AMENDMENT No. 5 to Cooperative Research and Development Agreement

Exhibit 10.1

AMENDMENT No. 5
to
Cooperative Research and Development Agreement

This Amendment No.5 (“Amendment is made as of July 15,2006 by and among NeoPharm, Inc. a Delaware corporation (“NeoPharm”), and United States Department of Health & Human Services, Public Health Service (“PHS”), Food and Drug Administration/Center for Biologics Evaluation and Research Dr. Raj Purl (“Principal Investigator”), and amends that certain Cooperative Research and Development Agreement No. 26-97 between NeoPharm and PHS; dated as of August 27, 1997 (the “CRADA”).

WHEREAS, the CRADA was effective for an original term from August 1997 through August 2001; and

WHEREAS, the parties executed Appendix C Revised to the CRADA dated January 1, 2000, amending the provisions of Appendix C ; and

WHEREAS, the parties executed an Addendum to Appendix B and Appendix C Revised.1 to the CRADA dated December 12, 2000, amending Appendices B and C and extending the term of the CRADA through December 31, 2003; and

WHEREAS, the parties executed Appendix B Revised.l and an updated Appendix C Revised.l dated March 11, 2004 to the CRADA, amending Appendices B and C and extending the term of the CRADA through February 28, 2005; and

WHEREAS, the parties executed Appendix C - Revised.2 to the CRADA, dated July 15, 2005, amending Appendix C and extending the term of the CRADA; and;

WHEREAS, the parties hereby amend Appendices B and C to the CRADA and extend the term of the CRADA through July 31, 2009;

NOW, THEREFORE, pursuant to Section 13.6 of the CRADA, the following changes are made:

1.                                        Article 4 is deleted in its entirety and replaced with the following:

Article 4.                                             Reports.

4.1          Interim Reports.   The Parties shall exchange formal written interim progress reports on a Schedule agreed to by the PIs, but at least within six (6) months after this Addendum becomes effective and at least within every six (6) months thereafter. Such reports shall set forth the technical progress made, identifying such problems as may have been encountered and establishing goals and objectives requiring further effort, any modifications to the Research Plan pursuant to Article 3.2 and identify Subject Inventions pursuant to Article 6.1.

4.2          Final Reports.   The Parties shall exchange final reports of their results within four (4) months after completing the projects described in the RP or after the expiration or termination of this CRADA.

4.3          Presentations.   PHS shall make live presentations explaining the contents of the Interim Reports of Section 4.1 to the Collaborator within two (2) months of exchanging each Interim Report and shall provide a presentation explaining the contents of the Final Report of Section 4.2 within two (2) months of exchanging the Final Report.

2.             The research objectives listed on Appendix B - Addendum 2 hereto are added to those described in Appendix B to the CRADA, and the term of the CRADA is extended through July 31, 2009.

3.             Appendix C - Revised.3 attached hereto replaces in full Appendix C - Revised.2 to the CRADA.

4.             All other provisions of the CRADA, as heretofore amended, are unchanged and shall remain in full force and effect.

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Appendix B - Addendum 2

The following research objectives are added to those described in the Research Plan, Appendix B of CRADA No. 26-97.

1.                                        Ongoing study of evaluation of synergistic therapeutic efficacy of IL13 with radiation therapy or temozolomide:

Since radiation induced tumor cell stasis/death and IL13-PE induced cell death involve different mechanisms, it is possible that the combination of radiation and IL13-PE therapy may lead to combined or synergistic effect on glioma cells.  As ILl3-PE is being studied in newly-diagnosed high-grade glioma along with radiation therapy to support development, additional in vitro and animal studies should be performed, to determine the optimal schedule of therapy with these two modalities. Similarly, since temozolomide (FDA approved for newly-diagnosed GBM and recurrent anaplastic astrocytoma) and IL13-PE will mediate therapeutic effect through different mechanisms, it is also possible that the combination of both drugs may mediate combined or synergistic effects.

Summary of ongoing studies:

1.                                       In vitro sublethal irradiation of glioma cell lines followed by culture with IL13-PE and conversely incubation with IL-13-PE followed by irradiation was performed and the growth, cell viability and cytotoxicity to IL-13-PE was assessed. These studies show that irradiation increases IL-13Ralpha2 mRNA expression but it does not enhance sensitivity to IL13-PE. Similarly, prior treatment with IL13-PE did not                enhance sensitivity to irradiation.

2.                                       Concomitant radiation and IL13-PE incubation demonstrated enhanced antitumor effect in vitro when compared to either modality alone. Confirmatory studies are ongoing, which are nearly completed.

3.                                       Pre-treatment irradiation of subcutaneous or intracranial xenografts followed by local delivery of IL13-PE are also planned and will be initiated in collaboration with Dr. Jann Sakaria at the Mayo Clinic. Immunocompetent tumor model will be used when available.  Currently, we do not use syngeneic mouse model in our labs.  Based on xenograft model syngeneic model will be developed.  Several experiments were performed in s.q. model, however, optimal dose (50 ug/kg dose showed toxicity in the model system) of lL13-PE has not been established.

4.                                       Concomitant effect of temozolomide and IL13-PE in various glioma cell lines in vitro and the effect of co-administration of temozolomide and IL- I3-PE by various routes subcutaneous and intracranial xenografts will continue to be evaluated.  Our results suggest that temozolomide synergies with IL13-PE in mediating antitumor activity in vitro and in vivo.  These studies are expected to be completed in 2006.  Additional syngeneic GBM model will be developed after the completion of xenograft studies and the combined effects will be investigated.

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