EXHIBIT 10.34
Confidential treatment requested.
Confidential portions indicated by "[*****]"
have been omitted and filed separately
with the Securities and Exchange Commission.
RESEARCH SERVICES AGREEMENT
BETWEEN
VION PHARMACEUTICALS, INC.
AND
XXX XXXXX AND COMPANY
VION PHARMACEUTICALS, INC.
XXXX XXXXXXX XXXX
XXX XXXXX, XXXXXXXXXXX 00000
("Company")
and
XXX LILLY AND COMPANY
LILLY XXXXXXXXX XXXXXX
XXXXXXXXXXXX, XXXXXXX 00000
("Lilly")
establish this agreement ("Agreement") to govern the conduct of the services
effective as of the date of last signature on this Agreement, in connection with
the translational research collaborations in pancreas cancer and non-small cell
lung cancer ("Research Projects"). The translational research protocol governing
the identification of molecular markers in tumor tissue taken from patients
participating in a Phase II Study of Triapine in combination with Gemzar in
Patients with Pancreatic Cancer ("Pancreas Trial") is attached hereto as Exhibit
A. The translational research protocol governing the identification of molecular
markers in tumor tissue taken from patients participating in a Phase II Study of
Triapine in combination with Gemzar in Patients with Non Small Cell Lung Cancer
("Lung Trial") is attached hereto as Exhibit B. The Pancreas Trial and the Lung
Trial may be referred to jointly as the "Clinical Trials". This Agreement is not
an exclusive contract. This Agreement shall continue to be effective until all
obligations to be performed under this Agreement are complete unless earlier
terminated consistent with Article XII of this Agreement.
Article I
Services
Section 1.01. Company will provide the following services ("Services"):
(a) Company will ensure that a number of investigators participating in
the Clinical Trials also participate in the Research Projects.
(b) Company will ensure that investigators participating in the Research
Projects are informed of the need to send properly packaged tumor
tissues to the laboratory agreed upon between Lilly and Company in
order to facilitate the analyses specified for the Research Projects.
All such tissue samples are, and shall remain, Company Proprietary
Materials, as defined in Section 7.02.
(c) Company agrees to direct investigators participating in the Clinical
Trials, via the protocol or any other appropriate means, to take
necessary steps, including but not limited to gaining necessary
approvals to permit Company to provide Lilly with access to the
appropriate clinical data from the Clinical Trials. Company agrees to
provide Lilly with access to all the clinical data from the Clinical
Trials relating to the subjects for whom samples have been submitted
for the Research Projects, as well as all of the data from the
Research Projects within a reasonable time after Lilly requests the
data.
Section 1.02. Lilly will appoint [*****] as a service provider ("Principal
Service Provider") to be responsible for the Lab Analysis (as hereinafter
defined). The Principal Service Provider will perform and/or coordinate
performance of the laboratory analysis as specified in the Research Projects
("Lab Analysis") with representatives designated by Lilly and Company, which
representatives shall have responsibility over all matters related to
performance of the Lab Analysis on behalf of Lilly and Company, respectively.
Company and Lilly further agree that [*****] is the designated Lilly
representative and [*****] is the designated Company representative.
Article II
Payment
Section 2.01. In consideration of the Services to be provided under this
Agreement, the budget ("Budget") attached hereto as Exhibit C, indicates that a
maximum amount of [*****] will be paid to Company. All payments due under the
Budget will be paid in accordance with the schedule set forth in Exhibit C.
In addition, Lilly agrees to provide Company with an adequate supply of Gemzar
to be used solely for individuals participating in the Clinical Trials.
Section 2.02. Company will submit reports listing the work performed and
amounts due in accordance with the Budget to:
Xxx Xxxxx and Company
Attn: [*****]
Lilly Corporate Center
Drop Code 6065
Xxxxxxxxxxxx, Xxxxxxx 00000
Article III
Compliance with Government Regulations
Section 3.01. Company will perform the Services in accordance with
generally accepted professional
standards as well as standards reasonably designated by Lilly in writing.
