TEXTED MARKED BY [***] HAS BEEN OMITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL
TREATMENT AND WAS FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE COMMISSION

 

Exhibit 10.1

 

EXECUTION VERSION

 

COLLABORATION AGREEMENT
FOR AN INVESTIGATOR-INITIATED CLINICAL TRIAL

 

In Madrid, July 31, 2019 (“Effective Date”)

 

GATHERED

 

On the one hand, Grupo Español de Investigación en Sarcomas (GEIS) with tax
identification number G81890212, and address at C/ Diego de Leon 47, 28006
Madrid, Spain (hereinafter the “Sponsor”) represented in this act by Dr. Claudia
Valverde Morales, in her capacity as President.

 

On the other hand, Lixte Biotechnology Holdings, Inc. with address at 248 Route
25A No. 2 East Setauket, New York 11733, United States (hereinafter “LIXTE”),
represented in this act by John S. Kovach, M.D. in his capacity as Chief
Executive Officer.

 

MANIFEST

 

I. Whereas, the Sponsor is a non-profit clinical research association dedicated
to improving the expectations of sarcoma patients, with special interest and
experience in conducting clinical trials in soft tissue sarcomas.

 

II. Whereas, LIXTE is a clinical-stage public pharmaceutical company dedicated
to discovering drugs for more effective treatments for cancer.

 

III. Whereas, the Sponsor intends to carry out the clinical trial entitled
“Randomized phase I/II trial of LB-100 plus doxorubicin vs. doxorubicin alone in
first line of advanced soft tissue sarcoma” (hereinafter the “Trial”) in
accordance with the trial protocol summarized in Appendix 5 (hereinafter the
“Protocol”).

 

IV. Whereas, the Sponsor has asked LIXTE for financial collaboration and the
supply of samples of LIXTE’S proprietary LB-100 drug (the “Trial Drug”) in order
to conduct the Trial.

 

V. Whereas, LIXTE, being interested in obtaining information about the efficacy
and safety of LB-100 in soft tissue sarcomas, has agreed to collaborate with the
Sponsor for the development of the Trial under the conditions detailed in this
agreement (the “Agreement”) .

 

By virtue of this, the parties, stating sufficient legal capacity, agree to
formalize this Agreement in accordance with the following·

 

I.
Purpose

 

1.1 The purpose of this Agreement is to establish the terms and conditions under
which LIXTE will collaborate with the Sponsor in the conduct of the Trial ,
through financial contribution and the supply of a number of samples of the
Trial Drug that are necessary to achieve the

 

 

 

 

II.
Coordinating Investigator, Participating Sites, and
Project Participants

 

2.1 The Sponsor states that Dr. Javier Martin Broto shall perform the functions
of coordinating investigator responsible for the practical execution of the
Trial (“Coordinating Investigator”), and that he is professionally qualified to
lead the Trial.

 

2.2 The Sponsor represents and warrants that the rest of the participating
centers where the Trial is to take place (collectively, the “Participating
Sites”) have the necessary professional qualifications and experience for
conduct of the Trial, and that they will carry out the Trial in accordance with
the obligations established in this Agreement.

 

2.3 In the event of an absence of thirty (30) days or cessation of participation
in the Trial by the aforementioned Coordinating Investigator, the Sponsor must
notify LIXTE as soon as possible and make best efforts to replace him with
another person of similar qualification. Sponsor will provide thirty (30) days’
notice to LIXTE, whenever practical, of any change of Coordinating Investigator.
LIXTE will have the right to review the qualifications of any Coordinating
Investigator replacement and raise any reasonable concerns which LIXTE may have
in that regard and, both parties shall seek in good faith to address such
concerns.

 

2.4 Before commencing the Trial, the Sponsor shall have obtained written
agreements with the Participating Sites governing conduct of the Trial, which
shall contain terms expressing the same commitments assumed by the Sponsor in
this Agreement.

 

2.5 The Sponsor and Coordinating Investigator shall require that all employees,
consultants and agents of the Sponsor, the Coordinating Investigator and the
Participating Sites who are assigned to perform services under this Agreement
(“Project Participants”) are made aware of the obligations contained in-this
Agreement and are bound by such obligations. In performing the services under
this Agreement, the Sponsor and Coordinating Investigator will reasonably
allocate personnel with the necessary licenses, qualifications and experience to
conduct the Trial in accordance with the Protocol. In particular, Sponsor and
the Coordinating Investigator shall ensure that all Project Participants are
trained in ICH Harmonised Tripartite Guideline For Good Clinical Practice E6(Rl)
Current Step 4 version dated 10 June 1996 (including the Post Step 4
corrections) (“GCP”). LIXTE will have the right, before executing this
Agreement, to review the qualifications of any key personnel, including Project
Participants whose participation in the Trial is expected for the duration of
the Trial, and raise any concerns which LIXTE may have in that regard. In the
event that LIXTE has concerns regarding the performance of any Project
Participant, the parties shall in good faith seek to resolve such concerns.
Sponsor will provide thirty (30) days’ notice to LIXTE, whenever practical, of
any changes to the Project Participants. Sponsor will provide project-specific
training to replacement Project Participants at its own expense. LIXTE will have
the right to review the qualifications of any Project Participant replacements
and raise any reasonable concerns which LIXTE may have in that regard and, both
parties shall seek in good faith to address such concerns.

 

2.6 The Sponsor and Coordinating Investigator will ensure that Sponsor, its
trustees, officers and directors, Coordinating Investigator, Participating
Sites, Project Participants and any sub-contractors: (i) are under no
contractual or other obligation or restriction that is inconsistent with the
Sponsor and Coordinating Investigator’s performance of or obligations under this
Agreement ; (ii) do not have a financial or other interest in LIXTE or the
outcome of the Trial that might interfere with their independent judgment; (iii)
have not been and are not under consideration to be (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.

