UNDERSTANDING UMBRELLA & BASKET TRIALS

CTO OCTOBER 2015

Precision Medicine and Adaptive Trial Design

Objectives

What is Precision Medicine?Adaptive Trial Design

Advantages/DisadvantagesUmbrella Trial Design

BATTLEBasket Trial Design

MATCHChallenges of New Trial Designs

Regulatory Operations

FDA

What is Precision Medicine?

Approach to deliver optimal patient outcomes by integrating clinical and molecular patient data to understand the biological basis of the disease

Guides selection of the most appropriate targeted therapy based on distinctive pt features and molecular features (such as specific biomarkers)

Optimize patient outcomes and provides favorable safety profiles

Precision Medicine

What does this mean?

Patients are receiving treatment that more specifically targets their tumor type based on biological characteristics such as biomarkers

Anticipated better outcomes overall

FROM EXCEPTION TO THE NORM

Precision Medicine Initiative

Precision Medicine Initiative

Goal is to revolutionize medicine and generate the scientific evidence needed to move the concept of precision medicine into every day clinical practice

Pres. Obama announced in early 2015 $215 million proposed investment for Presidential

2016 Budget Primary focus is cancer, but will expand to other

disease areas

NCI Involvement

Four broad focus areas of research: Expanding precision medicine clinical trials Overcoming drug resistance Developing new laboratory models for research Developing a National Cancer Knowledge System

Adapting Clinical Trial Design

Adaptive Trial Design

Allows researchers to analyze accumulating study data at prospective interim time points and to alter the course of a single patient’s study plan or trial itself

Ability to answer multiple questions Safety and efficacy How is drug best delivered? Who will get the most benefit from that drug?

Adaptive Trial Design

Design that uses accumulating data to decide on how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial

Learn from the accumulating data and to apply what is learned as quickly as possible

Common Types of Trial Adaptations

Stopping early/extending accrual with a conclusion of either superiority or futility

Adaptively assigning doses to more efficiently assess the dose-outcome relationship

Dropping/Adding arms or dosesSeamless phases of drug development within a

single trialChanging proportion of patients randomized to

each armChanging accrual rate

Traditional vs Precision

Advantages

Potential to speed up the process of drug development

Allocate resources more efficiently without lowering scientific and regulatory standards

Potential to receive marketing approval for multiple indications from a single successful trial

Shorter clinical time lines than conventional approaches

A feasible way to conduct well powered trials in rare cancers

Disadvantages

Disadvantages Breaking the blind early can lead to problems with

dissemination of study results and the study population might change between the early and late stages of drug testing

Often less statistically efficient than fixed plans Regulators are very disturbed by changing scientific

hypotheses Statistical methods for the design and analysis are

technically and computationally more complex than those associated with conventional designs

COMBINING CLINICAL TRIALS WITH PRECISION MEDICINE AND ADAPTIVE DESIGN

Umbrellas and Baskets

Umbrella Trial: Study Design

Complicated trial design that has arms moving in and out

Can test impact of different drugs on different mutations in a single type of cancer

Main protocol with several phase II sub-protocols

Umbrella Trial: Study Design

Patients are enrolled onto main protocol and then tested for mutations

Based on results of test, patients are randomized to one of the sub-protocols

BATTLE Trial

4 treatment groups of single or combination therapy targeting specific pathways

Patients enrolled and tested for 11 biomarkers/marker groups Adaptively randomized to the treatment groups

BATTLE Trial (2006)

Findings EGFR mutations were predictive for erlotinib benefit Benefit in sorafenib-treated patients with wild-type

and mutant KRAS mutations

BATTLE-2 (NCI R01 Funded) Patients enrolled with either EGFR or KRAS mutations

were randomized to one of four directed single or combination treatments

Validation of the use of molecular and sequencing lab technology to better identify patients who would benefit from a specific target therapy

Basket Trial: Study Design

Each arm or “basket” is for a drug targeting a specific mutation across all cancer types

Allows researchers to examine response of patients by not only cancer type but what is the impact of the drug on patients as a group (mutation)

Downside: have to test large number of patients to find those who are eligible

Basket Trial: Stud Design

Benefits: Tests specific hypothesis of a biopathway and its

response to a particular drug Pilot data can be expanded to separate Phase II trial

for increased enrollment and statistical significance

NCI-MATCH Trial

Design: Master protocol with multiple phase II subprotocols Tumor biopsies to confirm genetic abnormalities that

a targeted drug exists for Treatment is assigned based on abnormality

Seeks to determine whether treating cancers according to molecular abnormalities will show evidence of effectiveness

NCI-MATCH

Unique DNA sequencing test, requires testing of large number of patients to find those eligible for study 4000 variants across 143 genes

Study design is able to detect inhibition of driver mutations in multiple tumor types Goal is to have 25% of 1000 patients have rare cancer

Patients can have 2 screening biopsies and 2 treatments per biopsy

WHAT ARE THE ROADBLOCKS AND REGULATORY ISSUES THAT CAN ARISE FROM THESE TYPES OF

TRIALS?

Issues and Concerns

Who Sponsors Adaptive Trials?

Collaborative effort NCI, FDA Numerous academic centers Pharma and laboratories

Operational Considerations

Enrollment rate/# of subsites openDrug supply/management: need plan to

manage supply for adaptations during the trial

Randomization systems need s to be developed with the data analysis system

Regulatory Issues

Privacy and data sharing b/c adaptive trial evolves as data is collected, limited

access is keyHow will confidentiality be maintained?

Clearly id’ed who will see what data and how information will be disseminated?

Maintenance of Good Clinical PracticeIncreased site monitoring for improved data

availability and data quality

Regulatory Issues

Documentation

Communication Plan to manage changes to study conduct and how to

communicate those changes within the team

Regulatory Issues

All adaptations need to be specified prior to initiation

Maintaining the study blind is important to the trial’s integrity.

How best to ensure adequate consentAdditional Start Up Costs

Integration of the process and information technology

FDA

Draft Guidance Documents: “Guidance for Industry Adaptive Design Clinical Trials

for Drugs and Biologics - Draft Guidance” (2010)

References

Semin Oncol Nurs 2014 May; 30(2): 109-116 Gaydos B, Anderson KM, Berry D, Burnham N, Chuang-Stein C, Dudinak J et

al. Good Practices for Adaptive Clinical Trials in Pharmaceutical Product Development. Drug Info J. 2009; 43: 539-556

Quinlan J, Gaydos B, Maca J, Krams M. Barriers and Opportunities for Implementation of Adaptive Design in Pharmaceutical Product Development. Clin Trials 2010. 7: 167-173

Berry DA. Adaptive Clnical Trials in Oncology. Nat Rev Clin Oncol 2012. 9: 199-207

Desmond-Hellmann S. Toward precision medicine: a new social contract? Sci Transl Med. 2012; 4: 129ed123

Berry DA, Herbst RS, Rubin, EH. Reports from the 2010 Clinical and Translational Cancer Research Think Tank Meeting: Design and Strategies for Personalized Therapy Trials. Clin Cancer Res; 2012 February; 18(3) 638-644