R01CA262287

Development of a Phenotype-Based Predictive Analytic for Acute Myeloid Leukemia - Project Summary

The 5-year overall survival from Acute Myeloid Leukemia (AML) is less than 30%. While some patients are cured with initial induction therapy, most patients relapse, and the expected outcomes in patients with relapsed and refractory (R/R) AML are dismal. For this reason, developing methods to identify therapies likely to benefit R/R AML patients is a top priority.

This proposal aims to address critical unmet needs with a unique academic-industry partnership (AIP) between investigators at Vanderbilt University Medical Center, Karyopharm Therapeutics, and Notable Labs. The BCL2 inhibitor, Venetoclax (Ven), is transforming clinical practice for AML, but activity in R/R AML is less pronounced, and resistance occurs in most patients.

AIP investigators currently lead a multi-site investigator-sponsored study, testing Ven in combination with the selective inhibitor of nuclear export (SINE) Selinexor (Sel) in a phase I trial for R/R AML (NCT03955783). This Sel/Ven trial grew from the discovery that Sel synergizes with Ven and overcomes resistance mechanisms in some Ven-insensitive patient samples. Given this, our AIP team has worked together to develop a precision medicine functional platform for this novel combination in R/R AML.

Notable Labs utilizes an automated high-throughput, immunophenotype-based flow cytometry method to provide real-time drug sensitivity data on multiple, specific cell populations simultaneously within a given patient sample. Building from the only annotated cohort of patient samples treated with Sel/Ven in the world, we propose to develop a precision medicine functional assay to identify R/R AML patients most likely to benefit from SINE/Ven combination therapy.

We will build, refine, and optimize the functional platform for Sel/Ven with samples from our current phase I study and train the platform on samples from the phase II Sel/Ven clinical trial proposed by the AIP. Aim 1 will focus on determining assay parameters specifically for Sel/Ven in R/R AML. Aim 2 will train the model with the phase II clinical trial of Sel/Ven in R/R AML, and Aim 3 will contextualize the predictive analytic model on heterogeneous genotypes found in R/R AML.

At the conclusion of this study, the functional medicine platform will be a companion diagnostic ready for external validation, which we will lead in a phase III efficacy trial of Sel/Ven in R/R AML, and serve as proof-of-principle for the development of similar therapy-specific precision medicine tools.

Vanderbilt University Medical Center

NOT APPLICABLE

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Nashville, Tennessee 37232 United States

Single Zip Code

Academic-Industrial Partnerships for Translation of Technologies for Diagnosis and Treatment (R01 - Clinical Trial Optional) (PAR-18-530)

Amendment Since initial award the End Date has been extended from 08/31/26 to 02/28/27 and the total obligations have increased 440% from $597,007 to $3,225,139.