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NOVEL SMALL-MOLECULE TNF-A MODULATORS AS CHEMOPROTECTIVE AGENTS

Award Number: R44CA141749
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2009
PERIOD OF PERFORMANCE END DATE: 07/31/2013

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NOVEL SMALL-MOLECULE TNF-A MODULATORS AS CHEMOPROTECTIVE AGENTS - DESCRIPTION (provided by applicant): Cisplatin is a widely used cytotoxic agent with therapeutic activity against various tumors, but also with substantial side effects, including nephrotoxicity, hepatotoxicity and myelosuppression. Therefore, a chemoprotective agent which reduces the side effects of cisplatin without affecting its efficacy would have significant clinical benefit. Currently, amifostine is the only FDA approved chemoprotective drug for cisplatin therapy. Amifostine is a sulfur-containing agent that reduces side effects resulted from both chemotherapy (including cisplatin) and radiotherapy regimens. Unfortunately, there are significant limitations associated with amifostine including its potentially serious side effects and potential tumor-protective effect. An ideal chemoprotector should not interfere with cisplatin's therapeutic effect, and with little or no toxicity by itself. As such, in our recently completed SBIR Phase I study, we investigated a small-molecule modulator of tumor necrosis factor alpha (TNF-a), UTL-5g, as a leading chemoprotective agent. Based on this SBIR Phase I study, UTL-5g has been shown to reduce levels of blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), and alanine transaminase (ALT) elevated by cisplatin, indicating the protection of kidney and liver by UTL-5g. Blood levels of TNF-a elevated by cisplatin were also lowered by UTL-5g in a dose- dependent manner. An exciting finding is that not only UTL-5g did not reduce the antitumor effect of cisplatin in vivo, pre-treatment of UTL-5g actually increased the therapeutic effect of cisplatin. In addition, UTL-5g has a very low acute toxicity. All these exciting results from the SBIR Phase I study indicate that continued preclinical development is warranted. The specific aims of this SBIR Phase II study are: [Aim 1] Compare the chemoprotective effects by both oral gavage and ip injection (which was used in Phase I) in animal studies and determine the optimal oral dose of UTL-5g. If the ADME study shows that UTL-5g may be a pro-drug, we will also use the same protocol to study the chemoprotective effect of the metabolite(s). [Aim 2] Use the optimal oral dose of UTL-5g (determined in Aim 1) and increasing doses of cisplatin dose to find whether the MTD of cisplatin in mice can be increased by UTL-5g. If the MTD of cisplatin does increase, conduct a therapeutic assessment of cisplatin at the new MTD with and without UTL-5g. [Aim 3] Use the optimal oral dosage from Aim 1 to conduct the ADME study. [Aim 4] Scale up the synthesis of API and prepare up to 1 kg of UTL-5g. [Aim 5] Conduct the 28-day repeat- dose toxicity studies in two species under GLP condition, employing the oral dosage form of UTL-5g. [Aim 6] Develop an oral formulation of UTL-5g suitable for the first clinical trial; develop and validate an analytical method for the oral formulation; define the specification and conduct a stability study on the oral dosage form. [Aim 7] Prepare a draft protocol suitable for the first Phase I clinical trial. [Aim 8] Compile a pre-IND package in the format according to FDA's guidance for Industry and be ready for a pre-IND meeting with the FDA. PUBLIC HEALTH RELEVANCE: This SBIR Phase II study is the continuation of the successful SBIR Phase I study to conduct the preclinical development of a small-molecule TNF-a modulator, UTL-5g, as a chemoprotective agent to prevent/reduce side effects induced by cisplatin without compromising its therapeutic effect.


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: 2012 ( Subtotal = $542,156 )
2012	2012	21ST CENTURY THERAPEUTICS INC	52623 SEVEN OAKS	SHELBY TOWNSHIP	MI	48316	MACOMB	USA	Cancer Treatment Research	000	3	8/21/2012	NON-COMPETING CONTINUATION	$542,156
														Subtotal = $542,156

Issue Date FY: 2011 ( Subtotal = $591,522 )
2011	2011	21ST CENTURY THERAPEUTICS INC	52623 SEVEN OAKS	SHELBY TOWNSHIP	MI	48316	MACOMB	USA	Cancer Treatment Research	000	2	8/23/2011	COMPETING CONTINUATION	$591,522
														Subtotal = $591,522

Grand Total All Awards = $1,133,678

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NOVEL SMALL-MOLECULE TNF-A MODULATORS AS CHEMOPROTECTIVE AGENTS

Award Number: R44CA141749

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2009

PERIOD OF PERFORMANCE END DATE: 07/31/2013

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