Company also will comply with federal, state and local laws, regulations and
standards applicable to the Services. Specifically, Company will comply with all
applicable privacy laws and regulations in connection with the performance of
the Research Projects. Lilly shall, and shall ensure that the Principal Service
Provider will, perform their respective designated activities hereunder,
including without limitation, the Lab Analysis, in accordance with generally
accepted professional standards and will comply with federal, state and local
laws, regulations and standards applicable to such activities, including without
limitation, all applicable privacy laws and regulations in connection with the
performance of the Research Projects.
Article IV
Company Visits
Section 4.01. Lilly and Lilly-designated representatives may visit Company
at reasonable times and during normal business hours to observe the progress of
the Services. Company will assist Lilly in scheduling such visits. Information
obtained from such visits may be shared with Lilly and Lilly-designated
representatives. All such information shall be considered Company Proprietary
Materials and subject to Article VI.
Article V
Regulatory Authority Visits
Section 5.01. At Lilly's request, a representative of Company shall
accompany Lilly to meet with representatives of the U.S. Food and Drug
Administration ("FDA"), U.S. Environmental Protection Agency ("EPA"), or similar
domestic or foreign regulatory agencies (collectively "Regulatory Authority") to
explain or discuss any and all aspects of the Services. Such visit or visits to
the Regulatory Authority shall be arranged at times mutually agreeable to Lilly
and Company. All reasonable travel and living expenses incurred by Company in
connection with such visits shall be reimbursed by Lilly. Lilly shall pay
Company $[*****] for each day or part thereof for each Company representative
that so accompanies Lilly.
Section 5.02. Company shall notify Lilly of any request from a Regulatory
Authority, other federal or state agencies or any other third-party to inspect
or otherwise gain access to the information, data or materials pertaining to the
Services performed by Company under this Agreement. Company shall notify Lilly
of such requests prior to permitting any third-party access unless prior notice
is not possible.
Section 5.03. Company agrees to permit inspection of such information, data
and materials by authorized representatives of the Regulatory Authority and as
otherwise required by law. During such inspections, Company shall provide
appropriate scientific and quality assurance support for its Services. Lilly
reserves the right to provide additional scientific and quality assurance
support during regulatory inspections as related to the Services.
Article VI
Confidentiality and Non-Use
Section 6.01. Except as provided in Section 6.02, all proprietary
information provided to either party (the "Receiving Party") by the other party
or its designated representatives (the "Disclosing Party") in connection with
the Services, including without limitation, the Lilly Proprietary Materials and
Company Proprietary Materials (as such terms are defined in Sections 7.01 and
7.02, below), will be kept in confidence and not used for any purpose not
expressly provided for in this Agreement for at least [*****] after the
termination or conclusion of the Services, except to the extent that the
Disclosing Party gives written permission or particular information is required
by laws or regulations to be disclosed to local
regulatory agencies or the FDA. To the extent disclosure is requested by any
other person or entity, the Receiving Party shall promptly notify the Disclosing
Party and shall not disclose any information without the Disclosing Party's
prior written consent. If such disclosure is sought by a third party under a
claim of legal right, the Receiving Party will reasonably cooperate with the
Disclosing Party in the event Disclosing Party wishes to take legal action to
challenge such claim or the disclosure; provided, however, the Receiving Party
in no event shall be obligated to defy any law, regulation or judicial or
governmental order. Company and Lilly shall each be responsible for ensuring
that its employees, contractors and agents are obligated to these same terms of
confidentiality and non-use. The terms of confidentiality and non-use set forth
herein shall apply to tangible materials delivered, and proprietary information
that is orally or visually conveyed, by either party or its designated
representatives to the other party under this Agreement. The terms shall also
supersede any prior terms of confidentiality and non-use agreed to by the
parties in connection with the Services. The terms of this Agreement shall also
be considered confidential information and may be disclosed only to the extent
required by law or as permitted in Section 11.01(2).
The foregoing obligations of confidentiality and non-use will not apply to
information that:
(1) is or later becomes part of the public domain other than through the
Receiving Party's act or omission;
(2) was known by Receiving Party prior to disclosure by the Disclosing
Party or becomes known from an independent source or third party under
no obligation to the Disclosing Party or any other third party to keep
such information confidential, as can be shown by prior written
documentation; or
(3) is independently developed, as shown by written documentation, by the
Receiving Party's personnel who have not had access to such
confidential information provided by the Disclosing Party.
