EXECUTION COPY

 

 

 

 

 

 

 

 

 

 

 

 

CLINICAL TRIAL COLLABORATION AND SUPPLY AGREEMENT

 

 

 

by and among

 

 

 

Merck Sharp & Dohme B.V.

 

 

 

and

 

 

 

Antigen Express, Inc.

 

 

 

Dated: June 28, 2017

 -i- 

 

 

Page

    1. Definitions 1  2. Scope of the Agreement 8  2.1. Generally 8  2.2.
Manufacturing Delay 8  2.3. Compound Commitments 8  2.4. Delegation of
Obligations 9  2.5. Compounds 9  3. Conduct of the Study 9  3.1. Sponsor and
Combination IND 9  3.2. Performance 10  3.3. Debarred Personnel; Exclusions
Lists 10  3.4. Regulatory Matters 10  3.5. Documentation 10  3.6. Copies 10 
3.7. Samples 11  3.8. Ownership and Use of Clinical Data 11  3.9. Regulatory
Submission 12  3.10. Joint Development Committee 12  3.11. Final Study Report
13  3.12. Relationship 13  3.13. Licensing 13  3.14. Subsequent Study 13  4.
Protocol and Certain Other Documents 14  4.1. Protocol 14  4.2. Informed Consent
15  4.3. Financial Disclosure. 15  4.4. Transparency Reporting 15  5. Adverse
Event Reporting 16  5.1. Pharmacovigilance Agreement 16  5.2. Transmission of
SAEs 17  6. Term and Termination. 17  6.1. Term 17  6.2. Merck Termination Right
for Safety 17 

6.3. Termination for Material Breach 17  6.4. Termination for Patient Safety 17 
6.5. Termination for Regulatory Action; Other Reasons 18  6.6. Return of Merck
Compound 18  6.7. Termination Related to Anti-Corruption 18  6.8. Survival 18 
6.9. No Prejudice 18  6.10. Confidential Information 18  6.11. Manufacturing
Costs 19  7. Costs of Study 19  8. Supply and Use of the Compounds 19  8.1.
Supply of the Compounds 19  8.2. Clinical Quality Agreement 20  8.3. Minimum
Shelf Life Requirements 20  8.4. Provision of Compounds 20  8.5. Labeling and
Packaging; Use, Handling and Storage 21  8.6. Product Specifications 21  8.7.
Changes to Manufacturing 21  8.8. Product Testing; Noncompliance 21  8.9.
Investigations 23  8.10. Shortage; Allocation 23  8.11. Records; Audit Rights
23  8.12. Quality 23  8.13. Quality Control 23  8.14. Audits and Inspections 23 
8.15. Recalls 24  8.16. VAT 24  9. Confidentiality 24  9.1. Confidential
Information 24  9.2. Inventions 25  9.3. Personal Identifiable Data 25  10.
Intellectual Property 25  10.1. Joint Ownership and Prosecution 25  10.2.
Inventions Owned by 27  10.3. Inventions Owned by Merck 27  10.4. Mutual Freedom
to Operate for Combination Inventions 28  11. Reprints; Rights of
Cross-Reference 28  12. Publications; Press Releases 28  12.1. Clinical Trial
Registry 28  12.2. Publication 29  12.3. Press Releases 29  13. Representations
and Warranties; Disclaimers 29  13.1. Due Authorization 29  13.2. Compounds 29 
13.3. Results 30  13.4. Anti-Corruption 30  13.5. DISCLAIMER 32  14. Insurance;
Indemnification; Limitation of Liability 32  14.1. Insurance 32  14.2.
Indemnification 32  14.3. LIMITATION OF LIABILITY 33  15. Use of Name 33  16.
Force Majeure 33  17. Entire Agreement; Amendment; Waiver 34  18. Assignment and
Affiliates 34  19. Invalid Provision 34  20. No Additional Obligations 34  21.
Governing Law; Dispute Resolution 35  22. Notices 35  23. Relationship of the
Parties 36  24. Counterparts and Due Execution 36  25. Construction 36 

 

 -ii- 

 

 

EXECUTION COPY

 

 

 

 

 

 

 

 

 

 

 

 

CLINICAL TRIAL COLLABORATION AND SUPPLY AGREEMENT

 

 

 

by and among

 

 

 

Merck Sharp & Dohme B.V.

 

 

 

and

 

 

 

Antigen Express, Inc.

 

 

 

Dated: June 28, 2017

 

 

TABLE OF CONTENTS

 

Page

 

1.Definitions 1

2.Scope of the Agreement 8

2.1.Generally 8

2.2.Manufacturing Delay 8

2.3.Compound Commitments 8

2.4.Delegation of Obligations 9

2.5.Compounds 9

3.Conduct of the Study 9

3.1.Sponsor and Combination IND 9

3.2.Performance 10

3.3.Debarred Personnel; Exclusions Lists 10

3.4.Regulatory Matters 10

3.5.Documentation 10

3.6.Copies 10

3.7.Samples 11

3.8.Ownership and Use of Clinical Data 11

3.9.Regulatory Submission 12

3.10.Joint Development Committee 12

3.11.Final Study Report 13

3.12.Relationship 13

3.13.Licensing 13

3.14.Subsequent Study 13

4.Protocol and Certain Other Documents 14

4.1.Protocol 14

4.2.Informed Consent 15

4.3.Financial Disclosure. 15

4.4.Transparency Reporting 15

5.Adverse Event Reporting 16

5.1.Pharmacovigilance Agreement 16

5.2.Transmission of SAEs 17

6.Term and Termination. 17

6.1.Term 17

6.2.Merck Termination Right for Safety 17

 

 

6.3.Termination for Material Breach 17

6.4.Termination for Patient Safety 17

6.5.Termination for Regulatory Action; Other Reasons 18

6.6.Return of Merck Compound 18

6.7.Termination Related to Anti-Corruption 18

6.8.Survival 18

6.9.No Prejudice 18

6.10.Confidential Information 18

6.11.Manufacturing Costs 19

7.Costs of Study 19

8.Supply and Use of the Compounds 19

8.1.Supply of the Compounds 19

8.2.Clinical Quality Agreement 20

8.3.Minimum Shelf Life Requirements 20

8.4.Provision of Compounds 20

8.5.Labeling and Packaging; Use, Handling and Storage 21

8.6.Product Specifications 21

8.7.Changes to Manufacturing 21

8.8.Product Testing; Noncompliance 21

8.9.Investigations 23

8.10.Shortage; Allocation 23

8.11.Records; Audit Rights 23

8.12.Quality 23

8.13.Quality Control 23

8.14.Audits and Inspections 23

8.15.Recalls 24

8.16.VAT 24

9.Confidentiality 24

9.1.Confidential Information 24

9.2.Inventions 25

9.3.Personal Identifiable Data 25

10.Intellectual Property 25

10.1.Joint Ownership and Prosecution 25

10.2.Inventions Owned by 27

 

 

10.3.Inventions Owned by Merck 27

10.4.Mutual Freedom to Operate for Combination Inventions 28

11.Reprints; Rights of Cross-Reference 28

12.Publications; Press Releases 28

12.1.Clinical Trial Registry 28

12.2.Publication 29

12.3.Press Releases 29

13.Representations and Warranties; Disclaimers 29

13.1.Due Authorization 29

13.2.Compounds 29

13.3.Results 30

13.4.Anti-Corruption 30

13.5.DISCLAIMER 32

14.Insurance; Indemnification; Limitation of Liability 32

14.1.Insurance 32

14.2.Indemnification 32

14.3.LIMITATION OF LIABILITY 33

15.Use of Name 33

16.Force Majeure 33

17.Entire Agreement; Amendment; Waiver 34

18.Assignment and Affiliates 34

19.Invalid Provision 34

20.No Additional Obligations 34

21.Governing Law; Dispute Resolution 35

22.Notices 35

23.Relationship of the Parties 36

24.Counterparts and Due Execution 36

25.Construction 36

 

 

Appendices Appendix A Appendix B

 

Schedules

Schedule I

 

 

CLINICAL TRIAL COLLABORATION AND SUPPLY AGREEMENT

 

This CLINICAL TRIAL COLLABORATION AND SUPPLY AGREEMENT (this

“Agreement”), made as of June 28, 2017 (the “Effective Date”), is by and between
Merck Sharp & Dohme B.V., having a place of business at Waarderweg 39, 2031 BN
Haarlem, Netherlands (“Merck”), and Antigen Express, Inc., having a place of
business at 33 Redwing Road, Wellesley, MA, 02481 (“Antigen Express”). Merck and
Antigen Express are each referred to herein individually as “Party” and
collectively as “Parties”.

 

RECITALS

 

A.                 Merck is developing the Merck Compound for the treatment of
certain tumor types.

 

B.                 Antigen Express is developing the Antigen Express Compound
(as defined below) for the treatment of certain tumor types.

 

C.                 Antigen Express desires to sponsor a clinical trial in which
the Antigen Express Compound and the Merck Compound would be dosed concurrently
or in combination.

 

D.                 Merck and Antigen Express, consistent with the terms of this
Agreement, desire to collaborate as more fully described herein, including by
providing the Merck Compound and the Antigen Express Compound for the Study (as
defined below).

 

NOW, THEREFORE, in consideration of the premises and of the following mutual
promises, covenants and conditions, the Parties, intending to be legally bound,
mutually agree as follows:

 

1.Definitions.

 

For all purposes of this Agreement, the capitalized terms defined in this
Article 1 and throughout this Agreement shall have the meanings herein
specified.

 

1.1.    “Affiliate” means, with respect to either Party, a firm, corporation or
other entity which directly or indirectly owns or controls said Party, or is
owned or controlled by said Party, or is under common ownership or control with
said Party. The word “control” as used in this definition means (i) the direct
or indirect ownership of fifty percent (50%) or more of the outstanding voting
securities of a legal entity, or (ii) possession, directly or indirectly, of the
power to direct the management or policies of a legal entity, whether through
the ownership of voting securities, contract rights, voting rights, corporate
governance or otherwise.

 

1.2.    “Agreement” means this agreement, as amended by the Parties from time to
time, and as set forth in the preamble.

 

1.3.“Alliance Manager” has the meaning set forth in Section 3.10.

 

1.4.“Antigen Express” has the meaning set forth in the preamble.

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1.5.“Antigen Express Background Patents” has the meaning set forth in Section

10.4.1.

 

1.6.“Antigen Express Class Compound” means any Ii-Key modified cancer peptide

vaccine.

 

1.7.    “Antigen Express Compound” means AE37, an Ii-Key HER2776-790 cancer
peptide vaccine, excluding, however, any biosimilar version of AE37 other than a
biosimilar version Controlled by Antigen Express or its Affiliate.

 

1.8.“Antigen Express Inventions” has the meaning set forth in Section 10.2.

 

1.9.    “Applicable Law” means all federal, state, local, national and regional
statutes, laws, rules, regulations and directives applicable to a particular
activity hereunder, including performance of clinical trials, medical treatment
and the processing and protection of personal and medical data, that may be in
effect from time to time, including those promulgated by the United States Food
and Drug Administration (“FDA”), national regulatory authorities, the European
Medicines Agency (“EMA”) and any successor agency to the FDA or EMA or any
agency or authority performing some or all of the functions of the FDA or EMA in
any jurisdiction outside the United States or the European Union (each a
“Regulatory Authority” and collectively, “Regulatory Authorities”), and
including cGMP and GCP (each as defined below); all data protection requirements
such as those specified in the EU Data Protection Directive and the regulations
issued under the United States Health Insurance Portability and Accountability
Act of 1996 (“HIPAA”); export control and economic sanctions regulations which
prohibit the shipment of United States-origin products and technology to certain
restricted countries, entities and individuals; anti-bribery and anti-corruption
laws pertaining to interactions with government agents, officials and
representatives; laws and regulations governing payments to healthcare
providers; and any United States or other country’s or jurisdiction’s successor
or replacement statutes, laws, rules, regulations and directives relating to the
foregoing.

 

1.10.   “Business Day” means any day other than a Saturday, Sunday or a day on
which commercial banks located in the country where the applicable obligations
are to be performed are authorized or required by law to be closed.

 

1.11.   “cGMP” means the current Good Manufacturing Practices officially
published and interpreted by EMA, FDA and other applicable Regulatory
Authorities that may be in effect from time to time and are applicable to the
Manufacture of the Compounds.

 

1.12.   “Clinical Data” means all data (including raw data) and results
generated by or on behalf of either Party or at either Party’s direction, or by
or on behalf of the Parties together or at their direction, in the course of
each such Party’s performance of the Study; provided however, that Clinical Data
does not include Sample Testing Results.

 

1.13.“Clinical Quality Agreement” has the meaning set forth in Section 8.2.

 

1.14.   “CMC” means “Chemistry Manufacturing and Controls” as such term of art
is used in the pharmaceutical industry.

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1.15.   “Combination” means the use or method of using the Merck Compound and
the Antigen Express Compound in concomitant or sequential administration.

 

1.16.   “Compounds” means the Merck Compound and the Antigen Express Compound. A
“Compound” means either the Merck Compound or the Antigen Express Compound, as
applicable.

 

1.17.   “Confidential Information” means any information, Know-How or other
proprietary information or materials furnished to one Party (“Receiving Party”)
by or on behalf the other Party (“Disclosing Party”) in connection with this
Agreement, except to the extent that such information or materials: (a) was
already known to the Receiving Party, other than under an obligation of
confidentiality, at the time of disclosure by the Disclosing Party, as
demonstrated by competent evidence; (b) was generally available to the public or
otherwise part of the public domain at the time of its disclosure to the
Receiving Party; (c) became generally available to the public or otherwise part
of the public domain after its disclosure and other than through any act or
omission of the Receiving Party in breach of this Agreement; (d) was disclosed
to the Receiving Party by a Third Party who had no obligation to the Disclosing
Party not to disclose such information to others; or (e) was subsequently
developed by the Receiving Party without use of the Disclosing Party
Confidential Information, as demonstrated by competent evidence.

 

1.18.“Continuing Party” has the meaning set forth in Section 10.1.3.

 

1.19.   “Control” or “Controlled” means, with respect to particular information
or intellectual property, that the applicable Party owns or has a license to
such information or intellectual property and has the ability to grant a right,
license or sublicense to the other Party as provided for herein without
violating the terms of any agreement or other arrangement with any Third Party.

 

1.20.   “CTA” means an application to a Regulatory Authority for purposes of
requesting the ability to start or continue a clinical trial, which CTA may
consist of, or include, and IND.

 

1.21.   “Data Sharing/Sample Testing Schedule” means the schedule attached
hereto as Schedule I.

 

1.22.“Defending Party” has the meaning set forth in Section 14.2.3.

 

1.23.   “Delivery” with respect to the Merck Compound has the meaning set forth
in Section 8.4.1, and with respect to the Antigen Express Compound, the meaning
set forth in Section 8.4.2.

 

1.24.“Direct Manufacturing Costs” has the meaning set forth in Section 6.11.

 

1.25.   “Disclosing Party” has the meaning set forth in the definition of
Confidential Information.

 

1.26.“Disposition Package” has the meaning set forth in Section 8.8.1.

 

1.27.“Effective Date” has the meaning set forth in the preamble.

3 

 

1.28.“EMA” has the meaning set forth in the definition of Applicable Law.

 

1.29.“Exclusions List” has the meaning set forth in the definition of Violation.

 

1.30.“FDA” has the meaning set forth in the definition of Applicable Law.

 

1.31.   “Field” means the concomitant and/or sequenced administration of the
Merck Compound and the Antigen Express Compound in patients with metastatic
triple negative breast cancer.

 

1.32.“Filing Party” has the meaning set forth in Section 10.1.3.

 

1.33.“Final Study Report” has the meaning set forth in Section 3.11.

 

1.34.“Force Majeure” has the meaning set forth Section 16.

 

1.35.“GAAP” has the meaning set forth in Section 6.11.

 

1.36.   “GCP” means the Good Clinical Practices officially published by EMA, FDA
and the International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) that may be in effect from
time to time and are applicable to the testing of the Compounds.

 

1.37.   “Government Official” means: (a) any officer or employee of a government
or any department, agency or instrument of a government; (b) any Person acting
in an official capacity for or on behalf of a government or any department,
agency, or instrument of a government; (c) any officer or employee of a company
or business owned in whole or part by a government; (d) any officer or employee
of a public international organization such as the World Bank or United Nations;
(e) any officer or employee of a political party or any Person acting in an
official capacity on behalf of a political party; and/or (f) any candidate for
political office; who, when such Government Official is acting in an official
capacity, or in an official decision- making role, has responsibility for
performing regulatory inspections, government authorizations or licenses, or
otherwise has the capacity to make decisions with the potential to affect the
business of either of the Parties.

 

1.38.“HIPAA” has the meaning set forth in the definition of Applicable Law.

 

1.39.   “IND” means any Investigational New Drug Application filed or to be
filed with the FDA as described in Title 21 of the U.S. Code of Federal
Regulations, Part 312, and the equivalent application in the jurisdictions
outside the United States, including an “Investigational Medicinal Product
Dossier” filed or to be filed with Regulatory Authorities in the European Union.

 

1.40.“Indirect Manufacturing Costs” has the meaning set forth in Section 6.11.

 

1.41.   “Inventions” means all inventions and discoveries, whether or not
patentable, that are made, conceived, or first actually reduced to practice by
or on behalf of a Party, or by or on behalf of the Parties together, (i) in the
design or performance of the Study, or in the design or

4 

 

performance of any Subsequent Study for the Combination performed pursuant to
Section 3.14, or (ii) through use of unpublished Clinical Data

 

1.42.   “Joint Development Committee” or “JDC” has the meaning set forth in
Section 3.10.

 

1.43.“Joint Patent Application” has the meaning set forth in Section 10.1.3.

 

1.44.   “Joint Patent” means a patent, extension, registration, supplementary
protection certificate or the like that issues from a Joint Patent Application.

 

1.45.“Jointly Owned Invention” has the meaning set forth in Section 10.1.1.

 

1.46.   “Know-How” means any proprietary invention, innovation, improvement,
development, discovery, computer program, device, trade secret, method,
know-how, process, technique or the like, including manufacturing, use, process,
structural, operational and other data and information, whether or not written
or otherwise fixed in any form or medium, regardless of the media on which
contained and whether or not patentable or copyrightable, that is not generally
known or otherwise in the public domain.

 

1.47.“Liability” has the meaning set forth in Section 14.2.1.

 

1.48.   “Manufacture,” “Manufactured,” or “Manufacturing” means all activities
related to the manufacture of a Compound, including planning, purchasing,
manufacture, processing, compounding, storage, filling, packaging, waste
disposal, labeling, leafleting, testing, quality assurance, sample retention,
stability testing, release, dispatch and supply, as applicable.

 

1.49.   “Manufacturer’s Release” or “Release” has the meaning ascribed to such
term in the Clinical Quality Agreement.

 

1.50.   “Manufacturing Site” means the facilities where a Compound is
Manufactured by or on behalf of a Party, as such Manufacturing Site may change
from time to time in accordance with Section 8.7.

 

1.51.“Merck” has the meaning set forth in the preamble.

 

1.52.“Merck Background Patents” has the meaning set forth in Section 10.4.2.

 

1.53.   “Merck Compound” means pembrolizumab, a humanized anti-human PD-1
monoclonal antibody, excluding, however, any biosimilar version of pembrolizumab
other than a biosimilar version Controlled by Merck or its Affiliate.

 

1.54.“Merck Inventions” has the meaning set forth in Section 10.3.

 

1.55.   “NDA” means a New Drug Application, Biologics License Application,
Marketing Authorization Application, filing pursuant to Section 510(k) of the
United States Federal Food, Drug and Cosmetic Act, or similar application or
submission for a marketing

5 

 

authorization of a product filed with a Regulatory Authority to obtain marketing
approval for a biological, pharmaceutical or diagnostic product in that country
or in that group of countries.

 

1.56.   “Non-Conformance” means, with respect to a given unit of Compound, (i)
an event that deviates from an approved cGMP requirement with respect to the
applicable Compound, such as a procedure, Specification, or operating parameter,
or that requires an investigation to assess impact to the quality of the
applicable Compound or (ii) that such Compound failed to meet the applicable
representations and warranties set forth in Section 2.3. Classification of the
Non-Conformance is detailed in the Clinical Quality Agreement.

 

1.57.“Non-Filing Party” has the meaning set forth in Section 10.1.3.

 

1.58.“Other Party” has the meaning set forth in Section 14.2.3.

 

1.59.“Opting-out Party” has the meaning set forth in Section 10.1.3.

 

1.60.“Party” has the meaning set forth in the preamble.

 

1.61.   “PD-1 Antagonist” means any small or large molecule that blocks binding
of PD- L1 and/or PD-L2 to PD-1.

 

1.62.   “Person” means any individual, sole proprietorship, partnership,
corporation, business trust, joint stock company, trust, unincorporated
organization, association, limited liability company, institution, public
benefit corporation, joint venture, entity or governmental entity.

 

1.63.“Pharmacovigilance Agreement” has the meaning set forth in Section 5.1.

 

1.64.“Project Manager” has the meaning set forth in Section 3.10.

 

1.65.   “Protocol” means the written documentation that describes the Study and
sets forth specific activities to be performed as part of the conduct of the
Study, which is attached hereto as Appendix A.

 

1.66.   “Receiving Party” has the meaning set forth in the definition of
Confidential Information.

 

1.67.   “Regulatory Approvals” means, with respect to a Compound, any and all
permissions (other than the Manufacturing approvals) required to be obtained
from Regulatory Authorities and any other competent authority for the
development, registration, importation and distribution of such Compound in the
United States, Europe or other applicable jurisdictions for use in the Study.

 

1.68.   “Regulatory Authorities” has the meaning set forth in the definition of
Applicable Law.

 

1.69.   “Regulatory Documentation” means, with respect to the Compounds, all
submissions to Regulatory Authorities in connection with the development of such
Compounds,

6 

 

including all INDs and amendments thereto, NDAs and amendments thereto, drug
master files, correspondence with regulatory agencies, periodic safety update
reports, adverse event files, complaint files, inspection reports and
manufacturing records, in each case together with all supporting documents
(including documents that include Clinical Data).

 

1.70.   “Related Agreements” means the Pharmacovigilance Agreement and the
Clinical Quality Agreement.

 

1.71.   “Right of Reference” means the “right of reference” defined in 21 CFR
314.3(b), including with regard to a Party, allowing the applicable Regulatory
Authority in a country to have access to relevant information (by
cross-reference, incorporation by reference or otherwise) contained in
Regulatory Documentation (and any data contained therein) filed with such
Regulatory Authority with respect to a Party’s Compound, only to the extent
necessary for the conduct of the Study in such country or as otherwise expressly
permitted or required under this Agreement to enable a Party to exercise its
rights or perform its obligations hereunder.

 

1.72.“SAEs” has the meaning set forth in Section 5.2.

 

1.73.   “Samples” means biological specimens collected from subjects
participating in the Study, including urine, blood and tissue samples.

 

1.74.   “Sample Testing” means the analyses to be performed by each Party using
the applicable Samples, as described in the Data Sharing/Sample Testing
Schedule.

 

1.75.   “Sample Testing Results” means those data and results arising from the
Sample Testing performed by a Party.

 

1.76.   “Specifications” means, with respect to a given Compound, the set of
requirements for such Compound as set forth in the Clinical Quality Agreement.

 

1.77.   “Study” means a Phase I dose escalation study to evaluate the safety,
pharmacokinetics, pharmacodynamics and preliminary efficacy of the concomitant
and/or sequenced administration of the combination of the Antigen Express
Compound and the Merck Compound in patients with triple negative breast cancer.

 

1.78.“Study Completion” has the meaning set forth in Section 3.11.

 

1.79.“Subcontractors” has the meaning set forth in Section 2.4.

 

1.80.“Subsequent Study” has the meaning set forth in Section 3.14.1.

 

1.81.“Term” has the meaning set forth in Section 6.1.

 

1.82.   “Third Party” means any Person or entity other than Antigen Express,
Merck or their respective Affiliates.

7 

 

1.83.   “Toxicity & Safety Data” means all clinical adverse event information
and/or patient-related safety data included in the Clinical Data, as more fully
described in the Pharmacovigilance Agreement.

 

1.84.“VAT” has the meaning set forth in Section 8.16.

 

1.85.   “Violation” means that a Party or any of its officers or directors or
any other personnel (or other permitted agents of a Party performing activities
hereunder) has been: (1) convicted of any of the felonies identified among the
exclusion authorities listed on the U.S. Department of Health and Human
Services, Office of Inspector General (OIG) website, including 42 U.S.C.
1320a-7(a) (http://oig.hhs.gov/exclusions/authorities.asp); (2) identified in
the OIG List of Excluded Individuals/Entities (LEIE) database
(http://exclusions.oig.hhs.gov/) or listed as having an active exclusion in the
System for Award Management (http://www.sam.gov); or (3) listed by any US
Federal agency as being suspended, proposed for debarment, debarred, excluded or
otherwise ineligible to participate in Federal procurement or non-procurement
programs, including under 21 U.S.C. 335a
(http://www.fda.gov/ora/compliance_ref/debar/) ( (1), (2) and (3) collectively
the “Exclusions Lists”).

 

2.Scope of the Agreement.

 

2.1.    Generally. Each Party shall: (a) contribute to the Study such resources
as are necessary to fulfill its obligations set forth in this Agreement; and (b)
act in good faith in performing its obligations under this Agreement and each
Related Agreement to which it is a Party.

 

2.2.    Manufacturing Delay. Each Party shall notify the other Party as promptly
as possible in the event of any Manufacturing delay that is likely to adversely
affect supply of its Compound as contemplated by this Agreement.

 

2.3.Compound Commitments.

 

2.3.1.   Antigen Express agrees to Manufacture and supply the Antigen Express
Compound for purposes of the Study in accordance with Article 8, and Antigen
Express hereby represents and warrants to Merck that, at the time of Delivery of
the Antigen Express Compound, such Antigen Express Compound shall have been
Manufactured and supplied in compliance with: (i) the Specifications for the
Antigen Express Compound; (ii) the Clinical Quality Agreement; and (iii) all
Applicable Law, including cGMP and health, safety and environmental protections.

 

2.3.2.   Merck agrees to Manufacture and supply the Merck Compound for purposes
of the Study in accordance with Article 8, and Merck hereby represents and
warrants to Antigen Express that, at the time of Delivery of the Merck Compound,
such Merck Compound shall have been Manufactured and supplied in compliance
with: (i) the Specifications for the Merck Compound; (ii) the Clinical Quality
Agreement; and (iii) all Applicable Law, including cGMP and health, safety and
environmental protections.

8 

 

2.3.3.    Without limiting the foregoing, each Party is responsible for
obtaining all regulatory approvals (including facility licenses) that are
required to Manufacture its Compound in accordance with Applicable Law (provided
that, for clarity, Antigen Express shall be responsible for obtaining Regulatory
Approvals for the Study as set forth in Section 3.4).

