Combination Dose Finding Studies in Oncology

Combination dose finding studies in oncology:
an industry perspective
Jian Zhu, Ling Wang
Symposium on Dose Selection for Cancer Treatment Drugs
Stanford, May 12th 2017
Outline
• Overview
• Practical considerations in selecting good designs
• Summary
1 ｜Symposium on Dose Selection for Cancer Treatment Drugs | May 12, 2017
Background
• Exponentially increasing number of combination dose escalation

studies
• While researchers hope to find synergistic efficacy through

combinations of drugs, it is more difficult to find the MTD
• MTD is often not a single dose pair but a range of dose pairs
• New challenges require better designs
Challenges and Design Requirements for Oncology
Phase I Combination Studies
Phase I Study Challenges Design Requirements
Untested drug in resistant patients Escalating dose cohorts with small

numbers of patients (e.g. 3-6)
Primary objective: find MTD(s) Accurately estimate MTD
High toxicity potential: safety first Robustly avoid toxic doses

especially for synergistic toxicity (overdosing)
Most responses occur at 80% - 120% Avoid subtherapeutic doses while
of MTD controlling overdosing
Find best dose for dose expansion Enroll more patients at acceptable
(<=MTD), active doses (flexible cohort
sizes)
Complete trial in a timely fashion Use available information efficiently
Designs
• Two main types of designs

– Algorithmic, fixed, data-only rules
– Model-based: statistical design accounting for uncertainly of DLT rates
Algorithmic Model based
Applicability Easy More complex due to
statistical component
Flexibility Not very flexible Flexible: allows for
• fixed cohort size • different cohort sizes
• fixed doses • intermediate doses
Extendibility Difficult Easy: 2 or more treatment
arms, combinations
Inference for DLT rates Observed DLT rates only Full inference, uncertainty
assessed for true DLT
rates
Statistical requirements None Reasonable model, good
statistics
Overview of combination dose finding methods
• Rule based methods: 3+3+3 (Braun et al. 2011)
• Model based methods:

– Sequential CRM(Yuan and Yin 2008)
– gCRM (Braun et al. 2013)
– Bayesian logistic regression model (Thall and Lee 2003,
Neuenschwander et al. 2015)
• Other methods:
– Independent beta probabilities escalation (PIPE) (Mandera and
Sweeting 2015)
– Curve-free Bayesian method (Lee et al 2017)
‘3+3+3’ Fast Escalation Rule
• Fast escalation rule

– Can increase the probability of finding the correct MTD
– Often not recommended in practice
‘ 3+3+3 ’ Design Slow Escalation
• Slow escalation rule

- limit the ability to assign
patients to higher dose
combinations
- need a large sample size
BLRM for Combination Dose-finding
Parameterization with an explicit interaction term (Neuenschwander et al. 2015)
• Real no interaction model:

• Interaction model:
• Marginal single-agent models:
- interaction term could be more complicated, eg. adding covariates

• Priors for single agent models:
• Priors for interaction parameter :

- normal / log-normal / incorporate relevant information
BLRM-combo Design Implementation
Prior of parameters
Plugged
in model
BLRM-combo
Collect
Posterior of
DLT data
parameters
Toxicity
Continue intervals
with next Recommendation for next cohort
cohort
No
Stop Meet
the Yes Stopping
trial Rules?
BLRM-combo Implementation Demo
BLRM-combo Protocol Development
• Incorporating Prior Information

– Preclinical toxicity data
– Previous clinical trials
– Literature data on similar compounds
• Design Specification
– Pre-define provisional dose escalation rules
– Minimum cohort-size
– Pre-define DLT criteria and appropriate toxicity intervals
– Pre-define evaluable patients for DLT assessment
• Stopping rules for declaring the MTD
• Statistician test-runs the design
– Decisions under simple scenarios
– Operation characteristics (simulation testing)
• Clinicians review design performance
Practical Considerations for BLRM-combo
• Design should take advantage of all relevant information

available
– Anticipated MTD from preclinical data
– Previous single agent dose finding trials
– Previous combination dose finding trials in other regions
– Previous data of the same agents with different schedules
– Prior, especially the prior for interaction can affect the direction of
escalation
• Definition of toxicity levels: under-dosing, target toxicity, and

overdosing (e.g. 0.16-0.33 defined as the target toxicity)
• EWOC threshold (Posterior Probability of being overdosing)
Practical Considerations for BLRM-combo (cont’d)
• Escalation rules (other than EWOC)