 

 2 

 

 

2.7 Neither the Coordinating Investigator, Sponsor, nor any Participating Site
may subcontract the performance of any of its/his/her activities under this
Agreement to a third party without LIXTE’s prior written consent. In the event
that LIXTE consents to such subcontracting, Sponsor agrees that (a) such third
parties shall perform such activities in a manner consistent with the terms and
conditions of this Agreement, and (b) Sponsor remains liable for such third
parties’ performance.

 

2.8 The Sponsor shall ensure that all clinical data, trial data, documentation,
correspondence, and other information, data, and findings and results generated
in the conduct of the Trial (“Trial Data”) shall be recorded in a timely,
accurate, complete and legible manner. The Sponsor will take all reasonable and
customary precautions, including periodic backup of computer files, to prevent
the loss or alteration of such Trial Data. In the event that LIXTE is required
to use any Sponsor information systems and associated processes in order to
obtain access to any Trial Data, Sponsor will provide to LIXTE access rights, at
no additional charge, to such systems as is necessary for LIXTE to obtain access
to such Trial Data. Such Sponsor systems will be accessible by LIXTE during, at
minimum, normal business hours, and the Sponsor will promptly correct any
unavailability of, or defect or inadequacy in, such systems to the extent they
affect LIXTE’s ability to access such Trial Data. In no event will Sponsor use
or disclose, or permit any third party to use or disclose, the Trial Data for
any commercial purpose or to any commercial entity.

 

2.9 The Sponsor and Coordinating Investigator will collect, retain and/or use
blood, fluid and/or tissue samples collected from subjects of the Trial as may
be set forth in the Protocol, and tangible materials directly or indirectly
derived from such samples (collectively, “Biological Samples”) solely as set
forth in the Protocol.

 

III.
Compliance with Regulations

 

3.1 The Sponsor represents and warrants that it is aware of the laws and
regulations applicable to clinical trials of medicinal products for human use
and declares that it will comply with, and will cause the Coordinating
Investigator and the Participating Sites to comply with, all regulations and
guidelines applicable to the Trial, including but not limited to the Declaration
of Helsinki of the World Medical Association and the ICH Harmonised Tripartite
Guideline For Good Clinical Practice E6(Rl) Current Step 4 version dated 10 June
1996 (including the Post Step 4 corrections) as applied to the monitoring and/or
management of clinical trials.

 

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

 

IV.
Sponsor and Coordinating Investigator Responsibilities

 

4.1 Authorizations.

 

(a) The Sponsor is responsible for obtaining and maintaining in force the
authorizations required to carry out the Trial, and in particular and prior to
the start of the Trial: (a) the favorable opinion of the appropriate ethics
committee (“Ethics Committee”), (b) the authorization of the Spanish Agency of
Medicines and Medical Devices (“AEMPS”).

 

(b) The Sponsor. shall keep LIXTE informed at all times in relation to the
process of obtaining reports and authorizations and/or subsequent incidents that
may affect the validity or permissibility of the Trial under applicable law
(including those that may affect the Participating Sites), as well as the
progress _of the Trial.

 

 3 

 

 

(c) At LIXTE’s request, the Sponsor shall provide to LIXTE a copy of the AEMPS
authorization and the Ethics Committee’s approval. The Sponsor shall not make
any substantial modification to the Protocol without prior authorization from
LIXTE.

 

(d) The Sponsor is responsible for making all necessary arrangements and
obtaining all required authorizations for the import and use of the Trial Drug
in the. European Union. LIXTE will make reasonable efforts to furnish
documentation relating to the Tri!. al Drug required for Sponsor to make such
arrangements and obtain such authorizations.

 

4.2 Regulatory Framework. The Sponsor and the Coordinating Investigator will
conduct the Trial (and ensure that the Participating Sites conduct the Trial) in
accordance with:

 

(a) The Protocol;

 

(b) The regulatory authorization legally required for the conduct of the Trial
provided by the AEMPS of Spain;

 

(c) The conditions established by the Ethics Committee; and

 

(d) The anti-corruption clauses contained in Appendix 4 to this Agreement.

 

4.3 Trial Insurance. The Sponsor represents and warrants it will obtain
liability insurance adequate to cover the damages that may result from the Trial
for the subjects on whom it is to be performed, and that such liability
insurance will be adequate to cover damages that may result from the execution
of the responsibilities of the Sponsor, the Coordinating Investigator, the
Participating Sites, the Project Participants, and any sub-contractors. The
Sponsor will provide written evidence of such insurance to LIXTE upon request.

 

4.4 Information Communication and Publication of Results.

 

(a) The Sponsor shall keep LIXTE informed of the progress of the Trial, and
shall provide any information that LIXTE may request for this purpose. In any
case, the Sponsor will send to LIXTE all the results of the Trial (intermediate
and final) (including the Trial Data), during the sixty (60) days following the
date on which such results become available.

 

(b) The Sponsor will not communicate to any laboratory or other commercial
organization the data of the Trial, other than LIXTE.

 

(c) The Sponsor shall make public the results of the Trial via a written report
within one ye r of the end of the Trial. Prior to publication, the Sponsor will
send a draft of the report to LIXTE. Within thirty (30) days of receipt of the
report, LIXTE shall provide any comments and/or raise any reasonable concerns
LIXTE may have with the report, and both parties shall seek in good faith to
address such comments and concerns. If LIXTE determines that Confidential
Information or a LIXTE Invention is contained in the report, the Sponsor and
Coordinating Investigator shall defer publication or disclosure for up to an
additional sixty (60) days from the time LIXTE notifies the Sponsor or
Coordinating Investigator that LIXTE desires patent application(s) to be filed
on the LIXTE Invention. Sponsor shall include in the report a reference to
LIXTE’s participation as a “collaborator” (in the section “acknowledgements” or
similar).

 

 4 

 

 

(d) Notwithstanding the above, the Sponsor will not use the name and/or logos of
LIXTE in any advertising, press releases, announcements, communications, or for
any promotional purpose, without the prior written consent of LIXTE.

