Accelerated titration designs - Biometric Research Branch

4
Accelerated titration designs
Janet Dancey
Investigational Drug Branch, CTEp, DCTD, NCI, Bethesda,
Maryland, USA
Boris Freidlin and Larry Rubinstein
Biometric Research Branch, DCTD, NCI, Bethesda, Maryland, USA
4.1 Introduction
A decade ago, investigators in oncology had a clear interest in modifications to the
standard phase I design to make it more effcient, to treat fewer patients at nontoxic
dose levels (which may be less effcacious) and to increase the precision of phase II
dose recommendations. This was the conclusion of the 1996 Joint Meeting of the
US National Cancer Institute and the European Organization for the Research and
Treatment of Cancer (1,2). At approximately the same time, a review of the recent
phase I oncology literature revealed that few investigators were makng use of the
innovative phase I tral designs developed over the previous decade (3), which were
meant to accomplish these very objectives.
Approximately five years previous to this, Sheiner and coworkers published a series
of papers in which they argued for the use of dose-response models in the analysis
of 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, and
to analyze it separately for each dose. Rarely were attempts made to fit a dose-toxicity
model 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 the
constrction 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 maximize
the possibilty of individual patients receiving effcacious doses and to increase the
accuracy of the analysis of the phase I data. This was not commonly practised in
oncology phase I trals.
In response to the above, Simon et at. (7) developed a family of 'accelerated titration
designs' and proposed the use of an accompanying dose-toxicity model, based
on the work of Sheiner and coworkers (4, 5). The main distinguishing features of
these designs are (a) a rapid initial escalation phase, (b) intrapatient dose escalation
and (c) the ability to analyze tral results using a dose-toxicity model that incorporates
parameters for intrapatient and interpatient varation in toxicity and cumulative toxicity.
The distinguishing features of the model are its simplicity and the incorporation
of separate varables for interpatient and intrapatient varability, as well as for the
possibility 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, Simon
et at. used any grade 2 toxicity that was considered to be treatment related as moderate
toxicity. 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 is
observed. One instace of DLT leads to treatment of three additional patients at the
current dose level (with escalation continuing if no additional DLT is observed). Two
instances ofDLT, at a dose level, leads to a halt in dose escalation, with the prior dose
level declared the MTD so long as six patients have been treated at that level, with
one 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 dose
leveL. When the first instance of first-course DLT is observed or the second instance
of first-course moderate toxicity is observed, the cohort for the current dose level is
expanded 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 the
accelerated phase. Two 40 % dose steps correspond to approximately a doubling of
the actual dose. The accelerated phase ends, as with design 2, when the first instance of
first-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 DESIGNS
93
Design 4 is similar to design 3, except for the criterion that is used for trggering
the end of the accelerated phase. With designs 2 and 3, the accelerated phase ends with
the 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 instance
of any-course intermediate toxicity. In addition, when the first instace of moderate
toxicity is observed, two additional patients must have been treated at that dose, or a
higher dose (during any course), without experiencing moderate or worse toxicity, in
order that the accelerated phase continues. This may require the treatment of one or
two additional patients at that dose. Hence, design 4 may stop the accelerated phase
earlier 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 intrapatient
dose-escalation options.
