EXHIBIT
10.1


EXECUTION
COPY


 


INVESTIGATOR-INITIATED


CLINICAL
RESEARCH SUPPORT AGREEMENT


 


This
Investigator-Initiated Clinical Research Support Agreement (this “Agreement”) is made as of January 13, 2021
(“Effective Date”) by and between City of Hope National Medical Center and City of Hope Medical Foundation
(collectively, “Institution”), and Lixte Biotechnology Holdings, Inc., a Delaware corporation (“Corporation”).
The Institution and Corporation are each referred to herein as a “Party”, and collectively, as the “Parties”.


 


INTRODUCTION


 


This
Agreement is entered into to support the research and promote an increase in the useful clinical and scientific knowledge related
to the Investigator-sponsored study (the “Study”) conducted under an Institutional Review Board-approved, investigator-initiated
Protocol entitled: “A Phase Ib Open-Label Study Of LB-100 In Combination With Carboplatin/Etoposide/Atezolizumab In Untreated
Extensive-Stage Small Cell Lung Carcinoma, City Of Hope Protocol Number 20068” as described in Attachment A hereto (the
“Protocol”, as further defined below).


 


AGREEMENT


 


In
consideration of the above, and of the mutual covenants and promises contained herein and other good and valuable consideration,
the receipt and sufficiency of which are hereby acknowledged, the Parties further agree as follows:


 


1.
DEFINITIONS:


 


(a)
“Adverse Event” means any untoward or unfavorable medical occurrence in a participant, including any abnormal
sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant’s
participation in the research, whether or not considered related to the participant’s participation in the research.


 


(b)
“Corporation Information” means data, research results, formulas, technical data, and any other information
relating to the Study Drug or the use thereof, which is disclosed to Institution by Corporation or its designees.


 


(c)
“Institution Invention” any Invention that is not a Study Drug Invention.


 


(d)
“Inventions” means all inventions (whether patentable or not), discoveries and innovations conceived, reduced
to practice or made in connection with the Study or which otherwise result from the research conducted pursuant to this Agreement.


 


(e)
“Investigator” means Ravi Salgia, M.D.


 


(f)
“Material” means any and all Study Drug provided by Corporation to Institution hereunder together with any
progeny, mutants, derivatives or parts thereof, and any materials that could not be made but for the use of the Material and/or
Corporation Information. .


 


(g)
“Protocol” means the mutually agreed protocol for the conduct of the Study as specified in Attachment A (which
is incorporated herein and subject hereto), as such Protocol may amended in writing by mutual agreement of the Parties.


 




    	 



     


    

 


(h)
“Serious Adverse Events” means an adverse event that results in death, is life-threatening, requires inpatient
hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially
with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not
life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger
or require medical or surgical intervention to prevent one of the results listed above. “Study Drug” means
the compound designated LB-100, and all analogs, metabolites and/or active forms thereof, including any derivatives or parts thereof.


 


(i)
“Study” means the Investigator-Initiated Study conducted by Institution, in collaboration with Lixte, based
on the Protocol, including all research and development work relating thereto. For the avoidance of doubt, work in connection
with and furtherance of the Study and this Agreement done by Institution (whether alone or jointly with Lixte) prior to the Effective
Date, including without limitation development of the Protocol, is for purposes of this Agreement deemed to be within the meaning
of the term “Study” and subject to the terms of this Agreement. Without limiting the foregoing, any Confidential Information
disclosed or developed in connection with such pre-Effective Date activities shall be subject to Section 9, and any Inventions
developed in connection with such pre-Effective Date activities shall be subject to Section 8.


 


(j)
“Study Data” means all data resulting from the Study or other use of the Material by Institution, including
test results, clinical and/or non-clinical data, and formulation or dosage information.


 


(k)
“Study Drug Invention” means any Invention that is comprised or consists of, or is derived from or involves
the use of (including the identification or use of biomarkers related to the safety, efficacy or use of, and dosing for the treatment
of small cell lung carcinoma) the Study Drug.


 


2.
SCOPE OF WORK:


 


(a)
Institution will be the sponsor of the Study, and Institution shall ensure that Ravi Salgia, MD is the Investigator for the Study.
Institution shall comply with all obligations of a sponsor under applicable laws and regulations, and shall ensure that Investigator
complies with all obligations of an investigator under applicable laws and regulations. Corporation will provide Material and
funding for the Study as provided in this Agreement. No other person or entity is providing funding, or contributing proprietary
drugs or materials, for this Study.


 


(b)
Institution agrees to perform, and to cause Investigator to perform, the above titled Study in accordance with the Protocol attached
to this Agreement and incorporated herein by reference. Institution shall ensure that such Study is performed in compliance with
all applicable federal, state, and local statutes and regulations, with all Institutional requirements, and with all Protocol
requirements, including those relating to the documentation and submission of information and reports to regulatory entities,
including the FDA and Institution’s Institutional Review Board (“IRB”), all applicable privacy and data protection
laws and regulations; and publications of the International Conference on Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use including current Good Clinical Practice guidelines (“GCP”), and with this
Agreement. Institution agrees and acknowledges that Corporation’s support for the Study is not being used to reward Institution’s
support for any Corporation activities or to influence prescribing or formulary decisions at Institution.


 




    	 



     


    

 


(c)
Institution shall ensure that all employees, consultants and agents of the Institution, the Investigator, and any participating
centers where the Study is to take place (“Participating Sites”) who are assigned to perform services under
this Agreement (“Project Participants”) abide by the terms of this Agreement. In performing the Study, Institution
will reasonably allocate personnel with the necessary licenses, qualifications and experience to conduct the Study in accordance
with the Protocol. In particular, Institution shall ensure that all Project Participants are trained in GCP. Corporation will
have the right, before executing this Agreement, to review the qualifications of any key personnel, including Project Participants
whose participation in the Study is expected for the duration of the Study, and raise any concerns which Corporation may have
in that regard. In the event that Corporation has concerns regarding the performance of any Project Participant, the parties shall
in good faith seek to resolve such concerns. Institution will notify Corporation promptly of any proposed change in Investigator.
Institution will provide project-specific training to any replacement Investigator or Project Participants at its own expense.
Corporation will have the right to review the qualifications of any Institution, Investigator or Project Participant replacements
and raise any reasonable concerns which Corporation may have in that regard, and both parties shall seek in good faith to address
such concerns.


 


(d)
Corporation agrees to provide Institution with the quantities of Study Drug as specified in Attachment A. Institution will:
(i) verify receipt of the Study Drug by signing the appropriate documentation provided by Corporation or its designee; (ii) handle
and store all Study Drug securely, and as specified in the Protocol, the Study Drug labeling and/or in writing by Corporation;
(iii) if instructed by Corporation in writing, over-label the Study Drug using the labeling and any specific instructions provided
by Corporation, and confirm such over-labeling by promptly returning to Corporation any labeling records or documentation provided
by Corporation; (iv) maintain complete and accurate records of use and disposition of the Study Drug; (v) only dispense the Study
Drug to Study subjects in accordance with the Protocol; and (vi) upon completion or early termination of the Study, destroy or
return to Corporation or its designee all unused Study Drug, as well as any containers (whether containing unused Study Drug or
not) in accordance with Corporation’s instructions or as set forth in the Protocol, and provide Corporation with a Certificate
of Destruction/Incineration to Corporation’s reasonable satisfaction.


 


3.
TERM: The term of this Agreement will commence as of the Effective Date and will end upon the later of delivery of a final study
report for the Study from Institution to Corporation or one (1) year, unless terminated earlier as provided herein.


 


4.
PAYMENT AND SUPPORT:


 


(a)
Corporation has agreed to provide the funding to the Institution for the Study as set forth in Attachment B. Institution
agrees that the amounts payable or otherwise provided by Corporation under this Agreement represent amounts actually and reasonably
required to enable the work to be performed by Institution in connection with the Study and have not been determined in a manner
that takes into account the volume or value of any referrals or business. No funding or other consideration made under this Agreement
is intended to be, nor shall it be construed as, an offer or payment made, whether directly or indirectly, to induce the referral
of patients, the purchase, lease or order of any Corporation product, or the recommending or arranging for the purchase, lease
or order of any Corporation product. Institution will maintain complete and accurate records of the use and disposition of the
funding, and will make such records available to Corporation upon written request. All payments by Corporation shall be made directly
to Institution, and not to any Participating Site or Investigator. Institution shall be responsible for any payments required
to be made to Participating Sites or Investigator. Corporation will not be obligated to provide any quantity of Study Drug or
funding other than as specified in Attachment A and B unless additional Study Drug or funding is included in a written
amendment to this Agreement signed by Investigator, Institution and Corporation.


 


(b)
Checks shall be made payable to: City of Hope National Medical Center and sent to: 1500 East Duarte Road, Duarte, California 91010,
Attention: Office of Clinical Trial Support Services.


 




    	 



     


    

 


(c)
Corporation shall also provide, at no charge to Institution, sufficient quantities of the Study Drug to perform the Study as described
in the Protocol.


 


(d)
Subject to Section Error! Reference source not found. (Confidentiality), Institution agrees to accurately describe
Corporation’s support for the Study in accordance with any law, regulation and institutional or publication policies applicable
to the activities authorized by this Agreement. Institution agrees that: (i) all claims that Institution submit for reimbursement
to any national healthcare program or third party payor for any procedure that is subject to the funding provided hereunder or
that involves the Study Drug provided by or on behalf of Corporation will accurately reflect the provision of such Funding or
supply by or on behalf of Corporation; and (ii) Institution will not seek reimbursement from any national healthcare program or
third party payor for any amounts paid, or Study Drug supplied, by Corporation under this Agreement.


 


5.
STUDY DATA:


 


(a)
Initiation of the Study shall not begin until the relevant approvals are obtained at Institution, and Corporation has been informed
in writing of such approvals. Before submission for approval, Institution will supply Corporation with a copy of the Informed
Consent Form(s) that is to be signed by all subjects enrolled in the Study (as well as all amendments thereto) (the “Consent
Document”) for Corporation’s review and approval. Institution shall inform Corporation in writing of the Institutional
committees’ continuing reviews of the Study promptly after each such review takes place.


 


(b)
Institution will ensure that Corporation is named in the Consent Document, as parties to whom Study subjects’ personal data
(as that term is defined in the General Data Protection Regulation (GDPR)) (“Personal Data”) and Study Data
may be disclosed in connection with the Study, and that such Consent Document will permit Corporation and its designees access
to Study subjects’ Personal Data via Institution as may be necessary to audit the Study via the Institution and to use the
Study Data and Biological Samples (as defined below), including for research, regulatory submissions and drug development purposes.
“Biological Samples” means blood, fluid and/or tissue samples collected from Study subjects as may be set forth
in the Protocol, and tangible materials directly or indirectly derived from such samples. Institution will collect, retain and/or
use Biological Samples solely as set forth in the Protocol.


 


(c)
Institution shall ensure that all Study Data is recorded in a timely, accurate, complete and legible manner. Institution will
take all reasonable and customary precautions, including periodic backup of computer files, to prevent the loss or alteration
of such Study Data.


 


6.
PROTOCOL AND CONSENT DOCUMENT CHANGES: Institution will not make any changes to the Protocol or the Consent Document without first
informing Corporation of any such change and obtaining the written approval of the Institutional Committee and of Corporation
and, if necessary, making additional regulatory submission and/or modifying regulatory submissions. Institution agrees to immediately
incorporate into the Consent Document and Protocol any new core safety data provided by Corporation and to promptly seek or procure
approval of the Institutional Committee for such revised Consent Document. Institution will be responsible for providing Corporation
with a copy of the final Protocol and Consent Document approved by the Institutional Committee. The Protocol will be considered
final after it is approved by the Institutional Committee.


 




    	 



     


    

 


7.
OBLIGATIONS OF INSTITUTION:


 


(a)
Institution will ensure that all personnel conducting the Study (i) are qualified to conduct the Study; (ii) are subject to confidentiality
obligations substantially similar to those contained in this Agreement; (iii) are subject to a written agreement obligating them
to assign ownership to Institution of any rights they might have in the results of their work; and (iv) will do so under the direction
of Institution with the prior approval and ongoing review of all appropriate and necessary review authorities.


 


(b)
Institution will ensure that Institution, and Study Personnel (defined below): (i) are under no contractual or other obligation
or restriction that is inconsistent with Institution’s performance of or obligations under this Agreement; (ii) do not have
a financial or other interest in Corporation or the outcome of the Study that might interfere with their independent judgment;
(iii) are not currently: (1) debarred from providing services; (2) excluded, debarred or suspended from, or otherwise ineligible
to participate in any national or state health care programs; (3) disqualified by any government or regulatory agencies from performing
specific services, and are not subject to a pending disqualification proceeding; or (4) convicted of a criminal offense related
to the provision of health care items or services, or under investigation or subject to any such action that is pending. During
the Study and for a period of two (2) years following completion or early termination of the Study, Institution will promptly
notify Corporation if Institution or, or Study Personnel are subject to the foregoing. “Study Personnel” means,
collectively, Investigator, members of the Study team designated and supervised by the Investigator, on behalf of Institution,
to perform Study-related procedures and/or to make Study-related decisions (“Sub-investigators”), and other
Study Personnel.


 


(c)
In accordance with GCP and applicable local regulations, Institution is responsible for assessing all clinical safety information
obtained during the Study in order to produce all necessary safety reports. Institution will report all Adverse Events to the
applicable regulatory authorities and the appropriate Institutional Review Board (“IRB”) as required by the
Protocol, applicable law or regulation within the requisite applicable timeframes. Institution will conduct follow-up on Adverse
Events as required by the Protocol, applicable law or regulation. Institution will report Serious Adverse Events requiring expedited
reporting to applicable regulatory authorities via a FDA Form 3500 MEDWATCH report and concurrently provide a copy of such MEDWATCH
report to Corporation. For expedited reports, Institution will send the MEDWATCH report to Corporation no later than seven (7)
days for initial life-threatening and death reports, and fifteen (15) days for all other initial or follow-up serious and unexpected
suspected adverse reaction (SUSAR), from the time of receipt of the SAE by Investigator and Institution. For non-expedited reports
(i.e., unrelated to study drugs or a listed/expected event), Institution will send the MEDWATCH report to Corporation no later
than thirty (30) days from the time of receipt of the SAE by Institution. Institution shall send all MEDWATCH reports to Corporation
via email to Corporation’s regulatory group.


 


(d)
Institution will (i) notify Corporation of any communications from or to any regulatory authority having a direct impact on the
Study; (ii) include Corporation in any discussions or meetings with a regulatory authority regarding the Study where appropriate;
(iii) supply Corporation with a copy of any correspondence from a regulatory authority regarding the Study, including any approval
letter, and any other Study related correspondence; and (iv) allow Corporation a reasonable opportunity to comment on any correspondence
being sent to the regulatory authority by Institution regarding the Study, including any submitted annual reports.


 


8.
INTELLECTUAL PROPERTY:


 


(a)
Corporation retains title and all rights in and to all Material and Corporation Information provided by Corporation to Institution.
Institution shall have no rights in any such Material or Corporation Information, except for the limited use rights expressly
granted herein. Corporation hereby grants to Institution a limited, non-exclusive, revocable, non-sublicensable and non-transferable
right to use the Material and Corporation Information, solely during the term hereof, and solely internally at Institution for
scientific or academic research in connection with Study conducted pursuant to the Protocol. Other than the rights to use the
Materials and Corporation Information expressly granted herein, no rights are granted to Institution to any other intellectual
property rights (including any patents, trade secret, trademarks or copyrights) owned by Corporation or any other party; no rights
are granted hereunder by implication or estoppel; and all rights not expressly granted herein are reserved to Corporation.


 




    	 



     


    




 


(b)
Institution will disclose promptly to Corporation in writing any and all Study Data and Inventions.


 


(c)
All rights, title and interest in Institution Inventions shall be the sole and exclusive property of Institution if invented solely
by Institution, and jointly owned by Institution and Corporation if jointly developed by Institution and Corporation, subject
only to those rights of Corporation expressly provided herein. Corporation owns all rights, title and interest in any Study Drug
Inventions; subject to the publication rights of Institution as described in Section 11, and the use rights granted to
Institution in this Section 5(c). Institution hereby assigns to Corporation all rights, title and interests in and to the
Study Drug Inventions. Corporation hereby grants to Institution the non-exclusive, non-transferable right to use the Study Drug
Inventions solely for internal non-commercial academic or scientific research and patient care purposes.


 


(d)
Other than the funding payments specified herein, Corporation is not obligated to make any payments to Institution in consideration
of the rights and licenses granted to Corporation hereunder.


 


(e)
Institution grants to Corporation a worldwide, royalty-free, paid-up, perpetual non-exclusive license to make or use any Institution
Invention for research or development under all rights, title and interest which Institution may have or obtain in any Institution
Invention.


 


(f)
Following written notice to Corporation of an Institution Invention, Corporation shall have sixty (60) days to exercise an exclusive
right of first negotiation (an “ROFN”) to obtain an exclusive, worldwide, royalty-bearing license to all rights,
title and interest which Institution may have or obtain in such Invention, subject to (i) the royalty-free right of Institution
and its affiliates to practice such Invention for educational and research purposes, (ii) the right of Institution and its affiliates
to publicly disclose research results (subject to Section 11), and (iii) the right of Institution and its affiliates to
allow other collaborators to use such Inventions for the same purposes as (i) and (ii). If Corporation exercises its ROFN by providing
a written notice to Institution within sixty (60) days after receipt of written disclosure of any Invention, Corporation shall
have one hundred eighty (180) days thereafter (the “Negotiation Period”) to reach agreement with Institution
on license terms. If Corporation does not exercise its ROFN or if Corporation exercises its ROFN but the Parties do not complete
the execution of the subject license within the Negotiation Period, then Institution may license or practice its interest in any
such Inventions without the consent of and without accounting to Corporation, and Institution shall have no further obligation
to Corporation whatsoever with respect thereto, subject to the non-exclusive license granted to Corporation under this Section
8(f).


 


(g)
Institution acknowledges that except to the extent needed to exercise any rights granted to, or to perform any obligations required
of Institution under this Agreement, this Agreement does not grant to the Institution any rights under any Corporation patents
or any rights to use the Study Drug for commercial purpose.


 




    	 



     


    

 


9.
CONFIDENTIAL INFORMATION:


 


(a)
For purposes of this Agreement, the term “Confidential Information” shall mean all written information relating
to the Study, including but not limited to data; know-how; technical and nontechnical materials; and compound samples and specifications,
which a Party may disclose (the “Disclosing Party”) to the other Party (the “Receiving Party”)
pursuant to this Agreement. A Disclosing Party shall use reasonable efforts to: clearly mark “confidential” any information
disclosed in tangible form and considered by a Disclosing Party to be confidential or, if orally disclosed, to describe as confidential
when disclosed and reduce to writing within a reasonable period of time after disclosure and marked “confidential.”
Notwithstanding anything to the contrary herein, the Study Drug and Corporation Information are the Confidential Information of
Corporation.


 


(b)
Confidentiality: Each Receiving Party agrees to maintain the Disclosing Party’s Confidential Information in confidence
with the same degree of care it holds its own confidential information. Neither Receiving Party will use the Disclosing Party’s
Confidential Information except for the Study. Each Receiving Party will disclose the Confidential Information only to its officers,
consultants and employees directly concerned with the Study, and will not disclose information to any third party not involved
in the Study nor use the Confidential Information for any other purpose.


 


(c)
Exceptions to Confidentiality: Each Receiving Party’s obligation of nondisclosure and the limitations upon the right
to use the Confidential Information shall not apply to the extent that the Receiving Party can demonstrate that the information:
(a) is now, or hereafter becomes, through no act or failure to act on the part of the Receiving Party, generally known or available
to the public; (b) was known by the Receiving Party before receiving the information from the Disclosing Party; (c) is hereafter
rightfully obtained by the Receiving Party from a third party, without breach by the third party of any obligation to the Disclosing
Party; or (d) is independently developed by the Receiving Party without use of or reference to the Confidential Information by
persons who had no access to the Confidential Information. Each Receiving Party may disclose the Disclosing Party’s Confidential
Information if and to the extent that a disclosure is required by applicable law, provided that the Receiving Party uses reasonable
efforts to limit the disclosure by means of a protective order or a request for confidential treatment and provides the Disclosing
Party a reasonable opportunity to review the disclosure before it is made and to interpose its own objection to the disclosure.


 


(d)
Survival: All obligations regarding Confidential Information under this Agreement shall survive the termination of this
Agreement for a period of five (5) years; provided, however, that the obligations set forth in Section 6(e) below shall survive
termination of this Agreement indefinitely.


 


(e)
Corporation will take appropriate measures to protect the confidentiality and security of all protected health information (as
such term is defined in the Health Insurance Portability and Accountability Act) that it receives from Institution in connection
with the Study. If, in connection with the Study or performance of this Agreement, Corporation comes into contact with individually
identifiable health information relating to patients who are not Study subjects, Corporation agrees to maintain the confidentiality
of such information and not to use it for any purpose. If Corporation is permitted to receive any individually identifiable information
of Study subjects under the applicable informed consent form, Corporation shall only use and disclose such information as necessary
for the Study and shall promptly notify Institution of any unauthorized use or disclosure. The obligations in this paragraph shall
survive the termination of this Agreement indefinitely.


 


10.
USE OF STUDY DATA: Corporation acknowledges that Institution owns the Study Data; provided, that Corporation is hereby granted
an irrevocable, perpetual royalty-free right to receive and use all Study Data, except for the disclosure of subject-identifying
information, for any business purpose it deems appropriate, including, without limitation, for submission to any governmental
or regulatory agencies, domestic or foreign. Institution shall promptly disclose to Corporation all Study Data.


 




    	 



     


    

 


11.
REPORTS: Institution will maintain complete and up-to-date medical and other records relating to the Study and will keep Corporation
informed of any Study Data and status through written reports, as reasonably requested by Corporation but no less than on a monthly
basis. Institution shall furnish to Corporation a comprehensive written report within thirty (30) days after completion or early
termination of the Study. At mutually agreeable times, Institution will give Corporation and its designees access to all records
and documentation (however stored) relating to the Study or to the care of Study subjects, in order for Corporation to monitor
the Study for source document verification and/or audit purposes. Institution will also make those records and documents available
for the purposes of any audit by a regulatory authority and agree not to destroy those records and documents without first giving
Corporation written notice and the opportunity to store them at Corporation’s expense. Investigator and Institution are
free to publish the results of the Study, subject to the provisions in Section 11 (Publication), and to use data generated from
the Study for their own research, clinical and educational purposes and programs.


 


12.
PUBLICATION: Institution and Corporation recognize the traditional freedom of all scientists to publish and present promptly the
results of their research. Institution and Corporation also recognize that patent rights can be jeopardized by public disclosure
prior to the filing of suitable patent applications and that confidential information can be inadvertently disclosed. Therefore,
Institution will assure that all proposed publications (including abstracts) arising from research under this Agreement will be
submitted to Corporation promptly and before submission to a publisher for review. Corporation shall have thirty (30) days in
which to review the publication, which shall be extended for an additional sixty (60) days when Corporation discloses reasonable
need for such extension in order to file for patent protection. At Corporation’s request, Institution will delete any Corporation
Confidential Information from a proposed publication.


 


13.
INDEMNIFICATION:


 


(a)
Institution shall indemnify and hold Corporation and its directors, officers, agents, contractors and employees harmless from
any claim, liability, loss or demand by a third party arising from: (i) the negligence, recklessness or willful misconduct of
Institution or any of its agents, contractors or employees, (ii) Institution’s or any of its agents’, contractors’
or employees’ failure to comply with the Protocol or any applicable law or regulations.


 


(b)
Corporation agrees to indemnify and hold Institution, its affiliates, and their respective directors, officers, agents, contractors
and employees, harmless from any claim, liability, loss or demand by a third party and arising from (i) Corporation’s use
of the results of the Study Data, (ii) any defect in the Study Drug or other material supplied by Corporation for use in the Study,
(iii) the negligence, recklessness or willful misconduct of Corporation or any of its agents, contractors or employees, and (iv)
Corporation’s or any of its agents’, contractors’ or employees’ failure to comply with any applicable
law or regulations. Notwithstanding anything to the contrary herein, Corporation shall not have any indemnity obligation under
this Section 13(b) to the extent the claim, liability, loss or demand which arises from Institution’s breach of this
Agreement, gross negligence or willful misconduct.


 




    	 



     


    

 


(c)
The obligations of each Party under this Section are subject to: prompt notification to the indemnifying party by the indemnified
party of any claim or suit (but a delay in notice excuse an indemnitor’s obligations hereunder only if and to the extent
the indemnitor can show its was prejudiced by such delay); full control by the indemnifying party of any disposition or settlement
of said claim or suit; and cooperation by the indemnified party with the indemnifying party regarding such disposition or settlement;
provided, however, that, without the indemnified party’s prior written approval (such approval not to be unreasonably withheld),
the indemnifying party shall not settle or compromise any such claim or suit if such settlement or compromise would result in
an admission of liability or wrongdoing or impose any obligation on the indemnified party.


 


14.
ENTIRE AGREEMENT: This Agreement, including any exhibits and appendices attached hereto, sets forth the entire agreement between
Corporation and Institution as to its subject matter, and supersedes any and all other discussions, negotiations and representations
of any kind by and among the Parties. None of the terms of this Agreement shall be amended except in writing signed by both Parties;
provided, however, that the Protocol may be amended by Institution as reasonably necessary. Institution shall promptly provide
to Corporation a copy of any Protocol amendment. If there is any conflict between the provisions of the final study Protocol,
as it may be amended, and those of this Agreement, the provisions of this Agreement shall govern; provided, however, that the
provisions of the Protocol shall govern with respect to the performance of the Study.


 


15.
TERMINATION:


 


(a)
If any party breaches this Agreement, the other Party may terminate it if the breaching Party does not cure the breach within
thirty (30) days of written notice to the breaching Party of the same. The right of termination shall be in addition to any other
rights the terminating party may have, at law or equity, pursuant to this Agreement.


 


(b)
Each Party reserves the right to terminate this Agreement at any time effective immediately (i) if the authorization and approval
to conduct the Study is withdrawn by the FDA, IRB, or other regulatory authority, or (ii) for safety or efficacy concerns.


 


(c)
Upon receipt of notice of termination, (i) the Institution agrees to promptly terminate conduct of the Study and return any unused
Study Drug and other material, if any, provided by Corporation, if applicable, and (ii) if terminated by Corporation other than
for cause, will reimburse the Institution for all reasonable costs and non-cancelable commitments properly and actually incurred
prior to termination in the performance of the Study consistent with this Agreement.


 


16.
NOTICES: All notices or other communications that are required or permitted hereunder shall be in writing and delivered personally,
sent by a nationally-recognized overnight courier or sent by registered or certified mail, postage prepaid, return receipt requested,
to the addresses listed below or to such other addresses as each of the Parties may otherwise request. Any such communication
shall be deemed to have been given (i) when delivered, if personally delivered on a business day, (ii) on the business day after
dispatch, if sent by nationally-recognized overnight courier, and (iii) on the fifth business day following the date of mailing,
if sent by mail.


 


	If
    to Corporation: 	Lixte
    Biotechnology Holdings, Inc.
	  	248
    Route 25A, No. 2
	  	East
    Setauket, NY 11733, USA
	     	Attn:
    John S. Kovach, M.D.
	     	Tel:
    646.894.3135


 




    	 



     


    




 


	If
    to Institution for contract or administrative matters:	 
	 	City
    of Hope National Medical Center
	 	1500
    East Duarte Road
	 	Duarte,
    California 91010
	 	Attn:
    Office of Clinical Trial Support Services
	 	Email:
    CTSS-E@coh.org
	 	 
	If
    to Investigator for clinical or technical matters: 	 
	 	Ravi
    Salgia, MD
	 	1500
    East Duarte Road
	 	Duarte,
    California 91010
	 	Email:
    rsalgia@coh.org



 


17.
RELATIONSHIP OF THE PARTIES: The execution of this Agreement shall not confer upon the Parties any interest or benefits other
than those specifically set forth herein. In making and performing this Agreement, the Parties shall act at all times as independent
entities and nothing contained in this Agreement shall be construed or implied to create an agency, partnership or employer and
employee relationship between Corporation and Institution, Investigator, or Institution’s officers, employees, consultants
or agents. Except as specifically provided herein, at no time shall either Party make commitments or incur any charges or expenses
for or in the name of the other Party.


 


18.
INDEPENDENT RESEARCH: Nothing in this Agreement shall be construed to limit the freedom of Institution or Investigator or other
individuals participating in this Study, whether paid under this Agreement or not, to engage in research similar or competitive
to the Study independently under other grants, contracts or agreements with parties other than Corporation.


 


19.
SURVIVAL: Expiration or termination of this Agreement by any Party shall not affect the rights and obligations of the Parties
accrued prior to the effective date of the expiration or termination. The provisions of Sections 1, 4, 5(c), 7-30 shall survive
the termination or expiration of this Agreement for any reason.


 


20.
COMPLIANCE WITH LAWS: All parties shall comply in all material respects with the requirements of all applicable laws, rules, regulations
and orders of any government authority in performing the Study including, without limitation, all U.S. Food and Drug Administration
regulations relating to Good Clinical Practice and clinical trials.


 


21.
HUMAN SUBJECTS RESEARCH PROTECTION: In the event of a research injury, Institution will make medical care available to Study subjects,
when appropriate, as further set forth in the informed Consent Document approved by the IRB for this Study. Corporation will report
to Institution any new or unexpected Study Drug developments or information that may pose a significant health or safety risk
to Study participants.