Section 6.02. Notwithstanding the foregoing Section 6.01, Company may use
the data and results of the Research Projects to develop and commercialize
Triapine. In connection with such right, Company may disclose such data and
results to potential collaboration partners or to any potential acquirer, merger
partner or potential provider of financing and their advisors; provided, the
recipient of such data and results enters into confidentiality undertakings no
less restrictive than those contained in this Agreement.
Article VII
Proprietary Materials and Publications
Section 7.01. Except as provided in Sections 7.02 and 7.03, Lilly shall
have all right and title to [*****] that is generated in connection with the
Services by Company ("Lilly Proprietary Materials"). The Company hereby assigns
all right, title and interest that it has or may acquire in the Lilly
Proprietary Materials to Lilly. The Company agrees to execute without further
consideration all assignments or other documents that may be necessary or
helpful to establish Lilly's ownership of Lilly Proprietary Materials.
Section 7.02. Company possesses certain documentation, reports, records,
data, specimens or other intellectual property that existed before the parties
entered into this Agreement or will be generated outside the scope of the
Research Projects, including without limitation, documentation, reports, data,
specimens, including without limitation the tissue specimens provided under
Section 1.01(b), or other intellectual property relating to Triapine or the
Clinical Trials ("Company Proprietary Materials"). Company Proprietary Materials
and any improvements or modifications thereto that may be created hereunder are,
and shall continue to be, owned by Company. Lilly hereby assigns all right,
title and interest that it has or
may acquire in the Company Proprietary Materials to Company. Lilly agrees to
execute without further consideration all assignments or other documents that
may be necessary or helpful to establish Company's ownership of Company
Proprietary Materials. Any Company Proprietary Materials delivered to Lilly may
be used by Lilly only to the extent provided in this Agreement and shall remain
subject to the confidentiality and non-use provisions of Article VI.
Section 7.03. Lilly and Company shall jointly own [*****] ("Joint
Intellectual Property"). Each of Lilly and Company may make, use, sell, keep
license, assign or mortgage its interest in Joint Intellectual Property and
otherwise undertake all activities a sole owner might undertake with respect to
Joint Intellectual Property, without the consent of and without accounting to
the other party. Each party will promptly disclose to the other the making,
conception or reduction to practice of Joint Intellectual Property by employees
or others acting on behalf of such party. Each party agrees to execute such
assignments and take such further actions as a re reasonably necessary to vest
in the other party the ownership rights set forth in this Section 7.03. The
parties shall cooperate in patent prosecution, maintenance and enforcement
relating to Joint Intellectual Property. Each party shall make its employees,
agents or consultants available to the other party to the extent reasonably
necessary in connection with the foregoing. Each party will keep the other party
informed of the status of any patent applications filed with respect to Joint
Intellectual Property.
Section 7.04. Within six months following the completion of the Services,
Company shall contact Lilly and identify all Lilly Proprietary Materials in the
possession or control of Company which have not already been forwarded to Lilly.
With the exception of raw data in paper, magnetic, electronic and digital form
and any other documents Company must reasonably retain to meet regulatory
requirements, all Lilly Proprietary Materials will be transferred to Lilly
pursuant to instruction by Lilly. Within sixty (60) days following completion of
the Research Projects, Lilly shall provide to Company a copy of all data and
results of the Research Projects.
Section 7.05. Raw data in paper, magnetic, electronic and digital form and
other documents created by Company in connection with the Services which must be
retained by Company to meet regulatory requirements will be retained by the
Company for [*****] commencing upon conclusion or termination of the Services.
After the [*****] period ends, at the request of the Company and subject to
applicable laws or regulations, such data and documents shall be delivered to
Lilly, be destroyed or be retained by the Company for a standard storage fee to
be agreed upon by the parties.