Design Description
1
2
3
4
Escalation
A
B
Cohorts of 3 new patients per dose leveL. If i of 3 patients
experiences DLT in first course, expand to 6 patients
Cohorts of i patient per dose leveL. When first instance of
first-course DLT is observed, or second instance of first-course
grade 2 toxicity of any type, expand cohort for current dose
level and revert to use of design 1 for all furher cohorts
Same as design 2, except that double-dose steps are used
during initial accelerated stage of trial (both for
between-patient and within-patient escalation)
Cohort of 1 new patient per dose level and double-dose steps
are used durng the initial accelerated stage of the tral. When
the first instance of DLT is observed at any course, or the
second instance of any-course grade 2 toxicity of any type,
expand cohort for current dose level and revert to use of design
1 for all further cohorts. When the first instance of moderate
toxicity is observed, two additional patients must have been
treated at that dose, or a higher dose (during any course),
without experiencing moderate or worse toxicity, in order that
the accelerated phase continues
Description
No withn-patient dose escalation. De-escalate if grade 3 or
worse toxicity at previous course
Escalate if grade 0-1 toxicity at previous course. De-escalate
if grade 3 or worse toxicity at previous course
-,

94 ACCELERATED TITRATION DESIGNS
4.2.1 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 who
remains 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 observed
for the patient during the current course. If moderate toxicity occured, then the dose
stays the same for the next course for that patient. If DLT occurred, then the patient
generally goes off-study, but if not, then the dose is reduced. For design 2, single-dose
steps are used for intrapatient dose changes. For designs 3 and 4, double-dose steps
are used for intrapatient dose changes durng the accelerated stage, and single-dose
steps subsequently.
All four designs may be used with and without intrapatient dose-escalation. Simon
et at. (7) compared the performance of the four designs, with and without intrapatient
dose-escalation, in terms of toxicity, potential effcacy (reduction of treatment at doses
below the MTD) and tral length. Table 4.1 also summarzes the two intrapatient doseescalation
options.
4.3 Evaluation of performance
Simon et at. (7) fit the above model to data from 20 phase I trals (involving 9 distinct
agents). 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 vared
substantially in the other parameters and thus provide a broad range of experience for
evaluation of the accelerated titration designs.
Simon et at. (7) evaluated the performance of the accelerated titration designs by
simulating phase I data based on the 20 sets of parameters estimated from the 20 real
trals that they studied. For each of the 20 sets of parameters, they generated data for
1000 phase I trals and applied each of their designs to the simulated data. Figure 4.1
shows the average number of patients per tral utilzed by each of the designs. For
each design, the average is taken over the same 20000 simulated datasets generated
from the sets of parameters derived from the 20 actual trals analyzed. Results for
eight designs are shown. Designs 1 to 4 are as described above. The designs labeled
with B utilize intrapatient dose-escalation if the toxicity in the previous course is less
than intermediate. Designs labeled with A do not permt intrapatient dose-escalation.
Design lA corresponds to the standard design, although it does not use Fibonacci
dose steps. Design lB is the standard design augmented to permt intrapatient doseescalation.
As can be seen in Figure 4.1, the average number of patients is much greater
for the standard design lA or lB than for any of the accelerated titration designs. The
average number of patients is somewhat less for designs 3 and 4 that use doubledose
steps compared to design 2. Although the average differences are not great, the
differences for individual trals can be; i.e. for a tral in which the starng dose is
very low relative to the dose at which intermediate toxicity is expected, designs 2
and 3 wil require substantially fewer patients.

ACCELERATED TITRATION DESIGNS
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35
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Patients and Cohorts Distribution for
8 Designs
Total
patients
Cohorts
c: Design 1 A
. Design 1 8
o Design 2A
c: Design 28
. Design 3A
. Design 38
D Design 4A
. Design 48
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 each
design. 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 in
average time to complete the trals wil be much shorter for designs 2 to 4 if patients
are not instantaneously available, since the accelerated phase of those designs requires
only one patient per cohort.
Figure 4.2 shows the average number of patients experiencing each level of toxicity
as their worst toxicity durg their treatment on the tral. With the standard design, an
average of 23 patients experience less than intermediate toxicity (labeled 'no toxicity'
in the figure). These patients are underteated. For design 2B the average number of
underteated patients is about eight and for designs 3B and 4B the number is less than
five. Ths major reduction in the number of underteated patients is achieved with very
small increases in the average number of patients experiencing DLT or unacceptable
toxicity with the accelerated titration designs. Figure 4.3 shows the average percentage
of patients experiencing each level of toxicity as their worst toxicity during their
treatment on the tral.
