Cooperative Research And Development Agreement

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 Trial ...