Section 7.06. Company will be free to publish and present the results of
the Research Projects subject to the following conditions: Lilly will be
furnished with a copy of any proposed publication or presentation for review and
comment [*****] prior to such presentation or submission for publication. Such
[*****] period does not begin until receipt of the proposed publication or
presentation at Lilly in Indianapolis, Indiana. At the expiration of such
[*****] period, Company may proceed with the presentation or submission for
publication; provided, however, that in the event Lilly has notified Company in
writing that Lilly reasonably believes that prior to such publication or
presentation it must take action to protect its intellectual property interests,
such as the filing of a patent application claiming an invention or a trademark
registration application, or taking action to protect its data package
exclusivity interests, Company shall either (1) delay such publication or
presentation for an additional [*****] or until the foregoing action(s) have
been taken, whichever shall first occur, or (2) if Company is unwilling to delay
the publication, Company will remove from the publication or presentation the
information which Lilly has specified it reasonably believes would jeopardize
its intellectual property interests. Under certain circumstances, a shorter
review period may be granted in writing by Lilly. Company will assist Lilly in
obtaining reprints of Company publications resulting from the Research Project.
Article VIII
Independent Contractor
Section 8.01. Both Company and Lilly will be acting as independent
contractors and not as an agent, partner or employee of the other party. Neither
Company nor Lilly will have any authority to make agreements with third parties
that are binding on the other party.
Article IX
Force Majeure
Section 9.01. Company shall be excused from performing its obligations
under this Agreement if performance is delayed or prevented by any cause beyond
Company's control, including but not limited to, acts of nature, fire,
explosion, disease, weather, war, insurrection, civil strife, riots, government
action or power failure ("Disability"). Performance shall be excused only to the
extent of and during the reasonable continuance of such Disability. Any deadline
or time for performance specified which falls due during or subsequent to the
occurrence of any of the Disability shall be automatically extended for a period
of time equal to the period of such Disability. Company will immediately notify
Lilly if, by reason of any of the Disability, Company is unable to meet any
specified deadline or time for performance.
Article X
Debarment Certification
Section 10.01. Each of Company and Lilly agree that it is not and has not
been debarred or disqualified from participating in clinical research by any
United States regulatory authority or by any other regulatory authority, and
that each of Company and Lilly will not use or involve any person or
organization in connection with the Services, the Research Projects or the Lab
Analysis that is or has been debarred or disqualified by any regulatory
authority from participating in clinical research. In the event that Company,
Lilly or any person or organization Company or Lilly uses or involves in
connection with the Services, the Research Projects or the Lab Analysis should
become debarred or disqualified during the course of the Research Projects,
Company and Lilly each agree to promptly notify the other in writing.
Article XI
Publicity
Section 11.01. Consistent with the obligations of Confidentiality and
Non-Use set forth above, Company agrees to the following:
(1) Company will not use the name of Lilly at any educational or
scientific conferences or in any publication without prior written
permission from Lilly.
(2) Lilly must approve, in writing, press statements regarding the
Services before the statements are released. The initial press release
announcing this Agreement, the text of which is provided in Exhibit D,
has been approved by Lilly.
(3) During and after the Services, Company may receive inquiries from
reporters or financial analysts. Company agrees to confer with Lilly's
Corporate Communications Department (317-276-3655) before responding
to such inquiries to the extent such inquiries involve the disclosure
of Lilly's Proprietary Materials or the terms of this Agreement.
(4) Neither Lilly nor Company will use the name or names of the other
party or their employees in any advertising or sales promotional
material or in any publication without prior written permission.
Article XII
Termination
Section 12.01. Either party may terminate this Agreement at any time for
any reason prior to completion by giving thirty (30) days written notice to the
other party.
Section 12.02. Except as provided in Section 7.03, immediately upon the
earlier of, termination of this Agreement by either party or completion of the
Services, each party agrees to return to the other party all of such other
party's confidential information and Proprietary Materials of a returnable
nature that may have been provided hereunder. Following completion of the
Clinical Trials, Company shall return, retain or dispose of any Lilly drug which
may have been provided by Lilly in connection with the Services in accordance
with instructions to be provided by Lilly and regulatory requirements.
Section 12.03. In the event of termination, Company will use its best
efforts to reduce cost to Lilly. Payments will be made for all Services
performed up to the date of termination and reasonable non-cancelable costs
incurred in connection with the Services in accordance with the terms of this
Agreement. If an advance was paid or if any other payments exceed the amount
owed for Services performed, Company agrees to return the excess balance to
Lilly.