 




    	 



     


    




 


22.
REPRESENTATIONS AND WARRANTIES: The Institution and Corporation each represents and warrants that (i) it is a corporation duly
organized, validly existing and in good standing under the laws of its state of incorporation; (ii) it has the right and authority
to execute and deliver this Agreement and to consummate the transactions contemplated hereunder; (iii) this Agreement is a legal,
valid and binding agreement of the party and enforceable against it; (iv) the execution and delivery of this Agreement will not,
to each party’s knowledge, violate any statute, regulation or any other restriction upon the party; and (v) it has secured
all requisite authorizations and approvals necessary for the execution, delivery and performance of this Agreement. EXCEPT AS
EXPRESSLY PROVIDED HEREIN, ALL MATERIAL, INFORMATION, STUDY DATA AND INVENTIONS PROVIDED, SUBMITTED OR GENERATED HEREUNDER BY
THE INSTITUTION OR ITS PERSONNEL (INCLUDING WITHOUT LIMITATION THE INVESTIGATOR) IS PROVIDED, SUBMITTED OR GENERATED, AS APPLICABLE,
“AS-IS” WITH NO WARRANTY OF ANY KIND, AND ALL SUCH WARRANTIES THEREIN, WHETHER STATUTORY, EXPRESS OR IMPLIED (AND
INCLUDING WITHOUT LIMITATION WARRANTIES OF FITNESS FOR A PARTICULAR PURPOSE, MERCHANTABILITY, TITLE AND NON-INFRINGEMENT OF THIRD
PARTY RIGHTS), ARE HEREBY DISCLAIMED TO THE MAXIMUM EXTENT PERMISSIBLE BY LAW. THE PARTIES ACKNOWLEDGE THAT THE STUDY IS EXPERIMENTAL
AND THE INSTITUTION DISCLAIMS ANY WARRANTY THAT IT WILL BE ABLE TO COMPLETE THE STUDY AS CONTEMPLATED BY THE PROTOCOL OR THAT
THE STUDY WILL BE SUCCESSFUL. EXCEPT WITH RESPECT TO ANY INDEMNIFICATION OBLIGATIONS OF INSTITUTION AS SET FORTH IN THIS SECTION,
AND EXCEPT FOR A BREACH OF CONFIDENTIALITY, (I) THE INSTITUTION SHALL HAVE NO LIABILITY TO CORPORATION FOR ANY LOST PROFITS, LOST
OPPORTUNITIES, OR CONSEQUENTIAL, SPECIAL, INCIDENTAL, INDIRECT OR PUNITIVE DAMAGES, AND (II) THE INSTITUTION’S MAXIMUM LIABILITY
TO CORPORATION SHALL NOT EXCEED THE AMOUNTS PAID BY CORPORATION TO THE INSTITUTION UNDER THIS AGREEMENT.


 


23.
DEBARMENT: Corporation hereby certifies to Institution under penalty of perjury, that Corporation has not been convicted of a
criminal offense related to health care and is not currently debarred, excluded or otherwise ineligible for participation in federally
funded health care programs. Corporation agrees to notify Institution in writing immediately of any threatened, proposed or actual
conviction relating to health care, or any threatened, proposed or actual debarment or exclusion from participation in federally
funded health care programs, of the Corporation. Corporation will not employ or contract with individuals or entities excluded
from participation in a federally funded program. Any breach of this section of this Agreement by Corporation shall be grounds
for immediate termination of this Agreement by Institution.


 


24.
PUBLICITY: Neither Party shall use the other Party’s name, nor issue any public statement about this Agreement or the Study,
without the prior written permission of the other Party (which permission shall not be unreasonably withheld), except as required
by law (and, in such case, only with prior notice to the other Party); provided, however that Institution has the right to list
the Study name and information on its Clinical Trials Online (CTOL) website system and, in order for the Institution to satisfy
its reporting obligations, it may disclose the amount of support received from Corporation for the Study.


 


25.
ASSIGNMENT: This Agreement and all rights and obligations hereunder are personal to the Parties and may not be assigned without
the express written consent of the other Party, which consent will not be unreasonably withheld or delayed, provided that Corporation
may assign this Agreement in its entirety in connection with the sale of all or substantially all of the business of Corporation
to which this Agreement relates, including the sale of all or substantially all of Corporation’s equity or relevant, assets;
a merger of Corporation (including by operation of law), whether or not Corporation is the surviving entity of such merger; or
a reorganization of Corporation.


 


26.
CHOICE OF LAW AND JURISDICTION: This Agreement shall be construed in accordance with the laws of the State of California. All
actions arising under this Agreement shall be brought exclusively in the state and federal courts sitting in Los Angeles County,
California and each of the Parties hereby agrees to submit to the exclusive venue and personal jurisdiction of such courts, provided
that a claim for preliminary injunctive relief may be sought in any applicable jurisdiction.


 




    	 



     


    




 


27.
FORCE MAJEURE: Failure of either Party to perform its obligations under this Agreement (except the obligation to make payments)
shall not subject such Party to any liability or place such Party in breach of any term or condition of this agreement to the
other Party if such failure is the result of any event beyond the reasonable control of such nonperforming Party, including without
limitation acts of God, fire, explosion, flood, pandemic, drought, war, riot, sabotage, embargo, strike or other labor trouble,
failure in whole or in part of suppliers to deliver on schedule materials, equipment or machinery, interruption of or delay in
transportation, a national health emergency or compliance with any order or regulation of any government entity acting with color
of right provided that: (1) the non-complying party uses reasonable efforts to cure or mitigate the effect of such force majeure
event and to perform such obligation(s); (2) that party promptly (but in any event within ten (10) days of the occurrence of such
event) provides written notice to the other party of the occurrence of such force majeure event, its effect on performance, and
how long that party expects it to last, and thereafter provides notice(s) updating such information as reasonably necessary. For
the avoidance of doubt, an increase in prices or costs, or other change in general economic conditions, or a party not having
sufficient funds to comply with an obligation to pay money is not a force majeure event.


 


28.
Waiver: The failure of a Party to enforce any breach or provision of this Agreement shall not constitute a continuing waiver of
such breach or provision and such Party may at any time thereafter act upon or enforce such breach or provisions of this Agreement.
Any waiver of breach executed by either Party must be in writing and shall affect only the specific breach and shall not operate
as a waiver of any subsequent or preceding breach.


 


29.
Further Instruments and Acts: Each Party shall execute and deliver such further instruments and do such further acts and things
as reasonably may be required to carry out the intent and purpose of this Agreement.


 


30.
SEVERABILITY: If any clause or provision of this Agreement is declared invalid or unenforceable by a court of competent jurisdiction
or an arbitrator, such provision shall be severed and the remaining provisions of the Agreement shall continue in full force and
effect. The Parties shall use their best efforts to agree upon a valid and enforceable provision as a substitute for the severed
provision, taking into account the intent of this Agreement.


 


31.
COUNTERPARTS: This Agreement may be executed in any number of counterparts, each of which shall be an original as against the
Party whose signature appears thereon, but all of which taken together shall constitute but one and the same instrument.


 




    	 



     


    

 


IN
WITNESS WHEREOF, the Parties have caused this Agreement to be executed by duly authorized representatives as of the Effective
Date.


 


	Corporation	 	Institution
	 	 	 	 	 
	By:		 	By:	 
	 	 	 	 	 
	Name:	         	 	Name:	                                
	 	 	 	 	 
	Title:	 	 	Title:	 





 


As
Investigator to this Agreement, I attest that I have read the Agreement in its entirety, and that I consent to the terms herein:


 


	       	Investigator
	 	 	 
	       	By:
    	          
	 	 	 
	       	Name:
    	 


 






    	 



    	 



    

  


ATTACHMENT
A

PROTOCOL


 


[See
attached City Of Hope Protocol
Number 20068, Version 01]


 






    	 



    	 



    

 








ATTACHMENT
B


 


Study Budget and Payment Terms


 


	Protocol
    Number:	20068
	 	 
	Investigator:	Ravi
    Salgia, MD
	 	 
	Maximum
    Expected Enrollment: 	42
	 	 
	Corporation:  	Lixte
    Biotechnology Holdings, Inc.
	  	248
    Route 25A No. 2 
	   	East
    Setauket, NY 11733
	   	Attention:
    John S. Kovach, MD
	   	 
	Institution:  	City
    of Hope National Medical Center
		1500
    East Duarte Road
		Duarte,
    California 91010
		Attn:
    Clinical Trials Support Services
	 	 
	Tax
    ID Number:	95-1683875
	 	 
	Invoicing:  	Submit
    all invoices under this Agreement to:
		Lixte
    Biotechnology Holdings, Inc.
	   	248
    Route 25A No. 2 
	   	East
    Setauket, NY 11733
	   	Attention:
    Eric Forman
	   	646.894.3135
	   	ap@lixte.com,
    eforman@lixte.com


 


The
total cost will be paid by the Corporation in U.S. dollars.


 


The
total cost ($2,958,210.07) will be paid by the Corporation to Institution in installments according to the following schedule:


 


	1.
    	$240,508.00
     	Nonrefundable,
    upon execution of Agreement
	 	 	 
	2.
    	$285,019.78
    	Within
    30 days of Study activation   
	 	 	 
	3.
    	$285,019.78	Upon
    enrollment of 5 patients
	 	 	 
	4.
    	$285,019.78
    	Upon
    enrollment of 10 patients
	 	 	 
	5.
    	$285,019.78
    	Upon
    enrollment of 15 patients
	 	 	 
	6.
    	$285,019.78
    	Upon
    enrollment of 20 patients
	 	 	 
	7.
    	$285,019.78
    	Upon
    enrollment of 25 patients
	 	 	 
	8.
    	$285,019.78
    	Upon
    enrollment of 30 patients
	 	 	 
	9.
    	$285,019.78
    	Upon
    enrollment of 35 patients
	 	 	 
	10.
    	$285,019.78
    	Upon
    enrollment of 40 patients
	 	 	 
	11.	$114,007.91	Upon
    enrollment of 42 patients
	 	 	 
	12.
    	$147,910.50
    	Upon
    receipt of a Final Study Report. This payment is not dependent on the number of patients enrolled, only the receipt of a Final
    Study Report.


 


Notwithstanding
anything to the contrary in the Investigator-Initiated Clinical Research Support Agreement, only payment no. 1 is non-refundable,
and any other amounts paid in advance will be refunded in the event patients are not enrolled or if the trial does not otherwise
proceed, subject to the last sentence of this paragraph. Payment no. 2 will be refunded in its entirety if no patient is enrolled
within ninety (90) days of Study activation. In case Institution does not reach an enrollment milestone (payments 3 through 11),
Corporation agrees to prorate Institution’s expenses and agrees to pay for enrolled patients at a rate of $69,001.46 per
patient. Should Institution reasonably determine and can reasonably demonstrate that the payments do not adequately compensate
the Institution for services rendered, the Institution may request that Corporation consider a modification in payments. Corporation
shall consider such request in good faith.


 


All
payments will be due within thirty (30) days following receipt by the Corporation of an invoice from Institution.


 






    	 



    	Page 1 of 92



    

 


(i) CITY
OF HOPE NATIONAL MEDICAL CENTER


1500
E. DUARTE ROAD


 


DUARTE,
CA 91010


 


DEPARTMENT
OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 


 





	TITLE:	A
    PHASE Ib OPEN-LABEL STUDY OF LB-100 IN COMBINATION WITH
	 	CARBOPLATIN/ETOPOSIDE/ATEZOLIZUMAB
    IN UNTREATED EXTENSIVE-STAGE
    SMALL CELL LUNG CARCINOMA












 


	CITY
    OF HOPE PROTOCOL NUMBER:	20068	VERSION:	01
    


 


	SPONSOR/IND
    NUMBER:	City
    of Hope/IND 151424




 


	DISEASE
    SITE:	Lung
	STAGE
    (if applicable):	Extensive-stage
	MODALITY:	Combined
    immunotherapy and chemotherapy
	PHASE/TYPE:	Phase
    Ib



 


	PRINCIPAL
    INVESTIGATOR:	Ravi
    Salgia, MD, PhD
	 	 
	COLLABORATING
    INVESTIGATOR(S):	Vincent
    Chung, M.D.
	 	Marianna
                                         Koczywas, M.D.

        Erminia
        Massarelli, M.D.

        John
        Kovach, M.D.

	 	 
	(ii)
    PARTICIPATING CLINICIANS:	 
	 	 
	PARTICIPATING
    SITES:	City
    of Hope
	 	 
	INDUSTRY
    PARTNER:	Lixte
    Biotechnology Holdings, Inc.
	 	 
	AGENT
    NSC# AND IND#:	NSC
    D753810, IND 109777
	 	 
	COORDINATING
    CENTER:	City
    of Hope Comprehensive Cancer Center


 




    	 



    	Page 2 of 92



    

 


	II.	Protocol Team









 


	 	(i)	PRINCIPAL
    INVESTIGATOR:
	 		BIOSTATISTICIAN
	 	Ravi
    Salgia, Professor and Chair	Paul
    Frankel, PhD
	 	Department
    of Medical Oncology and Therapeutics	Division
    of Biostatistics
	 	Research	 
	 	1500
    E Duarte Ave.	1500
    E Duarte Ave.
	 	Duarte,
    CA 91010	Duarte,
    CA 91010
	 	Phone:
    626-218-3712	Phone:
    626-218-5265
	 	Fax:
    626-471-7322	e-mail:
    pfrankel@coh.org
	 	 e-mail: rsalgia@coh.org 	
	 	 	 
	 	(ii) COLLABORATING
    INVESTIGATORS:	 
	 	 	 
	 	Vincent
    Chung, M.D.	Marianna
    Koczywas, M.D.
	 	Department
    of Medical Oncology and Therapeutics 	Department
    of Medical Oncology and Therapeutics
	 	Research	Research
	 	 	 
	 	1500
    E Duarte Ave	1500
    E Duarte Ave.
	 	Duarte,
    CA 91010	Duarte,
    CA 91010
	 	Phone:
    626-218-3712	Phone:
    626-218-3712
	 	Fax:
    626-471-7322	Fax:
    626-471-7322
	 	e-mail:
    vchung@coh.org	e-mail:
    MKoczywas@coh.org
	 	 	 
	 	Erminia
    Massarelli, M.D.	John
    Kovach, M.D.
	 	Department
    of Medical Oncology and Therapeutics	Lixte
    Biotechnology Holdings, Inc
	 	Research	248
    Route 25A No. 2.
	 	1500
    E Duarte Ave.	East
    Setauket, NY 11733
	 	Duarte,
    CA 91010	Phone:
    631-880-2907
	 	Phone:
    626-218-3712	Fax:
    631-982-5050
	 	Fax:
    626-471-7322	e-mail:
    jkovach@lixte.com
	 	e-mail:
    emassarelli@coh.org	
	 	 	(iii) PROTOCOL
    DEVELOPMENT SCIENTIST:
	 	 	 
	 	Tim
    Synold, Pharm.D.	Sarah
    Cole
	 	Beckman
    Research Institute	Clinical
    Protocol Development Center
	 	1500
    E Duarte Ave.	1500
    E Duarte Ave.
	 	Duarte,
    CA 91010	Duarte,
    CA
	 	Phone:
    626-218-1110	Phone:
    626-218-0719
	 	e-mail:
    tsynold@coh.org	e-mail:
    scole@coh.org


 




    	 



    	Page 3 of 92



    

 


Study
Schema







 









 





 




    	 



    	Page 4 of 92



    

 


Protocol
Synopsis


 











 


Protocol
Title:


 


A
Phase Ib Open-Label Study of LB-100 in combination with Carboplatin/Etoposide/Atezolizumab in Untreated Extensive-Stage Small
Cell Lung Carcinoma


 


Rationale
for this Study:


 


More
than one million people died from lung cancer worldwide in 2017, and small cell carcinomas account for approximately 15% of all
lung cancers. Even with double or triple drug therapy combinations, median survival for SCLC with “extensive disease”
(ED-SCLC, 70% of patients) is only approximately 9 months and overall 5-year survival remains at around 5%. PP2A is ubiquitously
expressed in SCLC cells (unpublished data), however, its potential relevance in SCLC remains mostly unknown. Protein phosphatase
2A (PP2A) is a phosphatase involved in the regulation of key oncoproteins, such as c-Myc and Bcr-Abl in a wide range of cancer
subtypes including lung cancers and B cell-derived leukemias. A recently published study by Xiao et al (Cell 2018) demonstrated
that PP2A redirected glucose carbon utilization from glycolysis to the pentose phosphate pathway to salvage to oxidative stress
in B-lymphoid cells. Moreover, the same mechanism was observed in SCLC cell lines with PAX5 expression. These findings suggest
a previously unexplored rationale for specific targeting of PP2A in SCLC. LB-100 is a potent and selective antagonist of PP2A
that has shown efficacy in a number of pre-clinical models. The combination of LB-100 with carboplatin, etoposide and atezolizumab,
the standard of care for ED-SCLC, will be evaluated in treatment naïve patients to determine the recommended phase II dose
(RP2D).


 


Objectives:


 


The
primary objective of this study is to determine the recommended Phase II dose (RP2D) of LB-100 when given in combination with
standard doses of carboplatin, etoposide and atezolizumab in treatment naïve patients with extensive-stage small cell lung
cancer (ED-SCLC).


 


The
secondary objectives of the study are:


 


	●	Progression
    Free Survival (PFS)
	●	Objective
    response rate (ORR)
	●	Overall
    survival (OS)
	●	Duration
    of overall response (DOR)
	●	Safety/Adverse
    events


 


Exploratory
objectives of the study are:


 


	●	The
    pharmacokinetics (PK) of LB-100 and etoposide
	●	The
    biomarkers relevant to LB-100 and the disease state as well as their correlation to clinical outcomes


 


Study
Design:


 


Dose
Escalation: The Phase I dose-finding will use a traditional 3+3 to determine the maximum tolerated dose (MTD), based on first
cycle DLTs. A maximum of 4 dose levels of LB-100 will be explored. The determination of the recommended Phase II dose (RP2D) will
be based on the MTD (and will not exceed the MTD) with additional consideration of dose modifications, adverse events in subsequent
cycles, clinical activity and correlative studies.


 


Expanded
Cohort: Additional patients will be enrolled until 12 patients are treated at the proposed RP2D to help confirm the tolerability
of the RP2D and obtain preliminary data on efficacy


 




    	 



    	Page 5 of 92



    

 


Primary
and Secondary Endpoints:


 


Primary
endpoints:


 


	 	●	Determine
    recommended phase II dose (RP2D) of the combination using DLT (Definition Section 5.7) during the first cycle as assessed
    by CTCAE version 5.0


 


Secondary
endpoints:


 


	 	●	Objective
    response rate (ORR) by RECIST v1.1 (Appendix B)
	 	●	Duration
    of overall response by RECIST v1.1 (Appendix B)
	 	●	Safety
    and Adverse events by assessed by CTCAE version 5.0
	 	●	Progression-free
    survival (PFS) as defined by RECIST v1.1 (Appendix B)
	 	●	Overall
    survival, which is defined as the time from the date of study enrollment to the date of death from any cause. For patients
    who are still alive as of the data cutoff date, OS time will be censored on the date of the patient’s last contact (last
    contact for patients in post discontinuation is last known alive date in mortality status).


 


Sample
Size/Accrual/Study Duration:


 


Sample
Size: Minimum=14, Maximum=36, Expected=21


 


Estimated Accrual Duration: 1-1.5 years


 


Estimated
Study Duration: 18 -24 months


 


Estimated
Participant Duration: 6 months


 


Abbreviated
Eligibility Criteria:


 


Main
Inclusion Criteria:


 


	 	●	Histologically
    or cytologically confirmed extensive-stage disease small cell lung carcinoma per the Veterans Administration Lung Study Group
    (VALG) staging system, (Appendix E)
	 	●	Measurable
    disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix B)
	 	●	No
    prior systemic chemotherapy, immunotherapy, biological, hormonal, or investigational therapy for SCLC
	 	●	Adequate
    hematologic and organ function, including:
	 	 	Hematologic:
    absolute neutrophil (segmented and bands) count (ANC) ≥1.5x10/L, platelets ≥100x10/L, and hemoglobin ≥9 g/dL
	 	 	Hepatic:
    bilirubin ≤1.5 times upper limits of normal (ULN) may be enrolled, and alkaline phosphatase (AP), alanine aminotransferase
    (ALT) and aspartate aminotransferase (AST) ≤3.0 times ULN (AP, AST, and ALT ≤5 times ULN are acceptable if the liver
    has tumor involvement).
	 	 	Renal:
    calculated creatinine clearance (CrCl) ≥60 mL/min based on the Cockcroft and Gault formula (as defined in Section 3.3)


 




    	 



    	Page 6 of 92



    

 


Main
Exclusion Criteria:


 





	 	●	Diagnosis of NSCLC or mixed NSCLC and SCLC
	 	●	No prior malignancy other than SCLC, carcinoma in situ of the
    cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated 5 or more years prior
    to study entry with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score ≤6=Grade
    Group 1) localized prostate cancer will be eligible even if diagnosed less than 5 years prior to study entry



 


Investigational
Product Dosage and Administration:


 


One
Cycle is 21 Days. Patients will receive 4 cycles of induction LB-100 + atezolizumab/carboplatin/etoposide and then will proceed
to maintenance with atezolizumab + LB-100.


 


LB-100:
Intravenous (IV) at assigned dose (.83, 1.25, 1.75, 2.33 or 3.10 mg/m2), over 15 minutes, given first, Days 1 & 3 of each
cycle during induction and maintenance. Other drugs should be given 1 hour after the end of the LB-100 infusion.


 


Atezolizumab:
1,200 mg IV after LB-100, Day 1 of each cycle during induction and maintenance. Infused over 60 (± 15) minutes (for first
infusion, shortening to 30 [± 10] minutes for subsequent infusions, depending on patient tolerance), given after LB-100.


 


Carboplatin:
5 AUC IV, after the atezolizumab, over 30-60 minutes, Day 1 of each cycle during induction.


 


Etoposide:
100 mg/m2 IV, given last (after the carboplatin on Day 1 of each cycle, by itself Day 2 of each cycle, after LB-100 Day 3 of each
cycle) during induction. Infused over 60 minutes.


 


Clinical
Observations and Tests to be Performed:


 


Efficacy:
CT/PET/MRI scans


 


Safety:
Adverse events (AEs) by CTCAE 5.0/serious adverse events (SAEs), clinical chemistry, hematology


 


Bioanalytical:
Blood samples to measure plasma LB-100, endothall, and etoposide concentrations Pharmacokinetic: LB-100 and etoposide exposure


 


Abbreviated
Statistical Considerations:


 


Safety:
All patients who receive at least one dose of study drug will be evaluated for safety and toxicity. Safety analyses will include
the following: summaries of the adverse event rates (including all events and study drug-related events), all serious adverse
events (SAEs), deaths on-study, deaths within 30 days of the last dose of study drug, and discontinuations from study drug due
to adverse events; listings and frequency tables categorizing laboratory and nonlaboratory adverse events by maximum CTCAE 5.0
grade and relationship to study drug.


 


Expanded
Cohort:12 patients at the RP2D will help confirm the choice of RP2D. If during the expansion cohort, more than 30% of the
patients at initial RP2D experience a DLT, the study will hold accrual (accrual can also be held at the discretion of the PI for
non-DLT or other safety considerations). With 12 patients, any serious treatment-related adverse event that occurs with a true
frequency of 10%, will be observed at least once with a probability of 72%, and any such AE with a true frequency of 20% would
be observed at least once with a probability of 93%. The DLT rate can be estimated with a standard error of at most 14%.


 




    	 



    	Page 7 of 92



    

 

2.2 Table
of Contents


 



 


	SECTION	PAGE
	Protocol
    Team	2
	Table
    of Contents	7
	Abbreviations	12
	1.0
    Goals and Objectives (Scientific Aims)	13
	2.0
    Background	13
	2.1
    Introduction/Rationale for Development	13
	2.1.1
    Small Cell Lung Carcinoma	14
	2.1.2
    Treatment of Extensive-Stage Disease Small Cell Lung Carcinoma	15
	2.1.3
    PP2A	15
	2.1.4
    LB-100	16
	2.2
    Rationale and Overview of Proposed Study	16
	2.3
    Preclinical Toxicity Studies of LB-100	16
	2.3.1
    LB-100 in Rats	16
	2.3.2
    LB-100 in Dogs	17
	2.4
    Human Studies	19
	2.4.1
    Single-Agent Phase I Study LB-100	19
	3.0
    Patient Eligibility	22
	3.1
    Inclusion Criteria	22
	3.1.1
    Disease Status	22
	3.1.2
    Age Criteria, Performance Status, and Life Expectancy	22
	3.1.3
    Child Bearing Potential	22
	3.1.4
    Protocol-Specific Criteria	23
	3.1.5
    Informed Consent/Assent	23
	3.1.6
    Prior Therapy	23
	3.2
    Exclusion Criteria	23
	3.2.1
    Non-Compliance	23
	3.3
    Inclusion of Women and Minorities	25



 






    	 



    	Page 8 of 92



    

 


	4.0
    Screening and Registration Procedures	25
	4.1
    Pre-Enrollment Informed Consent and Screening Procedures	25
	4.2
    Participant Enrollment	25
	4.2.1
    COH DCC Availability and Contact Information	25
	4.2.2
    Slot verification and reservation	25
	4.2.3
    Registration Process	26
	4.3
    Screen Failures and Registered Participants Who Do Not begin Study Treatment	26
	4.4
    Screening Procedures	26
	4.5
    Informed Consent	26
	4.6
    Registration Requirements/Process	26
	4.7
    Dose Level Assignment	27
	5.0
    Treatment Program	27
	5.1
    Treatment Overview	27
	5.1.1
    Schedule	27
	5.2
    Planned Duration of Therapy	30
	5.2.1
    Baseline and Study Treatment Periods	30
	5.2.2
    Postdiscontinuation Period	31
	5.3
    Criteria for Removal from Treatment	31
	5.4
    Subject Follow-Up	32
	5.5
    Supportive Care, Other Concomitant Therapy, Prohibited Medications	32
	5.6
    Additional Studies	33
	5.7
    Definition of Dose-Limiting Toxicity (DLT)	34
	6.0
    Dose Delays/Modifications for Adverse Events	35
	6.1
    Dose Modifications	35
	6.2
    Carboplatin/Etoposide Dose Modifications	35
	6.2.1
    Hematologic Toxicity	36
	6.2.2
    Non-Hematologic Toxicity	36
	6.3
    Atezolizumab Dose Holding	36
	6.3.1
    Management of Atezolizumab-Specific Adverse Events	48
	6.4
    LB-100 Dose Modifications	49
	6.4.1
    Hematologic Toxicity	49
	6.4.2
    Non-hematologic Toxicity	50



 






    	 



    	Page 9 of 92



    

 


	6.5
    Pharmacokinetic Studies	50
	6.5.1
    Pharmacokinetics	50
	7.0
    Unanticipated Problems and Adverse Event Reporting	52
	7.1
    Definitions	52
	7.1.1
    Adverse Event	52
	7.1.2
    Serious Adverse Event (SAE)	53
	7.1.3
    Unanticipated Problems Involving Risks to Subjects or Others	53
	7.1.4
    Adverse Events of Special Interest (AESI)	54
	7.2
    Assessment of Adverse Events	54
	7.3
    Reporting of Adverse Events	55
	7.3.2
    Expediting Reporting Requirements of SAEs and UPs	56
	7.3.3.1.Reporting
    to the FDA	56
	7.3.3.2.Reporting
    to Lixte Biotechnology	56
	8.0
    Agent Information and Risks	57
	8.1
    LB-100	57
	8.1.1
    Description	57
	8.1.2
    Pharmacology – Handling, Storage, Dispensing and Disposal	57
	8.2
    Carboplatin	57
	8.2.1
    Description	57
	8.2.2
    Toxicology	58
	8.2.3
    Pharmacology – Handling, Storage, Dispensing and Disposal	58
	8.3
    VP-16 (Etoposide)	58
	8.3.1
    Description	58
	8.3.2
    Toxicology	59
	8.3.3
    Pharmacology – Handling, Storage, Dispensing and Disposal	59
	8.4
    Atezolizumab	60
	8.4.1
    Description	60
	8.4.2
    Toxicology	60
	8.4.3
    Pharmacology – Handling, Storage, Dispensing and Disposal	62
	9.0
    Correlative/Special Studies	62
	10.0
    Study Calendar	63
	11.0
    Endpoint Definitions	64



 






    	 



    	Page 10 of 92



    

 


	12.0
    Data Handling, Data Management, Record Keeping	64
	12.1
    Source Documents	64
	12.2
    Data Capture Methods and Management	65
	12.3
    Case Report Forms/Data Submission Schedule	65
	12.4
    Regulatory Records	66
	12.5
    Protocol Deviations and Single Subject Exceptions	66
	12.5.1.1
    Deviation	66
	13.0
    Statistical Considerations	67
	13.1
    Study Design	67
	13.2
    Sample Size Accrual Rate	68
	13.3
    Statistical Analysis Plan	68
	13.3.1
    General Considerations	68
	13.3.2
    Patient Disposition	68
	13.3.3
    Patient Characteristics	68
	13.3.4
    Concomitant Therapy	69
	13.3.5
    Postdiscontinuation Therapy	69
	13.3.6
    Treatment Compliance	69
	13.3.7
    Primary Outcome and Methodology	68
	13.3.8
    Pharmacokinetic/Pharmacodynamic Analyses	69
	13.3.9
    Safety Analyses	69
	13.3.10
    Interim Analyses	69
	14.0
    Human Subject Issues	70
	14.1
    Institutional Review Board	70
	14.2
    Recruitment of Subjects	70
	14.3
    Advertisements	70
	14.4
    Study location and Performance Sites	70
	14.5
    Confidentiality	70
	14.6
    Financial Obligations and Compensation	70
	14.7
    Informed Consent Processes/Regulatory Considerations	71
	14.7.1
    Regulatory Considerations	71
	14.7.2
    Investigator Information	72
	14.7.3
    Protocol Signatures	72
	14.7.4
    Final Report Signature.	72



 






    	 



    	Page 11 of 92



    

 


	15.0
    Study Oversight, Quality Assurance, and Data & Safety Monitoring	72
	15.1
    All Investigator Responsibilities	72
	15.2
    Study Principal Investigator Responsibilities	73
	15.3
    Protocol Management Team (PMT)	73
	15.4
    Monitoring	73
	15.5
    Quality Assurance	73
	15.6
    City of Hope Data and Safety Monitoring Committee	74
	16.0
    References	75
	Appendix
    A: Performance Status Scales	79
	Appendix
    B: RECIST v1.1 Criteria	80
	Appendix
    C: Registration Coversheet	87
	Appendix
    D: Expedited Reporting CoverSheet	88
	Appendix
    E: Veterans Administration Lung Study Group (VALG) Staging System for SCLC...	89
	Appendix
    F: Common Substrates of CYP450 Isoenzymes	90


 






    	 



    	Page 12 of 92



    




 


	III.	Abbreviations









 


	 	Abbreviation	Meaning
	 	AE	Adverse
    Event
	 	CFR	Code
    of Federal Regulations
	 	COH	City
    of Hope
	 	CR	Complete
    Response
	 	CRA	Clinical
    Research Associate
	 	CRF	Case
    Report Form
	 	CTCAE	Common
    Terminology Criteria for Adverse Events
	 	CTEP	Cancer
    Therapy Evaluation Program
	 	DLT	Dose
    Limiting Toxicity
	 	DSMC	Data
    Safety Monitoring Committee
	 	FDA	Food
    and Drug Administration
	 	GCP	Good
    Clinical Practice
	 	IB	Investigator
    Brochure
	 	ICF	Informed
    Consent Form
	 	IDS	Investigational
    Drug Services
	 	IND	Investigational
    New Drug
	 	IRB	Institutional
    Review Board
	 	MTD	Maximum
    Tolerated Dose
	 	NCI	National
    Cancer Institute
	 	PD	Progressive
    Disease
	 	PI	Principal
    Investigator
	 	PMT	Protocol
    Monitoring Team
	 	PR	Partial
    Response
	 	SAE	Serious
    Adverse Event
	 	SD	Stable
    Disease


 




    	 



    	Page 13 of 92



    

 


	IV.	1.0
    Goals and Objectives (Scientific Aims)









 


1.1.
Goals




 


This
is a Phase Ib open label study for subjects with extensive-stage disease SCLC who have not received prior treatment with
systemic therapy for SCLC. The Phase Ib study is a single arm study expected to enroll 18 evaluable patients (maximum 30)
entered in groups of 3 at escalating doses of LB-100 using the traditional 3+3 design. Patients will receive induction
therapy with carboplatin/etoposide/atezolizumab for 4 cycles. Each cycle is defined as 3 weeks (21 days). Patients will then
proceed to maintenance with LB-100 and atezolizumab. Patients who discontinue study therapy without disease progression will
continue to be evaluated for tumor response using RECIST v1.1 (Appendix B) guidelines every 6-8 weeks until disease
progression, death, or study closure. The primary endpoint is to determine the recommended phase II dose (RP2D) of LB-100
plus carboplatin/etoposide/atezolizumab in patients with extensive-stage small cell lung carcinoma.


