Document:

<PAGE>   1
                                                                EXHIBIT 10.21(b)

                                AMENDMENT NO. 1

                                       to

                    COLLABORATION AGREEMENT (K-ras PRODUCTS)
                                 BY AND BETWEEN
                   RHONE-POULENC RORER PHARMACEUTICALS, INC.
                                      AND
                          INTROGEN THERAPEUTICS, INC.
                                OCTOBER 7, 1994

For good and valuable consideration, receipt of which is acknowledged hereby,
the parties indicated below, intending to be legally bound, agree as follows:

(1)      In the introductory statement before the RECITALS, insert after
         "("RPRP")",--on behalf of RPR Gencell, a division of Rhone-Poulenc
         Rorer Inc.,--.

(2)      Insert as the last sentence in Section 2.2,--The ScFV pan-ras
         therapeutic product under development by Rhone-Poulenc Rorer S.A. shall
         be considered a "Collaboration Product."

The effective date of this amendment shall be September 27, 1995.

                                             RHONE-POULENC RORER
INTROGEN THERAPEUTICS, INC.                  PHARMACEUTICALS, INC.

By: /s/ DAVID NANCE                          By: /s/ K. R. PINA
    -----------------------                      ------------------------
        DAVID NANCE
        President

Date:   9-29-95                              Date:   9/27/95
      ---------------------                        ----------------------

<PAGE>   2

                               September 27, 1995

Introgen Therapeutics, Inc.
301 Congress Avenue, Suite 2025
Austin, Texas 78701
Attn: David G. Nance

Gentlemen:

This letter agreement is being entered into in connection with that certain
Collaboration Agreement for K-ras Products, dated October 7, 1994 by and between
Introgen Therapeutics, Inc. ("Introgen") and Rhone-Poulenc Rorer
Pharmaceuticals, Inc. ("RPRP")(the "Agreement") and Amendment No. 1 to the
Agreement dated as of September 27, 1995. Capitalized terms that are not
otherwise defined in this letter shall have the meaning defined in the
Agreement.

In addition to the Collaboration Products currently being developed under the
Agreement, RPRP has proposed to develop one or more additional products based
upon the transfer into tumor cells of a gene coding for a single chain antibody
that binds to the K-ras protein ("Single Chain Antibody Products"). Since the
proposed product is within the Field, the parties propose to develop and
commercialize such product pursuant to the Agreement, as follows:

         1. Product Plan and Budget. RPRP and Introgen will mutually agree upon
a Product Plan and Budget for the Single Chain Antibody Products, as
contemplated in Section 3.4 of the Agreement. Each product being developed under
such Product Plan and Budget (and/or any successor Product Plan and Budget), as
in effect from time to time (and subject to Section 6.1), shall be deemed a
Collaboration Product for all purposes of the Agreement.

         2. Reports. It is understood that the Agreement originally contemplated
that preliminary research and preclinical work through filing an IND for a
Collaboration Product would be performed by Introgen. However, RPRP and Introgen
acknowledge that much of the preliminary research and preclinical studies on the
Collaboration Products that are Single Chain Antibody Products may be performed
by RPRP in France.

         Accordingly, since Introgen will be responsible (as mutually agreed and
as contemplated in the Agreement) for the filing of an IND in the United States,
and for the conduct of Early Stage Clinical Development in North America, with
respect to such Collaboration Products, RPRP agrees to provide to Introgen in
English as soon as practicable all data, materials, results, reports
<PAGE>   3
Introgen Therapeutics, Inc.
September 27, 1995
Page 2

and other information as is reasonably necessary for Introgen to prepare and
file such IND to prepare and conduct such Early Stage Clinical Development
(including the manufacture of clinical trial materials) for such Collaboration
Products. In addition, RPRP agrees to include in the reports provided to the
Development Committee under Section 2.4.3 of the Agreement a summary of RPRP's
activities with respect to the research and development of the Single Chain
Antibody Products.

     3. Other Terms.  Except as expressly set forth in this letter agreement,
all terms and conditions of the Agreement shall remain in full force and
effect. Without limiting the foregoing, it is understood that Section 6.2 shall
continue to apply to all Single Chain Antibody Products that are not being
developed as Collaboration Products, and that funding for Introgen's conduct of
the Early Stage Clinical Development of the Collaboration Products that are
Single Chain Antibody Products will be as provided in Article 4 of the
Agreement.

                         RHONE-POULENC RORER
                         PHARMACEUTICALS, INC.

                         By: /s/ K. R. PINA
                             -------------------------
                         Name: K. R. Pina
                               -----------------------
                         Title: VP and General Counsel
                                ----------------------

Agreed to and Accepted as of this 27th day of September 1995:

/s/  DAVID G. NANCE
------------------------------
Introgen Therapeutics
by David G. Nance, President<PAGE>   1
                                                                   EXHIBIT 10.22

                            COOPERATIVE RESEARCH AND
                              DEVELOPMENT AGREEMENT

                                   (CACR-352)

                          CLINICAL DEVELOPMENT OF Adp53

                                      [*]
                                      [*]
                                      CTEP
                                      DCTD

                                      [*]
                    RHONE-POULENC RORER PHARMACEUTICALS, INC.

                                      [*]
                           INTROGEN THERAPEUTICS, INC.

                                  PREPARED BY
              TECHNOLOGY DEVELOPMENT AND COMMERCIALIZATION BRANCH
                           NATIONAL CANCER INSTITUTE

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   2

                              PUBLIC HEALTH SERVICE

                 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

This Cooperative Research and Development Agreement, hereinafter referred to as
"CRADA," consists of this Cover Page, an attached Agreement, and various
Appendices referenced in the Agreement. This Cover Page serves to identify the
Parties to this CRADA:

                  (1) the following Bureau(s), Institute(s), Center(s) or
Division(s) of the National Institutes of Health ("NIH"), the Food and Drug
Administration ("FDA"), and the Centers for Disease Control and Prevention
("CDC"):

                              THE CANCER THERAPY EVALUATION PROGRAM
                              DIVISION OF CANCER TREATMENT AND DIAGNOSIS
                              THE NATIONAL CANCER INSTITUTE

, hereinafter singly or collectively referred to as the Public Health Service
("PHS"); and

                  (2)         RHONE-POULENC RORER PHARMACEUTICALS, INC.,

which has offices at          500 ARCOLA ROAD
                              COLLEGEVILLE, PENNSYLVANIA 19426

, hereinafter referred to as "RPRP"
and

                  (3)         INTROGEN THERAPEUTICS, INC.,

which has offices at          301 CONGRESS AVENUE, SUITE 1850
                              AUSTIN, TEXAS 78701

, hereinafter referred to as "Introgen"

PHS CRADA CACR-0352
<PAGE>   3

                 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

ARTICLE 1. INTRODUCTION

This Cooperative Research and Development Agreement (CRADA) between PHS and the
Collaborator will be effective when signed by all Parties. The research and
development activities which will be undertaken by each of the Parties in the
course of this CRADA are detailed in the Research Plan (RP) which is attached as
Appendix A. The funding and staffing commitments of the Parties are set forth in
Appendix B. Any exceptions or changes to the CRADA are set forth in Appendix C.

ARTICLE 2. DEFINITIONS

As used in this CRADA, the following terms shall have the indicated meanings:

2.1      "AFFILIATE" means any corporation or other business entity controlled
         by, controlling, or under common control with Collaborator. For this
         purpose, "control" means direct or indirect beneficial ownership of at
         least fifty (50) percent of the voting stock or at least fifty (50)
         percent interest in the income of such corporation or other business.

2.2      "Cooperative Research and Development Agreement" or "CRADA" means this
         Agreement, entered into by PHS pursuant to the Federal Technology
         Transfer Act of 1986, as amended, 15 U.S.C. 3710a et seq. and
         Executive Order 12591 of October 10, 1987.

2.3      "GOVERNMENT" means the Government of the United States as represented
         through the PHS agency that is a Party to this agreement.

2.4      "IP" means intellectual property.

2.5      "INVENTION" means any invention or discovery which is or may be
         patentable or otherwise protected under title 35, United States Code,
         or any novel variety or plant which is or may be protectable under the
         Plant Variety Protection Act (7 U.S.C. 2321 et seq.).

2.6      "PRINCIPAL INVESTIGATOR(S)" or "PIS" means the persons designated
         respectively by the Parties to this CRADA who will be responsible for
         the scientific and technical conduct of the RP.

2.7      "PROPRIETARY/CONFIDENTIAL INFORMATION" means confidential scientific,
         business, or financial information provided that such information does
         not include:

         2.7.1    information that is publicly known or available from other
                  sources who are not under a confidentiality obligation to the
                  source of the information;

         2.7.2    information which has been made available by its owners to
                  others without a confidentiality obligation;

         2.7.3    information which is already known by or available to the
                  receiving Party without a confidentiality obligation; or

         2.7.4    information which relates to potential hazards or cautionary
                  warnings associated with the production, handling or use of
                  the subject matter of the Research Plan of this CRADA.

2.8      "RESEARCH MATERIALS" means all tangible materials other than Subject
         Data first produced in the

Model PHS CRADA
Form 053096 Page 2 of 11
<PAGE>   4

         performance of this CRADA.

2.9      "RESEARCH PLAN" or "RP" means the statement in Appendix A of the
         respective research and development commitments of the Parties to this
         CRADA.

2.10     "SUBJECT INVENTION" means any Invention of the Parties, conceived or
         first actually reduced to practice in the performance of the Research
         Plan of this CRADA.

2.11     "SUBJECT DATA" means all recorded information first produced in the
         performance of this CRADA by the Parties.

ARTICLE 3. COOPERATIVE RESEARCH

3.1      PRINCIPAL INVESTIGATORS. PHS research work under this CRADA will be
         performed by the PHS laboratory identified in the RP, and the PHS
         Principal Investigator (PI) designated in the RP will be responsible
         for the scientific and technical conduct of this project on behalf of
         PHS. Also designated in the RP is the Collaborator PI who will be
         responsible for the scientific and technical conduct of this project on
         behalf of the Collaborator.

3.2      RESEARCH PLAN CHANGE. The RP may be modified by mutual written consent
         of the Principal Investigators. Substantial changes in the scope of the
         RP will be treated as amendments under Article 13.6.

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 [*] after this CRADA becomes effective and at least within [*]
         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 all CRADA-related patent
         applications filed.

4.2      FINAL REPORTS. The Parties shall exchange final reports of their
         results within [*] after completing the projects described
         in the RP or after the expiration or termination of this CRADA.

ARTICLE 5. FINANCIAL AND STAFFING OBLIGATIONS

5.1      PHS AND COLLABORATOR CONTRIBUTIONS. The contributions of the Parties,
         including payment schedules, if applicable, are set forth in Appendix
         B. PHS shall not be obligated to perform any of the research specified
         herein or to take any other action required by this CRADA if the
         funding is not provided as set forth in Appendix B. PHS shall return
         excess funds to the Collaborator when it sends its final fiscal report
         pursuant to Article 5.2, except for staffing support pursuant to
         Article 10.3. Collaborator acknowledges that the U.S. Government will
         have the authority to retain and expend any excess funds for up to
         [*] subsequent to the expiration or termination of the CRADA to
         cover any costs incurred during the term of the CRADA in undertaking
         the work set forth in the RP.

5.2      ACCOUNTING RECORDS. PHS shall maintain separate and distinct current
         accounts, records, and other evidence supporting all its obligations
         under this CRADA, and shall provide the Collaborator a final fiscal
         report pursuant to Article 4.2.

5.3      CAPITAL EQUIPMENT. Equipment purchased by PHS with funds provided by
         the Collaborator shall be the property of PHS. All capital equipment
         provided under this CRADA by one party for the use of another Party
         remains the property of the providing Party unless other disposition is
         mutually agreed upon by in

Model PHS CRADA
Form 053096 Page 3 of 11

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   5
         writing by the Parties. If title to this equipment remains with the
         providing Party, that Party is responsible for maintenance of the
         equipment and the costs of its transportation to and from the site
         where it will be used.

ARTICLE 6. INTELLECTUAL PROPERTY RIGHTS AND PATENT APPLICATIONS

6.1      REPORTING. The Parties shall promptly report to each other in writing
         each Subject Invention resulting from the research conducted under this
         CRADA that is reported to them by their respective employees. Each
         Party shall report all Subject Inventions to the other Party in
         sufficient detail to determine inventorship. Such reports shall be
         treated as Proprietary/Confidential Information in accordance with
         Article 8.4.