 

2.4.    Delegation of Obligations. Each Party shall have the right to delegate
any portion of its obligations hereunder as follows: (a) to such Party’s
Affiliates, without the other Party’s consent; (b) to Third Parties that (i) are
conducting clinical trials of such Party’s Compound as of the Effective Date and
are set forth in the Protocol as performing such Study activities, or (ii) are
conducting Sample Testing for such Party, provided in each of (i) and (ii) that
both Parties have approved the use of such Third Parties in the performance of
such activities; (c) without restriction to the extent related to the
Manufacture of such Party’s Compound; and (d) upon the written consent of the
other Party. Any and all Third Parties to whom a Party delegates any of its
obligations hereunder are referred to as “Subcontractors.” Notwithstanding any
delegation of its obligations hereunder, each Party shall remain solely and
fully liable for the performance of its Affiliates and Subcontractors to which
such Party delegates the performance of its obligations under this Agreement.
Each Party shall ensure that each of its Affiliates and Subcontractors performs
such Party’s obligations pursuant to the terms of this Agreement, including the
Appendices and Schedules attached hereto. Each Party shall use reasonable
efforts to obtain and maintain copies of documents relating to the obligations
performed by such Affiliates and Subcontractors that are required to be provided
to the other Party under this Agreement.

 

2.5.    Compounds. Except as expressly set forth in Section 3.14, this Agreement
does not create any obligation on the part of Merck to provide the Merck
Compound for any activities other than the Study, nor does it create any
obligation on the part of Antigen Express to provide the Antigen Express
Compound for any activities other than the Study.

 

3.Conduct of the Study.

 

3.1.    Sponsor and Combination IND. Antigen Express shall act as the sponsor of
the Study. Antigen Express shall conduct the Study under a new IND specific for
the Combination (“Combination IND”), which will be prepared and submitted to FDA
by Antigen Express and will include a Right of Reference to the IND of the Merck
Compound as further described in Section 3.4. The Combination IND shall be filed
with a request for a waiver that exempts Merck from any requirement to notify
FDA of any Suspected Unexpected Serious Adverse Reactions (a “SUSAR Waiver”)
related to administration of the Merck Compound in any clinical study other than
as part of the Study. At Merck’s request, Merck shall have the right to review
all relevant documentation in connection with the Combination IND.
Notwithstanding the above, if FDA refuses to grant such SUSAR Waiver under the
Combination IND, Antigen Express shall instead sponsor the Study under its
existing IND for the Antigen Express Compound with a Right of Reference to the
IND of the Merck Compound as further described in Section 3.4; provided,
however, that in no event shall Antigen Express file an additional IND for the
Study, other than the Combination IND, unless required by Regulatory Authorities
to do so. If a Regulatory Authority requests such an additional IND for the
Study, the Parties shall meet and mutually agree on an approach to address such
requirement.

9 

 

3.2.    Performance. Antigen Express shall ensure that the Study is performed in
accordance with this Agreement, the Protocol and all Applicable Law, including
GCP.

 

3.3.    Debarred Personnel; Exclusions Lists. Notwithstanding anything to the
contrary contained herein, Antigen Express shall not employ or subcontract with
any Person that is excluded, debarred, suspended, proposed for suspension or
debarment, in Violation or otherwise ineligible for government programs for the
performance of the Study or any other activities under this Agreement or the
Related Agreements. Antigen Express hereby certifies that it has not employed or
otherwise used in any capacity and will not employ or otherwise use in any
capacity, the services of any Person suspended, proposed for debarment, or
debarred under United States law, including 21 USC 335a, or any foreign
equivalent thereof, in performing any portion of the Study or other activities
under this Agreement or the Related Agreements and that Antigen Express has, as
of the Effective Date, screened itself, and its officers and directors, against
the Exclusions Lists and that it has informed Merck whether it or any of its
officers or directors has been in Violation. Antigen Express shall notify Merck
in writing immediately if any such suspension, proposed debarment, debarment or
Violation occurs or comes to its attention, and shall, with respect to any
Person so suspended, proposed for debarment, debarred or in Violation, promptly
remove such Person from performing activities, function or capacity related to
the Study or otherwise related to activities under this Agreement or the Related
Agreements.

 

3.4.    Regulatory Matters. Antigen Express shall: (a) obtain, prior to
initiating the Study, all Regulatory Approvals from all Regulatory Authorities,
ethics committees and/or institutional review boards with jurisdiction over the
Study prior to initiating the Study; and (b) follow all directions from any such
Regulatory Authorities, ethics committees and/or institutional review boards.
Merck shall have the right (but not the obligation) to participate in any
discussions with a Regulatory Authority regarding matters related to the Merck
Compound. If a Right of Reference is necessary, each Party shall provide to the
other a cross-reference letter or similar communication to the applicable
Regulatory Authority if needed to effectuate the Right of Reference.
Notwithstanding anything to the contrary in this Agreement, neither Party shall
have any right to access the other Party’s CMC data with respect to such other
Party’s Compound. Merck shall authorize FDA and other applicable Regulatory
Authorities to cross- reference the appropriate Merck Compound INDs and CTAs to
provide data access to Antigen Express sufficient to support conduct of the
Study. If Merck’s CTA is not available in a given country, Merck will file its
CMC data with the Regulatory Authority for such country, referencing Antigen
Express’ CTA as appropriate (however, Antigen Express shall have no right to
directly access the CMC data).

 

3.5.    Documentation. Antigen Express shall maintain reports and all related
documentation in good scientific manner and in compliance with Applicable Law.
Antigen Express shall provide to Merck all Study information and documentation
reasonably requested by Merck to enable Merck to (a) comply with any of its
legal, regulatory and/or contractual obligations, or any request by any
Regulatory Authority, related to the Merck Compound and (b) determine whether
the Study has been performed in accordance with this Agreement.

 

3.6.    Copies. Antigen Express shall provide to Merck copies of all Clinical
Data, in electronic form or other mutually agreeable alternate form and on the
timelines specified in the

10 

 

Data Sharing/Sample Testing Schedule (if applicable) or upon mutually agreeable
timelines; provided, however, that and a complete copy of the Clinical Data
shall be provided to Merck no later than thirty (30) days following Study
Completion. Antigen Express shall ensure that all patient authorizations and
consents required under HIPAA, the EU Data Protection Directive (to the extent
any part of the Study is done in Europe), or any other similar Applicable Law in
connection with the Study permit such sharing of Clinical Data with Merck.

 

3.7.Samples.

 

3.7.1.   Antigen Express shall provide Samples to Merck as specified in the
Protocol or as agreed to by the Joint Development Committee. Each Party shall
(a) use the Samples only for the Sample Testing and (b) conduct the Sample
Testing solely in accordance with the Data Sharing/Sample Testing Schedule and
the Protocol.

 

3.7.2.   Merck shall own all Sample Testing Results arising from Sample Testing
performed by or on behalf of Merck. Solely to the extent specified on the Data
Sharing/Sample Testing Schedule as being shared, Merck shall provide to Antigen
Express the Sample Testing Results for the Sample Testing conducted by or on
behalf of Merck, in electronic form or other mutually agreeable alternate form,
on the timelines specified in the Data Sharing/Sample Testing Schedule or as
otherwise mutually agreed.

 

3.7.3.   Antigen Express shall own all Sample Testing Results arising from
Sample Testing performed by or on behalf of Antigen Express. Solely to the
extent specified on the Data Sharing/Sample Testing Schedule as being shared,
Antigen Express shall provide to Merck the Sample Testing Results for the Sample
Testing conducted by or on behalf of Antigen Express, in electronic form or
other mutually agreeable alternate form, on the timelines specified in the Data
Sharing/Sample Testing Schedule or as otherwise mutually agreed.

 

3.7.4.   Except to the extent otherwise agreed in a writing signed by authorized
representatives of each Party, each Party may use and disclose the Sample
Testing Results owned by the other Party and shared by such other Party in
accordance with the Data Sharing/Sample Testing Schedule solely for the purposes
of (i) seeking Regulatory Approval for the use of its respective Compound in the
Combination and (ii) filing and prosecuting Joint Patent Applications and
enforcing any Joint Patents in accordance with Article 10.

 

3.8.Ownership and Use of Clinical Data.

 

3.8.1.   All Clinical Data shall be jointly owned by Antigen Express and Merck.
Merck hereby assigns to Antigen Express an undivided one-half interest in, to
and under the Clinical Data. Antigen Express hereby assigns to Merck an
undivided one-half interest in, to and under the Clinical Data. If such
assignment cannot or does not occur, including in circumstances where such
assignment is precluded by law, the Party with the obligation to assign hereby
grants the other Party a non-exclusive license, with the right to grant
sublicenses and to assign its license rights to the Clinical Data to any Person,
in each case without the consent of the granting Party and without any
accounting to such Party. Antigen Express shall maintain the Clinical Data in
its internal database; provided, however, that at all times during the Term,
Antigen

11 

 

Express shall grant Merck access to all Clinical Data and any portions of
Antigen Express’ database that include Clinical Data.

 

3.8.2.   Notwithstanding the foregoing, and subject to the remaining provisions
of this Section 3.8, before publication of the Clinical Data in accordance
Article 12, (a) neither Party may disclose the Clinical Data publicly or to a
Third Party without the consent of the other Party; and (b) in no event may (i)
Merck use Clinical Data, directly or indirectly, to research, develop or
commercialize a compound that is an Antigen Express Class Compound (whether as a
monotherapy or in a combination other than pursuant to this Agreement) or (ii)
Antigen Express use Clinical Data, directly or indirectly, to research, develop
or commercialize a PD-1 Antagonist (whether as a monotherapy or in a combination
other than pursuant to this Agreement). Each Party’s use of unpublished Clinical
Data is restricted to (A) seeking regulatory approval for use of such Party’s
Compound in the Combination; (B) prosecuting and enforcing Jointly Owned
Inventions; (C) conducing Subsequent Studies; and (D) internal purposes related
to its own Compound; provided, however, that the foregoing shall not limit or
restrict either Party’s ability to (x) use or disclose the unpublished Clinical
Data as may be necessary to comply with Applicable Law or with such Party’s
internal policies and procedures with respect to pharmacovigilance and adverse
event reporting, or (y) share with Third Parties or Affiliates Toxicity & Safety
Data where because of severity, frequency or lack of reversibility either Party
needs to use such Toxicity & Safety Data with respect to its own Compound or the
Combination to ensure patient safety.

 

3.9.    Regulatory Submission. It is understood and acknowledged by the Parties
that positive Clinical Data could be used to obtain label changes for the
Compounds, and each Party may propose a Subsequent Study (as defined below) in
connection therewith in accordance with Section 3.14.

 

3.10.   Joint Development Committee. The Parties shall form a joint development
committee (the “Joint Development Committee” or “JDC”) made up of an equal
number of representatives of Merck and Antigen Express, with Antigen Express
members having one vote and Merck members having one vote, which shall have
responsibility for coordinating all regulatory and other activities under, and
pursuant to, this Agreement. Each Party shall designate a project manager (the
“Project Manager”) who shall be responsible for implementing and coordinating
activities and facilitating the exchange of information between the Parties with
respect to the Study and shall be a member of the JDC. Other JDC members will be
agreed by both Parties. The JDC shall meet as soon as practicable after the
Effective Date and then no less than twice yearly, and more often as reasonably
considered necessary at the request of either Party, to provide an update on the
progress of the Study. The JDC may meet in person or by means of teleconference,
Internet conference, videoconference or other similar communications equipment.
Prior to any such meeting, the Antigen Express Project Manager shall provide an
update in writing to the Merck Project Manager, which update shall contain
information about the overall progress of the Study, recruitment status, interim
analysis (if results available), final analysis and other information relevant
to the conduct of the Study. In addition to a Project Manager, each Party shall
designate an alliance manager (the “Alliance Manager”), who shall endeavor to
ensure clear and responsive communication between the Parties and the effective
exchange of information and shall serve as the primary point of contact for any
issues arising under this Agreement. The Alliance Managers shall have the right
to

12 

 

attend all JDC meetings and may bring to the attention of the JDC any matters or
issues either of them reasonably believes should be discussed and shall have
such other responsibilities as the Parties may mutually agree in writing. In the
event that an issue arises and the Alliance Managers cannot or do not, after
reasonable efforts, reach agreement on such issue, or if there is a decision to
be made by the JDC on which the members of the JDC cannot unanimously agree, the
issue shall be elevated to the Vice President of Clinical Oncology for Merck and
the Chief Operating Officer for Antigen Express. In the event such escalation
does not result in resolution or consensus: (a) Merck shall have final
decision-making authority with respect to issues related to Merck Compound; and
(b) Antigen Express shall have final decision-making authority with respect to
issues related to Antigen Express Compound.

 

3.11.   Final Study Report. Antigen Express shall provide Merck with an
electronic draft of the final study report promptly following Study Completion,
and Merck shall have thirty (30) days after receipt of such draft to provide
comments thereon. Antigen Express shall reasonably consider any comments
provided by Merck on the draft final study report and shall not include any
statements relating to the Merck Compound that have not been approved by Merck.
Antigen Express shall deliver to Merck a final version of the final study report
promptly following finalization thereof (the “Final Study Report”). “Study
Completion” shall occur upon database lock of the Study results.

 

3.12.   Relationship. Except as expressly set forth in this Agreement, nothing
in this Agreement shall: (a) prohibit either Party from performing clinical
studies other than the Study relating to its own Compound, either individually
or in combination with any other compound or product, in any therapeutic area;
or (b) create an exclusive relationship between the Parties with respect to any
Compound. Each Party acknowledges and agrees that nothing in this Agreement
shall be construed as a representation or inference that the other Party will
not develop for itself, or enter into business relationships with other Third
Parties regarding, any products, programs, studies (including combination
studies), technologies or processes that are similar to or that may compete with
the Combination or any other product, program, technology or process, including
Antigen Express Class Compound or PD-1 Antagonists, provided that the Clinical
Data, Confidential Information, Jointly Owned Inventions and Sample Testing
Results are not used or disclosed in connection therewith in violation of this
Agreement.

 

3.13.   Licensing. Nothing in this Agreement shall prohibit or restrict a Party
from licensing, assigning or otherwise transferring to an Affiliate or Third
Party such Party’s Compound or any Inventions, Confidential Information or
Sample Testing Results owned solely by such Party. A Party may license, assign
or transfer to an Affiliate or Third Party such Party’s interest in the Clinical
Data, Confidential Information owned jointly by the Parties and/or Jointly Owned
Inventions, and in connection therewith share the shared Sample Testing Results
owned by the other Party, solely to the extent such licensee, assignee or
transferee agrees in writing to be bound by the terms of this Agreement with
respect to such Clinical Data, Confidential Information, Jointly Owned
Inventions, and shared Sample Testing Results. For purposes of clarity, any
assignment or transfer of this Agreement must comply with Section 18 of this
Agreement.

 

3.14.Subsequent Study.

13 

 

3.14.1.  During the Term and for a period of twelve (12) months thereafter,
either Party shall have the option to propose additional studies for the purpose
of conducting a registration study for the Combination in the same indication as
the Study (each a “Subsequent Study”) by sending a written proposal to the other
Party. Antigen Express must offer Merck the option of participating in a
Subsequent Study prior to entering into an agreement with a Third Party to
conduct a registration study in the same indication and line of therapy as the
Study of the Antigen Express Compound in concomitant and/or sequential
administration with a PD-1 Antagonist.

 

3.14.2.  If the receiving Party desires to engage in discussions around the
proposed Subsequent Study, such Party shall notify the other Party, in writing,
no later than ninety (90) days after receipt of the written proposal. Following
such notification, the Parties shall negotiate in good faith the terms of an
amendment to this Agreement and the Related Agreements or a new agreement (a
“Subsequent Study Agreement”), as appropriate, but will have no obligation to
agree upon the details of, or execute, such amendment or Subsequent Study
Agreement. Any such amendment or Subsequent Study Agreement would include the
following:

 

(a)the Party that would sponsor such Subsequent Study:

 

(b)a full and final protocol;

 

(c)how costs would be allocated;

 

(d)that the Parties will jointly own all data (including raw data) and results
generated by or on behalf of either Party or at either Party’s direction, or by
or on behalf of the Parties together or at their direction in the course of each
such Party’s performance of the Subsequent Study (excluding any data and results
arising from a Party’s sample testing) and that the sponsor Party will provide
the other Party the unpublished summary data and results from the Subsequent
Study as promptly as reasonable after the data is available; and

 

(e)that the Parties shall jointly own the Jointly Owned Inventions.

 

4.Protocol and Certain Other Documents.

 

4.1.    Protocol. A protocol and statistical analysis plan for the Study,
entitled “A Phase II Clinical Trial of Pembrolizumab in combination with the
AE37 Peptide Vaccine in Patients with Metastatic Triple Negative Breast Cancer,”
has been agreed to by the Parties as of the Effective Date and is attached
hereto as Appendix A (the “Protocol”). The Protocol may be amended with the
approval of the JDC, subject to each Party’s decision making rights set forth in
this Section 4.1. To the extent there is a disagreement between the Parties
regarding the contents of the Protocol, Antigen Express shall have final
decision-making authority; provided, however, that any material changes to any
draft of the Protocol (other than material changes relating solely to the
Antigen Express Compound) from the draft of the Protocol previously provided to
Merck, any material changes to the approved final Protocol (other than material
changes relating solely to the Antigen Express Compound), and any changes to any
draft of the Protocol or approved

14 

 

final Protocol (whether or not material) relating to the Merck Compound
(including with respect to the quantities and/or presentations of Merck Compound
to be provided for the Study and/or the timing for Delivery thereof), shall
require Merck’s prior written consent. Any such proposed changes will be sent in
writing to Merck’s Project Manager and Merck’s Alliance Manager. Merck will
provide such consent, or a written explanation for why such consent is being
withheld, within fifteen (15) Business Days after Merck receives a copy of
Antigen Express’ requested changes.

 

4.1.1.   Notwithstanding anything to the contrary contained herein, Merck, in
its sole discretion, shall have the sole right to determine the dose and dosing
regimen for the Merck Compound and shall have the final decision on all matters
relating to the Merck Compound (including quantities of Merck Compound to be
supplied pursuant to Article 8) and any information regarding the Merck Compound
included in the Protocol.

 

4.1.2.   Notwithstanding anything to the contrary contained herein, Antigen
Express, in its sole discretion, shall have the sole right to determine the dose
and dosing regimen for the Antigen Express Compound and shall have the final
decision on all matters relating to the Antigen Express Compound (including
quantities of Antigen Express Compound to be supplied pursuant to Article 8) and
any information regarding the Antigen Express Compound included in the Protocol.

 

4.2.    Informed Consent. Antigen Express shall prepare the patient informed
consent form for the Study (which shall include provisions regarding the use of
Samples in Sample Testing) in consultation with Merck (it being understood and
agreed that the portion of the informed consent form relating to the Sample
Testing of the Merck Compound shall be provided to Antigen Express by Merck).
Any proposed changes to such form that relate to the Merck Compound, including
Sample Testing of the Merck Compound, shall be subject to Merck’s prior written
consent. Any such proposed changes will be sent in writing to Merck’s Project
Manager and Merck’s Alliance Manager. Merck will provide such consent, or a
written explanation for why such consent is being withheld, within fifteen (15)
Business Days after Merck receives a copy of Antigen Express’ requested changes.

 

4.3.    Financial Disclosure. Antigen Express shall (a) track and collect
financial disclosure information from all “clinical investigators” involved in
the Study and (b) prepare and submit the certification and/or disclosure of the
same in accordance with all Applicable Law, including, but not limited to, Part
54 of Title 21 of the United States Code of Federal Regulations (Financial
Disclosure by Clinical Investigators) and related FDA Guidance Documents. Prior
to the initiation of clinical activities under the Study, but in any event
within 60 days after the Effective Date, the parties shall determine whether
Antigen Express shall track and collect from all “clinical investigators”
involved in the Study separate certification and/or disclosure forms for each of
Merck and Antigen Express or one (1) “combined” certification and/or disclosure
form for both Merck and Antigen Express. For purposes of this Section 4.3, the
term “clinical investigators” shall have the meaning set forth in Part 54.2(d)
of Title 21 of the United States Code of Federal Regulations.

 

4.4.Transparency Reporting.

15 

 

4.4.1.   With respect to any annual reporting period in which Antigen Express is
not an entity that is required to make a Transparency Report under Applicable
Law, Antigen Express will: (a) notify Merck, in writing, within thirty (30) days
after the commencement of such reporting period that Antigen Express is not so
required; and (b) during such reporting period Antigen Express will track and
provide to Merck data regarding “indirect” payments or other transfers of value
by Antigen Express to such health care professionals to the extent such payments
or other transfers of value were required, instructed, directed or otherwise
caused by Merck pursuant to this Agreement in the format requested by Merck and
provided on a basis to be agreed upon by both Parties. Antigen Express
represents and warrants that any data provided by Antigen Express to Merck
pursuant to Section 4.4.1(b) above will be complete and accurate to the best of
Antigen Express knowledge.

 

4.4.2.   With respect to any annual reporting period in which Antigen Express is
required to make a Transparency Report under Applicable Law, Antigen Express
will provide to Merck, in writing, Antigen Express’ point of contact for
purposes of receiving information from Merck pursuant to this Section 4.4, along
with such contact’s full name, email address, and telephone number. Antigen
Express may update such contact from time to time by notifying Merck in writing
pursuant to Article 22 (Notices). Where applicable, Merck will provide to such
Antigen Express contact all information regarding the value of the Merck
Compound provided for use in the Study required for such reporting. In the event
that the value of the Merck Compound provided pursuant to this Section 4.4.2
changes, Merck shall notify Antigen Express of such revised value and the
effective date thereof.

 

4.4.3.   For purposes of this Section 4.4, “Transparency Report” means a
transparency report in connection with reporting payments and other transfers of
value made to health care professionals, including, without limitation,
investigators, steering committee members, data monitoring committee members,
and consultants in connection with the Study in accordance with reporting
requirements under Applicable Law, including, without limitation, the Physician
Payment Sunshine Act and state gift laws, and the European Federation of
Pharmaceutical Industries and Associations Disclosure Code, or a Party’s
applicable policies.

 

5.Adverse Event Reporting.

 

5.1.    Pharmacovigilance Agreement. Antigen Express will be solely responsible
for compliance with all Applicable Laws pertaining to safety reporting for the
Study and related activities. The Parties (or their respective Affiliates) will
execute a pharmacovigilance agreement (the “Pharmacovigilance Agreement”) prior
to the initiation of clinical activities under the Study, but in any event
within sixty (60) days after the Effective Date, to ensure the exchange of
relevant safety data within appropriate timeframes and in an appropriate format
to enable the Parties to fulfill local and international regulatory reporting
obligations and to facilitate appropriate safety reviews. In the event of any
inconsistency between the terms of this Agreement and the Pharmacovigilance
Agreement, the terms of this Agreement shall control. The Pharmacovigilance
Agreement will include safety data exchange procedures governing the
coordination of collection, investigation, reporting, and exchange of
information concerning any adverse experiences, pregnancy reports, and any other
safety information arising from or related to the use of the Merck Compound and
Antigen Express Compound in the Study, consistent with Applicable Law. Such
guidelines and procedures shall be in accordance with, and enable the

16 

 

Parties and their Affiliates to fulfill, local and international regulatory
reporting obligations to Government Authorities.

 

5.2.    Transmission of SAEs. Antigen Express will transmit to Merck all serious
adverse events (“SAEs”) as follows:

 

5.2.1.   For drug-related fatal and life-threatening SAEs, Antigen Express will
send a completely processed case (on a CIOMS-1 form in English) within three (3)
calendar days after receipt by Antigen Express of such SAEs.

 

5.2.2.   For all other SAEs, including non-drug-related fatal and
life-threatening SAEs, Antigen Express will send a completely processed case (on
a CIOMS-1 form in English) within five (5) calendar days after receipt by
Antigen Express of such SAEs.

 

6.Term and Termination.

 

6.1.    Term. The term of this Agreement shall commence on the Effective Date
and shall continue in full force and effect until the earlier of (i) delivery of
the Final Study Report and (ii) Study Completion plus three (3) months, or until
terminated by either Party pursuant to this Article 6 (the “Term”).

 

6.2.    Merck Termination Right for Safety. In the event that Merck in good
faith believes that the Merck Compound is being used in the Study in an unsafe
manner and notifies Antigen Express in writing of the grounds for such belief,
and Antigen Express fails to promptly incorporate changes into the Protocol
requested by Merck to address such issue or to otherwise address such issue
reasonably, Merck may terminate this Agreement and the supply of the Merck
Compound immediately upon written notice to Antigen Express.

 

6.3.    Termination for Material Breach. Either Party may terminate this
Agreement if the other Party commits a material breach of this Agreement, and
such material breach continues for thirty (30) days after receipt of written
notice thereof from the non-breaching Party; provided that if such material
breach cannot reasonably be cured within thirty (30) days, the breaching Party
shall be given a reasonable period of time to cure such breach; provided
further, that if such material breach is incapable of cure, then the notifying
Party may terminate this Agreement effective after the expiration of such thirty
(30) day period.

 

6.4.    Termination for Patient Safety. If either Party reasonably determines,
based on a review of the Clinical Data, Sample Testing Results or other
Study-related Know-How or other information, that the Study may unreasonably
affect patient safety, such Party shall promptly notify the other Party of such
determination. The Party receiving such notice may propose modifications to the
Study to address the safety issue identified by the other Party and, if the
notifying Party agrees, shall act to implement immediately such modifications;
provided, however, that if the notifying Party, in its sole discretion, believes
that there is imminent danger to patients, such Party need not wait for the
other Party to propose modifications and may instead terminate this Agreement
immediately upon written notice to such other Party. Furthermore, if the
notifying Party, in its sole discretion, believes that any modifications
proposed by the other Party will not resolve the patient safety issue, such
Party may terminate this Agreement effective upon written notice to such other
Party.

17

17 

 

6.5.    Termination for Regulatory Action; Other Reasons. Either Party may
terminate this Agreement immediately upon written notice to the other Party in
the event that any Regulatory Authority takes any action, or raises any
objection, that prevents the terminating Party from supplying its Compound for
purposes of the Study. Additionally, either Party shall have the right to
terminate this Agreement immediately upon written notice to the other Party in
the event that it determines in its sole discretion to withdraw any applicable
Regulatory Approval for its Compound or to discontinue development of its
Compound, for medical, scientific or legal reasons.

 

6.6.    Return of Merck Compound. In the event that this Agreement is
terminated, or in the event Antigen Express remains in possession (including
through any Affiliate or Subcontractor) of Merck Compound at the time this
Agreement expires, Antigen Express shall, at Merck’s sole discretion, promptly
either return or destroy all unused Merck Compound pursuant to Merck’s
instructions. If Merck requests that Antigen Express destroy the unused Merck
Compound, Antigen Express shall provide written certification of such
destruction.

 

6.7.    Termination Related to Anti-Corruption. Either Party shall have the
right to terminate this Agreement immediately upon written notice to the other
Party, if such other Party fails to perform any of its obligations under Section
13.4 or breaches any representation or warranty contained in Section 13.4.
Except as set forth in Section 6.11, the non-terminating Party shall have no
claim against the terminating Party for compensation for any loss of whatever
nature by virtue of the termination of this Agreement in accordance with this
Section 6.7.