 

(e) The Sponsor shall register the Trial, at its inception, on the web site
www.clinicaltrials.gov, and on other national and international clinical study
databases as required.

 

(f) LIXTE will be legitimated to make public the Trial results through· a
summary of them in the registry of clinical trials in the LIXTE web site. In
addition, LIXTE will be entitled to make public, at the beginning of the Trial,
a summary of the protocol in the clinical trial registry on the LIXTE website.

 

4.5 Inspections and Audits.

 

(a) The parties agree that LIXTE, or others designated by LIXTE may, at mutually
agreeable times and with prior written notice, during normal business hours,
arrange with the Sponsor, Coordinating Investigator or their respective
designee:

 

(i) to examine and inspect qualifications of the Project Participants and
Participating Sites required for performance of the Trial according to GCP; and

 

(ii) to inspect and make copies of all data and supporting Trial documentation
to confirm that the Trial is being conducted in conformance with the Protocol
and this Agreement, and in compliance with all applicable legal and regulatory
requirements.

 

(b) LIXTE agrees that all inspections and audits will be conducted in accordance
with the policies and procedures regarding access to the information systems of
the Sponsor or Participating Site, as applicable.

 

V.
Drug Supply

 

5.1 LIXTE undertakes to collaborate with the Sponsor by providing the Trial Drug
as described in Appendix 2.

 

5.2 No Trial Drug samples will be delivered to Participating Sites until the
Sponsor has obtained the necessary authorizations from the AEMPS and the
corresponding Ethics Committee. The Sponsor shall be responsible for the
management, handling, custody, including, if applicable, destruction, of the
Trial Drug in accordance with current legislation, the Protocol and this
Agreement.

 

5.3 The dispensation of the Trial Drug to the subjects of the Trial will be
carried out according to the description of the treatment that appears in the
Protocol. Any reformulation or modification in the composition of the Trial Drug
is prohibited.

 

5.4 ‘The Sponsor, Coordinating Investigator and Participating Sites shall use
the Trial Drug exclusively for the purpose stipulated in the Protocol and in
accordance with the applicable regulations. Unless expressly authorized by
LIXTE, the Sponsor shall not make the Trial Drug and/or any related information
provided by LIXTE available to any third party, except to the Coordinating
Investigator and Participating Sites.

 

 5 

 

 

5.5 The Sponsor shall at all times maintain, and shall cause the Coordinating
Investigator and Participating Sites to maintain, an updated record of the
number and date of dispensation of the Trial Drug samples to each subject of the
Trial.

 

5.6 At the end of the Trial or upon termination of this Agreement, whichever is
earlier, the Sponsor will cause the Coordinating Investigator to provide to
LIXTE a written account of the quantities of the Trial Drug used in the Trial
and will, at LIXTE’s election (i) return to LIXTE any and all remaining stock of
the Trial Drug or (ii) destroy any remaining stock of the Trial Drug, following
the requirements established by applicable legislation.

 

5.7 Any incidents related. to the delivery of the Trial Drug (e.g. damaged
goods, quantity, etc.) should be reported by the Sponsor to LIXTE within
fourteen (14) days of delivery.

 

VI.
Financial Compensation

 

6.1 In consideration for the performance of the Trial, LIXTE undertakes to
collaborate financially with the Sponsor in carrying out the Trial by means of a
maximum contribution of ***.

 

6.2 Payments will be made by bank transfer according to the schedule of
milestones established in Appendix 1. The parties may modify the schedule of
Appendix 1 via a writing signed by each party’s authorized representative.

 

6.3 The parties acknowledge that the amount to be paid by LIXTE hereunder is
reasonable compensation for the work to be performed during conduct of the Trial
and that neither Sponsor, any Participating Site, nor Coordinating Investigator
has received any other compensation or other inducement in connection with this
Agreement or its participation in the Trial

 

6.4 In the event that the number of patients recruited for the Trial is less
than the number set forth in the Protocol, the parties shall meet and confer to
discuss in good faith reduction in the payments due from LIXTE pursuant to
Appendix 1, taking into account the reduction in expenses of conducting the
Trial resulting from the lower number of patients.

 

6.5 Within thirty (30) days of the occurrence of each milestone set forth in
Appendix 1, Sponsor will issue an invoice to LIXTE for the corresponding payment
amount. The Sponsor will include in its invoices the protocol number and title
of the Trial and will send each invoice pursuant to the notification provisions
of Section 14.1. LIXTE shall pay each invoice by bank transfer within thirty
(30) days after receipt of such invoice.

 

6.6 All payments by LIXTE shall be made directly to Sponsor, and not to any
Participating Site or the Coordinating Investigator. Sponsor shall be
responsible for any payments required to be made to Participating Sites or the
Coordinating Investigator.

 

VII.
Exclusion of Liability and Indemnity

 

7.1 The Sponsor is the exclusive institution responsible for the Trial and
LIXTE’s participation is only as a collaborator via the contributions described
in Sections Five and Six. In all its relations with third parties, including the
subjects of the Trial, the Sponsor will not make statements that may indicate or
suggest that LIXTE’s role in the Tri.al is different.

 

7.2 LIXTE assumes no liability to the Sponsor, Coordinating Investigator,
Participating Sites, Project Participants and/or any third party for any losses,
damages, costs; claims, suits and expenses, including the cost and expense of
handling and defending such claims, proceedings, investigations and suits
arising from the conduct of the Trial. Sponsor exonerates and will indemnify
LIXTE from any liability in this regard pursuant to Section 7.3.