Section 12.04. The obligations under Regulatory Authority Visits,
Confidentiality and Non-Use, Proprietary Materials, Publications, Publicity,
Notice and Law and Venue shall survive the expiration, termination or
cancellation of this Agreement.
Article XIII
Assignment and Amendment
Section 13.01. This Agreement shall not be assigned by Company without the
prior written consent of Lilly; provided that without such prior Lilly consent,
this Agreement may be assigned to successor to all or substantially all of the
assets of Company to which this Agreement pertains.
Section 13.02. Except as provided in Section 1.02, Company shall not
sub-contract all or portions of this Agreement without prior written approval
from Lilly. Company may submit to Lilly for approval of sub-contractors. In the
event that Lilly approves the use of a sub-contractor for all or a portion of
the Services under this Agreement, Company must ensure that the sub-contractor
is held to the same terms to which Company is held in this Agreement, including
but not limited to, Compliance with Government Regulations, Confidentiality and
Non-Use, Company Visits, and Proprietary Materials and Publications. Company
agrees that it has policies and procedures for the selecting, auditing,
assessing and monitoring of sub-contractors. To the extent that the Principal
Service Provider or any other third party performs any portion of the Research
Projects at the direction of Lilly, including without limitation, the Lab
Analysis, Lilly shall ensure that such third parties are held to the same terms
to which Lilly is held in this Agreement, including but not limited to,
Compliance with Government Regulations, Confidentiality and Non-Use, and
Proprietary Materials and Publication. Lilly agrees that it has policies and
procedures for the selecting, auditing, assessing and monitoring of such third
parties.
Section 13.03. Any amendments or revisions to this Agreement must be
proposed in writing by either party and accepted in writing by both parties
before they shall become effective and binding.
Article XIV
Notice
Section 14.01. All notices required to be in writing under this Agreement
shall be delivered personally, by courier, sent by telegram or mailed to the
parties at the addresses set forth below or such other addresses as the parties
may designate in writing.
If to Lilly Law Division: If to Company:
Xxx Xxxxx and Company Vion Pharmaceuticals, Inc.
Drop Code 1104 Four Science Park
Lilly Corporate Center New Haven, CT 06511
Xxxxxxxxxxxx, Xxxxxxx 00000
Attention: [*****] Attention: [*****]
Article XV
Waiver
Section 15.01. No waiver of any term, provision or condition of this
Agreement, whether by conduct or otherwise in any one or more instances, shall
be deemed to be or construed as a further or continuing waiver of any such term,
provision or condition or of any other term, provision or condition of this
Agreement.
Section 15.02. No remedies described in this Agreement shall be construed
to limit or reduce either party's rights to any additional remedies available at
common law or in equity.
Article XVI
Law and Venue
Section 16.01. This Agreement shall be construed an accordance with the
laws of the State of Connecticut, without regard to its choice of law
provisions.
Section 16.02. In the event a dispute arises between or among the parties
over the interpretation and application of this Agreement, the parties shall
attempt to settle such dispute first by negotiation and consultation between
themselves. The parties also will consider alternative dispute resolution as a
means of resolving any such dispute.
Section 16.03. This Agreement represents the entire understanding between
the parties and supersedes all other agreements, express or implied, between the
parties concerning the subject matter hereof. This Agreement has been
thoughtfully considered by the parties and, consequently, shall not be strictly
construed against either party.
If the foregoing is acceptable, please sign the enclosed Agreements and
return one original to [*****]
XXX XXXXX AND COMPANY XXX LILLY AND COMPANY
----------------------------- ---------------------------------
[*****] [*****]
---------------------------------
[*****]
---------------------------------
[*****]
August 25, 2003
----------------------------- ----------------------------------
Date Date
AGREED AND ACCEPTED:
VION PHARMACEUTICALS, INC.