 


1.2. Objectives




 


1.2.1.
Primary Objectives



 


To
determine the recommended phase II dose (RP2D) of LB-100 when given in combination with standard carboplatin/etoposide/atezolizumab
in treatment naïve patients with extensive-stage small cell lung cancer (ED-SCLC).


 


1.2.2.
Secondary Objectives



 


The
secondary objectives of the study are to assess the following variables:


 


	 	●	Objective
    response rate (ORR)
	 	●	Progression-free
    survival (PFS)
	 	●	Overall
    survival (OS)
	 	●	Duration
    of overall response (DOR)
	 	●	Safety
    and adverse events (AEs)


 


1.2.3.
Exploratory Objectives


 


	 	●	The
    pharmacokinetics (PK) of LB-100 and etoposide
	 	●	The
    biomarkers relevant to LB-100 and the disease state as well as their correlation to clinical outcomes


 


	 	2.0	Background
	 	 	 
	 	2.1	Introduction/Rationale for Development




 


2.1.1
Small Cell Lung Carcinoma





 


Lung
cancer is the leading cause of cancer mortality worldwide, with one million new cases annually. Small cell lung cancer (SCLC)
is an aggressive form of cancer that is strongly associated with cigarette smoking. In United States, in 2010, 222,000 new cases
of lung cancer were diagnosed of which 35,000 were SCLC (American Cancer Society). The median age of SCLC patients is 63, and
more than 25% are over the age of 70 (1). Small cell lung cancer is a rapidly growing tumor with a high rate of metastases in
comparison to non-small cell lung cancer (NSCLC). Patients are staged according to a two-stage system, which was developed by
the Veterans Administration Lung Cancer Study Group, consisting of limited-stage disease (LD -SCLC) or extensive-stage disease
(ED-SCLC)(2). Limited-stage disease SCLC is confined to a single hemithorax region within an acceptable radiation field. Approximately
65% to 70% of patients with SCLC present with ED-SCLC, which is found beyond a hemithorax region. Untreated patients with ED-SCLC
have a median survival of approximately 5 weeks; patients treated with chemotherapy have a median survival of 7 to 11 months (3).
Extensive-stage disease-SCLC has a 2-year survival rate of less than 10% with current management options.


 




    	 



    	Page 14 of 92



    

 


2.1.2
Treatment of Extensive-Stage Disease Small Cell Lung Carcinoma


 


Combination
chemotherapy remains the focus of treatment for patients with ED-SCLC. In the 1970s and early 1980s, CAV (cyclophosphamide, doxorubicin,
and vincristine) was the most commonly used regimen. In the mid-1980s, etoposide was discovered as an active agent in SCLC, and
preclinical investigations demonstrated synergy between etoposide and cisplatin. Randomized clinical studies confirmed that this
combination was as effective as CAV, with less toxicity (3).


 


Several
other agents have been shown to have activity in SCLC, and many studies have compared 3-drug regimens to the standard 2-drug regimens
with no improvement in efficacy. A Phase 3 trial conducted by the Norwegian Lung Cancer Study Group randomized 436 patients, including
214 patients with LD-SCLC and 222 patients with ED-SCLC. Patients received etoposide plus cisplatin or a combination of cyclophosphamide,
epirubicin, and vincristine (CEV). Median survival for patients with ED-SCLC was 8.4 months in the etoposide plus cisplatin arm
and 6.5 months in the CEV arm (p=.21) (4). In 2005, Phase 3 study conducted by the Cancer and Leukemia Group B (CALGB) compared
the combination etoposide/cisplatin with or without paclitaxel and granulocyte colony-stimulating factor (G-CSF) in patients with
ED-SCLC (5). A total of 565 patients were randomized. Median progression-free survival time on the carboplatin/etoposide arm was
5.9 months compared with 6 months for patients receiving carboplatin/etoposide/paclitaxel, and median overall survival was 9.9
months on the etoposide/cisplatin arm and 10.6 months on the paclitaxel arm. Toxic deaths occurred in 2.4% of the patients not
receiving paclitaxel and 6.5% of patients being treated with paclitaxel. Thus, the addition of paclitaxel to etoposide and cisplatin
did not improve survival and was associated with unacceptable toxicity in patients with ED-SCLC (5). Results from one of the largest
studies ever conducted for patients with ED-SCLC were also reported in 2005. This study included 784 patients randomized to receive
either topotecan plus cisplatin or the standard etoposide plus cisplatin; efficacy was comparably seen in overall response rates
(63% versus 69%), median time to progression (24.1 versus 25.1 weeks), median survival (39.3 versus 40.3 weeks), and 1-year survival
rates (31.4% for both arms) (6).


 


More
recently the phase III IMpower133 randomized double-blind study evaluated whether adding a checkpoint inhibitor of programmed
death signaling (atezolizumab) might improve chemotherapy benefits in patients with ED-SCLC (7). A total of 201 patients were
randomly assigned to the platinum/etoposide/atezolizumab arm and 202 were assigned to the placebo arm. The median progression-
free survival time on the platinum/etoposide arm was 4.3 months as compared with 5.2 months with platinum/etoposide/atezolizumab.
The median overall survival was 12.3 months in the platinum/etoposide/atezolizumab arm and 10.3 months in the placebo group. The
addition of immunotherapy to etoposide and platinum chemotherapy improved overall survival and progression-free survival and was
not associated with unacceptable toxicity in patients with ED-SCLC (7). IMpower133 is considered the first study in 20 years to
show a clinically meaningful improvement in overall survival over the standard of care in frontline ED-SCLC.


 






    	 



    	Page 15 of 92



    

 


Carboplatin
has been studied in a variety of human solid tumors (ovarian, head and neck, non-small cell lung, and small cell lung) with objective
response rates between 10% and 85%. It has also been used successfully in combination with a number of other cytotoxic agents
for the treatment of ovarian cancer, NSCLC, and SCLC (8-10). A 1992 review of Phase 2 and 3 studies with carboplatin in patients
with SCLC determined carboplatin to be one of the most active agents in untreated SCLC (11).


 


Platinum-based
therapy (carboplatin or cisplatin) combined with etoposide is a current standard of care for patients with ED-SCLC. However, carboplatin
is often preferred over cisplatin, as it provides advantages such as fewer gastrointestinal, renal, auditory, and neurologic toxicities
as well as easier administration (12).








 


2.1.3
PP2A


 


Protein
phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that is a master tumor suppressor involved in key regulation
of oncoproteins, such as c-MYC and BCR-ABL in lung cancer and other cancer types. It has a broad range of cellular regulatory
functions such as cell survival, apoptosis, mitosis, and DNA-damage response (13). Previous
studies and a more recently a Phase I clinical trial have shown that PP2A inhibition can potentially sensitize tumors to radiation
and chemotherapy (14). In a Phase I clinical trial of LB-100, a small molecule inhibitor of
PP2A derived from natural compound cantharadin, in advanced solid tumors LB-100 was well tolerated and 10 out of 20 patients had
achieved stable disease (15). Given the ubiquity of PP2A, the inhibition of LB-100 likely has multiple downstream effects. Preclinical
studies indicate that PP2A inhibition with LB-100 can result in down regulation of DNA- damage response (16-18) abrogation of
cell cycle checkpoint (16, 19), increase HIF dependent tumor angiogenesis (20), and induction
of cellular differentiation by inhibition of N-CoR complex formation (16).


 


Moreover
Xiao et al. 2018 showed that PP2A redirected glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP)
to salvage oxidative stress, revealing a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently
targeted by small molecule inhibition of PP2A and G6PD(21).


 


2.1.4
LB-100


 


LB-100
(3-(4methylpiperazine-carbonyl)-7-oxalobicyclo[2.2.1]heptane-2-carboxylic acid; NSC D753810) is a small molecule (MW 268), which
inhibits protein phosphatase 2A (PP2A) about 80 fold more efficiently than protein phosphatase 1 (PP1). The compound has single
agent activity in vitro and in vivo and potentiates the activity of cytotoxic agents including temozolomide (TMZ), doxorubicin
(DOX), docetaxel, and ionizing radiation in vivo. The mechanism of potentiation appears to be inhibition of cell cycle and mitotic
checkpoints induced by non-specific DNA damaging agents, allowing dormant cancer cells to enter S phase and continue in mitosis
despite acute DNA damage (22). LB-100 also appears to affect the vasculature inducing transient reversible vessel “leakiness”
at high doses. Because of its unique mechanism of action and ability to enhance the activity of a broad spectrum of anti-cancer
agents including ionizing radiation, LB-100 has the potential to be useful for the treatment of many types of cancer as well as
being the first-in-class of a new type of signal transduction modulator.


 






    	 



    	Page 16 of 92



    

 


2.2
Rationale and Overview of Proposed Study


 


PP2A
has been shown to be ubiquitously expressed in SCLC cells but not adjacent normal tissue by immunohistochemistry (unpublished
data). Additionally, PP2A catalytic and structural subunits are abundantly expressed in SCLC cell lines H82, H524, H146 and H69,
but weakly expressed in control HBEC 3KTcells by western blot analysis (unpublished data). Protein phosphatase 2A (PP2A) is a
phosphatase involved in the regulation of key oncoproteins, such as c-Myc and Bcr-Abl in a wide range of cancer subtypes including
lung cancers and B cell-derived leukemias. A recently published study by Xiao et al (Cell 2018) demonstrated that PP2A redirected
glucose carbon utilization from glycolysis to the pentose phosphate pathway to salvage to oxidative stress in B-lymphoid cells.
Moreover, the same mechanism was observed in SCLC cell lines with PAX5 expression. These findings suggest a previously unexplored
rationale for specific targeting of PP2A in SCLC cells. LB-100 is a potent and selective antagonist of PP2A that has shown efficacy
in a number of pre-clinical models. LB-100 has shown in vitro and in vivo activity as a single agent as well as potentiating the
activity of cytotoxic agents including temozolomide (TMZ), doxorubicin (DOX), docetaxel and ionizing radiation in vivo (14). LB-100
is active in combination with TMZ or DOX against xenografts of glioblastoma multiforme (GBM) and neuroblastoma (16, 23), pheochromocytoma
(24), breast cancer (mouse and human, unpublished), fibrosarcoma, and melanoma (unpublished). Our recent studies have also shown
that LB-100 has in vitro and in vivo activity in combination with carboplatin, etoposide against cell lines and xenografts of
small cell lung cancer (unpublished). Racemic LB-100 used alone has modest single agent antitumor activity in vivo against diverse
cell types of human cancer. Combined with either TMZ or DOX, LB-100 potentiates their single agent activity, leading to regression
of human cancer xenografts for periods of time greater than achieved with either of the standard cytotoxic drugs alone. Thus,
the clinical potential of LB-100 lies in using it in combination with chemotherapy.


 


The
combination of LB-100 with carboplatin/etoposide/atezolizumab, the standard of care of ED-SCLC, will be evaluated in treatment
naïve patients to determine the RP2D of LB-100, the safety of the combination and to collect preliminary data on whether
benefit to progression free survival is observed.





 


2.3
Preclinical Toxicity Studies of LB-100


 


2.3.1
LB-100 in Rats


 


In
a non-GLP dose ranging study in rats conducted by the NCI, LB-100 was administered by daily intravenous (IV) infusion at 0.5,
0.75 and 1.5 mg/kg for 4 consecutive days. A no-observed-adverse-effect-level (NOAEL) was not established in this study. The
MTD was 0.75 mg/kg (about 4.5 mg/m2) when administered IV daily for 4 days. At 1.5 mg/kg/day, clinical observations included blood
in urine (Day 4), lethargy (Day 3 and 4), and hind limb paresis (Day 4). At 1.5 mg/kg/day, adverse effects in kidney (nephrosis)
in the distal convoluted tubules were seen in 3 of 3 rats; in the 0.75 mg/kg/day group, nephrosis was mild, and in the 0.5 mg/kg/day
group, nephrosis was minimal. Primary clinical signs of blood in the urine and clinical chemistry findings of increased blood
urea nitrogen and creatinine supported kidney and urinary bladder as target organs of toxicity. The transient hind limb paresis
observed at 1.5 mg/kg/day dose level had no histopathology correlates that would explain the paresis. Heart toxicity (epicardial
hyperplasia with inflammation primarily on the epicardium of the atria) was observed in the 0.75 and 1.5 mg/kg/day groups. The
hyperplasia was accompanied by subepicardial accumulation of mononuclear cells and eosinophils. One rat in the 1.5 mg/kg/day group
had a large focus of inflammation with eosinophils associated with the aorta. Kidney, heart, femoral bone, liver and urinary bladder
toxicity appeared to be dose-limiting toxicities in rats treated with LB-100 when administered IV once per day for 4 consecutive
days.


 






    	 



    	Page 17 of 92



    

 


In
the GLP repeat-dose study in rats, LB-100 administered via daily intravenous (slow bolus) injection for 5 consecutive days to
male and female Sprague Dawley rats at dose levels of 0.5, 0.75, and 1.25 mg/kg/day resulted in adverse, test article-related
nephrosis of the kidneys in the 0.75 and 1.25 mg/kg/day group males and females, which persisted or progressed in the 0.75 and
1.25 mg/kg/day group males at the recovery necropsy. Test article-related effects on urinalysis parameters were observed in all
treatment groups and included an increased in incidence and severity of urine occult blood in 0.5 mg/kg/day group males and 0.75
and 1.25 mg/kg/day group males and females, urine protein in 1.25 mg/kg/day females, and increase in microscopic observations
of leukocytes in males and females of the 1.25 mg/kg/day group, and in one female in both the 0.5 and 0.75 mg/kg/day group on
Day 5. These changes were reversible. LB-100 administration resulted in subacute subepicardial inflammation and/or mesothelial
hypertrophy in the atria of males at ≤ 0.5 mg/kg/day and at 1.25 mg/kg/day in the females at the primary necropsy and was considered
adverse in one 1.25 mg/kg/day group male. Minimal to mild subacute inflammation was observed in the epicardium and subepicardium
of the left and/or right atrium of the heart in the 0.5, 0.75, and 1.25 mg/kg/day group males and the 1.25 mg/kg/day group females.
One male in the 1.25 mg/kg/day group had mild subacute inflammation that was accompanied by minimal fibroplasia (plump fibroblasts)
in the right atrium. Inflammation was often accompanied by mesothelial hypertrophy. There was a higher incidence of mesothelial
hypertrophy in the 1.25 mg/kg/day group females when compared to the control group. Based on these findings, the severely toxic
dose in 10% of the animals (STD 10) for this study was determined as 0.75 mg/kg/day. This dose corresponded to AUClast values
of 596 and 691 ng*h/ml and C0 values of 1804 and 2347 ng/ml for males and females, respectively, on study Day 4.


 


2.3.2
LB-100 in Dogs


 


In
a non-GLP dose ranging study, LB-100 administered intravenously (slow bolus push) to beagle dogs at dose levels of 0.1, 0.25,
0.5, and 1.0 mg/kg given every 4 days x 4 doses (on study days 0, 4, 8, and 12) resulted in a no-observed-effect level (NOEL)
of 0.25 mg/kg. There were no LB-100-related effects on survival. A possible test article-related clinical observation of intermittent
tremors was noted in one female on study Day 13 following administration of LB-100 at 1.0 mg/kg. At dose levels of 0.5 and 1.0
mg/kg, lower body weight gains and food consumption were noted in females.


 


In
the GLP repeat dose dog study, LB-100 was administered by intravenous injection (slow bolus push) at dose levels of 0.15, 0.30,
and 0.75 mg/kg daily for 5 consecutive days. Test article-related lethality was observed 2 of 10 animals in the 0.75 mg/kg/day
group, a male and a female were found dead prior to administration of the fourth scheduled dose. The dosage level was reduced
to 0.50 mg/kg/day for the 4th and 5th doses (study days 3 and 4). Both animals dying after the 3rd dose at 0.75mg/kg had similar
test article-related macroscopic and microscopic findings affecting the gastrointestinal tract, kidneys, injection sites, spleen,
larynx, lungs (including acute inflammation) and/or liver. Both animals had experienced emesis, decreased defecation, yellow and
red mucoid feces, and red diarrhea; these changes were also observed in animals treated at the 0.3 mg/kg/day dose level.


 


Although
the most noteworthy findings (mitotic figures and single cell necrosis of the renal tubular epithelial cells from the outer medulla
and cortex) could be associated with altered renal function, these findings were not considered fatal lesions; therefore, the
cause of death for each animal was considered undetermined but directly attributed to test article administration. Note: a dose
of 0.75 mg/kg in the dog (average weight of 9 kg and BSA of 0.5 m2) is about 13.8 mg/ m2 or more than twice the MTD in the rat.
This highest dose was selected because the dose range study in the dog revealed almost no signs of toxicity following a single
dose of 1.0 mg/kg (approximately 18 mg/ m2) in the dose ranging study. All other animals survived to the scheduled primary (study
day 5) and recovery (study day 29) necropsies including the dogs receiving 0.75 mg/kg daily for 3 days and 0.5mg/kg for doses
4 and 5. Test article-related histological changes at the Day 5 necropsy included erosion and focal hemorrhage within the gastrointestinal
tract in the 0.75/0.5 mg/kg/day dose group. Single cell necrosis was observed throughout the gastrointestinal tract. These changes
were reported as resolved in the recovery period. There were no ophthalmic findings or changes in electrocardiography parameters
and blood pressures associated with test article administration in any treatment group.


 




    	 



    	Page 18 of 92



    

 


During
the recovery period, all surviving animals had body weight gains indicative of recovery, and the majority of the other observed
clinical signs resolved within the first few days of the recovery period. At the primary necropsy (Day 5), test article-related
macroscopic findings consisted of dark red discoloration of the kidneys, small spleens, and red discoloration (reddened mucosa
or dark red area) of various segments of the gastrointestinal tract in the 0.75/0.50 mg/kg/day group males and females. At the
recovery necropsy (Day 29), no test article-related macroscopic finding were observed. The primary cause of small spleen size
appeared to be due to less blood in the red pulp. Mild or moderate single cell (lymphoid) necrosis was seen in spleens microscopically.
Test article-related effects on hematology and coagulation parameters at hematocrit), lower platelet counts, and prolonged activated
partial thromboplastin time values in the animals of the 0.75/0.50 mg/kg/day group. In this group, lower platelet counts were
statistically significantly lower only in the males, with the group mean level lower than the historical control group mean level.
Lower platelet count in a female was not statistically significant but was considered test-article related. At the Day 29 evaluation,
there were no residual effects of test article administration on hematology or coagulation parameters. Test-article related changes
in urinalysis parameters observed at the day 5 evaluation included lower specific gravity, higher urine volume, and increased
presence of blood in the 0.75/0.50 mg/kg/day groups. At day 29, no test article-related changes in urinalysis parameters were
present.


 


Multilead
(I, II, III, aVR, aVL, aVF, and V2) ECGs were recorded for all animals prior to randomization (Day -8) and for all surviving animals
on Day 4 (recorded approximately 2 to 4 hours following dose administration) and Day 27. All the ECGs were qualitatively and quantitatively
interpreted and within normal limits. No test article-related effects attributable to the test article administration were found
at any dose level based on comparison of pretest and post-dosing group mean values and control values. No abnormalities in rhythm
were found.


 


Blood
pressure (systolic, diastolic, and mean arterial pressure) data were recorded for all animals once during the pretest period (Day
-8) and for all surviving animals on study Day 4 (recorded approximately 2 to 4 hours following dose administration) and Day 27.
Blood pressure was unaffected by test article administration. There were no statistically significant differences at the Days
4 and 27 evaluations when the control and test article-treated groups were compared.


 


In
conclusion, administration of LB-100 via daily intravenous (slow bolus) injection for 5 consecutive days to male and female beagle
dogs was well tolerated at the dosage level of 0.15 mg/kg/day. At dosage levels of 0.30 and 0.75/0.50 mg/kg/day, administration
of LB-100 resulted in adverse clinical observations, lower body weights, and histological findings (congestion and nephrosis in
kidneys, increased mitoses and single cell necrosis in liver, lymphoid depletion and single cell necrosis in thymus, and/or erosion
and/or hemorrhage in stomach or intestines) correlating with effects on clinical pathology, organ weight, and/or macroscopic findings
during the dosing period. Persistent adverse test article-related histological changes in the kidneys were observed in the 0.30
and 0.75/0.50 mg/kg/day group males and females at the Day 29 recovery necropsy. These changes were more indicative of a progression
towards chronicity rather than recovery. In addition, lethality was observed at 0.75 mg/kg/day. Therefore, the Highest Non-Severely
Toxic Dose (HNSTD) was 0.15 mg/kg, which corresponded to an AUClast for LB-100 of 267 and 335 ng•h/mL on study Day 4 for
males and females, respectively.


 




    	 



    	Page 19 of 92



    

 


(i)
2.4 Human
Studies


 


2.4.1
Single-Agent Phase I Study LB-100


 


A
single Phase 1 clinical trial with LB-100 in solid tumors (NCT01837667) has been completed (Chung et al. 2016). This open-label,
multicenter, dose-escalation, non-randomized, phase I study was performed to assess the safety, tolerability, and activity of
intravenous LB-100 administered for 3 consecutive days every 3 weeks. Pharmacokinetic studies were planned on three patients at
the maximum tolerable dose (MTD). The starting dose of 0.25mg/m2 intravenously daily for 3 days every 3 weeks was approximately
1/15th of the highest non-severely toxic dose in the dog.


 


LB-100
for Injection was supplied as a sterile, single use solution. The tested dose levels were 0.25, 0.50, 0.83, 1.25, 1.75, 2.33,
and 3.1mg/m2. For doses up to 2.33mg/m2/day, LB-100 was administered in 50mL of saline over 15 minutes. Beginning with the 2nd
patient at 2.33mg/m2, LB-100 was administered in 500 mL normal saline over 2 hours because of grade 3 asymptomatic reversible
increases in serum creatinine in 2 of 4 patients. The larger fluid volume of 500 mL saline was used to assure adequate hydration.


 


Patients
were eligible to receive up to 6 cycles of study therapy, unless unacceptable toxicity, disease progression, or inter-current
illness required discontinuation. Patients were allowed continue beyond 6 cycles if the responsible physician determined that
additional treatment might provide benefit. A total of 28 patients with advanced solid tumors were enrolled at four clinical sites.
Four patients were not evaluable for toxicity. Three of these had disease-associated complications prior to completing cycle 1:
a pulmonary embolism (NSCLC); hypoxia secondary to pulmonary metastases (NSCLC); intra-tumor hemorrhage and chronic anemia (uterine
cancer). A fourth patient, with atypical carcinoid of the lung, received one dose of LB-100 but was removed from study before
dose 2 because of pneumonia; this patient was re-entered on study 7 weeks later and achieved stable disease for 5 cycles. None
of these adverse events was considered related to drug administration. A colon cancer patient had a grade 2 increase in normal
pre-treatment creatinine after the second dose of LB-100 at 2.33 mg/m2. The treating physician elected not to administer the 3rd
dose although to do so would have been permitted by protocol.


 


There
were 24 patients who completed at least one 3-day cycle of LB-100. There was no symptomatic toxicity other than reversible mild
to moderate fatigue. There was no grade 4 or 5 toxicity. There was no DLT during the first 6 dose levels. At the 3.1 mg/m2 dose
level, one patient with prostate cancer and one with chondrosarcoma had no DLT during 4 and 9 cycles of treatment, respectively.
A third patient with ovarian cancer had a grade 3 increase in calculated creatinine clearance after cycle 1 with a return to normal
by day 8 and received 3 more cycles at a reduced dose of 2.33 mg/m2 before tumor progression. A fourth patient, with fibrosarcoma,
had a grade 3 increase in calculated creatinine clearance after the first course of LB-100 at 3.1 mg/m2. Because the creatinine
returned to pretreatment value by day 21 and the patient was asymptomatic, the safety review committee and sponsor approved a
second course at a reduced level of 2.33 mg/m2. This dose level
was associated with a grade 2 increase in creatinine clearance without other toxicity. Further treatment at 1.75 mg/m2 was given
for ten more cycles without toxicity and persistence of stable disease until disease progression after 36 weeks. Because 2/4 patients
at 3.1mg/m2 had grade 3 increases in calculated creatinine clearance during cycle one, three additional patients were evaluated
at the preceding dose level of 2.33 mg/m2 and had no limiting toxicity. There were no signs or symptoms suggestive of hepatic,
hematologic, neurologic, or immunologic toxicity.


 






    	 



    	Page 20 of 92



    

 


Thus,
LB-100 was well tolerated at all dose levels explored during the Phase I study (0.25 mg/m2, 0.5 mg/m2, 0.83 mg/m2, 1.25 mg/m2,
1.75 mg/m2, 2.33 mg/ m2 and 3.1 mg/m2) with few adverse events (AEs) and no drug related serious adverse events (SAEs). During
the dose-escalation phase (Arm 1), the maximum tolerated dose (MTD) was identified at 2.33 mg/ m2 daily for 3 days every 3 weeks
administered IV. Dose limiting toxicities of Grade 3 increased in creatinine in 2 of 4 patients were observed at 3.1 mg/m2. The
most common AEs that were present in more than one patient were fatigue, blood creatinine increase, aspartate aminotransferase
increase, headache, hypematremia, hypoalbuminemia, nausea, proteinuria, pyrexia, alanine aminotransferase increase, constipation,
neuropathy peripheral, edema peripheral, sinus tachycardia, and anemia.


 


As
LB-100 has not been studied to date in combination with carboplatin/etoposide/atezolizumab, the initial dose level for this study
(i.e. 1.75mg/m2 on day 1 and day 3 of the carboplatin/etoposide/atezolizumab regimen) was chosen at one dose level below that
which is tolerated in solid cancer patients given for three consecutive days with allotment of dose de-escalation/escalation based
on safety and tolerability.








 


2.4.2
LB-100 Human Pharmacokinetics


 


Plasma
concentrations of LB-100 and endothall were measured at the MTD of 2.33 mg/m2 of LB-100 administered as an intravenous infusion
over two hours. In one patient sampling was done on day 1 and in two patients, on day 1 and 3. Plasma samples were obtained prior
to the infusion and over 4 hours after completion of the infusion. The pharmacokinetics of LB-100 were characterized by low clearance
and a low volume of distribution resulting in a short half-life on day 1. The day 3 pharmacokinetic profile was similar to that
described for the first dose. Circulating plasma concentrations of endothall were low over the four-hour infusion. In one patient,
concentrations of endothall were below the limit of detection (5 ng/mL) at all time points. For the other two patients, the maximal
concentration of endothall was observed at the last sampling timepoint (4 h), which precluded determination of the elimination
half-lives for endothall.