 

 6 

 

 

7.3 Sponsor shall indemnify and hold harmless LIXTE and its affiliates and their
respective officers, directors, employees and agents (the “LIXTE Indemnitees”)
from and against any losses, damages, costs, claims, suits and expenses,
including the cost and expense of handling and defending such claims,
proceedings, investigations and suits, arising from a third party claim against
any LIXTE Indemnitee to the extent attributable to (i) a material breach of this
Agreement by Sponsor, or (ii) the gross negligence, malpractice or wrongful acts
of the Coordinating Investigator or participants in the project at any
Participating Site; as applicable. In connection with such indemnity, LIXTE
agrees: (1) to promptly notify Sponsor of any such claim or suit (provided,
however, that Sponsor shall not be released from its obligations under this
Section 7.3 if the failure to promptly notify Sponsor does not materially
prejudice the defense of such claim, proceeding, investigation or suit); (2) to
cooperate fully with Sponsor in defending against such claim or suit; and (3) in
the event of suit, to attend hearings and trials and assist in securing and
giving evidence, and to use reasonable efforts to obtain the attendance of
necessary and proper witnesses. Sponsor shall reimburse LIXTE for all reasonable
expenses incurred at Sponsor’s request in connection with items (ii) and (iii)
above. Sponsor shall have the right to settle any such claim, proceeding,
investigation or suit at the Sponsor’s sole expense provided that any settlement
will not include an admission of liability, wrongdoing or negligence of the
LIXTE Indemnitees or incur a financial obligation on behalf of a LIXTE
Indemnitee, without their prior written consent. Sponsor shall pay for separate
counsel to the extent representation of the LIXTE Indemnitee(s) and Sponsor by
the same counsel is a conflict of interest for such counsel.

 

VIII.
Protection of Personal Data and Informed Consent

 

8.1 The treatment of the personal data of the subjects participating in the
Trial will be in accordance with the General Data Protection Regulation (EU)
2016/679 (GDPR), as well as Law 41/2002 of Spain, which regulates the autonomy
of the patient, and other applicable laws on data protection and patient
autonomy. The Sponsor will comply with and ensure that the Coordinating
Investigator and Participating Sites comply with all the requirements
established by such regulations.

 

8.2 All the information or data concerning Trial that are sent by the Sponsor
and/or the Coordinating Investigator to LIXTE will be sent in an anonymized,
de-identified format, so that LIXTE does not have, in any case, access to the
personal data of Trial patients.

 

8.3 The Sponsor undertakes to ensure that all Participating Sites obtain the
informed consent of the subjects included in the Trial, such informed consent to
include, without limitation, an adequate description of the Trial, its risks,
possible alternatives and each subject’s rights and responsibilities.

 

IX.
Industrial and Intellectual Property Rights

 

9.1 The signature of this Agreement shall not affect the ownership of industrial
and intellectual property rights of which the parties were the holders before
signing it, nor imply the granting of any rights except as expressly stipulated
in this document.

 

 7 

 

 

9.2 All inventions, discoveries, developments, technology and data resulting
from the performance of this Agreement or the Trial, or the use of the Trial
Drug, whether patentable or not (“Inventions”), conceived, reduced to practice
or made by or on behalf of the Sponsor and/or Coordinating Investigator, solely
or jointly with others, that use, relate to, or incorporate the Trial Drug or
LIXTE’s Confidential Information, or that involve identification or use of
biomarkers related to the safety, efficacy or use of the Trial Drug (“LIXTE
Inventions”), shall be the sole and exclusive property of LIXTE, shall promptly
be disclosed in writing by the Sponsor and Coordinating Investigator only to
LIXTE, and Sponsor and the Coordinating Investigator hereby assign to LIXTE all
rights, title and interests in and to such Inventions and all intellectual
property rights therein. LIXTE shall have the sole and exclusive right to
obtain, at its option, patent protection in the United States and other
countries on any LIXTE Invention. LIXTE hereby grants to Sponsor a limited,
non-exclusive, non-transferable and nonsublicenseable license under such LIXTE
Invention, solely for internal non-commercial, academic, research and patient
care purposes. LIXTE shall own all rights in the Trial Data, provided that LIXTE
hereby grants to Sponsor a limited, non-exclusive, nontransferable and
non-sublicenseable license to use and disclose, as necessary, the Trial Data,
solely for (i) internal non-commercial, academic, research and patient care
purposes and (ii) as required to fulfill its obligations under applicable law as
the sponsor of the Trial, subject to Sections 4.4 and 11.

 

9.3 Other than the funding payments specified herein, LIXTE is not obligated to
make any payments to Sponsor in consideration of the licenses set forth herein.

 

9.4 All Inventions other than LIXTE Inventions shall be owned by Sponsor if
invented solely by Sponsor and jointly owned by Sponsor and LIXTE if jointly
invented by Sponsor and LIXTE; provided, however, that Sponsor hereby grants to
LIXTE a limited, non-exclusive, non-transferable and non-sublicenseable license
to use any such Inventions.

 

9.5 Sponsor shall require that all Project Participants and Participating Sites
have assigned to Sponsor their rights to any invention, discovery, development,
technology and data resulting from their performance of this Agreement.

 

9.6 LIXTE will remain at all times the exclusive owner of the Trial Drug,
including all its industrial, commercial, and marketing rights.

 

X.
Drug Safety Monitoring

 

10.1 Sponsor shall make the clinical safety data notifications set forth in
Appendix 3 to LIXTE within the time periods prescribed in Appendix 3. In
addition, the Sponsor shall notify LIXTE of any other clinical safety data
obtained during the Trial within thirty (30) days of such data becoming
available, and at any time when requested by LIXTE.

 

10.2 In accordance with ICH GCP standards and applicable local regulations, the
Sponsor is responsible for assessing all clinical safety information obtained
during the Trial in order to produce all necessary safety reports. These safety
reports shall include, without limitation, the prompt notification of individual
cases of suspected serious and unexpected adverse reactions (SUSAR) and the
Development Safety Update Reports (DSURs). The Sponsor will be responsible for
sending these reports to the competent health authorities, to the relevant
Ethics Committee and to the Coordinating Investigator and Project Participants,
as appropriate, within the relevant timeframes established by law.

