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1 Conventional 3 + 3 “Up & Stop” design

1 Conventional 3 + 3 “Up & Stop” design

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1



Overview of Oncology Drug Development



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has been applied for dose escalation purposes and is characterized by a 100 %

initial dose increment and thereafter by 67, 50, 40, and 30–35 % of the preceding

doses (Omura 2003). If one of the three patients at a dose level develops a drugrelated dose-limiting toxicity (DLT), the cohort is expanded to a total of six

patients. If two of the six patients in a cohort experience drug-related DLTs, the

next lower dose level is expanded and declared maximum tolerated dose (MTD) if

the predefined criteria are met. In order to further evaluate the safety and tolerability of the investigational drug, a few additional patients are normally enrolled at

MTD.

Over the past decade, several variations of “3 + 3” design have been developed

such as “2 + 4,” “3 + 3 + 3,” and “3 + 1 + 1” (Storer 2001). The major limitations of

conventional “3 + 3” design include an uncertainty about the MTD and the potential

for underestimation. As a result of the slow dose escalation process, many patients

receive subtherapeutic doses (Le Tourneau et al. 2009). In contrast to the newer

dose escalation methods discussed later in this chapter, only data from patients at

the current dose level are employed for determining the dose for the next cohort.



4.2



“Up-and-Down” designs



As shown in Fig. 1.1b, “up-and-down” designs evaluate a single patient or group of

three patients and explore a large number of dose levels. The dose escalation/deescalation process continues until a predetermined sample size is reached (Storer 1989).

The dose escalation and de-escalation decisions are based on the observed adverse

effect profile in the previously treated patients. These designs are not commonly used in

drug development as they tend to treat a lot of patients at low doses, although variations

have been developed to accelerate the process (Rogatko et al. 2007).

Design A (traditional): In the traditional Storer’s design, groups of three patients are

treated and dose escalation occurs if no DLT is observed in all three; otherwise an

additional three patients are treated at the same dose. If only one out of six patients

has experienced a DLT, the dose escalation process continues. If more than one out

of these six patients has experienced a DLT, the dose escalation stops. One of the

major disadvantages of this design is that it allows the clinical trial to stop prematurely due to the emergence of multiple terminating opportunities.

Design B: This design treats a single patient per dose level. The next patient is

treated at the next lower dose level if a DLT is observed, otherwise at the next

higher dose level until the predefined sample size is reached.

Design C: A group of three patients are treated at each dose level, and dose escalation

occurs if no DLT is observed and de-escalation occurs if more than one patient has

developed a DLT. If only one patient has experienced a DLT, the next group of three

is treated at the same dose level. This process continues until the sample size is

reached. This is similar to the traditional design except that it allows de-escalation.



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Fig. 1.1 (a) Conventional 3 + 3 “Up & Stop” design with modified Fibonacci sequence. (b)

“Up-and-down” design. (c) Accelerated titration design (ATD). (d) Pharmacologically guided

dose escalation method



1



Overview of Oncology Drug Development



Fig. 1.1



4.3



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(continued)



Accelerated Titration Designs



The contradictions between safety and efficacy in the first-in-man clinical trials are

considered in the “accelerated titration” designs. From the ethical point of view, an

ideal design should allow dose escalation to the MTD quickly, yet safely, to minimize the likelihood of treating patients at doses that are too low or high. Accelerated

titration designs evaluate a single patient per dose level during the initial phase

(accelerated phase) (Simon et al. 1997). If the first patient does not experience a

significant toxicity (predefined in the protocol) or a DLT, a second patient is treated

at the next higher level. Once the accelerated phase is complete, a standard “3 + 3”

design model is used to determine the probability of the MTD occurring by incorporating all toxicity data from the trial (Fig. 1.1c). Once the MTD has been determined, a final “confirmatory” cohort is treated at that dose.

