Considerations for Basket Trial Design under Multisource Exchangeability Assumptions

Michael Kane, Yale University

Alex Kaizer, University of Colorado, Denver

Nan Chen, MD Anderson

Brian Hobbs, The Cleveland Clinic

Goals of this talk

Describe the use of multi-source exchangeability models in early Phase II basket trials using Vemurafenib as an example

 

Provide simulation results illustrating "power borrowing" among baskets and explore its implications in the study

 

Propose alternate basket constructions that are not based on indication

Vemurafenib

​Causes programmed cell death in patients with V600E mutation

Indication Approval Date Governing Body
Melanoma August 17 2011 FDA
Melanoma Feb. 15 2012 Health Canada
Melanoma Feb. 20 2012 European Commission
Erdheim-Chester Disease November 6 2017 FDA

Approvals

Vemurafenib Label Expansion

Enrollment period April 11 2012 -- June 10 2014.

Indication Enrolled Evaluable Responses Prob [p > 0.15]
NSCLC 20 19 8 0.997
CRC (vemu) 10 10 0 0.06
CRC (vemu+cetu) 27 26 1 0.03
Bile Duct 8 8 1 0.47
ECD or LCH 18 14 6 0.977
ATC 7 7 2 0.847

Individual Arm Distribution

The Multisource Exchageability (MEM) Model Motivation

When the drug works, it is because of a common underlying mechanism of action.

 

Similar response is driven by the drug.

 

We should be able to borrow power across similarly responding baskets.

A Bayesian Hierarchical Model is Single-Source

Multiple Sources of Exchangeability 

The MEM Model

Finds pair-wise symmetric exchangeability relationships in all possible configurations.

 

Finds the posterior exchangeability probability (PEP) in all pairs.

 

Finds the Effective Sample Size (ESS) based on how much power can be borrowed.

 

Identifies basket clusters using PEP as a measure of similarity. 

Extent of Borrowing Between Two Baskets

Two baskets each with size 10

 

Response rate in basket 1 is 0.2

 

Response rate in basket 2 varies from 0.8 to 0.2

Effective Sample Size of Basket 2

Response Estimate of Basket 2

PEP

Back to Vemurafenib

Vemurafenib MEM Analysis

Indication Evaluable ESS Prob [p > 0.15] MEM Prob [p > 0.15
NSCLC 19 38 0.997 0.999
CRC (vemu) 10 52 0.06 0.025
CRC (vemu+cetu) 26 56 0.03 0.017
Bile Duct 8 10 0.47 0.287
ECD or LCH 14 38 0.977 0.999
ATC 7 32 0.847 0.995

PEP

Trial Simulation (1000 Resamples)

Fixed trial duration (26 periods, max number of evaluable patients)

 

Enrollment times are uniform over the enrollment duration

 

Responses are uniform over enrollments

 

Find expected success probability and ESS over time

Expected Arm Success

Sample Size

Going Beyond Basketing by Indication

Vemurfanib Response and Prior Therapy

Indication Enrolled Evaluable Responses Prior Therapy <= 1 Prior Therapy == 2  Prior Therapy >=3 MEM Prob [p > 0.15]
NSCLC 20 19 8 11 (0.55) 4 (0.2) 5 (0.25) 0.999
CRC (vemu) 10 10 0 1 (0.1) 2 (0.2) 7 (0.7) 0.025
CRC (vemu+cetu) 27 26 1 5 (0.185) 11 (0.407) 11 (0.407) 0.017
Bile Duct 8 8 1 2 (0.25) 1 (0.125) 5 (0.625) 0.287
ECD or LCH 18 14 6 9 (0.5) 7 (0.389) 2 (0.111) 0.999
ATC 7 7 2 5 (0.714) 1 (0.143) 1 (0.142) 0.995

Try a basket trial yourself

install.packages("basket")

vignette("using-the-basket-package")

Thanks

Considerations for Basket Trial Design under Multisource Exchangeability Assumptions

By Michael Kane

Considerations for Basket Trial Design under Multisource Exchangeability Assumptions

ICSA 2019

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