The accelerated titration designs without intrapatient dose-escalation, 2A, 3A and
4A, performed quite well with regard to reduction in average number of patients and
reduction of number of underteated patients. However, they do not provide patients
accrued early in the tral a full opportnity to be treated at a therapeutic dose. They
are also less effective in situations where interpatient varabilty in susceptibility to
toxicity is large.
These designs may be attactive, however, when there is concern about cumulative
toxicity. It is worth noting in ths regard that analysis of the 20 phase I trals used
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Figure 4.2 Average number of
the eight designs.
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Toxicity Distribution for 8 Designs
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ACCELERATED TITRATION DESIGNS
c: Design 1 A
.. Design 18
o Design 2A
D Design 28
.. Design 3A
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o Design 4A
II Design 48
patients with worst toxicity at each toxicity level, for
Toxicity Distribution for 8 Designs
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o Design 1 A
.. Design 18
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Figure 4.3 Average percentage of patients with worst toxicity at each toxicity level,
for the eight designs.
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ACCELERATED TITRATION DESIGNS 97
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16
14
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Comparison of Design 1 A vs Design 48
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Number of Patients
- Design 1 A
- Design 48
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 intrapatient
dose-escalation and lead the investigators to conclude that 'cumulative toxicity does
not appear to be a valid reason to prohibit intra-patient dose escalation, as it occurs
rarely' (1).
To ilustràte furter the effciency of the accelerated designs in comparson with
the standard, we give in Figure 4.4 a simulated comparson of the performance of design
4B versus design lA for a paricular dose-toxicity modeL. The accelerated design
completes the tral with less than half the number of patients required by the standard.
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 through
the portion of the dose-toxicity curve where DLT is unlikely. Of course, if the initial
dose of the tral is not defined so conservatively, the comparson is not so extreme.
4.4 Model-based analysis
By using a model for the statistical distrbution of toxicity, based on current and
previous doses, a graded toxicity scale, based on the unobserved continuous varable
associated with toxicity and multi course treatment results, the accelerated titration
designs allow for an effcient approach to analysis of phase I data. The model used in
Simon et at. (7) was based on measurng the worst toxicity experience for each patient
durng each course of treatment; i.e. the model does not consider separate toxicity for
each organ system, but takes the maximum over all organ systems' and records that
worst toxicity separately for each course of treatment for each patient. The model
was designed to represent different levels of worst toxicity. The toxicity experienced
in a paricular course was determned by the curent dose administered and the total
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ACCELERATED TITRATION DESIGNS
Table 4.2 Summar of the dose-toxicity model
for both the unobserved continuous toxicity
varable and the observed toxicity grade leveL.
Model relating toxicity to dose
Yij = log(dij + aDi) + ßi + êij
dij = dose for the ith patient in course j
a = cumulative toxicity parameter
Dij = cumulative dose up to course j
ßi = interpatient random effect, N (0, aÐ
êij = intrapatient random effect, N(Q, a;)
Yij -: K 1 grade 0-1 toxicity
Ki -: Yij -: K2 grade 2 toxicity
K 2 -: Yij -: K 3 grade 3 toxicity
Yij ~ K3 grade 4 toxicity
dose administered in the previous courses. The model incorporated parameters for
both intrapatient and interpatient varabilty, and for cumulative toxicity.
Suppose that the ith patient receives dose dij during dose j and received a total
dose 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 represents
interpatient varability in the toxic effects; ßi is taken to be normally distrbuted
with mean zero and varance aJ. The random varable Bij represents intrapatient
varabilty in the toxic response; B¡j is taen to be normally distrbuted with mean
zero and varance a;. These terms and random varables determne the unobserved
magnitude 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 to
moderate toxicity, values between K2 and K3 correspond to dose-limiting toxicity and
values greater than K3 correspond to life-theatening toxicity: If one does not wish
to 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 4.2
summarzes the characteristics of the modeL. Ths model is a generalization of the K max
model 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 each
course of each patient, the method of maxmum likelihood is used to estimate
the model parameters. Splus software for fitting the parameters is available at
http://inus.nci.nih.govlbrb. That website also contains an Excel macro for managing
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ACCELERATED TITRATION DESIGNS
1
0.9
0.8
~ 0.7
:E 0.6
B 0.5
e 0.4
D. 0.3
Probabilties of Grade 3+ Toxicity
(Chloroquinoxaline Sulfonamide)
0.2
0.1
o OC\""COC:OC\,,
.,.,.,.,.,C\C\C\
Dose Level
-Gr 3+ (16%tile)
- Gr 3+ (50%tie)
.. Gr 3+ (84%tie)
Figure 4.5 Probabilities of grade 3+ toxicity at varous dose levels for the mean
patient and the patients one standard deviation above and below the mean.
