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.	Definitions1



		2.	Scope
                                         of the Agreement8



		2.1.	Generally8



		2.2.	Manufacturing
                                         Delay8



		2.3.	Compound
                                         Commitments8



		2.4.	Delegation
                                         of Obligations9



		2.5.	Compounds9



		3.	Conduct
                                         of the Study9



		3.1.	Sponsor
                                         and Combination IND9



		3.2.	Performance10



		3.3.	Debarred
                                         Personnel; Exclusions Lists10



		3.4.	Regulatory
                                         Matters10



		3.5.	Documentation10



		3.6.	Copies10



		3.7.	Samples11



		3.8.	Ownership
                                         and Use of Clinical Data11



		3.9.	Regulatory
                                         Submission12



		3.10.	Joint
                                         Development Committee12



		3.11.	Final
                                         Study Report13



		3.12.	Relationship13



		3.13.	Licensing13



		3.14.	Subsequent
                                         Study13



		4.	Protocol
                                         and Certain Other Documents14



		4.1.	Protocol14



		4.2.	Informed
                                         Consent15



		4.3.	Financial
                                         Disclosure.15



		4.4.	Transparency
                                         Reporting15



		5.	Adverse
                                         Event Reporting16



		5.1.	Pharmacovigilance
                                         Agreement16



		5.2.	Transmission
                                         of SAEs17



		6.	Term
                                         and Termination.17



		6.1.	Term17



		6.2.	Merck
                                         Termination Right for Safety17





    	 



    	 



    

		6.3.	Termination
                                         for Material Breach17



		6.4.	Termination
                                         for Patient Safety17



		6.5.	Termination
                                         for Regulatory Action; Other Reasons18



		6.6.	Return
                                         of Merck Compound18



		6.7.	Termination
                                         Related to Anti-Corruption18



		6.8.	Survival18



		6.9.	No
                                         Prejudice18



		6.10.	Confidential
                                         Information18



		6.11.	Manufacturing
                                         Costs19



		7.	Costs
                                         of Study19



		8.	Supply
                                         and Use of the Compounds19



		8.1.	Supply
                                         of the Compounds19



		8.2.	Clinical
                                         Quality Agreement20



		8.3.	Minimum
                                         Shelf Life Requirements20



		8.4.	Provision
                                         of Compounds20



		8.5.	Labeling
                                         and Packaging; Use, Handling and Storage21



		8.6.	Product
                                         Specifications21



		8.7.	Changes
                                         to Manufacturing21



		8.8.	Product
                                         Testing; Noncompliance21



		8.9.	Investigations23



		8.10.	Shortage;
                                         Allocation23



		8.11.	Records;
                                         Audit Rights23



		8.12.	Quality23



		8.13.	Quality
                                         Control23



		8.14.	Audits
                                         and Inspections23



		8.15.	Recalls24



		8.16.	VAT24



		9.	Confidentiality24



		9.1.	Confidential
                                         Information24



		9.2.	Inventions25



		9.3.	Personal
                                         Identifiable Data25



		10.	Intellectual
                                         Property25



		10.1.	Joint
                                         Ownership and Prosecution25



		10.2.	Inventions
                                         Owned by27





    	 



    	 



    

		10.3.	Inventions
                                         Owned by Merck27



		10.4.	Mutual
                                         Freedom to Operate for Combination Inventions28



		11.	Reprints;
                                         Rights of Cross-Reference28



		12.	Publications;
                                         Press Releases28



		12.1.	Clinical
                                         Trial Registry28



		12.2.	Publication29



		12.3.	Press
                                         Releases29



		13.	Representations
                                         and Warranties; Disclaimers29



		13.1.	Due
                                         Authorization29



		13.2.	Compounds29



		13.3.	Results30



		13.4.	Anti-Corruption30



		13.5.	DISCLAIMER32



		14.	Insurance;
                                         Indemnification; Limitation of Liability32



		14.1.	Insurance32



		14.2.	Indemnification32



		14.3.	LIMITATION
                                         OF LIABILITY33



		15.	Use
                                         of Name33



		16.	Force
                                         Majeure33



		17.	Entire
                                         Agreement; Amendment; Waiver34



		18.	Assignment
                                         and Affiliates34



		19.	Invalid
                                         Provision34



		20.	No
                                         Additional Obligations34



		21.	Governing
                                         Law; Dispute Resolution35



		22.	Notices35



		23.	Relationship
                                         of the Parties36



		24.	Counterparts
                                         and Due Execution36



		25.	Construction36



 


 


	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.





