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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.
While researchers and drug developers are identifying molecular targets in a specific cancer subtype to improve outcomes, they have also been innovating on the clinical trial design front. At a late session during the 58th American Society of Hematology Annual Meeting & Exposition, being held December 3-6, in San Diego, California, representatives from 2 national clinical trials, 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 insight on trial design and progress reports.

Providing an update on the Beat AML trial was Brian Druker, MD, director of the Knight Cancer Institute at Oregon Health & Science University, which is collaborating with the Leukemia and Lymphoma Society on the trial.

Providing background on the disease, Druker said that AML is the most common leukemia in adults, with the median age at diagnosis of 67 years. However, despite all the progress with characterizing the molecular abnormalities associated with the disease, progress on the treatment front has been dismal.

“Treatment evolution for AML has lacked significantly,” Druker said, adding that disease outcomes have remained poor over the past decade and there have been very few approvals. “The fact that AML is a very heterogeneous disease could also have a role to play,” Druker added.

While the dozens of different molecular subtypes make it a very complicated disease to treat, Druker listed a few targeted agents that have seen some progress in treating AML, including syk inhibitors, IDH1/2 agents, kinases (FLT3, KIT), and the more recent immune checkpoint inhibitors.

Additional, conducting a clinical trial for AML remains a hurdle, Druker noted: “Challenges include the fact that the standard of care remains beneficial, single agent treatment will not be beneficial, genomic assays take long to deliver and trials are hard to recruit for.”

With all these challenges, the Beat AML trial has been designed with the following objectives:
  1. Perform genomic screening of patients at clinical trial entry
  2. Feasibility of waiting for 7 days for the genomic test results
  3. Assign therapy based on genomic screening
  4. Incorporate a marker negative arm so all patients have a treatment option
  5. Provide a network for junior clinical investigators
The trial has a multi-arm protocol, with:
  1. Each arm independent from the other with consistent eligibility
  2. Window design ensures documentation of all large effects in treatment-naïve patients
  3. Initial focus on those 60 and older
Trial eligibility criteria are straightforward: patients 60 years and older who have previously untreated AML can participate. Following genomic analysis of their tissue, patients will be assigned to independent treatment arms in the protocol.

“The primary objective of the Beat AML trial is to assess feasibility of trial design,” Druker said. “Secondary objectives are to determine how many patients can be successfully enrolled, determine if patients can reach allogenic stem cell transplant, and assess impact on outcomes.”

He listed the following treatment substudies and their start date:

AML Subtype Drug Start Date
Tet2/WT1/IDH1 CD33 (BI 836858) + Aza November 2016
CBF CD200 (Samalizumab) + induction November 2016
Marker negative CD33 (BI 836858) + Aza November 2016
MLL/MLL-PTD Syk inhibitor (Entosplentinib) December 2016
IDH2 IDH 2 inhibitor (AG221) +/- Aza December 2016
NPM1 In negotiations February 2017
p53/complex karyotype In negotiations February 2017
FLT3 FLT3 inhibitor + decitabine April 2017
IDH 1 mutation IDH 1 inhibitor April 2017
 
For biomarker assessment, Druker said that cytogenetics assays will be local. Meanwhile, biopsy samples will be sent to Foundation Medicine to conduct a more long-term 300-gene panel assay. “However, critical genes will be assayed by the company in 7 days, including NPM1, IDH1/2, and FLT3.”

Order of patient assignment to a treatment arm will be based on:
  1. Chemotherapy response
  2. Molecular marker with high variant allele frequency
  3. Higher risk group that may confound efficacy
  4. Marker negative
Trial endpoints are standard, Druker told the audience, and include primary endpoints of complete response and response duration. Secondary endpoints include event-free survival, progression-free survival (PFS), overall survival, and minimal residual disease.

Still in its early stages of conception, Beat AML has “enrolled 4 patients till date,” Druker said. “The goal is to allow patients to be enrolled in active treatment arms and the master protocol allows switching between the arms.” He added that in the future, the trial would like to include additional arms on the protocol and also test novel combinations.



 
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