6.2      COLLABORATOR EMPLOYEE INVENTIONS. If the Collaborator does not elect to
         retain its IP rights, the Collaborator shall offer to assign these IP
         rights to the Subject Invention to PHS pursuant to Article 6.5. If PHS
         declines such assignment, the Collaborator may release its IP rights as
         it may determine.

6.3      PHS EMPLOYEE INVENTIONS. PHS on behalf of the U.S. Government may elect
         to retain IP rights to each Subject Invention made solely by PHS
         employees. If PHS does not elect to retain IP rights, PHS shall offer
         to assign these IP rights to such Subject Invention to the Collaborator
         pursuant to Article 6.5. If the Collaborator declines such assignment,
         PHS may release IP rights in such Subject Invention to its employee
         inventors pursuant to Article 6.6.

6.4      JOINT INVENTIONS. Each Subject Invention made jointly by PHS and
         Collaborator employees shall be jointly owned by PHS and the
         Collaborator. The Collaborator may elect to file the joint patent or
         other IP application(s) thereon and shall notify PHS promptly upon
         making this election. If the Collaborator decides to file such
         applications, it shall do so in a timely manner and at its own expense.
         If the Collaborator does not elect to file such application(s), PHS on
         behalf of the U.S. Government shall have the right to file the joint
         application(s) in a timely manner and at its own expense. If either
         Party decides not to retain its IP rights to a jointly owned Subject
         Invention, it shall offer to assign such rights to the other Party
         pursuant to Article 6.5. If the other Party declines such assignment,
         the offering Party may release its IP rights as provided in Articles
         6.2, 6.3, and 6.6.

6.5      FILING OF PATENT APPLICATIONS. With respect to Subject Inventions made
         by the Collaborator as described in Article 6.2, or by PHS as described
         in Article 6.3, a Party exercising its right to elect to retain IP
         rights to a Subject Invention agrees to file patent or other IP
         applications in a timely manner and at its own expense and after
         consultation with the other Party. The Party shall notify the other
         Party of its decision regarding filing in countries other than the
         United States in a timely manner. The Party may elect not to file a
         patent or other IP application thereon in any particular country or
         countries provided it so advises the other Party ninety (90) days prior
         to the expiration of any applicable filing deadline, priority period or
         statutory bar date, and hereby agrees to assign its IP right, title and
         interest in such country or countries to the Subject Invention to the
         other Party and to cooperate in the preparation and filing of a patent
         or other IP applications. In any countries in which title to patent or
         other IP rights is transferred to the Collaborator, the Collaborator
         agrees that PHS inventors will share in any royalty distribution that
         the Collaborator pays to its own inventors.

6.6      RELEASE TO INVENTORS. In the event neither of the Parties to this CRADA
         elects to file a patent or other IP application on a Subject Invention,
         either or both (if a joint invention) may retain or release their IP
         rights in accordance with their respective policies and procedures.
         [*]

6.7      PATENT EXPENSES. The expenses attendant to the filing of patent or
         other IP applications generally shall be paid by the Party filing such
         application. If an exclusive license to any Subject Invention is
         granted to the

Model PHS CRADA
Form 053096 Page 4 of 11

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   6
         Collaborator, the Collaborator shall be responsible for [*] past and
         future out-of-pocket expenses in connection with the preparation,
         filing, prosecution and maintenance of any applications claiming such
         exclusively-licensed inventions and any patents or other IP grants that
         may issue on such applications. The Collaborator may waive its
         exclusive license rights on any application, patent or other IP grant
         at any time, and incur no subsequent compensation obligation for that
         application, patent or IP grant.

6.8      PROSECUTION OF INTELLECTUAL PROPERTY APPLICATIONS. Within one month of
         receipt or filing, each Party shall provide the other Party with copies
         of the applications and all documents received from or filed with the
         relevant patent or other IP office in connection with the prosecution
         of such applications. Each Party shall also provide the other Party
         with the power to inspect and make copies of all documents retained in
         the patent or other IP application files by the applicable patent or
         other IP office. Where licensing is contemplated by Collaborator, the
         Parties agree to consult with each other with respect to the
         prosecution of applications for PHS Subject Inventions described in
         Article 6.3 and joint Subject Inventions described in Article 6.4. If
         the Collaborator elects to file and prosecute IP applications on joint
         Subject Inventions pursuant to Article 6.4, PHS will be granted an
         associate power of attorney (or its equivalent) on such IP
         applications.

ARTICLE 7. LICENSING

7.1      OPTION FOR COMMERCIALIZATION LICENSE. With respect to Government IP
         rights to any Subject Invention not made solely by the Collaborator's
         employees for which a patent or other IP application is filed, PHS
         hereby grants to the Collaborator an option to elect an exclusive or
         nonexclusive commercialization license, which is substantially in the
         form of the appropriate model PHS license agreement. This option does
         not apply to Subject Inventions conceived prior to the effective date
         of this CRADA that are reduced to practice under this CRADA, if prior
         to that reduction to practice, PHS has filed a patent application on
         the invention and has licensed it or offered to license it to a third
         party. The terms of the license will fairly reflect the nature of the
         invention, the relative contributions of the Parties to the invention
         and the CRADA, the risks incurred by the Collaborator and the costs of
         subsequent research and development needed to bring the invention to
         the marketplace. The field of use of the license will be commensurate
         with the scope of the RP.

7.2      EXERCISE OF LICENSE OPTION. The option of Article 7.1 must be exercised
         by written notice mailed within [*] after either (i) Collaborator
         receives written notice from PHS that the patent or other IP
         application has been filed; or (ii) the date Collaborator files such IP
         application; whichever comes first. Exercise of this option by the
         Collaborator initiates a negotiation period that expires [*] after the
         exercise of the option. If the last proposal by the Collaborator has
         not been responded to in writing by PHS within this [*] period, the
         negotiation period shall be extended to expire [*] after PHS
         so responds, during which month the Collaborator may accept in writing
         the final license proposal of PHS. [*]. In the event that the
         Collaborator elects the option for an exclusive license, but no such
         license is executed during the negotiation period, PHS agrees not to
         make an offer for an exclusive license on more favorable terms to a
         third party for a period of [*] without first offering Collaborator
         those more favorable terms.

7.3      LICENSE FOR PHS EMPLOYEE INVENTIONS AND JOINT INVENTIONS. Pursuant to
         15 U.S.C. 3710a(b)(1)(A), for inventions made by PHS employees or
         jointly with a Collaborator under this CRADA, pursuant to Articles 6.3
         and 6.4, the Collaborator grants to PHS a nonexclusive,
         nontransferable, irrevocable, paid-up license to practice the invention
         or have the invention practiced throughout the world by or on behalf of
         the Government. In the exercise of such license, the Government shall
         not publicly disclose trade secrets or commercial or financial
         information that is privileged or confidential within the meaning of 5
         U.S.C. 552(b)(4) or which would be considered as such if it had been
         obtained from a non-Federal party.

7.4      LICENSE IN COLLABORATOR INVENTIONS. Pursuant to 15 U.S.C. 3710a(b)(2),
         for inventions made solely by

Model PHS CRADA
Form 053096 Page 5 of 11

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   7
         Collaborator employees under this CRADA, pursuant to Article 6.2, the
         Collaborator grants to PHS a nonexclusive, nontransferable,
         irrevocable, paid-up license to practice the invention or have the
         invention practiced throughout the world by or on behalf of the
         Government for research or other Government purposes.

7.5      THIRD PARTY LICENSE. Pursuant to 15 U.S.C. 3710a(1)(B), if PHS grants
         an exclusive license to a Subject Invention made wholly by PHS
         employees or jointly with a Collaborator under this CRADA, pursuant to
         Articles 6.3 and 6.4, the Government shall [*] to use the invention in
         Collaborator's licensed field of use on terms that are [*]; or if the
         Collaborator fails to [*], to [*]. The exercise of such rights by the
         Government shall only be in exceptional circumstances and only if the
         Government determines (i) the action is necessary to meet health or
         safety needs that are not reasonably satisfied by Collaborator, (ii)
         the action is necessary to meet requirements for public use specified
         by Federal regulations, and such requirements are not reasonably
         satisfied by the Collaborator; or (iii) the Collaborator has failed to
         comply with an agreement containing provisions described in 15 U.S.C.
         3710a(c)(4)(B). The determination made by the Government under this
         Article is subject to administrative appeal and judicial review under
         35 U.S.C. 203(2).

7.6      JOINT INVENTIONS NOT EXCLUSIVELY LICENSED. In the event that the
         Collaborator does not acquire an exclusive commercialization license to
         IP rights in all fields in joint Subject Inventions described in
         Article 6.4, then each Party shall have the right to use the joint
         Subject Invention and to license its use to others in all fields not
         exclusively licensed to Collaborator. The Parties may agree to a joint
         licensing approach for such IP rights.

ARTICLE 8. PROPRIETARY RIGHTS AND PUBLICATION

8.1      RIGHT OF ACCESS. PHS and the Collaborator agree to exchange all Subject
         Data produced in the course of research under this CRADA, whether
         developed solely by PHS or jointly with the Collaborator. Research
         Materials will be shared equally by the Parties to the CRADA unless
         other disposition is agreed to by the Parties. All Parties to this
         CRADA will be free to utilize Subject Data and Research Materials for
         their own purposes, consistent with their obligations under this CRADA.

8.2      OWNERSHIP OF SUBJECT DATA AND RESEARCH MATERIALS. Subject to the
         sharing requirements of Paragraph 8.1 and the regulatory filing
         requirements of Paragraph 8.3, the producing Party will retain
         ownership of and title to all Subject Inventions, all Subject Data and
         all Research Materials produced solely by their investigators. Jointly
         developed Subject Inventions, Subject Data and Research Materials will
         be jointly owned.

8.3      DISSEMINATION OF SUBJECT DATA AND RESEARCH MATERIALS. To the extent
         allowed under law, the Collaborator and PHS agree to use reasonable
         efforts to keep Subject Data and Research Materials confidential until
         published or until corresponding patent applications are filed. Any
         information that would identify human subjects of research or patients
         will always be maintained confidentially. Collaborator shall have the
         exclusive right to use any and all CRADA Subject Data in and for any
         regulatory filing by or on behalf of Collaborator, except that PHS
         shall have the exclusive right to use Subject Data for that purpose,
         and authorize others to do so, if the CRADA is terminated or if
         Collaborator abandons its commercialization efforts.

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

Model PHS CRADA
Form 053096 Page 6 of 11

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   8
         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., patient-
         identifying data, should be similarly limited and treated. 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.

8.5      PROTECTION OF PROPRIETARY/CONFIDENTIAL INFORMATION. Proprietary/
         Confidential Information shall not be disclosed, copied, reproduced or
         otherwise made available to any other person or entity without the
         consent of the owning Party except as required under court order or the
         Freedom of Information Act (5 U.S.C. Section 552). Each Party agrees to
         use its best efforts to maintain the confidentiality of
         Proprietary/Confidential Information. Each Party agrees that the other
         Party is not liable for the disclosure of Proprietary/Confidential
         Information which, after notice to and consultation with the concerned
         Party, the other Party in possession of the Proprietary/Confidential
         Information determines may not be lawfully withheld, provided the
         concerned Party has been given an opportunity to obtain a court order
         to enjoin disclosure.

8.6      DURATION OF CONFIDENTIALITY OBLIGATION. The obligation to maintain the
         confidentiality of Proprietary/Confidential Information shall expire at
         the earlier of the date when the information is no longer Proprietary
         Information as defined in Article 2.5 or three (3) years after the
         expiration or termination date of this CRADA. The Collaborator may
         request an extension to this term when necessary to protect
         Proprietary/Confidential Information relating to products not yet
         commercialized.

8.7      PUBLICATION. The Parties are encouraged to make publicly available the
         results of their research. Before either Party submits a paper or
         abstract for publication or otherwise intends to publicly disclose
         information about a Subject Invention, Subject Data or Research
         Materials, the other Party shall be provided thirty (30) days to review
         the proposed publication or disclosure to assure that
         Proprietary/Confidential Information is protected. The publication or
         other disclosure shall be delayed for up to thirty (30) additional days
         upon written request by any Party as necessary to preserve U.S. or
         foreign patent or other IP rights.

ARTICLE 9. REPRESENTATIONS AND WARRANTIES

9.1      REPRESENTATIONS AND WARRANTIES OF PHS. PHS hereby represents and
         warrants to the Collaborator that the official signing this CRADA has
         authority to do so.