dose assignments to patients durng accelerated titration design trals. The macro
assists investigators in quality controlling the dose assignment and provides a convenient
way of recording dose assignments in a systematic manner that makes the data
available for subsequent analysis.
Figure 4.5 ilustrates the power of the model-based analysis to constrct a dosetoxicity
curve, not only for the typical patient (50th percentile) but also for the patient
who falls one standard deviation below the typical in terms of increased susceptibility
to toxicity (16th percentile). The standard approach to defining the MID is based on
the probabilty of toxicity at a given dose for the population as a whole, which often
roughly corresponds to the probabilty of toxicity for the typical patient. With this
approach, the initial phase II dose would be set, for Figure 4.5, at dose level 16 or
17, to keep the probabilty of DLT below 30 %. However, the model-based analysis
reveals that such a dose level results in at least a 40-0 % likelihood of DLT for a
nontrvial 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 initial
phase II dose, to accommodate the susceptibilty of this subgroup.
Figure 4.6 ilustrates the power of the model-based analysis to constrct comparative
dose-toxicity cures for the different levels of toxicity. For example, the
analysis suggests that the dose-toxicity cures for grade 2 versus grade 3 toxicity are
separated 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 four
dose levels beyond moderate toxicity, suggesting that accelerated dose-escalation is
likely to be safe, both for the population and for a given individual. Even though the
dose-toxicity curve for DLT is relatively steep, it is well separated from the curve for
moderate toxicity.
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ACCELERATED TITRATION DESIGNS
Probabilties of Toxicity (50%tie Patient)
(Chloroquinoxaline Sulfonamide)
10 12 14 16 18 20 22 24
Dose Level
- Gr 2+ toxicity
- Gr 3+ toxicity
- Gr 4+ toxicity
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 I
trals a decade ago. They are stil rarely used, despite their potential for facilitating
the definition of a phase II staring dose.
4.5 Clinical applications
First-in-man phase I tral designs of oncology agents share the following characteristics:
selection of a 'safe' starng dose, sequential dose-escalation in cohorts of
patients and determnation of a recommended dose based on a prespecified primar
endpoint, usually the occurrence of unacceptable toxicity in a defined number of patients
treated at a given dose leveL. Optimal phase I designs result in the identification
of 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 patients
per dose level to ensure safety of the dose and smaller dosing increments. Phase I
designs must strke a balance between these elements. Accelerated titration designs
proposed 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 dose
level 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 a
minimum of thee patients in each cohort are recruited, expanding to six in the event
that one of thee has a DLT in the protocol prescribed observation period (usually
one cycle or 4-8 weeks of chronic therapy) and the dose-escalation increments are
reduced.
