AMENDMENT #2









EXHIBIT 10.15




 




AMENDMENT #2




 




COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT #303




 




CLINICAL DEVELOPMENT OF O6-BENZYLGUANINE




 




The purpose of this amendment is to change

certain terms of the above referenced Cooperative Research and Development

Agreement (CRADA).  These changes are

reflected below and, except for these changes and those of any previous

amendments, all other provisions of the original CRADA remain in full force and

effect.  Three originals of this

amendment are provided for execution; one is to remain with the National Cancer

Institute; one with Procept, Inc. and one with AOI Pharmaceuticals, Inc.




 




1.             Collaborator name and address:




 




Effective as of the date of final signature

of this Amendment, AOI Pharmaceuticals, Inc. will replace Procept, Inc. as the

CRADA Collaborator.  The new address for

the CRADA Collaborator will be:




 




AOI Pharmaceuticals, Inc.




750 Lexington Avenue, 26th

Floor




New York, New York 10022




 




2.             The Research Plan, CRADA #303,

Appendix A, is amended as follows:




 




I. Paragraph C, “DCTD, NCI

Responsibilities,” item 2, shall be amended to include the following active,

approved, completed or closed clinical trials:




 




Sub-Sections

2 through and including 5 are deleted and replaced with the following:




 




	

  2.


  	

  As of the effective date

  of this CRADA Amendment, the following active, approved, completed or closed

  Clinical Trials are a part of this CRADA:


  





 




Phase

1 Trials:




 




•      #237: Phase 1 trial and pharmacokinetic

study of temozolomide and O6-benzylguanine in childhood solid

tumors.  National Cancer Institute,

Pediatric Oncology Branch, Frank M. Balis, P.I.




 




•      #490: Phase 1 trial of temodar plus O6-benzylguanine

in the treatment of patients with newly diagnosed (part 1) or

recurrent/progressive (parts 1 and 2) cerebral anaplastic gliomas.  Duke University Medical Center, Henry S.

Friedman, P.I.




 





























 




•      #NABTC-9702: A phase 1 trial of

pre-surgical O6-benzylguanine in the treatment of patients with

malignant glioma.  North American Brain

Tumor Consortium, Michael D. Prados, P.I.




 




•      #NABTT-9803: Phase 1/2 gliadel and

continuous infusion of intravenous O6-benzylguanine trial in

patients with recurrent malignant glioma. 

NABTT Brain Tumor Consortium, Jon Weingart, P.I.




 




•      #POG-9870: A trial of O6-benzylguanine

and BCNU in children with CNS tumors. 

Pediatric Oncology Group, Denise M. Adams, P.I.




 




•      #T97-0029: Phase 1 trial of O6-benzylguanine

and BCNU in cutaneous T-cell lymphoma. 

Case Western Reserve University, Seth R. Stevens, P.I.




 




•      #T97-0060: Mutant MGMT gene transfer into

human hematopoietic progenitors to protect hematopoiesis during O6-benzylguanine

(BG, NSC 637037) and BCNU therapy of advanced solid tumors.  Case Western Reserve University, Stanton

Gerson, P.I.




 




•      #T98-0038: Determination of optimal O6-benzylguanine

dose to achieve O6-Alkylguanine-DNA alkyltransferase depletion in

patients with surgically resectable solid tumors.  University of Chicago, Mark J. Ratain, P.I.




 




•      #972: A pilot study of O6-benzylguanine

and BCNU in patients with B Cell malignancies: Assessment of marrow protection

by an O6-benzylguanine resistant methylguanine methyltransferase

gene.  Indiana University, K. Cornetta,

P.I.




 




•      PBTC-005: Phase 1 trial of temozolomide

and O6-benzylguanine in pediatric patients with recurrent brain

tumors.  Pediatric Brain Tumor

Consortia, A. Gajjar, P.I.




 




Completed

Phase 1 Trials:




 




•      #T96-0041: Phase 1 Trial of Pre-surgery O6-Benzylguanine

in the Treatment of Patients with Newly Diagnosed or Recurrent Cerebral

Anaplasti.  Duke University, H.S.

