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Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia using Duplex Sequencing

Award Number: R44CA233381
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia using Duplex Sequencing - Problem: With a 5-year survival of ~30%, AML is the 6th deadliest cancer, and >20,000 new patients are diagnosed each year in the United States. Although most patients achieve Complete Remission (CR) with aggressive therapy, most will eventually relapse. The criteria for CR, however, is based on historical diagnostic methods, and patients in CR may carry up to 1010 residual leukemia blasts. Significant effort has gone into developing tools to detect Minimal amounts of Residual Disease (MRD), including multi-parametric flow cytometry (MFC) and polymerase chain reaction (PCR). MRD is the strongest predictor of relapse, and several AML trials have demonstrated that survival was significantly better when MRDpos patients were subjected to intensified therapy. Yet, lack of sensitivity is a clear problem with MFC and PCR. For example, relapses occur in ~40% of patients who are MRDneg by MFC after chemotherapy. Next Generation Sequencing (NGS) holds the promise to identify MRD by detecting mutations associated with residual AML cells. Yet, the sensitivity of conventional NGS is limited by a relatively high error rate, which makes it difficult to differentiate sequencing errors from true low-frequency mutations. Solution: Duplex Sequencing (DS) is an ultra-sensitive NGS technology which uses specialized biochemistry and informatics to improve the accuracy of standard DNA sequencers by more than ten-thousand-fold. In our prior Phase I SBIR study, we developed a broadly-applicable DS-based AML MRD assay that overcomes the above limitations. The DS assay targets many MRD-relevant genes simultaneously, with sensitivity and specificity rivaling or exceeding single-gene PCR assays. In Phase II, we demonstrated excellent reproducibility across labs, applied the optimized assay to retrospectively banked cohorts, and showed superior clinical performance vs. MFC. However, based on many customer interviews, the most substantial barrier to widespread commercial adoption we face is the lack of large-scale prospective clinical trial data. Specific Aims: In the present Phase 2b application we propose generating this comprehensive clinical utility data set through collaboration with the world-class US National Marrow Donor Program (NMDP) and other top AML MRD key opinion leaders. The primary goals of our proposed study include: Aim 1: Prospectively validate the prognostic value of pre-transplantation DS AML MRD testing for predicting post-transplant relapse and survival; Aim 2: Prospectively generate data supporting the ability of post-transplantation DS AML MRD testing to assess relapse risk for patients treated with different transplant conditioning intensities; and Aim 3: Demonstrate the potential of using tumor-informed DS AML MRD testing for patients without a driver gene variant targeted by our fixed gene panel. Impact: This combined approach may bring NGS MRD testing up to 100% patient applicability. Blood MRD comparison may present an equally sensitive but less invasive alternative to marrow. Our anticipated data will also support the use of the technology in assigning high-risk patients to intensified therapies and as an early marker of anti-leukemic efficacy for novel drug development efforts.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,985,831 )
2025	2025	TWINSTRAND BIOSCIENCES INC	3131 ELLIOTT AVE	SEATTLE	WA	98121	KING	USA	Cancer Detection and Diagnosis Research	001	6	2/13/2025	NON-COMPETING CONTINUATION	$1,985,831
2025	2023	TWINSTRAND BIOSCIENCES INC	3131 ELLIOTT AVE	SEATTLE	WA	98121	KING	USA	Cancer Detection and Diagnosis Research	000	5	10/15/2024	COMPETING CONTINUATION	$0
														Subtotal = $1,985,831

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TWINSTRAND BIOSCIENCES INC	3131 ELLIOTT AVE	SEATTLE	WA	98121	KING	USA	Cancer Detection and Diagnosis Research	000	5	10/20/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,139,103 )
2023	2023	TWINSTRAND BIOSCIENCES INC	3131 ELLIOTT AVE	SEATTLE	WA	98121	KING	USA	Cancer Detection and Diagnosis Research	001	5	8/15/2023	COMPETING CONTINUATION	$1,139,103
2023	2021	TWINSTRAND BIOSCIENCES INC	3131 ELLIOTT AVE	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	000	4	5/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,139,103

Issue Date FY: 2021 ( Subtotal = $859,730 )
2021	2021	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	002	4	7/28/2021	NON-COMPETING CONTINUATION	$249,982
2021	2021	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	001	4	3/23/2021	NON-COMPETING CONTINUATION	$30,486
2021	2021	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	000	4	1/13/2021	NON-COMPETING CONTINUATION	$579,262
														Subtotal = $859,730

Issue Date FY: 2020 ( Subtotal = $690,175 )
2020	2020	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	000	3	12/23/2019	NON-COMPETING CONTINUATION	$690,175
														Subtotal = $690,175

Issue Date FY: 2019 ( Subtotal = $690,175 )
2019	2019	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	001	2	5/2/2019	EXTENSION WITH OR WITHOUT FUNDS	$690,175
2019	2018	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	002	1	7/17/2019	NEW	$0
2019	2018	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	000	1	5/2/2019	NEW	$0
														Subtotal = $690,175

Issue Date FY: 2018 ( Subtotal = $299,790 )
2018	2018	TWINSTRAND BIOSCIENCES, INC.	3131 ELLIOT AVE STE 750	SEATTLE	WA	98121	KING	USA	Cancer Cause and Prevention Research	000	1	7/16/2018	NEW	$299,790
														Subtotal = $299,790

Grand Total All Awards = $5,664,804

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Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia using Duplex Sequencing

Award Number: R44CA233381

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/16/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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