-----------------------------
[*****]
September 8, 2003
-----------------------------
Date
EXHIBIT A
RESEARCH PROJECT: PANCREAS TRIAL
Confidential Information
The information contained in this protocol is confidential
and is intended for the use of clinical investigators. It
is the property of Xxx Xxxxx and Company or its subsidiaries
and should not be copied by or distributed to persons not
involved in the clinical investigation of gemcitabine
hydrochloride (LY188011) unless such persons are bound by a
confidentiality agreement with Xxx Lilly and Company or its
subsidiaries.
Companion Translational Research Protocol
Xxx Xxxxx and Company
Vion Pharmaceuticals, Inc.
Companion Translational Research Protocol
1. Introduction
While new chemotherapeutic agents have improved response rates and median
survival times, the overall impact of new therapies on lung cancer still must be
considered limited. As a result, investigators are using other strategies to
improve patient outcome. One of the more interesting approaches involves the
identification of molecular markers that can serve as predictors of response to
specific treatments. For example, high levels of the gene product for the
excision repair cross-complementing 1 (ERCC1) gene, which is crucial in the
repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the
effectiveness of CDDP-based therapy for gastric and ovarian cancers (Xxxxxxxxx
et al. 1994; Xxxxxxx et al. 1998). Lord et al. have shown that patients whose
tumors expressed low levels of ERCC1 had a higher median overall survival (61.6
weeks, 95% CI 42.4 to 80.7) when compared with patients with high expression
tumors (20.4 weeks, 95% CI 6.9 to 33.9), in patients receiving the combination
of gemcitabine and cisplatin (Lord et al. 2002). With respect to gemcitabine,
over expression of ribonucleotide reductase has been correlated with resistance
to gemcitabine in human oropharyngeal epidermoid carcinoma KB cell lines (Goan
et al. 1999) whereas sensitization of gastrointestinal cancer cell lines to
gemcitabine has been correlated to downregulation of the ribonucleotide
reductase (RR) M2 subunit (Jung et al. 2001). Also, low RR M1 subunit levels
have shown a tendency toward correlation with better response in patients
treated with cisplatin and gemcitabine (Xxxxxx et al. 2002). At this point, it
is unclear if any of the identified molecular markers are predictive of a
response to specific therapies or are general prognostic indicators of response
to all therapies. However, it is hoped thatidentification of molecular markers
predictive of response to specific therapeutic regimens will eventually lead
to tailored patient-specific cancer therapy, and ultimately improved
treatment outcome.
TRIAPINE'r' (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a potent
small molecule inhibitor of ribonucleotide reductase (references in parent
protocol). [*****]
--------------------------------------------------------------------------------
Protocol Attachment .1.
Protocol Signatures
--------------------------------------------------------------------------------
Protocol Signatures
I confirm that I have read this protocol, I understand it, and I will work
according to this protocol. I will conduct this study in a manner that is in
accordance with the ethical principles and the applicable laws and regulations
of my local region. I will promptly submit the protocol to applicable ethical
review board(s). I confirm that if I or any of my staff are members of the
ethical review board, we will abstain from voting on this protocol.
Instructions to the investigator: Please SIGN
and DATE both copies of this signature page.
PRINT your name, title, and the name of the
facility in which the study will be conducted
on both copies. Return one of the signed copies
to Lilly.
------------------------------------------------- ---------------------------
Signature of Investigator Date
-------------------------------------------------
Investigator Name (print or type)
-------------------------------------------------
Investigator Title
-------------------------------------------------
Name of Facility
-------------------------------------------------
Location of Facility
(City, State (if applicable), Country)
------------------------------------------------- ---------------------------
Signature of Representative of Date
Vion Pharmaceuticals (or Subsidiary)
-------------------------------------------------
Title of Representative of Vion Pharmaceuticals (or Subsidiary)
Protocol Signatures
I confirm that I have read this protocol, I understand it, and I will work
according to this protocol. I will conduct this study in a manner that is in
accordance with the ethical principles and the applicable laws and regulations
of my local region. I will promptly submit the protocol to applicable ethical
review board(s). I confirm that if I or any of my staff are members of the
ethical review board, we will abstain from voting on this protocol.
Instructions to the investigator: Please SIGN
and DATE both copies of this signature page.
PRINT your name, title, and the name of the
facility in which the study will be conducted
on both copies. Return one of the signed copies
to Lilly.