 


2.4.3
LB-100 Anti-tumor Activity in Solid Tumor Patients


 


Of
20 patients with measurable disease, one patient with pancreatic cancer had a partial regression, noted after 10 cycles and lasting
for 5 more cycles, and 16 patients had no progression of their indicator lesion. Only 3 patients, one with duodenal and two with
colonic adenocarcinomas, had significant increases in the size of their indicator lesion by RECIST criteria and were removed from
study for either the appearance of a new lesion or symptoms judged to represent clinical progression. Achieving partial regression
or stability of disease was not clearly dose-dependent, occurring at 0.83 mg/m2 in pancreatic cancer (15 cycles) and atypical
carcinoid of the lung (5 cycles); at 1.25 mg/m2 in breast cancer (4 cycles) and testicular cancer (5 cycles); and at 1.75 mg/m2
in malignant thymoma (8 cycles) and ovarian cancer (6 cycles). At 3.1 mg/m2, a patient with chondrosarcoma was stable for 8 cycles
of LB-100 without any alteration in normal renal function whereas a patient with fibrosarcoma started at 3.1 mg/m2 was stable
for 12 cycles after two dose reductions. Thus ten of 20 patients had stable disease for four or more cycles with one pancreatic
adenocarcinoma patient exhibiting partial response after 10 cycles, which was maintained for five additional cycles. It was noted
that the stabilization of disease occurred over a range of doses (0.83-2.33 mg/m2 daily for 3 days). The only expected toxicity
from LB-100 is reversibly increases in serum creatinine that may result from transient reversible inhibition of PP2A in the renal
tubules and not from renal tissue damage. As discussed earlier, we expect LB-100 to increase the mechanisms of antitumor activity
of carboplatin and etoposide which could increase their toxicity. However, the effect of LB-100 on the toxicity of the PD-L1 compound
is unknown.


 






    	 



    	Page 21 of 92



    

 


2.4.4
LB-100 Dosage and Schedule Considerations


 


The
optimal rate of LB-100 infusion and the dosing schedule are not known. In the Phase 1 trial, as specified per protocol, PK was
done was done in three patients at the MTD, 2.33 mg/m2 in 500 mL saline over two hours. Two were sampled day 1 and day 3, and
one on day 1 only. Peak plasma concentrations of LB-100 at the end of the infusion (n=5) averaged 150 ng/ml (~ 0.6 uM) and declined
rapidly. As expected, at the end of the two-hour infusion in all patients on day 1 infusion, there was no detectable endothall
in plasma. In one of two patients, endothall was present at 17.6 ug/mL (~0.1 uM) in the pretreatment sample on day 3 before the
3rd infusion, suggesting that 24 hours after the day 2 infusion, some endothall was still in tissues, compatible with its relatively
slow elimination (t 1⁄2 ~7 hours) compared to LB-100 with a t 1/2 of less than 1 hour. However, there is no estimate of the
concentrations of LB-100 and endothall in tissues and PK studies were not done after infusion of LB-100 over 15 minutes. Based
on the above data for this trial and subsequent studies, it is recommended that LB-100 be infused over 15 minutes on days 1 and
3 of the standard carboplatin/etoposide/atezolizumab regimen to maximize peak plasma concentration and to avoid tissue accumulation
of the active metabolite, endothall, which is now known to have a plasma half-life of up to 7 hours. Thus, the Investigator Brochure
may be updated during the course of this study with additional risks and benefits. Please see the current Investigator Brochure
for further details about the potential risks and benefits associated with this study.


 


In
the Phase 1 trial of LB-100 in solid tumor patients, three patients received a dose of 1.75 mg/m2 in 50 mL normal saline over
15 minutes daily for three consecutive days without any significant toxicity. In the present trial the starting dose of LB-100
is 1.75 mg/m2 in 50 mL normal saline on day 1 and day 3. Thus, we anticipate no toxicity attributable to LB-100 itself, allowing
recognition of any potentiation of the standard toxicities associated with the other agents.


 


LB-100
is supplied as a sterile solution for intravenous administration. LB-100 is stored at -20C (range: - 25C to -10C). Each vial contains
LB-100 at a concentration of 1 mg/mL. The proper dose is drawn up in a sterile syringe and added to 50 mL of normal saline (0.9%)
and infused over 15 +/- 5 minutes. Following dilution in normal saline, LB-100 should be administered within 4 hours.


 


2.5
Carboplatin/Etoposide/Atezolizumab


 


Carboplatin
is an analog of cisplatin that has a more favorable toxicity profile (Ruckdeschel 1994). In interacts with DNA and forms both
intra- interstrand links. The most commonly observed side effects include thrombocytopenia, neutropenia, leukopenia, and anemia.
Like other platinum-containing compounds, carboplatin may induce anaphylactic-type reactions such as facial edema, wheezing, tachycardia,
and hypotension that may occur within a few minutes of drug administration. These reactions may be controlled with adrenaline,
corticosteroids, or antihistamines. Please see package insert for further information.


 


Etoposide
is a semisynthetic derivative of podophyllotoxin that exhibits cytostatic activity in vitro by preventing cells from entering
mitosis or by destroying them at a premitotic stage. Etoposide interferes with the synthesis of DNA and appears to arrest human
lymphoblastic cells in the late S-G2 phase of the cell cycle. The most commonly observed side effects include leukopenia and thrombocytopenia.
Please see package insert for further information.


 


Etoposide
is indicated in combination with other antineoplastics in the treatment of SCLC, NSCLC, malignant lymphoma, and testicular malignancies
(approved indications may vary depending on the specific country). Etoposide is also used in clinical studies against many other
types of cancer including head and neck, brain, bladder, cervical, and ovarian.


 






    	 



    	Page 22 of 92



    

 


Atezolizumab
is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets programmed death receptor 1 ligand (PD-L1) and inhibits
the interaction between PD-L1 and its receptors, programmed death receptor 1 (PD-1) and B7-1 (also known as CD80), both of which
function as inhibitory receptors expressed on T cells. Intravenous atezolizumab has been approved in the US and EU for the treatment
of adult patients with advanced urothelial carcinoma that have failed or are ineligible for a platinum based regimen.(25, 26)
Additionally, atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin has been approved in the US for the first-line
treatment of adult patients with metastatic NSCLC with no EGFR or ALK genomic tumor aberrations and as monotherapy in locally
advanced and metastatic NSCLC after prior chemotherapy.(27) Recently, atezolizumab was also granted accelerated approval in the
US, in combination with nab-paclitaxel for patients with unresectable locally advanced or metastatic triple negative breast cancer
whose tumors express PD-L1.(28) Finally, atezolizumab was approved for first-line treatment, in combination with carboplatin and
etoposide, in adult patients with extensive-stage small cell lung cancer, showing improved survival (median OS 12.3 months in
the platinum/etoposide/atezolizumab arm vs. 10.3 months platinum/etoposide/placebo). The addition of immunotherapy to etoposide
and platinum chemotherapy in ED-SCLC also improved progression-free survival and was not associated with unacceptable toxicity.
(7) Treatment with atezolizumab is generally well-tolerated, but can be associated with immune-related adverse events (irAEs).
Please see package insert for further information.








 


	 	3.0	Patient Eligibility
	 	 	 
	 	3.1	Inclusion Criteria




 


Patients
are eligible to be included in the study only if they meet all of the following criteria:


 


3.1.1
Disease Status


 


	 	[1]	histologically or
    cytologically confirmed extensive-stage disease small cell lung carcinoma per the Veterans Administration Lung Study Group
    (VALG) staging system, (Appendix E)




 


	 	[2]	measurable disease
    as defined by Response Evaluation Criteria in Solid Tumors (RECIST): Revised RECIST Guideline (version 1.1; Eisenhauer et
    al. 2009, Appendix B)




 


3.1.2
Age Criteria, Performance Status, and Life Expectancy


 


	 	[3]	at least 18 years
    old at the time of screening




 


	 	[4]	estimated life expectancy
    of at least 12 weeks




 


3.1.3
Childbearing Potential


 


	 	[5]	For women: Must
    be surgically sterile (surgical procedure: bilateral tubal ligation), post-menopausal (at least 12 consecutive months of amenorrhea)
    or have a negative pregnancy test. Women of childbearing potential must be compliant with a medically approved contraceptive
    regimen (intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after the treatment period;
    must have a negative serum or urine pregnancy test within 14 days before study drug treatment and must not be breastfeeding.




 


For
men: agreement to remain abstinent or use medically approved contraceptive measures, as defined below:


 


With
female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during study
therapy and for at least 6 months after the last dose of study therapy to avoid exposing the embryo.


 






    	 



    	Page 23 of 92



    

 


3.1.4
Protocol-Specific Criteria


 


	 	[6]	a performance status
    of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale (Appendix A)




 


	 	[7]	adequate hematologic
    and organ function, including:




 


Hematologic:
absolute neutrophil (segmented and bands) count (ANC) ≥1.5x10/L, platelets ≥100x10/L,
and hemoglobin ≥9 g/dL


 


Hepatic:
bilirubin ≤1.5 times upper limits of normal (ULN) may be enrolled, and alkaline phosphatase (AP), alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) ≤3.0 times ULN (AP, AST, and ALT ≤5 times ULN are acceptable if the liver has
tumor involvement).


 


Renal:
calculated creatinine clearance (CrCl) ≥60 mL/min based on the Cockcroft and Gault formula below:


 


	 	Males:	 	 	 
	 	 	 	 	 
	 	Creatinine
    CL	=	Weight
    (kg) x (140 – Age) .	 
	 	(mL/min)	 	72
    x serum creatinine (mg/dL)	 
	 	 	 	 	 
	 	Females:	 	 	 
	 	 	 	 	 
	 	Creatinine
    CL	=	Weight
    (kg) x (140 – Age)	x
    0.85
	 	(mL/min)	 	72
    x serum creatinine (mg/dL)	 








 


3.1.5
Informed Consent/Assent


 


	 	[8]	All subjects must
    have the ability to understand and the willingness to sign a written informed consent.




 


3.1.6
Prior Therapy


 


	 	[9]	no prior systemic
    chemotherapy, immunotherapy, biological, hormonal, or investigational therapy for SCLC




 


3.2
Exclusion Criteria


 


	 	[10]	currently enrolled
    in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use
    of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically
    compatible with this study




 


	 	[11]	diagnosis of NSCLC
    or mixed NSCLC and SCLC




 


	 	[12]	no prior malignancy
    other than SCLC, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and
    definitively treated 5 or more years prior to study entry with no subsequent evidence of recurrence. Patients with a history
    of low grade (Gleason score ≤6=Gleason Group 1) localized prostate cancer will be eligible even if diagnosed less than
    5 years prior to study entry




 


	 	[13]	serious concomitant
    systemic disorder that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the
    protocol




 


	 	[14]	active or ongoing
    infection during screening requiring the use of systemic antibiotics




 






    	 



    	Page 24 of 92



    

 


	 	[15]	serious cardiac
    condition, such as myocardial infarction within 6 months, angina, or heart disease as defined by the New York Heart Association
    Class III or IV




 


	 	[16]	clinical evidence
    of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated
    CNS metastases, are asymptomatic, and have had no requirement for steroid medication for 1 week prior to the first dose of
    study drug and have completed radiation 2 weeks prior to the first dose of study drug




 


	 	[17]	known or suspected
    allergy to any agent given in association with this trial




 


	 	[18]	pregnant or lactating
    women




 


	 	[19]	History of autoimmune
    disease, including minor/mild autoimmune disease not requiring immunosuppressants (such as eczema on less than 10% of the
    body surface area and long term diabetes mellitus type 1on stable insulin).




 


	 	[20]	Known hepatitis
    B or hepatitis C




 


	 	[21]	Known human immunodeficiency
    virus (HIV) positive










 


	 	[22]	Treatment with systemic
    corticosteroid or other immunosuppressive medication. The use of inhaled corticosteroids for chronic obstructive pulmonary
    disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids
    for adrenocortical insufficiency are allowed.




 


	 	[23]	Administration of
    a live, attenuated vaccine within 28 days prior to study




 


	 	[24]	Uncontrolled pleural
    effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients
    with indwelling catheters are allowed.




 


	 	[25]	Uncontrolled or
    symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN).
    Patients who are receiving denosumab prior to study entry must be willing and eligible to discontinue its use and replace
    it with a bisphosphonate while in the study.




 


	 	[29]	History of idiopathic
    pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis,
    or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis)
    is permitted.




 


	 	[30]	Prior allogeneic
    bone marrow transplantation or solid organ transplant.




 


	 	[31]	QTcF (Fridericia
    Correction Formula) > 470 on 2 out of 3 EKG’s.




 


	 	[32]	Diagnosis of congenital
    long QT syndrome.




 


	 	[33]	Treatment, within
    7 days prior to first dose of study drug, with medications that are known to prolong the QT interval and/or are associated
    with a risk of Torsades de Pointes.




 


	 	[34]	Treatment with CYP450
    substrates (see Appendix F) within 7 days prior to first dose of study drug.




 


	 	[35]	Treatment with nephrotoxic
    compounds within 7 days prior to first dose of study drug.




 


	 	[36]	Treatment with warfarin
    within 7 days prior to first dose of study drug.




 


	 	[37]	Treatment with antiepileptic
    medications that may increase etoposide clearance (including but not limited to phenytoin, phenobarbital, carbamazepine, and
    valproic acid) within 7 days prior to first dose of study drug.




 


	 	[38]	Treatment with strong
    P-glycoprotein inhibitors within 7 days prior to first dose of study drug.




 


3.2.1
Non-Compliance


 


	 	[39]	Subjects, who in
    the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.




 




    	 



    	Page 25 of 92



    

 


3.3
Inclusion of Women and Minorities


 


The
study is open to anyone regardless of gender or ethnicity. Efforts will be made to extend the accrual to a representative population,
but in a trial which will accrue approximately 18 subjects, a balance must be struck between subject safety considerations and
limitations on the number of individuals exposed to potentially toxic or ineffective treatments on the one hand and the need to
explore gender, racial, and ethnic aspects of clinical research on the other. If differences in outcome that correlate to gender,
racial, or ethnic identity are noted, future studies may explore those differences.


 


	 	4.0	Screening
    and Registration Procedures
	 	 	 
	 	4.1	Pre-Enrollment
    Informed Consent and Screening Procedures




 


Diagnostic
or laboratory studies performed exclusively to determine eligibility will be done only after obtaining written informed consent.
Studies or procedures that are performed for clinical indications (not exclusively to determine study eligibility) may be used
for baseline values and/or to determine pre- eligibility, even if the studies were done before informed consent was obtained.


 


The
informed consent process is to be fully documented (see Section 14.7), and the prospective participant must receive a copy of
the signed informed consent document. Screening procedures are listed in Section 10.0 (Study Calendar).


 


4.2
Participant Enrollment


 


4.2.1
COH DCC Availability and Contact Information


 


Eligible
participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City of Hope.


 


DCC
staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except holidays).


 


	 	o	E-mail: DCC@coh.org




 


4.2.2
Slot verification and reservation


 


A
designated study team member should email the DCC to verify current slot availability, and to reserve a slot for a specific prospective
subject (provide DCC with subject initials), including a tentative treatment date. Slots can only be held for a limited time,
at the discretion of the study PI.


 


The
DCC should be notified of cancellations of prospective participants holding slots as soon as possible.


 


4.2.3
Registration Process


 


Allow
up to 24 hours for the DCC to review eligibility. To register a participant the subsequent procedure is to be followed:


 


	 	1.	The study team should
    contact the DCC via email to provide notification regarding the pending registration and communicate desired timeline of the
    registration, especially if it must be completed promptly to meet the registration window.



 






    	 



    	Page 26 of 92



    

 


	 	2.	The study team will
    email a Complete Eligibility Packet to the DCC, which consists of a copy of the following documents:




 


	 	o	Registration
    Cover Sheet (Appendix C)
	 	o	Completed
    eligibility checklist (printed from Section 3.0 of the protocol) with required signature(s)
	 	o	Source
    documents that support all eligibility criteria listed in the eligibility checklist
	 	o	Signed
    Informed Consent
	 	o	Signed
    HIPAA authorization form (if separate from informed consent)
	 	o	Signed
    subject’s bill of Rights (California only)








 


	 	3.	When all source
    documents are received, the DCC will review to verify eligibility, working with the study team to resolve any missing required
    source elements. Any missing documents may delay review and registration. A participant failing to meet all protocol eligibility
    requirements will not be registered and the study team will be immediately notified.




 


	 	4.	Once eligibility
    is confirmed, the DCC will send a Confirmation of Registration Form and signed Eligibility Checklist, including the Subject
    Study Number and cohort assignment to:




 


	 	o	The
    study team: Site Lead Investigator, treating physician/sub-investigator, protocol nurse, CRC and pharmacy (as needed).
	 	o	The
                                         COH Study PI and COH study team designees (including but not limited to study monitor(s)
                                         and statistician(s)).


 


	 	5.	Upon receipt of
    the Confirmation of Registration Form, COH study team will register the patient in OnCore.




 


4.3
Screen Failures and Registered Participants Who Do Not begin Study Treatment


 


Notify
the DCC immediately if the participant screen fails after registration or if the participant does not start treatment. Issues
that would cause treatment delays should be discussed with the Study Principal Investigator.


 


4.4
Screening Procedures


 


Diagnostic
or laboratory studies performed exclusively to determine eligibility for this trial will be done only after obtaining written
informed consent. Studies or procedures that were for clinical indications (not exclusively to determine study eligibility) may
be used for baseline values, even if the studies were done before informed consent was obtained. Reference is made to Section
10.0 – Study Calendar.


 


4.5
Informed Consent


 


The
investigational nature and objectives of the trial, the procedures and treatments involved and their attendant risks and discomforts,
and potential alternative therapies will be carefully explained to the subject and a signed informed consent will be obtained.
Documentation of informed consent for screening will be maintained in the subject’s research chart and medical record.


 


4.6
Registration Requirements/Process


 


Prior
to registration and any study-specific evaluations being performed, all patients must have given written informed consent for
the study and must have completed the pre-study evaluations (see Section 10.0). Patients must meet all of the eligibility requirements
listed in Section 3.0. Patients will be registered on the study by DCC, after review of the eligibility criteria checklist, source
documentation, informed consent, HIPAA and Bill of rights.


 






    	 



    	Page 27 of 92



    

 


4.7
Dose Level Assignment


 


Prior
to enrollment into the study, an eligibility check must be conducted for every patient by the investigational site to confirm
that the patient meets all enrollment criteria.








 


	 	5.0	Treatment Program
	 	5.1	Treatment
    Overview




 


This
Phase Ib study of LB-100 diluted in 50 mL of normal saline for injection will be administered intravenously in the outpatient
clinic over 15 minutes in patients with extensive-stage small cell lung cancer.


 


5.1.1
Schedule


 


For
a tabular view of the treatment monitoring and follow-up schedule, see study calendar in Section 10.


 


Patients
will receive an intravenous infusion of LB-100 diluted in 50 mL of normal saline (0.9%) over 15 +/- 5 minutes on days 1 and 3
of each 21 day cycle at escalating doses starting at Dose Level 1 (see Table 5.1). The LB-100 should be given first and should
end one hour before the start of other drugs. All three patients at each dose level will be assessed for evidence of limiting
toxicity through their return visit day 21 (and any delay prior to the start of cycle 2) before the decision is made for dose
escalation in the next cohort. The MTD is defined as the highest dose level below which DLT is manifested in ≥33% of the patients
(unless the highest dose to be tested does not have ≥33% of patients with a DLT) and where at least 6 patients have been treated.


 


The
study is based on a standard 3+3 patient dose escalation design. It is planned that there will be 3 possible dose escalations
(and one possible de-escalation level if needed). Thus, a maximum of 24 patients will be enrolled during dose finding, with an
expected sample-size of 12 during escalation/de-escalation (additional patients to achieve 12 patients at the RP2D will follow
for an expected sample-size of 18 total patients and maximum of 30).


 


All
patients who are not evaluable for DLT (dose-limiting toxicity) will be replaced. Patients who do not receive the planned doses
without a DLT, will be considered inevaluable as will patients where inadequate follow-up assessments are conducted for reasons
unrelated to toxicity. Patients will be enrolled at most in cohorts of 3.


 


If
0/3 patients have a DLT attributable to the combination, then the next 3 patients will be treated at the next dose level.


 


If
a DLT treatment occurs in 1/3 patients, then 3 more patients (for a total of 6) will be treated at the same dose level. If no
additional DLT attributable to treatment is observed at the expanded dose level (i.e. 1/6 with DLT), then the LB-100 dose will
be escalated to the next level. If two or more patients (i.e. 2/6) have a DLT then one level below that dose will be tested.


 


Dose
escalation will terminate as soon as two or more patients have a DLT at a given dose level or the highest dose level is tested.


 


There
will be no dose escalation within a patient.


 


The
MTD is defined as the highest LB-100 dose tested in which none or only one patient had a DLT during the first cycle of therapy,
when at least six patients were treated at that dose and are evaluable for toxicity assessment. The MTD is one dose level below
the lowest dose tested in which 2 patients had a DLT attributable to treatment unless the highest dose is deemed safe.




    	 



    	Page 28 of 92



    
 


In
addition to these rules, all dose modifications and later cycle toxicities will be reviewed prior to escalation or expansion and
can modify the decision to be more conservative (e.g. to not escalate when the standard rules state escalate, or de-escalate when
the standard rules state expand the dose).


 


Any
severe immune-related event that requires discontinuation of therapy will also prompt a review by the DSMC, regardless of cycle
of therapy.


 


Table
5.1.1 Dose Levels: LB-100 on Days 1 and 3 of a 21 Day cycle, at escalating doses prior to standard doses of carboplatin/atezolizumab/etoposide


 


	Dose
    Level	 	LB-100
    (mg/m2)
	-2(a)	 	0.50
	-1(b)	 	0.83
	1
    (Starting dose)	 	1.25
	2	 	1.75
	3	 	2.33
	4	 	3.10


 


	 	a)	For
    within patient dose de-escalation only.
	 	b)	In
    the event that 2 or more DLT’s are observed at Dose Level 1, subsequent patients will be enrolled in Dose Level -1.


 


LB-100:


 


LB-100
is supplied as a sterile solution for intravenous administration. LB-100 is stored at -20C (range: - 25C to -10C). Each vial contains
10 mL of LB-100 at a concentration of 1 mg/mL. The proper dose is drawn up in a sterile syringe and added to 50 mL of normal saline
(0.9%) and infused over 15 +/- 5 minutes prior to administration of atezolizumab on Day 1 and prior to etoposide on Day 3. Following
dilution in normal saline, LB-100 should be administered within 4 hours


 


Carboplatin:


 


Carboplatin
is supplied as a sterile lyophilized powder available in single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin
for administration by intravenous injection. Each vial contains equal parts by weight of carboplatin and mannitol. Immediately
before use, the content of each vial must be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in Water,
or 0.9% Sodium Chloride Injection, USP, according to the following schedule:


 


	Vial
    Strength	 	Diluent
    Volume
	50
    mg	 	5
    mL
	150
    mg	 	15
    mL
	450
    mg	 	45
    mL


 






    	 



    	Page 29 of 92



    

 


These
dilutions all produce a carboplatin concentration of 10 mg/mL. Carboplatin can be further diluted to concentrations as low as
0.5 mg/mL with 5% Dextrose in Water or 0.9% Sodium Chloride Injection, USP (NS).


 


VP-16
(Etoposide):


 


100
mg of VP-16 is supplied as 5 mL of solution in Sterile Multiple Dose Vials for injection. The pH of the yellow clear solution
is 3-4. Each mL contains 20 mg VP-16, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80/tween 80, 650 mg polyethylene
glycol 300 and 30.5% (v/v) alcohol. VP-16 must be diluted prior to use with either 5% Dextrose Injection, USP or 0.9% sodium Chloride
Injection, USP. The time before precipitation occurs depends on concentration, however, when at a concentration of 0.2 mg/mL it
is stable for 96 hours at room temperature and at 0.4 mg/mL it is stable for 48 hours.


 


Atezolizumab
(Tecentriq):


 


Atezolizumab
is a sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing
one 1200 mg/20 mL single-dose vial (NDC 50242-917-01). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F)
in original carton to protect from light. Do not freeze. Do not shake.


 


Table
5.1.2 Study drug schedule, dose, route and timing


 


The
induction phase is four cycles (Cycles 1-4). The maintenance phase is Cycle 5 and beyond.


 




    	 



    	Page 30 of 92



    

 


	Drug	 	Dose	 	Route	 	Schedule	 	Notes
	LB-100

        (Induction
        and Maintenance)
	 	As
                                         assigned

        (.83,
        1.25,

        1.75,
        2.33

        or
        3.10

        mg/m2)
	 	IV	 	Days
    1 and 3 of each 21 day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward)	 	Infused
    over 15 minutes. Given first. Other drugs should start 1 hour after end of LB-100 infusion.
	Atezolizumab
                                         (Tecentriq)

        (Induction
        and Maintenance)
	 	1200
    mg/20 mL	 	IV	 	Day
    1 of each 21 day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward)	 	Infused
    over 60 (± 15) minutes (for first infusion, shortening to 30 [± 10] minutes for subsequent infusions, depending
    on patient tolerance.
	Carboplatin
    (Induction)	 	AUC
    5	 	IV	 	Day
    1 of the 21 day cycle; repeat every 21 days for 4 cycles	 	Given
    after atezolilzumab. Infused over 30-60 minutes.
	VP-16
    (Etoposide) (Induction)	 	100
    mg/m2	 	IV	 	Days
    1, 2 and 3 of the 21 day cycle; repeat every 21 days for 4 cycles	 	Given
    last. Infused over 60 minutes.


 


5.2
Planned Duration of Therapy


 


5.2.1
Baseline and Study Treatment Periods


 


Within
4 weeks before the first dose of study treatment, baseline tumor measurement(s) will be performed on each patient. At baseline:
computed tomography (CT) [or magnetic resonance imaging (MRI)] of the head, chest, abdomen, pelvis, and a bone and/or PET scan.
Ultrasound will not be permitted as a method of tumor measurement. The same method used at baseline must be used consistently
for tumor assessment and will be repeated every 6-8 weeks until disease progression. Confirmation of response will occur no less
than 4 weeks from the first evidence of response. A bone and/or PET scan can be repeated per the investigator’s discretion
but must be repeated to confirm a complete response (CR) if bone lesions were present at baseline.


 


Patients
may continue to receive study therapy unless unacceptable toxicity, disease progression, intercurrent illness or one of the criteria
listed in 5.3 require discontinuation


 


For
reasonable cause, either the Investigator or the Sponsor may terminate this study permanently. Written notification of the termination
is required. Conditions that may warrant termination include, but are not limited to.


 


	 	●	The
    discovery of an unexpected significant or unacceptable risk to the patients enrolled in the study.
	 	 	 
	 	●	Failure
    of the Investigator to enter patients at an acceptable rate.


 




    	 



    	Page 31 of 92



    

 


	 	●	Insufficient
    adherence to protocol requirements (non-compliance).
	 	 	 
	 	●	Lack
    of evaluable and/or complete data.
	 	 	 
	 	●	Decision
    to modify the developmental plan of the drug.
	 	 	 
	 	●	A
    decision on the part of the Sponsor to suspend or discontinue development of the drug.


 


In
the case that the trial is discontinued due to reasons other than unforeseen risk, patients who are currently receiving drug and
are deriving benefit from the treatment may be allowed to continue receiving treatment.


 


5.2.2
Post discontinuation Period


 


Each
enrolled patient will have a 30-day safety follow-up period which will occur 30 days after the last dose of study drug. The investigative
sites will continue to monitor patients per routine clinical practice. Patients who complete treatment or discontinue without
disease progression will continue to be evaluated for tumor response using the RECIST v1.1 guidelines (Eisenhauer et al. 2009,
Appendix B) every 6-8 weeks until disease progression, death, or until study closure, whichever occurs first. The date of first
documented disease progression must be recorded on the CRF even if progression occurs after the patient has started a new therapy.
Monitoring for survival may also continue following progression on a monthly basis. Information will be collected regarding dates
of disease progression, death and any post discontinuation systemic therapy, radiotherapy, or surgical intervention until the
date of study closure.


 


5.3
Criteria for Removal from Treatment



 


The
criteria for enrollment must be followed explicitly. If a patient who does not meet enrollment criteria is inadvertently enrolled,
Lixte Biotechnology Holdings, Inc must be contacted. In these cases, the investigator must obtain documented approval John Kovach,
M.D. President and CEO of Lixte Biotechnology Holdings, Inc to allow the patient to continue to receive the study drug. Dr. Kovach’s
contact information is: telephone 631-880-2907 and email jkovach@lixte.com.


 


In
addition, patients will be discontinued from the study drug and from the study in the following circumstances:


 


	 	●	Enrollment
    in any other clinical trial involving an investigational product or enrollment in any other type of medical research judged
    not to be scientifically or medically compatible with this study.
	 	 	 
	 	●	Investigator/Physician
    Decision


 


	 	o	The
    investigator/physician decides that the patient should be withdraw from the study or study drug.
	 	o	If
    the patient, for any reason, requires treatment with another therapeutic agent that has been demonstrated to be effective
    for treatment of the study indication, discontinuation from the study drug occurs prior to introduction of the new agent.


 


	 	●	Patient
    Decision


 


	 	o	The
    patient [or patient’s designee (for example, parents or legal guardian)] requests to be withdrawn from the study or
    study drug.