 

6.8.    Survival. The provisions of Sections 3.4 through 3.8 (inclusive), 3.9,
3.13, 4.3, 6.6 through 6.11 (inclusive), 8.5.2, 8.11, 8.14 through 8.16
(inclusive), 13.4.6, 14.2, and 14.3, and Articles 1, 5, 9 through 12
(inclusive), 17, and 20 through 25 (inclusive) shall survive the expiration or
termination of this Agreement.

 

6.9.    No Prejudice. Termination of this Agreement shall be without prejudice
to any claim or right of action of either Party against the other Party for any
prior breach of this Agreement.

 

6.10.   Confidential Information. Upon termination of this Agreement, each Party
and its Affiliates shall promptly return to the Disclosing Party or destroy any
Confidential Information of the Disclosing Party (other than Clinical Data,
Sample Testing Results and Inventions) furnished to the Receiving Party by the
Disclosing Party; provided, however that the Receiving Party may retain one copy
of such Confidential Information in its confidential files, solely for purposes
of exercising the Receiving Party’s rights hereunder, satisfying its obligations
hereunder or complying with any legal proceeding or requirement with respect
thereto, and provided further that the Receiving Party shall not be required to
erase electronic files created in the ordinary course of business during
automatic system back-up procedures pursuant to its electronic record retention
and destruction practices that apply to its own general electronic files and
information so long as such electronic files are (i) maintained only on
centralized storage servers (and not on personal computers or devices), (ii) not
accessible by any of its personnel (other than its information technology
specialists), and (iii) are not otherwise accessed subsequently except with the
written consent of the Disclosing Party or as required by law or

 

18

18 

 

legal process. Such retained copies of Confidential Information shall remain
subject to the confidentiality and non-use obligations herein.

 

6.11.   Manufacturing Costs. In the event of termination by Merck pursuant to
Section 6.2, 6.3 or 6.7 above, Merck shall be entitled to reimbursement by
Antigen Express for the Direct Manufacturing Costs and Indirect Manufacturing
Costs (as defined herein) incurred by Merck for its Compound Delivered for the
Study. “Direct Manufacturing Costs” shall be calculated consistent with
Generally Accepted Accounting Principles (“GAAP”) and include manufacturing
fees, raw materials, direct labor, freight and duty, and factory overhead costs
that can be directly attributed to the Compound, including but not limited to
equipment maintenance and repair, supplies, ongoing stability program costs,
other plant services, indirect labor and depreciation on direct capital assets.
“Indirect Manufacturing Costs” shall be calculated consistent with GAAP and
include allocations of indirect factory overhead and site support costs,
including but not limited to utilities, quality, planning, engineering,
maintenance, safety, site science and technology, and depreciation on indirect
capital assets, procurement, warehousing, and corporate services. Allocations
shall be based on each Compound’s utilization relative to a manufacturing site’s
total activity. In the event of termination by Antigen Express pursuant to
Section 6.3 or 6.7 above, and in order to complete the Study it is necessary for
Antigen Express to purchase Merck Compound, Merck shall reimburse Antigen
Express’ out of pocket costs for the purchase of Merck Compound (from a Third
Party) necessary to complete the Study as contemplated by the Protocol;
provided, however, that in no event shall Merck’s obligation to reimburse
Antigen Express subject to this sentence exceed one hundred thousand US Dollars
($100,000) in the aggregate.

 

7.Costs of Study.

 

The Parties agree that: (a) Merck shall provide the Merck Compound for use in
the Study, as described in Article 8 below; (b) each Party will be responsible
for its own internal costs and expenses to support the Study and the costs of
any Sample Testing conducted by such Party in connection with the Study; and (c)
Antigen Express shall bear all other costs associated with the conduct of the
Study, including that Antigen Express shall provide the Antigen Express Compound
for use in the Study, as described in Article 8 below. For the avoidance of
doubt, Antigen Express will not be required to reimburse Merck for any costs or
expenses incurred by Merck or its Affiliates in connection with the Study
(except as provided in Section 6.11) and Merck will not be required to reimburse
Antigen Express for any costs or expenses incurred by Antigen Express or its
Affiliates in connection with the Study.

 

8.Supply and Use of the Compounds.

 

8.1.    Supply of the Compounds. Subject to the terms and conditions of this
Agreement, each of Antigen Express and Merck will use commercially reasonable
efforts to supply, or cause to be supplied, the quantities of its respective
Compound as are set forth in Appendix B, on the timelines set forth in Appendix
B, in each case for use in the Study; provided, however, in the event the Study
will be conducted under a Combination IND in accordance with Section 3.1, no
Merck Compound shall be supplied until after the SUSAR Waiver has been obtained.
If the initial supply timelines in Appendix B need to be altered as a result of
a delay in obtaining the SUSAR Waiver or the need to re-submit the Study to FDA
under a supplement to the existing

19 

 

IND of the Antigen Express Compound, such timelines may be altered without
amending the Agreement, by mutual consent of the Parities in writing via email.
If the Protocol is changed in accordance with Section 4 in such a manner that
may affect the quantities of Compound to be provided or the timing for providing
such quantities, the Parties shall amend Appendix B to reflect any changes
required to be consistent with the Protocol. Each Party shall also provide to
the other Party a contact person for the supply of its Compound under this
Agreement. Notwithstanding the foregoing, or anything to the contrary herein, in
the event that either Party is not supplying its Compound in accordance with the
terms of this Agreement, or is allocating under Section 8.10, then the other
Party shall have no obligation to supply its Compound, or may allocate
proportionally.

 

8.2.    Clinical Quality Agreement. Within forty five (45) days from the
Effective Date of this Agreement, but in any event before any supply under this
Agreement of the Merck Compound, the Parties (or their respective Affiliates)
shall enter into a quality agreement that shall address and govern issues
related to the quality of clinical drug supply to be supplied by the Parties for
use in the Study (the “Clinical Quality Agreement”). In the event of any
inconsistency between the terms of this Agreement and the Clinical Quality
Agreement, the terms of this Agreement shall control. The Clinical Quality
Agreement shall, among other things:

(i)   detail classification of any Compound found to have a Non-Conformance;
(ii) include criteria for Manufacturer’s Release and related certificates and
documentation; (iii) include criteria and timeframes for acceptance of Merck
Compound; (iv) include procedures for the resolution of disputes regarding any
Compounds found to have a Non-Conformance; and (v) include provisions governing
the recall of Compounds.

 

8.3.    Minimum Shelf Life Requirements. Each Party shall use commercially
reasonable efforts to supply its Compound hereunder with an adequate remaining
shelf life at the time of Delivery to meet the Study requirements.

 

8.4.Provision of Compounds.

 

8.4.1.   Merck will deliver the Merck Compound DAP (INCOTERMS 2010) to Antigen
Express’, or its designee’s, location as specified by Antigen Express
(“Delivery” with respect to such Merck Compound). Title and risk of loss for the
Merck Compound shall transfer from Merck to Antigen Express at Delivery. All
costs associated with the subsequent transportation, warehousing and
distribution of Merck Compound shall be borne by Antigen Express. Antigen
Express will, or will cause its designee to: (i) take delivery of the Merck
Compound supplied hereunder; (ii) perform the acceptance (including testing)
procedures allocated to it under the Clinical Quality Agreement; (iii)
subsequently label and pack the Merck Compound (in accordance with Section 8.5),
and promptly ship the Merck Compound to the Study sites for use in the Study, in
compliance with cGMP, GCP and other Applicable Law and the Clinical Quality
Agreement; and (iv) provide, from time to time at the reasonable request of
Merck, the following information: any applicable chain of custody forms,
in-transport temperature recorder(s), records and receipt verification
documentation, such other transport or storage documentation as may be
reasonably requested by Merck, and usage and inventory reconciliation
documentation related to the Merck Compound.

20 

 

8.4.2.   Antigen Express is solely responsible, at its own cost, for supplying
(including all Manufacturing, acceptance and release testing) the Antigen
Express Compound for the Study, and the subsequent handling, storage,
transportation, warehousing and distribution of the Antigen Express Compound
supplied hereunder. Antigen Express shall ensure that all such activities are
conducted in compliance with cGMP, GCP and other Applicable Law and the Clinical
Quality Agreement. For purposes of this Agreement, the “Delivery” of a given
quantity of the Antigen Express Compound shall be deemed to occur when such
quantity is packaged for shipment to a Study site.

 

8.5.Labeling and Packaging; Use, Handling and Storage.

 

8.5.1.   The Parties’ obligations with respect to the labeling and packaging of
the Compounds are as set forth in the Clinical Quality Agreement.
Notwithstanding the foregoing or anything to the contrary contained herein,
Merck shall provide the Merck Compound to Antigen Express in the form of
unlabeled vials, and Antigen Express shall be responsible for labeling,
packaging and leafleting such Merck Compound in accordance with the terms and
conditions of the Clinical Quality Agreement and otherwise in accordance with
all Applicable Law, including cGMP, GCP, and health, safety and environmental
protections.

 

8.5.2.   Antigen Express shall: (i) use the Merck Compound solely for purposes
of performing the Study; (ii) not use the Merck Compound in any manner that is
inconsistent with this Agreement or for any commercial purpose; and (iii) label,
use, store, transport, handle and dispose of the Merck Compound in compliance
with Applicable Law and the Clinical Quality Agreement, as well as all
instructions of Merck. Antigen Express shall not reverse engineer, reverse
compile, disassemble or otherwise attempt to derive the composition or
underlying information, structure or ideas of the Merck Compound, and in
particular shall not analyze the Merck Compound by physical, chemical or
biochemical means except as necessary to perform its obligations under the
Clinical Quality Agreement.

 

8.6.    Product Specifications. A certificate of analysis shall accompany each
shipment of the Merck Compound to Antigen Express. Upon request, Antigen Express
shall provide Merck with a certificate of analysis covering each shipment of
Antigen Express Compound used in the Study.

 

8.7.    Changes to Manufacturing. Each Party may make changes from time to time
to its Compound or the Manufacturing Site, provided that such changes shall be
in accordance with the Clinical Quality Agreement.

 

8.8.Product Testing; Noncompliance.

 

8.8.1.   After Manufacturer’s Release. After Manufacturer’s Release of the Merck
Compound and concurrently with Delivery of the Compound to Antigen Express,
Merck shall provide Antigen Express with such certificates and documentation as
are described in the Clinical Quality Agreement (“Disposition Package”). Antigen
Express shall, within the time defined in the Clinical Quality Agreement,
perform with respect to the Merck Compound, the acceptance (including testing)
procedures allocated to it under the Clinical Quality Agreement. Antigen Express
shall be solely responsible for taking all steps necessary to determine that

21 

 

Merck Compound or Antigen Express Compound, as applicable, is suitable for
release before making such Merck Compound or Antigen Express Compound, as
applicable, available for human use, and Merck shall provide cooperation or
assistance as reasonably requested by Antigen Express in connection with such
determination with respect to the Merck Compound. Antigen Express shall be
responsible for storage and maintenance of the Merck Compound until it is tested
and/or released, which storage and maintenance shall be in compliance with (a)
the Specifications for the Merck Compound, the Clinical Quality Agreement and
Applicable Law and (b) any specific storage and maintenance requirements as may
be provided by Merck from time to time. Antigen Express shall be responsible for
any failure of the Merck Compound to meet the Specifications to the extent
caused by shipping, storage or handling conditions after Delivery to Antigen
Express hereunder.

 

8.8.2.Non-Conformance.

 

(a)                              In the event that either Party becomes aware
that any Compound may have a Non-Conformance, despite testing and quality
assurance activities (including any activities conducted by the Parties under
Section 8.8.1), such Party shall immediately notify the other Party in
accordance with the procedures of the Clinical Quality Agreement. The Parties
shall investigate any Non-Conformance in accordance with Section 8.9
(Investigations) and any discrepancy between them shall be resolved in
accordance with Section 8.8.3.

 

(b)                             In the event that any proposed or actual
shipment of the Merck Compound (or portion thereof) shall be agreed to have a
Non-Conformance at the time of Delivery to Antigen Express, then unless
otherwise agreed to by the Parties, Merck shall replace such Merck Compound as
is found to have a Non-Conformance (with respect to Merck Compound that has not
yet been administered in the course of performing the Study). Unless otherwise
agreed to by the Parties in writing, the sole and exclusive remedies of Antigen
Express with respect to any Merck Compound that is found to have a
Non-Conformance at the time of Delivery shall be (i) replacement of such Merck
Compound as set forth in this Section 8.8.2(b), (ii) indemnification under
Section 14.2.2 (to the extent applicable), and (iii) termination of this
Agreement pursuant to Section 6.3 (to the extent applicable, but subject to the
applicable cure periods set forth therein); provided that, for clarity, Antigen
Express shall not be deemed to be waiving any rights under Section 8.15. In the
event Merck Compound is lost or damaged by Antigen Express after Delivery, Merck
shall provide additional Merck Compound (if available for the Study) to Antigen
Express; provided that Antigen Express shall reimburse Merck for the Direct
Manufacturing Costs and Indirect Manufacturing Costs (as such terms are defined
in Section 6.11) of such replaced Merck Compound; and provided further that
Merck shall have no obligation to provide additional Merck Compound more than
once. Except as set forth in the foregoing sentence, Merck shall have no
obligation to provide replacement Merck Compound for any Merck Compound supplied
hereunder other than such Merck Compound as has been agreed or determined to
have a Non-Conformance at the time of Delivery to Antigen Express.

 

(c)                              Antigen Express shall be responsible for, and
Merck shall have no obligation or liability with respect to, any Antigen Express
Compound supplied hereunder that is found to have a Non-Conformance. Antigen
Express shall replace any Antigen Express Compound as is found to have a
Non-Conformance (with respect to Antigen Express Compound that has not yet been
administered in the course of performing the Study). Unless otherwise

22 

 

agreed to by the Parties in writing, the sole and exclusive remedies of Merck
with respect to any Antigen Express Compound that is found to have a
Non-Conformance at the time of Delivery shall be (i) replacement of such Antigen
Express Compound as set forth in this Section 8.8.2(c),

(ii)   indemnification under Section 14.2.1 (to the extent applicable), and
(iii) termination of this Agreement pursuant to Section 6.3 (to the extent
applicable, but subject to the applicable cure periods set forth therein);
provided that, for clarity, Merck shall not be deemed to be waiving any rights
under Section 8.15.

 

8.8.3.   Resolution of Discrepancies. Disagreements regarding any determination
of Non-Conformance by Antigen Express shall be resolved in accordance with the
provisions of the Clinical Quality Agreement.

 

8.9.    Investigations. The process for investigations of any Non-Conformance
shall be handled in accordance with the Clinical Quality Agreement.

 

8.10.   Shortage; Allocation. In the event that a Party’s Compound is in short
supply such that a Party reasonably believes that it will not be able to fulfill
its supply obligations hereunder with respect to its Compound, such Party will
provide prompt written notice to the other Party thereof (including the
shipments of Compound hereunder expected to be impacted and the quantity of its
Compound that such Party reasonably determines it will be able to supply) and
the Parties will promptly discuss such situation (including how the quantity of
Compound that such Party is able to supply hereunder will be allocated within
the Study). In such event, the Party experiencing such shortage shall (i) use
its commercially reasonable efforts to remedy the situation giving rise to such
shortage and to take action to minimize the impact of the shortage on the Study,
and (ii) allocate to the other Party an amount of Compound at least
proportionate to the total amount of the Compound shipments hereunder expected
to be impacted by the shortage divided by the total demand for the Compound for
the impacted time period.

 

8.11.   Records; Audit Rights. Antigen Express shall keep complete and accurate
records pertaining to its use and disposition of Merck Compound (including its
storage, shipping (cold chain) and chain of custody activities) and, upon
request of Merck, shall make such records open to review by Merck for the
purpose of conducting investigations for the determination of Merck Compound
safety and/or efficacy and Antigen Express’ compliance with this Agreement with
respect to the Merck Compound.

 

8.12.   Quality. Quality matters related to the Manufacture of the Compounds
shall be governed by the terms of the Clinical Quality Agreement in addition to
the relevant quality provisions of this Agreement.

 

8.13.   Quality Control. Each Party shall implement and perform operating
procedures and controls for sampling, stability and other testing of its
Compound, and for validation, documentation and release of its Compound and such
other quality assurance and quality control procedures as are required by the
Specifications, cGMPs and the Clinical Quality Agreement.

 

8.14.   Audits and Inspections. The Parties’ audit and inspection rights related
to this Agreement shall be governed by the terms of the Clinical Quality
Agreement.

23 

 

8.15.   Recalls. Recalls of the Compounds shall be governed by the terms of the
Clinical Quality Agreement.

 

8.16.VAT.

 

8.16.1.  It is understood and agreed between the Parties that any payments made
and any other consideration given under this Agreement are each exclusive of any
value added or similar tax (“VAT”), which shall be added thereon as applicable
and at the relevant rate. Subject to Section 8.16.2, where VAT is properly
charged by the supplying Party and added to a payment made or other
consideration provided (as applicable) under this Agreement, the Party making
the payment or providing the other consideration (as applicable) will pay the
amount of VAT properly chargeable only on receipt of a valid tax invoice from
the supplying Party issued in accordance with the laws and regulations of the
country in which the VAT is chargeable. Each Party agrees that it shall provide
to the other Party any information and copies of any documents within its
Control to the extent reasonably requested by the other Party for the purposes
of (i) determining the amount of VAT chargeable on any supply made under this
Agreement, (ii) establishing the place of supply for VAT purposes, or (iii)
complying with its VAT reporting or accounting obligations.

 

8.16.2.  Where one Party or its Affiliate (the “First Party”) is treated as
making supply of goods or services in a particular jurisdiction (for VAT
purposes) for non-cash consideration, and the other Party or its Affiliate (the
“Second Party”) is treated as receiving such supply in the same jurisdiction,
thus resulting in an amount of VAT being properly chargeable on such supply, the
Second Party shall only be obliged to pay to the First Party the amount of VAT
properly chargeable on such supply (and no other amount). The Second Party shall
pay such VAT to the First Party on receipt of a valid VAT invoice from the First
Party (issued in accordance with the laws and regulations of the jurisdiction in
which the VAT is properly chargeable). Each Party agrees to (i) use its
reasonable efforts to determine and agree the value of the supply that has been
made and, as a result, the corresponding amount of VAT that is properly
chargeable and (ii) provide to the other Party any information or copies of
documents in its Control as are reasonably necessary to evidence that such
supply will take, or has taken, place in the same jurisdiction (for VAT
purposes).

 

9.Confidentiality.

 

9.1.    Confidential Information. Subject to Section 13.4.8, Antigen Express and
Merck agree to hold in confidence any Confidential Information provided by or on
behalf of the other Party, and neither Party shall use Confidential Information
of the other Party except to fulfill such Party’s obligations under this
Agreement or exercising its rights. Without limiting the foregoing, the
Receiving Party may not, without the prior written permission of the Disclosing
Party, disclose any Confidential Information of the Disclosing Party to any
Third Party except to the extent disclosure (i) is required by Applicable Law;
(ii) is pursuant to the terms of this Agreement; or (iii) is necessary for the
conduct of the Study, and in each case ((i) through (iii)) provided that the
Receiving Party shall provide reasonable advance notice to the Disclosing Party
before making such disclosure. For the avoidance of doubt, Antigen Express may,
without Merck’s consent, disclose Confidential Information to clinical trial
sites and clinical trial investigators performing the Study, the data safety
monitoring and advisory board relating to the

24 

 

Study, and Regulatory Authorities working with Antigen Express on the Study, in
each case to the extent necessary for the performance of the Study and provided
that such Persons (other than governmental entities) are bound by an obligation
of confidentiality at least as stringent as the obligations contained herein.

 

9.2.    Inventions. Notwithstanding the foregoing: (i) Inventions that
constitute Confidential Information and are jointly owned by the Parties, shall
constitute the Confidential Information of both Parties and each Party shall
have the right to use and disclose such Confidential Information consistent with
Articles 10, 11 and 12; and (ii) Inventions that constitute Confidential
Information and are solely owned by one Party shall constitute the Confidential
Information of that Party and each Party shall have the right to use and
disclose such Confidential Information consistent with Articles 10, 11 and 12.

 

9.3.    Personal Identifiable Data. All Confidential Information containing
personal identifiable data shall be handled in accordance with all data
protection and privacy laws, rules and regulations applicable to such data.

 

10.Intellectual Property.

 

10.1.   Joint Ownership and Prosecution.

 

10.1.1.  All rights to all Inventions relating to, or covering, the combined use
of the Antigen Express Compound and the Merck Compound that are not Merck
Inventions or Antigen Express Inventions (each a “Jointly Owned Invention”)
shall be owned jointly by Antigen Express and Merck. Merck hereby assigns to
Antigen Express an undivided one-half interest in, to and under the Jointly
Owned Inventions that are invented or created solely by Merck or by Persons
having an obligation to assign such rights to Merck. Antigen Express hereby
assigns to Merck an undivided one-half interest in, to and under any Jointly
Owned Inventions that are invented or created solely by Antigen Express or by
Persons having an obligation to assign such rights to Antigen Express. For those
countries where a specific license is required for a joint owner of a Jointly
Owned Invention to practice such Jointly Owned Invention in such countries: (i)
Merck hereby grants to Antigen Express a perpetual, irrevocable, non-exclusive,
worldwide, royalty-free, fully paid-up license, transferable and sublicensable,
under Merck’s right, title and interest in and to all Jointly Owned Inventions
to use such Inventions in accordance with the terms of this Agreement; and (ii)
Antigen Express hereby grants to Merck a perpetual, irrevocable, non-exclusive,
worldwide, royalty-free, fully paid-up license, transferable and sublicensable,
under Antigen Express’ right, title and interest in and to all Jointly Owned
Inventions to use such Inventions in accordance with the terms of this
Agreement. For clarity, the terms of this Agreement do not provide Antigen
Express or Merck with any rights, title or interest or any license to the other
Party’s intellectual property except as necessary to conduct the Study and as
expressly provided under this Agreement, including as set forth in Section 10.4.

 

10.1.2.  Each Party shall have the right to freely exploit each Jointly Owned
Invention both within and outside the scope of the Study, without accounting to
or any other obligation to the other Party; provided, however, that Merck may
not use the Jointly Owned Inventions, directly or indirectly, to research,
develop or commercialize a compound that is an

 

25

25 

 

Antigen Express Class Compound, and Antigen Express may not use the Jointly
Owned Inventions, directly or indirectly, to research, develop or commercialize
a PD-1 Antagonist.

 

10.1.3.  Promptly following the Effective Date, but in any event as soon as
practicable after the discovery of a Jointly Owned Invention, patent
representatives of each of the Parties shall meet (in person or by telephone) to
discuss the patenting strategy for any Jointly Owned Inventions that may arise.
In particular, the Parties shall discuss which Party will file and prosecute a
patent application (including any provisional, substitution, divisional,
continuation, continuation in part, reissue, renewal, reexamination, extension,
supplementary protection certificate and the like) in respect of any Jointly
Owned Invention (each, a “Joint Patent Application”) and whether the Parties
wish to appoint counsel that is mutually acceptable to the Parties. In any
event, the Parties shall consult and reasonably cooperate with one another in
the preparation, filing, prosecution (including prosecution strategy) and
maintenance of such patent application and shall equally share the expenses
associated with the Joint Patent Applications and any corresponding Joint
Patents. In the event that one Party (the “Filing Party”) wishes to file a
patent application for a Jointly Owned Invention and the other Party (the
“Non-Filing Party”) does not want to file a patent application for such Jointly
Owned Invention or does not want to file in a particular country, the Non-Filing
Party shall execute in a timely manner and at the Filing Party’s reasonable
expense an assignment of such Jointly Owned Invention to the Filing Party (in
such country or all countries, as applicable) and any additional documents as
may be reasonably necessary to allow the Filing Party to file and prosecute such
patent application. If a Party (the “Opting-out Party”) wishes to discontinue
the prosecution and maintenance (or sharing in the costs with respect thereto)
of a Joint Patent Application or Joint Patent (in one or more countries), the
other Party, at its sole option (the “Continuing Party”), may continue such
prosecution and maintenance. In such event, the Opting-out Party shall execute
in a timely manner and at the Continuing Party’s reasonable expense an
assignment of such Joint Patent Application or Joint Patent to the Continuing
Party (in such country or all countries, as applicable) and any additional
documents as may be necessary to allow the Continuing Party to prosecute and
maintain such Joint Patent Application or Joint Patent. Any Jointly Owned
Invention, Joint Patent Application or Joint Patent so assigned shall thereafter
be owned solely by the Continuing Party or Filing Party (as applicable), shall
no longer be considered jointly owned, and the Non-Filing Party or Opting-out
Party (as applicable) shall have no right to practice under such Joint Patent
Application or Joint Patent in the applicable country or countries.

 

10.1.4.  Except as expressly provided in Section 10.1.3 and in furtherance and
not in limitation of Section 9.1, each Party agrees to make no patent
application based on the other Party’s Confidential Information, and to give no
assistance to any Third Party for such application, without the other Party’s
prior written authorization.

 

10.1.5.  Antigen Express shall have the first right to initiate legal action to
enforce all Joint Patents against infringement and to protect all Jointly Owned
Inventions from misappropriation by any Third Party, where such infringement or
misappropriation results from the development or sale of a product that includes
an Antigen Express Class Compound but not a PD-1 Antagonist or to defend any
declaratory judgment action relating thereto, at its sole expense. In the event
that Antigen Express fails to initiate or defend such action within thirty

(30) days after being first notified of such infringement, Merck shall have the
right to do so at its 26

26 

 

sole expense. Merck shall have the first right to initiate legal action to
enforce all Joint Patents against infringement and to protect all Jointly Owned
Inventions from misappropriation by any Third Party, where such infringement or
misappropriation results from the development or sale of a product that includes
a PD-1 Antagonist but not an Antigen Express Class Compound or to defend any
declaratory judgment action relating thereto, at its sole expense. In the event
that Merck fails to initiate or defend such action within thirty (30) days after
being first notified of such infringement, Antigen Express shall have the right
to do so at its sole expense. The Parties shall reasonably cooperate to
coordinate legal action to enforce all Joint Patents against infringement, and
to protect all Jointly Owned Inventions from misappropriation, by any Third
Party where such infringement or misappropriation results from the development
or sale of a product that includes both a PD-1 Antagonist and an Antigen Express
Class Compound, or to defend any declaratory judgment action relating thereto,
and shall share the costs and expenses of such litigation equally.

 

10.1.6.  If one Party brings any prosecution or enforcement action or proceeding
against a Third Party with respect to any Joint Patent, the second Party agrees
to be joined as a party plaintiff where necessary and to give the first Party
reasonable assistance and authority to file and prosecute the suit. The costs
and expenses of the Party bringing suit under Section

10.1.5 shall be borne by such Party, and any damages or other monetary awards
recovered shall be shared as follows: (i) the amount of such recovery actually
received by the Party controlling such action shall be first applied to the
out-of-pocket costs of each Party in connection with such action; and then (ii)
any remaining proceeds shall be divided evenly between Antigen Express and
Merck. A settlement or consent judgment or other voluntary final disposition of
a suit under Section 10.1.5 may not be entered into without the consent of the
Party not bringing the suit.