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ACCELERATED TITRATION DESIGNS
To assess the use and utilty of the accelerated titration designs in the evaluation
of novel oncology therapeutics, we conducted a literature search using the ISI Web
of Knowledge Database (Thomson ISI, Thomson Corporation, Philadelphia, Pennsylvania)
in May and August 2005. All aricles in the database that cited the original
paper by Simon et at. (7) were retreved and reviewed. In tota, 106 publications were
identified. Aricles that focused on statistical methodology of phase I studies (10),
were not of phase I studies (4), that evaluated combinations of agents (12), were
review aricles (34), or of phase I studies that did not use the Simon et at. (7) accelerated
titration designs (10), were not included in our review. In total, 36 publications
of phase I trals of novel cancer therapeutics were identified. From the tral publications,
the following details were abstracted: agent/class, schedule, type of design,
study-specific modifications to the design (e.g. patients/cohort and dose-escalation
increments during the accelerated phase, rules for termnating the accelerated phase,
dose-escalation increments following termnation of the accelerated phase, dose levels
evaluated and the number of dose levels evaluated during the accelerated phase
and 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 the
utilzation of the designs. Firstly, the classes of agents selected for evaluation using an
accelerated titration design favor agents that belong to chemical classes that have been
previously studied or to biological agents not associated with significant risk of severe,
irreversible organ toxicity. This is not surprising, as agents with these characteristics
would engender a level of comfort regarding the safety of using an accelerated titration
design. Secondly, designs 3 and 4, which utilize single-patient cohorts and 100 % doseescalations,
are the most commonly used. Thirdly, almost half of the studies do not
utilze intrapatient dose-escalation. Fourtly, the most common modifications to the
designs are those determning the dose-escalation increments following termnation
of the accelerated phase and/or modifications to rules for termnating the accelerated
phase. Most trals with modifications in the dose increments following termnation
of 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 modified
Fibonacci 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 accelerated
titration design dose-escalation increments and termnation rules.
To assess the effciency and safety of the accelerated designs, the numbers of
patients and dose levels, overall and during the accelerated phase, were evaluated
across the 36 studies. Patients treated above the ultimately recommended phase II
dose (RP2D) were identified. If a patient was treated at a dose level prescribed by
the accelerated phase dose increase and that dose exceeded the RP2D, then the dose
level was considered to have exceeded the recommended dose due to the accelerated
phase rules. Similarly, patients that died on the study due to obvious or suspected
treatment-related toxicity were identified. Those fatalities which occured at doses
prescribed during the accelerated phase of the study were classified as deaths during
101

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0N Table 4.3 Phase I trials using accelerated titration design.
Intra patient
Author/ dose- Recommended
reference Agent Schedule Design escalation dose
LoRusso 5-Fluoro-pyrimidinone Orally daily for 5 days 4B Yes 625 mg/m2/day orally for
eta!. (10) every 4 weeks 5 days every 4 weeks
Goetz 17 -(Allylamino )-17- iv weekly x 3 every 2B Yes 308 mg/m2 weekly x 3
et at. (11) demethoxygeldanamycin 4 weeks every 4 weeks
Grem 17 -(Allylamino )-17- 1 hour is iv infusion 2B Yes 40 mg/m2 daily x 5 every
et ai. (12) demethoxygeldanamycin daily for 5 days every 3 weeks
3 weeks
Sessa BBR3464, cationic iv daily x 5 every 4B Yes 0.12 mg/m2/day x 5 every
et at. (13) triplatinum complex 3 weeks 3 weeks
n
Mross BBR3576, iv infusion every 4A No 150 mg/m2 every 4 weeks f)
et at. (14) aza-anthrapyrazole 4 weeks
Plummer BMS-184476, taxane analog iv weekly x 3 every 4B Yes 50 mg/m2/week x 2 every ~
tr
et at. (15) 4 weeks, later 21 days
~
amended to
weekly x 2 every
~
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21 days
""
Mani BMS-247550, derivative of 1 hour iv infusion every Modified 4B Yes 40 mg/m2 every 3 weeks ~
et at. (16) Epothilone B 3 weeks ~ ""
Abraham BMS-247550, derivative of 1 hour iv infusion Modified 3B Yes 6 mg/m2/day x 5 every 0
Z
et ai. (17) Epothilone B daily x 5 every 21 days ei
tr
21 days
cr
""
Gadgeel BMS-247550, derivative of 1 hour iv infusiwyery Modified 2B Yes 40 mg/m2 every 21 days ci
Z
et at. (18) Epothilone B 21 days
cr
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Undevia CEP-2563, receptor 1 hour iv daily x 5 every Modified 3B Yes 256 mg/m2/day x 5 every
et at. (19) tyrosine kinase inhibitor 21 days 21 days n
Hovstadius CHS 828, cyanoguanidine orally once 4B Yes 20 mg once daily for tr
r;
et at. (20) daily x 5 days every 5 days (100 mg/cycle) ìO
4 weeks every 4 weeks ~
Rudek COL-3, matrix orally daily 4A No 36 mg/m2/d without m
0
et at. (21) metalloproteinase sunblock d
inhibitor i-
Syed COL-3, matrix Orally daily 2A No 50 mg/m2/day
et at. (22) metalloproteinase ~ ¡.