Friedman, P.I.




 




Closed

Phase 1 Trials:




 




•      #T94-0022: Phase 1 Trial of O6-Benzylguanine

and BCNU: A Biochemical Modulation Trial Based Upon Depletion of O6-Alkylguanine

DNA Alkyltransferase Directed DNA Repair. 

Case Western University, T.P. Spiro, P.I.




 




•      #T94-0082: Phase 1 Clinical and

Pharmacologic Study of O6-Benzylguanine (NSC 637037) and Carmustine

(BCNU) in Patients with Advanced Cancer. 

University of Chicago, R.L. Schilsky, P.I.




 




1





























 




•      #T94-0080: Phase 1 Trial of BCNU Plus O6-Benzylguanine

in the Treatment of Patients with Recurrent, Persistent or Progressive Cerebral

Anaplastic Gliomas.  Duke University,

H.S. Friedman, P.I.




 




Phase

2 Trials:




 




•      #89: Phase 2 trial of O6-benzylguanine

and BCNU in patients with colon and rectal carcinoma.  Case Western Reserve University, Smitha S. Krishnamurthi, P.I.




 




•      #T97-0021: Phase 2 trial of O6-benzylguanine

(NSC 637037) and BCNU in patients with multiple myeloma.  Case Western Reserve University, Stanton L.

Gerson, P.I.




 




•      #T99-0088: A phase 2 trial of O6-benzylguanine

(NSC 637037) and BCNU (carmustine) in patients with advanced soft tissue

sarcoma.  University of Chicago,

Christopher Ryan, P.I.




 




•      #T99-0111: A phase 2 trial of O6-benzylguanine

(NSC 637037) and BCNU (carmustine) in patients with metastatic melanoma.  University of Chicago, Jeffrey A. Sosman,

P.I.




 




•      #5632: Phase 2 trial of BCNU plus O6-benzylguanine

in the treatment of patients with newly diagnosed glioblastoma multiforme.  Duke University, H.S. Friedman, P.I.




 




Completed

Phase 2 Trials:




 




•      #T98-0059: Phase 2 Trial of BCNU Plus O6-Benzylguanine

in the Treatment of Patients with Recurrent or Progressive Cerebral Anaplastic

Gliomas.  Duke University, H.S.

Friedman, P.I.




 




Phase

3 Trials:




 




•      #S0001: Phase 3 study of radiation therapy

(RT) and O6-benzylguanine (O6-BG) plus BCNU versus RT and

BCNU alone for newly diagnosed glioblastoma multiforme (GBM) and

gliosarcoma.  Southwest Oncology Group,

Alexander M. Spence, P.I.




 




The remaining Sub-sections

of Paragraph C, DCTD, NCI Responsibilities, are renumbered appropriately.




 




II.        Paragraph

D, “Collaborator Responsibilities,” shall be amended to include the following:




 




9.             Collaborator must file an IND

within six (6) months of the execution of this Amendment.  The IND will cross reference the NCI IND;

the NCI will provide an appropriate Letter of Cross Reference to the

Collaborator at the time of IND filing. 

If the IND is not filed within this six-month time frame, Collaborator,

at a minimum, must have requested and have a fixed date with the FDA for a

pre-IND meeting.  All CRADA payments 




 




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due

through January 31, 2002 must be paid in full and be current prior to NCI

furnishing the Letter of Cross Reference.




 




	

  10.


  	

  Collaborator must pay the

  NCI for all costs associated with the Agent production, formulation and

  distribution that NCI has incurred for the provision of Agent for clinical

  trials until such time as Collaborator is capable of providing an adequate

  supply of Agent for all current, ongoing or approved NCI sponsored clinical

  trials.  These costs will be detailed

  in the amended language for Appendix B.


  





 




Collaborator will provide

adequate Agent quantities to the NCI within 90 days of filing its IND in

accordance with Appendix A, Paragraph D, “Collaborator Responsibilities,” item

9 (see above).  In all cases, a

six-month lead-time for notification of clinical trial supply quantities is

required from the NCI to ensure that the Collaborator has sufficient time to

comply.  In the event that NCI notifies

Collaborator less than six months in advance, Collaborator will do everything

reasonably possible to work with the NCI to negotiate a mutually acceptable

delivery date.