 

10.2.   Inventions Owned by Antigen Express. Notwithstanding anything to the
contrary contained in Section 10.1, the Parties agree that all rights to
Inventions relating solely to, or covering solely, the Antigen Express Compound
or an Antigen Express Class Compound, and any improvements related thereto,
regardless of whether such Invention or improvement was invented solely by
Antigen Express or Merck or jointly by the Parties, are the exclusive property
of Antigen Express (“Antigen Express Inventions”). Antigen Express shall be
entitled to file and prosecute in its own name relevant patent applications and
to own resultant patent rights for any Antigen Express Invention. For the
avoidance of doubt, any Invention generically encompassing the Antigen Express
Compound or another Antigen Express Class Compound (and not the Merck Compound)
within its scope, even where the Antigen Express Compound or Antigen Express
Class Compound is not disclosed per se, is an Antigen Express Invention. Merck
hereby assigns its right, title and interest to any and all Antigen Express
Inventions to Antigen Express.

 

10.3.   Inventions Owned by Merck. Notwithstanding anything to the contrary
contained in Section 10.1, the Parties agree that all rights to Inventions
relating solely to, or covering solely, the Merck Compound or a PD-1 Antagonist,
and any improvements related thereto, regardless of whether such Invention or
improvement was invented solely by Merck or Antigen Express or jointly by the
Parties, are the exclusive property of Merck (“Merck Inventions”). Merck shall
be entitled to file and prosecute in its own name relevant patent applications
and to own resultant patent rights for any Merck Invention. For the avoidance of
doubt, any Invention

27

27 

 

generically encompassing the Merck Compound or another PD-1 Antagonist (and not
the Antigen Express Compound) within its scope, even where the Merck Compound or
other PD-1 Antagonist is not disclosed per se, is a Merck Invention. Antigen
Express hereby assigns its right, title and interest to any and all Merck
Inventions to Merck.

 

10.4.Mutual Freedom to Operate for Combination Inventions.

 

10.4.1.  Antigen Express License to Merck. Antigen Express hereby grants to
Merck a non-exclusive, worldwide, royalty-free, fully paid-up license,
transferable and sublicensable, to any patent Controlled by Antigen Express that
(a) has a priority claim that is earlier than the initiation of the Study (i.e.,
first dosing of the first patient in the Study) and (b) claims the Combination
(the “Antigen Express Background Patents”) solely for the purpose of conducting
the Study; provided, however, that in no event shall Merck have the right to use
Antigen Express Background Patents to commercialize the Antigen Express Compound
or any Antigen Express Class Compound.

 

10.4.2.  Merck License to Antigen Express. Merck hereby grants to Antigen
Express a non-exclusive, worldwide, royalty-free, fully paid-up license,
transferable and sublicensable, to any patent Controlled by Merck that (a) has a
priority claim that is earlier than the initiation of the Study (i.e., first
dosing of the first patient in the Study) and (b) claims the Combination (the
“Merck Background Patents”) solely for the purpose of conducting the Study;
provided, however, that in no event shall Antigen Express have the right to use
Merck Background Patents to commercialize the Merck Compound or any PD-1
Antagonist.

 

10.4.3.  No Other Rights. For clarity, the terms of this Section 10.4 do not
provide Merck or Antigen Express with any rights, title or interest or any
license to the other Party’s intellectual property rights that do not have a
priority claim that is earlier than the initiation of the Study or do not claim
the Combination (i.e., intellectual property owned or licensed by either Party
that does not constitute an Invention and does not claim or cover the
Combination), except as necessary to conduct the Study.

 

10.4.4.  Termination. Any and all licenses granted under this Section 10.4 shall
terminate upon the latest of (i) the termination of this Agreement and (ii) the
completion of the Study or any Subsequent Study conducted pursuant to Section
3.14.

 

11.Reprints; Rights of Cross-Reference.

 

Consistent with applicable copyright and other laws, each Party may use, refer
to, and disseminate reprints of scientific, medical and other published articles
and materials from journals, conferences and/or symposia relating to the Study
that disclose the name of a Party, provided, however, that such use does not
constitute an endorsement of any commercial product or service by the other
Party.

 

12.Publications; Press Releases.

 

12.1.   Clinical Trial Registry. Antigen Express shall register the Study with
the Clinical Trials Registry located at www.clinicaltrials.gov and is committed
to timely publication of the results following Study Completion, after taking
appropriate action to secure intellectual

28 

 

property rights (if any) arising from the Study. The publication of the results
of the Study will be in accordance with the Protocol.

 

12.2.   Publication. Each Party shall use reasonable efforts to publish or
present scientific papers dealing with the Study in accordance with accepted
scientific practice. The Parties agree that prior to submission of the results
of the Study for publication or presentation or any other dissemination of such
results including oral dissemination, the publishing Party shall invite the
other to comment on the content of the material to be published, presented, or
otherwise disseminated according to the following procedure:

 

12.2.1.  At least forty-five (45) days prior to submission for publication of
any paper, letter or any other publication, or thirty (30) days prior to
submission for presentation of any abstract, poster, talk or any other
presentation, the publishing Party shall provide to the other Party the full
details of the proposed publication, presentation, or dissemination in an
electronic version (cd-rom or email attachment). Upon written request from the
other Party, the publishing Party agrees not to submit data for
publication/presentation/dissemination for an additional ninety (90) days in
order to allow for actions to be taken to preserve rights for patent protection.

 

12.2.2.  The publishing Party shall give reasonable consideration to any request
by the other Party made within the periods mentioned in Section 12.2.1 to modify
the publication and the Parties shall work in good faith and in a timely manner
to resolve any issue regarding the content for publication.

 

12.2.3.  The publishing Party shall remove all Confidential Information of the
other Party before finalizing the publication.

 

12.3.   Press Releases. Unless otherwise required by Applicable Law, neither
Party shall make any public announcement concerning this Agreement or the Study
or otherwise communicate with any news media without the prior written consent
of the other Party. To the extent a Party desires to make such public
announcement, such Party shall provide the other Party with a draft thereof at
least seven (7) Business Days prior to the date on which such Party would like
to make the public announcement.

 

13.Representations and Warranties; Disclaimers.

 

13.1.   Due Authorization. Each of Antigen Express and Merck represents and
warrants to the other that: (i) it has the corporate power and authority and the
legal right to enter into this Agreement and perform its obligations hereunder;
(ii) it has taken all necessary corporate action on its part required to
authorize the execution and delivery of this Agreement and the performance of
its obligations hereunder; and (iii) this Agreement has been duly executed and
delivered on behalf of such Party and constitutes a legal, valid and binding
obligation of such Party that is enforceable against it in accordance with its
terms.

 

13.2.Compounds.

 

13.2.1.  Antigen Express Compound. Antigen Express hereby represents and
warrants to Merck that: (i) Antigen Express has the full right, power and
authority to grant all of

29 

 

the licenses granted to Merck under this Agreement; and (ii) Antigen Express
Controls the Antigen Express Compound.

 

13.2.2.  Merck Compound. Merck hereby represents and warrants to Antigen Express
that: (i) Merck has the full right, power and authority to grant all of the
licenses granted to Antigen Express under this Agreement; and (ii) Merck
Controls the Merck Compound.

 

13.3.   Results. Antigen Express does not undertake that the Study shall lead to
any particular result, nor is the success of the Study guaranteed. Neither Party
shall be liable for any use that the other Party may make of the Clinical Data
nor for advice or information given in connection therewith.

 

13.4.Anti-Corruption.

 

13.4.1.  In performing their respective obligations hereunder, the Parties
acknowledge that the corporate policies of Antigen Express and Merck and their
respective Affiliates require that each Party’s business be conducted within the
letter and spirit of the law. By signing this Agreement, each Party agrees to
conduct the business contemplated herein in a manner that is consistent with all
Applicable Law, including the Stark Act, Anti-Kickback Statute, Sunshine Act,
and the U.S. Foreign Corrupt Practices Act, good business ethics, and its ethics
and other corporate policies and agrees to abide by the spirit of the other
Party’s guidelines, which may be provided by such other Party from time to time.

 

13.4.2.  Specifically, each Party represents and warrants that it has not, and
covenants that it, its Affiliates, and its and its Affiliates’ directors,
employees, officers, and anyone acting on its behalf, will not, in connection
with the performance of this Agreement, directly or indirectly, make, promise,
authorize, ratify or offer to make, or take any action in furtherance of, any
payment or transfer of anything of value for the purpose of influencing,
inducing or rewarding any act, omission or decision to secure an improper
advantage; or improperly assisting it in obtaining or retaining business for it
or the other Party, or in any way with the purpose or effect of public or
commercial bribery.

 

13.4.3.  Neither Party shall contact, or otherwise knowingly meet with, any
Government Official for the purpose of discussing activities arising out of or
in connection with this Agreement, without the prior written approval of the
other Party, except where such meeting is consistent with the purpose and terms
of this Agreement and in compliance with Applicable Law.

 

13.4.4.  Each Party represents and warrants that it (i) is not excluded,
debarred, suspended, proposed for suspension or debarment, in Violation or
otherwise ineligible for government programs; and (ii) has not employed or
subcontracted with any Person for the performance of the Study who is excluded,
debarred, suspended, proposed for suspension or debarment, or is in Violation or
otherwise ineligible for government programs.

 

13.4.5.  Each Party represents and warrants that, except as disclosed to the
other in writing prior to the Effective Date, such Party: (1) does not have any
interest that directly or indirectly conflicts with its proper and ethical
performance of this Agreement; (2) shall maintain arm’s length relations with
all Third Parties with which it deals for or on behalf of the other in

30 

 

performance of this Agreement; and (3) has provided complete and accurate
information and documentation to the other Party, the other Party’s Affiliates
and its and their personnel in the course of any due diligence conducted by the
other Party for this Agreement, including disclosure of any officers, employees,
owners or Persons directly or indirectly retained by such Party in relation to
the performance of this Agreement who are Government Officials or relatives of
Government Officials. Each Party shall make all further disclosures to the other
Party as are necessary to ensure the information provided remains complete and
accurate throughout the Term. Subject to the foregoing, each Party agrees that
it shall not hire or retain any Government Official to assist in its performance
of this Agreement, with the sole exception of conduct of or participation in
clinical trials under this Agreement, provided that such hiring or retention
shall be subject to the completion by the hiring or retaining Party of a
satisfactory anti-corruption and bribery (e.g., FCPA) due diligence review of
such Government Official. Each Party further covenants that any future
information and documentation submitted to the other Party as part of further
due diligence or a certification shall be complete and accurate.

 

13.4.6.Each Party shall have the right during the Term, and for a period of two

(2) years following termination of this Agreement, to conduct an investigation
and audit of the other Party’s activities, books and records, to the extent they
relate to that other Party’s performance under this Agreement, to verify
compliance with the terms of this Section 13.4. Such other Party shall cooperate
fully with such investigation or audit, the scope, method, nature and duration
of which shall be at the sole reasonable discretion of the Party requesting such
audit.

 

13.4.7.  Each Party shall use commercially reasonable efforts to ensure that all
transactions under the Agreement are properly and accurately recorded in all
material respects on its books and records and that each document upon which
entries in such books and records are based is complete and accurate in all
material respects. Each Party further represents, warrants and covenants that
all books, records, invoices and other documents relating to payments and
expenses under this Agreement are and shall be complete and accurate and reflect
in reasonable detail the character and amount of transactions and expenditures.
Each Party shall maintain a system of internal accounting controls reasonably
designed to ensure that no off-the-books or similar funds or accounts will be
maintained or used in connection with this Agreement.

 

13.4.8.  Each Party agrees that in the event that the other Party reasonably
believes that there has been a possible violation of any provision of Section
13.4, such other Party may make full disclosure of such belief and related
information needed to support such belief at any time and for any reason to any
competent government bodies and agencies, and to anyone else such Party
determines in good faith has a legitimate need to know.

 

13.4.9.  Each Party shall comply with its own ethical business practices policy
and any corporate integrity agreement (if applicable) to which it is subject,
and shall conduct its Study-related activities in accordance with Applicable
Law. Each Party shall ensure that all of its employees involved in performing
its obligations under this Agreement are made specifically aware of the
compliance requirements under this Section 13.4. In addition, each Party shall
ensure that all such employees participate in and complete mandatory compliance
training to be conducted by each Party, including specific training on
anti-bribery and corruption, prior to his/her performance of any obligations or
activities under this Agreement. Each Party shall

31

31 

 

certify its continuing compliance with the requirements under this Section 13.4
on a periodic basis during the Term in such form as may be reasonably specified
by the other Party.

 

13.4.10.      Each Party shall have the right to terminate this Agreement
immediately upon violation of this Section 13.4 in accordance with Section 6.7.

 

13.5.   DISCLAIMER. EXCEPT AS EXPRESSLY PROVIDED HEREIN, MERCK MAKES NO
WARRANTIES, EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE MERCK COMPOUND, AND
ANTIGEN EXPRESS MAKES NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY
OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, WITH RESPECT TO THE
ANTIGEN EXPRESS COMPOUND.

 

14.Insurance; Indemnification; Limitation of Liability.

 

14.1.   Insurance. Each Party warrants that it maintains a policy or program of
insurance or self-insurance at levels sufficient to support the indemnification
obligations assumed herein. Upon request, a Party shall provide evidence of such
insurance.

 

14.2.Indemnification.

 

14.2.1.  Indemnification by Antigen Express. Antigen Express agrees to defend,
indemnify and hold harmless Merck, its Affiliates, and its and their employees,
directors, subcontractors and agents from and against any loss, damage,
reasonable costs and expenses (including reasonable attorneys’ fees and
expenses) incurred in connection with any claim, proceeding, or investigation by
a Third Party arising out of this Agreement or the Study (a “Liability”), except
to the extent that such Liability was directly caused by (i) negligence or
willful misconduct on the part of Merck (or any of its Affiliates, or its and
their employees, directors, subcontractors or agents); (ii) a breach on the part
of Merck of any of its representations and warranties or any other covenants or
obligations of Merck under this Agreement; or (iii) a breach of Applicable Law
by Merck.

 

14.2.2.  Indemnification by Merck. Merck agrees to defend, indemnify and hold
harmless Antigen Express, its Affiliates, and its and their employees,
directors, Subcontractors and agents from and against any Liability to the
extent such Liability was directly caused by (i) negligence or willful
misconduct on the part of Merck (or any of its Affiliates, or its and their
employees, directors, subcontractors or agents); (ii) a breach on the part of
Merck of any of its representations and warranties or any other covenants or
obligations of Merck under this Agreement; or (iii) a breach of Applicable Law
by Merck.

 

14.2.3.  Procedure. The obligations of Merck and Antigen Express under this
Section 14.2 are conditioned upon the delivery of written notice to Merck or
Antigen Express, as the case might be, of any potential Liability within a
reasonable time after a Party becomes aware of such potential Liability. The
indemnifying Party will have the right to assume the defense of any suit or
claim related to the Liability (using counsel reasonably satisfactory to the
indemnified Party) if it has assumed responsibility for the suit or claim in
writing; provided that the indemnified Party may assume the responsibility for
such defense to the extent the

32 

 

indemnifying Party does not do so in a timely manner). The indemnified Party may
participate in (but not control) the defense thereof at its sole cost and
expense. The Party controlling such defense (the “Defending Party”) shall keep
the other Party (the “Other Party”) advised of the status of such action, suit,
proceeding or claim and the defense thereof and shall consider recommendations
made by the Other Party with respect thereto. The Defending Party shall not
agree to any settlement of such action, suit, proceeding or claim without the
prior written consent of the Other Party, which shall not be unreasonably
withheld. The Defending Party, but solely to the extent the Defending Party is
also the indemnifying Party, shall not agree to any settlement of such action,
suit, proceeding or claim or consent to any judgment in respect thereof that
does not include a complete and unconditional release of the Other Party from
all liability with respect thereto or that imposes any liability or obligation
on the Other Party without the prior written consent of the Other Party.

 

14.2.4.  Study Subjects. Antigen Express shall not offer compensation on behalf
of Merck to any Study subject or bind Merck to any indemnification obligations
in favor of any Study subject. Merck shall not offer compensation on behalf of
Antigen Express to any Study subject or bind Antigen Express to any
indemnification obligations in favor of any Study subject.

 

14.3.   LIMITATION OF LIABILITY. IN NO EVENT SHALL EITHER PARTY (OR ANY OF ITS
AFFILIATES OR SUBCONTRACTORS) BE LIABLE TO THE OTHER PARTY UNDER ANY THEORY FOR,
NOR SHALL ANY INDEMNIFIED PARTY HAVE THE RIGHT TO RECOVER, ANY SPECIAL,
INDIRECT, INCIDENTAL, PUNITIVE OR CONSEQUENTIAL DAMAGES (INCLUDING LOST PROFITS
OR DAMAGES FOR LOST OPPORTUNITIES), WHETHER IN CONTRACT, WARRANTY, NEGLIGENCE,
TORT, STRICT LIABILITY OR OTHERWISE, ARISING OUT OF (X) THE MANUFACTURE OR USE
OF ANY COMPOUND SUPPLIED HEREUNDER OR (Y) ANY BREACH OF OR FAILURE TO PERFORM
ANY OF THE PROVISIONS OF THIS AGREEMENT OR ANY REPRESENTATION, WARRANTY OR
COVENANT CONTAINED IN OR MADE PURSUANT TO THIS AGREEMENT, EXCEPT THAT SUCH
LIMITATION SHALL NOT APPLY TO DAMAGES PAID OR PAYABLE TO A THIRD PARTY BY AN
INDEMNIFIED PARTY FOR WHICH THE INDEMNIFIED PARTY IS ENTITLED TO INDEMNIFICATION
HEREUNDER OR WITH RESPECT TO DAMAGES ARISING OUT OF OR RELATED TO A PARTY’S
BREACH OF ITS OBLIGATIONS UNDER THIS AGREEMENT WITH RESPECT TO USE, DISCLOSURE,
LICENSE, ASSIGNMENT OR OTHER TRANSFER OF CLINICAL DATA, CONFIDENTIAL
INFORMATION, JOINTLY-OWNED INVENTIONS AND SAMPLE TESTING RESULTS.

 

15.Use of Name.

 

Except as otherwise provided herein, neither Party shall have any right, express
or implied, to use in any manner the name or other designation of the other
Party or any other trade name, trademark or logo of the other Party for any
purpose in connection with the performance of this Agreement without the other
Party’s prior written consent.

 

16.Force Majeure.

33 

 

If, in the performance of this Agreement, one of the Parties is prevented,
hindered or delayed by reason of any cause beyond such Party’s reasonable
control (e.g., war, riots, fire, strike, acts of terror, governmental laws),
such Party shall be excused from performance to the extent that it is
necessarily prevented, hindered or delayed (“Force Majeure”). The non-
performing Party shall notify the other Party of such Force Majeure within ten
(10) days after such occurrence by giving written notice to the other Party
stating the nature of the event, its anticipated duration, and any action being
taken to avoid or minimize its effect. The suspension of performance will be of
no greater scope and no longer duration than is necessary and the non-
performing Party shall use commercially reasonable efforts to remedy its
inability to perform.

 

17.Entire Agreement; Amendment; Waiver.

 

This Agreement, together with the Appendices and Schedules hereto and the
Related Agreements, constitutes the sole, full and complete agreement by and
between the Parties with respect to the subject matter of this Agreement, and
all prior agreements, understandings, promises and representations, whether
written or oral, with respect thereto are superseded by this Agreement. In the
event of a conflict between a Related Agreement and this Agreement, the terms of
this Agreement shall control. No amendments, changes, additions, deletions or
modifications to or of this Agreement shall be valid unless reduced to writing
and signed by the Parties hereto. Any term or condition of this Agreement may be
waived at any time by the Party that is entitled to the benefit thereof, but no
such waiver shall be effective unless set forth in a written instrument duly
executed by or on behalf of the Party waiving such term or condition. The waiver
by either Party of any right hereunder or of the failure to perform or of a
breach by the other Party shall not be deemed a waiver of any other right
hereunder or of any other breach or failure by said other Party whether of a
similar nature or otherwise.

 

18.Assignment and Affiliates.

 

Neither Party shall assign or transfer this Agreement without the prior written
consent of the other Party; provided, however, that either Party may assign all
or any part of this Agreement to one or more of its Affiliates without the other
Party’s consent, and any and all rights and obligations of either Party may be
exercised or performed by its Affiliates, provided that such Affiliates agree to
be bound by this Agreement.

 

19.Invalid Provision.

 

If any provision of this Agreement is held to be illegal, invalid or
unenforceable, the remaining provisions shall remain in full force and effect
and will not be affected by the illegal, invalid or unenforceable provision. In
lieu of the illegal, invalid or unenforceable provision, the Parties shall
negotiate in good faith to agree upon a reasonable provision that is legal,
valid and enforceable to carry out as nearly as practicable the original
intention of the entire Agreement.

 

20.No Additional Obligations.

 

Antigen Express and Merck have no obligation to renew this Agreement or apply
this Agreement to any clinical trial other than the Study. Nothing in this
Agreement obligates the Parties to enter into any other agreement (other than
the Related Agreements) at this time or in the future.

34 

 

21.Governing Law; Dispute Resolution.

 

21.1.   The Parties shall attempt in good faith to settle all disputes arising
out of or in connection with this Agreement in an amicable manner. Any claim,
dispute or controversy arising out of or relating to this Agreement, including
the breach, termination or validity hereof or thereof, shall be governed by and
construed in accordance with the substantive laws of the State of New York,
without giving effect to its choice of law principles.

 

21.2.   Nothing contained in this Agreement shall deny either Party the right to
seek injunctive or other equitable relief from a court of competent jurisdiction
in the context of a bona fide emergency or prospective irreparable harm, and
such an action may be filed or maintained notwithstanding any ongoing
discussions between the Parties.

 

22.Notices.

 

All notices or other communications that are required or permitted hereunder
shall be in writing and delivered personally, sent by facsimile (and promptly
confirmed by personal delivery or overnight courier), or sent by
internationally-recognized overnight courier addressed as follows:

 

If to Antigen Express, to:

 

Antigen Express, Inc. 33 Redwing Road

Wellesley, MA 02481 Attention: Eric von Hofe

 

If to Merck, to:

 

Merck Sharp & Dohme B.V. Waarderweg 39

2031 BN Haarlem Netherlands Attention: Director

Facsimile: +31 23 514 8677

With copies (which shall not constitute notice) to: Merck Sharp & Dohme Corp.

One Merck Drive PO Box 100

Whitehouse Station, NJ 08889-0100 Attention: Office of Secretary

 

Merck Sharp & Dohme Corp. 351 North Sumneytown Pike Mailstop UG4CD-16

35 

 

North Wales, PA 19454-2505

Attention: Senior Vice President, Research Science

 

Merck Sharp & Dohme Corp. 2000 Galloping Hill Road Mailstop K-1-3045 Kenilworth,
NJ 07033-1310

Attention: Assistant General Counsel, Corporate Transactions

 

23.Relationship of the Parties.

 

The relationship between the Parties is and shall be that of independent
contractors, and does not and shall not constitute a partnership, joint venture,
agency or fiduciary relationship. Neither Party shall have the authority to make
any statements, representations or commitments of any kind, or take any actions,
that are binding on the other Party, except with the prior written consent of
the other Party to do so. All Persons employed by a Party will be the employees
of such Party and not of the other Party and all costs and obligations incurred
by reason of any such employment shall be for the account and expense of such
Party.

 

24.Counterparts and Due Execution.

 

This Agreement and any amendment may be executed in any number of counterparts
(including by way of facsimile or electronic transmission), each of which shall
be deemed an original, but all of which together shall constitute one and the
same instrument, notwithstanding any electronic transmission, storage and
printing of copies of this Agreement from computers or printers. When executed
by the Parties, this Agreement shall constitute an original instrument,
notwithstanding any electronic transmission, storage and printing of copies of
this Agreement from computers or printers. For clarity, facsimile signatures and
signatures transmitted via PDF shall be treated as original signatures.

 

25.Construction.

 

Except where the context otherwise requires, wherever used, the singular will
include the plural, the plural the singular, the use of any gender will be
applicable to all genders, and the word “or” is used in the inclusive sense
(and/or). Whenever this Agreement refers to a number of days, unless otherwise
specified, such number refers to calendar days. The captions of this Agreement
are for convenience of reference only and in no way define, describe, extend or
limit the scope or intent of this Agreement or the intent of any provision
contained in this Agreement. The term “including” as used herein shall be deemed
to be followed by the phrase “without limitation” or like expression. The term
“will” as used herein means shall. The terms “hereof”, “hereto”, “herein” and
“hereunder” and words of similar import when used in this Agreement refer to
this Agreement as a whole and no to any particular provision of this Agreement.
References to “Article,” “Section”, “Appendix” or “Schedule” are references to
the numbered sections of this Agreement and the appendices attached to this
Agreement, unless expressly stated otherwise. Except where the context otherwise
requires, references to this “Agreement” shall include the appendices attached
to this Agreement. The language of this Agreement shall

36 

 

be deemed to be the language mutually chosen by the Parties and no rule of
strict construction will be applied against either Party hereto.

 

[Remainder of page intentionally left blank.]

37 

 

IN WITNESS WHEREOF, the respective representatives of the Parties have executed
this Agreement as of the Effective Date.

 

 

 [image_015.gif]

 

 

Merck Sharp & Dohme B.V.

By: _ _

_ _ _

_ _ _

_ _ _

 

 

 

Name

 

 

[image_008.gif]

 

Title

38 

 

 

 

IN WITNESS WHEREOF , the respective representatives of the Parties have executed
this Agreement as of the Effective Date.

 

 

Antigen Express, Inc.

 

By:

Name: Eric von Hofe

Title: President

 

 

[image_009.gif]

 

39 

 

Appendix A PROTOCOL

 

 

[image_008.jpg]

[image_010.gif]

 

DRAFT PROTOCOL NSABP B-001_v05-11

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

40 

 

NSABP PROTOCOL B-001

A Phase II Clinical Trial of Pembrolizumab in Combination with the AE37 Peptide
Vaccine in Patients with Metastatic Triple Negative Breast Cancer

 

 

 

NSABP Foundation, Inc.

Nova Tower 2 − Two Allegheny Center – Suite 1200 Pittsburgh, PA 15212

 

TELEPHONE: 1-800-270-3165 E-MAIL: industry.trials@nsabp.org CLINICAL QUESTIONS:
1-800-270-3165

 

 

 

KEY STUDY PERSONNEL

 

NSABP Chair: Norman Wolmark, MD Protocol Chair: Shannon Puhalla, MD Protocol
Officer: Samuel Jacobs, MD Protocol Statistician: Greg Yothers, PhD Clinical
Research Scientist: TBD

 

 

Protocol B-001 IND #XXXX sponsored by NSABP Foundation, Inc.