– Diagonal escalation?
– Dose skipping?
– Escalation cap?
• Stopping rules
– Need sufficient number of patients to declare MTD while avoiding oscillation
• Parallel cohorts
– Can do parallel searches when multiple eligible dose pairs have very close
posterior probabilities of hitting the target toxicity
• Flexible cohort sizes
– More patients closer to MTD?
– Enrich patients with certain characteristics
– Operational flexibility for enrollment
• Intermediate doses
– Formulation, schedule
BLRM-combo Escalation Rules Demo
Decision for dose escalation often not by BLRM alone
• MTD is the primary interest of dosing finding algorithms , may not be

sufficient
• Severity or the nature of the DLT, level of AE can override the model
recommendation
• Other available information such as clinical experience, PK/PD or
efficacy data should be considered together to make the final
decision
– Apart from the dose pairs deemed overly toxic by the model, there is
much room for escalation
Evaluation of designs for a trial through simulations
• Designs to be considered
• Design assumptions
• Consider various DLT scenarios
• Fair comparison:
– BLRM performance may be sensitive to whether the true DLT rates are
on or close to the boundaries of the toxicity levels
– For other methods with target toxicity, performance is also often
sensitive when the true DLT rates are close to the target toxicity
Evaluation criteria
• Accuracy of identifying the MTDs
• Average proportions of patients assigned to under-dosing, target-

dosing, and overdoing per study
• Average sample size (Maximum sample size) per study
• Average number of DLTs per study
One example requiring conservativeness
• Suppose clinicians have concerns with the potentially high

synergistic toxicity of the combination
• Rule based methods such as 3+3+3 (conservative method) are often

considered
– Slow escalation
• BLRM-combo with conservative escalation rules may have desirable

properties in terms of both safety and accuracy
– No diagonal escalation
– No dose-skipping
– Assuming synergistic interaction prior
– Lower EWOC threshold
– Allows re-escalation
Other factors in selecting a design
• Depending on whether number of doses for one drug is small and/or

fixed
– Small and fixed: 3+3+3
– Small: single BLRM incorporating one drug as covariates
– General: BLRM-combo
• MTD on the ‘border’ or diagonal
• Utility function based decisions
Considerations for other designs
• Models considering ordinal data: no DLT, low toxicity, DLT

– Need to carefully define the severity
• Joint modeling of toxicity and efficacy

– Efficacy measurements usually take longer time, which can affect
timeline
– Change in population in later phases
– Surrogate endpoint
• Joint modeling of PK and DLT data

– PK data may have large variability and usually take longer time
Summary
• One-design-fits-all is very unlikely
• A good design should be flexible to incorporate various practical

considerations
• Performance evaluation should also take all aspects into

consideration
– Statistical performance
– Ethical considerations
– Timeline
– Operational considerations
– Simplicity
Reference
• Bailey, Neuenschwander, Laird, Branson (2009). A Bayesian case study in oncology phase I
combination dose-finding using logistic regression with covariates. Journal of Biopharmaceutical
Statistics, 19:369-484
• Neuenschwander, Branson, Gsponer (2008). Critical aspects of the Bayesian approach to phase I
cancer trials. Statistics In Medicine, 27:2420-2439
• Mathew, Thall, Jones, Perez, Bucana, Troncoso, Kim, Fidler, and Logothetis (2004). Platelet-
derived Growth Factor Receptor Inhibitor Imatinib Mesylate and Docetaxel: A Modular Phase I Trial
in Androgen-Independent Prostate Cancer Journal of Clinical Oncology, 16, 3323-3329.
• Neuenschwander, Branson, Gsponer (2008) Critical aspects of the Bayesian approach to Phase I
cancer trials. Statistics in Medicine, 27:2420-2439.
• Thall, Lee (2003) Practical model-based dose-finding in phase I clinical trials: methods based on
toxicity. Int J Gynecol Cancer 13: 251-261
• Sweeting, Michael J., and Adrian P. Mander. "Escalation strategies for combination therapy Phase
I trials." Pharmaceutical statistics 11.3 (2012): 258-266.
• Braun, Thomas M., and Todd A. Alonzo. "Beyond the 3+ 3 method: expanded algorithms for dose-
escalation in Phase I oncology trials of two agents." Clinical Trials 8.3 (2011): 247-259.
• Bailey, Stuart, et al. "A Bayesian case study in oncology phase I combination dose-finding using
logistic regression with covariates." Journal of biopharmaceutical statistics 19.3 (2009): 469-
484.
• Yuan, Y. and Yin, G. (2008), Sequential continual reassessment method for two-dimensional dose
finding. Statist. Med., 27: 5664–5678. doi:10.1002/sim.3372
• Lee BL, Fan S, Lu Y. (2017) A curve-free Bayesian decision-theoretic design for two-agent phase I
trials. Journal of Biopharmaceutical Statistics, 27(1):34-43. PMID: 26882373.
Thank you !
Backup slides
3+3+3 Fast Escalation Rule
 Fast escalation rule