9.2      REPRESENTATIONS AND WARRANTIES OF THE COLLABORATOR.

         (a) The Collaborator hereby represents and warrants to PHS that the
         Collaborator has the requisite power and authority to enter into this
         CRADA and to perform according to its terms, and that the
         Collaborator's official signing this CRADA has authority to do so. The
         Collaborator further represents that it is financially able to satisfy
         any funding commitments made in Appendix B.

         (b) The Collaborator certifies that the statements herein are true,
         complete, and accurate to the best of its knowledge. The Collaborator
         is aware that any false, fictitious, or fraudulent statements or claims
         may subject it to criminal, civil, or administrative penalties.

ARTICLE 10. TERMINATION

10.1     TERMINATION BY MUTUAL CONSENT. PHS and the Collaborator may terminate
         this CRADA, or portions thereof, at any time by mutual written consent.
         In such event the Parties shall specify the disposition of all

Model PHS CRADA
Form 053096 Page 7 of 11
<PAGE>   9

         property, inventions, patent or other IP applications and other results
         of work accomplished or in progress, arising from or performed under
         this CRADA, all in accordance with the rights granted to the Parties
         under the terms of this Agreement.

10.2     UNILATERAL TERMINATION. Either PHS or the Collaborator may unilaterally
         terminate this entire CRADA at any time by giving written notice at
         least thirty (30) days prior to the desired termination date, and any
         rights accrued in property, patents or other IP rights shall be
         disposed of as provided in paragraph 10.1.

10.3     STAFFING. If this CRADA is mutually or unilaterally terminated prior to
         its expiration, funds will nevertheless remain available to PHS for
         continuing any staffing commitment made by the Collaborator pursuant to
         Article 5.1 above and Appendix B, if applicable, for a period of
         [*] after such termination. If there are insufficient funds to
         cover this expense, the Collaborator agrees to pay the difference.

10.4     NEW COMMITMENTS. No Party shall make new commitments related to this
         CRADA after a mutual termination or notice of a unilateral termination
         and shall, to the extent feasible, cancel all outstanding commitments
         and contracts by the termination date.

10.5     TERMINATION COSTS. Concurrently with the exchange of final reports
         pursuant to Articles 4.2 and 5.2, PHS shall submit to the Collaborator
         for payment a statement of all costs incurred prior to the date of
         termination and for all reasonable termination costs including the cost
         of returning Collaborator property or removal of abandoned property,
         for which Collaborator shall be responsible.

ARTICLE 11. DISPUTES

11.1     SETTLEMENT. Any dispute arising under this CRADA which is not disposed
         of by agreement of the Principal Investigators shall be submitted
         jointly to the signatories of this CRADA. If the signatories are unable
         to jointly resolve the dispute within thirty (30) days after
         notification thereof, the Assistant Secretary for Health (or his/her
         designee or successor) shall propose a resolution. Nothing in this
         Article shall prevent any Party from pursuing any additional
         administrative remedies that may be available and, after exhaustion of
         such administrative remedies, pursuing all available judicial remedies.

11.2     CONTINUATION OF WORK. Pending the resolution of any dispute or claim
         pursuant to this Article, the Parties agree that performance of all
         obligations shall be pursued diligently in accordance with the
         direction of the PHS signatory.

ARTICLE 12. LIABILITY

12.1     PROPERTY. The U.S. Government shall not be responsible for damages to
         any Collaborator property provided to PHS, where Collaborator retains
         title to the property, or any property acquired by Collaborator for its
         own use pursuant to this CRADA.

12.2     NO WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES
         MAKE NO EXPRESS OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER,
         INCLUDING THE CONDITIONS OF THE RESEARCH OR ANY INVENTION OR PRODUCT,
         WHETHER TANGIBLE OR INTANGIBLE, MADE, OR DEVELOPED UNDER THIS CRADA, OR
         THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF
         THE RESEARCH OR ANY INVENTION OR PRODUCT.

12.3     INDEMNIFICATION. The Collaborator agrees to hold the U.S. Government
         harmless and to indemnify the Government for all liabilities, demands,
         damages, expenses and losses arising out of the use by the Collaborator
         for any purpose of the Subject Data, Research Materials and/or Subject
         Inventions produced in whole or part by PHS employees under this CRADA,
         unless due to the negligence or willful misconduct

Model PHS CRADA
Form 053096 Page 8 of 11

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.
<PAGE>   10

         of PHS, its employees, or agents. The Collaborator shall be liable for
         any claims or damages it incurs in connection with this CRADA. PHS has
         no authority to indemnify the Collaborator.

12.4     FORCE MAJEURE. Neither Party shall be liable for any unforeseeable
         event beyond its reasonable control not caused by the fault or
         negligence of such Party, which causes such Party to be unable to
         perform its obligations under this CRADA, and which it has been unable
         to overcome by the exercise of due diligence. In the event of the
         occurrence of such a force majeure event, the Party unable to perform
         shall promptly notify the other Party. It shall further use its best
         efforts to resume performance as quickly as possible and shall suspend
         performance only for such period of time as is necessary as a result of
         the force majeure event.

ARTICLE 13. MISCELLANEOUS

13.1     GOVERNING LAW. The construction, validity, performance and effect of
         this CRADA shall be governed by Federal law, as applied by the Federal
         Courts in the District of Columbia. Federal law and regulations will
         preempt any conflicting or inconsistent provisions in this CRADA.

13.2     ENTIRE AGREEMENT. This CRADA constitutes the entire agreement between
         the Parties concerning the subject matter of this CRADA and supersedes
         any prior understanding or written or oral agreement.

13.3     HEADINGS. Titles and headings of the articles and subarticles of this
         CRADA are for convenient reference only, do not form a part of this
         CRADA, and shall in no way affect its interpretation.

Model PHS CRADA
Form 053096 Page 9 of 11
<PAGE>   11

13.4     WAIVERS. None of the provisions of this CRADA shall be considered
         waived by any Party unless such waiver is given in writing to the other
         Party. The failure of a Party to insist upon strict performance of any
         of the terms and conditions hereof, or failure or delay to exercise any
         rights provided herein or by law, shall not be deemed a waiver of any
         rights of any Party.

13.5     SEVERABILITY. The illegality or invalidity of any provisions of this
         CRADA shall not impair, affect, or invalidate the other provisions of
         this CRADA.

13.6     AMENDMENTS. If either Party desires a modification to this CRADA, the
         Parties shall, upon reasonable notice of the proposed modification or
         extension by the Party desiring the change, confer in good faith to
         determine the desirability of such modification or extension. Such
         modification shall not be effective until a written amendment is signed
         by the signatories to this CRADA or by their representatives duly
         authorized to execute such amendment.

13.7     ASSIGNMENT. Neither this CRADA nor any rights or obligations of any
         Party hereunder shall be assigned or otherwise transferred by either
         Party without the prior written consent of the other Party.

13.8     NOTICES. All notices pertaining to or required by this CRADA shall be
         in writing and shall be signed by an authorized representative and
         shall be delivered by hand or sent by certified mail, return receipt
         requested, with postage prepaid, to the addresses indicated on the
         signature page for each Party. Notices regarding the exercise of
         license options shall be made pursuant to Article 7.2. Any Party may
         change such address by notice given to the other Party in the manner
         set forth above.

13.9     INDEPENDENT CONTRACTORS. The relationship of the Parties to this CRADA
         is that of independent contractors and not agents of each other or
         joint venturers or partners. Each Party shall maintain sole and
         exclusive control over its personnel and operations. Collaborator
         employees who will be working at PHS facilities may be asked to sign a
         Guest Researcher or Special Volunteer Agreement appropriately modified
         in view of the terms of this CRADA.

13.10    USE OF NAME OR ENDORSEMENTS. By entering into this CRADA, PHS does not
         directly or indirectly endorse any product or service provided, or to
         be provided, whether directly or indirectly related to either this
         CRADA or to any patent or other IP license or agreement which
         implements this CRADA by its successors, assignees, or licensees. The
         Collaborator shall not in any way state or imply that this CRADA is an
         endorsement of any such product or service by the U.S. Government or
         any of its organizational units or employees. Collaborator issued press
         releases that reference or rely upon the work of PHS under this CRADA
         shall be made available to PHS at least 7 days prior to publication for
         review and comment.

13.11    EXCEPTIONS TO THIS CRADA. Any exceptions or modifications to this CRADA
         that are agreed to by the Parties prior to their execution of this
         CRADA are set forth in Appendix C.

13.12    REASONABLE CONSENT. Whenever a Party's consent or permission is
         required under this CRADA, such consent or permission shall not be
         unreasonably withheld.

Model PHS CRADA
Form 053096 Page 10 of 11
<PAGE>   12

ARTICLE 14. DURATION OF AGREEMENT

14.1     DURATION. It is mutually recognized that the duration of this
         project cannot be rigidly defined in advance, and that the contemplated
         time periods for various phases of the RP are only good faith
         guidelines subject to adjustment by mutual agreement to fit
         circumstances as the RP proceeds. In no case will the term of this
         CRADA extend beyond the term indicated in the RP unless it is revised
         in accordance with Article 13.6.

14.2     SURVIVABILITY. The provisions of Articles 4.2, 5-8, 10.3-10.5, 11.1,
         12.2-12.4, 13.1, 13.10 and 14.2 shall survive the termination of this
         CRADA.

Model PHS CRADA
Form 053096 Page 11 of 11
<PAGE>   13

                              CRADA SIGNATURE PAGE

By executing this Agreement, each of the undersigned represents and confirms
that he or she is fully authorized to bind the identified entity to its terms.
Each of the undersigned expressly certifies or affirms that the contents of any
statement made or reflected in this document are truthful and accurate.

AGREED TO AND ACCEPTED BY:

FOR THE NATIONAL CANCER INSTITUTE:

/s/ ALAN S. RABSON                                                  9/11/98
------------------------------------------                      ----------------
ALAN S. RABSON, M.D.                                            DATE
DEPUTY DIRECTOR, NCI

Mailing Address for Notices:

National Cancer Institute
Technology Development and Commercialization Branch
Executive Plaza South, Room 450
6120 Executive Boulevard
Rockville, MD, 20852

FOR RHONE-POULENC RORER PHARMACEUTICALS, INC.    FOR INTROGEN THERAPEUTICS, INC.

/s/ ROSS J. OEHLER                               /s/ DAVID G. NANCE
---------------------------                      -----------------------------
ROSS J. OEHLER                                   DAVID G. NANCE
ASSISTANT SECRETARY                              PRESIDENT AND CEO

10/13/98                                         October 30, 1998
---------------------------                      -----------------------------
Date                                             Date

                                    Page S-1
<PAGE>   14

                                                                        CACR-352
                                   APPENDIX A

                                  RESEARCH PLAN

TITLE OF CRADA: [*]

NIH/ADAMHA PRINCIPAL INVESTIGATORS:         [*]
and his/her laboratory:                     [*]

                                            CTEP DCTD

COLLABORATOR PRINCIPAL INVESTIGATOR:        [*]
                                            [*]
                                            RHONE-POULENC RORER
                                              PHARMACEUTICALS, INC.

                                            [*]
                                            [*]
                                            INTROGEN THERAPEUTICS, INC.

TERM OF CRADA: [*]

CONFLICTS OF INTEREST INFORMATION: Describe any relevant past, present or
contemplated relationships between the NIH/ADAMHA Principal Investigator and
his/her Laboratory and the Collaborator in sufficient detail to permit reviewers
of this CRADA to determine whether or not any conflicts of interest exist:

SEE CONFLICT OF INTEREST FORM ATTACHED HERETO.

The Research Plan which follows this page should be concise but of sufficient
detail to permit reviewers of this CRADA to evaluate the scientific merit of the
proposed collaboration. The RP should explain the scientific importance of the
collaboration and the research goals of NIH/ADAMHA and the Collaborator. The
respective contributions in terms of expertise and/or research materials of
NIH/ADAMHA and Collaborator should be summarized. Initial and subsequent
projects contemplated under the RP, and the time periods estimated for their
completion, should be described, and pertinent methodological considerations
summarized. Pertinent literature references may be cited and additional relevant
information included. Include additional pages to identify the Principal
Investigators of all other Parties to this CRADA.

         [*] Certain information on this page has been omitted and filed
             separately with the Commission. Confidential treatment has been
             requested with respect to the omitted portions.