 

10.3 In the event that LIXTE has its own Investigator’s Brochure (“IB”) for the
Trial Drug, LIXTE will provide the Sponsor throughout the Trial, for information
purposes, both the IB and its updates and/or supplements.

 

10.4 In the event that LIXTE produces safety reports of the Trial Drug, LIXTE
agrees, for the duration of the Trial, to send a copy of each such safety report
to Sponsor within thirty (30) days of such report’s completion.

 

10.5 In the event that LIXTE prepares periodic SUSAR notification reports to be
sent to investigators for the Trial Drug, LIXTE agrees, for the duration of the
Trial, to send a copy of each such safety report to Sponsor within thirty (30)
days of such report’s completion.

 

 8 

 

 

10.6 LIXTE will ensure that any urgent safety issues relating to the Trial Drug
are reported to the Sponsor by any means that LIXTE, in its absolute discretion,
considers approximate.

 

10.7 The Sponsor will notify LIXTE in advance of any review meetings of the
Independent Data Monitoring Committee (“IDMC”), or equivalent. The Sponsor shall
provide LIXTE, within thirty (30) days following completion of such meeting,
with the minutes of the protocol meetings, and any recommendations or requests
addressed to the Sponsor. The Sponsor shall communicate within forty-eight (48)
hours any urgent safety issues relating to the LIXTE investigational medicinal
product(s) identified at these meetings.

 

10.8 The Sponsor will notify LIXTE within twenty-four (24) hours after learning
of any serious adverse effect or drug reaction affecting any subject in the
Trial.

 

10.9 If a subject of the Trial is injured or becomes ill as a result of
participating in the Trial, the Sponsor and/or Coordinating Investigator will be
solely responsible for providing, at their expense, the medical treatment
necessary to diagnose and treat such injury or illness.

 

XI.
Confidentiality

 

11.1 During the term of this Agreement, the parties may obtain certain
Confidential Information, as hereinafter defined, from each other or as a result
of performing the Trial. “Confidential Information” shall mean all information
provided by LIXTE (including, but not limited to, information about the Trial
Drug), as well as all the information obtained during the development of the
Trial and the personal data of the subjects recruited in the Trial.

 

11.2 Sponsor and Coordinating Investigator agree to, and agree to cause the
Participating Sites to: (i) use the Confidential Information only in connection
with their performance of this Agreement, (ii) treat the Confidential
Information as they would their own proprietary and confidential information,
and (iii) to take all reasonable precautions to prevent disclosure of the
Confidential Information to any third party, except for legal and financial
counsel involved in the Trial.

 

11.3 The foregoing obligations of Section 11.2 shall not be mandatory with
respect to information that (i) has been published by LIXTE or is in the public
domain for reasons other than non-compliance by the Sponsor, (ii) was previously
accredited by evidence in the Sponsor’s possession, (iii) is required by law or
regulation to be disclosed; provided that the Sponsor shall notify LIXTE of any
proceedings or requests that could result in disclosure under this Section 11.3
in sufficient time to permit LIXTE to take the appropriate measures to prevent
such disclosures or (iv) is made available to the Sponsor or coordinating
Investigator for use or disclosure from any third party having a legal right to
do so and who is not under any obligation to keep such information confidential.

 

11.4 The Sponsor and the Coordinating Investigator agree to maintain, and agree
to cause the Participating Sites to maintain, all Confidential Information in
the strictest confidence for a period of ten (10) years from the termination of
this Agreement.

 

11.5 Upon LIXTE’s written request, the Sponsor shall, and shall cause the
Coordinating Investigator and Participating Sites to, promptly deliver to LIXTE
or to destroy if so requested, as applicable, all originals, copies, and
summaries of documents, materials, and other tangible manifestations of
Confidential Information belonging to LIXTE and any other property of LIXTE, as
applicable, in its possession or under its control, in whatever media; provided,
however, that Sponsor or Coordinating Investigator shall be entitled to retain
in confidence under this Agreement, (i) one (1) archived copy of the
Confidential Information, including without limitation notes and memoranda,
solely for the purpose of administering its obligations or exercising its rights
under this Agreement; and (ii) Confidential Information contained in its
electronic back-up files that are created in the normal course of business
pursuant to its standard protocol for preserving its electronic records.

 

 9 

 

 

XII.
Duration

 

12.1 Except in the cases of early termination described below, this Agreement
shall remain in force until the completion of the Trial and the fulfillment of
all the obligations contemplated therein.

 

12.2 The Trial is expected to be carried out in the following stages:

 

  ● Administrative start-up: 4 months         ● First subject visit (FSV): Q4
2019         ● Total recruitment period: 24 months         ● Treatment period: 6
months         ● Follow-up period: 6 months         ● Close-out: 4 months      
  ● Estimated end of study: Q3 2022

 

XIII.
Early Termination of the Agreement

 

13.1 Termination for Breach. Either party may terminate this Agreement for any
material breach by the other party if it: (i) provides written notification of a
material breach to the other party and (ii) the other party fails to cure such
material breach within thirty (30) days of receipt of such notification.

 

13.2 Termination by LIXTE. Without prejudice to LIXTE’s right to claim any
damages, LIXTE shall be entitled to terminate this Agreement at any time,
without any requirement other than prior notice to Sponsor and without having to
pay any indemnity to the Sponsor for such early termination.

 

13.3 Termination for Health or Safety. Finally, either party may immediately
terminate this Agreement if: (i) it believes that immediate termination is
necessary due to an evaluation of risks to the safety and/or health of the
subjects involved in it or (ii) it is informed that approval to conduct the
Trial has been withdrawn by AEMPS or other applicable regulatory authority.

 

13.4 Effect of Termination. In the event of any termination:

 

(a) The Sponsor shall cause the Coordinating Investigator to issue a report as
to remaining amounts of the Trial Drug, and return or destroy such remaining
amounts of the Trial Drug pursuant to Section 5.6.

 

(b) The Sponsor shall return to LIXTE the amount corresponding to those expenses
that at the time of the suspension had not yet occurred.