New cohort at a new
dose combination: enroll
3 patients
DLT = 0/3 DLT >= 2/3 DLT = 1/3

Go to next higher Split the trial into two Enroll 3 additional pts
dose combination parallel searches at the same dose
along the diagonal eg. ( k, k ) combination
DLT >= 3/6 DLT <= 1/6

Begin the search at Begin the search at Split the trial into DLT = 2/6
Enroll 3 additional Go to next higher
( k, k-1 ), escalate ( k-1, k ), escalate two parallel
pts at the same dose combination
doses of Agent 1 doses of Agent 2 searches
dose combination along the diagonal
DLT >= 3/9 DLT <= 2/9

Split the trial into two Go to next higher dose
parallel searches or combination along the
declare it as MTD if both diagonal
attains the highest level
3+3+3 Fast Escalation Rule
 Parallel Searches Begin the search at

( k*, k-1 ), escalate doses
of Agent 1
DLT = 0/3 DLT >= 2/3 DLT = 1/3

Go to next higher dose Declare ( k*-1, k-1) as one Enroll 3 additional pts at the
combination recommendation of the same dose combination ( k*,
( k*+1, k-1 ) MTD k-1)
DLT >= 3/6 DLT <= 1/6

Declare ( k*-1, k-1) as DLT = 2/6 Go to next higher
one recommendation Enroll 3 additional pts dose combination
of the MTD at the same dose
combination ( k*, k-1 ) ( k*+1, k-1 )
DLT >= 3/9 DLT <= 2/9

Declare ( k*-1, k-1) as one Go to next higher dose
recommendation of the combination
MTD ( k*+1, k-1 )
Bayesian Logistic Regression Model: a combination
of clinical and statistical expertise
Clinical, PK,
Historical Data
PD Expertise
(prior info)
Trial Data DLT rates Dose

0/3,0/3,1/3,… p1,p2,…,pMTD Recommendations
(uncertainty)
Model based
dose-DLT Final Dose
relationship Escalation
Decision

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Combination dose finding studies in oncology:

• Practical considerations in selecting good designs

• Exponentially increasing number of combination dose escalation

• While researchers hope to find synergistic efficacy through

• New challenges require better designs

Phase I Study Challenges Design Requirements

Untested drug in resistant patients Escalating dose cohorts with small

High toxicity potential: safety first Robustly avoid toxic doses

• Two main types of designs

• Rule based methods: 3+3+3 (Braun et al. 2011)

• Model based methods:

• Fast escalation rule

• Slow escalation rule

• Real no interaction model:

- interaction term could be more complicated, eg. adding covariates

• Priors for interaction parameter :

• Incorporating Prior Information

• Design should take advantage of all relevant information

• Definition of toxicity levels: under-dosing, target toxicity, and

• EWOC threshold (Posterior Probability of being overdosing)

• Escalation rules (other than EWOC)

• MTD is the primary interest of dosing finding algorithms , may not be

• Consider various DLT scenarios

• Accuracy of identifying the MTDs

• Average proportions of patients assigned to under-dosing, target-

• Average sample size (Maximum sample size) per study

• Average number of DLTs per study

• Suppose clinicians have concerns with the potentially high

• Rule based methods such as 3+3+3 (conservative method) are often

• BLRM-combo with conservative escalation rules may have desirable

• Depending on whether number of doses for one drug is small and/or

• MTD on the ‘border’ or diagonal

• Utility function based decisions

• Models considering ordinal data: no DLT, low toxicity, DLT

• Joint modeling of toxicity and efficacy

• Joint modeling of PK and DLT data

• One-design-fits-all is very unlikely

• A good design should be flexible to incorporate various practical

• Performance evaluation should also take all aspects into

 Fast escalation rule

DLT = 0/3 DLT >= 2/3 DLT = 1/3

DLT >= 3/6 DLT <= 1/6

DLT >= 3/9 DLT <= 2/9

 Parallel Searches Begin the search at

DLT = 0/3 DLT >= 2/3 DLT = 1/3

DLT >= 3/6 DLT <= 1/6

DLT >= 3/9 DLT <= 2/9

Trial Data DLT rates Dose

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