                                    Page A-i

<PAGE>   15
                                   APPENDIX A

                                 RESEARCH PLAN

            [*]

            [*] Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                             Al
<PAGE>   16
      [*]

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

                                A2
<PAGE>   17

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       A3
<PAGE>   18

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       A4
<PAGE>   19

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       A5
<PAGE>   20

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       A6
<PAGE>   21

                                                                        CACR-352

                                   APPENDIX B

               FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES

                [Insert the Financial and Staffing Contributions
                        as Appendix B behind this page.]

                                    Page B-i
<PAGE>   22
                                   APPENDIX B

               FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES

                             ALLOCATION OF RESOURCES

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       B1
<PAGE>   23

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       B2

<PAGE>   24

[*]

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

                                       B3
<PAGE>   25

                                                                      CACR-352

                                   APPENDIX C

                   EXCEPTIONS OR MODIFICATIONS TO THIS CRADA

                                    Page C-i
<PAGE>   26
                                   APPENDIX C

                   EXCEPTIONS OR MODIFICATIONS TO THIS CRADA

AMEND ARTICLE 1 "INTRODUCTION" TO READ AS FOLLOWS:

ARTICLE 1. INTRODUCTION

This Cooperative Research and Development Agreement (CRADA) among PHS,
RHONE-POULENC RORER PHARMACEUTICALS, INC., AND INTROGEN THERAPEUTICS, INC., will
be effective when signed by all Parties, retroactive to April 9, 1996 (Letter of
Intent). The research and development activities which will be undertaken by
each of the Parties in the course of this CRADA are detailed in the Research
Plan (RP) which is attached as Appendix A. The funding and staffing commitments
of the Parties are set forth in Appendix B. Any exceptions or changes to the
CRADA are set forth in Appendix C. The Intellectual Property and Licensing is
set forth in Appendix D. A sample "Annual Scientific, Commercial, and Financial
Report" is included as Appendix E. A model Amendment is included as Appendix F.
A model termination letter is included as Appendix G. A model expiration letter
is included in Appendix H. This CRADA is made under the authority of the Federal
Technology Transfer Act, 15 U.S.C. Section 3710a and is governed by its terms.

AMEND SECTION 2.1 TO READ AS FOLLOWS:

2.1  "AFFILIATE" means any corporation or other business entity controlled by,
     controlling, or under common control with RPRP and/or Introgen. For this
     purpose, "control" means direct or indirect beneficial ownership of at
     least fifty (50) percent of the voting stock or at least fifty (50) percent
     interest in the income of such corporation or other business.

AMEND SECTION 2.6 TO READ AS FOLLOWS:

2.6  "PRINCIPAL INVESTIGATOR(S)" OR "PIS" means the persons designated
     respectively by the Parties to this CRADA who will be responsible for the
     scientific and technical conduct of the Research Plan (as

                                      C 2
<PAGE>   27
     defined in Section 2.9)

AMEND SECTION 2.7.4 TO READ AS FOLLOWS:

2.7.4     information which relates to potential hazards or cautionary warnings
          associated with the production, handling or use of the Agent
          designated in the Research Plan of this CRADA (as defined in Section
          2.13 below).

ADD THE FOLLOWING NEW SECTIONS TO ARTICLE 2. "DEFINITIONS":

2.12 "ADVERSE DRUG EXPERIENCE" means an adverse clinical experience as defined
     under 21 C.F.R. 310.305 and 312.32 where applicable.

2.13 "AGENT" means Adenovirus p53 vector (Adp53).

2.14 "ANNUAL REPORT" means the brief report of the progress of an IND associated
     investigation which the IND sponsor is required to submit to the FDA within
     60 days of the anniversary date that the IND went into effect (pursuant to
     21 C.F.R. 312.33).

2.15 "CLINICAL DATA AND RESULTS" means all information, data and results
     developed or obtained in connection with clinical trials conducted under
     the Research Plan whether by intramural research scientists or extramural
     grantee or contract investigators.

2.16 "CLINICAL DATA AND RESULTS AND RAW DATA IN NIH'S POSSESSION AND CONTROL"
     means all information, data and results collected from NIH intramural
     preclinical or clinical studies performed pursuant to the Research Plan,
     all data obtained by NIH under contracts with extramural contract
     investigator(s) for completion of studies within the scope of the Research
     Plan, and all information and data in the NCI-sponsored IND for Agent.

2.17 "CONTRACT" means a funding agreement that is a research and development
     contract that provides that the contractor perform for the benefit of the
     Government, with an expectation of completion of the stated research goals
     and the delivery of a report, data, materials or other product. Generally,
     Contracts are administered under the Federal

                                      C 3
<PAGE>   28
     Acquisition Regulations (FAR) codified at Title 48 C.F.R., Chapter 1 or the
     Health Services Acquisition Regulations (HSAR) codified at Title 48 C.F.R.,
     Chapter 3.

2.18 "CTA" means Clinical Trial Agreement.

2.19 "CTEP" means the Cancer Therapy Evaluation Program, DCTD, NCI, the program
     within NCI which plans, assesses and coordinates all aspects of clinical
     trials including extramural clinical research programs, internal resources,
     treatment methods and effectiveness, and compilation and exchange of data.

2.20 "DCTD" means Division of Cancer Treatment and Diagnosis, NCI.

2.21 "ENTITY" means a party that is not a Party to this CRADA.

2.22 "FDA" means the US Food and Drug Administration.

2.23 "GRANT" means a funding agreement that is an award of financial assistance
     which may be provided for support of basic research in a specific field of
     interest to the funding Federal agency.

2.24 "IND" means an Investigational New Drug Application submitted to the FDA to
     receive approval to conduct experimental clinical trials.

2.25 "MULTI-PARTY DATA" means clinical data from clinical studies sponsored by
     NCI pursuant to CTAs or CRADAs, where such data are collected under
     protocols involving combinations of investigational agents from more that
     one CTA or CRADA collaborator.

2.26 "NCI" means the National Cancer Institute, NIH, PHS, DHHS.

2.27 "PROTOCOL REVIEW COMMITTEE" (OR "PRC") means the CTEP/DCTD committee that
     reviews and approves studies involving NCI investigational agents and/or
     activities supported by NCI.

2.28 "RAW DATA" means the primary quantitative and empirical data first
     collected by the intramural and extramural investigators from experiments
     and clinical trials conducted within the scope of the

                                      C 4

<PAGE>   29
     Research Plan of this CRADA.

2.29 "STEERING COMMITTEE" means the joint NCI, RPRP, and Introgen research and
     development team whose composition and responsibilities with regard to the
     clinical experiments performed under this CRADA are described in Article
     3.3 of this CRADA.

2.30 "SUMMARY DATA" means a summary of the Raw Data provided to the NCI by the
     extramural investigators that will be included by NCI in an Annual Report
     to an NCI-sponsored IND, and made available by NCI to RPRP and Introgen.

AMEND SECTION 3.1 TO READ AS FOLLOWS:

3.1   PRINCIPAL INVESTIGATORS. The PHS Principal Investigators (PIs) designated
      in the RP will be responsible for the scientific and technical conduct of
      this project on behalf of PHS. RPRP and Introgen have jointly designated
      [*] and [*] respectively, as the Collaborator PIs who will be responsible
      for the scientific and technical conduct of this project on behalf of RPRP
      and Introgen, coordinating RPRP and Introgen's activities under this
      CRADA. [*] will be the primary contact and correspondent under the CRADA
      with respect to Phase II and later clinical trials conducted under the
      CRADA. [*] will be the Primary contact and correspondent under the CRADA
      with respect to Phase I clinical trials conducted under the CRADA.

ADD A NEW SECTION 3.3 AS FOLLOWS:

3.3  STEERING COMMITTEE AND CRADA RESEARCH. The Parties agree to establish a
     Steering Committee comprising at least the Principal Investigators
     designated pursuant to Article 3.1 to conduct and monitor the research of
     the Agent in accordance with the Research Plan. Members of the Steering
     Committee shall continue to remain employed by their respective employers
     under their

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

                                      C 5
<PAGE>   30
     respective terms of employment.

     Agent's clinical development under the Research Plan shall be a
     collaborative undertaking by RPRP, Introgen, and NCI. Details of this
     development beyond those set forth in the Research Plan shall be formulated
     and approved in Steering Committee meeting(s) before implementation of
     large-scale or resource intensive studies. The clinical development plans
     formulated and approved by the Steering Committee shall be implemented
     either intramurally at the NCI or extramurally under NCI-sponsored funding
     agreements.

     Additional CRADA information, including Steering Committee meeting reports,
     Protocol Review Committee records, clinical trial protocols, Institutional
     Review Board approval information, IND and general regulatory information,
     and preclinical and clinical data in NCI's possession and control shall
     remain on file with NCI.

     RPRP and/or Introgen, have the option to sponsor their own clinical trials
     and hold their own IND(s) for studies performed which are independent of
     this CRADA from which all data is proprietary solely to the sponsoring
     Party or Parties.

ADD A NEW SECTION 3.4 AS FOLLOWS:

3.4  CLINICAL PROTOCOLS. Clinical protocol proposals for each study within the
     scope of the Research Plan will be solicited from selected intramural and
     extramural clinical investigators. Each clinical protocol should describe
     in detail the research to be conducted at each center and must be submitted
     to the PRC for approval prior to implementation. Each clinical protocol
     received by NCI will be forwarded to RPRP and Introgen for review and
     comment approximately two weeks before it is reviewed by the PRC. Comments
     from RPRP and/or Introgen received by CTEP before the PRC meeting will be
     discussed by the PRC, will be given due consideration, and will
     incorporated into the protocol, absent good cause. Comments from RPRP,
     Introgen or the CTEP staff that are agreed upon in the PRC meeting

                                      C 6
<PAGE>   31
     will be formatted as a consensus review, which is returned to the
     investigator for necessary and/or suggested changes before the protocol can
     be given final approval and submitted to the FDA. A copy of the final
     approved protocol will be forwarded to RPRP and Introgen at the same time
     as it is submitted to the FDA consistent with Section 3.5 below.

          3.4.1 CLINICAL BROCHURES. Introgen and RPRP shall provide all clinical
          brochures for use in studies conducted hereunder, and only such
          clinical brochures which are inclusive of NCI study information if
          pertinent and appropriate, on Adp53 shall be used.

ADD A NEW SECTION 3.5 AS FOLLOWS TO REFLECT THE IND SPONSORSHIP UNDER THIS
CRADA:

3.5  INVESTIGATIONAL NEW DRUG APPLICATION. The Parties expect that either NCI,
     RPRP and/or Introgen will submit an IND or INDs for the studies conducted
     under the Research Plan, which may cross-reference an IND or Drug Master
     File held by the other(s). All information in INDs will be fully shared
     among NCI, RPRP, and Introgen for the studies conducted under the Research
     Plan, except as follows: If NCI files an IND for AGENT that is the subject
     of this CRADA, RPRP and/or Introgen, may, at its/their option, supply
     information in support of the IND in the form of a Drug Master File
     directly to the FDA so long as RPRP and/or Introgen grant(s) NIH a right to
     cross-reference such information in its IND filing. In the event that RPRP
     and/or Introgen supplies CONFIDENTIAL information directly to NCI in
     support of an NCI IND, such information will be protected in accordance
     with the corresponding Confidentiality provisions of Article 8 of this
     Agreement. All protocols and clinical studies conducted under this CRADA
     will be as mutually agreed by RPRP, Introgen and NCI.

ADD A NEW SECTION 3.6 AS FOLLOWS:

3.6  DRUG INFORMATION AND SUPPLY. Introgen and/or RPRP agree to provide NCI
     [*] clinical-grade Agent in

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

                                      C 7
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     sufficient quantity to complete the preclinical studies and clinical trial
     protocol(s) sponsored by NCI that are within the scope of the Research
     Plan. Furthermore, Introgen agrees to provide [*] Agent or
     unformulated analytical grade Agent or metabolites, if available, to NCI to
     supply extramural investigators for the development of mutually agreed upon
     analytical assays or ancillary correlative studies conducted in conjunction
     with NCI-sponsored protocols. Introgen will provide Certificates of
     Analysis to NCI for each lot of finished product provided. PHS agrees to
     use any materials provided by Introgen and/or RPRP, including, but not
     limited to Agent, solely for the purposes of conducting approved studies
     under this CRADA. [*]

     The contact person for NCI will be Mr. Alfred Fallavollita, Chief,
     Pharmaceutical Management Branch (Telephone Number 301-496-5725) and the
     Introgen contact will be Dr. James Merritt, (Telephone Number
     713-797-9960).

