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ASH 2016

Innovative Approach to Precision Trial Design: NCI-MATCH and Beat AML

Surabhi Dangi-Garimella, PhD
Representatives from the Beat acute myeloid leukemia (AML) and National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH), which incorporate genomic profiling to assign patients to different treatment arms, provided an insight on trial design and a progress report.
The second presentation of the session, by Keith Flaherty, MD, provided an update on the NCI-MATCH trial. Flaherty, director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital and associate professor of Medicine at the Harvard Medical Center, also chairs ECOG-ACRIN, which is collaborating with NCI on this trial.

Flaherty was very excited to share with the audience that the trial was expected to hit its 6000 patient enrollment target in the next 6 months. We are currently enrolling 120-150 patients being each week, he said.

The objective of this phase 2 precision-med trial is to match genetic abnormalities of tumors with a suitable targeted drug, regardless of cancer type, Flaherty explained. Its a signal-finding trial, meaning promising treatments can be expanded to a more definitive trial in the future.

Eligibility criteria for enrollment in NCI-MATCH include adults over 18 years, those who lack or have exhausted standard treatment, patients who have developed either solid or liquid tumors, patients with a good ECOG performance status and adequate organ function, and patients who can tolerate being off treatment for 6 weeks.

Flaherty listed the following criteria for source material for genetic and immunohistochemistry analysis:
  1. The trial mandates a fresh tumor biopsy to identify gene abnormalities
  2. Patients can be screened with local next-generation sequencing, but results have to be confirmed on an NCI-MATCH assay
  3. Biopsy and sequencing on progression for responders
  4. Planned assays for research purposes
    • Whole-exome DNA sequencing
    • RNA analysis by whole transcriptome analysis
    • microRNA assay
The following Levels of Evidence strategy is being implemented by NCI-MATCH:
Level 1: gene variant credentialed for selection of an approved drug
Level 2a: variant eligible for an ongoing clinical trial
Level 2b: variant identified in an N of one response
Level 3: preclinical inferential data
Levels of Evidence for drugs in NCI-MATCH include:
Level 1: FDA-approved for any indication for that target
Level 2: agent met a clinical endpoint with evidence of target inhibition
Level 3: agent demonstrated evidence of clinical activity with evidence of target inhibition at some level

Among the 6000 patients that will be the final enrollment, there are 929 treatment enrollments anticipated across 24 gene abnormalities that are currently being evaluated as part of this trial. Primary trial endpoint is overall response rate, with secondary endpoints of PFS, time to progression, toxicity, and biomarker expression.
Flaherty explained that the trial demands 4 core biopsies at initial entry, which are shipped to the central lab at MD Anderson. H&E sections are assayed by a pathologist for tumor type, content, percent necrosis, and inflammation and scanned into a high-resolution image database. RNA and DNA are then extracted and then distributed to a network of laboratories.
Currently, immunohistochemistry analysis is being conducted for PTEN, MLH1, MSH2, and Rb. We have also added mismatch repair genes and are evaluating PD-1 expression, he added. The trial has incorporated a customized Oncomine assay, which has been developed by Thermo Fischer. The panel includes 143 genes, 2530 amplicons in the DNA panel, and 207 amplicons in the RNA panel.
Flaherty provided a very uplifting picture on patient wait times:
  • Sample submission from sites to central lab at MD Anderson: 7 days
  • Completion of tumor testing by lab network and return of results to site: 15 days
  • Further secondary screening for patients assigned to a treatment arm: 14 days.
As of November 27, we have 3149 patients with tumor samples, of whom 2589 have received their test results; 468 had a genetic abnormality matching an available treatment, Flaherty told the audience. Twenty-two percent of currently enrolled patients have a gene abnormality that matches one being studied in the trial, he added.
Although the trial currently has 24 arms, this number is expected to increase.

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