There are three variations of an accelerated titration design with minor differences among them (Simon et al. 1997). Two of these designs evaluate a single

patient per cohort with 40 % and 100 % dose escalation, respectively. The dose escalation returns to a standard “3 + 3” design when a single DLT or two moderate toxicities are encountered during the first treatment cycle of subchronic treatment. The

third design is similar except that it returns to “3 + 3” design when one DLT or two

moderate toxicities are observed during any cycle.

In order to reduce the number of patients treated at subtherapeutic doses, intrapatient dose escalation is often employed. But there remains a concern that cumulative or delayed toxicities may be caused by intrapatient dose escalation. Hence,

safety interpretation becomes more difficult to assign to a specific dose. Because

escalation of dose occurs within an individual patient, these designs can allow for

treatment of a greater proportion of patients at higher doses and make the dose escalation process more rapid. Another potential advantage is that cumulative toxicity

and interpatient variability information from all patients can also be used in

establishing the MTD/RP2D. Penel et al. (2009) compared the performance of



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accelerated titration designs against conventional “3 + 3” designs in 270 published

first-in-human trials. The accelerated titration design permitted exploration of more

dose levels and reduced the rate of patients treated at doses below MTD/

RP2D. However, it did not shorten the accrual time nor increase the efficacy of

trials.



4.4



The Rolling Six Design



One of the primary reasons for the development of the rolling six design was to

shorten the overall development timeline of new agents in pediatric oncology. This

design was introduced in 2008 to allow accrual of two to six patients concurrently

at a dose level without waiting for the toxicity results of the first three patients. The

dose escalation or de-escalation depends on several factors including the number of

patients currently enrolled, the number of DLTs, and the number of patients still at

risk of developing a DLT. Hence, a new patient is allowed to enter in the trial when

other patients in the cohort are still at the risk of developing DLT. The results of a

simulation study reported by Skolnik et al. (2008) showed that the rolling six design

reduced trial duration when compared to the standard design without an increase in

toxicity events.



4.5



Pharmacologically Guided Dose Escalation Design



The rationale behind the pharmacologically guided dose escalation design shifts the

focus from predicting DLTs from dose level to drug exposure (Graham and

Workman 1992). This design involves extrapolating preclinical data to predict the

drug exposure (AUC) associated with toxicity, under the assumption that similar

exposures in animals and humans will have similar effects and toxicities.

Subsequently, real-time pharmacokinetic data are obtained from individual patients

and used during the dose escalation process (Fig. 1.1d). If the observed human

exposure is far from the predicted toxic exposure, large dose escalation steps may

occur. Once the predetermined toxic exposure level is reached, further evaluation

can proceed in patient cohorts using any variation of the escalation approaches previously described. For example, single-patient cohorts with a 100 % dose escalation

design which revert to the traditional “3 + 3” design (with smaller dose increments

afterwards) may be employed. This method has the advantage of providing a rapid

and safe completion of the study with fewer patients receiving subtherapeutic doses,

but suffers from limitations associated with determining MTD in drugs with large

interpatient variability in metabolism and the need for real-time bioanalysis and

pharmacokinetic analysis for decision-making purposes. Neither of these conditions is attractive in oncology development, and the pharmacologically guided dose

escalation design has not been widely used in oncology drug development.



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Overview of Oncology Drug Development



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A modification of this design is based on predicting an optimal dose based on an

exposure or dose necessary to achieve a maximum target inhibition (MTI) (Meany

et al. 2010). The rationale behind a trial design using MTI is based on the concept

that the MTD for a new class of molecularly targeted drugs may be well above the

dose required to achieve target modulation and efficacy. This approach requires

identification of an appropriate drug target, developing a validated real-time assay

for quantifying target modulation, and availability of suitable tissue (tumor or surrogate) for analysis. Further evaluation of this trial design in the development of

molecularly targeted agents is warranted.