 


	 	●	Sponsor
    Decision


 




    	 



    	Page 32 of 92



    

 


	 	o	The
    investigator or DSMB or Sponsor stops the study or stops the patient’s participation in the study for medical, safety,
    regulatory, or other reasons consistent with applicable laws, regulations, and good clinical practice.


 


	 	●	The
    patient is significantly noncompliant with study procedures and/or treatment
	 	 	 
	 	●	The
    patient has evidence of disease progression
	 	 	 
	 	●	Unacceptable
    toxicity
	 	 	 
	 	●	The
    patient becomes pregnant or fails to use adequate birth control (for those patients who are of childbearing potential).


 


The
reason and date for discontinuation will be collected for all patients. All randomized patients who discontinue regardless of
whether they received study drug or not, will have procedures performed as shown in the Study Schedule (Section 10.0).


 


5.4
Subject Follow-Up



 


The
short-term safety follow-up period begins one day after the last dose of study drug and lasts 30 days. All AEs should be reported
for a minimum of 30 days from the last dose of study drug.


 


The
long-term follow-up period begins after patients have either completed cycle 4 or have been discontinued from study drug and continues
until disease progression or death. Patients may continue to be followed for survival following progression.


 


The
study will be considered complete following the data cutoff date and data lock for the final analysis. The statistical analysis
will be performed after study completion.


 


5.5
Supportive Care, Other Concomitant Therapy, Prohibited Medications



 


Premedication
with antihistamines may be administered. GCSF may be given in any cycle other than Cycle 1.


 


The
following therapies should continue while patients are in the study:


 


	●	Oral
    contraceptives
	●	Hormone-replacement
    therapy
	●	Prophylactic
    or therapeutic anticoagulation therapy (such as low molecular weight heparin or warfarin at a stable dose level)
	●	Palliative
    radiotherapy (e.g., treatment of known bony metastases) provided it does not interfere with the assessment of tumor target
    lesions (e.g., the lesion being irradiated is not the only site of disease, as that would render the patient not evaluable
    for response by tumor assessments according to RECIST v1.1)
	●	Inactive
    influenza vaccinations
	●	Megestrol
    administered as an appetite stimulant
	●	Inhaled
    corticosteroids for chronic obstructive pulmonary disease
	●	Mineralocorticoids
    (e.g., fludrocortisone)
	●	Low-dose
    corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency


 




    	 



    	Page 33 of 92



    

 


In
general, investigators should manage a patient’s care with supportive therapies as clinically indicated per local standards.
Patients who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine,
and/or famotidine or another H2 receptor antagonist per standard practice. Serious infusion-associated events manifested by dyspnea,
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive
therapies as clinically indicated (e.g., supplemental oxygen and β2- adrenergic agonists).


 


Cautionary:
Systemic corticosteroids and TNF-α inhibitors may attenuate potential beneficial immunologic effects of treatment with atezolizumab.
Therefore, in situations where systemic corticosteroids or TNF-α inhibitors would be routinely administered, alternatives,
including antihistamines, should be considered first by the treating physician. If the alternatives are not clinically appropriate,
systemic corticosteroids and TNF-α inhibitors may be administered per Section 6.3 or after discussion with the Principal
Investigator, except in the case of patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast
allergy or impaired renal clearance).


 


Systemic
corticosteroids are recommended, with caution, at the discretion of the treating physician, for the treatment of specific adverse
events when associated with atezolizumab therapy, per Section 6.3.


 


Prohibited:
Any concomitant therapy intended for the treatment of cancer, whether health authority−approved or experimental, is prohibited
for various time periods prior to starting study treatment, and during study treatment until disease progression is documented
and patient has discontinued study treatment. This includes, but is not limited to, chemotherapy, hormonal therapy, immunotherapy,
radiotherapy, investigational agents, or herbal therapy (unless otherwise noted).


 


The
following medications are prohibited while on study, unless otherwise noted:


 


	 	●	Traditional
    herbal medicines, because their use may result in unanticipated drug-drug interactions that may cause or confound assessment
    of toxicity
	 	●	Denosumab;
    patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead
    while in the study
	 	●	Any
    live, attenuated vaccine (e.g., FluMist®) within 28 days prior to first study drug, during treatment, or within
    90 days following the last dose of atezolizumab
	 	●	Use
    of steroids to premedicate patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy
    or impaired renal clearance); in such patients, non-contrast CT scans of the chest and non-contrast CT scans or MRIs of the
    abdomen and pelvis should be performed
	 	●	Medications
    that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes.
	 	●	CYP450
    substrates (see Appendix F).
	 	●	Nephrotoxic
    compounds.
	 	●	Warfarin.
	 	●	Antiepileptic
    medications that may increase etoposide clearance (including but not limited to phenytoin, phenobarbital, carbamazepine, and
    valproic acid).
	 	●	Strong
    P-glycoprotein inhibitors.


 


5.6
Additional Studies



 


Not
applicable.


 




    	 



    	Page 34 of 92



    

 


5.7
Definition of Dose-Limiting Toxicity (DLT)



 


The
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be used to grade toxicity. Per section 5.5 GCSF is
not allowed in Cycle 1, as it may suppress a toxicity that might otherwise occur. If a protocol deviation occurs and a patient
does receive GCSF in Cycle 1, they will be considered inevaluable for DLT and replaced, unless they experience a DLT in Cycle
1. DLT is defined as any of the following adverse events occurring in the first cycle of treatment and considered to be possibly,
probably, or definitely related to study treatment:


 


	 	●	Nausea/vomiting
    of Grade 3 or greater despite maximal antiemetic therapy.
	 	●	Any
    Grade 4 (immune-related adverse events (irAE)
	 	●	Diarrhea
    of Grade 3 or greater despite maximal antidiarrheal therapy.
	 	●	Any
    ≥ Grade 3 colitis (infectious etiologies should have been ruled out and endoscopic verification is strongly encouraged)
	 	●	Any
    Grade 3 or 4 noninfectious pneumonitis irrespective of duration
	 	●	Any
    Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of maximal supportive care
	 	●	Any
    Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 within 3 days after onset of the event
    despite optimal medical management including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within
    14 days
	 	●	Concurrent
    elevation of AST or ALT > 3X ULN AND total bilirubin > 2X ULN
	 	●	AST
    or ALT > 8X ULN or total bilirubin > 3X ULN, even if asymptomatic, unless it is related to a definite progression of
    liver metastases or another clearly identifiable etiology.
	 	●	Grade
    4 neutropenia observed for greater than 5 days duration or Grade 3 neutropenia associated with fever of any duration or where
    sepsis results or Grade 3 neutropenia lasting > 7 days.
	 	●	Grade
    4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or Grade 3 thrombocytopenia lasting >
    7 days.
	 	●	Grade
    4 anemia.
	 	●	Any
    ≥ Grade 3 AE, except for the exclusions listed below:


 


	 	o	Grade
    3 fatigue lasting ≤ 7 days
	 	o	Grade
    3 laboratory abnormalities, other than ALT or AST, that are not considered clinically significant and that return to grade
    2 or less within 72 hours
	 	o	Grade
    3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with or without systemic corticosteroid
    therapy and/or hormone replacement therapy and the subject is asymptomatic
	 	o	Grade
    3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory reaction at sites of metastatic disease,
    lymph nodes, etc.)
	 	o	Concurrent
    vitiligo or alopecia of any AE grade
	 	o	Grade
    3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that resolves within 6 hours with
    appropriate clinical management
	 	o	Grade
    3 or 4 lymphopenia


 




    	 



    	Page 35 of 92



    

 


	 	6.0	Dose Delays/Modifications
for Adverse Events
	 	 	 
	 	6.1	Dose Modifications





 


It
is anticipated that most of the treatment related toxicity on this trial will be caused by carboplatin/etoposide/atezolizumab.
Myelosuppression, predominantly neutropenia, will occur frequently; common non-hematologic toxicities include fatigue, nausea,
vomiting, and mucositis. In contrast, LB-100 is anticipated to be well tolerated; few toxicities observed in phase I overlapped
the known toxicity profile of carboplatin, etoposide and atezolizumab. The following general dose modification rules will, therefore,
be used for patients on the LB-100 treatment arm:


 


If
the initiation of a cycle is delayed due to carboplatin/etoposide/atezolizumab toxicity, the LB-100 will also be delayed to begin
concurrently with the carboplatin/etoposide/atezolizumab.


 


If
atezolizumab is held then LB-100 should be held as well, as it is a potential immunomodulator


 


If
toxicity is typical of carboplatin/etoposide/atezolizumab and requires dose reductions, the dose of LB-100 should not be reduced.


 


If
the toxicity is attributed specifically to one or two agents (carboplatin, etoposide, atezolizumab), the attributed agents will
be dose reduced; otherwise, the doses of all 3 drugs should be reduced.


 


Patients
who require a treatment delay of more than 28 days due to toxicity will be discontinued from the study. An exception is given
for tapering of steroids. If a patient must be tapered off steroids used to treat adverse events, atezolizumab may be withheld
until steroids are discontinued or reduced to prednisone dose (or dose equivalent) ≤ 10 mg/day.


 


6.2
Carboplatin/Etoposide Dose Modifications



 


Two
dose reductions of carboplatin and etoposide are allowed. Patients who require dose reductions will not have re-escalation. If
grade 3/4 toxicity reoccurs after 2 dose reductions have occurred, the offending agent or agents will be discontinued. If carboplatin,
etoposide and atezolizumab must be discontinued due to toxicity, LB-100 will also be discontinued. Patients who require a treatment
delay of more than 28 days due to toxicity will be discontinued from the study.


 


Dose
reductions for carboplatin and etoposide are shown in Table 6.2.0


 


Table
6.2.0 Dose Reductions for Carboplatin & Etoposide


 


	Dose
    Level	 	Carboplatin
    (AUC)	 	Etoposide
    (mg/ m2)
	Starting
    Dose	 	5.0	 	100
    x 3 days
	-1	 	4.5	 	75
    x 3 days
	-2	 	4.0	 	50
    x 3 days


 




    	 



    	Page 36 of 92



    

 


6.2.1
Hematologic Toxicity



 


Dose
adjustment will be based on the blood count measured on Day 1 (+/- 2 days) of each cycle. No dose modifications will be based
on nadir counts. See Table 6.2.1 below.


 


Table
6.2.1 Dose adjustments for carboplatin and for hematologic toxicity


 


	Blood
    Counts	 	Carboplatin
    (AUC)	 	Etoposide
    (mg/ m2)
	ANC
                                         ≥ 1500/ μL and Platelets

        ≥100,000/μL
	 	No
    dose modification	 	No
    dose modification
	ANC
                                         <1500/ μL or Platelets

        <100,000/
        μL
	 	Delay
                                         dosea

         

        Resume
        with one level dose reduction. Consider the addition of prophylactic G-CSF
	 	Delay
                                         dosea

         

        Resume
        with one level dose reduction. Consider the addition of prophylactic G-CSF

	 	 	 	 	 
	Febrile
    neutropenia (ANC ≤ 1000/ μL and Temp ≥101° F (38.5 °C)]	 	Delay
                                         doseb

         

        Resume
        with one level dose reduction. Consider the addition of prophylactic G-CSF
	 	Delay
                                         doseb

         

        Resume
        with one level dose reduction. Consider the addition of prophylactic G-CSF



 


a
Check counts at least weekly until ANC ≥1500/ μL and platelets ≥ 100,000/, μL then proceed with Day 1 dose


b
Delay dose until the infection is adequately treated and blood counts are ANC ≥1500/ μL and platelets ≥100,000/ μL


 


6.2.2
Non-Hematologic Toxicity


 


If
grade 3 or 4 non-hematologic toxicity occurs:


 


	 	●	Delay
    treatment with all drugs
	 	 	 
	 	●	Make
    an assessment regarding which drug or drugs produced the toxicity
	 	 	 
	 	●	Reevaluate
    the patient at least once weekly until the toxicity resolves to ≤ grade 1
	 	 	 
	 	●	Reduce
    the dose of the offending agent or agents by one dose level
	 	 	 
	 	●	If
    toxicity is irreversible or has not resolved to ≤ grade 1 after a 3-week treatment delay, the patient should be removed
    from the study
	 	 	 
	 	●	Creatinine
    clearance (Cockcroft and Gault formula) should be ≥45 mL/min prior to the start of any cycle.


 


6.3
Atezolizumab Dose Holding



 


There
will be no dose reduction for atezolizumab, but patients may temporarily suspend treatment with atezolizumab for up to 4 weeks
beyond the last dose if they experience an adverse event that requires a dose to be held. An exception is given for tapering of
steroids. If a patient must be tapered off steroids used to treat adverse events, atezolizumab may be withheld until steroids
are discontinued or reduced to prednisone dose (or dose equivalent) ≤ 10 mg/day.


 




    	 



    	Page 37 of 92



    

 


6.3.1
Management of Atezolizumab-Specific Adverse Events



 


Additional
tests, such as autoimmune serology or biopsies, should be used to determine a possible immunogenic etiology.


 


Although
most immune-mediated adverse events observed with immunomodulatory agents have been mild and self-limiting, such events should
be recognized early and treated promptly to avoid potential major complications. Discontinuation of atezolizumab may not have
an immediate therapeutic effect and, in severe cases, immune-mediated toxicities may require acute management with topical corticosteroids,
systemic corticosteroids or other immunosuppressive agents.


 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	Abdominal
    pain	 	Acute
    Abdominal pain	 	Symptoms
                                         of abdominal pain associated with elevations of amylase and lipase, suggestive of pancreatitis,
                                         have been associated with administration of other immunomodulatory agents. The differential
                                         diagnosis of acute abdominal pain should include pancreatitis.

         

        Appropriate
        workup should include an evaluation for obstruction, as well as serum amylase and lipase tests. See the guidelines for
        “Amylase and/or lipase increase” and “Immune- related pancreatitis” elsewhere in this table, as
        needed.

         

        Right
        upper-quadrant abdominal pain and/or unexplained nausea or vomiting should be evaluated for potential hepatotoxicity (see the
        “Hepatotoxicity” guideline elsewhere in

        this
        table).

	 	 	 	 	 
	Adrenal
    insufficiency	 	Grade
    2+	 	Hold
                                         atezolizumab. (symptomatic)

         

        Consider
        referral of patient to endocrinologist.

         

        Perform appropriate imaging.

         

        Initiate
        treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent and convert to 1−2 mg/kg/day oral
        prednisone or equivalent upon improvement.



 




    	 



    	Page 38 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	 

        If
        event resolves to Grade 1 or better and patient is stable on replacement therapy (if required) within 4 weeks, taper corticosteroids
        over ≥1 month and resume atezolizumab.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better or patient is not stable on replacement therapy
        within 4 weeks.

	 	 	 	 	 
	Amylase
    and/or lipase increased	 	Grade
    1	 	Continue
                                         atezolizumab.

         

        Monitor
        amylase and lipase prior to dosing.

	 	 	 	 	 
	 	 	Grade
    2	 	Continue
                                         atezolizumab.

         

        Monitor
        amylase and lipase weekly.

         

        For
        prolonged elevation (e.g., >3 weeks), consider treatment with 10 mg/day oral prednisone or equivalent

	 	 	 	 	 
	 	 	Grade
    3 or 4	 	Hold
                                         atezolizumab.

         

        Consider
        referral of patient to gastrointestinal (GI) specialist.

         

        Monitor amylase and lipase every other day.

         

        If
        no improvement, consider treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks.

         

        For
        recurrent events, permanently discontinue atezolizumab.

	 	 	 	 	 
	Dermatologic
    toxicity/rash	 	Grade
    1	 	Continue
    atezolizumab.


 




    	 



    	Page 39 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	(e.g.,

        maculopapular
        or purpura)
	 	 	 	Consider
    topical steroids and/or other symptomatic therapy (e.g., antihistamines).
	 	 	Grade
    2	 	Continue
                                         atezolizumab. Consider dermatologist referral.

         

        Administer
        topical corticosteroids.

	 	 	 	 	 
	 	 	Grade
    3	 	Hold
                                         atezolizumab.

         

        Refer
        patient to dermatologist. Administer oral prednisone 10 mg or equivalent. If the event does not improve within 48−72
        hours, increase dose to 1–2 mg/kg/day or equivalent. Restart atezolizumab if event resolves to Grade 1 or better
        within 4 weeks.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks.

	 	 	 	 	 
	 	 	Grade
    4	 	Permanently
                                         discontinue atezolizumab.

         

        Patient
        may not resume treatment, regardless of benefit. Otherwise, manage as above.

	 	 	 	 	 
	 	 	Persistent
                                         and/or severe rash or pruritus, any

        grade
	 	A
    dermatologist should evaluate the event. A biopsy should be performed, unless contraindicated.
	Diarrhea
    or colitis	 	Any
    grade	 	Patients
                                         should be advised to inform the investigator if any diarrhea occurs, even if it is mild.

         

        All
        events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. For events of significant
        duration or magnitude or associated with signs of systemic inflammation or acute-phase reactants (e.g., increased
        CRP, platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three
        to

        five
        specimens for standard paraffin block to check for



 




    	 



    	Page 40 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	inflammation
and lymphocytic infiltrates to confirm colitis diagnosis.

	 	 	 	 	 
	 	 	Grade
    1	 	Continue
                                         atezolizumab.

         

        Initiate
        symptomatic treatment.

         

        Endoscopy
        is recommended if symptoms persist for >7 days.

         

        Monitor closely

	 	 	 	 	 
	 	 	Grade
    2	 	Hold
                                         atezolizumab.

         

        Initiate
        symptomatic treatment.

         

        Patient
        referral to GI specialist is recommended.

         

        For
        recurrent events or events that persist >5 days, initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks. Resumption of atezolizumab may be
        considered, after consultation with the trial PI, in patients who are deriving benefit and have fully recovered from the
        immune-related event.

	 	 	 	 	 
	 	 	Grade
    3	 	Hold
                                         atezolizumab.

         

        Refer
        patient to GI specialist for evaluation and confirmatory biopsy.

         

        Initiate
        treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent and convert to 1−2 mg/kg/day oral
        prednisone or equivalent upon improvement.



 




    	 



    	Page 41 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	 

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks. Resumption of atezolizumab may be
        considered, after consultation with the Principal Investigator, in patients who are deriving benefit and have fully recovered
        from the immune-related event.

	 	 	 	 	 
	 	 	Grade
    4	 	Permanently
                                         discontinue atezolizumab. Patient may not resume treatment, regardless of benefit.

         

        Refer
        patient to GI specialist for evaluation and confirmation biopsy.

         

        Initiate
        treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent and convert to 1−2 mg/kg/day oral
        prednisone or equivalent upon improvement.

         

        If
        event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.

         

        If
        event resolves to Grade 1 or better, taper corticosteroids over ≥1 month.

	 	 	 	 	 
	Hepatotoxicity	 	Right
                                         upper- abdominal pain &/or nausea

        or
        vomiting
	 	Risk
                                         of immune-mediated hepatitis. LFTs should be performed immediately, and LFTs should be
                                         reviewed before administration of the next dose of study drug. For patients with unexplained
                                         elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic etiologies
                                         should be considered and addressed, as appropriate.

         

        Symptoms
        of abdominal pain associated with elevations of amylase and lipase, suggestive of pancreatitis, have been associated with
        the administration of atezolizumab. The differential diagnosis of acute abdominal pain should also include pancreatitis,
        as described below.



 




    	 



    	Page 42 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	Grade
    1 hepatic event	 	Continue
                                         atezolizumab.

         

        Monitor
        LFTs until values resolve to within normal limits.

	 	 	 	 	 
	 	 	Grade
    2 hepatic event, ≤ 5 days	 	Continue
                                         atezolizumab.

         

        Monitor
        LFTs more frequently until values resolve to baseline values.

	 	 	 	 	 
	 	 	Grade
    2 hepatic event, > 5 days	 	Hold
                                         atezolizumab.

         

        Initiate
        treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.

         

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks.

	 	 	 	 	 
	 	 	Grade
    3 or 4 hepatic event	 	Permanently
                                         discontinue atezolizumab.

         

        Consider
        patient referral to GI specialist for evaluation and liver biopsy to establish etiology of hepatic injury.

         

        Initiate
        treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.

         

        If
        event resolves to Grade 1 or better, taper corticosteroids over > 1 month. Continue atezolizumab.

	 	 	 	 	 
	Hyperglycemia	 	Grade
    1 or 2	 	Initiate
                                         treatment with insulin if needed.

         

        Monitor
        for glucose control.

	 	 	 	 	 
	 	 	Grade
    3 or 4	 	Hold
    atezolizumab.


 




    	 



    	Page 43 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	Initiate
                                         treatment with insulin.

                                                          

                                                         Monitor for glucose control.

         

        Resume
        atezolizumab when symptoms resolve and glucose levels are stable.

	 	 	 	 	 
	Hyperthyroidism	 	Grade
    1 (asymptomatic)	 	TSH
                                         > 0.1mU/L and <0.5mU/L: Continue atezolizumab. Monitor TSH every 4 weeks.

         

        TSH
        < 0.1mU/L: Follow guidelines for symptomatic hyperthyroidism.

	 	 	 	 	 
	 	 	Grade
    2+ (symptomatic)	 	Hold
                                         atezolizumab.

         

        Initiate
        treatment with anti-thyroid drug such as methimazole or carbimazole as needed.

         

        Consider
        patient referral to endocrinologist.

         

        Resume
        atezolizumab when symptoms are controlled and thyroid function is improving.

         

        Permanently
        discontinue atezolizumab for life-threatening immune-related hyperthyroidism.

	 	 	 	 	 
	Hypothyroidism	 	Grade
    1 (asymptomatic)	 	Continue
                                         atezolizumab.

         

        Start
        thyroid-replacement hormone. Monitor TSH weekly.

	 	 	 	 	 
	 	 	Grade
    2+	 	Hold
    atezolizumab.
	 	(symptomatic)	 	 
	 	 	 	Start
    thyroid-replacement hormone. Consider referral to an endocrinologist. 
	 	 	 	
	 	 	 	Monitor
    TSH weekly.


 




    	 



    	Page 44 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	Restart
    atezolizumab when symptoms are controlled and thyroid function is improving
	 	 	 	 	 
	Meningo-	 	All
    grades	 	Permanently
    discontinue atezolizumab. Patient may not resume
    treatment, regardless of benefit.
	encepahlitis,	 	 	 	
	immune-related	 	 	 	 
	(signs
    and	 	 	 	Refer
    patient to neurologist.
	symptoms
    in	 	 	 	 
	absence
    of an identified alternate etiology)	 	 	 	Initiate
    treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 1−2 mg/kg/day oral prednisone
    or equivalent upon improvement.
		 	 	 	 
	 	 	 	 	If
    event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.
	 	 	 	 	 
	 	 	 	 	If
    event does not improve within 48 hours after initiating corticosteroids,
    consider adding an immunosuppressive agent.
	 	 	 	 	 
	Myasthenia

                                                                                gravis and

                                                                                Guillain-Barré

                                                                                syndrome
	 	All
    grades	 	Permanently
        discontinue atezolizumab. Patient may not resume treatment, regardless of benefit.

         

        Refer
        patient to neurologist.

         

        Initiate
        treatment as per institutional guidelines.

         

        Consider
        initiation of 1−2 mg/kg/day oral or IV prednisone or equivalent.

	 	 	 	 	 
	Myocarditis	 	All
    grades	 	Permanently
    discontinue atezolizumab. Patient may not resume treatment, regardless of benefit.
	 	 	 	 	 
	Nephritis	 	Grade
    2	 	Withhold
                                         atezolizumab.

         

        Refer
        patient to renal specialist and consider renal biopsy and supportive measures as indicated. Corticosteroids and/or additional
        immunosuppressive agents should be administered

        as
        clinically indicated.



 




    	 



    	Page 45 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	If
    event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.
	 	 	 	 	 
	 	 	Grade
    3-4	 	Permanently
                                         discontinue atezolizumab.

         

        Refer
patient to renal specialist and consider renal biopsy and supportive measures as indicated. Corticosteroids and/or additional
immunosuppressive agents should be administered as clinically indicated.

	 	 	 	 	 
	Neuropathy,
                                         immune-related

         

        (sensory
        and/or motor)
	 	Grade
    1	 	Continue
                                         atezolizumab.

         

         

        Evaluate
        for alternative etiologies.

	 	 	Grade
    2	 	Hold
                                         atezolizumab.

         

        Evaluate
        for alternative etiologies.

         

        Initiate
        treatment as per institutional guidelines.

         

        Resume
        atezolizumab if event resolves to Grade 1 or better within 4 weeks.

	 	 	 	 	 
	 	 	Grade
    3 or 4	 	Permanently
                                         discontinue atezolizumab.

         

        Initiate
        treatment as per institutional guidelines.

	 	 	 	 	 
	Ocular
    event (e.g., uveitis, retinal events	 	Grade
    1	 	Continue
                                         atezolizumab.

         

        Patient
        referral to ophthalmologist is strongly recommended.

         

        Initiate
        treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.

         

        If
        symptoms persist, treat as a Grade 2 event.

	 	 	 	 	 
	 	 	Grade
    2	 	Withhold
    atezolizumab.


 




    	 



    	Page 46 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	 

        Patient
        referral to ophthalmologist is strongly recommended.

         

        Initiate
        treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.

         

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥1 month and resume atezolizumab.

        Permanently
        discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks.

	 	 	 	 	 
	 	 	Grade
    3 or 4	 	Permanently
                                         discontinue atezolizumab.

                                                          

                                                         Refer patient to ophthalmologist.

         

        Initiate
        treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. For Grade 3 AEs, patient may only resume
        treatment after consultation with the trial PI; for Grade 4, patient cannot resume treatment, regardless of benefit.

	 	 	 	 	 
	Pancreatitis,	 	Grade
    2 or 3	 	Hold
    atezolizumab.
	immune
    related	 	 	 	 
	 	 	 	 	Refer
    patient to GI specialist.
	 	 	 	 	 
	 	 	 	 	Initiate
    treatment with 1−2 mg/kg/day intravenous methylprednisolone
    or equivalent and convert to 1−2 mg/kg/day
    oral prednisone or equivalent upon improvement.
	 	 	 	 	
	 	 	 	 	If
    event resolves to Grade 1 or better within 4 weeks, taper corticosteroids
    over ≥ 1 month and resume atezolizumab.


 




    	 



    	Page 47 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	Permanently
                                         discontinue atezolizumab if event does not resolve to Grade 1 or better within 4 weeks.
                                         Patient may only resume treatment after consultation with the trial PI.

         

        For
        recurrent events, permanently discontinue atezolizumab. Patient may not resume treatment, regardless of benefit.

	 	 	 	 	 
	 	 	Grade
    4	 	Permanently
                                         discontinue atezolizumab. Patient may not resume treatment, regardless of benefit.

         

        Refer
        patient to GI specialist.

         

        Initiate
        treatment with 1−2 mg/kg/day intravenous methylprednisolone or equivalent and convert to 1−2 mg/kg/day oral
        prednisone or equivalent upon improvement.

         

        If
        event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.

         

        If
event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.

	 	 	 	 	 
	Pulmonary
    toxicity	 	All
    events	 	Evaluate
                                         thoroughly for other commonly reported etiologies such as pneumonia/infection, lymphangitic
                                         carcinomatosis, pulmonary embolism, heart failure, chronic obstructive

        pulmonary
        disease (COPD), or pulmonary hypertension.

	 	 	 	 	 
	 	 	Grade
    1	 	Continue
                                         atezolizumab and monitor closely.

                                                          

                                                         Re-evaluate on serial imaging.

         

        Consider
        patient referral to a pulmonary specialist.

         

        For
        recurrent pneumonitis, treat as a Grade 3 or 4 event.

	 	 	 	 	 
	 	 	Grade
    2	 	Hold
    atezolizumab.


 




    	 



    	Page 48 of 92



    

 


	Atezolizumab
    AE Management and Dose Interruption Guidelines for Specific Toxicities
	 
	Toxicity	 	Severity/
    Duration	 	Management
	 	 	 	 	Refer
                                         patient to pulmonary and infectious disease specialists and consider bronchoscopy or
                                         bronchoscopic alveolar lavage (BAL).

         

        Initiate
        treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event resolves to Grade 1 or better within 4 weeks, taper corticosteroids over ≥ 1 month and resume atezolizumab.

	 	 	 	 	 
	 	 	Grade
    3 or 4	 	Hold
                                         atezolizumab.

         

        Bronchoscopy
        or BAL is recommended.

         

        Initiate
        treatment with 1−2 mg/kg/day oral prednisone or equivalent.

         

        If
        event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.

         

        If
        event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. For Grade 3 AEs, patient may only resume
        treatment after consultation with the Principal Investigator; for Grade 4, patient cannot resume treatment, regardless
        of

        benefit.