------------------------------------------------- ---------------------------
Signature of Investigator Date
-------------------------------------------------
Investigator Name
-------------------------------------------------
Investigator Title
-------------------------------------------------
Name of Facility
-------------------------------------------------
Location of Facility
(City, State (if applicable), Country)
------------------------------------------------- ---------------------------
Signature of Representative of Date
Xxx Xxxxx and Company (or Subsidiary)
-------------------------------------------------
Title of Representative of Xxx Lilly and Company (or Subsidiary)
EXHIBIT B
RESEARCH PROJECT: LUNG TRIAL
Confidential Information
The information contained in this protocol is
confidential and is intended for the use of
clinical investigators. It is the property of
Xxx Xxxxx and Company or its subsidiaries and
should not be copied by or distributed to
persons not involved in the clinical
investigation of gemcitabine hydrochloride
(LY188011) unless such persons are bound by a
confidentiality agreement with Xxx Lilly and
Company or its subsidiaries.
Companion Translational Research Protocol
Xxx Xxxxx and Company
Companion Translational Research Protocol
1. Introduction
The overall impact of current and newer therapies on pancreatic cancer must
be considered limited. As a result, investigators are using other strategies to
improve patient outcome. One of the more interesting approaches involves the
identification of molecular markers that can serve as predictors of response to
specific treatments. For example, high levels of the gene product for the
excision repair cross-complementing 1 (ERCC1) gene, which is crucial in the
repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the
effectiveness of CDDP-based therapy for gastric and ovarian cancers (Xxxxxxxxx
et al. 1994; Xxxxxxx et al. 1998). Lord et al. have shown that patients whose
tumors expressed low levels of ERCC1 had a higher median overall survival (61.6
weeks, 95% CI 42.4 to 80.7) when compared with patients with high expression
tumors (20.4 weeks, 95% CI 6.9 to 33.9), in patients receiving the combination
of gemcitabine and cisplatin (Lord et al. 2002). With respect to gemcitabine,
over expression of ribonucleotide reductase has been correlated with resistance
to gemcitabine in human oropharyngeal epidermoid carcinoma KB cell lines (Goan
et al. 1999) whereas sensitization of gastrointestinal cancer cell lines to
gemcitabine has been correlated to downregulation of the ribonucleotide
reductase (RR) M2 subunit (Jung et al. 2001). Also, low RR M1 subunit levels
have shown a tendency toward correlation with better response in NSCLC patients
treated with cisplatin and gemcitabine (Xxxxxx et al. 2002). At this point, it
is unclear if any of the identified molecular markers are predictive of a
response to specific therapies or are general prognostic indicators of response
to all therapies. However, it is hoped that identification of molecular markers
predictive of response to specific therapeutic regimens will eventually lead to
tailored patient-specific cancer therapy, and ultimately improved treatment
outcome.
TRIAPINE'r' (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a potent
small molecule inhibitor of ribonucleotide reductase (references in parent
protocol). [*****]
--------------------------------------------------------------------------------
Protocol Attachment .1.
Protocol Signatures
--------------------------------------------------------------------------------
I confirm that I have read this protocol, I understand it, and I will work
according to this protocol. I will conduct this study in a manner that is in
accordance with the ethical principles and the applicable laws and regulations
of my local region. I will promptly submit the protocol to applicable ethical
review board(s). I confirm that if I or any of my staff are members of the
ethical review board, we will abstain from voting on this protocol.
Instructions to the investigator: Please SIGN
and DATE both copies of this signature page.
PRINT your name, title, and the name of the
facility in which the study will be conducted
on both copies. Return one of the signed copies
to Lilly.
------------------------------------------------- ---------------------------
Signature of Investigator Date
-------------------------------------------------
Investigator Name (print or type)
-------------------------------------------------
Investigator Title
-------------------------------------------------
Name of Facility
-------------------------------------------------
Location of Facility
(City, State (if applicable), Country)
------------------------------------------------- ---------------------------
Signature of Representative of Date
Vion Pharmaceuticals (or Subsidiary)
-------------------------------------------------
Title of Representative of Vion Pharmaceuticals (or Subsidiary)
Protocol Signatures
I confirm that I have read this protocol, I understand it, and I will work
according to this protocol. I will conduct this study in a manner that is in
accordance with the ethical principles and the applicable laws and regulations
of my local region. I will promptly submit the protocol to applicable ethical
review board(s). I confirm that if I or any of my staff are members of the
ethical review board, we will abstain from voting on this protocol.
