit from the agent for the,individual patient and it increases the experience at higher dose levels. Acceleratedtitration designs proposed by Simon et at. (7) allow intrapatient dose escalation if notoxicity :: grade 1 was seen in the first cycle at the assigned dose leveL. Whle it didnot appreciably shorten the study duration, it did allow more patients to be treated ator near the recommended phase II dose and increased the number of cycles evaluatedat the higher dose levels.

Although the rationale supportng intrapatient dose-escalation is appealing, itdoes not seem to be widely applied. Thus, despite the appeal of escalating patientsto higher doses than they were assigned initially, should safety criteria be met, someissues remain with its routine application in phase I protocols. Many phase I pro-tocols continue to be written prohibiting intrapatient escalation since it is believedto have a minimal impact on tral effciency while bringing with it concerns aboutpractical issues regarding the 'rules' for implementing dose-escalation and safety.Studies that have allowed intrapatient escalation withn their protocols have gener-ally allowed dose-escalation to occur after the patient has been evaluated at the currentdose level for the duration of the observation period and where the patient has hadminimal/no toxicity. Less commonly used are rules that require not only that the pa-tient has not had significant toxicity but also that the next higher dose level has beenevaluated in one or more new patients - a more strngent and cumbersome criterionthat may be favored to enhance safety and also to distinguish between acute ver-sus cumulative toxic events. Although experience with intrapatient dose-escalationwithn phase I studies is limited, to date its use within phase I studies using an ac-celerated titration design did not appear to compromise patient safety or complicatethe interpretation of the study results. Of note, withn a given protocol, it is impor-tant to require a minimum number of newly recruited patients at each dose leveland to base furter dose-escalation decisions upon the behavior of the drg in these

individuals.

'0.1

; ~ f"~~ ;~.~ ;:.;;.Î'31 !

J.-r"

~~ I

~ ¡'/11

4.6 Conclusions

Accelerated titration designs can dramatically reduce the number of patients accruedto a phase I tral, in comparson to the standard phase I design. They can also sub-stantially shorten the duration of the phase I tral. With intrapatient dose-escalationand application of a dose-toxicity model, they provide much greater information thanthe stadard design and analysis with regard to cumulative toxicity, interpatient and

t...

1

~


intrapatient varability, steepness of the dose-toxicity curve and separation of thedose-toxicity curves for the varing toxicity levels. They also provide all patientsentered in the tral a maximum opportunity to be treated at a therapeutic dose.

Despite this, we find that the designs are not widely used, which is likely tobe due to the conservativeness of investigators. Even when they are used, theyare often used with an initial dose set much more conservatively than would bedone for the standard design and without use of intrapatient dose-escalation, therebyreducing their effectiveness. A recent comprehensive review of the risk-benefit rela-tionship for phase I trals conducted over the past decade reveals an overall tox-

icity death rate of only O.OOS (46). An accompanying editorial (47) argues thatsuch a low toxicity death rate, in the context of treatment for an often rapidly fa-tal disease, suggests that phase I trals may be conducted in an overly cautiousfashion. Appropriate utilization of designs such as the accelerated titration designsmight increase the potential for benefit in phase I trals, with little increase inrisk.

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--

~'Y


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ii


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