 

 

 

Version Date: May 11, 2017

 

CONFIDENTIAL

41 

 

TABLE OF CONTENTS

Information Resources iii Glossary of Abbreviations and Acronyms iv 1.0 OVERVIEW
OF STUDY DESIGN   2.0 BACKGROUND 10 2.1 Background 10 2.2 Rationale for Immune
checkpoint therapy in triple-negative breast cancer 10 2.3 Rationale for HER2
vaccine in triple-negative breast cancer 11 2.4 Pembrolizumab background and
clinical trials 12 2.5 HER2 vaccine, AE37 13 3.0 STUDY AIMS AND ENDPOINTS 14 3.1
Co-Primary aims and endpoints 14 3.2 Secondary aims and endpoints 14 3.3
Exploratory translational science 14 4.0 PATIENT ELIGIBILITY AND INELIGIBILITY
15 4.1 Conditions for patient eligibility 15 4.2 Conditions for patient
ineligibility 16 5.0 REQUIREMENT FOR STUDY ENTRY AND DURING TREATMENT AND
FOLLOW-UP 21 6.0 PATHOLOGY AND CORRELATIVE SCIENCE STUDIES 21 6.1 Overview of
requirements 21 6.2 Use of specimens 21 6.3 Tumor and blood sample submissions
22 6.4 Rationale for correlative science studies 23 7.0 STUDY THERAPY 24 7.1
AE37 Vaccine 24 7.2 Study regimen 25 7.3 Supportive therapy 26 7.4
Contraindications and precautions 26 7.5 Contraception 27 7.6 Pregnancy 27 7.7
Participation in other clinical trials 27 8.0 TREAMENT MANAGEMENT 28 8.1 General
instructions 28 8.2 Treatment management for study therapy 28 8.3 Supportive
care guidelines for pembrolizumab 33 8.4 Liver dysfunction (Hy's Law) 35 9.0
DRUG INFORMATION 37 9.1 AE37 peptide vaccine 37 9.2 Pembrolizumab (MK-3475,
KEYTRUDAÒ) (NSC-776864) 38 9.3 Study therapy procurement 39 9.4 Study therapy
storage 40 9.5 Transfer of study therapy 40 9.6 Destruction of study therapy
vials 40 9.7 Drug inventory records 40 9.8 Drug accountability 40 10.0 ADVERSE
EVENT REPORTING REQUIREMENTS 42 10.1 Definition of an AE 42

 

42 

 

 

10.2 Definition of an SAE 42 10.3 Events requiring expedited reporting 43 10.4
Pregnancy 44 10.5 Grading the severity of the AE 45 10.6 Expedited reporting
instructions 45 10.7 Time period and frequency for routine reporting of AEs 46
10.8 Documentation requested following death 46 11.0 ASSESSMENT OF EFFECT 47
11.1 Definitions 47 11.2 Response criteria 48 11.3 Evaluation of best overall
response 48 11.4 Symptomatic deterioration 49 12.0 PATIENT ENTRY PROCEDURES 50
12.1 Patient consent form 50 12.2 Study entry 50 12.3 Patient study number and
treatment assignment 50 12.4 Investigator-initiated discontinuation of study
therapy 50 12.5 Patient-initiated discontinuation of study therapy 50 12.6
Patient-initiated withdrawal from the study 51 13.0 DATA HANDLING AND
RECORDKEEPING 52 14.0 STATISTICAL CONSIDERATION 53 14.1 Sample size
determination and protocol duration for the primary endpoint 53 14.2 Statistical
analysis plan 53 14.3 Monitoring 53 15.0 PUBLICATION INFORMATION 54 16.0
REFERENCES 55 APPENDEX A DETERMINIATION OF PERFORMANCE STATUS 59 APPENDIX B
CONTRACEPTION 60

INFORMATION RESOURCES   iii  GLOSSARY OF ABBREVIATIONS AND ACRONYMS   iv  Table
1. B-001 Safety Run-In (N=13 patients)   7  Figure 1 B-001 Schema   9  Table 2.
Tests, exams, and other requirements prior to study entry   18  Table 3. Tests,
exams, and other requirements following study entry   19  Table 4. Summary of
patient sample submission requirements   21  Table 5: Safety Cohort Study
Therapy   25  Table 6: Expansion Cohort Study Therapy   26  Table 7. AE37
vaccine local reaction assessment   29  Table 8. Dose levels for AE37 vaccine 
 29  Table 9. Dose modification and toxicity management guidelines for
immune-related AEs associated with pembrolizumab   30  Table 10. Infusion
Reaction Treatment Guidelines   34  Table 11. Determination of response   48 

43 

 

INFORMATION RESOURCES

NSABP Department of Site and Study Management

NSABP Operations Center Nova Tower 2

Nova Tower 2 − Two Allegheny Center– Suite 1200 Pittsburgh, PA 15212

Phone: 1-800-270-3165 E-mail: industry.trials@nsabp.org

For questions regarding:

•         IRB review & informed consent

•         Submission of IRB approval

•         Study entry information

•         Eligibility

•         Treatment regimen

•         Dose modifications/delays

•         Other clinical aspects of the trial

•         Adverse event reporting including SAE reporting

•         eCRF completion

 

 

 

 

 

 

Department of Site and Study Management (DSSM)

 

 

 

 

 

 

Phone: 1-800-270-3165

E-mail: industry.trials@nsabp.org

For questions regarding data management Department of Site and Study Management
(DSSM)

Phone: 1-800-270-3165

E-mail: industry.trials@nsabp.org

 

Request for research sample collection kits

NSABP Division of Pathology 1307 Federal Street – Suite 303

Pittsburgh, PA 15212

Phone: 412-697-6611

E-mail: pathology.questions@nsabp.org Refer to the B-001Pathology and
Correlative Science Instructions

 

Requests for study drug

Department of Site and Study Management (DSSM)

 

E-mail: B001.drugorders@nsabp.org

Questions regarding drug shipment Department of Site and Study Management (DSSM)

Phone: 1-800-270-3165

E-mail: industry.trials@nsabp.org

44 

 

GLOSSARY OF ABBREVIATIONS AND ACRONYMS

AE    adverse event ALT (SGPT) alanine aminotransferase ANC absolute neutrophil
count ASCO American Society of Clinical Oncology AST (SGOT) aspartate
aminotransferase BP        blood pressure BSA body surface area BUN blood urea
nitrogen CA        Canada CAP College of American Pathologists CBC complete
blood count CD3ζ cluster of differentiation zeta chain CD4 cluster of
differentiation 4 CD8 cluster of differentiation 8 CD28 cluster of
differentiation 28 CDK4,6 cyclin-dependent kinase 4,6 CHF congestive heart
failure CI     confidence interval CR     complete response CT      computed
tomography CTCAE v4.0 Common Terminology Criteria for Adverse Events Version 4.0
CTEP Cancer Therapy Evaluation Program DLT dose-limiting toxicity DSSM
Department of Site and Study Management DTH delayed type hypersensitivity ECG
electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF electronic case
report form ELISA enzyme-linked immunosorbent assay ER        estrogen receptor
ErbB epidermal growth factor receptor FDA Food and Drug Administration FFPE
formalin fixed paraffin embedded FNA fine needle aspiration FoxP3+ Forkhead Box
protein p3 GCP Good Clinical Practice G-CSF granulocyte colony stimulating
factor GM-CSF granulocyte macrophage-colony stimulating factor H&P history and
physical HER2 human epidermal growth factor receptor 2 HIV human
immunodeficiency virus HLA human leucocyte antigen HR    hazard ratio HRT
hormone replacement therapy IB     Investigator's Brochure IBC Institutional
Biosafety Committee ID    identification IDO indolamine-2, 3-dioxygenase

45 

 

GLOSSARY OF ABBREVIATIONS AND ACRONYMS (continued)

IFNγ Interferon gamma IHC immunohistochemistry IND investigational new drug INR
international normalized ratio irAE immune-related adverse event IRB
institutional review board IV intravenous KEYNOTE-001 Study of Pembrolizumab
(MK-3475) in Participants With Progressive Locally Advanced or Metastatic
Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma
(P07990/MK-3475-001/KEYNOTE-001) kg kilogram LD longest diameter LFT liver
function test LLN lower limit of normal LRMK N-terminal-linked with Ii-Key
tetramer mAb monoclonal antibody mg milligram MHC major histocompatibility
complex MRI magnetic resonance imaging mTNBC metastatic triple-negative breast
cancer NCCN National Comprehensive Cancer Network NCI National Cancer Institute
NSABP NSABP Foundation, Inc. NSCLC non-small cell lung cancer ORR overall
response rate OTC over-the-counter p probability PBMC peripheral blood
mononuclear cells pCR pathologic complete response PD progressive disease PDs
pharmacodynamics PD-1 Programmed cell death-1, proficient PD-L1 programmed death
ligand-1 PET positron emission tomography PFS progression-free survival PK
pharmacokinetic PO     by mouth PR  partial response PT    prothrombin time q
every Q2W every 2 weeks Q3W every 3 weeks RECIST Response Evaluation Criteria in
Solid Tumors RNA Ribonucleic acid RT       radiation therapy SABCS San Antonio
Breast Cancer Symposium SAE serious adverse event SC  subcutaneous SD stable
disease TILS tumor-infiltrating lymphocytes

46 

 

GLOSSARY OF ABBREVIATIONS AND ACRONYMS (continued)

T-cell T lymphocyte  TGFβ Transforming growth factor beta  TNBC triple negative
breast cancer  ULN upper limit of normal  US      United States (of America) 
WOCBP women of childbearing potential 

47 

 

1.0 OVERVIEW OF STUDY DESIGN

 

The B-001 is an open label, phase II study using pembrolizumab in combination
with AE37 peptide vaccine (AE37) in patients with metastatic triple negative
breast cancer (mTNBC). The primary objectives for this study are to establish
the recommended biologic dose of AE37 in combination with pembrolizumab that
will enhance the tumor-specific immune response and demonstrate efficacy in
patients with advanced triple negative breast cancer.

This study will have a Simon two-stage design. In Stage I (safety cohort), 13
patients will receive combination therapy of AE37 vaccine (without GM-CSF
adjuvant) 1000 micrograms in two split intradermal injections on Day 1 of cycles
1 through 5 and pembrolizumab 200 mg intravenous infusion (IV) given Day 1 of
each cycle for 2 years (1 cycle =21 days). See Table 1.

During a safety run-in, the first 3 patients will be closely followed for 6
weeks following the first dose of study therapy (2 cycles) without further
accrual of patients. If one or less of the first 3 patients experience ≥ Grade 3
systemic toxicity attributable to study therapy during the observation period,
the safety run-in portion of the study will proceed to full enrollment at the
proposed study therapy dose (AE37 1000 micrograms and pembrolizumab 200 mg IV
infusion). If there are two or more patients in the safety run-in with ≥ Grade 3
systemic toxicities requiring a

≥ 2 week delay in starting Cycle 2, the dose of AE37 will be decreased to dose
level −1 (500 micrograms) to complete stage I accrual.

If Grade 3 systemic toxicity attributable to the vaccine is observed during the
safety run-in or in > 25% (4 or more) of patients in Stage I, the AE37 dose will
be de-escalated to 500 micrograms (dose level −1) for all patients to complete
stage I accrual. If systemic toxicity occurs in ≥ 3 patients at dose level −1
accrual will be halted and the toxicity reviewed by the study team. .

Table 1. B-001 Safety Run-In (N=13 patients)

AE37 1000mcg Patient # 1-13 DLT/ patients AE37 Dose modification 1 0/1 or 1/1
Continue at 1000mcg 2 0/2 or 1/2 Continue at 1000mcg 2/2 Decrease Dose level -1
(500mcg) 3 0/3, 1/3 Continue at 1000mcg 2/3 Decrease Dose level -1 (500mcg) All
subsequent patients* 0/13, 1/13, 2/13, 3/13 Continue at 1000mcg

[image_011.gif] [image_012.gif]

*However, if 4 or more patients experience Grade 3 systemic toxicity
attributable to the AE37 vaccine, the starting dose will be decreased to Dose
Level −1 (500mcg) for all subsequent patients enrolled to the study and the
Safety Run-In will commence as outlined below.

AE37 500mcg Patient # DLT/ patients AE37 Dose modification 1st  patient on
500mcg 0/1, 1/1 Continue at 500mcg 2nd  patient on 500mcg 0/2, 1/2 Continue at
500mcg 2/2 Hold AE37 3rd  patient on 500mcg 0/3, 1/3, Continue at 500mcg 2/3
Hold AE37 All subsequent patients 0, 1, 2** Continue at 500mcg **If 3 or more
patients experience Grade 3 systemic toxicity at AE37 500mcg attributable to the
AE37 vaccine, the trial will be halted and reevaluated.          

48 

 

 

If > 2 patients in the first stage have an objective response, the study will
proceed to Stage II (expansion cohort). The expansion cohort will enroll 16
additional patients to receive the combination therapy: AE37 (at the dose
established in the initial safety cohort [i.e., 1000 micrograms or 500
micrograms]) x on Day 1 for five cycles, and pembrolizumab 200mg IV on Day 1 of
every cycle x 2 years. If ≥ 8 patients have objective response, the study
therapy will be considered for further testing.

All patients (safety and expansion cohorts) will receive two delayed type
hypersensitivity inoculations (DTH): the first within one week prior to
beginning study therapy and the second approximately 42 days after the last AE37
vaccine dose.

Toxicity will be graded according to the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events version 4.0. Oversight and
determination/attribution of all AEs during the safety run-in and the subsequent
study will be reviewed by NSABP Department of Site and Study Management at
monthly intervals.

There will be up to 29 evaluable patients; accrual will occur over 24 months.
Trial duration is about 4 years.

Correlative science includes the submission of archived primary tumor tissue and
blood samples as a study requirement for all patients and two optional tissue
sample collections from consenting patients.

49 

 

 

 

Figure 1

B-001 Schema

 

[image_016.gif] 

 

 

50 

 

2.0BACKGROUND

 

2.1Background

Triple-negative breast cancers (TNBC) are defined as tumors with low expression
of estrogen receptor, progesterone receptor, and HER2. Approximately 20% of
women with breast cancer have triple- negative disease. As a group, these
patients have a relatively poor prognosis.

Chemotherapy is the mainstay of therapy as these tumors lack a biomarker for
targeted therapy such as endocrine treatment or traditional anti-HER2 therapy
(e.g., trastuzumab). TNBC more frequently occurs in younger women of < 40 years
of age and is more common in black women than in white women. Recurrence after
initial diagnosis and treatment more often occurs within the first few years of
diagnosis compared to hormone positive disease in which late recurrences are
frequent. Because targeted therapies are ineffective in triple-negative disease,
survival after recurrence is often short.

 

2.2Rationale for Immune checkpoint therapy in triple-negative breast cancer

The use of immune checkpoint therapy has recently joined the other modalities of
therapy as one of the pillars of modern cancer treatment. The development of
agents that target immune checkpoints has dramatically altered treatment in many
difficult to treat cancers such as lung cancers, melanoma, specific
subpopulations of colorectal cancer, bladder cancer, chemo- refractory Hodgkin's
disease, and others. Immune surveillance in controlling outgrowth of neoplastic
transformation has been recognized for decades (Disis 2010). Accumulating
evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in
cancer tissue and favorable prognosis in various malignancies (Dong 2002; Sharpe
2002; Brown 2003; Francisco 2010; Thompson 2007). The magnitude of lymphocytic
infiltration is not the only factor modulating disease progression as the
phenotype of the lymphocytic infiltrate may be most important

(Stanton 2016). In particular, the presence of CD8+ T-cells and the ratio of the
CD8+ effector T- cells/FoxP3+ regulatory T-cells seems to correlate with
improved prognosis and long-term

survival in many solid tumors. In breast cancer there is variation in the
incidence and magnitude of TILs. TNBC demonstrates the highest incidence of
TILs. CD8+ T-cell infiltrates indicative of type 1immunity were found in 60% of
TNBC. There are many factors that may contribute to the magnitude of TILs in
TNBC. For example, hormone receptor negative cancers have been shown to have
more genomic instability and more chromosomal instability than hormone-receptor-
positive tumors (Disis 2015; Stephens 2012). A greater number of mutations raise
the chance that mutated protein sequences will be expressed and potentially be
recognized as novel antigens by the immune system.

In addition, PD-L1 is expressed on many cancer and immune cells and in doing so
plays an important role in disrupting cancer surveillance and maintaining an
immunosuppressive

microenvironment. A recent study of 43 breast tumors demonstrated that 89% of
PD-L1+ cancers were associated with increased TIL infiltration compared with 24%
of PD-L1− tumors. The PD-L1 receptor-ligand interaction is a major pathway
hijacked by tumors to suppress

immune control. The normal function of PD-1, expressed on the cell surface of
activated T-cells under healthy conditions, is to down-modulate unwanted or
excessive immune responses, including autoimmune reactions.

Blocking PD-1 pathway invigorated the immune system, for example by enhancing
tumor antigen-specific CD8+ T cell responses. Pembrolizumab is a humanized
monoclonal antibody

that binds to the PD-1 receptor and blocks interactions with its ligands, PD-L1
and PD-L2. This in turn releases the immune inhibitory effects of PD-1 and can
enhance anti-tumor immune response.

In a phase 1 trial in heavily treated TNBC patients (20% had ≥ 5 or more lines
of therapy) (n=32) selected for PD-L1+ staining in the tumor or tumor stroma,
the response to pembrolizumab was

51 

 

encouraging: 18.5% (1 complete response [CR] and 2 partial responses [PRs]). The
median time to response was 18 weeks and the duration of response was not
reached. The 6 month progression free survival (PFS) rate was 23.3% (Nanda
2016). While encouraging, there is still low overall response to single agent
immune therapy in TNBC. This is further demonstrated in a recent study of
avelumab, a PD-1 targeted agent presented at SABCS in 2015. This trial had a low
objective response rate of 5.4% in the entire cohort; however in the TNBC cohort
tumors with PD-L1 expressing immune cells in the tumor, there were 44.4% of
patients receiving PR (Dirix 2015). Because of the durability in response,
current strategies are aimed at increasing the number of responsing patients.

 

2.3Rationale for HER2 vaccine in triple-negative breast cancer

The HER2/neu protein was shown to be a tumor antigen that stimulates immune
responses, as evidenced by specific antibodies and T cells against HER2/neu
detected in blood samples from breast cancer patients (Disis 1994). The multiple
immunogenic epitopes within the HER2/neu protein led to the discovery of
specific HER2/neu peptides that stimulate cytotoxic T lymphocytes to recognize
and eliminate HER2/neu expressing breast and ovarian cancer cells (Peoples
1995). Two peptide vaccines, E75 and GP2, containing epitopes derived from
HER2/neu, have been shown in Phase I and II trials to safely and effectively
stimulate antigen-

specific immune responses and cytolytic activity via CD8+ T cells in tumors of
breast cancer

patients expressing HER2/neu (Benavides 2009; Mittendorf 2006). However, these
first generation peptide vaccines are HLA-A2 restricted and require booster
vaccinations as they do not demonstrate sustained-immunity.

AE37, which is not HLA-A2 restricted, has been tested in Phase I and II clinical
trials with breast and prostate cancer patients determined to express any level
of the HER2/neu protein. Significant increases in T cell proliferation were
detected 1 month post-vaccination and long term (6 months after completion of
vaccinations [3 years after completion in our Phase I prostate cancer study, see
below]) with DTH reactions noted for all patients that received vaccine. The
vaccine was well tolerated with 73% experiencing Grade 1 systemic toxicities
(fatigue, nausea, myalgias, rhinitis, diarrhea, headache and cough) and 13%
experiencing Grade 2 toxicities (joint pain and stiffness). In the larger Phase
II breast cancer study, Grade 3 toxicities were observed in 1% of 298 patients
enrolled (Mittendorf 2016). This was a controlled, randomized and single blinded
study comparing the AE37 vaccine plus GM-CSF versus GM-CSF alone. The toxicities
were observed equally both in the AE37 plus GM-CSF as well as the GM-CSF only
arms of the study, indicating that toxicities were attributable to GM-CSF and
not AE37. Given that AE37 on its own is sufficient to generate a T cell
response, the current study will employ AE37 without GM-CSF.

AE37 was also tested in a Phase 1 study of 32 castrate-sensitive and castrate
resistant prostate cancer patients with any level of HER2/neu expression at 500
micrograms AE37 peptide/125 micrograms GM-CSF in 6 monthly intradermal
inoculations (Perez 2010). The vaccine was very well tolerated with mild Grade 1
and 2 toxicities attributed largely to GM-CSF. In vitro immune responses were
noted in 72% of patients demonstrated by increases in the percentages of
circulating CD4+ and CD8+ T cells as well as increased production of IFN-γ noted
post vaccination and long term. Interestingly, in vitro immune responses were
significantly higher in patients expressing low levels of HER2/neu (IHC 1+ or
2+) which is consistent with results seen in the E75 vaccine trial in breast
cancer patients (Benavides 2009). Importantly, it has been shown that tumor
cells with low level HER2 expression are still good targets for killing by
activated T cells (Weidanz 2006). This is because activated T cells recognize
target protein peptides in the context of MHC molecules as opposed to the native
target protein as is the case for monoclonal antibodies. The limiting factor is
thus more closely dependent upon the level of expression of MHC molecules rather
than the level of target protein expression. As patients in this category are
considered HER2 negative by ASCO/CAP guidelines (Nitta 2016) they are
represented in the triple negative breast cancer population. In addition to
establishing a specific

52 

 

activation of both CD4+ and CD8+ T cells, the Phase I trial of AE37 also
demonstrated a reduction in circulating T regulatory cells as well as TGFβ. This
is significant as it suggests that AE37 treatment reduces immune suppressive
function as it increases specific effector function.

 

2.4Pembrolizumab background and clinical trials

Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1)
receptor, thus inhibiting its interaction with programmed cell death ligand 1
(PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in
vitro data, pembrolizumab has high affinity and potent receptor blocking
activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile
and is in clinical development as an intravenous (IV) immunotherapy for advanced
malignancies.

Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a
number of indications. For more details on specific indications refer to the
Investigator brochure.

2.4.1       Rationale for pembrolizumab dose selection

The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The
dose recently approved in the United States and several other countries for
treatment of melanoma subjects is 2 mg/kg Q3W. Information on the rationale for
selecting 200 mg Q3W is summarized below.

In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety,
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor
activity of pembrolizumab when administered as monotherapy. The dose escalation
portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg and 10
mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts evaluated 2
mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors. All dose
levels were well tolerated and no dose- limiting toxicities were observed. This
first-in-human study of pembrolizumab showed evidence of target engagement and
objective evidence of tumor size reduction at all dose levels. No maximum
tolerated dose (MTD) has been identified. In addition, two randomized cohort
evaluations of melanoma subjects receiving pembrolizumab at a dose of 2 mg/kg
versus 10 mg/kg Q3W have been completed, and one randomized cohort evaluating 10
mg/kg Q3W versus 10 mg/kg Q2W has also been completed. The clinical efficacy and
safety data demonstrate a lack of important differences in efficacy or safety
profile across doses.

An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is
expected to provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg
Q2W. Previously, a flat pembrolizumab exposure-response relationship for
efficacy and safety has been found in subjects with melanoma in the range of
doses between 2 mg/kg and 10 mg/kg. Exposures for 200 mg Q3W are expected to lie
within this range and will be close to those obtained with 2 mg/kg Q3W dose.

A population pharmacokinetic (PK) model, which characterized the influence of
body weight and other patient covariates on exposure, has been developed. The PK
profile of pembrolizumab is consistent with that of other humanized monoclonal
antibodies, which typically have a low clearance and a limited volume of
distribution. The distribution of exposures from the 200 mg fixed dose are
predicted to considerably overlap those obtained with the 2 mg/kg dose and
importantly will maintain individual patient exposures within the exposure range
established in melanoma as associated with maximal clinical response.
Pharmacokinetic properties of pembrolizumab, and specifically the
weight-dependency in clearance and volume of distribution are consistent with no
meaningful advantage to weight-based dosing relative to fixed dosing.

53 

 

In translating to other tumor indications, similarly flat exposure-response
relationships for efficacy and safety as observed in subjects with melanoma can
be expected, as the anti-tumor effect of pembrolizumab is driven through immune
system activation rather than through a direct interaction with tumor cells,
rendering it independent of the specific tumor type. In addition, available PK
results in subjects with melanoma, NSCLC, and other tumor types support a lack
of meaningful difference in pharmacokinetic exposures obtained at tested doses
among tumor types. Thus the 200 mg Q3W fixed-dose regimen is considered an
appropriate fixed dose for other tumor indications as well.

A fixed dose regimen will simplify the dosing regimen to be more convenient for
physicians and to reduce potential for dosing errors. A fixed dosing scheme will
also reduce complexity in the logistical chain at treatment facilities and
reduce wastage. The existing data suggest 200 mg Q3W as the appropriate dose for
pembrolizumab.

 

2.5HER2 vaccine, AE37

The HER2/neu proto-oncogene is a tumor associated antigen that has been
investigated in many types of cancers including breast, prostate, and ovarian.
HER2/neu codes for a 185kD

trans-membrane protein in the epidermal growth factor receptor family which is
found to be over- expressed in 20-30% of breast cancers and has also been
correlated with more aggressive tumor behavior (Slamon 1989). It has been shown
to be expressed in an additional 50% of breast cancers at low to intermediate
levels.

AE37 is a fifteen amino-acid peptide from the HER2 protein to which the four
amino-acid sequence LRMK has been added, it is produced by a solid-phase peptide
synthesis. The peptide sequence is AC-LRMK-GVGSPYVSRLLGICL-NH2. Studies have
demonstrated that the AE37 peptide stimulates a robust helper T-cell response
leading to effective cytotoxic T lymphocyte (CTL) activity against tumors
expressing even low levels of HER2 regardless of HLA status.

AE37 is a hybrid Ii-Key/HER2 peptide. Ii-Key hybrids have been shown to display
>250 times potency in terms of T-cell stimulation in vitro compared to the
unmodified naturally-occurring peptide. AE37 has been shown to be recognized
both by CD4+ T helper cells as well as CD8+ CTLs (HER2 Hybrid Peptide AE37 IB).

Antigen Express has developed a novel method for dramatically increasing
antigen-specific stimulation of T helper cells. This involves the addition of a
small portion of the major histocompatibility complex (MHC) class II-associated
Ii protein (termed Ii-Key) to class II epitopes (Lee 2000). The Ii-Key segment
of the Ii protein was found to bind to an allosteric site on MHC class II
molecules, thereby facilitating the direct charging of a vaccine peptide into
the antigenic peptide-binding site of MHC class II molecules (Sotiriadou 2007).
The resulting Ii- Key/antigenic epitope hybrid displays up to 250 times greater
potency in vitro compared to the unmodified class II epitope (Sotiriadou 2007).
Studies have shown that Ii-Key hybrid peptides derived from a variety of
disease-related antigens more potently activate CD4+ T helper cells in vivo as
well as in vitro when compared to epitope only peptides. The consequence of this
increased yet specific T helper cell stimulation is more robust CTL activation
and the production of immunological memory.