 


6.3.1.1
Systemic Immune Activation


 


Systemic
immune activation is a rare condition characterized by an excessive immune response. Given the mechanism of action of atezolizumab,
systemic immune activation is considered a potential risk. Systemic immune activation should be included in the differential diagnosis
for patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome after administration of atezolizumab,
and the initial evaluation should include the following:


 


	 	●	CBC
    with peripheral smear
	 	 	 
	 	●	PT,
    PTT, fibrinogen, and D-dimer
	 	 	 
	 	●	Ferritin
	 	 	 
	 	●	Triglycerides


 




    	 



    	Page 49 of 92



    

 


	 	●	AST,
    ALT, and total bilirubin
	 	 	 
	 	●	LDH
	 	 	 
	 	●	Complete
    neurologic and abdominal examination (assess for hepatosplenomegaly)


 


6.4
LB-100 Dose Modifications



 


Two
dose reductions of LB-100 are allowed. Re-escalation is allowed once at the discretion of the investigator. Patients with a delay
of more than 21 days of LB-100 must be discontinued from study therapy. If grade 3/4 toxicity attributed to LB-100 occurs after
2 previous dose reductions, LB-100 will be discontinued. Patients who are benefiting from treatment may continue carboplatin/etoposide/atezolizumab.
Dose reductions of LB-100 are outlined in Table 6.4.0


 


Table
6.4.0 LB-100 Dose Levels


 


	Dose
    Level	 	LB-100
    Dose
	-2*	 	0.50
    mg/m2
	-1	 	0.83
    mg/m2
	1	 	1.25
    mg/m2
	2	 	1.75
	3	 	2.13
	4	 	3.10
	*for
    within patient dose de-escalation only


 


6.4.1
Hematologic Toxicity



 


Myelosuppression
may infrequently occur with LB-100. Therefore, if grade 3/4 myelosuppression occurs, for the first occurrence the doses of carboplatin
and etoposide will be reduced, but LB-100 will stay the same. For the second occurrence of Grade 3/4 myelosuppression LB-100 will
be reduced. Atezolizumab will be delayed or discontinued if autoimmune cyctopenias occur. There were no notable adverse events
reported in the Phase I trial and we do not expect dose reductions or interruptions.


 






    	 



    	Page 50 of 92



    

 


6.4.2
Non-hematologic Toxicity



 


The
non-hematologic toxicity attributed to LB-100 should be managed as outlined in Table 6.4.2.


 


Table
6.4.2 Dose adjustments of LB-100








 


	Toxicity	 	Management	 	Dose
    Reduction
	Injection
    Site Reaction, grade 3	 	1.)
                                         Interrupt LB-100

        2.)
        Administer topical treatment as necessary
	 	Reduce
    1 dose level
	 	 	 	 	 
	Grade
    2 Nephrotoxicity	 	1.)
                                         Interrupt LB-100

        2.)
        Reexamine patient at least weekly until toxicity improved to ≤ grade 1
	 	Prolong
    infusion time to 2 hours.
	 	 	 	 	 
	Grade
    3 or 4 Nephrotoxicity	 	1.)
                                         Interrupt LB-100

        2.)
        Reexamine patient at least weekly until toxicity improved to ≤ grade 1
	 	Reduce
    1 dose level and prolong infusion time to 2 hours.
	 	 	 	 	 
	Other
    Grade 2 clinically significant non-hematologic toxicity*	 	1.)
                                         Interrupt LB-100

        2.)
        Reexamine patient at least weekly until toxicity improved to ≤ grade 1
	 	First
                                         occurrence: Maintain Dose

        Second
        occurrence: Reduce 1 dose level

	 	 	 	 	 
	Other
    Grade 3-4 clinically significant non-hematologic toxicity*	 	1.)
                                         Interrupt LB-100

        2.)
        Reexamine patient at least weekly until toxicity improved to ≤ grade 1
	 	Reduce
    1 dose level
	 	 	 	 	 
	Any
    toxicity requiring a hold of atezolizumab	 	1.)
                                         Interrupt LB-100

        2.)
        Reexamine patient at least weekly until atezolizumab can be restarted
	 	Maintain
    dose level.


 


*Alopecia,
and clinically insignificant lab abnormalities are examples of things that would not be considered clinically significant


 


6.5
Pharmacokinetic Studies


 


6.5.1
Pharmacokinetic Sampling


 



Plasma
for pharmacokinetic (PK) measurements of LB-100, and its major metabolite endothall will be collected in all patients according
the sample schedule shown in Table 6.5.1. The sampling schedule allows for determination of LB-100 and endothall PK when LB-100
is given prior to etoposide (Day 1) and when it is given together with etoposide (Day 3). Etoposide PK will also be assessed in
patients in the expanded MTD cohort both alone (Day 2) and in combination with LB-100 (Day 3). For measurement of LB-100 and endothall,
5 mL of venous blood will be drawn into a chilled heparin collection tube (sodium or lithium)and kept on ice until the plasma
is separated. Plasma will be aliquoted (two aliquots) into appropriately labeled polypropylene tubes (1.8-2 mL cryovials) containing
0.5N NaOH. For every 1.0 mL of plasma aliquoted 0.1 mL of 0.5N NaOH is to be added. Samples will be stored at -70° C until
the time of shipment. For measurement of etoposide, an additional 4 mL of venous blood will be drawn into EDTA-containing collection
tubes at the times indicated in Table 6.5.1. Tubes will be kept on ice until plasma is separated and aliquoted into appropriately
labeled cryovials and stored at < -70°C for subsequent batch analysis.


 


Procedures
for the processing, storage, and shipment of the samples are located in the Laboratory Manual.


 




    	 



    	Page 51 of 92



    

 


(ii)
Table 6.5.1: Pharmacokinetic Sample Schedule


 


	 

        Study
        Day
	 	 

        Draw
        Time
	 	One
                                         (1) 5 mL heparin tube for LB-100

        and
        endothall
	 	One
                                         (1) 4 mL EDTA

        tube
        for etoposide*

	Day
    1	 	pre-dose	 	X	 	 
	 	 	immediately
    at end of LB-100 infusion	 	X	 	 
	 	 	15
    minutes (± 5 minutes) post LB-100 infusion	 	X	 	 
	 	 	30
    minutes (± 5 minutes) post LB-100 infusion	 	X	 	 
	 	 	1
    hour (± 15 minutes) post LB-100 infusion	 	X	 	 
	 	 	2
    hours (± 15 minutes) post LB-100 infusion	 	X	 	 
	 	 	4
    hours (± 30 minutes) post LB-100 infusion and prior to etoposide.	 	X	 	 
	Day
    2	 	Pre-treatment
    (24 hours (± 60 minutes) post LB-100 infusion on day 1)	 	X	 	X*
	 	 	immediately
    prior to the end of etoposide infusion	 	 	 	X*
	 	 	2
    hours (± 30 minutes) post etoposide infusion	 	 	 	X*
	 	 	6
    hours (± 30 minutes) post etoposide infusion	 	 	 	X*
	Day
    3	 	Pre-treatment
    [48 hours (± 60 minutes) post LB-100 infusion on day 1 and 24 hours (± 60 minutes) etoposide infusion on day
    2]	 	X	 	X*
	 	 	immediately
    at end of LB-100 infusion	 	X	 	 
	 	 	15
    minutes (± 5 minutes) post LB-100 infusion	 	X	 	 
	 	 	30
    minutes (± 5 minutes) post LB-100 infusion	 	X	 	 


 




    	 



    	Page 52 of 92



    

 


	 	 	1
    hour (± 15 minutes) post LB-100 and pre etoposide	 	X	 	X*
	 	 	2
    hours (± 15 minutes) post LB-100 and immediately prior to end of etoposide infusion	 	X	 	X*
	 	 	3
    hours (± 30 minutes) post LB-100 and 1 hours (± 30 minutes) post etoposide	 	X	 	 
	 	 	4
    hours (± 30 minutes) post LB-100 and 2 hours (± 30 minutes) post etoposide	 	X	 	X*
	 	 	8
    hours (± 30 minutes) post LB-100 and 6 hours (± 30 minutes) post etoposide	 	X	 	X*
	Day
    4	 	Post-treatment
    [24 hours (± 60 minutes) post LB-100 and 22 hours (± 60 minutes) post etoposide on day 3]	 	X	 	X*


 


*Samples
for etoposide PK will be collected only in patients enrolled in the expanded MTD cohort.


 


6.5.2
Pharmacokinetic Data Analysis



 


Plasma
PK data will be analyzed using both non-compartmental and compartmental methods to derive the relevant secondary PK parameters.
Non-compartmental PK methods will be used to determine the parameters (e.g. Cmax, Tmax t1/2, AUC0-t, and CL) for LB-100 and its
major metabolite endothall. Compartmental PK analyses of the etoposide data will be performed using ADAPT 5 software (USC Biomedical
Simulations Resource, Los Angeles CA), and secondary PK parameters (e.g. CLsys, Vd, t1/2, AUC0-∞) will be determined for
each individual. Individual non-compartmental and compartmental PK parameters for each drug and metabolite will be summarized,
and potential exposure-response relationships for both safety and efficacy will be assessed.


 


	 	7.0	Unanticipated Problems
and Adverse Event Reporting
	 	 	 
	 	7.1	Definitions




 


	 	7.1.1	Adverse
    Event


 


An
adverse event is any untoward medical experience or change of an existing condition that occurs during or after treatment, whether
or not it is considered to be related to the protocol intervention.


 




    	 



    	Page 53 of 92



    

 


	 	7.1.2	Serious
    Adverse Event (SAE)


 


A
serious adverse event is any expected or unexpected adverse events that result in any of the following outcomes:


 


	 	●	Death
	 	 	 
	 	●	Is
    life-threatening experience (places the subject at immediate risk of death from the event as it occurred)
	 	 	 
	 	●	Unplanned
    hospitalization (equal to or greater than 24 hours) or prolongation of existing hospitalization
	 	 	 
	 	●	A
    persistent or significant disability/incapacity
	 	 	 
	 	●	A
    congenital anomaly/birth defect
	 	 	 
	 	●	Secondary
    malignancy*
	 	 	 
	 	●	Any
    other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s health and may require
    medical or surgical intervention to prevent one of the outcomes listed above (examples of such events include allergic bronchospasm
    requiring intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that do not result in inpatient
    hospitalization, or the development of drug dependency or drug abuse).


 


*Modified
from 21 CFR 312.32


 


	 	7.1.3	Unanticipated
    Problems Involving Risks to Subjects or Others


 


An
unanticipated problem is any incident, experience, or outcome that meets all three of the following criteria:


 


	 	1.	Unexpected
    (in terms of nature, severity, or frequency) given the following: a) the research procedures described in the protocol-related
    documents such as the IRB approved research protocol, informed consent document or Investigator Brochure (IB); and b) the
    characteristics of the subject population being studied; AND
	 	 	 
	 	2.	Related
    or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident,
    experience, or outcomes may have been caused by the drugs, devices or procedures involved in the research); AND
	 	 	 
	 	3.	Suggests
    that the research places subjects or others at greater risk of harm (including physical, psychological, economic, or social
    harm) than previously known or recognized.


 


	 	7.1.4	Adverse
    Events of Special Interest (AESI)


 


Specific
adverse events, or groups of adverse events, will be followed as part of standard safety monitoring activities. These events,
regardless of seriousness, will be reported.


 




    	 



    	Page 54 of 92



    

 


	 	7.1.4.1	Study
    specific AESIs


 


Currently,
there are no specific adverse events for this study.


 


	 	7.1.5	Pregnancy


 


Any
pregnancy diagnosed during the study, or that occurs within 30 days after stopping study medication, must be reported immediately
to the Investigator. Pregnancy, in and of itself, is not regarded as an adverse event, unless there is a suspicion that study
medication may have interfered with the effectiveness of a contraceptive medication. If the patient becomes pregnant while on-study,
the study drug should be immediately discontinued. Pregnancy information about a female patient or female partner of a male patient
should be reported immediately from the time the Investigator first becomes aware of a pregnancy or its outcome.


 


Any
pregnancy complication, spontaneous abortion, elective termination of a pregnancy for medical reasons, the outcome of stillbirth,
congenital anomaly/birth defect, or serious adverse event in the mother will be recorded as an SAE and will be reported as described
in Section 7.3.


 


7.2
Assessment of Adverse Events


 


The
site Investigator will be responsible for determining the event name, assessing the severity (i.e. grade), expectedness, and attribution
of all adverse events.


 


	 	7.2.1	Assessment
    of Adverse Event Name and Grade


 


Adverse
events will be characterized using the descriptions and grading scales found in the most recent version of CTCAE version 5.0.
A copy of the scale can be found at https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. The determination
of severity for all other events not listed in the CTCAE version 5.0. should be made by the investigator based on medical judgment
and the severity categories of Grade 1 to 5 as defined below:


 


	 	●	Grade
    1 (mild) – An event that is usually transient and may require only minimal treatment or therapeutic intervention. The
    event does not generally interfere with usual activities of daily living.
	 	 	 
	 	●	Grade
    2 (moderate) – An event that is usually alleviated with additional specific therapeutic intervention. The event interferes
    with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the subject.
	 	 	 
	 	●	Grade
    3 (severe) – An event that requires intensive therapeutic intervention. The event interrupts usual activities of daily
    living, or significantly affects the clinical status of the subject.
	 	 	 
	 	●	Grade
    4 (life threatening) – An event, and/or its immediate sequelae, that is associated with an imminent risk of death or
    with physical or mental disabilities that affect or limit the ability of the subject to perform activities of daily living
    (eating, ambulation, toileting, etc.).
	 	 	 
	 	●	Grade
    5 (fatal) – Death (loss of life) as a result of an event.


 




    	 



    	Page 55 of 92



    

 


	 	7.2.2	Assessment
    of Attribution


 


The
following definitions will be used to determine the causality (attribution) of the event to the study agent or study procedure.


 


	 	●	Unrelated
    – The event is clearly related to other factors such as the participant’s clinical state, other therapeutic
    interventions, or concomitant medications administered to the participant.
	 	 	 
	 	●	Unlikely
    – The event is doubtfully related to the investigational agent(s). The event was most likely related to other factors
    such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.
	 	 	 
	 	●	Possible
    – The event follows a reasonable temporal sequence from the time of drug administration, but could have been produced
    by other factors such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.
	 	 	 
	 	●	Probable
    – The event follows a reasonable temporal sequence from the time of drug administration, and follows a known response
    pattern to the study drug. The event cannot be reasonably explained by other factors such as the participant’s clinical
    state, therapeutic interventions, or concomitant drugs.
	 	 	 
	 	●	Definite
    – The event follows a reasonable temporal sequence from the time of drug administration, follows a known response
    pattern to the study drug, cannot be reasonably explained by other factors such as the participant’s condition, therapeutic
    interventions, or concomitant drugs, AND occurs immediately following study drug administration, improves upon stopping the
    drug, or reappears on re-exposure.


 


	 	7.2.3	Assessment
    of Expectedness


 


The
following definitions will be used to determine the expectedness of the event:


 


	 	●	Unexpected
    – An adverse event is unexpected if it is not listed in the investigator’s brochure and/or package insert;
    is not listed at the specificity or severity that has been observed; is not consistent with the risk information described
    in the protocol and/or consent; is not an expected natural progression of any underlying disease, disorder, condition, or
    predisposed risk factor of the research participant experiencing the adverse event. *Modified from 21 CFR 312.32 (a)
	 	 	 
	 	●	Expected
    – An adverse event is expected if it does not meet the criteria for an unexpected event, OR is an expected natural
    progression of any underlying disease, disorder, condition, or predisposed risk factor of the research participant experiencing
    the adverse event.


 


	 	7.3	Reporting
    of Adverse Events


 


	 	7.3.1	Routine
    Reporting of Non-Serious Adverse Events


 


Routine
AE recording will occur via data entry into the study eCRF. Recording of adverse events will begin once the patient is consented
and will continue until 30 days after last study drug. Adverse events will be monitored by the Protocol Management Team (PMT).
Adverse events that do not meet the criteria of serious OR are not unanticipated problems do not require expedited reporting.
AEs reported through expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be reported in routine study data
submissions.


 




    	 



    	Page 56 of 92



    

 


	 	7.3.2	Expediting
    Reporting Requirements of SAEs and UPs


 


Adverse
events that meet the criteria of serious OR are unanticipated problems will be reported according to the approved City of Hope’s
Institutional policy via the AE/UP reporting form in iRIS. Reportable serious adverse events must be followed until
the event is resolved, stabilized, or determined to be irreversible by the investigator. Follow-up SAE reports must be submitted
for all events that require expedited reporting when the status of the event changes and until the resolution or stabilization
of the event.


 


	 	7.3.3	Additional
    AE Reporting Requirements


 


	 	7.3.3.1	Reporting
    to the FDA


 


The
study PI (or designee) will be responsible for contacting the Office of IND Development and Regulatory Affairs (OIDRA) at COH
to ensure prompt reporting of safety reports to the FDA. OIDRA will assist the PI with the preparation of the report and submit
the report to the FDA in accordance with the approved City of Hope’s Institutional policy. (Appendix D).


 


Serious
Adverse Events meeting the requirements for expedited reporting to the Food and Drug Administration (FDA), as defined in 21
CFR 312.32, will be reported as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting.


 


The
criteria that require reporting using the MedWatch 3500A are:


 


	 	●	Any
    unexpected fatal or life threatening adverse experience associated with use of the drug must be reported to the FDA no later
    than 7 calendar days after initial receipt of the information [21 CFR 312.32 (c) (2)]
	 	●	Any
    adverse experience associated with use of the drug that is both serious and unexpected must be submitted no later than 15
    calendar days after initial receipt of the information [21 CFR 312.32 (c) (1)]
	 	●	Any
    follow-up information to a study report shall be reported as soon as the relevant information becomes available. [21 CFR
    312.32 (d) (3)]


 


In
addition, the study PI will submit annually within 60 days (via COH OIDRA) of the anniversary date of when the IND went into effect,
an annual report to the FDA which is to include a narrative summary and analysis of the information of all FDA reports within
the reporting interval, a summary report of adverse drug experiences, and history of actions taken since the last report because
of adverse drug experiences.


 


	 	7.3.3.2	Reporting
    to Lixte Biotechnology


 


All
serious adverse events, AESIs (initial and follow-up information) and pregnancies will be reported by the study PI to Lixte Biotechnology
(via Theradex Oncology) within 24 hours of becoming aware of the event.


 


	 	Theradex
    Safety Desk 
	 	Telephone:
    (609) 799-7580
	 	 
	 	Fax:
    (609) 799-1567
	 	 
	 	Email:
    SafetyDeskUS@Theradex.com


 




    	 



    	Page 57 of 92



    

 


	V.	8.0 Agent Information
and Risks






 





(i) 8.1
LB-100


 


8.1.1
Description



 


LB-100
has been shown in a Phase I clinical trial of solid tumors that it can be well tolerated at doses associated with partial response
and stable disease in patients who had failed multiple treatment regimens (Chung 2016). This and other preclinical studies have
shown that LB-100 has efficacy alone and in combination with standard cytotoxic chemotherapy and/or radiation without enhancing
toxicity.


 


Chemistry:
LB-100 (3-[(4-Methylpiperazin-1-yl)carbonyl]-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid], NSC D753810 is a water-soluble small
molecule inhibitor of PP2A.


 


Mechanism
of Action: LB-100 inhibits PP2A which leads to hyperactivation of Ras signaling and the stabilization of c-Myc during the
G2 phase that eventually drives cells into mitosis through the accumulation of cyclin E: Cdk1 complexes.


 


Human
Toxicology: As of April 2020, 29 people have received LB-100. The following side effects have been seen: >25% of patients:
Fatigue. > 10% but < 25% of patients: Aspartate aminotransferase increased, Blood creatinine increased, Headache,
Hypernatraemia, Hypoalbuminaemia, Nausea, Proteinuria, Pyrexia. <10% of patients: Abdominal discomfort, Abdominal distension,
Accelerated hypertension, Alanine aminotransferase increased, Anaemia, Arthralgia, Blood alkaline phosphatase increased, Blood
urea increased, Candidiasis, Chest pain, Chills, Constipation, Creatinine renal clearance, Decreased appetite, Dermatitis acneiform,
Diarrhoea, Dizziness, Dyspnoea, Ejection fraction decreased, Electrocardiogram qt prolonged, Gait disturbance, Gastrointestinal
disorder, Generalised oedema, Gingival pain, Hypercalcaemia, Hyperkalaemia, Hypertension, Hypoaesthesia, Hypokinesia, Hyponatraemia,
Hypotension, Hypoxia, Insomnia, Lymphocyte count decreased, Mucosal inflammation, Muscle twitching, Muscular weakness, Neuropathy
peripheral, Neutropenia, Oedema, Oedema peripheral, Pain of skin, Peripheral coldness, Peripheral sensory neuropathy, Platelet
count decreased, Pleural effusion, Sinus tachycardia, Tachypnoea, Tremor, Vomiting, Weight decreased.


 


	 	8.1.2	Pharmacology
    – Handling, Storage, Dispensing and Disposal


 


LB-100
will be supplied as a sterile solution for intravenous administration. LB-100 is to be stored at -20C (allowable range -25C to
-10C). Each vial contains 10 mL of LB-100 at a concentration of 1 mg/ml. The proper dose is drawn up in a sterile syringe and
added to 50 mL of normal saline (0.9%). Following dilution in normal saline, LB-100 should be administered within 4 hours. On
Days 1 and 3 of each cycle, LB-100 will be infused over 15 minutes ± 5 minutes.


 


8.2
Carboplatin


 


	 	8.2.1	Description


 


Carboplatin
is an analog of cisplatin that has a more favorable toxicity profile (Ruckdeschel 1994). It interacts with DNA and forms both
intra- and interstrand links. The most commonly observed side effects include thrombocytopenia, neutropenia, leukopenia, and anemia.
Like other platinum-containing compounds, carboplatin may induce anaphylactic-type reactions such as facial edema, wheezing, tachycardia,
and hypotension that may occur within a few minutes of drug administration. These reactions may be controlled with adrenaline,
corticosteroids, or antihistamines.


 




    	 



    	Page 58 of 92



    

 


Chemistry:
Carboplatin (carboplatin for injection or platinum diamine [1,1-cyclobutane-decarbozxylate (2—0,0’)-,(SP-4-2)]
is a platinum compound used as a chemotherapeutic agent.


 


Mechanism
of Action: Carboplatin undergoes activation inside cells and forms reactive platinum complexes that cause the intra- and inter-strand
cross-linkage of DNA molecules within the cell. This modifies the DNA structure and inhibits DNA synthesis. This may affect a
cell in all the phases of its cycle.


 


	 	8.2.2	Toxicology


 


Side
effects of carboplatin (CBDCA) include myelosuppression, nausea, vomiting, abdominal pain, diarrhea, and constipation. Other toxicities
include allergic reaction (including hypersensitivity, i.e., rash, urticaria, erythema, pruritus, bronchospasm and hypotension),
peripheral neuropathy, paresthesia, loss of hair, hearing loss, visual disturbances, and change in taste. Serum creatinine elevations
and blood urea elevations have occurred as well as abnormal liver function tests and decreased serum electrolyte values. Although
rare, pain, asthenia, cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred in some patients. Cancer-associated
hemolytic uremic syndrome has been reported rarely. The renal effects of nephrotoxic compounds may be potentiated by carboplatin.
Carboplatin is contraindicated in patients with a history of severe allergic reactions to cisplatin or other platinum containing
compounds or mannitol. This drug should not be used in patients with severe bone marrow depression or significant bleeding. The
occurrence of acute leukemia has been reported rarely in patients treated with anthracycline/alkylator combination chemotherapy.


 


Pregnancy
and Lactation: Carboplatin may cause fetal harm; therefore, women of childbearing potential should be advised to avoid becoming
pregnant.


 


	 	8.2.3	Pharmacology
    – Handling, Storage, Dispensing and Disposal


 


Carboplatin
is commercially available and will not be provided by the study sponsor. Carboplatin should be stored at room temperature (15C
to 25C) and protected from light. Once diluted, it should be stored at room temperature or refrigerated. Since no antibacterial
preservatives are contained in the formulation, it is recommended that any carboplatin solution be discarded after 8 hours from
the time of dilution if stored at room temperature or after 24 hours if stored under refrigeration.


 


8.3
VP-16 (Etoposide)


 


	 	8.3.1	Description


 


Etoposide
is a semisynthetic derivative of podophyllotoxin that exhibits cytostatic activity in vitro by preventing cells from entering
mitosis or by destroying them at a premitotic stage. Etoposide interferes with the synthesis of DNA and appears to arrest human
lymphoblastic cells in the late S-G2 phases of the cell cycle. The most commonly observed side effects include leukopenia and
thrombocytopenia. Etoposide is indicated in combination with other antineoplastics in the treatment of SCLC, NSCLC, malignant
lymphoma, and testicular malignancies (approved indications may vary depending on the specific country). Etoposide is also used
in clinical studies against many other types of cancer including head and neck, brain, bladder, cervical, and ovarian.


 


Chemistry:
VP-16 is a semi-synthetic podophyllotoxin derivative from the plant podophyllum pletatum, and has antineoplastic properties
in experimental animals and in man. The empiric formula C29H32O13 has a molecular weight of 588.


 


Mechanism
of Action: The epipodophyllotoxins exert phase specific spindle poison activity with metaphase arrest, but in contrast to
the vinca-alkaloids, have an additional activity of inhibiting cells from entering mitosis. Suppression of tritiated thymidine,
uridine, and leucine incorporation in human cells in tissue culture suggests effects against DNA, RNA, and protein synthesis.


 




    	 



    	Page 59 of 92



    

 


	 	8.3.2	Toxicology


 


Animal
Toxicology: The predominant toxicities of VP-16 in animal studies involve the hematopoietic system, with toxicity to the liver
and GI tract occurring only at doses producing profound myelosuppression. Anemia, leukopenia and lymphoid involution occur in
mice, rats and monkeys. Acute toxicity investigations have been complicated by the toxicity of the solvent system. The LD-50 of
the solvent plus drug approached that of the solvent alone.


 


Immunosuppressive
effects occur within an inhibition of antibody production in mice and monkeys, and prevention of experimental allergic encephalomyelitis
in rats (cell-mediated immunity).


 


Human
Toxicology: Reversible myelotoxicity has been uniformly observed to be the major toxicity of VP- 16 and to represent the only
clinically significant side effect. Following a single IV injection, peak myelotoxicity occurs at seven to nine days. Following
daily IV injections for five to seven days, myelotoxicity is maximal between 12-16 days from the initiation of therapy. Bone marrow
suppression is mainly manifested as granulocytopenia, with thrombocytopenia and anemia occurring to a lesser extent. Gastrointestinal
toxicities including transient modest nausea, vomiting, and diarrhea are common. Other reactions could include aftertaste, rash,
pigmentation, pruritus, abdominal pain, constipation, and dysphagia. Occasional alopecia is reported. VP-16 does not produce phlebitis,
or nephrotoxicity. Rarely, anaphylactic-like reactions have been reported, as well as, hypotension. Hypotension can be managed
by infusing the drug over at least a 30-minute period. Occasionally, chills, fever, peripheral neurotoxicity, stomatitis, hepatotoxicity,
transient cortical blindness and radiation recall dermatitis may be a result of VP- 16 administration. The occurrence of acute
leukemia has been reported rarely in patients treated with VP- 16 in association with other antineoplastic agents. VP-16 can cause
fetal harm when administered to pregnant women.


 


Pregnancy
and Lactation: Etoposide can cause fetal harm when administered to a pregnant woman. Etoposide has been shown to be teratogenic
in mice and rats. In these studies, etoposide caused dose-related material toxicity, embryotoxicity and teratogenicity. Fetal
abnormalities included decrease weight, major skeletal abnormalities, exencephaly, encephalocele, anophthalmia, and retarded ossification.
No information is available on excretion of this drug in human milk. Because many drugs are excreted in human milk and because
of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued.


 


	 	8.3.3	Pharmacology
    – Handling, Storage, Dispensing and Disposal.


 


Etoposide
is commercially available and will not be provided by the study sponsor. Etoposide should be stored at room temperature (15C to
25C) and protected from light. It should not be administered by intravenous push. Sites must not store any unused portion of a
vial for future use and must discard unused portions of product. Follow reconstitution and dilution instructions in the package
insert.


 




    	 



    	Page 60 of 92



    

 


8.4
Atezolizumab



 


	 	8.4.1	Description


 


Atezolizumab
is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that binds to and blocks programmed death-ligand
1 (PD-L1) approved for certain types of urothelial cancer and non-small cell lung cancer (NSCLC). It is indicated for the treatment
of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy,
or who are ineligible for cisplatin and have high tumor expression of PD-L1, or who are ineligible for other platinum-containing
chemotherapy regardless of tumor PD-L1 expression; it is also indicated for the treatment of metastatic NSCLC. In an ongoing multicenter,
randomized trial in previously untreated patients with metastatic urothelial carcinoma who are eligible for platinum-containing
chemotherapy (IMvigor130), patients with PD-L1 expression of less than 5% had decreased survival with atezolizumab monotherapy
compared to those who received platinum-based chemotherapy; the monotherapy arm of this trial was closed to accrual for patients
with low PD-L1 expression upon the recommendation of the independent Data Monitoring Committee. Treatment with atezolizumab may
result in severe immune-related adverse reactions requiring interruption or discontinuation of therapy, as well as treatment
with high-dose corticosteroids. Infusion-related reactions may also occur.


 


Chemistry:
Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that inhibits programmed death ligand
1 (PD-L1) interactions with the PD-1 and B7.1 receptors.


 


Mechanism
of Action: Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa monoclonal antibody that inhibits programmed
death ligand 1 (PD-L1) interactions with the PD-1 and B7.1 receptors. PD-L1 may be expressed on tumor cells and/or tumor-infiltrating
immune cells, and can contribute to inhibition of the anti-tumor immune response in the tumor microenvironment; PD-1 and B7.1
receptors are found on T-cells and antigen-presenting cells. The PD-1 pathway regulates the balance between T-cell activation
and protection of healthy tissues from immune-mediated damage. In cancer, the PD-1 pathway is thought to play an important role
in the interaction of tumor cells with the host immune response. Binding of PD-L1 to the PD-1 and B7.1 receptors suppresses cytotoxic
T-cell activity, T-cell proliferation, and cytokine production; PD-L1 expression in a tumor cell may provide adaptive immune resistance
and lead to poor outcomes. Atezolizumab binds to PD-L1 and prevents its interaction with both PD-1 and B7.1 receptors, releasing
the PD-L1/PD-1 mediated inhibition of an anti-tumor immune response without inducing antibody-dependent cellular cytotoxicity.
In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.