    	1 



    	 



    

		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.




    	2 



    	 



    

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-procurementprograms,includingunder21U.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




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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




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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




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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




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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.




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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




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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




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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.




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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




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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




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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.


 


 


 


 


 


Merck
Sharp & Dohme B.V.


By:
_ _


_
_ _


_
_ _


_
_ _


 


 


 


Name


 


 


 


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


 


 








 




    	39 



    	 



    

Appendix
A PROTOCOL


 


 


 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 



    	 



    

1.0OVERVIEW
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
	
        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


 


 








 


 




    	50 



    	 



    

		2.0	BACKGROUND



 


		2.1	Background



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.


 


		2.2	Rationale
                                         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.


 


		2.3	Rationale
                                         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.


 


		2.4	Pembrolizumab
                                         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.


KeytrudaTM
(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.


 


		2.5	HER2
                                         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 



    	 



    

		3.0	STUDY
                                         AIMS AND ENDPOINTS



		3.1	Co-Primary
                                         aims and endpoints



		3.1.1	Determination
                                         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


 


		3.1.2	Response
                                         rate



Aim:
Objective response rate (ORR)


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


 


		3.2	Secondary
                                         aims and endpoints



		3.2.1	Progression-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


 


		3.2.2	Overall
                                         Survival (OS)



Aim:
To determine OS rate at 1 year


Endpoint:
Time from study entry through 1 year


 


		3.2.3	Toxicity



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).


 


		3.3	Exploratory
                                         translational science



Aim:
Exploratory analysis of immune parameters


Aim:
To determine presence of in vivo responses to DTH




    	55 



    	 



    

		4.0	PATIENT
                                         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.


		4.1	Conditions
                                         for patient eligibility



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


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



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



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



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



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



		4.1.6	There
                                         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.


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



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



		4.1.9	Patient
                                         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.



		4.1.10	Demonstrate
                                         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.



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





    	56 



    	 



    

		4.1.12	International
                                         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


 


		4.1.13	Female
                                         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.



		4.1.14	Study
                                         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.



 


		4.2	Conditions
                                         for patient ineligibility



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


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



		4.2.2	Is
                                         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.



		4.2.3	Has
                                         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.



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



		4.2.5	Has
                                         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.



		4.2.6	Prior
                                         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.



		4.2.7	Blood
                                         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.



		4.2.8	Has
                                         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.



		4.2.9	Has
                                         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 



    	 



    

		4.2.10	Has
                                         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.


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



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



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



		4.2.14	Has
                                         an active infection requiring systemic therapy.



		4.2.15	Has
                                         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.



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



		4.2.17	Is
                                         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.



		4.2.18	Prior
                                         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.



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



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



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



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





    	58 



    	 



    

		5.0	REQUIREMENT
                                         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)


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



		b	Updated
                                         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).



		c	The
                                         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



		d	Should
                                         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.



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



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



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



		h	The
                                         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.



		i	WOCBP
                                         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.



		j	A
                                         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.



		k	Tumor
                                         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.



		l	Optional
                                         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 



    	 



    

		6.0	PATHOLOGY
                                         AND CORRELATIVE SCIENCE STUDIES



		6.1	Overview
                                         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.



 


		6.2	Use
                                         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.


 


		6.3	Tumor
                                         and blood sample submissions



		6.3.1	Required
                                         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.


		6.3.2	Optional
                                         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 



    	 



    

		6.4	Rationale
                                         for correlative science studies



		6.4.1	AE37
                                         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).



		6.4.2	Tissue
                                         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 



    	 



    

		7.0	STUDY
                                         THERAPY



		7.1	AE37
                                         Vaccine



		7.1.1	Delayed
                                         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.


		7.1.2	DTH
                                         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).



		7.1.3	DTH
                                         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 



    	 



    

		7.1.4	Dose-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.


 


		7.2	Study
                                         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





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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



 


		7.3	Supportive
                                         therapy



		7.3.1	Growth
                                         factor support



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


		7.3.2	Erythropoietin



The
use of erythropoiesis-stimulating agents is not permitted.


