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DIPHTHERIA FUSION PROTEIN THERAPY OF AML

Award Number: R01CA076178
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 12/12/1997
PERIOD OF PERFORMANCE END DATE: 12/31/2006

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DIPHTHERIA FUSION PROTEIN THERAPY OF AML - Ten thousand people in the U.S. develop acute myeloid leukemia (AML) each year. While many patients achieve remissions with combination chemotherapy, most relapse and die with drug resistant disease. We have produced a diphtheria fusion protein (DT388GMCSF) consisting of the catalytic and translocation domains of diphtheria toxin fused to human granulocyte-macrophage colony- stimulating factor. We initiated a phase I single-arm, inter-patient dose escalation clinical trial of five daily intravenous infusions for patients with relapsed or refractory AML. To date, we have observed dose- related transient elevations in liver enzymes and circulating inflammatory cytokines. Half of the patients were found to have pre- treatment antibodies to DT388GMCSF >2mu g/mL associated with reductions in the peak blood concentrations of DT388GMCSF. Clinical remissions have been observed at the higher dose levels. In the next funding period, we propose to better define the potential role for DT388GMCSF in the care of AML patients. We will complete the on- going phase I study and expand the cohort of patients at the maximal tolerated dose to better estimate the preliminary response rate and side effects. Further, we propose three areas of laboratory studies to be carried out to facilitate our understanding of the molecular pharmacology of DT388GMCSF in these patients. In Specific Aim 1, the molecular mechanism for the liver damage and cytokine release will be investigated. The amount and types of cytokines released into the blood will be measured. Patient cytokine gene polymorphisms will be determined. A rat model will be used to determine whether the cytokines induce the liver injury. Methods of prevention of the cytokine release and liver injury in the rat will be tested. If successful, such measures may be tested in patients. In Specific Aim 2, anti- DT388GMCSF antibody formation and DT388GMCSF serum levels will continue to be measured and correlated with toxicity and response. In Specific Aim 3, pre-treatment blast proliferation sensitivity to DT388GMCSF will be measured and correlated with clinical response. These studies should lead to the design of pivotal phase II clinical trials to determine the role of this therapeutic in AML management.


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: 2006 ( Subtotal = $277,672 )
2006	2006	SCOTT & WHITE MEMORIAL HOSPITAL	2401 SOUTH 31ST STREET	TEMPLE	TX	76508	BELL	USA	Cancer Treatment Research	000	10	4/20/2006	NON-COMPETING CONTINUATION	$277,672
														Subtotal = $277,672

Issue Date FY: 2005 ( Subtotal = $270,747 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	8	12/3/2004	NON-COMPETING CONTINUATION	$270,747
														Subtotal = $270,747

Issue Date FY: 2004 ( Subtotal = $270,747 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	7	12/19/2003	NON-COMPETING CONTINUATION	$270,747
														Subtotal = $270,747

Issue Date FY: 2003 ( Subtotal = $294,707 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Treatment Research	000	6		OTHER REVISION	$294,707
														Subtotal = $294,707

Issue Date FY: 2002 ( Subtotal = $276,688 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Treatment Research	000	5	1/22/2002	COMPETING CONTINUATION	$276,688
														Subtotal = $276,688

Issue Date FY: 2001 ( Subtotal = $97,462 )
2001	2001	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Treatment Research	001	4	3/22/2001	SUPPLEMENT FOR EXPANSION	$97,462
														Subtotal = $97,462

Issue Date FY: 2000 ( Subtotal = $194,924 )
2000	2000	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Treatment Research	000	4	12/1/1999	NON-COMPETING CONTINUATION	$194,924
														Subtotal = $194,924

Issue Date FY: 1999 ( Subtotal = $189,245 )
1999	1999	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Treatment Research	000	3	3/3/1999	NON-COMPETING CONTINUATION	$189,245
														Subtotal = $189,245

Issue Date FY: 1998 ( Subtotal = $182,467 )
1998	1998	MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 Ashley Ave	CHARLESTON	SC	29425	CHARLESTON	USA	Cancer Treatment Research	000	1	12/9/1998	NEW	$52,285
1998	1998	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Treatment Research	000	2	12/9/1998	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$130,182
														Subtotal = $182,467

Grand Total All Awards = $2,054,659

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DIPHTHERIA FUSION PROTEIN THERAPY OF AML

Award Number: R01CA076178

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 12/12/1997

PERIOD OF PERFORMANCE END DATE: 12/31/2006

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