54 

 

3.0STUDY AIMS AND ENDPOINTS

3.1Co-Primary aims and endpoints

3.1.1Determination of recommended dose for further study

Aim: To evaluate the safety and tolerability of AE37 peptide vaccine given in
combination with pembrolizumab in patients with metastatic triple negative
breast cancer

Endpoint: Recommended dose of AE37 that can safely be administered with
pembrolizumab as a combination in an expanded cohort

 

3.1.2Response rate

Aim: Objective response rate (ORR)

Endpoint: Overall objective response rate as measured by RECIST 1.1 with
modifications for progressive disease confirmation

 

3.2Secondary aims and endpoints

3.2.1Progression-free survival (PFS)

Aim: To evaluate the progression free survival (PFS) with pembrolizumab in
combination with AE37 peptide vaccine at the recommended biologic dosage

Endpoint: Time to progression or death from any cause

 

3.2.2Overall Survival (OS)

Aim: To determine OS rate at 1 year

Endpoint: Time from study entry through 1 year

 

3.2.3Toxicity

Aim: To evaluate the overall toxicity of AE37 peptide vaccine in combination
with pembrolizumab

Endpoint: Frequency and severity of adverse events categorized using the NCI
Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

 

3.3Exploratory translational science

Aim: Exploratory analysis of immune parameters

Aim: To determine presence of in vivo responses to DTH

55 

 

4.0PATIENT ELIGIBILITY AND INELIGIBILITY

 

Investigators should consider each of these factors when selecting patients for
this trial. Investigators should also consider all other relevant factors
(medical and non-medical), as well as the risks and benefits of the study
therapy, when deciding if a patient is an appropriate candidate for this trial.

4.1Conditions for patient eligibility

A patient cannot be considered eligible for this study unless all of the
following conditions are met:

4.1.1In order to be eligible for participation in this trial, the patient must
be willing and able to provide written informed consent for the trial.

4.1.2Be female and ≥ 18 years of age on day of signing informed consent.

4.1.3Have a performance status of 0 or 1 on the ECOG Performance Scale. (See
Appendix A.)

4.1.4Patients must have histologic or cytologic confirmation of the diagnosis of
invasive adenocarcinoma of the breast.

4.1.5The primary or metastatic tissue must be triple negative (ER/PR < 9%, HER2
negative by ASCO/CAP guidelines).

4.1.6There must be documentation that the patient has evidence of measurable

metastatic breast cancer based on RECIST 1.1. Tumor lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated in such lesions. Histologic confirmation of metastatic disease is
not required.

4.1.7At least 1 of the tumor sites must be amenable to core needle biopsy.

4.1.8Patients with treated, stable, asymptomatic metastatic disease to the brain
not requiring chronic corticosteroids are eligible (per discretion of the
treating investigator).

4.1.9Patient must have resolution of toxic effect(s) of the most recent
chemotherapy ≤ to Grade 1 (except alopecia). If the patient has received major
surgery or radiation therapy of > 30 Gy, they must have recovered from the
toxicity and/or complication from the intervention.

4.1.10Demonstrate adequate organ function, all screening labs should be
performed within two weeks of treatment initiation.

•ANC count ≥ 1,500/mm3

•Platelets ≥ 100,000/mm3

•Hemoglobin ≥ 9 g/dL

•Creatinine ≤ 1.5x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (CrCl) ≥ 60mL/min for patients with creatinine levels >
1.5x institutional ULN. (Glomerular filtration rate (GFR) can also be used in
place of creatinine or CrCl.)

•Total bilirubin ≤ 1.5x ULN OR Direct bilirubin ≤ ULN for patients with total
bilirubin levels > 1.5 x ULN.

•AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN OR ≤ 5 x ULN for patients with liver
metastases.

4.1.11A ≤ Grade 1 skin reaction to the first DTH inoculation is required to
begin study therapy. See Section 7.1 and Table 7.

56 

 

4.1.12International normalized ratio (INR) or prothrombin time (PT) must be
≤1.5xULN unless the patient is receiving anticoagulant therapy as long as PT or
PTT is within therapeutic range of intended use of anticoagulants. Partial
Thromboplastin Time (aPTT) and

≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use of anticoagulants

 

4.1.13Female patients of childbearing potential should have a negative urine or
serum pregnancy within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.

4.1.14Study patients of childbearing potential should be willing to use an
adequate method of contraception as outlined in (Section 7.5 and Appendix B) or
be surgically sterile, or abstain from heterosexual activity for the course of
the study through 120 days after the last dose of study medication. Patients of
childbearing potential are those who have not been surgically sterilized or have
not been free from menses for > 1 year.

 

4.2Conditions for patient ineligibility

Any patient with one or more of the following conditions will be ineligible for
this study:

4.2.1Greater than 4 prior lines of therapy for metastatic disease.

4.2.2Is currently participating in or has participated in a study of an
investigational agent or using an investigational device within 4 weeks of the
first dose of treatment.

4.2.3Has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to
the first dose of trial treatment. The use of physiologic doses of
corticosteroids must be discussed with DSSM.

4.2.4A ≥ Grade 2 skin reaction to the first DTH inoculation will exclude that
patient from beginning study therapy.

4.2.5Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior
to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
adverse events due to agents administered more than 4 weeks earlier.

4.2.6Prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or
at baseline) from adverse events due to a previously administered agent. Note:
Patients with alopecia are an exception to this criterion and may qualify for
the study.

4.2.7Blood products (including platelets or red blood cells) or administration
of colony stimulating factors (including G-CSF, GM-CSF or recombinant
erythropoietin) within 4 weeks prior to beginning study therapy.

4.2.8Has a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy, or in
situ cancers.

4.2.9Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Patients with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging
for at least four weeks prior to the first dose of trial treatment and any
neurologic symptoms have returned to baseline), have no evidence of new or
enlarging brain metastases, and are not using steroids for at least 7 days prior
to trial treatment.

57 

 

4.2.10Has an active autoimmune disease that has required systemic treatment
within the past

2 years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency and bone anti-resorptive agents etc.) is not considered a form of
systemic treatment.

4.2.11Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.

4.2.12Has a history of or active interstitial lung disease, autoimmune lung
disease, severe asthma requiring daily medication.

4.2.13Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease,
resection of the stomach or small bowel, or other disease or condition
significantly affecting gastrointestinal function.

4.2.14Has an active infection requiring systemic therapy.

4.2.15Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with a
patient’s participation for the full duration of the trial, or is not in the
best interest of the patient to participate, in the opinion of the treating
investigator.

4.2.16Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.

4.2.17Is pregnant or breastfeeding, or expecting to conceive a child within the
projected duration of the trial, starting with the pre-screening or screening
visit through 120 days after the last dose of trial treatment.

4.2.18Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways) is not allowed.

4.2.19Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).

4.2.20Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g.,
HCV RNA [qualitative] is detected).

4.2.21Has received a live vaccine within 30 days prior to the first dose of
trial treatment. Seasonal flu vaccines are permitted.

4.2.22Has severe hypersensitivity to pembrolizumab and/or any of its excipients.

58 

 

5.0REQUIREMENT FOR STUDY ENTRY AND DURING TREATMENT AND FOLLOW-UP

 

Tests and exams required before study entry are listed on Table 2. Requirements
following study entry are outlined on Table 3.

Table 2. Tests, exams, and other requirements prior to study entry

Requirements Prior to Study Entry Consent form for the B-001 trial signed by the
patient X Agreement of local pathology department to release the primary tumor
tissue slides from the diagnostic biopsy or other previous surgerya

 

X

History & physical examb X

 

 

 

 

 

Within 2 weeks

Performance status (see Appendix A) X Height & weight X
CBC/differential/platelet count X

Total bilirubin/AST (SGOT)/ALT (SGPT), alkaline phosphatase, serum sodium,
chloride, potassium,

CO2, calcium, protein, glucose, creatininec, BUN

(e.g., Comprehensive metabolic panel)

 

X

Thyroid function tests: TSHd X Imaging of cheste X Within 4 weeks Imaging of
abdomen and pelvisf X Pregnancy testg X

After patient signs consent and within 1 week of planned

start of study therapy

Required study blood samplesh X Vaccine allergen skin test (DTH)i X

a        The archived primary tumor tissue from the previous surgery must be
requested and the pathology department must agree before study entry to release
these slides or an archived paraffin tumor block if slides are unavailable (see
Section 6.0). Submit the tumor tissue within 60 days after study entry.

b       Complete H&P by physician or other healthcare professional (on FDA Form
1572).

c        Serum creatinine OR measured or calculated creatinine clearance (CrCl)
> 60mL/min for patients with creatinine levels > 1.5 x institutional ULN.
(Glomerular filtration rate (GFR) can also be used in place of creatinine or
CrCl.)

d        If TSH abnormal, (outside normal range) obtain free triiodothyronine
(T3) and thyroxine (T4).

e        Preferred imaging options for chest: CT scan with contrast or PET/CT
scan with contrast.

f          Preferred imaging for abdomen and pelvis: CT scan with contrast or
PET/CT with or without contrast; MRI with contrast. (MRI with contrast can be
substituted for CT scan.)

g        For WOCBP should have a negative urine or serum pregnancy within 72
hours prior to receiving the first delayed type hypersensitivity (DTH).
Pregnancy testing should be performed according to institutional standards

h       Blood samples collected for research study purposes should be drawn
concurrently with blood samples required for study entry. See Section 6.0. For
all blood and tissue sample collections and submissions see B-001 Pathology and
Correlative Science Instructions.

i         The DTH inoculation is to be performed within one week prior to
beginning study therapy. DTH inoculation sites are to be assessed for
hypersensitivity reactions within 48-72 hours after the inoculation. A negative
response is required for study entry. See Section 7.1 and Table 7.

59 

 

 

Table 3. Tests, exams, and other requirements following study entry

 

 

Requirements

Within 72 hours before Day 1 of

Cycle 1

Within 72 hours before Day 1 of

Cycle 2

Within 72 hours before Day 1 of

Cycle 3

Within 72 hours before Day 1 of

Cycle 4

Within 72 hours before Day 1 of

Cycle 5

Within 72 hours before Day 1 of

Cycle 6

Within 72 hours before Day 1 of

Cycle 7

Within 72 hours before Day 1 of

Cycles 8

through 34

Follow-up

30 days following discontinuation of study therapy (Within +/- 7 days)

History & physical exama, b X X X X X X X X X Vital signs X X X X X X X X X

 

Adverse event Assessmentc, d

X

(And within 48 -72

hours after Day 1)

X

(And within 48 -72

hours after Day 1)

X

(And within 48 -72

hours after Day 1)

X

(And within 48 -72

hours after Day 1)

X

(And within 48 -72

hours after Day 1)

 

X

(And within 48 -72

hours after Day 1)

 

 

X

DTH intradermal inoculatione            

X

(On Day 1)

    CBC/differential/platelet countf   X X X X X X X X

Total bilirubin/AST (SGOT)/ALT (SGPT), alkaline phosphatase Serum sodium,
chloride, potassium, CO2, calcium, protein, glucose,

creatinine, BUN (e.g., Comprehensive metabolic panel)f

 

 

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

 

X

 

Thyroid function tests: g

 

 

X

 

 

X

 

 

X

 

X

(Cycle 8 and every

even cycle)

 

X

 

Measurement of target lesionsh

   

 

X

   

 

X

 

X

(Cycle 9 and then every 3 cycles)

 

X

Pregnancy testi   X X X X X X X   Blood samplesj

X

(Required)

   

X

(Required)

   

X

(Required)

 

X

(Optional upon disease progression)

Tumor tissue samplek,l

X

(Required)

   

Xl

(Required)

       

Xl

(Optional: upon disease progression)

Table 3 continues on next page

60 

 

 

Table 3. Tests, exams, and other requirements following study entry (continued)

aAt the discretion of the investigator, additional exams, bloodwork, x-rays,
ECGs, scans, and other testing may be performed as clinically indicated.

bUpdated H&P with exams, adverse event assessment, and assessments during
therapy and follow-up by physician or other appropriate healthcare professional
(on FDA Form 1572).

cThe AE37 intradermal injection sites (DTH and study therapy dose) are to be
assessed for hypersensitivity reactions within 48-72 hours after each dose
(e.g., DTH inoculations on Days 3 or 4; AE37 vaccinations: on Days 3 or 4).
Note: An assessment of a negative response is required from initial DTH
inoculation for the patient to enter the study. See Section 7.1

dShould the patient stop study therapy (e.g. due to disease progression or
second primary) and begin a new treatment prior to the last dose of study
therapy AE assessments should be collected only up to the date the new therapy
begins. See Section 10.0. SAE/AE assessments 90 days (+/− 14 days) after the
last dose of study therapy.

eThe second DTH inoculation will be given approximately 42 days after the last
AE37 vaccination (e.g., Day 1 Cycle 7). See Section 7.1.

fCBC/Diff, blood chemistries, LFTs done at screening may be used as baseline
assessment results for Cycle 1/Day 1.

gBeginning with Cycle 2, obtain thyroid function tests: TSH, free
triiodothyronine (T3) and thyroxine (T4) every 6 weeks (e.g., every even Cycle).

hThe same imaging method (PET/CT scan, CT scan or MRI), used at baseline should
be used every 3 cycles from start of therapy. Assessment of measurable disease
is every 3 cycles by RECIST 1.1. See Section 11.0.

iWOCBP should have a negative urine or serum pregnancy within 72 hours prior to
receiving the first dose of study medication. Pregnancy testing should be
performed monthly according to institutional standards.

jA required research blood sample will be collected from all patients prior to
starting study therapy and within 72 hours of beginning Cycle 4 (with biopsy),
and within 72 hours of cycle 7. Optional research blood samples will be
collected from consenting patients at the time of disease progression. Blood
samples collected for research study purposes should be drawn concurrently with
blood samples required for the study. See Section 6.0.

kTumor tissue requirement: A tissue core biopsy from an accessible metastatic
site will be collected prior to starting study therapy and within 72 hours of
beginning Cycle 4. See Section 6.0.

lOptional blood samples and tumor tissue core biopsies from an accessible
metastatic site will be collected from consenting patients upon disease
progression.

See Section 6.0.

For all blood and tissue sample collections and submissions see B-001 Pathology
and Correlative Science Instructions.

61 

 

6.0PATHOLOGY AND CORRELATIVE SCIENCE STUDIES

6.1Overview of requirements

Collection and submission of all patient samples (blood, tumor) listed below is
a requirement for all patients participating in the NSABP B-001 study. By
signing the B-001 consent form, the patient has agreed to all required sample
collections and submissions.

Non-submission of required patient samples will be a protocol violation. Patient
samples will be collected at the specified time points as outlined in Table 3
and Table 4. (See B-001 Pathology and Correlative Science Instructions for tumor
and blood sample processing and submission).

Table 4. Summary of patient sample submission requirements

Study requirements

for ALL patients

Prior to beginning study therapy Prior to Day 1 of Cycle 4 Prior to Day 1 of
Cycle 7 At the time of disease progression

 

Submission of archived primary tumor tissuea

 

YES

(Required)

     

 

Collection and submission of blood samplesb

 

YES

(Required)

 

YES

(Required)

 

YES

(Required)

  Collection and submission of tissue samplesc,d

YES

(Required)

YES

(Required)

 

YES

(Optional)

a       Archived paraffin block of primary tumor tissue is preferable. See
Section 6.3.1.

b        Required blood sample collections: Blood samples collected for research
study purposes should be drawn concurrently with blood samples required for
study: prior to beginning study therapy and Day 1 of Cycle 7. See Section 6.3.1.

c        Required tissue biopsy procurement: Core biopsy specimens (2 to 4
cores) from an accessible metastatic site will be collected from all patients
prior to starting study therapy and within 72 hours prior to beginning Cycle 4
and Cycle 7. Samples should be submitted on the same day as procurement

d        Optional tissue and blood samples: Blood samples and procurement of
core biopsy specimens (2 to 4 cores) from an accessible metastatic site and at
disease progression should be requested and collected from consenting patients.
Samples should be submitted on the same day as procurement

NOTE: Refer to the B-001 Pathology and Correlative Science Instructions for
tumor and blood sample submission instructions.

 

6.2Use of specimens

The blood and tumor samples collected in this study will be used for B-001
studies as described in Section 6.4 and for analyses to be conducted in the
future related to the purposes of the B-001 study but not currently described in
the protocol document. Additionally, the specimens procured may be used for
future studies involving gene and protein conferring susceptibility to cancer or
other diseases. If hereditary genetic studies are conducted, an anonymization
process will be used. Results of the correlative science studies, including raw
sequencing data, will not be reported directly to the patient or the physician
and will not have any bearing on patient treatment.

62 

 

The results of the study will be communicated through publication, in peer
reviewed scientific literature and/or through presentations at scientific
meetings. Anonymized or de-identified research data (as deemed appropriate by
the NSABP), including genome sequencing data, may be submitted to public
research databases for data sharing with controlled access to scientific
researchers outside of the NSABP.

 

6.3Tumor and blood sample submissions

6.3.1Required tissue and blood samples

•Archived primary tumor tissue block: Use of the archived paraffin block of
primary tumor tissue is permitted; however submission of a fresh core biopsy
specimen is preferred. Refer to the B-001 Pathology and Correlative Science
Instructions for tumor tissue submission instructions.

•Required tissue samples: Core biopsy specimens (2 to 4 cores) from an
accessible metastatic site will be collected from all patients:

−prior to starting study therapy, and

−within 72 hours of beginning Day 1 of Cycle 4.

•Study blood samples: Peripheral blood may be analyzed for AE37 antigen-specific
T cell immune responses in peripheral blood. Blood samples will be collected:

−prior to initiation of pembrolizumab plus AE37 peptide vaccine therapy and

−prior to receiving study therapy on Day 1 of cycle 7.

Note: Refer to the B-001 Pathology and Correlative Science Instructions for
study blood sample collection, processing, and submission instructions.

6.3.2Optional tissue and blood samples

•Optional tumor tissue samples should be collected from consenting patients at
the time of disease progression.

Note: When disease progression has been confirmed by imaging per RECIST
criteria, biopsy specimens are to be collected from consenting patients
preferably from a new accessible metastatic lesion or one that increased in size
when compared to the previous imaging scan result from consenting patients.
Biopsy specimens at the time of progression must be collected prior to
initiating any new therapy and within 30 days following discontinuation from
study therapy.

•Optional research blood samples should be collected optional blood sample from
consenting patients at time of progression.

All tissue and blood samples will be submitted to the NSABP Division of
Pathology (see Information Resources) where the samples will be logged into the
database and assigned a unique code number. The samples will be stripped of any
remaining patient identifiers (except the NSABP B-001 Patient ID numbers),
processed, and stored. A portion of the samples may be shipped to collaborating
laboratories including Merck & Co. Inc. and their vendor who will perform assay
for PDL-1 expression and PanCancer nanostring mRNA assay including approximately
800 genes. Refer to the B-001 Pathology and Correlative Science Instructions for
tissue and blood specimen collection and submission instructions.

63 

 

6.4Rationale for correlative science studies

6.4.1AE37 antigen-specific T cell immune responses in peripheral blood

To determine whether pembrolizumab plus AE37 Peptide Vaccine in study patients
induces AE37 antigen-specific T cell immune responses in peripheral blood and
enhances T cell immune responses in tumor tissues, peripheral blood may be
analyzed for AE37 antigen-specific T cell immune responses (Fourcade 2014; Hamid
2013.

Fourcade 2012; Fourcade 2010; Fourcade 2009). These include:

•Analysis of AE37 antigen-specific T cell immune responses in peripheral blood.

−Intracellular cytokine ex-vivo assay: The frequency of AE37 antigen-specific
CD4+ and CD8+ T cells in peripheral blood will be analyzed by ex-vivo
intracellular cytokine assays for IFN-g, TNF, IL-2, and IL-21 as previously
reported (Fourcade 2014; Hamid 2013. Fourcade 2012; Fourcade 2010; Fourcade
2009).

−Ex-vivo CD107a degranulation assays: CD107a cell surface expression as a
surrogate of lytic function will be investigated using overlapping peptides from
AE37 antigens as previously reported (Fourcade 2014).

•Change of CD4+CD25+FOXP3+ Treg cells in peripheral blood lymphocytes (Gates
2010).

•To determine potential correlation between TGF-β levels in plasma samples by
ELISA and clinical tumor response (Perez 2014; Perez 2013; Perez 2010).

•To determine potential correlation between HLA-A*24 and/or HLA-DRB1*11 and
clinical tumor response (Anastasopoulou 2015).

6.4.2Tissue studies

•Optional tumor biopsy prior to initiation of pembrolizumab plus AE37 Peptide
vaccine therapy and prior to cycle 4 may be used for the following:

−Evaluation of CD8+ T cell infiltrates in tumor tissues using the Immunoscore.
The distribution and density of CD8+ T cells may be analyzed by quantitative IHC
analysis for standard T-cell subsets using antibodies to CD3, CD4, and CD8 in
the invasive tumor margin and within the tumor parenchyma, as previously
reported (Tumeh 2014; Galon 2006; Pages 2005; Llosa 2015).

−IHC analysis of genes involved in immune checkpoint pathways in tumor tissues:
IHC analysis of PD-1, PD-L1, LAG-3, CTLA-4 and IDO1 in tumor tissues may be
performed, as previously reported (Tumeh 2014; Llosa 2015; Pierer 2007; Irie
2005).

•Analysis of TCR β-chain usage in tumor infiltrating lymphocytes (TILs):

A more restricted TCR β-chain usage reflects a T-cell population that is less
diverse in repertoire and more clonal in nature, and is significantly correlated
with clinical response to pembrolizumab plus AE37 Peptide vaccine therapy (Tumeh
2014;Zhu 2013).

To determine whether the frequency of mutation-associated neoantigens in tumor
tissue correlates with tumor response to prior to initiation of pembrolizumab
plus AE37 Peptide vaccine therapy, tumor tissues collected prior to initiation
of pembrolizumab plus AE37 Peptide vaccine therapy may be analyzed for tumor
gene mutations. Analysis of the frequency of mutation-associated neoantigens in
tumor tissues (Vogelstein 2013; Alexandrov 2013; Snyder 2014; Yadav 2014; Le
2015; Rizvi 2015).

64 

 

7.0STUDY THERAPY

7.1AE37 Vaccine

7.1.1Delayed type hypersensitivity (DTH) monitoring

Each enrolled patient will receive a delayed type hypersensitivity (DTH)
intradermal injection (100 mcg AE37 peptide/0.5 ml normal saline) at two times
during the study:

•Within one week prior to the first dose of study therapy (see Section 4.1.11
and Table 3); and

•Approximately 42 days after delivery of the final inoculation (e.g., Cycle
7/Day 1).

Note: Women of child bearing potential must have a negative pregnancy test
within 72 hours of each DTH inoculation.

7.1.2DTH inoculation administration

The contents of the first AE37 DTH vial for a newly enrolled patient’s
inoculation regimen will be administered in the following manner:

•One frozen, sterile AE37 DTH vial containing 100 micrograms is removed from the
-20ºC freezer and thawed at room temperature (RT). The thawed solution is
withdrawn into a single-dose, sterile syringe and immediately administered by
intradermal injection on the left anterior thigh approximately 9 inches superior
to the knee. See Section 9.1.6.

•After the above is accomplished, 0.5 ml of normal sterile saline is withdrawn
into a single-dose, sterile syringe. The 0.5 ml inoculum is immediately
administered by intradermal injection on the right anterior thigh approximately
9 inches superior to the knee. (This second inoculum of sterile saline is
administered to serve as a negative control for the DTH test).

7.1.3DTH reaction assessment

The DTH reaction will be measured in 2 dimensions at 48-72 hours post
inoculation and compared between peptide and sterile saline and between
pre-inoculation and post- inoculation. The low dose of peptide used in the DTH
test is not expected to induce a long term immune response; however, any
response that is induced is expected to be transitory in nature.

Patients are to be monitored post-injection for 1 hour to note any local or
systemic reactions to the vaccine and are required to return to the clinic
within 48-72 hours after inoculation for assessment of local and/or systemic
reactions. A photograph of the DTH response will be obtained for the purpose of
documentation and reporting. These results will also be recorded in the response
database. See Section 8.2.3 and Table 7.

Additionally, patients should be given the phone number to the treatment clinic,
and emergency department in case of reaction/side effects, and educated about
the local and systemic signs of infection. If any adverse events occur, these
will be reported per the protocol. If infection is detected, then vaccinations
will be halted and the sterility of the remaining single dose vials
re-confirmed. The patient will be medically treated as appropriate.

Note: A ≤ Grade 1 skin reaction DTH response is required to begin study therapy.
See

4.1.11 and Table 7.

65 

 

7.1.4Dose-limiting toxicity for AE37

If Grade 3 systemic toxicity that require a ≥ 2 week delay in starting Cycle 2
is observed during the safety run-in or in > 25% (4 or more) of patients, the
AE37 dose will be de- escalated to 500 micrograms (dose level −1) to complete
stage I accrual. If systemic toxicity occurs in 3 or more patients at this dose
(dose level −1) accrual will be halted and the toxicity reviewed by the study
team.

 

7.2Study regimen

Study therapy should begin within 2 weeks following study entry. (Note: Women of
child bearing potential must have a negative pregnancy test within 72 hours of
each dose of study therapy.) see Section 4.1.13, Table 2 and Table 3). See
Sections 7.1.1, 7.1.2, 7.1.3, 4.1.11 and Table 7 for DTH response assessment
prior to beginning study therapy.) Study therapy should be given in the order
outlined in Table 5 and Table 6. See Section 8 for treatment management.

Table 5: Safety Cohort Study Therapy:

Drug Dose Dosing Interval Planned Duration AE37 peptide vaccine a,b,c 1000
micrograms via intradermal injection Day 1 of each 21 day cycle x 5 doses

15 weeks

(5 cycles)

Pembrolizumabd 200 mg IV over 30 minutes Day 1 of each 21 day cycle Until
disease progression or intolerable toxicity (Maximum 35 cycles; 2 years)

a        See Section 6.0 for required correlative study blood sample and
optional tissue collection and submission instructions. Refer to the B-001
Pathology and Correlative Science Instructions.

b       Patients must have negative reaction to DTH inoculation to begin study
therapy. See Section 7.1 and Table 7. Patients will receive 1000 micrograms as
two 500 microgram intradermal injections of approximately 5cm apart on the
anterior or medial side of the same thigh. See Section

9.1.6 for AE37 administration instructions.

Note: If there is a large local reaction (>100 mm) such that the reaction at the
two sites begins to merge, the subsequent dose of AE37 is reduced by one half,
(i.e., 500 micrograms, dose

level −1). If Grade 3 systemic toxicity is observed in > 25% of patients the
AE37 dose will be de-escalated to 500 micrograms (dose level 1) for subsequent
patients in Stage I of the study. See Section 8.2.2 , Table 7 and Table 8.

c        A 1-hour observation period is required following each AE37
vaccination, before pembrolizumab can be administered.

d       Pembrolizumab should be administered intravenously over 30 minutes
through an intravenous line containing a sterile, non-pyrogenic, low-protein
binding 0.2 micron to 5 micron in-line or add-on filter. See Section 8.0 and
Table 10 for treatment management of infusion reactions; Section 9.2 for drug
information and preparation instructions.