ADD A NEW SECTION 3.7 AS FOLLOWS:

3.7  PROTECTION OF HUMAN SUBJECTS AND APPROPRIATE CARE OF LABORATORY ANIMALS.
     All human clinical trials performed under this CRADA shall conform to the
     appropriate Federal law, including, but not limited to all applicable FDA
     regulations and DHHS regulations relating to the protection of human
     subjects (see 45 C.F.R. Part 46). NCI, RPRP and Introgen also agree to
     comply with all applicable Federal statutes and Public Health Service
     policies relating to the use and care of laboratory animals (see 7 U.S.C.
     2131 et seq.) Additional information is available from the Office of
     Protection from Research Risk, Telephone: 301-496-7163.

ADD THE FOLLOWING TO THE END OF ARTICLE 4.1 "INTERIM REPORTS":

     Steering Committee reports or copies of Annual Reports updating the

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

                                       C 8
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     progress of the CRADA research shall satisfy the reporting requirements
     under this Article 4.1. In addition, copies of the Annual Reports and other
     pertinent IND data (including, but not limited to, clinical brochure data,
     and formulation and preclinical data, including toxicology findings)
     created hereunder, shall be exchanged by the Parties as they become
     available.

ADD A NEW SECTION 4.3 AS FOLLOWS:

4.3  ADVERSE DRUG EXPERIENCE REPORTING. DCTD shall report all serious or
     unexpected adverse events to FDA in accordance with the reporting
     obligations of 21 CFR 312.32 and will, concurrently, forward all such
     reports to RPRP and Introgen. All other adverse event reports received by
     DCTD shall be reported to the FDA consistent with 21 CFR 312.32 and 312.33.
     In addition, copies of the Annual Reports and other pertinent IND data
     (including, but not limited to, Clinical Brochure data, formulation and
     preclinical data, including toxicology findings) will be provided to RPRP
     and Introgen as they become available.

     In the event that RPRP and/or Introgen, inform(s) the FDA of any serious or
     unexpected adverse events, RPRP and/or Introgen must notify the NCI at the
     same time. NCI will then notify the investigator(s) conducting studies
     under NCI-sponsored protocols.

ADD A NEW SECTION 4.4 AS FOLLOWS:

4.4  ANNUAL REPORTS. NCI shall provide RPRP and Introgen with a copy of the
     Annual Report simultaneously with the submission of the Annual Report to
     the FDA.

AMEND ARTICLE 5 "FINANCIAL AND STAFFING OBLIGATIONS" TO READ AS FOLLOWS:

5.1  PHS, RPRP AND INTROGEN CONTRIBUTIONS. The contributions of the Parties,
     including payment schedules, if applicable, are set forth in Appendix B.
     PHS shall not be obligated to perform any of the research specified herein
     or to take any other

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<PAGE>   34
     action required by this CRADA if the funding is not provided as set forth
     in Appendix B. PHS shall return excess funds to RPRP when it sends its
     final fiscal report pursuant to Article 5.2, except for staffing support
     pursuant to Article 10.3. RPRP and Introgen acknowledge that the U.S.
     Government will have the authority to retain and expend any excess funds
     for up to [*] subsequent to the expiration or termination of the
     CRADA to cover any costs incurred during the term of the CRADA in
     undertaking the work set forth in the RP.

5.2  ACCOUNTING RECORDS. PHS shall maintain separate and distinct current
     accounts, records, and other evidence supporting all its obligations under
     this CRADA, and shall provide RPRP and Introgen a final fiscal report
     pursuant to Article 4.2.

5.3  CAPITAL EQUIPMENT. Equipment purchased by PHS with funds provided by RPRP
     and/or Introgen shall be the property of PHS. All capital equipment
     provided under this CRADA by a Party or Parties for the use of another
     Party or Parties remains the property of the providing Party or Parties
     unless other disposition is mutually agreed upon by in writing by the
     respective Parties. If title to this equipment remains with the providing
     Party or Parties, that/those Party/Parties shall be responsible for
     maintenance of the equipment and the costs of its transportation to and
     from the site where it will be used.

AMEND ARTICLE 6 "INTELLECTUAL PROPERTY RIGHTS AND PATENT APPLICATIONS" TO READ
AS FOLLOWS:

6.1  REPORTING. The Parties shall promptly report to each other in writing each
     Subject Invention resulting from the research conducted under this CRADA
     that is reported to them by their respective employees. Each Party shall
     report all Subject Inventions to the other Parties in sufficient detail to
     determine inventorship. Such reports shall be treated as Proprietary/
     Confidential Information in accordance with Article 8.4.

6.2  RPRP AND/OR INTROGEN EMPLOYEE INVENTIONS. RPRP and Introgen may elect to
     retain intellectual property rights to each

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

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         Subject Invention made solely or jointly by their respective employees.
         If RPRP and/or Introgen does not elect to retain its respective sole or
         joint IP rights, RPRP and/or Introgen shall offer to assign said IP
         rights to the Subject Invention to PHS pursuant to Article 6.5. If PHS
         declines such assignment, RPRP and/or Introgen may release their IP
         rights as they may individually or jointly determine.

6.3      PHS EMPLOYEE INVENTIONS. PHS on behalf of the U.S. Government may
         elect to retain IP rights to each Subject Invention made solely by
         PHS employees. If PHS does not elect to retain IP rights, PHS shall
         offer to assign these IP rights to such Subject Invention to RPRP and
         Introgen collectively pursuant to Article 6.5. If RPRP or Introgen
         decline such an offer, the other company may obtain these IP rights.
         If both RPRP and Introgen decline such assignment, PHS may release IP
         rights in such Subject Invention to its employee inventors pursuant
         to Article 6.6.

6.4      PHS JOINT INVENTIONS WITH RPRP AND/OR INTROGEN. Each Subject Invention
         made jointly by PHS and RPRP and/or Introgen employees shall be jointly
         owned by PHS and the Party or Parties making the invention. In
         accordance with Section 6.7, Introgen may elect to file the joint
         patent or other IP application(s) on behalf of both Introgen and RPRP
         thereon and shall notify PHS promptly upon making this election whether
         the joint Subject Invention is owned by PHS and Introgen and/or RPRP.
         If Introgen decides to file such applications, it shall do so in a
         timely manner and at its own expense. If Introgen does not elect to
         file such application(s), PHS on behalf of the U.S. Government shall
         have the right to file the joint application(s) in a timely manner and
         at its own expense. If any Party decides not to retain its IP rights to
         a jointly owned Subject Invention, it shall offer to assign such rights
         to the other inventing Party/Parties pursuant to Article 6.5. If the
         other Party declines such assignment, the offering Party may release
         its IP rights as provided in Articles 6.2, 6.3, and 6.6.

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6.5  FILING OF PATENT APPLICATIONS. With respect to Subject Inventions made by
     RPRP and/or Introgen as described in Article 6.2, or by PHS as described in
     Article 6.3, a Party exercising its right to elect to retain IP rights to a
     Subject Invention agrees to file patent or other IP applications in a
     timely manner and at its own expense and after consultation with the other
     Parties. The Parties shall notify the other Parties of their decision
     regarding filing in countries other than the United States in a timely
     manner. The Parties may elect not to file a patent or other IP application
     thereon in any particular country or countries provided it so advises the
     other Parties ninety (90) days prior to the expiration of any applicable
     filing deadline, priority period or statutory bar date, and hereby agrees
     to assign its/their IP right, title and interest in such country or
     countries to the Subject Invention to the other Parties and to cooperate in
     the preparation and filing of a patent or other IP applications. In any
     countries in which title to patent or other IP rights made under this CRADA
     is transferred to RPRP and/or Introgen, RPRP and/or Introgen agrees that
     PHS inventors will share in any royalty distribution that RPRP and/or
     Introgen pays to its own inventors.

6.6  RELEASE TO INVENTORS. In the event none of the Parties to this CRADA elects
     to file a patent or other IP application on a Subject Invention, the
     Parties (if a joint invention) may retain or release their IP rights in
     accordance with their respective policies and procedures.[*]

6.7  PATENT EXPENSES. The expenses attendant to the filing of patent or other IP
     applications generally shall be paid by the Party filing such application.
     Introgen expressly agrees to assume full responsibility, at its expense,
     for taking all action with respect to filing, prosecuting, and obtaining
     patents and other suitable forms of protection for Collaborator Subject
     Inventions made by Introgen and/or RPRP, and if Introgen so elects under
     Article 6.4 for PHS joint inventions made with RPRP and/or Introgen under
     the RP provided that Introgen's

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

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choice of patent counsel is mutually acceptable to RPRP. If an exclusive or a
co-exclusive license to any Subject Invention is granted to either or both RPRP
and Introgen, the respective Party or Parties shall be responsible for [*] past
and future out-of-pocket expenses in connection with the preparation, filing,
prosecution and maintenance of any applications claiming such licensed
inventions and any patents or other IP grants that may issue on such
applications. RPRP and/or Introgen may waive its license rights on any
application, patent or other IP grant at any time, and incur no subsequent
compensation obligation for that application, patent or IP grant.

6.8     PROSECUTION OF INTELLECTUAL PROPERTY APPLICATIONS.  Within one month of
receipt or filing, each Party shall provide the other Parties with copies of the
applications and all documents received from or filed with the relevant patent
or other IP office in connection with the prosecution of such applications. Each
Party shall also provide the other Parties with the power to inspect and make
copies of all documents retained in the patent or other IP application files by
the applicable patent or other IP office. Where co-exclusive licensing is
contemplated by RPRP and Introgen, the Parties agree to consult with each other
with respect to the prosecution of applications for PHS Subject Inventions
described in Article 6.3 and joint Subject Inventions described in Article 6.4.
Introgen expressly agrees to assume full responsibility at its expense for
taking all action with respect to filing, prosecuting, and obtaining patents and
other suitable forms of protection for Subject Inventions made by Introgen
and/or RPRP, and if Introgen so elects under Article 6.4 for PHS joint
inventions made with RPRP and/or Introgen under the RP provided that Introgen's
choice of patent counsel is mutually acceptable to RPRP. If either RPRP and/or
Introgen elect to file and prosecute IP applications on joint Subject Inventions
pursuant to Article 6.4, PHS will be granted an associate power of attorney (or
its equivalent) on such IP applications.

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

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<PAGE>   38
AMEND ARTICLE 7 "LICENSING" TO READ AS FOLLOWS:

7.1  OPTION FOR COMMERCIALIZATION LICENSE. With respect to Government IP rights
     to any Subject Invention not made solely by the employees of RPRP or
     Introgen, for which a patent or other IP application is filed, PHS grants
     to RPRP and Introgen, individually, an option to elect a co-exclusive
     commercialization license which is substantially in the form of the
     appropriate model PHS license agreement/s. In the event that either party
     declines the option for a co-exclusive license, the other Party may
     exercise the option to an exclusive license. Unless agreed otherwise,
     Introgen shall negotiate on behalf of Introgen and/or RPRP. This option
     does not apply to Subject Inventions conceived prior to the effective date
     of this CRADA that are reduced to practice under this CRADA, if prior to
     that reduction to practice, PHS has filed a patent application on the
     invention and has licensed it or offered to license it to an Entity. The
     terms of the license will fairly reflect the nature of the invention, the
     relative contributions of the Parties to the invention and the CRADA, the
     risks incurred by RPRP and Introgen individually, and the costs of
     subsequent research and development needed to bring the invention to the
     marketplace. The field of use of the license will be commensurate with the
     scope of the RP. PHS acknowledges that Agent has been actually reduced to
     practice with respect to the treatment of cancer, independent of the CRADA
     and prior to the performance of the Research Plan.

7.2  EXERCISE OF LICENSE OPTION. The option of Article 7.1 must be exercised by
     written notice mailed within [*] after either (i) RPRP and
     Introgen, respectively, receives written notice from PHS that the patent or
     other IP application has been filed; or (ii) the date Introgen files such
     IP application (Party responsible for patent prosecution); whichever comes
     first. Exercise of this option by either or both RPRP and Introgen
     initiates a negotiation period that expires [*] after the
     exercise of the option. If the last proposal by RPRP and/or Introgen has
     not been responded to in writing by PHS within this [*] period,
     the negotiation period shall be extended

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

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<PAGE>   39
         to expire [*] after PHS so responds, during which month RPRP and/or
         Introgen may accept in writing the final license proposal of PHS. [*]
         In the event that RPRP and/or Introgen elects the option for a
         co-exclusive license but no such license is executed during the
         negotiation period, PHS agrees not to make an offer for an exclusive
         license on more favorable terms to an Entity for a period of [*]
         without first offering RPRP and Introgen those more favorable terms.
         These times may be extended at the sole discretion of PHS upon good
         cause shown in writing by Collaborator.