 


	 	8.4.2	Toxicology


 


Animal
Toxicology: In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections 404 and enhanced
inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit 405 markedly decreased survival compared with wild-type
controls, which correlated with increased 406 bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1
knockout 407 mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following 408 infection with lymphocytic
choriomeningitis virus.


 


Human
Toxicology:


 


Urothelial
Carcinoma: Atezolizumab was investigated in Study 1, a multicenter, open-label, two-cohort trial that included patients with locally
advanced or metastatic urothelial carcinoma. In Cohort 2 of Study 1, 310 patients with locally advanced or metastatic urothelial
carcinoma who had disease progression during or following a platinum-containing chemotherapy regimen or who had disease progression
within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen were treated with atezolizumab.
This study excluded patients who had: a history of autoimmune disease, active or corticosteroid-dependent brain metastases, administration
of a live, attenuated vaccine within 28 days prior to enrollment, or administration of systemic immunostimulatory agents or systemic
immunosuppressive medications. Patients received an intravenous infusion of 1200 mg of atezolizumab every 3 weeks until unacceptable
toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 9 weeks for the first
54 weeks and every 12 weeks thereafter. Major efficacy outcome measures included confirmed objective response rate (ORR) as assessed
by independent review facility (IRF) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response
(DoR).


 




    	 



    	Page 61 of 92



    

 


In
this cohort, the median age was 66 years, 78% were male, 91% patients were Caucasian. Twenty-six percent had non-bladder urothelial
carcinoma and 78% of patients had visceral metastases. Sixty-two percent of patients had an ECOG score of 1 and 35% of patients
had a baseline creatinine clearance of <60 mL/min. Nineteen percent of patients had disease progression following prior platinum-containing
neoadjuvant or adjuvant chemotherapy. Forty-one percent of patients had received ≥ 2 prior systemic regimens in the metastatic
setting. Seventy-three percent of patients received prior cisplatin, 26% had prior carboplatin, and 1% were treated with other
platinum-based regimens.


 


Tumor
specimens were evaluated prospectively using the Ventana PD-L1 (SP142) Assay at a central laboratory, and the results were used
to define subgroups for pre-specified analysis. Of the 310 patients, 32% were classified as having PD-L1 expression of ≥ 5%
(defined as PD-L1 stained tumor-infiltrating immune cells [ICs] covering ≥ 5% of the tumor area). The remaining, 68% of patients,
were classified as having PD-L1 expression of <5% (PD-L1 stained tumor-infiltrating ICs covering <5% of the tumor area).


 


Confirmed
ORR in all patients and the two PD-L1 subgroups are summarized in Table 8.4.2 below. The median follow-up time for this cohort
was 14.4 months. In 59 patients with disease progression following neoadjuvant or adjuvant therapy, the ORR was 22.0% (95% CI:
12.3, 34.7%).


 


Table
8.4.2 Overall Response by PD-L1 Expression


 


	 	All
    Patients	 	PD-L1
    Expression Subgroups
	 	N=310	 	PD-L1
                                         expression of

                                                                     <5% in ICs1 (N=210)
	 	PD-L1
expression of

                                                                     ≥5%
                                         in ICs1 (N=100)

	Number
    of IRF- assessed Confirmed Responders	46	 	20	 	26
	ORR
    % (95% CI)	14.8%
    (11.1, 19.3)	 	9.5%
    (5.9, 14.3)	 	26.0%
    (17.7, 35.7)
	Complete
    Response (CR) (%)	5.5%	 	2.4%	 	12.0%
	Partial
    Response (PR) (%)	9.4%	 	7.1%	 	14.0%
	Median
    DoR, months (range)	NR
    (2.1+, 13.8+)	 	12.7
    (2.1+, 12.7)	 	NR
    (4.2, 13.8+)
	NR
                                         = Not reached

        +
        Denotes a censored value

        1
        PD-L1 expression in tumor-infiltrating immune cells (ICs)



 




    	 



    	Page 62 of 92



    

 


	 	8.4.3	Pharmacology
    – Handling, Storage, Dispensing and Disposal


 


Atezolizumab
is commercially available and will not be provided by the study sponsor. Atezolizumab is a sterile, preservative-free, and colorless
to slightly yellow solution for intravenous injection supplied as a carton containing one 1200 mg/20 mL single-dose vial (NDC
50242-917-01). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from
light. Do not freeze. Do not shake.


 


9.0
Correlative/Special Studies


 


The
main objectives of the monitoring will be to characterize changes in T cell subsets, monocytes, and other immune cell subsets
that can be correlated with the clinical outcome. We will analyze by both single cell RNA sequencing (scRNAseq), with validation
of immune cell classification on a subset of samples using multicolor flow cytometry. These studies will measure the following:


 


	 	1.	The
    relative abundance of immune cell populations before, during and after treatment.
	 	 	 
	 	2.	The
    signaling states that evolve in immune cells during treatment and that differentiate responders from non-responders.


 


We
expect to see differences in abundance effector memory T cell populations and classical monocytes before and during treatment.
We also expect the pathway analysis using the scRNAseq data to identify those signaling changes that occur during treatment and
that distinguish responsive patients. Samples collected in this clinical trial will allow to determine more precisely at what
time point the immunological effects are the most significant.


 


	 	1.	Peripheral
    blood collected at baseline (screening) and pre-treatment of Cycles 1, 4, 7, 10 and EOT.
	 	 	 
	 	2.	Samples
    will be collected in 10 ml BD Vacutainer CPT tubes.
	 	 	 
	 	3.	Sample
    Processing:


 


CPT
tubes will be processed using the following method: Following collection, samples can be stored in an upright position for up
two hours at room temperature. Remix the blood samples immediately following collection and prior to centrifugation by gently
inverting the tubes 8-10 times. Centrifuge samples at room temperature in a horizontal rotor (swing-out head) at 820g for 10 min
at room temperature, with the centrifuge brake off.


 


For
plasma: Transfer 1mL aliquots of the plasma to sterile 2mL microtubes. Take care to avoid any buffy coat layer in this step.
Label each aliquot by the order in which it was isolated, 1 thru n for n aliquots. Centrifuge plasma aliquots in a bench top centrifuge
at 16,000-20,000g (maximum speed) for 10 min to pellet any remaining cellular debris. Carefully transfer 1ml aliquots of supernatant
from plasma to sterile 2 mL screw-capped microtubes. Freeze plasma aliquots at -80 °C or LN2 freezer.


 


For
PBMC/buffy coat: Centrifuge 15 min at 300 RCF. Aspirate as much supernatant as possible without disturbing the cell pellet.
Resuspend cell pellet by gently tapping the tube with index finger. Add 10 ml of PBS. Cap tubes and mix cells by inverting tube
5 times. Centrifuge 10 minutes at 300 RCF. Aspirate as much supernatant as possible without disturbing cell pellet. Resuspend
cell pellet by gently tapping the tube with index finger. Add 2 ml of Recovery Cell Culture freezing Medium (Life Technology)
or 10% DMSO, 40% FBS and 50% RPMI. Transfer cells with a Pasteur pipette to a 1.5ml cryotube. Add 2-propanol at RT into Nalgene
Cryofreezing Container. Place the cryovials into the container. Put the freezing container into -80°C freezer for a minimum
of 12 hours.


 


During
the freezing time avoid opening the freezer in order to avoid shaking the cryovials or raising the freezer’s temperature.
If Nalgene Cryofreezing containers are not available, place the cryovials in a Styrofoam tube container (they are supplied with
the 15ml conical tubes) to reduce direct contact with cold surfaces and to slow the rate of freezing. Put the freezing container
into -80°C freezer for a minimum of 12 hours. During the freezing time avoid opening the freezer in order to avoid shaking
the cryovials or raising the freezer’s temperature.


 


All
samples will be sent to the Viable Cell Biorepository.


 




    	 



    	Page 63 of 92



    

 


	VI.	10.0 Study
    Calendar  








 


	 

        Induction=4
        cycles
	w/in

        #
        days of start
	One
    Cycle=21 Days	 
	 

        Pre-Study
	Days
1& 3,Week 1
	Day
                                         1,

        Week
        2
	Day
                                         1,

        Week
        3
	Off
    Study	Follow-
    up
	LB-100,
    Atezolizumab, Carboplatin, Etoposide (Induction Cycles 1-4)	 	 	X
    see section 5.1	 	 	 	 
	LB-100,
    Atezolizumab, (Maintenance Cycle 5 and beyond)	 	 	X
    see section 5.1	 	 	 	 
	Informed
    consent	 	X	 	 	 	 	 
	Demographics	 	X	 	 	 	 	 
	Medical
    history	 	X	 	 	 	 	 
	Concurrent
    meds	14	X	 	 	 	 	 
	Physical
    exam	14	X	Day
    1 only	 	 	X	X6
	Vital
    sign, Weight	14	X	Day
    1 only	 	 	X	X6
	Height	 	X	 	 	 	 	 
	Performance
    Status	14	X	Day
    1 only	 	 	X	X6
	CBC
    w/diff, plts	14	X	Day
    1 only	X	X	X	X6
	Serum
    chemistry	14	X	Day
    1 only	X	X	X	X6
	Urinalysis	14	X	Day
    1 only	X	X	 	 
	TSH,
    free T3, free T4	14	X	Day
    1 only	 	 	 	 
	EKG
    (triplicate) 8	14	X	Cycles
    1&2 only7	X8	X8	X	 
	Adverse
    event evaluation	 	 	——————X——————	 
	Tumor
    measurements (RECIST)1,2	28	X	Measurements
    repeated every 6-8 weeks (± 7 days)1	X5
	Radiologic
    evaluation	28	X	Should
    be performed every 6-8 weeks (± 7 days)	X5
	B-HCG	14	X	 	 	 	 	 
	PK	 	 	Cycle3
    1	 	 	 	 
	Blood
    for correlatives	 	X4	Cycles4
                                         1,

        4,
        7 & 10
	 	 	X4	 
	Survival
    Follow-up	 	 	 	 	 	 	X


 


	 	1	Documentation
    (radiologic) must be provided for patients removed from study for progressive disease.
	 	2	Appendix
    B
	 	3	See
    Section 6.5.1. Cycle 1 only. Collect blood in a 5 mL chilled heparin tube Day 1: pre-infusion, end of infusion, and 15 minutes,
    30 minutes, 1, hour, 2 hours, 4 hours and 8 hours post. Day 2: pre-infusion.


 




    	 



    	Page 64 of 92



    

 


	 	4	See
    Section 9.1 Collect peripheral blood in a 10 mL BD Vacutainer CPT tube at screening, and pre-treatment on Day 1 of Cycles
    1, 4,7, 10 and off treatment.
	 	5	For
    patients that come off study for reasons other than progressive disease. 6 30 Days post last study drug
	 	7	End
    of LB-100 infusion
	 	8	As
    clinically indicated throughout the study


 


11.0
Endpoint Definitions


 


11.1
Primary endpoints:


 


	 	●	Determine
    recommended phase II dose (RP2D) of the combination using DLT (Definition Section 5.7) during the first cycle as assessed
    by CTCAE version 5.0.


 


11.2 
Secondary endpoints:


 


	 	●	Objective
    response rate (ORR) as defined by RECIST v1.1 (Appendix B)
	 	 	Patients
    who respond to treatment and die without PD (including death from study disease), duration of response will be censored at
    the date of the last objective progression-free disease assessment. For responding patients not known to have died as of the
    data cut-off date and who do not have PD, duration of response will be censored at the last progression-free assessment date.
	 	 	 
	 	 	For
    responding patients who receive subsequent anticancer therapy (after discontinuation from all study treatment excluding PCI)
    prior to disease progression, duration of response will be censored at the date of last progression-free assessment prior
    to the initiation of post discontinuation anticancer therapy
	 	 	 
	 	●	Duration
    of overall response as defined by RECIST v1.1 (Appendix B)
	 	●	Safety
    and Adverse events by assessed by CTCAE version 5.0
	 	●	Progression-free
    survival (PFS) as defined by RECIST v1.1 (Appendix B)
	 	●	Overall
    survival, which is defined as the time from the date of study enrollment to the date of death from any cause. For patients
    who are still alive as of the data cutoff date, OS time will be censored on the date of the patient’s last contact (last
    contact for patients in post discontinuation is last known alive date in mortality status).


 


11.3
Exploratory endpoints


 


	 	●	The
    pharmacokinetics (PK) of LB100 and its metabolite endothall.
	 	●	The
    relative abundance of immune cell populations before, during and after treatment.
	 	 	The
    signaling states that evolve in immune cells during treatment and that differentiate responders from non-responders.


 


12.0
Data Handling, Data Management, Record Keeping


 


12.1
Source Documents


 


Source
documents are original documents, data, and records (e.g., medical records, pharmacy dispensing records, recorded data from automated
instruments, laboratory data) that are relevant to the clinical trial. The investigator or their designee will prepare and maintain
adequate and accurate source documents. These documents are designed to record all observations and other pertinent data for each
patient enrolled in this clinical trial. Source documents must be adequate to reconstruct all data transcribed onto the case report
forms.


 




    	 



    	Page 65 of 92



    

 


12.2
Data Capture Methods and Management


 


Data
for this trial will be collected using City of Hope’s electronic capture system that is compliant with 21 CFR Part 11. Study
personnel will enter data from source documents corresponding to a subject’s visit into the protocol-specific electronic
Case Report Form (eCRF).


 


12.3
Case Report Forms/Data Submission Schedule


 


Study
personnel will enter data from source documents corresponding to a subject’s visit into the protocol- specific electronic
Case Report Form (eCRF) when the information corresponding to that visit is available.


 


The
investigator is responsible for all information collected on subjects enrolled in this study. All data collected during this study
must be reviewed and verified for completeness and accuracy by the investigator. All case report forms must be completed by designated
study personnel. The completed case report forms must be reviewed, signed and dated by the Investigator or designee in a timely
fashion.


 


All
data will be collected using electronic data collection, stored as indicated in Section 12.2, and will be submitted according
to the timelines indicated in Table 12.3.1.


 


Table
12.3.1: Data Submission Schedule


 


	Form	 	Submission
    Timeline
	Eligibility Checklist	 	Complete prior to registration
	On Study Forms	 	Within 14 calendar days of registration.
	Baseline Assessment
    Forms	 	Within 14 calendar days of registration.
	Treatment Forms	 	Within 10 calendar days of treatment administration.
	Adverse
    Event Report Forms	 	Window
                           period: Within 7 calendar days of AE assessment/notification.

                           Post-window
period: Within 10 calendar days of AE assessment/notification. 

	Response Assessment
    Forms	 	Within 10 calendar days of the response assessment.
	Other Assessment
    Forms (concomitant medications)	 	Within 10 calendar days of the assessment.
	Off Treatment/Off
    Study Forms	 	Within 10 calendar days of end of treatment/study.
	Follow up/Survival
    Forms	 	Within 14 calendar days of the follow up activity.


 




    	 



    	Page 66 of 92



    

 


12.4
Regulatory Records


 


The
investigator will maintain regulatory records, including updating records in accordance with Good Clinical Practice guidelines
and FDA regulations


 


12.5
Protocol Deviations and Single Subject Exceptions


 


It
is understood that deviations from the protocol should be avoided, except when necessary to eliminate an immediate hazard to a
research participant. Brief interruptions and delays may occasionally be required because of travel delays, airport closures,
inclement weather, family responsibilities, security alerts, government holidays, and so forth. Delays can also extend to complications
of disease or unrelated medical illnesses not related to disease progression. The PI has the discretion to deviate from the protocol
when necessary so long as such a deviation does not threaten patient safety or protocol scientific integrity. As a result of deviations,
corrective actions are to be developed by the study staff and implemented promptly.


 


12.5.1
Definitions


 


	 	12.5.1.1	Deviation


 


A
deviation is a divergence from a specific element of a protocol that occurred without prior IRB approval. Investigators may deviate
from the protocol to eliminate immediate hazard(s) for the protection, safety, and well-being of the study subjects without prior
IRB approval. Examples include, but are not limited to: a) dose adjustments based on excessive patient weight; b) alteration in
treatment schedule due to non-availability of the research participant for treatment; and c) laboratory test results which are
slightly outside the protocol requirements but at levels that do not affect participant safety.


 


	 	12.5.1.2	Single
    Subject Exceptions (SSE)


 


An
SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures called for in a protocol are
not in the best interests of a specific patient. It is a deviation that is anticipated and receives prior approval by the Principal
Investigator and the COH IRB.


 


12.5.2.
Reporting of Deviations and SSEs


 


	 	12.5.2.1	Reporting
    Deviations


 


For
any deviation, the Investigator will notify the COH DSMC and IRB within 5 calendar days of its occurrence via iRIS in accordance
with the Clinical Research Protocol Deviation policy.


 


2.2.2
Reporting Single Subject Exceptions


 





The
SSE must be submitted as a “Single Subject Exception Amendment Request” via iRIS in accordance with IRB guidelines
and the Clinical Research Protocol Deviation policy. An IRB approved SSE does not need to be submitted as a deviation to
the DSMC.


 


In
addition, if contractually obligated, the sponsor must also approve the deviation


 




    	 



    	Page 67 of 92



    

 


	 	13.0	Statistical
    Considerations

 








 


13.1
Study Design


 


The
Phase I dose-finding will use a traditional 3+3 to determine the MTD. These designs are based on first cycle DLTs. The determination
of the RP2D will be based on the MTD (and will not exceed the MTD) and additional consideration of dose modifications, adverse
events in subsequent cycles, clinical activity and correlative studies.


 


Safety:
All patients who receive at least one dose of study drug will be evaluated for safety and toxicity. Safety analyses will include
the following: summaries of the adverse event rates (including all events and study drug-related events), all serious adverse
events (SAEs), deaths on-study, deaths within 30 days of the last dose of study drug, and discontinuations from study drug due
to adverse events; listings and frequency tables categorizing laboratory and nonlaboratory adverse events by maximum CTCAE grade
and relationship to study drug. Safety and efficacy will be reviewed at least every six months by COH DSMC.


 


Expanded
Cohort: Expansion to 12 patients at the initial recommended Phase 2 dose (RP2D) will help confirm the choice of RP2D. In particular,
if during the expansion cohort, more than 30% of the patients at the initial RP2D experience a DLT, the study will hold accrual
(accrual can also be held at the discretion of the PI for non-DLT or other safety considerations). In addition, with 12 patients,
any serious treatment-related adverse event that occurs with a true frequency of 10%, will be observed at least once with a probability
of 72%, and any such AE with a true frequency of 20% would be observed at least once with a probability of 93%. The DLT rate can
be estimated with a standard error of at most 14%.


 


Pharmacokinetic:
PK analyses will be collected on all patients in the Phase I portion of the study. Exploratory graphical analysis will be conducted.
PK/PD modeling may be conducted if deemed appropriate and necessary.


 


Patients
will plan to receive treatment until progression, unacceptable toxicity or one of the criteria in 5.3 requires discontinuation.
Each cycle is defined as 3 weeks (21 days). Patients who discontinue without disease progression will continue to be evaluated
for tumor response using RECIST v1.1 (Appendix B) guidelines every 6-8 weeks until disease progression, death, or study closure.


 




    	 



    	Page 68 of 92



    

 


Figure
1 illustrates the study design


 








 


13.2
Sample Size Accrual Rate


 


The
Phase Ib study accrual is expected to require 15 patients to determine the MTD (minimum 8, maximum 30, assuming the lowest dose
is tolerated). With the expanded cohort, the expected sample-size is 21, and the maximum is 36 patients. This does not include
patients who are not evaluable for DLT consideration during the dose finding. The study duration of the Phase Ib will be approximately
18-24 months.


 


13.3
Statistical Analysis Plan


 


	 	13.3.1	General
    Considerations


 


Efficacy
and safety analyses will include all randomized patients who received at least one dose of study drug. Patients will be grouped
according to treatment received in Cycle 1. If a patient is randomized and it is confirmed later that they do not have SCLC then
they will not be analyzed for efficacy but safety only.


 


Unless
otherwise specified, missing data will not be imputed and kept missing in the data analysis. If patients miss a planned assessment,
and have progression on the next assessment, the date of progression for purposes of analysis will be based on the planned assessment
date that was missed.


 


	 	13.3.2	Patient
    Disposition


 


A
detailed description of patient disposition will be provided. It will include a summary of the number and percentage of patients
entered into the study, enrolled in the study, and treated as well as number and percentage of patients completing the study,
or discontinuing (overall and by reason for discontinuation). A summary of all important protocol violations will be provided.


 


	 	13.3.3	Patient
    Characteristics


 


Patient
demographics including age, gender, screening height and weight, and other demographic characteristics will be summarized using
descriptive statistics.


 


Baseline
disease characteristics will be summarized by presenting frequency counts and percentages for disease characteristics as appropriate.


 




    	 



    	Page 69 of 92



    

 


	 	13.3.4	Concomitant
    Therapy


 


Concomitant
medications will be summarized for the safety population.


 


	 	13.3.5	Postdiscontinuation
    Therapy


 


The
numbers and percentages of patients reporting postdiscontinuation therapies will be provided overall, by type of therapy (surgery,
radiotherapy, or systemic therapy), and by drug name.


 


	 	13.3.6	Treatment
    Compliance


 


The
number of dose omissions, reductions and delays will be summarized for all treated patients per treatment arm.


 


	 	13.3.7	Primary
    Outcome and Methodology


 


The
primary outcome measure for this study is to determine the recommended dose of LB-100 with carboplatin/etoposide/atezolizumab
in patients with ED-SCLC.


 


	 	13.3.8	Pharmacokinetic/Pharmacodynamic
    Analyses


 


Pharmacokinetics
and Pharmacodynamic analyses will be conducted on all available LB-100 plasma concentration and pharmacodynamic data. These analyses
are exploratory in nature. Graphical representation of the data will be conducted. PK/PD modeling may be pursued if deemed appropriate
and necessary.


 


	 	13.3.9	Safety
    Analyses


 


All
safety summaries and analyses will be based upon the Safety Population as defined in Section 13.1.


 


Overall
exposure to study drug, the numbers of patients completing each cycle, and the will be summarized using descriptive statistics.


 


An
overall summary of AEs will be provided for AEs deemed by the investigator to be possibly related to study drug, and for all causalities.


 


A
treatment-emergent adverse event (TEAE) is defined as an event that first occurred or worsened in severity after baseline.


 


The
number of patients who experienced a TEAE, SAE, TEAE related to study drug, died, or discontinued from the study due to an AE
will be summarized by treatment.


 


Common
Terminology Criteria for Adverse Events v 5.0 will be used when reporting AEs by CTCAE terms. Laboratory and non-laboratory CTCAEs
will be summarized by CTCAE term and maximum CTCAE grade, including the total for maximum Grade 3 and 4. These summaries will
be provided for events regardless of study drug causality, and for events deemed by the investigator to be possibly related to
study medication.


 


Reasons
for death will be summarized separately for on-therapy and within 30 days of last dose of study drug. Serious adverse events will
be summarized by PT.


 


Hospitalizations
and transfusions during the study treatment period or during the 30-day follow-up period will be summarized by treatment group.


 


	 	13.3.10	Interim
    Analyses


 


No
formal interim analyses are planned for this study other than the safety assessments and scheduled external review.


 




    	 



    	Page 70 of 92



    
 


	 	14.0	Human Subject Issues
	 	 	 
	 	14.1	Institutional
Review Board






 


In
accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR
46 and 21 CFR 50, 56 and State of California Health and Safety Code, Title 17, must review and approve this protocol and the informed
consent form prior to initiation of the study. All institutional, NCI, Federal, and State of California regulations must be fulfilled.


 


14.2
Recruitment of Subjects




 


Patients
will be recruited at City of Hope by their Medical Oncologist based on their diagnosis and eligibility criteria. A Clinical Trial
Research Nurse will screen the patient for the trial and if they meet all eligibility criteria they will be enrolled into the
study.


 


14.3
Advertisements




 


Advertisements
to include print, media (radio, television, billboards), telephone scripts, lay summary to be posted on City of Hope’s public
Clinical Trials On-LineSM website, etc., will be reviewed and approved by the IRB prior to their use to recruit potential study
subjects.


 


14.4
Study location and Performance Sites




 


This
study will be performed at COH.


 


14.5
Confidentiality




 


This
research will be conducted in compliance with federal and state of California requirements relating to protected health information
(PHI).


 


14.6
Financial Obligations and Compensation




 


The
investigational drug, LB-100, will be provided free of charge by Lixte Biotechnology, Inc. East Setauket, NY 11133. Should this
drug become commercially available during the course of your treatment, the research participant and/or the insurance carrier
may be asked to pay for the costs of the drug.


 


The
standard of care drugs and procedures provided will be the responsibility of the research participant and/or the insurance carrier.
The research participant will be responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures
as set forth by the insurance carrier. The research participant and/or the insurance carrier will be billed for the costs of treatment
and diagnostic procedures in the same way as if the research participant were not in a research study. However, neither the research
participant nor the insurance carrier will be responsible for the research procedures related to this study.


 


In
the event of physical injury to a research participant, resulting from research procedures, appropriate medical treatment will
be available at the City of Hope to the injured research participant, however, financial compensation will not be available.


 


The
research participant will not be paid for taking part in this study.


 




    	 



    	Page 71 of 92



    

 


14.7
Informed Consent Processes/Regulatory Considerations




 


The
Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of the study, potential risks,
alternatives and potential benefits, and all other information contained in the informed consent document. In addition, they will
review the experimental subject’s bill of rights and the HIPAA research authorization form. Research subjects will be informed
that they may withdraw from the study at any time and for any reason without prejudice, including as applicable, their current
or future care or employment at City of Hope or any relationship they have with City of Hope. Research subjects will be afforded
sufficient time to consider whether or not to participate in the research.


 


Should
sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be made and the questionnaire
repeated until a satisfactory result is obtained. Prospective research subjects who cannot adequately comprehend the fundamental
aspects of the research study with a reasonable amount of discussion, education and proctoring will be ineligible for enrollment.
For those subjects who do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed by
eligibility testing. The research team will review the results of eligibility testing and determine if the subject is a candidate
for study enrollment.


 


The
Informed Consent Form (ICF) will be used to explain the potential risks and benefits of study participation to the patient in
simple terms before the patient is entered into the study, and to document that the patient is satisfied with his or her understanding
of the risks and benefits of participating in the study and desires to participate in the study.


 


The
investigator is responsible for ensuring that informed consent is given by each patient or legal representative. This includes
obtaining the appropriate signatures and dates on the ICF prior to the performance of any protocol procedures and prior to the
administration of study drug.


 


As
used in this protocol, the term “informed consent” includes all consent and assent given by patients or their legal
representatives.


 


14.7.1
Regulatory Considerations


 


This study will be conducted in accordance with:


 


	 	1)	Consensus
    ethics principles derived from international ethics guidelines, including the declaration of Helsinki and Council for International
    Organizations of Medical Sciences (CIOMS) International Ethical Guidelines
	 	 	 
	 	2)	The
    International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) Guideline [E6]
	 	 	 
	 	3)	Applicable
    laws and regulations


 


The
investigator or designee will promptly submit the protocol to applicable ERB(s). LB-100 is being studied in the United States
(US) under a US Investigational New Drug (IND) application. The US IND number is 151424.


 


All
or some of the obligations of the sponsore will be assigned to a CRO.


 


An
identification code assigned by the investigator for each patient will be used in lieu of the patient’s name to protect
the patient’s identity when reporting AEs and/or other trial-related data.


 




    	 



    	Page 72 of 92



    

 


14.7.2
Investigator Information




 


Site-specific
contact information is provided in a separate document.


 


14.7.3
Protocol Signatures




 


After
reading the protocol, each principal investigator will signt he protocol signature page and send a copy of the signed page to
a City of Hope representative or designee.


 


14.7.4
Final Report Signature.




 


The
sponsor’s responsible medical officer and responsible statistician will approve the final clinical study report for this
study, confirming that, to the best of his or her knowledge, the report accurately describes the conduct and results of the study.


 


	 	15.0	Study
Oversight, Quality Assurance, and Data & Safety Monitoring
	 	 	 
	 	15.1	All Investigator
Responsibilities






 


An
investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the
investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s
care; and for the control of drugs under investigation.


 


All
Investigators agree to:


 


	 	●	Conduct
    the study in accordance with the protocol and only make changes after notifying the Sponsor (or designee), except when necessary
    to protect the safety, rights or welfare of subjects.
	 	 	 
	 	●	Personally
    conduct or supervise the study (or investigation).
	 	 	 
	 	●	Ensure
    that the requirements relating to obtaining informed consent and IRB review and approval meet federal guidelines, as stated
    in § 21 CFR, parts 50 and 56.
	 	 	 
	 	●	Report
    to the Sponsor or designee any AEs that occur in the course of the study, in accordance with §21 CFR 312.64.
	 	 	 
	 	●	Ensure
    that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations in
    meeting the above commitments.
	 	 	 
	 	●	Maintain
    adequate and accurate records in accordance with §21 CFR 312.62 and to make those records available for inspection with
    the Sponsor (or designee).
	 	 	 
	 	●	Ensure
    that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for initial and continuing review
    and approval of the clinical study.
	 	 	 
	 	●	Promptly
    report to the IRB and the Sponsor all changes in the research activity and all unanticipated problems involving risks to subjects
    or others (to include amendments and IND safety reports).
	 	 	 
	 	●	Seek
    IRB and Sponsor approval before any changes are made in the research study, except when necessary to eliminate hazards to
    the patients/subjects.
	 	 	 
	 	●	Comply
    with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements listed
    in § 21 CFR part 312.