 




11.           Collaborator will be responsible for

the sponsorship of all new clinical studies under the Collaborator IND.  Sponsorship of new clinical studies will be

provided, only after the Collaborator makes a scientific review of the request

and determines that the proposed studies are in accordance with their development

strategy.  With respect to approved LOI

#5613, Collaborator will supply Agent and sponsor the study under its IND; NCI

acknowledges that the study is funded under an NCI grant.  NCI will assist Collaborator by providing

Agent to Collaborator to initiate the study, if Collaborator does not have a

supply of Agent.




 




12.           Collaborator agrees to permit the NCI

to distribute Agent for mutually agreeable pre-clinical studies following the

execution of an appropriate Materials Transfer Agreement.




 




3.             Financial

and Staffing Contributions of the Parties, Appendix B, is amended to include

the following:




 




I.              Funding:




 




Collaborator will be

responsible for providing sufficient funds to cover the costs of Agent

production, formulation, approved labeling/vialing, distribution and supportive

analytical testing of the Agent for completed, on-going and approved clinical

studies subsequent to the execution of this CRADA amendment.  Payment shall be made directly to the NCI.




 




The total costs through

September, 2001 for the production of two lots of Agent are $200,000.00.  This includes the costs of API synthesis,

drug product manufacturing, analytical and quality control, and distribution

for clinical studies.




 




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NCI acknowledges that it has

been informed by AOI that Procept is responsible for the costs associated with

the production of these two lots.




 




Collaborator is also

responsible for the costs associated with the formulation of the next batch of

Agent scheduled for the Fall, 2001 for the ongoing and approved clinical

trials.  The estimated per batch cost is

$65,000, accounted for as follows:




 




	

  Per batch formulation:


  	

   


  	

  $


  	

  50,000


  	

   


  
	

  Per

  batch shelf-life studies:


  	

   


  	

  $


  	

  10,000


  	

   


  
	

  Per

  batch distribution:


  	

   


  	

  $


  	

  5,000


  	

   


  





 




In addition, Collaborator is

responsible for the costs associated with a stability study on the current

active lot of Agent.  The cost for this

stability study will be $20,000.




 




Collaborator shall be

responsible for funding NIH approved travel costs as permitted under the DHHS

Travel Manual Chapters 1-70.  Travel costs

are limited by the Federal Travel Rules and Regulations for all government

staff whether paid by government funds or private Collaborators.  Collaborator may provide direct support,

under the 348 travel mechanism, for the travel and associated costs for

attendance of NCI staff at selected scientific or development meetings.




 




II.            Payment

Schedule is replaced in its entirety with the following:




 




Payment Schedule:




 




An annual CRADA payment of

$125,000.00 will be made by the Collaborator for general support of this

CRADA.  These payments will be made

quarterly, the first payment due within 30 days of the execution of CRADA.  Checks should be made payable to the

National Cancer Institute and sent via Federal Express to:




 




CRADA Funds Coordinator




Technology Transfer Branch




National Cancer Institute




6120 Executive Blvd.,

Executive Plaza South, Suite 450




Rockville, MD 20852-7181




 




with a clear reference to

the NCI CRADA Number and Title: CACR-0303, “Clinical Development of O6-Benzylguanine

(O6BG).”




 




Payment for the current

development costs through September 2001 ($200,000.00) shall be due by January

31, 2002.




 




Payment for the batch costs

and stability studies ($85,000.00) shall be due by January 31, 2002.




 




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4.             Exceptions and Modifications to

this CRADA, Appendix C, is amended as follows:




 




I.              Modify

Article 2.11 to read as follows where underline denotes addition:




 




	

  2.11


  	

  “Subject

  Data” means all recorded information first produced in the performance of

  this CRADA by the parties.  “Subject

  Data” shall specifically exclude “Identifiable Private Information.”