7.3      LICENSE FOR PHS EMPLOYEE INVENTIONS AND JOINT INVENTIONS. Pursuant to
         15 U.S.C. Section 3710a(b)(1)(A), for Subject Inventions made under
         this CRADA by PHS employee(s) or jointly by such employee(s) and
         employees of RPRP and/or Introgen pursuant to Articles 6.3 and 6.4 and
         licensed pursuant to the option of Article 7.1, RPRP and/or Introgen,
         as applicable, grant(s) to PHS a nonexclusive, nontransferable,
         irrevocable, paid-up license to practice the invention or have the
         invention practiced throughout the world by or on behalf of the
         Government. In the exercise of such license, the Government shall not
         publicly disclose trade secrets or commercial or financial information
         that is privileged or confidential within the meaning of 5 U.S.C.
         552(b)(4) or which would be considered as such if it had been obtained
         from a non-Federal party.

7.4      LICENSE IN RPRP AND INTROGEN INVENTIONS. Pursuant to 15 U.S.C. Section
         3710a(b)(2), for inventions made solely by RPRP and/or Introgen
         employees under this CRADA, pursuant to Article 6.2, RPRP and Introgen
         grants to the Government a nonexclusive, nontransferable, irrevocable,
         paid-up license to practice the invention or have the invention
         practiced throughout the world by or on behalf of the Government for
         research or other Government purposes.

      [*] Certain information on this page has been omitted and filed
          separately with the Commission. Confidential treatment has been
          requested with respect to the omitted portions.

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7.5  LICENSE TO AN ENTITY. Pursuant to 15 U.S.C. Section 3710a(1)(B), if PHS
     grants an exclusive or co-exclusive license to a Subject Invention made
     wholly by PHS employees or jointly with RPRP and/or Introgen under this
     CRADA, pursuant to Articles 6.3 and 6.4, the Government shall [*]  to use
     the [*] on terms that are [*]; or if RPRP and/or Introgen fail to [*], to
     [*]. The exercise of such rights by the Government shall only be in
     exceptional circumstances and only if the Government determines (i) the
     action is necessary to meet health or safety needs that are not reasonably
     satisfied by RPRP and/or Introgen, (ii) the action is necessary to meet
     requirements for public use specified by Federal regulations, and such
     requirements are not reasonably satisfied by RPRP and/or Introgen or (iii)
     RPRP and/or Introgen has failed to comply with an agreement containing
     provisions described in 15 U.S.C. 3710a(c)(4)(B). The determination made by
     the Government under this Article is subject to administrative appeal and
     judicial review under 35 U.S.C. 203(2).

7.6  JOINT INVENTIONS NOT EXCLUSIVELY LICENSED. In the event that RPRP and/or
     Introgen do(es) not acquire a co-exclusive or exclusive commercialization
     license to IP rights in all fields in joint Subject Inventions described
     in Article 6.4, then each Party shall have the right to use the joint
     Subject Invention and to license its use to others in all fields not
     exclusively or co-exclusively licensed to RPRP and Introgen. The Parties
     may agree to a joint licensing approach for such IP rights.

AMEND SECTION 8.1 TO READ AS FOLLOWS:

8.1  RIGHT OF ACCESS. PHS, RPRP and Introgen agree to exchange all Subject Data
     produced in the course of research under this CRADA, whether developed
     solely or jointly by and Party/Parties. Research Materials will be shared
     equally by the Parties to the CRADA unless other disposition is agreed to
     by the

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

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         Parties. All Parties to this CRADA will be free to utilize Subject Data
         and Research Materials for their own purposes, consistent with their
         obligations under this CRADA.

AMEND SECTION 8.3 TO READ AS FOLLOWS:

8.3      DISSEMINATION OF SUBJECT DATA AND RESEARCH MATERIALS. To the extent
         allowed under law, RPRP, Introgen and PHS agree to use reasonable
         efforts to keep Subject Data and Research Materials confidential until
         published or until corresponding patent applications are filed. Any
         information that would identify human subjects of research or patients
         will always be maintained confidentially. To the extent permitted by
         law, RPRP and Introgen, respectively, shall have the co-exclusive right
         to use any and all CRADA Subject Data in and for any regulatory filing,
         or for any commercialization purpose, consistent with Articles 8.7 and
         13.10, except that PHS shall have the exclusive right to use Subject
         Data for said purpose/s, and authorize others to do so, if the CRADA is
         terminated or if RPRP and Introgen abandon their commercialization
         efforts consistent with the terms of Section 10.6.

AMEND SECTION 8.4 AS FOLLOWS:

8.4      PROPRIETARY/CONFIDENTIAL INFORMATION. Each Party agrees to limit its
         disclosure of Proprietary/Confidential Information received from
         another Party to this CRADA to other Entities 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 of another Party pursuant to this CRADA, 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
         RPRP or Introgen may be designated as Proprietary/Confidential
         Information when they are wholly separable from the Subject Data and
         Research Materials developed jointly with

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         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., patient-identifying data, should be similarly
         limited and treated. Jointly developed Subject Data and Research
         Material derived from the Research Plan may be disclosed by RPRP and/or
         Introgen 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.

                  In addition, a Party may disclose Proprietary/Confidential
                  Information of another Party with the written consent of such
                  other Party, which consent will not be unreasonably withheld.

AMEND SECTION 8.6 AS FOLLOWS:

8.6      DURATION OF CONFIDENTIALITY OBLIGATION. The obligation to maintain the
         confidentiality of Proprietary/Confidential Information shall expire
         at the earlier of the date when the information is no longer
         Proprietary/Confidential Information as defined in Article 2.7 or
         three (3) years after the expiration or termination date of this CRADA
         unless, after the said three (3) years, any Party informs the other
         Parties that the Proprietary/Confidential Information is still secret
         and confidential, in which case the obligation shall extend for a
         further period of two (2) additional years. RPRP and/or Introgen may
         request additional extensions to this term when necessary to protect
         Proprietary/Confidential Information relating to products not yet
         commercialized.

AMEND SECTION 8.7 AS FOLLOWS:

8.7      PUBLICATION. The Parties are encouraged to make publicly available the
         results of their research. Except as provided at the end of this
         paragraph with respect to abstracts, before NCI, RPRP, Introgen or any
         combination thereof, submits a paper for publication or otherwise
         intends to publicly disclose information about a Subject Invention,
         Subject Data, additional Clinical Data and Results and Raw Data in
         NIH's Possession and Control, or Research Materials, the other Parties
         shall be provided thirty (30) days to review the proposed publication
         or disclosure to assure that

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     Proprietary/Confidential Information is protected. The publication or other
     disclosure shall be delayed for up to thirty (30) additional days upon
     written request by any Party as necessary to preserve U.S. or foreign
     patent or other IP rights. Abstracts presented by NCI investigators will be
     sent to NCI's Regulatory Affairs Branch for forwarding to RPRP and Introgen
     after submission but prior to presentation or publication to permit
     preservation of U.S. and foreign patent rights.

ADD A NEW SECTION 8.8 AS FOLLOWS:

8.8  EXTRAMURAL RESEARCH AND DATA. In pursuing the development of Agent pursuant
     to this CRADA, NIH may utilize extramural investigators for part or all of
     the completion of this Research Plan through either Federal Grants or
     Federal Contracts. Participation by extramural contract or grantee
     investigators shall be determined after competitive solicitation and review
     of study protocols by NIH. However, said extramural contract or grantee
     investigators are not Parties to this CRADA, and this CRADA does not
     address rights to intellectual property created by such investigators.
     Nonetheless:

     a.  Subject to the other provisions of Article 8 of this CRADA, NIH shall
         maintain, to the extent permitted by law, all IND, Clinical Data and
         Results and Raw Data in NIH's Possession and Control as Proprietary and
         CONFIDENTIAL, and make them available co-exclusively to RPRP and
         Introgen for each Party's (including sublicensees and affiliates) own
         use and for use in obtaining FDA approval for the commercial marketing
         of Subject Inventions and Agent products. Accordingly, said data shall
         not be transferable to an Entity without the written permission of the
         NCI.

     b.  NIH shall not execute a Contract for preclinical studies or clinical
         trials for the development of Agent unless the extramural contract
         investigator agrees to confidentiality provisions at least as
         restrictive as provided in this CRADA and to the co-exclusive use of
         data, by RPRP and Introgen, in accordance with Article 8.8 (a), for
         each Party's own use and for use in obtaining FDA approval for

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          the commercial marketing of Agent. The NCI investigators agree to use
          Agent only for the conduct of the approved protocols.

     c.   NCI shall urge all extramural grantee investigators participating in
          the studies sponsored by NCI and using Agent to cooperate
          co-exclusively with RPRP and Introgen in providing Clinical Data and
          Results and Raw Data for use in obtaining pharmaceutic regulatory
          approval for the commercial marketing of Agent. However, NCI's urging
          will not constitute a term or condition for making a grant award to
          said extramural investigators.

     d.   In seeking direct access to Clinical Data and Results and Raw Data or
          any other information that is in the possession of extramural contract
          or grantee investigators working with Agent under the sponsorship of
          NCI, RPRP and/or Introgen shall first contact the Regulatory Affairs
          Branch, (RAB) NCI [telephone: 301-496-7912]. Subsequent to
          authorization by RAB, RPRP and/or Introgen may directly contact the
          extramural investigators. Costs associated with providing Clinical
          Data and Results or Raw Data to RPRP and/or Introgen in customized
          formats shall be borne by the requesting party or parties.

     e.   RPRP's and Introgen's co-exclusive access under subsection (a) above
          to Clinical Data and Results and Raw Data in NIH's Possession and
          Control is dependent, however, upon RPRP and/or Introgen's continued
          development and commercialization of the technology. In the event that
          RPRP and Introgen discontinue development or commercialization of the
          technology without the transfer of its development efforts to another
          party, NCI retains the right to make the Clinical Data and Results and
          Raw Data in NIH's Possession and Control available to another
          collaborator, consistent with the terms of Section 10.6.

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ADD A NEW ARTICLE 8.9 "MULTI-PARTY DATA RIGHTS" AS FOLLOWS:

8.9  MULTI-PARTY DATA RIGHTS. For clinical protocol(s) where Agent is used in
     combination with another proprietary investigational agent supplied to NCI
     pursuant to a CTA or CRADA between NCI and an Entity, the access and use of
     Multi-Party Data by RPRP and Introgen, and Entity, shall be co-exclusive as
     follows:

     a.  NCI will provide RPRP, Introgen and Entity with notice regarding the
         existence and nature of the agreements governing their collaborations
         with NIH, the design of the proposed combination protocol(s), and the
         existence of any obligations that might restrict NCI's participation in
         the proposed combination protocols.

     b.  RPRP and Introgen shall agree to permit use of the Multi-Party Data
         from these trials by Entity to the extent necessary to allow Entity to
         develop, obtain regulatory approval for, or commercialize its own
         investigational agent(s). However, this provision will not apply unless
         Entity also agrees to RPRP's and Introgen's reciprocal use of
         Multi-Party Data.

     c.  RPRP, Introgen and Entity must agree in writing prior to the
         commencement of the combination trials that each will use the
         Multi-Party Data solely for the development, regulatory approval, and
         commercialization of its own investigational agent(s).

AMEND ARTICLE 9 "REPRESENTATIONS AND WARRANTIES" TO READ AS FOLLOWS:

9.1  REPRESENTATIONS AND WARRANTIES OF PHS. PHS hereby represents and warrants
     to RPRP and Introgen that the official signing this CRADA has authority to
     do so.

9.2  REPRESENTATIONS AND WARRANTIES OF RPRP AND INTROGEN.

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     (a) RPRP and Introgen, each individually, hereby represents and warrants to
     PHS that it has the requisite power and authority to enter into this CRADA
     and to perform according to its terms, and that RPRP's Official and
     Introgen's Official signing this CRADA, each individually, has authority to
     do so. RPRP and Introgen, each individually, further represents that it is
     financially able to satisfy any funding commitments made in Appendix B.