		7.3.3	Other
                                         supportive care



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


 


		7.4	Contraindications
                                         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.



 


		7.5	Contraception



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.



 


		7.6	Pregnancy



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.


 


		7.7	Participation
                                         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).




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		8.0	TREAMENT
                                         MANAGEMENT



 


		8.1	General
                                         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).



 


		8.2	Treatment
                                         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.


		8.2.1	Treatment
                                         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.



		8.2.2	Dose
                                         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.





    	69 



    	 



    

 


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


 


		8.2.3	Treatment
                                         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.



		8.2.4	Dose
                                         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.




    	70 



    	 



    

 


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.




    	71 



    	 



    

 


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.




    	72 



    	 



    

 


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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		8.3	Supportive
                                         care guidelines for pembrolizumab



		8.3.1	Supportive
                                         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.


		8.3.2	Management
                                         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).




    	74 



    	 



    

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.


 


		8.3.3	Other
                                         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


 


		8.4	Liver
                                         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).


		8.4.1	Definition
                                         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.



		8.4.2	Evaluation
                                         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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		9.0	DRUG
                                         INFORMATION



 


		9.1	AE37
                                         peptide vaccine



		9.1.1	AE-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.


		9.1.2	Toxicity



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


		9.1.3	Contraindications



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


		9.1.4	Concomitant
                                         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).


		9.1.5	Preparation



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.


		9.1.6	Method
                                         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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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.



 


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



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


		9.2.1	Description



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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		9.2.2	Supply



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.


		9.2.3	Toxicity



Refer
to the current pembrolizumab IB for toxicity information.


		9.2.4	Preparation



		•	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.



 


		9.3	Study
                                         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.




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		9.4	Study
                                         therapy storage



		9.4.1	AE
                                         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).


		9.4.2	Pembrolizumab



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.


 


		9.5	Transfer
                                         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.


 


		9.6	Destruction
                                         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.



 


		9.7	Drug
                                         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.


 


		9.8	Drug
                                         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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		10.0	ADVERSE
                                         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.


 


		10.1	Definition
                                         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.



 


		10.2	Definition
                                         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.


 


		10.3	Events
                                         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.


		10.3.1	SAEs



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


		10.3.2	Other
                                         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).



		10.3.3	Clinical
                                         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).



		10.3.4	Disease-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.


 


		10.4	Pregnancy



		•	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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		10.5	Grading
                                         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).


 


		10.6	Expedited
                                         reporting instructions



		10.6.1	Time
                                         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.



		10.6.2	Reporting
                                         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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		10.7	Time
                                         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.



 


		10.8	Documentation
                                         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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		11.0	ASSESSMENT
                                         OF EFFECT



 


		11.1	Definitions



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.


		11.1.1	Measurable
                                         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.


		11.1.2	Non-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.


		11.1.3	Target
                                         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.


		11.1.4	Non-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.




    	88 



    	 



    

		11.2	Response
                                         criteria



		11.2.1	Evaluation
                                         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.


		11.2.2	Evaluation
                                         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



		11.3	Evaluation
                                         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




    	89 



    	 



    

		11.4	Symptomatic
                                         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 



    	 



    

		12.0	PATIENT
                                         ENTRY PROCEDURES



 


		12.1	Patient
                                         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.


 


		12.2	Study
                                         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.


 


		12.3	Patient
                                         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



 


		12.4	Investigator-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.


 


		12.5	Patient-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 



    	 



    

		12.6	Patient-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 



    	 



    

		14.0	STATISTICAL
                                         CONSIDERATION



 


		14.1	Sample
                                         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.


 


		14.2	Statistical
                                         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.


 


		14.3	Monitoring



		•	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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JD, Clifton, GT, Benavides LC, et al. Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after
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2013


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O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369(2):134-144.


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TV, Kim DK, Peoples GE, et al. Secretion of CXC chemokine IP-10 by peripheral blood mononuclear cells from healthy donors and
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2015


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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%




    	100 



    	 



    

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.




    	101 



    	 



    

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


 


 





 




    	102 



    	 



    

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.


 








    	103