 

(c) The Sponsor shall return or destroy all Confidential Information or other
property of Lixte pursuant to Section 11.5.

 

 10 

 

 

13.5 Survival of Provisions. Sections 2.8, 3.1, 4.3, 4.4, 4.5, 6.3, 7, 8, 9, 10,
11, .13, 14 and any other provision required for the interpretation thereof
shall survive termination of this Agreement.

 

XIV.
Miscellaneous

 

14.1 Notices. All communications related to this Agreement will be addressed in
writing, in English, and (i) mailed posted repaid by certified or registered
mail, return receipt re-· quested, or (ii) personally delivered to the
appropriate party via electronic delivery or reputable overnight service with
written verification of receipt, or (iii) emailed, in each case to the
appropriate addresses indicated below:

 

Grupo Español de Investigación en Sarcomas

C/ Diego de León 47

28006 Madrid, Spain

Email: secretaria@grupogeis.org

Lixte Biotechnology Holdings, Inc.

248 Route 25A No. 2

East Setauket, New York 11733, USA

Email: [jkovach@lixte.com

 

Notices shall be deemed to have been received at the earlier of receipt or five
(5) days from the date of mailing (in the case of a letter).

 

14.2 Law and Jurisdiction. This Agreement and its appendices shall be governed
by Spanish law. In order to resolve any discrepancy that may occur in the
application or interpretation of the provisions of this Agreement, the parties
submit, expressly waiving any jurisdiction that may correspond to them, to the
jurisdiction of the Courts of Madrid, Spain.

 

14.3 Compliance with Law. Any provisions of law that invalidate, or otherwise
are inconsistent with, the terms of this Agreement, or that would cause any of
the parties to be in violation of the law, shall be deemed to supersede the
terms of this Agreement; provided, however, that the parties shall use their
best efforts to amend this Agreement to accommodate any such changes that most
closely approximate the intent and economic effect of the invalid provision. In
the event that this Agreement cannot be so amended, this Agreement shall
terminate, and the provisions of Section 13.4 shall apply.

 

14.4 Assignment. Neither party may assign this Agreement without the prior
written consent of the other party, which consent will not be unreasonably
withheld; provided, however, that either party may assign this Agreement without
consent to a successor-in-interest to substantially all of the business of that
party to which the subject matter of this Agreement relates upon delivery to the
other party of notice of such assignment, provided that the successor agrees to
assume all responsibilities and obligations under this Agreement. This
Agreement, including the indemnification obligations under Section 7.3, shall be
binding upon and inure to the benefit of the ·parties hereto, their respective
permitted successors, assigns, legal representatives and heirs.

 

14.5 Independent Contractors. For purposes of this Agreement, LIXTE shall not be
deemed an agent, servant, partner, joint venturer or employee of Sponsor. Thus
it does not have the authority to take action on Sponsor’s behalf or to bind
Sponsor without Sponsor’s prior written consent. Lixte is acting in the capacity
of an independent contractor of Sponsor.

 

14.6 No Waiver. Either party’s failure to require the other party to comply with
any provision of this Agreement shall not be deemed a waiver of such provision
or any other provision of this Agreement.

 

14.7 Entire Agreement. This Agreement represents the entire understanding of the
parties with respect to the subject matter hereof, and supersedes all prior and
contemporaneous agreements between the parties, whether written or oral. Any
modification, amendment or supplement to this Agreement or Appendices attached
hereto shall be in a writing signed by an authorized representative of each
party.

 

 11 

 

 

14.8 Severability. If any clause, section or paragraph of this Agreement is
determined by a court of competent jurisdiction to be illegal, invalid or
unenforceable, it will be deemed severed from the remainder of this Agreement
and will have no effect on the legality, validity or enforceability of the
remaining provisions of this Agreement. The parties shall negotiate in good
faith to replace any illegal, invalid or unenforceable provision with a legal,
valid and enforceable one such that the objectives contemplated by the parties
when entering this Agreement may be realized.

 

14.9 Rules of Construction and Interpretation. Unless the context otherwise
requires: (i) references in this Agreement to any gender include references to
all genders, and references to the singular include references to the plural and
vice versa; (ii) the words “include”, “includes” and “including” when used in
this Agreement shall be deemed to be followed by the phrase “without
limitation”; (iii) references in this Agreement to Articles, Sections,
Appendices and Schedules shall be deemed references to Articles and Sections of,
and Appendices and Schedules to, this Agreement, as applicable; (iv) the words
“hereof’, “hereby” and “herein” and words of similar meaning when used in this
Agreement refer to this Agreement in its entirety and not to any particular
Article,. Section or provision of this Agreement; (v) where either party’s
“consent” or “approval” is required hereunder, except as otherwise specified
herein, such party’s consent or approval may be granted or withheld in such
party’s sole discretion; (vi) the words “shall,” “will,” or “agrees” are
mandatory and “may” is permissive; (vii) the word “or” is not exclusive; (viii)
any definition or reference to any agreement, instrument or other document
herein shall be construed as referring to such agreement, instrument or other
document as from time to time amended, supplemented or otherwise modified
(subject to any restrictions on such amendments, supplements or modifications
set forth herein or therein); (ix) all references to contracts, agreements,
leases or other arrangements shall refer to oral as well as written matters; (x)
any reference to any laws herein shall be construed as referring to such laws as
from time to time enacted, repealed or amended and (xi) any reference herein to
any person shall be construed to include the person’s successors and permitted
assigns.

 

14.10 Representations and Warranties. Sponsor and LIXTE each represent and
warrant that: (i) it is a corporation or other legal entity duly incorporated or
established, validly existing and in good standing, (ii) such party has the
legal authority and right to enter into this Agreement, (iii) it has taken all
necessary actions on its part to authorize the execution, delivery and
performance of the obligations undertaken in this Agreement, and no other
corporate actions are necessary with respect thereto, (iv) it has no obligation
to any other party which is in conflict with its obligations under this
Agreement, and (v) it is duly licensed, authorized or qualified to do business
and is in good standing in every jurisdiction in which a license, authorization
or qualification is required for it to perform its obligations under this
Agreement.