     (b) RPRP and Introgen, each individually, certifies that the statements
     herein are true, complete, and accurate to the best of its knowledge. RPRP
     and Introgen, respectively, is aware that any false, fictitious, or
     fraudulent statements or claims may subject it to criminal, civil, or
     administrative penalties.

AMEND SECTION 10.1 TO READ AS FOLLOWS:

10.1 TERMINATION BY MUTUAL CONSENT. PHS, RPRP and/or Introgen, may terminate
     this CRADA, or portions thereof, at any time by mutual written consent. In
     such event the Parties shall specify the disposition of all property,
     inventions, patent or other IP applications and other results of work
     accomplished or in progress, arising from or performed under this CRADA,
     all in accordance with the rights granted to the Parties under the terms of
     this Agreement.

AMEND SECTION 10.2 TO READ AS FOLLOWS:

10.2 UNILATERAL TERMINATION. Either PHS or RPRP or Introgen may unilaterally
     terminate this entire CRADA at any time by giving written notice at least
     thirty (30) days prior to the desired termination date, and any rights
     accrued in property, patents or other IP rights shall be disposed of as
     provided in paragraph 10.1. However, in the event of unilateral termination
     or early expiration, RPRP's and Introgen's respective obligations under
     Article 3.6 will survive termination to the extent necessary to complete
     approved clinical studies under mutually agreed upon protocols.

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<PAGE>   47

AMEND SECTION 10.3 TO READ AS FOLLOWS:

10.3 STAFFING. If this CRADA is mutually or unilaterally terminated prior to its
     expiration, funds will nevertheless remain available to PHS for continuing
     any staffing commitment made by RPRP and/or Introgen pursuant to Article
     5.1 above and Appendix B, if applicable, for a period of [*] after such
     termination. If there are insufficient funds to cover this expense, RPRP
     and/or Introgen agree/s to pay the difference.

AMEND SECTION 10.5 TO READ AS FOLLOWS:

10.5 TERMINATION COSTS. Concurrently with the exchange of final reports pursuant
     to Articles 4.2 and 5.2, PHS shall submit to RPRP and/or Introgen, as
     applicable, for payment a statement of all costs incurred prior to the date
     of termination and for all reasonable termination costs including the cost
     of returning RPRP and/or Introgen's property or removal of abandoned
     property, for which RPRP and/or Introgen shall be responsible.

ADD A NEW SECTION 10.6 AS FOLLOWS:

10.6 RESEARCH LICENSE AND ALTERNATIVE SOURCES OF SUPPLY IN THE EVENT RPRP AND
     INTROGEN TERMINATE DEVELOPMENT OF AGENT.

     If both RPRP and Introgen terminate development of AGENT without the
     transfer of development efforts to another Entity, and NCI elects to
     continue its development of the Agents, then:

     a. RPRP and Introgen hereby grant/s to NCI a nonexclusive, nontransferable,
     irrevocable, paid-up license to practice or have practiced solely for use
     in preclinical studies and clinical trials described in the Research Plan
     any patentable invention which RPRP and/or Introgen owns on Agent, its
     manufacture, or on the process of the use of the Agent, throughout the
     world, and solely for [*];

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

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and

b. For use solely in preclinical studies and approved clinical trials, RPRP
and/or Introgen will supply to NCI, [*], Agent from RPRP's and/or Introgen's
inventory, or arrange for an independent contractor to manufacture and supply
NCI with Agent, [*].

RPRP's and/or Introgen's obligation shall last until either a date on which an
alternate source of equivalent materials, acceptable to NCI, can be obtained by
NCI, or [*] after the date of notification from RPRP and/or Introgen to NCI that
RPRP and Introgen terminate their development of Agent whichever comes first.

AMEND SECTION 12.1 TO READ AS FOLLOWS:

12.1 PROPERTY. The U.S. Government shall not be responsible for damages to any
     RPRP and/or Introgen property provided to PHS, where RPRP and/or Introgen
     retains title to the property, or any property acquired by RPRP and/or
     Introgen for its own use pursuant to this CRADA.

AMEND SECTION 12.3 TO READ AS FOLLOWS:

12.3 INDEMNIFICATION. No indemnification for any loss, claim, damage or
     liability is intended or provided by any party under this agreement. Each
     party shall be liable for any loss, claim, damage or liability that said
     party incurs as a result of its activities under this agreement, except
     that the NIH, as an agency of the United States, assumes liability only to
     the extent provided under the Federal Tort claims Act, 28 U.S.C. 2671 et
     seq.

AMEND SECTION 12.4 TO READ AS FOLLOWS:

12.4 FORCE MAJEURE. No Party shall be liable for any unforeseeable event beyond
     its reasonable control not caused by the fault or negligence of such Party,
     which causes such Party to be

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                      C 24
<PAGE>   49
     unable to perform its obligations under this CRADA, and which it has been
     unable to overcome by the exercise of due diligence. In the event of the
     occurrence of such a force majeure event, the Party unable to perform shall
     promptly notify the other Parties. The Party shall further use reasonable
     efforts to resume performance as quickly as possible and shall suspend
     performance only for such period of time as is necessary as a result of the
     force majeure event.

ADD SECTION 12.5 AS FOLLOWS:

12.5 LIABILITIES OF RPRP AND INTROGEN. It is understood and agreed that all
     liabilities and obligations of RPRP and Introgen hereunder are the separate
     obligations of such Parties and not joint several liabilities.

ADD SECTION 12.6 AS FOLLOWS:

12.6 NO EFFECT ON EXISTING AGREEMENTS BETWEEN RPRP AND INTROGEN.

     The provisions of this Agreement are not intended to modify or amend the
     provisions of any existing agreement between RPRP and Introgen.

AMEND SECTION 13.4 TO READ AS FOLLOWS:

13.4 WAIVERS. None of the provisions of this CRADA shall be considered waived by
     any Party unless such waiver is given in writing to the other Parties. The
     failure of a Party to insist upon strict performance of any of the terms
     and conditions hereof, or failure or delay to exercise any rights provided
     herein or by law, shall not be deemed a waiver of any rights of any Party.

AMEND SECTION 13.6 TO READ AS FOLLOWS:

13.6 AMENDMENTS. If any Party desires a modification to this CRADA, the Parties
     shall, upon reasonable notice of the proposed modification or extension by
     the Party desiring the change, confer in good faith to determine the
     desirability of such modification or extension. Such modification shall not
     be effective until a written

                                      C 25
<PAGE>   50

      amendment is signed by the signatories to this CRADA or by their
      representatives duly authorized to execute such amendment.

AMEND SECTION 13.7 TO READ AS FOLLOWS:

13.7  ASSIGNMENT. Neither this CRADA nor any rights or obligations of any Party
      hereunder shall be assigned or otherwise transferred by any Party without
      the prior written consent of the other Parties. Such consent will not
      unreasonably be withheld by any Party. Not withstanding the foregoing,
      Introgen and RPRP each shall have the right to assign this Agreement to
      their subsidiaries, affiliates or successors.

AMEND SECTION 13.9 TO READ AS FOLLOWS:

13.9  INDEPENDENT CONTRACTORS. The relationship of the Parties to this CRADA is
      that of independent contractors and to agents of each other or joint
      venturers or partners. Except as set forth herein, no Party shall have the
      authority to bind or act on behalf of any other Party. Each Party shall
      maintain sole and exclusive control over its personnel and operations.
      RPRP and Introgen employees who will be working at PHS facilities may be
      asked to sign a Guest Researcher or Special Volunteer Agreement
      appropriately modified in view of the terms of this CRADA.

AMEND SECTION 13.10 TO READ AS FOLLOWS:

13.10 USE OF NAME OF ENDORSEMENTS. By entering into this CRADA, PHS does not
      directly or indirectly endorse any product or service provided, or to be
      provided, whether directly or indirectly related to either this CRADA or
      to any patent or other IP license or agreement which implements this CRADA
      by its successors, assignees, or licensees. RPRP and Introgen shall not in
      any way state or imply that this CRADA is an endorsement of any such
      product or service by the U.S. Government or any of its organizational
      units or employees. RPRP and/or Introgen issued press releases that
      reference or rely upon the work of PHS under this CRADA shall be made
      available to PHS at least 7 days prior to publication for review and
      comment.

                                      C 26
<PAGE>   51
ADD A NEW SECTION 13.13 "FDA MEETINGS" AS FOLLOWS:

13.13 FDA MEETINGS. All meetings with FDA concerning clinical studies for the
      development of Agent within the scope of the Research Plan will be
      discussed by RPRP, Introgen and NCI in advance and will be held on
      mutually agreed upon dates. RPRP and Introgen each reserve the right to
      set, jointly  with NCI, the agenda for and attend any such meeting.

AMEND SECTION 14.2 "SURVIVABILITY" BY INCLUDING ARTICLES 4.3 (ADVERSE DRUG
EXPERIENCE REPORTING) AND 10.6 (RESEARCH LICENSE AND ALTERNATIVE SOURCES OF
SUPPLY IN THE EVENT THAT COLLABORATOR TERMINATES DEVELOPMENT OF AGENT) AND THE
LAST SENTENCE OF ARTICLE 10.2 (REGARDING DRUG SUPPLY IN THE EVENT OF EITHER
RPRP'S OR INTROGEN'S UNILATERAL TERMINATION) AS PROVISIONS THAT WILL
SURVIVE TERMINATION OF THIS CRADA.

                                      C 27
<PAGE>   52
                                                                      CACR-352

                                   APPENDIX D

                      INTELLECTUAL PROPERTY AND LICENSING

                                    PAGE D-i
<PAGE>   53
                                                                        CACR-352
                                   APPENDIX D
                      INTELLECTUAL PROPERTY AND LICENSING
--------------------------------------------------------------------------------

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                      D-1
<PAGE>   54

                                      [*]

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                      D-2
<PAGE>   55

                                                                      CACR-352

                                   APPENDIX E

              ANNUAL SCIENTIFIC, COMMERCIAL, AND FINANCIAL REPORTS

                                    Page E-i
<PAGE>   56
NCI Office of Technology Development and Commercialization Branch, 1992 CACR-352

                         ANNUAL SCIENTIFIC, COMMERCIAL
                              AND FINANCIAL REPORT

As required under Article 4, "Reports," the NIH/ADAMHA Principal Investigator
and Collaborator Principal Investigator will complete this report by "setting
forth technical progress made, identifying such problems as may have been
encountered and establishing goals and objectives requiring further effort." If
necessary, please use additional space and send this report to the NCI Office
of Technology Development and Commercialization Branch, Executive Plaza South,
Room 450, 6120 Executive Boulevard, Rockville, Maryland, 20852.

Please describe any scientific or technical progress:

Please describe any commercial development including staffing and financial
resources involved:

Please provide an accounting and balance of staffing and financial resources
provided to the NIH/ADAMHA principal investigator (i.e.: personnel, equipment
and supplies):

--------------------------------------------------------------------------------
I certify that, to the best of my knowledge, all of the above information is
true and accurate.

   NIH/ADAMHA Principal Investigator's Signature

 ------------------------------------------------      -------------------------
                         [*]                            Date

 ------------------------------------------------      -------------------------
                         [*]                            Date

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.
<PAGE>   57

                                                                      CACR-352

                                   APPENDIX F
                                   AMENDMENTS

                   A model Amendment follows this cover page.

                                    Page F-i
<PAGE>   58
                                   AMENDMENT

CURRENT CRADA TERMS
--------------------------------------------------------------------------------

                              CURRENT CRADA TERMS

<TABLE>
<S>                                   <C>                  <C>
     CRADA #: 00352            TERM EXTENSION(s)(mo):       NIH PI: [*]
     EFFECTIVE DATE: 4/9/96           [ ]                   INSTITUTE: NCI
     EXECUTED DATE:                   [ ]                   DIVISION: DCTD
     ORIG.TERM (MO):                  [ ]                   LABORATORY: CTEP
     TOTAL TERM (MO):                 [ ]                   COLLABORATING PI: [*]
     EXPIRATION:                      [ ]                   COLLABORATOR: RPRP & INTROGEN
</TABLE>

Title: CLINICAL DEVELOPMENT OF Adp53

--------------------------------------------------------------------------------

NEW CRADA TERMS

The purpose of this amendment is to change certain terms of the above
referenced Cooperative Research and Development Agreement. These changes are
reflected below and except for these changes and those of any previous
amendments, all other provisions including the research plan of the original
CRADA remain in full force and effect. Two originals of this amendment are
provided for execution--one is to remain with NCI and the other with the
collaborator.