1 cycle = 21 days

66 

 

Table 6: Expansion Cohort Study Therapy

Drug Dose Dosing Interval Planned Duration AE37 peptide vaccinea, b, c *X
micrograms via intradermal injections Day 1 of each 21 day cycle x 5 doses 15
weeks Pembrolizumabd 200 mg IV over 30 minutes Day 1 of each 21 day cycle Until
disease progression or intolerable toxicity (Maximum 35 cycles; 2 years)

a        See Section 6.0 for required correlative study blood sample
instructions. Refer to the B-001 Pathology and Correlative Science Instructions.

b       Patients must have negative reaction to DTH inoculation to begin study
therapy. See Section

7.1 and Table 7.

*Note: Patients will receive the AE37 vaccine dose established during Stage I of
the study [i.e., 1000 micrograms or 500 micrograms]) x on Day 1 for five
cycles.. See Section 8.2.3. The dose of AE37 vaccine will be administered in two
split dose intradermal injections on the anterior or medial side of the same
thigh (See Section 9.1.6 for AE37 administration instructions.)

Note: If the Stage II starting dose is 1000 micrograms, a patient has local
toxicity the AE37 dose may be de-escalated to dose level − 1. See Table 7 and
Table 8.

c       A 1-hour observation period is required following the each AE37
vaccination, before pembrolizumab can be administered.

d       Pembrolizumab should be administered intravenously over 30 minutes
through an intravenous line containing a sterile, non-pyrogenic, low-protein
binding 0.2 micron to 5 micron in-line or add-on filter. See Section 8.0 and
Table 10 for treatment management of infusion reactions. See Section

9.2 for drug information and preparation instructions.

1 cycle = 21 days

 

7.3Supportive therapy

7.3.1Growth factor support

The use of growth factors (e.g., G-CSF, GM-CSF) is not permitted.

7.3.2Erythropoietin

The use of erythropoiesis-stimulating agents is not permitted.

7.3.3Other supportive care

Patients should receive supportive care for other treatment-related symptoms at
the investigator's discretion.

 

7.4Contraindications and precautions

•Study therapy is contraindicated in patients who are pregnant or lactating. See
Sections 4.2.16, 7.5, and Section 10.4.

•Immunotherapy not specified in this protocol is not permitted.

•Antineoplastic systemic chemotherapy is not permitted.

•Radiation therapy is not permitted.

•The use of systemic glucocorticoids (e.g., prednisone 10 mg orally per day or
equivalents) is

permitted to modulate symptoms of suspected immunologic adverse events.

−Note: Inhaled steroids are allowed for the management of asthma.

−Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV
contrast dye) is permitted.

67 

 

•Live attenuated vaccinations within 30 days prior to the first dose of study
treatment and while participating in the trial. Seasonal influenza vaccines for
injection are generally killed viruses and are allowed. However, intranasal
influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not
allowed.

•Patients should not donate blood while participating in this study or for at
least 120 days after the last infusion of study therapy.

•Patients should not donate eggs while participating in this study or for at
least 120 days following the last infusion of study therapy.

 

7.5Contraception

Study therapy may have adverse effects on a fetus in utero. It is not known if
pembrolizumab has transient adverse effects on the composition of sperm. Female
patients of reproductive potential must agree to use (or have their partner use)
acceptable contraception during heterosexual activity to avoid becoming pregnant
or impregnating a partner, respectively, while receiving study drug and for 120
days after the last dose of study drug. See Appendix B for acceptable methods of
contraception.

For this trial, male partners of female patients of child bearing potential will
be considered to be of non-reproductive potential if they have azoospermia
(whether due to having had a vasectomy or due to an underlying medical
condition).

Female patients will be considered of non-reproductive potential if they are
either:

•postmenopausal (defined as at least 12 months with no menses without an
alternative medical cause; in women < 45 years of age a high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to
confirm a post-menopausal state in women not using hormonal contraception or
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a
single FSH measurement is insufficient.); or

•have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; or

•has a congenital or acquired condition that prevents childbearing.

 

7.6Pregnancy

If a female patient should inadvertently become pregnant while on treatment with
pembrolizumab, the patient will immediately be removed from the study. The site
will contact the patient at least monthly and document the patient’s status
until the pregnancy has been completed or terminated. See Section 10.4 for
reporting requirements.

 

7.7Participation in other clinical trials

If a patient enrolled on B-001 is considering participation in another clinical
trial (including supportive therapy trials), contact the NSABP DSSM (see
Information Resources).

68 

 

8.0TREAMENT MANAGEMENT

 

8.1General instructions

•The NCI CTCAE v4.0 must be used to Grade the severity of AEs.

•All treatment decision must be based on the AE requiring the greatest
modification.

•AE37 vaccine doses that have been reduced may not be re-escalated.

•All hematologic, gastrointestinal, and genitourinary toxicities must be < Grade
2 prior to initiating Dose 1 of study therapy. Patients unable to receive Dose 1
(i.e. Day 1/ Cycle 1 dose) will be considered screen failures.

•Each study cycle is 21 days; missed cycles will not be made up.

•Pembrolizumab, unless otherwise discontinued due to toxicity, patient request
or disease progression, should continue for up to 2 years after the first dose
(Day 1) of the first treatment cycle regardless of any missed doses or treatment
delays (maximum 35 cycles).

 

8.2Treatment management for study therapy

The study treatment schedule should be maintained. If necessary, the timing of a
treatment may be adjusted to 3 days earlier or 3 days later than the scheduled
date of treatment. All doses administered or missed must be recorded. See Table
9 for treatment management.

8.2.1Treatment decisions when therapy must be held

•Study therapy will be given on the same day. However if pembrolizumab is held
for toxicity, AE37 should still be given. When toxicity has resolved, resume
pembrolizumab on Day 1 of the next cycle. See Table 9 for treatment management.

•If a scheduled dose of study therapy is missed, the study therapy may be given
within 7 days of the appointed time (which resets the date for further
vaccinations) or be considered a missed dose.

•AE37 vaccine dosing:

−In order to receive a subsequent vaccination, patients who have vaccination-
related toxicity must have recovered to ≤ Grade 1 toxicity for the parameters
used to assess levels of organ function required for eligibility after each
vaccination.

8.2.2Dose modifications

•There are no dose reductions for pembrolizumab.

−Adverse events (both non-serious and serious) associated with pembrolizumab
exposure may represent an immunologic etiology. These adverse events may occur
shortly after the first dose or several months after the last dose of treatment.
Pembrolizumab must be withheld for drug-related toxicities and severe or
life-threatening AEs as per Table 9.

•AE37 dose modifications

−A reduction in the dose of AE37 may be required depending upon the local
reaction to multiple doses (see Table 7). AE37 is given as split dose
intradermal injections at two sites on the upper thigh 5 cm apart. If there is a
large local reaction (>100 mm) such that the reaction at the two sites begins to
merge, the subsequent dose of AE37 is reduced by one half (i.e., dose

level – 1). See Table 7 and Table 8.

−Vaccine-related toxicities requiring a ≥ 2 week delay in starting Cycle 2 or
subsequent cycles will result in a dose level reduction for subsequent AE37
vaccinations. See Section 7.1.4, Table 7 and Table 8.

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Table 7. AE37 vaccine local reaction assessment

 

Local skin reaction at vaccination sites

Grade 1 Grade 2 Grade 3 Grade 4

 

Mild erythema

Non-confluent erythema, mild tenderness at site Confluent erythema, ulceration
and/or severe pain at site Severe ulceration, necrosis; urgent intervention
necessary

 

Table 8. Dose levels for AE37 vaccine

 

AE37

Vaccine

Dose Level 0

Starting Dose

Dose Level −1 Dose Level −2 Dose Level −3 Dose Level − 4 1000 mcg 500 mcg 250
mcg 125 mcg Discontinue

 

8.2.3Treatment decisions when therapy must be discontinued

Treatment must be permanently discontinued if:

•Pembrolizumab must be held for greater than 12 weeks study therapy.

•Greater or equal to Grade 2 toxicity attributed to the AE37 vaccine persists
for

> 28 days. The patient will not receive further vaccination and will discontinue
study therapy. See Table 3.

Note: Should pembrolizumab be permanently discontinued prior to Cycle 5; AE37
vaccinations should continue per study schedule unless otherwise
contraindicated.

•Consent is withdrawn or patient is lost to follow-up.

•An adverse event occurs that, in the opinion of the investigator or sponsor,
contradicts further dosing. See Table 9.

•The patient becomes pregnant or intends to conceive a child while actively on
study.

•Grade 3 or greater infusion reaction occurs.

•If tumor progression occurs during study therapy.

8.2.4Dose modification and toxicity management guidelines for immune-related AEs
associated with pembrolizumab

AEs associated with pembrolizumab exposure may represent an immunologic
etiology. These immune-related AEs (irAEs) may occur shortly after the first
dose or several months after the last dose of pembrolizumab treatment and may
affect more than one body system simultaneously. Therefore, early recognition
and initiation of treatment is critical to reduce complications. Based on
existing clinical trial data, most irAEs were reversible and could be managed
with interruptions of pembrolizumab, administration of corticosteroids and/or
other supportive care. For suspected irAEs, ensure adequate evaluation to
confirm etiology or exclude other causes. Additional procedures or tests such as
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation.
Based on the severity of irAEs, withhold or permanently discontinue
pembrolizumab and administer corticosteroids. Dose modification and toxicity
management guidelines for irAEs associated with pembrolizumab are provided in
Table 9.

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Table 9. Dose modification and toxicity management guidelines for immune-related
AEs associated with pembrolizumab

General instructions:

1.       Corticosteroid taper should be initiated upon AE improving to Grade 1
or less and continue to taper over at least 4 weeks.

2.       For situations where pembrolizumab has been withheld, pembrolizumab can
be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve
within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg
prednisone or equivalent per day within 12 weeks.

3.       For severe and life-threatening irAEs, IV corticosteroid should be
initiated first followed by oral steroid. Other immunosuppressive treatment
should be initiated if irAEs cannot be controlled by corticosteroids.

Immune- related AEs Toxicity grade or conditions (CTCAEv4.0) Action taken to
pembrolizumab irAE management with corticosteroid and/or other therapies

 

Monitor and follow-up

Pneumonitis Grade 2 Withhold •     Administer corticosteroids (initial dose of
1-2mg/kg prednisone or equivalent) followed by taper

•         Monitor patients for signs and symptoms of pneumonitis

•         Evaluate patients with suspected pneumonitis with radiographic imaging
and initiate corticosteroid treatment

•         Add prophylactic antibiotics for opportunistic infections

•         Report ≥ Grade 2 events to DSSM.

Grade 3 or 4, or recurrent

Grade 2

Permanently discontinue Diarrhea / colitis Grade 2 or 3 Withhold •    
Administer corticosteroids (initial dose of 1-2mg/kg prednisone or equivalent)
followed by taper

•        Monitor patients for signs and symptoms of enterocolitis (i.e.
diarrhea, abdominal pain, blood or mucus in stool with or without fever) and of
bowel perforation (i.e. peritoneal signs and ileus).

•        Patients with ≥ Grade 2 diarrhea suspecting colitis should consider GI
consultation and performing endoscopy to rule out colitis.

•        Patients with diarrhea/colitis should be advised to drink liberal
quantities of clear fluids. If sufficient oral fluid intake is not feasible,
fluid and electrolytes should be substituted via IV infusion.

•        Report ≥ Grade 2 events to DSSM.

Grade 4 Permanently discontinue

Table 9 continues on next page.

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Table 9. Dose modification and toxicity management guidelines for immune-related
AEs associated with pembrolizumab (continued)

Immune-related AEs Toxicity grade or conditions (CTCAEv4.0) Action taken to
pembrolizumab irAE management with corticosteroid and/or other therapies

 

Monitor and follow-up

AST / ALT

elevation or Increased Bilirubin

Grade 2 Withhold •     Administer corticosteroids (initial dose of 0.5- 1mg/kg
prednisone or equivalent) followed by taper

•        Monitor with liver function tests (consider weekly or more frequently
until liver enzyme value returned to baseline or is stable

•        Report ≥ Grade 2 events to DSSM.

Grade 3 or 4 Permanently discontinue •     Administer corticosteroids (initial
dose of 1-2mg/kg prednisone or equivalent) followed by taper Type 1 diabetes
mellitus (T1DM) or Hyperglycemia

Newly onset T1DM or

Grade 3 or 4 hyperglycemia associated with evidence of b-cell failure

Withhold

•     Initiate insulin replacement therapy for patients with T1DM

•     Administer anti-hyperglycemic in patients with hyperglycemia

•         Monitor patients for hyperglycemia or other signs and symptoms of
diabetes.

•         Report ≥ Grade 2 events to DSSM.

Hypophysitis Grade 2 Withhold •      Administer corticosteroids and initiate
hormonal replacements as clinically indicated.

•         Monitor for signs and symptoms of hypophysitis (including
hypopituitarism and adrenal insufficiency)

•         Report ≥ Grade 2 events to DSSM.

Grade 3 or 4 Withhold or permanently discontinue1 Hyperthyroidism Grade 2
Continue •     Treat with non-selective beta- blockers (e.g. propranolol) or
thionamides as appropriate

•         Monitor for signs and symptoms of thyroid disorders.

•         Report ≥ Grade 2 events to DSSM.

Grade 3 or 4 Withhold or Permanently discontinue Hypothyroidism Grade 2-4
Continue •      Initiate thyroid replacement hormones (e.g. levothyroxine or
liothyroinine) per standard of care

•         Monitor for signs and symptoms of thyroid disorders.

•         Report ≥ Grade 2 events to DSSM.

Table 9 continues on next page.

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Table 9. Dose modification and toxicity management guidelines for immune-related
AEs associated with pembrolizumab (continued)

Immune-related AEs Toxicity grade or conditions (CTCAEv4.0) Action taken to
pembrolizumab irAE management with corticosteroid and/or other therapies Monitor
and follow-up Nephritis and renal dysfunction Grade 2 Withhold •      Administer
corticosteroids (prednisone 1-2mg/kg or equivalent) followed by taper.

•         Monitor changes of renal function

•         Report ≥ Grade 2 events to DSSM.

Grade 3 or 4 Permanently discontinue All Other immune-related AEs Grade 3, or
intolerable/ persistent Grade 2 Withhold •      Based on severity of AE
administer corticosteroids

•         Ensure adequate evaluation to confirm etiology or exclude other causes

•         Report ≥ Grade 2 events to DSSM.

Grade 4 or recurrent Grade 3 Permanently discontinue

NOTES:

1.       Withhold or permanently discontinue pembrolizumab is at the discretion
of the investigator or treating physician.

2.       For patients with Grade 3 or 4 immune-related endocrinopathy where
withhold of pembrolizumab is required, pembrolizumab may be resumed when AE
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or
achieved metabolic control (in case of T1DM).

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8.3Supportive care guidelines for pembrolizumab

8.3.1Supportive care measures for the management of AEs with potential
immunologic etiology

Patients should receive appropriate supportive care measures as deemed necessary
by the treating investigator. Suggested supportive care measures for the
management of AEs with potential immunologic etiology are outlined along with
the dose modification guidelines in Section8.2.4, (Table 9) and Section 8.3.2
(Table 10). Where appropriate, these guidelines include the use of oral or IV
treatment with corticosteroids, as well as additional anti-inflammatory agents
if symptoms do not improve with administration of corticosteroids. Note that
several courses of steroid tapering may be necessary as symptoms may worsen when
the steroid dose is decreased.

For each disorder, attempts should be made to rule out other causes such as
metastatic disease or bacterial or viral infection, which might require
additional supportive care. The treatment guidelines are intended to be applied
when the Investigator determines the events to be related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related
to pembrolizumab, the Investigator does not need to follow the treatment
guidance. Refer to (Table 9) in Section 8.2.4 and Section 8.3.3 for guidelines
regarding dose modification and supportive care. It may be necessary to perform
conditional procedures such as bronchoscopy, endoscopy, or skin photography as
part of evaluation of the event.

8.3.2Management of Infusion Reactions

Signs and symptoms usually develop during or shortly after drug infusion and
generally resolve completely within 24 hours of completion of infusion. Table 10
below shows treatment guidelines for patients who experience an infusion
reaction associated with administration of pembrolizumab (MK-3475).

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Table 10. Infusion Reaction Treatment Guidelines

NCI CTCAE Grade Treatment Premedication at subsequent dosing

Grade 1

Mild reaction; infusion interruption not indicated; intervention not indicated.

Increase monitoring of vital signs as medically indicated until the patient is
deemed medically stable in the opinion of the investigator.

 

None

Grade 2

Requires infusion interruption but responds promptly to symptomatic treatment
(e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications
indicated for ≤ 24 hrs

Stop Infusion and monitor symptoms.

Additional appropriate medical therapy may include but is not limited to:

•         IV fluids

•         Antihistamines

•         NSAIDS

•         Acetaminophen

•         Narcotics.

Increase monitoring of vital signs as medically indicated until the patient is
deemed medically stable in the opinion of the investigator.

If symptoms resolve within one hour of stopping drug infusion, the infusion may
be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50
mL/hr). Otherwise dosing will be held until symptoms resolve and the patient
should be premedicated for the next scheduled dose.

Patients who develop Grade 2 toxicity despite adequate premedication should be
permanently discontinued from further trial treatment administration.

The patient may be premedicated 1.5h (+/− 30 minutes) prior to infusion of
pembrolizumab

(MK-3475) with:

•         Diphenhydramine 50 mg PO (or equivalent dose of antihistamine).

•         Acetaminophen 500- 1000 mg PO (or equivalent dose of antipyretic).

Table 10 continues on next page.

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Table 10 Infusion Reaction Treatment Guidelines (continued)

NCI CTCAE Grade Treatment Premedication at subsequent dosing

Grades 3 or 4 Grade 3:

Prolonged (i.e., not rapidly

responsive to symptomatic medication and/or brief interruption of infusion);
recurrence of symptoms following initial improvement; hospitalization indicated
for other clinical sequelae (e.g., renal impairment, pulmonary infiltrates)

Grade 4:

Life-threatening; pressor or ventilatory support indicated

Stop Infusion.

Additional appropriate medical therapy may include but is not limited to:

•      IV fluids

•      Antihistamines

•      NSAIDS

•      Acetaminophen

•      Narcotics

•      Oxygen

•      Pressors

•      Corticosteroids

•      Epinephrine.

Increase monitoring of vital signs as medically indicated until the patient is
deemed medically stable in the opinion of the investigator.

Hospitalization may be indicated. The patient is permanently discontinued from
further trial treatment administration.

 

 

 

 

 

 

 

 

 

No subsequent dosing

Appropriate resuscitation equipment should be available in the room and a
physician readily available during the period of drug administration.

 

8.3.3Other allowed dose interruption for pembrolizumab

Pembrolizumab may be interrupted for situations other than treatment-related AEs
such as medical / surgical events or logistical reasons not related to study
therapy. Patients should be placed back on study therapy within 3 weeks of the
scheduled interruption, unless otherwise discussed with DSSM. The reason for
interruption should be documented in the patient's study record

 

8.4Liver dysfunction (Hy's Law)

Hy’s Law is based on the observation that pure hepatocellular injury sufficient
to cause hyperbilirubinemia is an ominous indicator of the potential for a drug
to cause serious liver injury. A diagnosis of potential drug-induced liver
injury caused by a study drug can only be determined/inferred by excluding other
potential causes of liver injury (e.g., other drugs or viral hepatitis) and by
ruling out an obstructive cause for the elevated bilirubin (e.g., alkaline
phosphatase should not be substantially elevated) (FDA 2009; Temple 2006).

8.4.1Definition of cases potentially meeting Hy's Law criteria

Patients who present with the following laboratory abnormalities should be
evaluated further to definitively determine the etiology of the abnormal
laboratory values:

•Patients with AST or ALT baseline values within the normal range who
subsequently present with AST or ALT > 3 times the ULN concurrent with a total
bilirubin

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> 2 times the ULN with no evidence of hemolysis and an alkaline phosphatase

< 2 times the ULN or not available.

•Patients with pre-existing AST or ALT baseline values above the normal range
who subsequently present with AST or ALT > 2 times the baseline values and > 3
times the ULN, or ³ 8 times the ULN (whichever is smaller) concurrent with a
total bilirubin of > 2 times the ULN and increased by one ULN over baseline or >
3 times the ULN (whichever is smaller) with no evidence of hemolysis and an
alkaline phosphatase < 2 times the ULN or not available.

8.4.2Evaluation of potential Hy's Law cases

The patient should return to the investigational site and be evaluated as soon
as possible, preferably within 48 hours from awareness of the abnormal results.
This evaluation should include laboratory tests, detailed history, and physical
assessment. In addition to repeating AST and ALT, laboratory tests should
include albumin, creatine kinase, total bilirubin, direct and indirect
bilirubin, gamma-glutamyl transferase (GGT), international normalized ratio
(INR) and alkaline phosphatase. A detailed history, including relevant
information, such as review of ethanol, recreational drug and supplement
consumption, family history, sexual history, travel history, history of contact
with a jaundiced patient, surgery, blood transfusion, history of liver or
allergic disease, and work exposure, should be collected. Further testing for
acute hepatitis A, B, or C infection and liver imaging (e.g. biliary tract) may
be warranted. The possibility of progressive disease should be considered.

Potential Hy's Law cases should be reported as serious adverse events (see
Sections 10.3.3 and 10.6).

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9.0DRUG INFORMATION

 

9.1AE37 peptide vaccine

9.1.1AE-37 Description

The AE37 peptide is a nineteen amino-acid peptide referred to as AE37
(Ii-Key/HER2 776-790 hybrid). The drug substance, AE37, is provided by
PolyPeptide Laboratories San Diego. The suspended substance (lypophilized
peptide suspended in sterile, normal saline) is formulated into plastic
cryovials containing 1000 mcg of peptide + saline.

9.1.2Toxicity

Refer to the current AE-37 vaccine IB for safety and toxicity information.

9.1.3Contraindications

Patients with autoimmune diseases should not be administered the AE37 vaccine.

9.1.4Concomitant medications and other substances

Corticosteroid use, prescription anti-inflammatory drugs, or other
immunosuppressants which in the opinion of the investigator would preclude
participation in this immunotherapy trial should be used sparingly and not in
close proximity with the immunizations (one week before or after immunization).

9.1.5Preparation

The suspended peptide will be formulated by [PLACEHOLDER for a company to be
determined later] and shipped to the individual study site pharmacy. Per the
site Standard of Practice, the site pharmacist or research nurse coordinator
will remove one frozen sterile vial containing 1000 mcg peptide/1.0 mL saline
from the freezer and will thaw it at room temperature.

Mixing of the 1 mL solution is accomplished by repeatedly withdrawing the fluid
into the syringe and gently injecting it back into the container using aseptic
technique.

9.1.6Method of Administration

Patients will receive two intradermal injections of approximately 0.5 mL volume
on the anterior or medial side of the same thigh. The general area of
vaccination will be at a location midway between the inguinal ligament and the
knee and will be administered in the same lymph node draining area. The
vaccinations will be given every 21 days for 5 doses total.

Intradermal vaccinations should be given in a method similar to the “PPD Skin
Test” through a 26- or 27-gauge needle (3/8 inch) in the anterior thigh midway
between the inguinal ligament and the knee. The whole 1 mL vaccination volume
will be administered in 2 different sites approximately 5 cm (about 2 inches)
apart from each other, by carefully injecting 500 μL (0.5 cc) at each
vaccination site by intradermal injection per the diagram shown below.

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[image_010.jpg]

 

The vaccinations will be administered using sterile technique by a well-trained
research nurse or trained study staff. The patient must be monitored for 1 hour
after the vaccination for signs of any adverse reaction.

•Cleanse the area by swabbing the skin (an approximately 4 to 5 inch circle)
with alcohol pads.

•Hold the skin taut before injecting. Place the 2 intradermal vaccinations in 2
quadrants of the cleansed circle.

•As depicted below keep the syringe low and flat along the skin surface (inject
with needle bevel side up). Inject 500 μL forming a nice “bleb” under the skin.

•Slowly retract the needle and allow the “bleb” to resorb. Repeat 1 more time to
completely administer the full 1.0 mL volume. Observe the patient and injection
sites for 1 hour.

•Place a 4x6 sterile gauze bandage over the site on the thigh to protect from
irritation for 12 to 24 hours.

•Any leakage of the dose onto the skin or inability to deliver the full 1 mL
volume to the 2 sites should be noted in the eCRF.

•Patients must be observed immediately after vaccinations for signs of an acute
allergic reaction. If symptoms such as difficulty breathing, angioedema, diffuse
and significant urticaria, and/or hypotension are observed, immediate emergency
medical attention will be provided.

 

9.2Pembrolizumab (MK-3475, KEYTRUDAÒ) (NSC-776864)

Pembrolizumab is an investigational agent in the B-001 study.

9.2.1Description

Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1)
receptor, thus inhibiting its interaction with programmed cell death ligand 1
(PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical in
vitro data, pembrolizumab has high affinity and potent receptor blocking
activity for PD 1.

Pembrolizumab has an acceptable preclinical safety profile and is in clinical
development as an intravenous (IV) immunotherapy for advanced malignancies.

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9.2.2Supply

Pembrolizumab (MK-3475) Solution for Infusion is a sterile, non-pyrogenic
aqueous solution supplied in single-use Type I glass vial containing 100 mg/4 mL
of pembrolizumab. The product is preservative-free solution which is essentially
free of extraneous particulates.

9.2.3Toxicity

Refer to the current pembrolizumab IB for toxicity information.

9.2.4Preparation

•Allow pembrolizumab to equilibrate to room temperature for 15 – 30 minutes.

•Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride
Injection, USP (normal saline) with a final concentration of pembrolizumab
between 1 mg/mL and 10 mg/mL.

•Pembrolizumab SHOULD NOT BE MIXED WITH OTHER DILUENTS.

•Pembrolizumab is compatible with the following infusion bag materials: PVC
plasticized with DEHP, non-PVC (polyolefin), EVA, and PE lined polyolefin.

•After adding the required amount of drug into the infusion bag, gently invert
the bag 10-15 times to mix the solution.

•Once a dose is prepared, pembrolizumab should be administered within 4 hours.
Pembrolizumab solutions may be stored at room temperature for a cumulative time
of up to 4 hours. This includes room temperature storage of admixture solutions
in the IV bags and the duration of infusion.

•In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F
to 46 °F) for up to 20 hours. If refrigerated, allow the IV bags to come to room
temperature prior to use.

•Parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration. Discard the drug product vial if
extraneous particulate matter other than translucent to white proteinaceous
particles is observed.

•Sites should follow their SOPs for drug transport and delivery, with all
possible effort to minimize agitation of the drug product between the pharmacy
and the clinic.

•Do not use pembrolizumab if discoloration is observed.

•Do not shake or freeze the vial(s).

•Do not administer the product as an IV push or bolus.

•Do not combine, dilute, or administer it as an infusion with other medicinal
products.