4.6



Bayesian Designs (Continual Reassessment Method

and Related Designs)



Using mathematical models based on Bayes probability to define DLTs and stopping rules, the continual reassessment method (CRM) incorporates all the available toxicity information from previously treated patients to determine the dose for

the next patient cohort (O’Quigley et al. 1990). These designs offer some flexibility in choosing the number of patients per cohort. Once a “prior” guess is made as

to the shape of the dose–response (or dose–toxicity) profile, the first patient is

assigned to the “prior” MTD. The outcome of this patient is then used to update the

“prior” guess once the required follow-up is complete. The next patient is assigned

to a new “posterior” MTD. The trial is stopped when either (1) the prespecified

stopping rules have been met or (2) the estimated DLT probability at the next dose

level is higher than acceptable. Although, the original design allowed multiple

dose escalations and de-escalations, several modifications have been made to

improve patient safety. The escalation with overdose control (EWOC) is a modified CRM which avoids exposure of patients to high toxic doses (Babb et al. 1998).

The time-to-event continual reassessment method (TITE-CRM) has an additional

advantage of incorporating time-to-toxicity information for each patient and allows

acknowledgment of late-onset or cumulative toxicities (Cheung and Chappell

2000). Other variants that also use efficacy endpoints have been developed (Yin

et al. 2006).

Altogether, Bayesian designs are highly flexible, allowing enrollment of

groups of any size, and they can be modified to allow incomplete information

(e.g., it can incorporate prior information). However, despite these advantages,

most of the CRM and related designs have not been widely implemented in clinical practice. Some of the logistical difficulties presented by these designs include

a need to have the “prior” estimate of the MTD and real-time biostatistical support for computations after each patient or cohort of patients has completed their

first cycle of treatment. In addition, the model may fail to reach the RP2D/MTD

if the prior guess for dose–response (toxicity) curve was incorrect or insufficient

(Paoletti et al. 2006).



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4.7



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Phase Ib Combination Trial Designs



Phase Ib combination trial designs determine the safety, dose, and schedule of two

or more investigational drugs that are administered together. In this design, one drug

is often administered at or near its recommended full dose, and the dose of combination drug is adjusted in sequential cohorts. Hence, considerations for the existing

preclinical and clinical data include important decisions for which drug will be

given at (or near) the full recommended dose and determining the initial and subsequent dose levels of the second drug. The objective is to increase the dose of each

drug as close to the single-agent MTD as possible while carefully monitoring for

tolerability. This is achieved by escalating one agent to the RP2D or MTD, while

keeping the other agent at a fixed dose. Phase Ib combination trial designs are usually able to explore only a limited number of dose levels and are conducted using

both traditional and Bayesian designs (Thall et al. 2003). Bayesian designs guide

the dose escalation process of the agents based on the observed toxicities in previous cohorts of patients.

The complete phase Ib clinical trial design: One of the primary reasons for the

proposition of the complete phase Ib clinical trial design was to shorten the overall

timeline for the development of new drugs in oncology and was introduced to allow

the conduct of several combination phase I trials simultaneously within a single

protocol (Von Hoff et al. 2007). This design involves administration of the first drug

at full dose, whereas three patients are treated at one-third dose of investigational

drug, three patients at two-thirds of the dose of investigational drug, and three to six

patients at full dose of the investigational drug simultaneously. The initial results

reported by Von Hoff et al. (2007) suggested that this approach may be safe with

rapid accrual (of less pretreated patients) and efficient with several potential advantages over multiple sequential combination phase Ib studies that are conducted traditionally. Further evaluation of this trial design in the development of molecularly

targeted agents is warranted.



5



Novel Designs for Phase II Clinical Trials



The main scientific objectives of a phase II trial of an investigational drug are to

provide an initial assessment of its clinical activity at the RP2D and further verify

safety. Phase II trials are performed to identify promising new drugs for further

evaluation and screen out ineffective drugs from further development. Although

phase II trials, which are often single arm, provide further evaluation of the RP2D,

they can incorporate a few dose levels and may provide additional pharmacokinetic information. The primary endpoint of these studies is binary in nature, e.g.,

response vs. nonresponse. These trials typically enroll as few patients as necessary



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