  





 




II.            Add the

following new section to Article 2. Definitions:




 




	

  2.30


  	

  “Identifiable

  Private Information” means patient-identifying data from

  medical records or attached to patient specimens, to be obtained

  prospectively or from stored medical records or specimens, that can be linked

  to individual human subjects, either directly or indirectly through codes.


  





 




III.           Amend

Article 3.6, Drug Information and Supply, as follows where strikeout denotes

deletion and underline denotes addition:




 




The contact person for NCI

will be Mr. Alfred Fallavollita, Chief, Pharmaceutical Management Branch

(Telephone Number 301-496-5725) and the Collaborator contact will be Melynda

L. Holmes, Director of Clinical Research (Telephone Number 203-406-1725 X2504).




 




IV.           Modify

Article 8.4 to read as follows where underline denotes addition:




 




	

  8.4


  	

  Proprietary/Confidential

  Information.  Each Party agrees to

  limit its disclosure of Proprietary/Confidential Information to the amount

  necessary to carry out the Research Plan of this CRADA, and shall place a

  confidentiality notice on all such information.  Confidential oral communications shall be reduced to writing

  within 30 days by the disclosing Party.  Each Party receiving Proprietary/Confidential Information agrees

  that any information so designated shall be used by it only for the purposes

  described in the attached Research Plan. 

  Any Party may object to the designation of information as

  Proprietary/Confidential Information by another Party.  Subject Data and Research Materials

  developed solely by the Collaborator may be designated as

  Proprietary/Confidential Information when they are wholly separable from the

  Subject Data and Research Materials developed jointly with PHS investigators,

  and advance designation of such data and material categories is set forth in

  the RP.  The exchange of other

  confidential information, e.g., Identifiable Private Information, shall

  be subject to the  terms of Article 8.10.  Jointly developed Subject Data and Research Material derived

  from the Research Plan may be disclosed by Collaborator to a third party

  under a confidentiality agreement for the purpose of possible sublicensing

  pursuant to the Licensing Agreement and subject to Article 8.7.


  





 




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V.            Add a new

Article 8.10 “Access, Review and Receipt of Identifiable Private Information”

as follows:




 




	

  8.10


  	

  Access, Review and Receipt

  of identifiable Private Information. 

  Collaborator access to and review of Identifiable Private Information

  shall be only for on-site quality auditing. 

  Collaborator will receive Identifiable Private Information only for

  purposes of satisfying FDA or other health authorities’ reporting

  requirements, and for internal research purposes directly related to

  obtaining regulatory approval of Agent. 

  Collaborator is prohibited from access, review, receipt, or use of

  such information for other purposes. 

  All IRB approved protocol and informed consent documents related to

  this research project will clearly describe this practice.  If the Collaborator will have access to

  Identifiable Private Information, the protocol and the informed consent must

  clearly state (i) the existence of the Collaborator; (ii) the Collaborator’s

  access to Identifiable Private Information, if any; and (iii) the extent to

  which confidentiality will be maintained. 

  For clinical protocol involving a third party, the other party’s

  access, review, receipt, or use of Identifiable Private Information shall be

  subject to the same limitations as described in this Article 8.10.


  





 




SIGNATURES BEGIN ON THE NEXT PAGE




 




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AGREED TO

AND ACCEPTED BY:




 




For the

National Cancer Institute:




 




	

  /s/ Alan S. Rabson


  	

   


  	

  January 4, 2002


  	

   


  
	

  Alan S. Rabson, M.D.


  	

  (Date)


  
	

  Deputy Director/National

  Cancer Institute


  	

   


  





 




For AOI

Pharmaceuticals, Inc.:




 




	

  /s/ I. Craig Henderson


  	

   


  	

  January 17, 2002


  	

   


  
	

  I. Craig Henderson, M.D.


  	

   


  	

  (Date)


  	

   


  
	

  President


  	

   


  	

   


  	

   


  





 




For

Procept, Inc.:




 




	

  /s/ Salvatore A. Bucci


  	

   


  	

  February 28, 2002


  	

   


  
	

  Salvatore A. Bucci


  	

  (Date)


  
	

  President and CEO


  	

   


  





 




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