 

14.11 Further Assurances. Each party hereto agrees to duly execute and deliver,
or cause to be duly executed and delivered such further instruments and do and
cause to be done such further acts and things, including without limitation, the
filing of such additional assignments, agreements, documents and instruments,
that may be necessary or as the other party hereto may at any time and from time
to time reasonably request in connection with this Agreement or to carry out
more effectively the provisions and purposes hereof or to better assure and
confirm unto such other party its rights and remedies under this Agreement.

 

14.12 Counterparts. This Agreement may be executed in several counterparts, each
of which shall be deemed an original but all of which shall constitute one and
the same instrument. This Agreement may be executed electronically. Each
counterpart shall be considered an original whether or not such counterpart is
executed electronically.

 

 12 

 

 

In proof of conformity, the parties sign this Agreement in duplicate as of the
Effective Date.

 

Grupo Español de Investigación en Sarcomas   Lixte Biotechnology Holdings, Inc.
      By:     By:   Name: Claudia Valverde Morales   Name: John S. Kovach, M.D.
Title: President   Title: President & CEO Date:     Date:  

 

 13 

 

 

Appendix 1: Budget & Payment Schedule

 

Protocol reviewed by FDA and delivery of required documentation/permits

 

Payment No.   Total***   Milestone   Estimated Date 1       Upon CTA signature  
Q3 2019 2       Protocol reviewed by FDA and delivery of required
documentation/permits for LB-100 import and use in the EU   Q3 2019 3       EC
and RA approvals in Spain   Q4 2019 4       Phase 1: First patient in   Q4 2019
5       Phase 1: Final clinical report   Q2 2020 6       EC and RA approval in
Country 2   Q1 2020 7       Phase 2: First patient in   Q2 2020 8       Phase 2:
20% of patients enrolled (30)   Q3 2020 9       Phase 2: 40% of patients
enrolled (60)   Q4 2020 10       Phase 2: Interim analysis report   Q1 2021 11  
    Phase 2: 60% of patients enrolled (90)   Q2 2021 12       Phase 2: 80% of
patients enrolled (120)   Q3 2021 13       Phase 2: 100% of patients enrolled
(150)   Q4 2021 14       Phase 2: Final clinical report   Q1 2022 15       Phase
2: First publication in congress   Q2 2022 16       Phase 2: All sites
closed-out   Q3 2022 17       Phase 2: Manuscript published in journal   Q4 2022

 

 Appendix 1 - Page 1 

 

 

Appendix 2: Drug Supply

 

Samples provided for protocol:

 

“Randomized phase I/II trial of LB-100 plus doxorubicin vs. doxorubicin alone in
first line of advanced soft tissue sarcoma”

 

LIXTE will provide the Sponsor with the samples described below for use in the
Trial only.

 

Name of the product:   LB-100 for intravenous injection Product code:     Item
Code:     Type of sample:   Glass vials each containing 10 mL of 1.0 mg/mL LB100
Presentation/Content:     Quantity:     Technical storage conditions:   Frozen
at minus 10° C to minus 25° C or lower Period of technical validity:   To March
30, 2020 Packaging components:   Frozen vials Reference documents:    

 

Reception and Storage

 

Upon receipt of the product, check that the seal is intact and contents are
frozen. Ensure that the material is. stored in a -20° C freezer or colder in
accordance with Good Manufacturing Practice (GMP) or local regulations in force.
If there is any sign of deterioration, contact LIXTE immediately.

 

Postprocessing

 

Any further processing must be carried out in accordance with GMP standards or
local regulations in force.

 

The Sponsor will be responsible for ensuring that the packaging/labeling
complies with local regulations, product separation and appropriate controls to
prevent product mixing.

 

Subsequent delivery, monitoring and other rearrangement activities will also be
under the responsibility of the Trial Sponsor.

 

Notifications and Complaints

 

If during the Trial LIXTE becomes aware of any problem that may affect the
quality of the samples, LIXTE will promptly notify the Sponsor. The
responsibility for claiming any investigational medication rests with the
Sponsor, after consultation with LIXTE and/or any other company that supplied
the products.

 

The Sponsor must notify LIXTE of protocol changes that may affect the use of the
samples provided for the clinical trial.

 

Destruction

 

The destruction will be performed by the Sponsor in accordance with Good
Manufacturing Practice, Good Clinical Practice and national legal requirements.

 

 Appendix 2 - Page 1 

 

 

Appendix 3: Notifications of Safety Data

 

Definition of Adverse Event and Serious Adverse Event

 

For the purposes of this Agreement, an adverse event .(AB) means any harmful
incident to a clinical trial subject’s health, whether or not causally related
to the drugs (or other materials) used in the Trial, and a serious adverse event
(SAE) means any adverse event that results in death, life threatening, disabling
or incapacitating, requiring hospitalization or prolongation of hospitalization.

 

Serious Adverse Events

 

The Sponsor shall notify LIXTE and Theradex Oncology of all SAEs that occur
during the Trial in subjects exposed to the LIXTE drug(s) (in accordance with
the protocol) by sending a copy of the original pages of the SAE forms,
completed in English within 24 hours of becoming aware of the event, regardless
of the causal assessment established by the Sponsor/Investigator.

 

PDF’s of SAE are emailed to:

 

TBD

TBD

Theradex Oncology

4365 Route 1 South

Suite 101

Princeton, NJ 08540 USA

 

John S. Kovach

jkovach@lixte.com

Lixte Biotechnology

248 Rout 25A No. 2

East Setauket, NY 11733 USA

 

Pregnancy Notification

 

The Sponsor will notify LIXTE of the pregnancy status of any patient who becomes
pregnant while participating in the Trial and has been exposed to a LIXTE
medication under the Trial by sending copies of the original pregnancy
notification form to LIXTE within two weeks of becoming aware of the pregnancy.
It will also follow up to determine the outcome of the pregnancy, including
premature pregnancy termination.