0
inhibitor Z
Rustin Combretastatin A4 iv x 5 for 2 weeks every Modified 4B Yes 52-68 mg/m2 x 5 for 0
tr
et at. (23) phosphate, ubulin 3 weeks 2 weeks every 3 weeks en
¡.
targeting agent a
Z
Chatterjee DRF-1042, camptothecin Orally daily x 5 for Modified 3B Yes 80 mg/m2 x 5 for 2 weeks en
et at. (24) analog 2 weeks every every 3 weeks
3 weeks
Vilalona- Ecteinascidin-743, iv daily x 5 every Modified 3A No 325 g/m2/day daily x 5
Calero tetrahydroisoquinoline 3 weeks
et at. (25) alkaloid
Ko et at. (26) EMD 273066 (huKS-IL2) iv daily x 3 every Modified 4A No 6.4 mg/m2/day x 3 every
immunocytokine 4 weeks 4 weeks
Goel GEM23 1 , oligonucleotide to 3 day (1 patient) or a Modified 4A No 120 mg/m2/day x 5 days
et at. (27) type i regulatory subunit 5 day continuous iv
of protein kinase A infusion
Chen GEM23 1 , oligonucleotide to 2 hour iv infusions Modified 4A No 240 mg/m2 twice weekly
et at. (28) type I regulatory subunit twice weekly
of protein kinase A ..
( Continued) 0 UJ
i

~~.."" . -" .-~---~-~~.~_...
0
.-
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Table 4.3 ( Continued)
Intra patient
dose- Recommended
Author/
reference Agent Schedule Design escalation dose
Borchmann H22xKi-4, bispecific IV days 1,3,5, 4B Yes 80 mg/m2 per cycle
et al. (29) anti-CD30 and CD64 7-21 days
monoclonal antibody
0 ZC/
C/ ..
Gadgeel KRN5500, spicamycin 1 hour iV daily x 5 2B Yes 4.3 mg/m2/day x 5 every
et al. (30) derivative every 3 weeks
3 weeks
Schoemaker MAG-CPT, polymer IV infusion over 3 days Modified 2A No 68 mg/m2/day for 3 days
et at. (31) conjugate of every 4 weeks
every 4 weeks
camptothecin
Matsumura MCC-465, doxorubicin 1 hour IV infusion every ATD No 32.5 mg/m2 every 3 weeks ~
et al. (32) PEG immunoliposome 3 weeks planned n
Clive Antagonist G substance P IV every 3 weeks until Modified 4A No 400 mg/m2 weekly 6 hour
~
et al. (33) analog the target maximum
IV infusion
plasma concentration
~
of 10 p,M then weekly
~
Matsumura NK9l1, micelle IV every 3 weeks Modified 3A No 50 mg/m2 every 3 weeks i- -i et at. (34) encaps!llated doxorubicin
de Jonge PNU -159548, alky1cycline IV every 3 weeks Modified 4B Yes 12 and 14 mg/m2 IV every ~
3 weeks in HP and MP -
et al. (35)
(2 studies)
0
patients
Z
ci
Lockhar PNU -166196A, brostallcin, IV weekly x 3 every Modified 3B Yes 2.4 mg/m2/week tI
et al. (36) a nonalkylating DNA 4 weeks
minor groove binder
';;.::,:,¡:
\~;i::;\,~,.:" .