 




    	 



    	Page 73 of 92



    

 


15.2
Study Principal Investigator Responsibilities




 


The
Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing that sponsor responsibilities
as defined in § 21 CFR 312. Subpart D are executed in accordance with federal regulations.


 


15.3
Protocol Management Team (PMT)




 


The
Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, research nurse, clinical research
associate/coordinator, and the study biostatistician, is responsible for ongoing monitoring of the data and safety of this study,
including implementation of the stopping rules for safety/toxicity.


 


The
PMT is recommended to meet (in person or via teleconference) at least monthly to review study status. This review will include,
but not be limited to, reportable AEs and UPs, and an update of the ongoing study summary that describes study progress in terms
of the study schema. The meeting will be a forum to discuss study related issues including accrual, SAE/AEs experienced, study
response, deviations/violations and study management issues. The appropriateness of further subject enrollment and the specific
intervention for subsequent subject enrollment are addressed. It is recommended that minutes of these discussions be taken to
document the date of these meetings, attendees and the issues that were discussed (in a general format).


 


15.4
Monitoring




 


Clinical
site monitoring is conducted to ensure that the rights of human subjects are protected, that the study is implemented in accordance
with the protocol and regulatory requirements, and that the quality and integrity of study data and data collection methods are
maintained. Monitoring for this study will be performed by the City of Hope Office of Clinical Trials Auditing and Monitoring
(OCTAM).


 


The
Investigator will permit the study monitors and appropriate regulatory authorities direct access to the study data and to the
corresponding source data and documents to verify the accuracy of this data. The Investigator will allocate adequate time for
such monitoring activities. The Investigator will also ensure that the monitor or other compliance or quality assurance reviewer
is given access to all the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory,
etc.), and has adequate space to conduct the monitoring visit.


 


Details
of clinical site monitoring are documented in the OCTAM SOP. This document specifies the frequency of monitoring, monitoring procedures,
the level of clinical site monitoring activities (e.g., the percentage of subject data to be reviewed), and the distribution of
monitoring reports. Staff from OCTAM will conduct monitoring activities and provide reports of the findings and associated action
items in accordance with the details described in the SOP. Documentation of monitoring activities and findings will be provided
to the study team, and the COH DSMC.


 


15.5
Quality Assurance




 


The
City of Hope Clinical Research Information Support will provide support for this trial as detailed in the COH DCC Operations Plan
provided as a supplement to this document.


 




    	 



    	Page 74 of 92



    

 


Quality
assurance (QA) audits will be conducted by Theradex Oncology. The QA audits will be conducted on an annual schedule with the first
QA audit conducted approximately 6 months after initiation of patient enrollment. QA audits will be conducted similar to those
conducted on behalf of the NCI Experimental Therapeutics Clinical Trial Network (ETCTN) guidelines: https://ctep.cancer.gov/branches/ctmb/clinicalTrials/docs/ETCTN_Audit_Guidelines.pdf


 


15.6
City of Hope Data and Safety Monitoring Committee




 


This
is a risk level4 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan. This determination
was made because the study involves a COH held IND.


 


The
DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of participants in clinical trials, and
the conduct, progress, validity, and integrity of the data for all clinical trials that are sponsored by City of Hope. The committee
is composed of clinical specialists with experience in oncology and who have no direct relationship with the study. The committee
reviews the progress and safety of all active research protocols that are not monitored by another safety and data monitoring
committee or board.


 


The
Study Principal Investigator is required to submit periodic status reports (the PMT report) according to the guidelines outlined
in the City of Hope Institutional Data and Safety Monitoring Plan. The PMT report will be submitted to the COH DSMC quarterly
from the date of activation.


 


The
COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data from this trial. The DSMC will
review up-to-date participant accrual; summary of all adverse events captured via routine and expedited reporting; a summary of
deviations; any response information; monitoring reports, and summary comments provided by the study team. Other information (e.g.
scans, laboratory values) will be provided upon request. For Phase I studies, a Phase I Tracking Log will be utilized and reviewed
by the DSMC to monitor data and safety for dose escalation. A review of outcome results (response, toxicity and adverse events)
and factors external to the study (such as scientific or therapeutic developments) is discussed, and the Committee votes on the
status of each study. Information that raises any questions about participant safety will be addressed with the Principal Investigator,
statistician and study team.


 




    	 



    	Page 75 of 92



    

 


	VII.	16.0 References














 


1.
Quoix E, Breton JL, Daniel C, Jacoulet P, Debieuvre D, Paillot N, Kessler R, Moreau L, Coetmeur D, Lemarie E, Milleron B. Etoposide
phosphate with carboplatin in the treatment of elderly patients with small-cell lung cancer: a phase II study. Ann Oncol. 2001;12(7):957-62.
Epub 2001/08/28. PubMed PMID: 11521802.


 


2.
Maghfoor I, Perry MC. Lung cancer. Ann Saudi Med. 2005;25(1):1-12. Epub 2005/04/13. PubMed PMID: 15822487; PMCID: PMC6150570.


 


3.
Niell HB, Perry MC, Clamon G, Crawford J, Miller AA, Herndon J, 2nd, Green MR. Carboplatin/etoposide/paclitaxel in the treatment
of patients with extensive small-cell lung cancer. Clin Lung Cancer. 2001;2(3):204-9. Epub 2004/01/01. PubMed PMID: 14700479.


 


4.
Sundstrom S, Bremnes RM, Kaasa S, Aasebo U, Hatlevoll R, Dahle R, Boye N, Wang M, Vigander T, Vilsvik J, Skovlund E, Hannisdal
E, Aamdal S, Norwegian Lung Cancer Study G. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine
regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol. 2002;20(24):4665-72.
Epub 2002/12/19. doi: 10.1200/JCO.2002.12.111. PubMed PMID: 12488411.


 


5.
Niell HB, Herndon JE, 2nd, Miller AA, Watson DM, Sandler AB, Kelly K, Marks RS, Perry MC, Ansari RH, Otterson G, Ellerton J, Vokes
EE, Green MR, Cancer, Leukemia G. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel
and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B
Trial 9732. J Clin Oncol. 2005;23(16):3752-9. doi: 10.1200/JCO.2005.09.071. PubMed PMID: 15923572.


 


6.
Eckardt JR, von Pawel J, Papai Z, Tomova A, Tzekova V, Crofts TE, Brannon S, Wissel P, Ross G. Open-label, multicenter, randomized,
phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with
extensive-disease small-cell lung cancer. J Clin Oncol. 2006;24(13):2044-51. Epub 2006/05/02. doi: 10.1200/JCO.2005.03.3332. PubMed
PMID: 16648504.


 


7.
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok
T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV, Group IMS. First-Line Atezolizumab
plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220- 9. doi: 10.1056/NEJMoa1809064. PubMed
PMID: 30280641.


 


8.
Bunn PA, Jr. Review of therapeutic trials of carboplatin in lung cancer. Semin Oncol. 1989;16(2 Suppl 5):27-33. Epub 1989/04/01.
PubMed PMID: 2541506.


 




    	 



    	Page 76 of 92



    

 


9.
Bunn PA, Jr., Kelly K. A phase I study of carboplatin and paclitaxel in non-small cell lung cancer: a University of Colorado Cancer
Center study. Semin Oncol. 1995;22(4 Suppl 9):2-6. Epub 1995/08/01. PubMed PMID: 7644924.


 


10.
Prendiville J, Lorigan P, Hicks F, Leahy B, Stout R, Burt P, Thatcher N. Therapy for small cell lung cancer using carboplatin,
ifosfamide, etoposide (without dose reduction), mid-cycle vincristine with thoracic and cranial irradiation. Eur J Cancer. 1994;30A(14):2085-
90. Epub 1994/01/01. PubMed PMID: 7857708.


 


11.
Gatzemeier U, Hossfeld DK, Neuhauss R, Reck M, Achterrath W, Lenaz L. Phase II and III studies with carboplatin in small cell
lung cancer. Semin Oncol. 1992;19(1 Suppl 2):28-36. Epub 1992/02/01. PubMed PMID: 1329220.


 


12.
Larive S, Bombaron P, Riou R, Fournel P, Perol M, Lena H, Dussopt C, Philip-Joet F, Touraine F, Lecaer H, Souquet PJ, Groupe Lyon-Saint
Etienne d’Oncologie T. Carboplatin-etoposide combination in small cell lung cancer patients older than 70 years: a phase
II trial. Lung Cancer. 2002;35(1):1-7. Epub 2001/12/26. PubMed PMID: 11750705.


 


13.
Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol. 2013;14(6):e229-38. Epub 2013/05/04.
doi: 10.1016/S1470-2045(12)70558-2. PubMed PMID: 23639323; PMCID: PMC3913484.


 


14.
Hong CS, Ho W, Zhang C, Yang C, Elder JB, Zhuang Z. LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing
potential. Cancer Biol Ther. 2015;16(6):821-33. Epub 2015/04/22. doi: 10.1080/15384047.2015.1040961. PubMed PMID: 25897893; PMCID:
PMC4623051.


 


15.
Chung V, Mansfield AS, Braiteh F, Richards D, Durivage H, Ungerleider RS, Johnson F, Kovach JS. Safety, Tolerability, and Preliminary
Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation,
First-in-Human, Phase I Trial. Clin Cancer Res. 2017;23(13):3277-84. Epub 2017/01/01. doi: 10.1158/1078-0432.CCR-16-2299. PubMed
PMID: 28039265.


 


16.
Lu J, Kovach JS, Johnson F, Chiang J, Hodes R, Lonser R, Zhuang Z. Inhibition of serine/threonine phosphatase PP2A enhances cancer
chemotherapy by blocking DNA damage induced defense mechanisms. Proc Natl Acad Sci U S A. 2009;106(28):11697-702. Epub 2009/07/01.
doi: 10.1073/pnas.0905930106. PubMed PMID: 19564615; PMCID: PMC2710674.


 


17.
Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, Wang Y, Chang H, Qian W, Shi J, Iqbal K, Gong CX, Cheng C, Liu F. Cross talk between
PI3K-AKT- GSK-3beta and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging. 2015;36(1):188-200. Epub 2014/09/16.
doi: 10.1016/j.neurobiolaging.2014.07.035. PubMed PMID: 25219467.


 


18.
Liu GP, Wei W, Zhou X, Shi HR, Liu XH, Chai GS, Yao XQ, Zhang JY, Peng CX, Hu J, Li XC, Wang Q, Wang JZ. Silencing PP2A inhibitor
by lenti-shRNA interference ameliorates neuropathologies and memory deficits in tg2576 mice. Mol Ther. 2013;21(12):2247-57. Epub
2013/08/08. doi: 10.1038/mt.2013.189. PubMed PMID: 23922015; PMCID: PMC3863796.


 




    	 



    	Page 77 of 92



    

 


19.
Gordon IK, Lu J, Graves CA, Huntoon K, Frerich JM, Hanson RH, Wang X, Hong CS, Ho W, Feldman MJ, Ikejiri B, Bisht K, Chen XS,
Tandle A, Yang C, Arscott WT, Ye D, Heiss JD, Lonser RR, Camphausen K, Zhuang Z. Protein Phosphatase 2A Inhibition with LB100
Enhances Radiation-Induced Mitotic Catastrophe and Tumor Growth Delay in Glioblastoma. Mol Cancer Ther. 2015;14(7):1540-7. Epub
2015/05/06. doi: 10.1158/1535-7163.MCT- 14-0614. PubMed PMID: 25939762; PMCID: PMC4497833.


 


20.
Zhu XN, Chen LP, Bai Q, Ma L, Li DC, Zhang JM, Gao C, Lei ZN, Zhang ZB, Xing XM, Liu CX, He ZN, Li J, Xiao YM, Zhang AH, Zeng
XW, Chen W. PP2A-AMPKalpha-HSF1 axis regulates the metal-inducible expression of HSPs and ROS clearance. Cell Signal. 2014;26(4):825-32.
Epub 2014/01/15. doi: 10.1016/j.cellsig.2014.01.002. PubMed PMID: 24412756.


 


21.
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T,
Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Muschen M. B-Cell-Specific Diversion of Glucose
Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell. 2018;173(2):470-84 e18. Epub 2018/03/20. doi:
10.1016/j.cell.2018.02.048. PubMed PMID: 29551267; PMCID: PMC6284818.


 


22.
Zhuang Z, Lu J, Lonser R, Kovach JS. Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and
DNA- damage defenses through global modification of the serine/threonine phospho-proteome. Cell Cycle. 2009;8(20):3303-6. Epub
2009/10/07. doi: 10.4161/cc.8.20.9689. PubMed PMID: 19806030.


 


23.
Lu J, Zhuang Z, Song DK, Mehta GU, Ikejiri B, Mushlin H, Park DM, Lonser RR. The effect of a PP2A inhibitor on the nuclear receptor
corepressor pathway in glioma. J Neurosurg. 2010;113(2):225-33. Epub 2009/12/17. doi: 10.3171/2009.11.JNS091272. PubMed PMID:
20001590.


 


24.
Martiniova L, Lu J, Chiang J, Bernardo M, Lonser R, Zhuang Z, Pacak K. Pharmacologic modulation of serine/threonine
phosphorylation highly sensitizes PHEO in a MPC cell and mouse model to conventional chemotherapy. PLoS One.
2011;6(2):e14678. Epub 2011/02/23. doi: 10.1371/journal.pone.0014678. PubMed PMID: 21339823; PMCID: PMC3038858.


 


25.
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian
A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano
D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab
in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-20. Epub 2016/03/10. doi: 10.1016/S0140-6736(16)00561-4.
PubMed PMID: 26952546; PMCID: PMC5480242.


 




    	 



    	Page 78 of 92



    

 


26.
Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL,
Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Duran
I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE, 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thastrom A, Abidoye
OO, Fine GD, Bajorin DF, Group IMS. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced
and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76. Epub 2016/12/13.
doi: 10.1016/S0140-6736(16)32455-2. PubMed PMID: 27939400; PMCID: PMC5568632.


 


27.
Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh
F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A, Group PS. Atezolizumab versus docetaxel for patients with
previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet.
2016;387(10030):1837-46. Epub 2016/03/14. doi: 10.1016/S0140-6736(16)00587-0. PubMed PMID: 26970723.


 


28.
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L,
Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, Investigators IMT. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative
Breast Cancer. N Engl J Med. 2018;379(22):2108-21. Epub 2018/10/23. doi: 10.1056/NEJMoa1809615. PubMed PMID: 30345906.


 




    	 



    	Page 79 of 92



    

 


	 	(i)	APPENDIX A: PERFORMANCE STATUS SCALES




 


	Karnofsky
    Scale %	 	Karnofsky
    Description	 	ECOG

        Scale*
	 	ECOG

        Description

	100	 	Normal,
    no complaints, no evidence of disease.	 	0	 	Fully
    active, able to carry on all pre-disease activities without restriction
	90	 	Able
    to carry on normal activity, minor symptoms or signs of disease.	 	1	 	Restricted
    in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature e.g. light house
    work, office work.
	80	 	Normal
    activity with effort, some signs or symptoms of disease.	 	 
	70	 	Cares
    for self, unable to carry on normal activity or to do active work.	 	2	 	Ambulatory
    and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours
	60	 	Requires
    occasional assistance, but is able to care for most of own needs.	 	 
	50	 	Requires
    considerable assistance and frequent medical care.	 	3	 	Capable
    of only limited self care, confined to bed or chair more than 50% of waking hours
	40	 	Disabled,
    requires special care and assistance.	 	 
	30	 	Severely
    disabled, hospitalization is indicated although death is not imminent.	 	4	 	Completely
    disabled. Cannot carry on any self care. Totally confined to bed or chair
	20	 	Hospitalization
    necessary, very sick, active supportive treatment necessary.	 	 
	10	 	Moribund,
    fatal processes	 	 
	Dead	 	 	 	5	 	Dead


 


*also
known as Zubrod, SWOG or WHO scale


 




    	 



    	Page 80 of 92



    

 


	 	(ii)	APPENDIX B:
RECIST V1.1 CRITERIA




 


1.1
Antitumor Effect – RECIST V1.1 Solid Tumors




 


Response
and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation
Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the
RECIST criteria.


 


1.1.1
Definitions




 


Evaluable
for Toxicity. All patients will be evaluable for toxicity from the time of their first treatment.


 


Evaluable
for Objective Response. Only those patients who have measurable disease present at baseline, have received at least one cycle
of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their
response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior
to the end of cycle 1 will also be considered evaluable.)


 


Evaluable
Non-Target Disease Response. Patients who have lesions present at baseline that are evaluable but do not meet the definitions
of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered
evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the
lesions.


 


1.1.2
Disease Parameters




 


Measurable
Disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter
to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).


 


Note:
Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable.


 


Malignant
Lymph Nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 cm) in short
axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up,
only the short axis will be measured and followed.


 




    	 



    	Page 81 of 92



    

 


Non-Measurable
Disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] or
pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease.
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable.


 


Note:
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions
(neither measurable nor non-measurable) since they are, by definition, simple cysts.


 


‘Cystic
lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of
measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection
as target lesions.


 


Target
Lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved
organs, 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), be representative of all involved organs, but in addition should
be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion
does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly
should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short
axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression
in the measurable dimension of the disease.


 


Non-Target
Lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should
be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required,
but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.


 


1.1.3
Methods for Evaluation of Measurable Disease




 


All
measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed
as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.


 




    	 



    	Page 82 of 92



    

 


The
same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline
and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed
cannot be imaged but are assessable by clinical exam.


 


Clinical
Lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable
lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions,
documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.


 


Chest
X-Ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated
lung. However, CT is preferable.


 


Conventional
CT and MRI. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness
is 5 mm (0.5 cm) or less. If CT scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).


 


Use
of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition
variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability
of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should
be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should
be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope
of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally,
the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior
scans. Body scans should be performed with breath-hold scanning techniques, if possible.


 


PET-CT.
At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT
quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements
and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the
PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed.


 


Ultrasound.
Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations
cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot
be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified
by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at
CT, MRI may be used instead of CT in selected instances.


 




    	 



    	Page 83 of 92



    

 


Endoscopy,
Laparoscopy. The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may
be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence
following complete response (CR) or surgical resection is an endpoint.


 


Tumor
Markers. Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they
must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in
recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer Intergroup has
developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials
in ovarian cancer [JNCI 92:1534-1535, 2000].


 


Cytology,
Histology. These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare
cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain).


 


The
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable
tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion
may be a side effect of the treatment) and progressive disease.


 


FDG-PET.
While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning
to complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New lesions on the basis
of FDG-PET imaging can be identified according to the following algorithm:


 


	 	a.	Negative
    FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.
	 	b.	No
    FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of
    disease confirmed by CT, this is PD. If the positive FDG- PET at follow-up is not confirmed as a new site of disease on CT,
    additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date
    of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing
    site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
	 	c.	FDG-PET
                                         may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where
                                         a residual radiographic abnormality is thought to represent fibrosis or scarring. The
                                         use of FDG-PET in this circumstance should be prospectively described in the protocol
                                         and supported by disease-specific medical literature for the indication. However, it
                                         must be acknowledged that both approaches may lead to false positive CR due to limitations
                                         of FDG-PET and biopsy resolution/sensitivity.

        



 




    	 



    	Page 84 of 92



    

 


Note:
A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding
tissue on the attenuation corrected image.


 


1.1.4
Response Criteria




 


Evaluation
of Target Lesions


 


Complete
Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have
reduction in short axis to <10 mm (<1 cm).


 


Partial
Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum
diameters.


 


Progressive
Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum
on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum
must also demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new lesions is also
considered progressions).


 


Stable
Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference
the smallest sum diameters while on study.


 


(b) Evaluation
of Non-Target Lesions


 


Complete
Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological
in size (<10 mm [<1 cm] short axis).


 


Note:
If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical
response.


 


Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.


 




    	 



    	Page 85 of 92



    

 


Progressive
Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status
change, not a single lesion increase.


 


Although
a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician should prevail
in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).


 


(c) 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). The patient’s best
response assignment will depend on the achievement of both measurement and confirmation criteria.


 


(i)
For Patients with Measurable Disease (i.e., Target Disease)


 


	Target
    Lesions	 	Non-Target

                                                                                Lesions
	 	New
    Lesions	 	Overall
    Response	 	Best
                                         Overall Response 

        when
        Confirmation is Required*

	CR	 	CR	 	No	 	CR	 	≥4
    wks. Confirmation**
	CR	 	Non-CR/Non-PD	 	No	 	PR	 	 
	CR	 	Not
    evaluated	 	No	 	PR	 	≥4
    wks. Confirmation**
	PR	 	Non-CR/Non-
    PD/not evaluated	 	No	 	PR	 	 
	SD	 	Non-CR/Non-
    PD/not evaluated	 	No	 	SD	 	Documented
    at least once ≥4 wks. from baseline**
	PD	 	Any	 	Yes
    or No	 	PD	 	 
	Any	 	PD***	 	Yes
    or No	 	PD	 	no
    prior SD, PR or CR
	Any	 	Any	 	Yes	 	PD	 	 


 


	*	See
    RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
	**	Only
    for non-randomized trials with response as primary endpoint.
	***
    	In
    exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.


 


	Note:	 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.” Every effort should be made
    to document the objective progression even after discontinuation of treatment.


 




    	 



    	Page 86 of 92



    

 


For
Patients with Non-Measurable Disease (i.e., Non-Target Disease)


 


	Non-Target
    Lesions	 	New
    Lesions	 	Overall
    Response
	CR	 	No	 	CR
	Non-CR/non-PD	 	No	 	Non-CR/non-PD*
	Not
    all evaluated	 	No	 	not
    evaluated
	Unequivocal
    PD	 	Yes
    or No	 	PD
	Any	 	Yes	 	PD


 


	*	‘Non-CR/non-PD’
    is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for assessment
    of efficacy in some trials so to assign this category when no lesions can be measured is not advised


 


1.1.5
Duration of Response




 


Duration
of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as
reference for progressive disease the smallest measurements recorded since the treatment started).


 


The
duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive
disease is objectively documented.


 


Duration
of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met,
taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.


 


1.1.6
Progression-Free Survival




 


PFS
is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.


 




    	 



    	Page 87 of 92



    

 


	 	(ii)	APPENDIX C: REGISTRATION COVERSHEET











 





COH
IRB# 20068: A PHASE Ib OPEN-LABEL STUDY OF LB-100 IN COMBINATION WITH


CARBOPLATIN/ETOPOSIDE/ATEZOLIZUMAB
IN UNTREATED EXTENSIVE-STAGE


SMALL
CELL LUNG CARCINOMA


 


	Data
    Coordinating Center: 	 	Site
    Principal Investigator
	City
                                         of Hope

        1500
        Duarte Road

        Duarte,
        CA 91010

        Tel:
        (626)-218-7904

        Email:
        DCC@coh.org (use #secure# in subject line)
	 	Name:
    Ravi Salgia, MD, PhD


 


	CRA/Study
    Coordinator: 	Contact
    Number: 
	Patient’s
    Initials: (F M L): 	Institution:
    
	PI/
    Sub-Investigator: 
	Patient’s
    DOB: 	IRB
    approval valid until (date): 
	Sex:
    ____Male ____Female 	Date
    Informed Consent Signed: 
	Projected
    start date of treatment: 
	Race
    	Ethnicity
    	 	Method
    of Payment: _____ 
	[  ]	Black
    	[  ]	Hispanic
    	 	Codes:
    
	[  ]	Caucasian
    	[  ]	Non-Hispanic
    	 	01
    Private 	06
                                         Military or Veterans

        Adm.
        sponsored

	[  ]	Asian
    	[  ]	Other	 	02
    Medicare 	07
                                         Self-pay (no

        insurance)

	[  ]	American
    Indian 	 	 	03
    Medicare & private ins. 	08
                                         No means of payment

        (no
        insurance)

	[  ]	Native
    Hawaiian/Pacific Islander 	04
    Medicaid 	09
    Unknown 
	[  ]	Other
    ____	05
    Medicaid & Medicare 


 


Reason
for Screen Failure:


 


 


Reason
for Failing to Initiate Protocol Therapy:


 




    	 



    	Page 88 of 92



    

 


	 	(iii)	APPENDIX D:
EXPEDITED REPORTING COVERSHEET






 


NOTIFICATION
OF UNANTICIPATED PROBLEM/SERIOUS ADVERSE EVENT


 


THIS
FORM ALONG WITH A COPY OF THE MEDWATCH 3500 OR IRB REPORTING FORM MUST BE EMAILED TO DCC@COH.ORG WITHIN 24 HOURS OF KNOWLEDGE
OF ONSET OF SERIOUS ADVERSE EVENT OR UNANCTICIPATED PROBLEM


 


(iv)
COH IRB # 20068


 


	From:
    	Date:
    
	Phone
    No.: 	Email:
    
	Reporting
    Investigator: 	 
	Event:
    	 
	Participant
    ID: 	Institution:
    
	Date
    Event Met Reporting Criteria (as defined in protocol): 	 


 


	Type
    of Report: 	[  ]
    Initial [  ] Follow-up 
	CTCAE
    Grade: 	[  ]
    G1/mild [  ] G2/moderate [  ] G3/severe [  ] G4/life threatening [  ] G5 
	Attribution
    to Agent xx: 	[  ]
    Not Applicable* [  ] Unrelated [  ] Unlikely [  ] Possible [  ] Probable [  ]
    Definite 
	Attribution
    to Agent xxy: 	[  ]
    Not Applicable* [  ] Unrelated [  ] Unlikely [  ] Possible [  ] Probable [  ]
    Definite 
	Historical/Known
    Correlation to Agent xx: 	 

        [  ]
        Expected [  ] Unexpected

	Historical/Known
    Correlation to Agent xxy: 	 

        [  ]
        Expected [  ] Unexpected

	Meets
    Definition of Serious AE: 	[  ]
    Serious [  ] Non-serious 
	Meets
    Definition of Unanticipated Problem: 	 

        [  ]
        UP [  ] Not a UP

	Has
    the event been reported to the following institution’s IRB? 	 

        [  ]
        No [  ] Yes; Date:___/___/_____



 


*
Not Applicable should only be used if subject has not received this agent.


 


	Authorized
                                         Investigator Signature:

        
	Date:____/____/_____



 




    	 



    	Page 89 of 92



    

 





	 	(v)	APPENDIX E:
VETERANS ADMINISTRATION LUNG STUDY GROUP (VALG) STAGING SYSTEM FOR SCLC











 


Veterans
Administration Lung Study

Group (VALG) Staging System for SCLC


 


	Stage	 	Characteristics
	Limited
    SCLC	 	Disease
    confined to the ipsilateral hemithorax which can be safely encompassed within a radiation field
	 	 	 
	Extensive
    SCLC	 	Disease
    beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases
	 	 	 



SCLC = small cell lung
cancer



 




    	 



    	Page 90 of 92



    

 


APPENDIX
F: COMMON SUBSTRATES OF CYP450 ISOENZYMES


 


These
are only examples, please consult an updated source, such as the FDA website for the latest and most accurate information. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers#classSub


 


	CYP3A
    group (includes 4, 5, and 7)	 	Amiodarone

                                                                                Amlodipine

                                                                                Aripiprazole

                                                                                Atorvastatin

                                                                                Buspirone

                                                                                Ciclosporin

                                                                                Clarithromycin

                                                                                Dexamethasone

                                                                                Diazepam

                                                                                Diltiazem

                                                                                Domperidone

                                                                                Erythromycin

                                                                                Estradiol

                                                                                Felodipine

                                                                                Fentanyl

                                                                                Finasteride

                                                                                Hydrocortisone

                                                                                Indinavir

                                                                                Lercanidipine

                                                                                Methadone

                                                                                Nelfinavir

                                                                                Nifedipine

                                                                                Progesterone

                                                                                Ritonavir

                                                                                Saquinavir

                                                                                Sildenafil



 




    	 



    	Page 91 of 92



    

 


	 	 	Simvastatin

                                                                                Tacrolimus

                                                                                Testosterone

                                                                                Verapamil

                                                                                R-Warfarin

	CYP2D6	 	Amitriptyline

                                                                              Carvedilol

                                                                              Chlorphenamine

                                                                              Chlorpromazine

                                                                              Clomipramine

                                                                              Codeine

                                                                              Dextromethorphan

                                                                              Donepezil

                                                                              Duloxetine

                                                                              Fluoxetine

                                                                              Haloperidol

                                                                              Imipramine

                                                                              Metoclopramide

                                                                              Metoprolol

                                                                              Ondansetron

                                                                              Oxycodone

                                                                              Paroxetine

                                                                              Propranolol

                                                                              Tamoxifen

                                                                              Timolol

                                                                              Tramadol

                                                                              Venlafaxine

	CYP2C9	 	Celecoxib

                                                                              Diazepam

                                                                              Diclofenac

                                                                              Fluoxetine



 




    	 



    	Page 92 of 92



    

 


	 	 	Fluvastatin

                                                                                Glibenclamide

                                                                                Glimepiride

                                                                                Glipizide

                                                                                Ibuprofen

                                                                                Irbesartan

                                                                                Losartan

                                                                                Meloxicam

                                                                                Naproxen

                                                                                Phenytoin

                                                                                S-Warfarin

	CYP2C19	 	Amitriptyline

                                                                              Citalopram

                                                                              Clopidogrel

                                                                              Diazepam

                                                                              Lansoprazole

                                                                              Omeprazole

                                                                              Pantoprazole

                                                                              Proguanil

                                                                              Propanolol

                                                                              R-Warfarin

	CYP1A2	 	Amitriptyline

                                                                              Clomipramine

                                                                              Clozapine

                                                                              Imipramine

                                                                              Theophylline

                                                                              R-Warfarin

                                                                              Caffeine