 

9.3Study therapy procurement

Pembrolizumab will be supplied free of charge by Merck and Company, Inc. and
distributed via an external vendor. AE37 vaccine will be supplied free of charge
by Antigen Express and distributed via external vender. Pembrolizumab and AE37
vaccine must be requested by the principal investigator (or his/her authorized
designee) at each participating institution

(see Information Resources). The initial supply of pembrolizumab and AE37 may be
requested at the time the first patient signs the B-001 consent form.
Pembrolizumab and AE37 vaccine will be shipped directly to the investigator
whose sites are participating in B-001.

80 

 

9.4Study therapy storage

9.4.1AE 37 Vaccine

The AE37 peptide suspended in sterile saline is stored at ≤ -20 ˚C. At room
temperature, the AE37 suspension should be used within two hours per label
instructions. However, it can be prepared 24 hours prior to injection as long as
it is kept refrigerated (4°C).

9.4.2Pembrolizumab

Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/4 mL vial: Vials should be
stored at refrigerated conditions (2 – 8 °C). Note: Vials should be stored in
the original box to ensure the drug product is protected from light.

 

9.5Transfer of study therapy

Study therapy may not be used outside the scope of B-001, nor can study therapy
be transferred or licensed to any party not participating in this clinical
trial.

 

9.6Destruction of study therapy vials

•Pembrolizumab:

At the end of an infusion for an individual patient, any remaining or unused
study drug should be destroyed at the site according to the institution’s policy
for drug destruction. At the completion of the study, all unused study drugs
will also be destroyed at the site as per institutional policy for drug
destruction after the monitoring review is completed by DSSM.

•AE37 vaccine and DTH

All unopened, partially used, or vial bottles of study therapy shall be
destroyed by study sites in accordance with the local institution standard
operating procedures.

•Written documentation of destruction must contain the following:

-identity (distribution numbers) of study therapy destroyed;

-quantity of study therapy vials destroyed;

-date of destruction (date discarded in designated hazardous container for
destruction);

-name and signature of the person who discarded the study therapy vials in a
hazardous container for destruction.

•Maintain appropriate records of the disposal, including dates and quantities.

 

9.7Drug inventory records

The investigator, or a responsible party designated by the investigator, must
maintain a careful record of the receipt, return, and destruction of all study
therapy vials received through the

B-001 study using an Investigational Agent Accountability Record Form.

 

9.8Drug accountability

The investigator, or a responsible party designated by the investigator, must
maintain a careful record of the receipt, disposition, and return of all drug
received through the B-001 study using an investigational agent accountability
record form.

Records or logs must comply with applicable regulations and guidelines, and
should include:

•Amount received and placed in storage area,

•Amount currently in storage area,

•Label ID number or batch/lot number,

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•Dates and initials of person responsible for each study drug inventory
entry/movement,

•Amount dispensed and returned for each patient, including unique patient
identifiers,

•Amount transferred to another area for dispensing or storage,

•Non-study disposition (e.g., lost, wasted, broken), and

•Amount destroyed.

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10.0ADVERSE EVENT REPORTING REQUIREMENTS

 

The investigator is responsible for the detection and documentation of events
meeting the criteria and definition of an adverse event (AE) or a serious
adverse event (SAE), as provided in this protocol. Routine, adverse events of
special interest (AESI), and expedited adverse event report forms and their
supporting documentation must be submitted to DSSM according to the instructions
in Sections 10.3, 10.4 and 10.6.

 

10.1Definition of an AE

An AE is any untoward, undesired, or unplanned event in the form of signs,
symptoms, disease, laboratory findings, or other physiologic observations
occurring in a patient participating in

B-001. The event does not need to be causally related to study therapy or other
requirements of the B-001 trial to be considered an AE.

•Examples of an AE include, but are not limited to, the following:

-Any toxicity related to study therapy.

-Any clinically significant worsening of a pre-existing condition.

-An AE occurring from a symptomatic overdose of any study therapy, whether
accidental or intentional. See Section 10.3.2.

-A symptomatic AE that has been associated with the discontinuation of the use
of any of the agents included in the study therapy.

-An AE occurring during a clinical study that is not related to the study
therapy, but is considered by the investigator or sponsor to be related to the
study requirements, for example, an AE may be an untoward event related to a
medical procedure required by the protocol.

•A laboratory test result should be reported as an AE if it meets any of the
following criteria:

-Accompanied by clinical symptoms.

-Results in a change in study treatment (e.g., dosage modification, treatment
interruption or treatment discontinuation).

-Results in medical intervention (e.g., potassium supplementation for
hypokalemia) or treatment discontinuation.

-Clinically significant per the investigator.

•Examples of clinical events that should not be considered AEs:

-Medical or surgical procedure (e.g., endoscopy, appendectomy). Note, the
condition that leads to the procedure may be an AE, but the procedure itself is
not.

-Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)
present or detected at the start of the study that do not worsen.

-Progression of the cancer under study is not considered an adverse event unless
it is considered drug-related by the investigator.

 

10.2Definition of an SAE

An SAE is any untoward medical occurrence that, at any dose, causes one of the
following:

•Results in death.

•Is life-threatening.

The term 'life-threatening' in the definition of 'serious' refers to an event in
which the patient was at risk of death at the time of the event. It does not
refer to an event, which might have caused death, if it were more severe.

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•Requires hospitalization or prolongation of existing hospitalization

Hospitalization is any inpatient admission to a health care facility even if for
less than

24 hours. Hospitalization or prolongation of a hospitalization constitutes a
criterion for an AE to be serious; however, it is not in itself considered an
SAE. In the absence of an AE, a hospitalization or prolongation of a
hospitalization should not be reported as an SAE. For example, the following
hospitalizations would not require expedited reporting for an SAE:

-hospitalization or prolongation of hospitalization needed for a procedure
required by the protocol or as part of another routine procedure; or

-hospitalization for a pre-existing condition that has not worsened.

•Results in persistent or significant incapacity or substantial disruption of
the ability to conduct normal life functions.

This is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea,
influenza, and accidental trauma (e.g., sprained ankle) which may interfere or
prevent everyday life functions but do not constitute a substantial disruption.

•Is a congenital anomaly/birth defect.

Also, appropriate medical judgment should be exercised in deciding whether SAE
reporting is required in other situations, such as important medical events that
may not result in death, be life-threatening, or require hospitalization, but
may jeopardize the patient and may require medical or surgical intervention to
prevent one of the other outcomes listed in the definition of an SAE. Examples
of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or development of drug dependency or drug abuse.

 

10.3Events requiring expedited reporting

All events listed in Sections 10.3 and 10.4 must be reported in an expedited
manner according to the instructions in Section 10.6.

10.3.1SAEs

All events meeting the definition of an SAE (Section 10.2) require expedited
reporting.

10.3.2Other events requiring expedited reporting

Other events must be recorded, reported, and followed up as indicated for an SAE
(see

10.3 and 10.6 for reporting procedures). This includes the following events:

•Pregnancy exposure to study therapy. (If a pregnancy is confirmed, use of study
therapy must be discontinued immediately. See Section 10.4.)

•Lactation exposure to study therapy.

•Medication errors involving study therapy with or without AE symptoms,
including product confusion and potential product confusion. (A medication error
is any preventable event that may cause or lead to inappropriate use or harm
while the study therapy is in control of the healthcare professional or patient.
Examples of reportable medication error include administration of unassigned
treatment and administration of expired study therapy.)

•Overdose

-In this study an overdose for pembrolizumab is defined as ≥1000 mg (5 times the
dose). An overdose of vaccine is defined as a study patient receiving a dose of
study therapy in excess of that specified in this protocol or the Investigator’s
Brochure.

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-Any overdose of a study patient with or without associated AEs/SAEs, is
required to be reported within 24 hours of knowledge of the event to DSSM.
Overdose does not automatically make an AE serious, but if the consequences of
the overdose are serious, for example death or hospitalization, the event is
serious and must be recorded and reported as an SAE (see Section 10.3.2 and
10.6). There is currently no specific treatment in the event of an overdose of
study therapy. The investigator will use clinical judgment to treat any
overdose.

•Any death, excluding death due to progression of colon cancer.

•Potential Hy's Law cases (see Section 8.4 and 10.3.3).

10.3.3Clinical laboratory abnormalities

•Abnormal laboratory findings (e.g., clinical chemistry and hematology) or other
abnormal assessments (e.g., x-rays and scans) will be recorded as AEs or SAEs if
they meet the definition of an AE or SAE, as defined in Sections 10.1, 10.2,
respectively, and if the abnormality meets reporting requirements as described
in Section 10.3.3.

•Special reporting requirements related to Hy’s Law: All cases confirmed on
repeat testing as meeting one of the criteria described in Section 8.4 with no
other cause for LFT abnormalities identified at the time should be considered
potential Hy’s Law cases regardless of availability of all the results of the
investigations performed to determine etiology of the abnormal LFTs. Such
potential Hy’s Law cases should be reported as serious adverse events (see
Section 10.3.3).

10.3.4Disease-related events and/or disease-related outcomes not qualifying as
SAEs

An event that is part of the natural course of breast cancer does not need to be
reported as an SAE. Progression breast cancer will be reported in the
appropriate eCRF.

Note: Any occurrence of secondary malignancy (leukemia secondary to oncology
chemotherapy [AML], myelodysplastic syndrome [MDS]) and/or treatment-related
secondary malignancy is to be reported as an SAE.

 

10.4Pregnancy

•If a patient becomes pregnant while receiving study therapy, discontinue study
therapy and notify DSSM (see Information Resources). The investigator will
record pregnancy information on the Pregnancy eCRF and submit it as an expedited
report (within 24 hours) upon learning of a patient’s pregnancy. (See separate
consent for release of pregnancy outcome information.)

•Information about the use in pregnancy encompasses the entire course of
pregnancy and delivery, and perinatal and neonatal outcomes even if there were
no abnormal findings. Information on the status of the mother and child will be
forwarded to DSSM. Generally, follow-up will be no longer than 6 to 8 weeks
following the estimated delivery date. Any premature termination of the
pregnancy will also be reported.

•Any pregnancy complication or elective termination of a pregnancy for medical
reasons will be recorded as an AE or SAE. A spontaneous abortion is always
considered to be an SAE and will be reported as such.

•Any SAE occurring in association with pregnancy brought to the investigator's
attention after the patient has completed the study and considered by the
investigator as possibly related to study therapy, must be reported to the DSSM.

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10.5Grading the severity of the AE

The NCI CTCAE v4.0 must be used to determine the Grade of the AE. The CTCAE
provides descriptive terminology and a grading scale for each AE listed.
Information regarding the CTCAE can be found on the CTEP Web site at
http://ctep.cancer.gov. If further assistance is needed, contact DSSM (see
Information Resources).

 

10.6Expedited reporting instructions

10.6.1Time period for reporting SAEs and other events requiring expedited
reporting

•All SAEs and other events as noted in Sections 10.2, and 10.3 regardless of
relationship to study therapy will be reported in an expedited manner as
described in Section 10.6. Reporting SAEs (and other applicable events)
regardless of relationship to study therapy begins with the first dose of study
therapy and continues until 30 days after the last dose of study therapy.

•Any SAE assessed as related to study participation (e.g., protocol-mandated
procedures) will be recorded from the time a patient consents to participate in
the study up to and including any follow-up contact.

•Following the AE assessment 90 days after the last dose of study therapy, only
SAEs determined to be related to study therapy will be reported in an expedited
manner using B-001 CRF.

•The investigator must follow up on all SAEs until the events have subsided,
until values have returned to baseline, or until the condition has stabilized.

10.6.2Reporting instructions

•All SAEs and other events requiring expedited reporting must be reported using
B-001 SAE CRF and submitted to DSSM within 24 hours of the study site
personnel's initial notification of the event.

•When reporting potential Hy's Law cases, the SAE CRF should include the
following:

-Seriousness Criteria = Important Medical Event

-Assessment/Narrative: Include the term “Potential Hy’s Law case” in the
narrative; the text should also detail what additional study results are
available at the time of reporting and what other studies are planned or results
pending to further investigate alternative causes of the abnormal ALT/AST or
bilirubin that triggered the report. The timing of planned patient follow-up
should also be noted. See Section 8.4.

•NSABP will forward expedited report forms that meet reporting requirements
concurrently to the FDA and to Merck and Antigen Express pharmacovigilance
divisions with the causality assessment.

•Investigators are responsible for reporting AEs that meet specific criteria to
their local IRBs.

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10.7Time period and frequency for routine reporting of AEs

•Patients will be monitored for the occurrence of AEs at each scheduled
assessment and during any contact with the patient during the study.

•All AEs, including SAEs and other AEs that have been reported on B-001SAE CRF,
regardless of relationship to study therapy, will be recorded on Form AE of the
CRF from the first dose of study therapy until 90 days after the last dose of
study therapy.

•If the patient stops study therapy and begins a new treatment prior to the last
dose of study therapy, AE assessments should be collected only up to the date
the new therapy begins.

•For routine reporting, all ³ Grade 1 AEs will be reported on Form AE of the
CRF.

•The investigator must follow up on all AEs until the events have subsided,
until values have returned to baseline, or until the condition has stabilized.

 

10.8Documentation requested following death

For deaths that occur within 30 days of the last dose of study therapy:

•Autopsy reports should be secured whenever possible and should be submitted to
DSSM.

•A copy of the death certificate should be forwarded to DSSM if it is readily
available or if it contains important cause-of-death information that is not
documented elsewhere.

•Submit the last clinic/office note made before the death or the investigator’s
note summarizing events resulting in death.

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11.0ASSESSMENT OF EFFECT

 

11.1Definitions

RECIST 1.1 (Eisenhauer 2009) will be adapted to account for the unique tumor
response characteristics seen with treatment of pembrolizumab. Immunotherapeutic
agents such as pembrolizumab may produce antitumor effects by potentiating
endogenous cancer-specific immune responses. The response patterns seen with
such an approach may extend beyond the typical time course of responses seen
with cytotoxic agents, and can manifest a clinical response after an initial
increase in tumor burden or even the appearance of new lesions. Standard RECIST
may not provide an accurate response assessment of immunotherapeutic agents such
as pembrolizumab. Therefore, RECIST 1.1 will be used with the following
adaptations:

•Patients with progressive radiographic metastatic disease who are clinically
asymptomatic and without other significant reason to discontinue therapy (i.e.,
toxicity, physician's judgement or patient's decision to stop therapy) may
continue to receive study therapy per protocol until the next scheduled tumor
assessment (Table 3) to confirm progression.

•If progression is confirmed the date of progression will be at the time of the
initial scan indicating progression.

If repeat imaging shows < 20% tumor burden compared to nadir, stable or improved
previous new lesion (if identified as cause for initial progressive disease
[PD]), and stable/improved non-target disease (if identified as cause for
initial PD), treatment may be continued / resumed.

11.1.1Measurable disease

Measurable lesions are defined as those that can be accurately measured in at
least one dimension (longest diameter to be recorded) as ³ 20 mm with
conventional techniques (PET/CT, CT scan, or MRI) or as ³ 10 mm with spiral CT
scan with 5 mm cuts. All tumor measurements must be recorded in millimeters (or
decimal fractions of centimeters). The same method (CT or MRI) used at baseline
should be used at all other tumor measurement time points.

11.1.2Non-measurable disease

All other lesions, including small lesions (longest diameter ≥ 20 mm with
conventional techniques or < 10 mm using spiral CT scan with 5 mm cuts) are
considered to be

non-measurable disease.

11.1.3Target lesions

Up to a maximum of five measurable lesions (maximum 2 lesions/organ), should be
identified as target lesions and recorded and measured at baseline. Target
lesions should be selected on the basis of their size (lesions with the longest
diameter) and their suitability for accurate repeated measurements by CT scan or
MRI. A sum of the longest diameter (LD) for all target lesions will be
calculated and reported as the baseline sum LD. The baseline sum LD will be used
as reference by which to characterize the objective tumor response.

11.1.4Non-target lesions

All sites of disease which are not used as target lesions should be identified
as non-target lesions. Location of individual lesions within the liver does not
have to be specifically recorded. All sites of non-target lesions must be
assessed along with the target lesions.

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11.2Response criteria

11.2.1Evaluation of target lesions

•Complete response (CR)

Disappearance of all target lesions

•Partial response (PR)

At least a 30% decrease in the sum of the of LD of target lesions, taking as
reference the baseline sum LD

•Progressive disease (PD)

At least a 20% increase in the sum of the LD of target lesions, taking as
reference the smallest sum LD recorded since baseline or the appearance of one
or more new lesions

•Stable disease (SD)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, taking as reference the smallest sum LD since baseline.

11.2.2Evaluation of non-measurable/non-target lesions

•Complete response (CR): disappearance of all non-target lesions

•Incomplete response/stable disease (SD): persistence of one or more non-target
lesion(s)

•Progressive disease (PD): appearance of one or more new lesions and/or
unequivocal progression of existing non-target lesions

11.3Evaluation of best overall response

The best overall response is the best response recorded from the start of the
treatment until disease progression/recurrence (taking as reference for
progressive disease the smallest measurements recorded since the treatment
started).

Refer to Table 11 for a summary of the criteria that contribute to the
determination of response.

Table 11. Determination of response

Target Lesions Non-Target Lesions New Lesions Overall Response CR CR No CR CR
Incomplete response/SD No PR PR Non-PD No PR SD Non-PD No SD PD Any Yes or No PD
Any PD Yes or No PD Any Any Yes PD

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11.4Symptomatic deterioration

Patients with a global deterioration of health status requiring discontinuation
of treatment without objective evidence of disease progression at that time
should be reported as "symptomatic deterioration." This is also true for
"symptomatic deterioration" after therapy is completed.

Every effort should be made to document objective progression even after
discontinuation of treatment.

90 

 

12.0PATIENT ENTRY PROCEDURES

 

12.1Patient consent form

Before study entry, the consent form including any addenda, must be signed and
dated by the patient and the person obtaining informed consent. In addition,
before study entry, a copy of the signed and dated consent form must be
forwarded to DSSM. All patient signatures (except initials of first, middle, and
last names) should be expunged prior to submission.

 

12.2Study entry

DSSM will verify that the institution has current IRB approval for the study.
Entry will not take place if the IRB approval is not current for the institution
with IRB oversight responsibility.

All patients must be enrolled through DSSM. Once the entry eCRFs have begun to
be entered, submit copies of the redacted signed consent form, and supporting
documents to industry.trials@nsabp.org.

The entry material must be received by DSSM no later than 4:00 p.m. Eastern
Time, Monday through Friday, excluding holidays. Once received the review
process will begin. When the review is complete and approved, an enrollment
confirmation will be sent. This process could involve some unavoidable delays.
Therefore, it is necessary to plan adequate time (at least 24 hours) between
study entry and the initiation of the patient’s study therapy.

 

12.3Patient study number and treatment assignment

•After all the entry materials have been reviewed and approved, the institution
will receive the following via e-mail:

-confirmation of registration and study entry;

-Patient Identification number.

-Patient cohort assignment

 

12.4Investigator-initiated discontinuation of study therapy

In addition to the conditions outlined in the protocol, the investigator may
require a patient to discontinue study therapy if one of the following occurs:

•the patient develops a serious side effect that cannot be tolerated or that
cannot be controlled with other medications,

•the patient’s health gets worse,

•the patient is unable to meet the study requirements, or

•new information about the study drugs or other treatments for colon cancer
becomes available.

If study therapy is stopped, study data and other materials should be submitted
according to the study schedule unless the patient withdraws from the study or
until there is a diagnosis of a secondary malignancy.

 

12.5Patient-initiated discontinuation of study therapy

Even after a patient agrees to take part in this study, the patient may stop
study therapy at any time. If study therapy is stopped, no new therapy begins
and the patient still allows the study doctor to submit information, study data
and other materials should be submitted according to the study schedule (Table
3).

91 

 

12.6Patient-initiated withdrawal from the study

If a patient chooses to have no further interaction regarding the study, the
investigator must provide DSSM with written documentation of the patient’s
decision to fully withdraw from the study. Any data collected up to the time of
withdrawal from the study will continue to be used.

92 

 

13.0       DATA HANDLING AND RECORDKEEPING

 

Refer to the "B-001 eCRF Completion Guidelines" for detailed instructions
regarding data collection, AE reporting, and electronic case report form
completion.

93 

 

14.0STATISTICAL CONSIDERATION

 

14.1Sample size determination and protocol duration for the primary endpoint

The hypothesis tested to determine the activity of AE37 plus pembrolizumab (at
the recommended biologic dose) expressed in terms of ORR:

 

H0: ORR <0.15

 

HA: ORR >0.40

 

With the specified null and alternative hypotheses, a type I error rate of 0.05
and power of 0.90 to reject H0 if the true response rate is 40%, a Simon two
stage design consists of initially treating 13 evaluable patients (Simon 1989).
Enrollment should end for an inadequate response if no more than 2 patients have
an objective response. If 3 or more have an objective response, enrollment
continues to a total of 29 patients. If at least 8 responses are seen (ORR >
0.276), the treatment will be considered worth testing further.

 

14.2Statistical analysis plan

This trial uses a Simon two-step design. In step 1, we will evaluate the overall
response rate to possibly stop for futility according to the plans described in
the sample size determination. In addition, after step 1 we will also evaluate
the dose of AE37. If 4 or more of the first 13 patients (> 25%) have Grade 3 or
higher toxicity we will de-escalate the dose from 1000 to 500 micrograms daily.

Following step 2, we will declare the combination therapy suitable for further
study if at least 8 of 29 total patients have objective response. 95% confidence
intervals will be reported along with the objective response rate. All patients
with a baseline tumor measurement and receiving any protocol treatment will be
included in efficacy analysis.

 

All secondary aims will be analyzed after the end of the study, that is after
step 1 if the study closes early or after step 2 otherwise. Kaplan-Meier
estimates of PFS and OS will be provided. Tabulations of maximum Grade observed
for each patient for each observed toxicity will be provided along with a
summary of maximum Grade observed for each patient for any toxicity.

 

14.3Monitoring

•A medical review team comprising of the Protocol Chair, Medical Director of
DSSM, study statistician, Director of the DSSM, designated physician(s), and
designated DSSM staff will formally monitor the study on a monthly basis to
identify accrual, toxicity, and any endpoint problems that might be developing.

•The Protocol Officer and designated DSSM staff will participate in a weekly
web-ex with investigators who have patients enrolled on the B-001 study.
Investigators who have patients receiving study therapy are required to
participate. All B-001 investigators and study team members are encouraged to
attend.

•The maximum grade for each type of toxicity will be recorded for each patient
and frequency tables will be reviewed to determine toxicity patterns.

94 

 

15.0       PUBLICATION INFORMATION

 

The publication or citation of study results will be made in accordance with the
publication policy of the NSABP that is in effect at the time the information is
to be made publicly available.

95 

 

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mutations by combining mass spectrometry and exome sequencing. Nature 2014;
515(7528):572-576.

Zhu 2013

Zhu J, Peng T, Johnston C, et al. Immune surveillance by CD8alpha.alpha+
skin-resident T-cells in human herpes virus infection. Nature 2013; 497:494-497.

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APPENDIX A DETERMINATION OF PERFORMANCE STATUS

 

 

 

ECOG or Zubrod Scale   Karnofsky Score

 

0

Fully active; able to carry on all pre-disease performance without restriction

 

90–100%

 

1

Restricted in physically strenuous activity but ambulatory

 

70–80%

 

2

Ambulatory and capable of self-care, but unable to carry out any work activities

 

50–60%

 

3

Capable of only limited self- care; confined to bed or chair more than 50% of
waking hours

 

30–40%

4 Completely disabled 10–20%

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APPENDIX B CONTRACEPTION

 

The following are acceptable methods of contraception for patients and partners
of child-bearing potential:

Single method (one of the following is acceptable):

•Female patient of child-bearing potential

−intrauterine device (IUD)

−contraceptive rod implanted into the skin

•Male partner of a female patient of child-bearing potential

−vasectomy

Combination method (requires use of two of the following):

•diaphragm with spermicide (cannot be used in conjunction with cervical
cap/spermicide)

•cervical cap with spermicide (nulliparous women only)

•contraceptive sponge (nulliparous women only)

•male condom or female condom (cannot be used together)

•hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or
subcutaneous contraceptive injection.

 

If a contraceptive method listed above is restricted by local
regulations/guidelines, then it does not qualify as an acceptable method of
contraception for patients participating at sites in this country/region.

Note: Abstinence (relative to heterosexual activity) can be used as the sole
method of contraception if it is consistently employed as the patient’s
preferred and usual lifestyle and if considered acceptable by local regulatory
agencies and ERCs/IRBs. Periodic abstinence

(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and
withdrawal are not acceptable methods of contraception.

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Appendix B SUPPLY OF COMPOUND

 

 

 

Schedule of Deliveries for AE37

 

Delivery Date Quantity of Vials (Immunization) (Liquid – 0.5mL, 0.5mg vial)
November 2017 347 Total 347

 

Delivery Date Quantity of Vials (DTH*) (Liquid – 0.5mL, 0.1mg vial) November
2017 70 Total 70

 

*Delayed Type Hypersensitivity

 

Schedule of Deliveries for KEYTRUDA®

 

 

Delivery Date

Quantity of Vials (Liquid - 4mL, 100mg vial) November 2017 525 June 2018 100
Total 625

 

 

 

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Schedule I

 

DATA SHARING / SAMPLE TESTING SCHEDULE

 

 

Study Procedures

Shared between the Two Parties Not Shared Timing to provide item (data/sample,
etc.) Party to Analyze Data/Sample

Clinical Data

(includes clinical /oncologic / medication history; vital signs / weight;
physical examinations; ECOG performance status; 12-lead ECG; routine laboratory
tests; pregnancy test; serologic tests; endocrine function assessments; other
baseline physiological measurements)

 

 

 

X

 

 

 

 

Within 30 days of top-line results memo (format TBD)

 

 

 

Antigen Express

Tumor Imaging

“If warranted”: assessment to support all efficacy analyses in a format that is
in compliance with SDTM 3.1.3, the raw imaging data in a DICOM format that is
de-identified, and if collected, all radiologist reporting, including tumor
measurements and assessment of response and progression

 

 

 

X

 

 

 

 

Within 30 days of top-line results memo (format TBD)

 

 

 

Antigen Express

All clinical safety data

(line listings of adverse events / SAEs)

X   Every three  months (also reference PV agreement) Antigen Express Results
from any additional Pharmacodynamic and Biomarker Studies specified in protocol

 

X

  Within 30 days of top-line results memo Antigen Express

 

 

Results from Biomarker including any other exploratory biomarkers

 

 

X

 

For secondary objective data (PK and specified BM) within 30 days of top-line
results memo (format TBD).

Same timeline planned for data related to exploratory objectives, if available

 

 

Antigen Express

 

*Tumor PD-L1 Biomarker Assay: categorical result (If run by Merck)

 

 

X

  Quarterly based on Merck’s chosen IHC vendor. Ad hoc data transfers will be
determined as needed by the JDC.

 

 

Merck

*Tumor PD-L1 Biomarker Assay: scoring and raw data (If run by Merck)   X N/A
Merck RNA Profiling (tissue) X   Within 30 days of top-line results memo Merck
DNA analysis for mutational load X   Within 30 days of top-line results memo
Antigen Express * Only one PD-L1 assay will be run.

 

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