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ACCELERATED TITRATION DESIGNS
Table 4.4 Summar of phase I studies using accelerated titration design.
Trials (n)
Patients (n)
Design
Intrapatient
doseescalation
Modifications
Types of
modifications
Patients/study
(n)
Dose levels (n)
Fold dose range
Patients treated
Above RP2D
Dose levels
Above RP2D
Deaths due to
toxicity
Type
1
2
3
4
Unknown
Yes
No
Yes
No
Median
5
3
o
o
Dose-escalation during
the accelerated phase
Patients/cohort during
the accelerated phase
Rules for termination
of accelerated phase
Dose-escalation
following
accelerated phase
During accelerated phase
o
Range
0-15
0-12
0-
0-1
(4 of 36 studies had a
dose level that
exceeded the RP2D
durng the ATD)
0-1
(1 patient across all
studies died due to
toxicities)
Median
22
6
16
6
1
For study
o
(13 patients across
all studies died
due to toxicities)
36
911
Trials (n)
1
6
10
18
1
20
16
15
11
3
2
8
19
Range
7-74
3-15
2-320
0-28
0-3
0-3
"
,I'
.,1i
I
1
i
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-
ACCELERATED TITRATION DESIGNS 107
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 recommended
phase II dose. Only 4 of 36 exceeded the recommended phase II dose during the
accelerated titration phase and only 1 death from toxicity occurred during the accelerated
titration phase, among the 91 I patients enrolled in these studies. (It should be
noted, however, that the use of acceleration may have contrbuted, in some trials, to
exceeding 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 may
have increased the overall number of patients treated above the RP2D, even beyond
the acceleration phase itself, and thus contrbuted to a greater death rate from toxicity.)
Based on its utilization in these selected studies, the accelerated titration design
appears to provide an enhanced effciency with acceptable safety. However, there
are a number of issues investigators might consider prior to selecting an accelerated
titration 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 be
advantageous under the following circumstances: (a) the agent is of a chemical class
that has been widely studied; (b) tle agent is predicted to have minimal interpatient
varability in pharacokinetics; (c) the agent's anticipated toxicity is unlikely to be
severe or ireversible and is amenable to close monitoring and supportive interventions.
Examples of agents most amenable to evaluation using a phase I accelerated
titration design might be the following: a new formulation of a previously studied
agent (e.g.liposomal formulation ofpaclitaxel), a biological agent with minimal toxicity
based on animal models (e.g. antibody or small molecule inhibitor of a receptor
tyrosine 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 I
study. Under these circu:Qstances, the increased effciency and presumed safety of an
accelerated design might make it preferable.
Conversely, there are situations where an accelerated titration design may not
provide the optimal balance between safety and effciency as either larger numbers
of patients/dose cohort and/or smaller dose increments would be preferable. Agents
associated with steep dose-response curves for toxicity, severe ireversible toxicity,
unexplained mortalty in anmal toxicology studies or large varabilty in doses or
plasma drg levels eliciting effects may require alternative designs to balance safety
and effciency optimally. For example, larger patient numbers/dose cohorts may be
preferred if there is anticipated wide interpatient varabilty in toxic effects due to
pharacokinetic or pharacogenomic differences between patients. For this circumstance,
larger patient numbers per dose level is appropriate since decisions about the
safety 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 the
primar endpoint, larger numbers of patients per dose level are recommended due to
anticipated interpatient varability in these endpoints. With either situation, the use
of an accelerated titration design with single-patient cohorts may not be optimal.
There are also situations where small dose-escalation increments may be advisable.
