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Reduction of Relapse Risk Through Incorporation of Novel Biologic Agents Following Reduced Intensity Haploidentical Donor Transplant for Acute Myeloid Leukemia.

Award Number: UG1HL109526
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Lack of an HLA-matched donor has historically been a major obstacle to accessing allogeneic hematopoietic cell transplantation (allo-HCT) in many patients, particularly those from ethnic minorities and mixed race backgrounds. Recent work pioneered by a few centers including ours has demonstrated that the use of T- replete grafts from HLA-haploidenical donors and post-transplant cyclophosphamide to control alloreactivity (HIDTptCy) is safe with low rates of treatment related mortality and chronic GVHD. This advance has heralded the possibility of almost universal timely donor availability for patients that need allo-HCT. Furthermore, the relatively low graft-acquisition costs of HIDTptCy will improve access to allogeneic transplantation in underserved communities and developing nations. When HIDTptCy are performed for neoplastic diseases, relapse or progression of malignancy remains the most important cause of treatment failure. This is particularly so when non-myeloablative or reduced-intensity preparative regimens (RIC) are used. Administration of proteasome inhibitor drugs post allo-HCT may reduce relapse through direct anti-cancer activity as well potential stimulation natural killer (NK) cell alloreactivity. Furthermore, proteasome inhibitors have been demonstrated to inhibit graft-versus host disease. In an institutional pilot trial we have assessed the safety of the administration of the orally bioavailable proteasome inhibitor ixazomib for 12 months following HIDTptCy using RIC. Preliminary analysis of this trial has shown minimal toxicity with relatively low rates of relapse albeit with short follow-up. Another agent with potential to decrease relapse rates post HIDTptCy is the anti-SLAMF7 monoclonal antibody elotuzumab. This antibody has been shown to activate NK cells through binding of this receptor and may be particularly effective post HIDTptCy given the existing evidence that NK cell alloreactivity is important at preventing relapse in this setting. The activity of elotuzumab may also be augmented by co- exposure to a proteasome inhibitor. The proposed trial will be a randomized phase II study comparing the post- transplant administration of ixazomib versus elotuzumab versus ixazomib + elotuzumab during the first year post HIDTptCy using RIC for acute myeloid leukemia. It will specifically test the hypothesis that these agents alone or in combination will decrease the relapse rate which has been previously documented to be 43% at 12 months in this setting without use of these novel agents. Furthermore, it will test the hypothesis that these agents will not increase the rate of non-relapse mortality and will be well tolerated. Accrual to the three arms will be stratified for factors shown to be significant predictors of relapse following HIDTptCy using RIC for AML in multivariable analysis. This trial will also determine which of the three arms has the most promising outcomes and thus merits formal comparison to the standard-of care (HIDTptCy using RIC for AML without post-transplant novel agent use) in a future randomized phase III trial.


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: 2023 ( Subtotal = $60,094 )
2023	2023	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	13	10/1/2022	NON-COMPETING CONTINUATION	-$91,957
2023	2023	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	001	13	7/7/2023	NON-COMPETING CONTINUATION	$152,051
														Subtotal = $60,094

Issue Date FY: 2022 ( Subtotal = $153,075 )
2022	2022	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	12	7/1/2022	NON-COMPETING CONTINUATION	$153,075
														Subtotal = $153,075

Issue Date FY: 2021 ( Subtotal = $154,100 )
2021	2021	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	11	6/17/2021	NON-COMPETING CONTINUATION	$154,100
														Subtotal = $154,100

Issue Date FY: 2020 ( Subtotal = $155,199 )
2020	2020	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	10	6/9/2020	NON-COMPETING CONTINUATION	$155,199
														Subtotal = $155,199

Issue Date FY: 2019 ( Subtotal = $156,263 )
2019	2019	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	9	6/13/2019	NON-COMPETING CONTINUATION	$156,263
														Subtotal = $156,263

Issue Date FY: 2018 ( Subtotal = $149,563 )
2018	2018	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	8	6/16/2018	NON-COMPETING CONTINUATION	$149,563
														Subtotal = $149,563

Issue Date FY: 2017 ( Subtotal = $150,674 )
2017	2017	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	001	7	8/22/2017	COMPETING CONTINUATION	$0
2017	2017	NORTHSIDE HOSPITAL, INC.	1000 JOHNSON FERRY RD	ATLANTA	GA	30342	FULTON	USA	Blood Diseases and Resources Research	000	7	7/28/2017	COMPETING CONTINUATION	$150,674
														Subtotal = $150,674

Grand Total All Awards = $978,968

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Reduction of Relapse Risk Through Incorporation of Novel Biologic Agents Following Reduced Intensity Haploidentical Donor Transplant for Acute Myeloid Leukemia.

Award Number: UG1HL109526

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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