Instructions to the investigator: Please SIGN
and DATE both copies of this signature page.
PRINT your name, title, and the name of the
facility in which the study will be conducted
on both copies. Return one of the signed copies
to Lilly.
------------------------------------------------- ---------------------------
Signature of Investigator Date
-------------------------------------------------
Investigator Name
-------------------------------------------------
Investigator Title
-------------------------------------------------
Name of Facility
-------------------------------------------------
Location of Facility
(City, State (if applicable), Country)
------------------------------------------------- ---------------------------
Signature of Representative of Date
Xxx Xxxxx and Company (or Subsidiary)
-------------------------------------------------
Title of Representative of Xxx Lilly and Company (or Subsidiary)
EXHIBIT C
BUDGET
[*****]
EXHIBIT D
PRESS RELEASE
[Vion logo]
COMPANY CONTACT:
Vion Pharmaceuticals, Inc.
Xxxxxx X. Xxxxxxx, CFO
(000) 000-0000 phone
Vion and Lilly Enter into Research Services Agreement
NEW HAVEN, CT, July XX, 2003 - VION PHARMACEUTICALS, INC. (NASDAQ SMALLCAP:
VION) announced today that it had entered into a research services agreement
with Xxx Xxxxx and Company ("Lilly") related to the Phase 2 trials of its
anticancer agent Triapine'r' in combination with Lilly's anticancer agent,
Gemzar'r'.
The agreement relates to the measurement of the expression of several genes in
tumor tissue and blood samples from patients participating in Vion's Phase 2
trials of the combination therapy in non-small-cell lung cancer and pancreatic
cancer.
Xx. Xxxxx Xxxxx, Vice President, Clinical Affairs, stated, "We are very pleased
to collaborate with Lilly scientists on correlative scientific studies in
patients entered in our Triapine'r' and Gemzar'r' combination trials." He added,
"The types of studies that will be conducted may provide greater understanding
of the genetic makeup of patients and their tumors that determine responsiveness
to Gemzar'r', and could also identify populations of patients that could benefit
from the addition of Triapine'r' to Gemzar'r'."
Triapine'r' is designed to be a potent inhibitor of ribonucleotide reductase, an
enzyme important for DNA synthesis. Gemzar'r' is a nucleoside analogue sold for
the treatment of certain solid tumors by Xxx Xxxxx & Company.
Vion Pharmaceuticals, Inc. is a biopharmaceutical company developing novel
agents for the treatment of cancer. Vion's portfolio of agents includes:
Triapine'r', a potent inhibitor of a key step in DNA synthesis; VNP40101M, a
unique DNA alkylating agent; and TAPET'r', a modified Salmonella vector used to
deliver anticancer agents directly to tumors. For additional information on Vion
and its research and product development programs, visit the company's Internet
web site at xxx.xxxxxxxxx.xxx.
This news release contains forward-looking statements. Such statements are
subject to certain risk factors which may cause Vion's plans to differ or
results to vary from those expected, including Vion's ability to continue as a
going concern, which is dependent on securing external sources of funding to
continue its operations, the inability to access capital and funding on
favorable terms, continued operating losses and the inability to continue
operations as a result, its dependence on regulatory approval for its products,
delayed or unfavorable results of drug trials, the possibility that favorable
results of earlier clinical trials are not predictive of safety and efficacy
results in later clinical trials, the need for additional research and testing,
and a variety of other risks set forth from time to time in Vion's filings with
the Securities and Exchange Commission, including but not limited to the risks
discussed in Vion's Annual Report on Form 10-K for the year ended December 31,
2002. Except in special circumstances in which a duty to update arises under law
when prior disclosure becomes materially misleading in light of subsequent
events, Vion does not intend to update any of these forward-looking statements
to reflect events or circumstances after the date hereof or to reflect the
occurrence of unanticipated events.