For example, if the agent is predicted to have severe, ireversible or potentially

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108
ACCELERATED TITRATION DESIGNS
fatal organ toxicity based on animal toxicology, paricularly if associated with a steep
dose-response curve for toxicity, relatively small changes in dose/concentration may
lead from minimal toxicity to severe toxicity, and thus smaller dose-escalation increments
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 but
also allowing dose-escalation within individual patients. Intrapatient dose-escalation
provides two advantages: it improves the lielihood of benefit from the agent for the,
individual patient and it increases the experience at higher dose levels. Accelerated
titration designs proposed by Simon et at. (7) allow intrapatient dose escalation if no
toxicity :: grade 1 was seen in the first cycle at the assigned dose leveL. Whle it did
not appreciably shorten the study duration, it did allow more patients to be treated at
or near the recommended phase II dose and increased the number of cycles evaluated
at the higher dose levels.
Although the rationale supportng intrapatient dose-escalation is appealing, it
does not seem to be widely applied. Thus, despite the appeal of escalating patients
to higher doses than they were assigned initially, should safety criteria be met, some
issues remain with its routine application in phase I protocols. Many phase I protocols
continue to be written prohibiting intrapatient escalation since it is believed
to have a minimal impact on tral effciency while bringing with it concerns about
practical issues regarding the 'rules' for implementing dose-escalation and safety.
Studies that have allowed intrapatient escalation withn their protocols have generally
allowed dose-escalation to occur after the patient has been evaluated at the current
dose level for the duration of the observation period and where the patient has had
minimal/no toxicity. Less commonly used are rules that require not only that the patient
has not had significant toxicity but also that the next higher dose level has been
evaluated in one or more new patients - a more strngent and cumbersome criterion
that may be favored to enhance safety and also to distinguish between acute versus
cumulative toxic events. Although experience with intrapatient dose-escalation
withn phase I studies is limited, to date its use within phase I studies using an accelerated
titration design did not appear to compromise patient safety or complicate
the interpretation of the study results. Of note, withn a given protocol, it is important
to require a minimum number of newly recruited patients at each dose level
and to base furter dose-escalation decisions upon the behavior of the drg in these
individuals.
4.6 Conclusions
Accelerated titration designs can dramatically reduce the number of patients accrued
to a phase I tral, in comparson to the standard phase I design. They can also substantially
shorten the duration of the phase I tral. With intrapatient dose-escalation
and application of a dose-toxicity model, they provide much greater information than
the stadard design and analysis with regard to cumulative toxicity, interpatient and
~
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--
ACCELERATED TITRATION DESIGNS 109
intrapatient varability, steepness of the dose-toxicity curve and separation of the
dose-toxicity curves for the varing toxicity levels. They also provide all patients
entered 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 to
be due to the conservativeness of investigators. Even when they are used, they
are often used with an initial dose set much more conservatively than would be
done for the standard design and without use of intrapatient dose-escalation, thereby
reducing their effectiveness. A recent comprehensive review of the risk-benefit rela-
tionship for phase I trals conducted over the past decade reveals an overall toxicity
death rate of only O.OOS (46). An accompanying editorial (47) argues that
such a low toxicity death rate, in the context of treatment for an often rapidly fatal
disease, suggests that phase I trals may be conducted in an overly cautious
fashion. Appropriate utilization of designs such as the accelerated titration designs
might increase the potential for benefit in phase I trals, with little increase in
risk.
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ACCELERATED TITRATION DESIGNS
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ACCELERATED TITRATION DESIGNS
45. B.C. Goh, M.J. Ratain, D. Bertucci, R Smith, S. Mani, N.J. Vogelzang, R.L. Schilsky,
M. Hutchison, M. Smith, S. Averbuch and E. Douglass (2001) Phase I study of ZD9331
on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing
recommendations. J. Clin. Oncology, 19(5), 1476-84.
46. E. Horstmann, M.S. McCabe, L. Grochow, S. Yamamoto, L. Rubinstein, T. Budd, D.
Shoemaker, E.J. Emanuel and C. Grady (2005) Risks and benefits of phase 1 oncology
trals, 1991 through 2002. N. Engl. J. Medicine, 352(9),895-904.
47. R Kurzrock and RS. Benjamin (2005) Risks and benefits of phase I oncology trals,
revisited. N. Engl. 1. Medicine, 352(9), 930-2.
113