================================================================================
ACCEPTED AND AGREED TO:
NCI                                                      RPRP & INTROGEN

-----------------------                                  -----------------------
ALAN S. RABSON, M.D.
Deputy Director, NCI

-----------------------                                  -----------------------
Date                                                     Date

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.
<PAGE>   59
                                   APPENDIX G

                                  TERMINATION

              A model termination letter follows this cover page.

                                    Page G-i
<PAGE>   60
              [DEPARTMENT OF HEALTH AND HUMAN SERVICES LETTERHEAD]

Dear Collaborator:

As stipulated in Article 10, "Termination," the NIH/ADAMHA and/or the
Collaborator may terminate the CRADA referenced below by the either mutual
consent (Article 10.1) or unilaterally (Article 10.2). If terminated by mutual
consent, both parties will sign below and shall specify the disposition of all
property, inventions, patent or other intellectual property rights. Two
originals of this termination letter are provided for execution -- one is to
remain with the NCI and the other with the collaborator. If unilateral
termination occurs, this CRADA will cease to exist in thirty (30) days to the
date of this letter and, again, any rights accrued in property, patents or any
other intellectual rights will be specified and disposited.

If this CRADA is either mutually or unilaterally terminated prior to its
expiration, any remaining funds will nevertheless remain available to
NIH/ADAMHA for any continuing staffing commitments made by the Collaborator
pursuant to Articles 5.2 & 10.3 and Appendix B, if applicable, for a period of
six (6) months after such termination. If there are insufficient funds to cover
this expense, the Collaborator agrees to pay the difference (Article 10.3). In
addition, all reasonable termination costs will also be incurred by the
Collaborator. Finally, pursuant to Articles 4.2 and 5.2, a final report is
enclosed and provisions of article 4.2, 5.1, 5.2, 5.3, Articles 6-8, 10.3,
10.5, 11.1, 12.3 and 13.10 shall survive the termination of this CRADA.

                            CRADA MANAGEMENT MODULE
<TABLE>
<S>                                  <C>
          CACR    00352                 NIH/ADAMHA Principal Investigator   [*]
                                                                Institute   NCI
Effective Date                                                   Division   DCTD
                                                               Laboratory   CTEP
  Term (years)    [*]                Collaborating Principal Investigator   [*]
                                                             Collaborator   RPRP & INTROGEN
    Expiration

Title     CLINICAL DEVELOPMENT OF Adp53
</TABLE>

Accepted and Agreed To:

NATIONAL CANCER INSTITUTE                   RPRP & INTROGEN

----------------------------------          ------------------------------------
 Alan S. Rabson, M.D.
 Deputy Director, NCI

-----------------------                     -----------------------
Date                                        Date

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.
<PAGE>   61
                                   APPENDIX H

                                   EXPIRATION

               A model expiration letter follows this cover page.

                                    Page H-i
<PAGE>   62
                                   APPENDIX A

               [DEPARTMENT OF HEALTH & HUMAN SERVICES LETTERHEAD]

                                                            Coordinator
                                                            Document Type:
                                                                          -----
                                                            File Numbers: 00352
                                                                          -----

March 26, 1996

Mr. Martin Savitsky
General Counsel
RPR Gencell
500 Arcola Road
P.O. Box 1200
Collegeville, PA 19426

Re:            Proposed Cooperative Research and Development Agreement (CRADA)
               NCI Principal Investigator:       [*]
               Collaborator Investigator:        [*]
               Title:      Clinical Development of Adenovirus - P53
               RPR FILE NO. A2172, NCI CRADA # 352

Dear Mr. Savitsky,

It is my understanding that a cooperative research and development project
between the parties referenced below is being considered. Accordingly, until a
formal Collaborative Research and Development Agreement (CRADA) is reviewed by
the CRADA Subcommittee and approved by the Director, National Cancer Institute
(NCI), this Letter is offered to permit joint research to commence.

o         The Parties agree that all such trials which may begin prior to the
          execution of the formal CRADA Agreement shall be preceded by the
          appropriate US Food and Drug Association IND approval (or
          international equivalents thereof).

o         The Parties acknowledge that cooperative research pursuant to the
          Research Plan, attached as Appendix A, will be conducted informally by
          the NCI Principal Investigator and Collaborator pending formal
          approval of this CRADA. It is further acknowledged that patentable
          inventions may be made by NCI employees and employees of the
          Collaborator. Pursuant to its authority under Federal Technology
          Transfer Act of 1986, NCI agrees that should this CRADA be approved,
          it will have retroactive effect to the date that the last party has
          executed the Letter for any inventions that may be made under this
          Research Plan.

o         NCI further agrees that this CRADA will have retroactive effect to the
          date that the last party has executed this Letter for confidentiality
          obligations specified in the NIH Model CRADA.

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

                                       1
<PAGE>   63
o           The NIH Model CRADA provisions for the protection of proprietary
            information are incorporated by reference and in the event that any
            conflict arises between the provisions set forth in the NIH Model
            CRADA and the negotiated CRADA, the terms of the negotiated CRADA
            will control. These provisions include, but are not limited to,
            Article 2.5 and Articles 8.1 to 8.7. The NIH Model CRADA is attached
            as Appendix B.

This letter is not a commitment on the part of either party to enter into a
CRADA. Further, this Letter is effective for a term of (1) year. The one year
term may be extended, provided the CRADA is under active negotiation and the
collaborative research is continuing.

Assuming the necessary approvals are forthcoming, we look forward to a
successful collaboration.

Sincerely,

/s/ THOMAS D. MAYS

Thomas D. Mays, Ph.D., J.D.
Director, NCI Office of Technology Development

================================================================================

ACCEPTED AND AGREED TO:

NATIONAL CANCER INSTITUTE               RHONE POULENC RORER PHARMACEUTICALS INC.

/s/ ALAN RABSON, M.D.                   /s/ KENNETH R. PINA, ESQ.
-----------------------------           -----------------------------------
ALAN RABSON, M.D.                       KENNETH R. PINA, ESQ.
Deputy Director, NCI                    Vice President, General Counsel &
                                        Secretary

March 29, 1996                          April 8, 1996
-----------------                       -----------------
Date                                    Date

INTROGEN THERAPEUTICS, INC.

/s/ DAVID NANCE
-----------------------------
DAVID NANCE
President

April 9, 1996
-----------------
Date

Attachments:
     Appendix A: Proposed Research Plan
     Appendix B: NCI Model CRADA

                                       2
<PAGE>   64
                                   Appendix B

               [DEPARTMENT OF HEALTH & HUMAN SERVICES LETTERHEAD]

March 28, 1997

Mr. Robert Werner
General Counsel
RPR Gencell
500 Arcola Road
P.O. Box 1200
Collegeville, PA 19426

Re:    Proposed Cooperative Research and Development Agreement (CRADA)
       CRADA #: 352
       NCI Principal Investigator: [*]
       Collaborator Investigator:  [*]
       Title: Clinical Development of Adenovirus - p53

Dear Mr. Werner:

It is my understanding that a cooperative research and development project
between the parties referenced below is being considered. Accordingly, until a
formal Cooperative Research and Development Agreement (CRADA) is reviewed by
the CRADA Subcommittee and approved by the Director, National Cancer Institute
(NCI), this Letter is offered to extend the original Letter of Intent, executed
April 8, 1996, in order to permit the joint research to continue. A copy of the
Original Letter of Intent is attached as Appendix A.

o      The Parties agree that all such trials which may begin prior to the
       execution of the formal CRADA Agreement shall be preceded by the
       appropriate U.S. Food and Drug Administration IND approval (or
       international equivalents thereof).

o      The Parties acknowledge that cooperative research pursuant to the
       Research Plan, attached as Appendix B, will be conducted informally by
       the NCI Principal Investigator and Collaborator pending formal approval
       of this CRADA. It is further acknowledged that patentable inventions may
       be made by NCI employees and employees of the Collaborator. Pursuant to
       its authority under Federal Technology Transfer Act of 1986, NCI agrees
       that should this CRADA be approved, it will have retroactive effect to
       the date that the last party has executed the original Letter of Intent
       (April 8, 1996) for any inventions that may be made under this Research
       Plan.

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.
<PAGE>   65
o           NCI further agrees that this CRADA will have retroactive effect to
            the date that the last party has executed this Letter for
            confidentiality obligations specified in the NIH Model CRADA,
            revised 5/30/96 (this model supersedes the CRADA model revised
            12/15/95 attached as Appendix B to the original Letter of Intent
            executed April 8, 1996).

o           The NIH Model CRADA (revised 5/30/96) provisions for the protection
            of proprietary information are incorporated by reference and in the
            event that any conflict arises between the provisions set forth in
            this NIH Model CRADA and the negotiated CRADA, the terms of the
            negotiated CRADA will control. These provisions include but are not
            limited to, Article 2.5 and Articles 8.1 to 8.7. The NIH Model CRADA
            is attached as Appendix C.

This letter is not a commitment on the part of either party to enter into a
CRADA. Further, this Letter is effective for a term not to exceed six (6)
months.

Assuming the necessary approvals are forthcoming, we look forward to a
successful collaboration.

Sincerely,

/s/ THOMAS D. MAYS, PH.D., J.D.
-------------------------------
Thomas D. Mays, Ph.D., J.D.
Director, NCI Office of Technology Development

================================================================================

ACCEPTED AND AGREED TO:

NATIONAL CANCER INSTITUTE               RHONE POULENC RORER PHARMACEUTICALS INC.

/s/ ALAN S. RABSON, M.D.                /s/ KENNETH R. PINA, ESQ.
-----------------------------           -----------------------------------
Alan S. Rabson, M.D.                    Kenneth R. Pina, Esq.
Deputy Director NCI                     Vice President, General Counsel &
                                        Secretary

April 4, 1997                           April 4, 1997
-----------------                       -----------------
Date                                    Date

INTROGEN THERAPEUTICS, INC.

/s/ DAVID NANCE
-----------------------------
David Nance
President

April 16, 1997
-----------------
Date

Attachments:
     Appendix A: Original Letter of Intent
     Appendix B: Proposed Research Plan
     Appendix C: NCI Model CRADA

                                       2
<PAGE>   66
[DEPARTMENT OF HEALTH AND HUMAN SERVICES LOGO]   PUBLIC HEALTH SERVICE
-------------------------------------------------------------------------------
                                                 National Institutes of Health
                                                 National Cancer Institute
                                                 Technology Development and
                                                   Commercialization Branch
                                                 Executive Plaza South, Room 450
                                                 6120 Executive Blvd.
                                                 Rockville, MD 20852
                                                 (301) 496-0477
                                                 (301) 402-2117 Fax

Dear Collaborator:

The Cooperative Research and Development Agreement (CRADA) referenced below is
to or has recently expired. It is agreed that both parties do not want the term
of this CRADA to extend beyond the term indicated. Pursuant to Articles 4.2 and
5.2, a final report is enclosed and provisions of article 4.2, 5.1, 5.2, 5.3,
Articles 6-8, 10.3, 10.5, 11.1, 12.3, and 13.10 shall survive the termination of
this CRADA.

Please sign this letter acknowledging that the CRADA has expired and return a
copy so that this file can be closed out. We hope that this collaboration has
been a positive experience and look forward to future cooperative projects.

Please contact me should you have any questions.

Sincerely,

Suzanne M. Frisbie, Ph.D.

                            CRADA MANAGEMENT MODULE
<TABLE>
<S>                                  <C>
          CACR    00352                 NIH/ADAMHA Principal Investigator   [*]
                                                                Institute   NCI
Effective Date                                                   Division   DCTD
                                                               Laboratory   CTEP
  Term (years)    [*]                Collaborating Principal Investigator   [*]
                                                             Collaborator   RPRP & INTROGEN
    Expiration

Title     CLINICAL DEVELOPMENT OF Adp53
</TABLE>

I hereby acknowledge that this CRADA has expired.

NATIONAL CANCER INSTITUTE                   RPRP & INTROGEN

----------------------------------          ------------------------------------
 Sherry S. Ansher & James Zwiebel            Martine George   &   James Merritt

-----------------------                     -----------------------
Date                                        Date

         [*]    Certain information on this page has been omitted and filed
                separately with the Commission. Confidential treatment has been
                requested with respect to the omitted portions.

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