 

How Safety Clinical Data Will Be Submitted to LIXTE

 

The above notices and information, shall be communicated to LIXTE in English to
the following address:

 

248 Route 25A No. 2

East Setauket, New York 11733, United States

Attention: CEO

 

Reporting Period

 

AEs that are subject to the above provisions are those that occur after the
first dose of the LIXTE Trial drug(s) up to 28 days after discontinuation of the
LIXTE Trial drug(s).

 

Request for Follow-Up Information

 

The Sponsor will provide LIXTE with details of to whom LIXTE should address
requests for followup information regarding the AEs cases reported in this
Trial, and undertakes to update these details as appropriate.

 

 Appendix 3 - Page 1 

 

 

Appendix 4: Anti-Corruption Clauses

 

These anti-corruption clauses form part of the terms and conditions of the
Agreement between the Sponsor and LIXTE. Any supply of product and services to
Veolia incorporates these terms by reference.

 

1. In carrying out the Trial, the Sponsor hereby undertakes to strictly comply
with applicable laws prohibiting the bribery of public officials and private
persons, ·influence peddling, money laundering that may in particular entail a
public contract debarment. The Sponsor undertakes to put in place and implement
all necessary and reasonable policies and measures to prevent corruption.

 

2. The Sponsor declares that to its knowledge, its legal representatives,
directors, employees, agents, and anyone providing services do not and will not
directly or indirectly offer, give, agree to give, authorize, solicit, or accept
the giving of money or anything else of value or grant any advantage or gift to
any person, company or undertaking whatsoever including any government official
or employee, political party official, candidate. for political office, person
holding a legislative, administrative or judicial position of any kind for or on
behalf of any country, public agency or state owned company, official of a
public international organization, for the purpose of corruptly influencing such
person in their official capacity, or for the purpose of rewarding or inducing
the improper performance of a relevant function or activity by any person in
order to obtain or retain any business or to gain any advantage in the conduct
of business.

 

3. The Sponsor further undertakes to ensure that neither the Sponsor nor any of
its legal representatives, directors, employees, agents, sub-contractors and
anyone performing services under this Agreement has been, or is listed ·by any
government agency as being debarred, suspended, proposed for suspension or
debarment.

 

4. The·Sponsor agrees to notify any breach of any term of these clauses, to
LIXTE within a reasonable time.

 

5. If LIXTE notifies the Sponsor that it has reasonable grounds to believe that
the Sponsor has breached any term of these clauses:

 

(a) LIXTE is entitled to suspend performance of this Agreement without notice
for as long as LIXTE considers necessary to investigate the relevant conduct
without incurring any liability or obligation to the Sponsor for such
suspension;     (b) The Sponsor is obliged to take all reasonable steps to
prevent the loss or destruction of any evidence in relation to the relevant
conduct.

 

 Appendix 4 - Page 1 

 

 

Appendix 5: Protocol Synopsis

 

CLINICAL TRIAL SUMMARY

 

Trial Title   Randomized phase I/II trial of LB-100 plus doxorubicin vs.
doxorubicin alone in first line of advanced soft tissue sarcomas       Study
Type   Phase I-II, two-arm, randomized, open-label, multicenter, international
clinical trial       Sponsor  

Grupo Español de Investigación en Sarcomas (GEIS)

C/ Diego de León, 47

28006, Madrid, Spain

www.grupogeis.org

      CRO  

Sofpromed Investigación Clinica, SLU

C/ del Ter, 27 - 2nd Floor - Office 8D

07009 Palma de Mallorca, Spain

Tel: +34 648 414 261

Fax: +34 971 570 222

E-mail: ensayos@sofpromed.com

      Study Indentifiers  

Study Acronym:

Sponsor Protocol Number: GEIS-74

EudraCT Number: 2019-003034-16

      Coordinating Investigators   Clinical Coordinating Investigator:

 

    ● Dr. Javier Martin - Hospital Universitario Virgen del Rocío (Seville)

 

    Translational Coordinating Investigator:

 

    ● Dr. David da Silva Moura - Hospital Universitario Virgen del Rocío
(Seville)         Planned Calendar   ● Administrative start-up: 4 months        
    ● First subject first visit (FSFV): Q4 2019             ● Total recruitment
period duration: 24 months             ● Treatment: 6 months             ●
Follow-up period: 6 months             ● Close-out: 4 months             ●
Estimated end of study date: Q3 2022

 

Estimated Accrual Rate   6-7 cases per month (at international level)

 

 Appendix 5 - Page 1 

 

 

Clinical Study Objectives  

PHASE I

 

Primary clinical study objective

 

    ● To determine the maximum tolerated dose (MTD) of LB-100 in combination
with doxorubicin (to be used as recommended dose for the phase II part).

 

    Secondary clinical study objectives

 

    ● To evaluate the safety profile according to CTCAE 4.03.             ● To
assess the activity of this combination (ORR, median PFS, median OS)            
● To assess pharmacodynamic parameters in tumor tissue

 

   

PHASE II

 

Primary clinical study objective

 

    ● To comparatively evaluate the efficacy of the LB-100 plus doxorubicin
combination vs. doxorubicin alone as measured by median progression-free
survival (PFS) in patients with advanced soft tissue sarcomas.

 

    Secondary clinical study objectives

 

    ● To determine the objective response rate (ORR).             ● To evaluate
overall survival (OS).             ● To evaluate the safety profile.            
● To evaluate quality of life.             ● To correlate translational
parameters (biomarkers) with clinical outcome.

 

 Appendix 5 - Page 2 

 

 

Analytical Endpoints  

PHASE I

 

Primary clinical study objective

 

    ● The MTD of LB- I 00 in combination with doxorubicin will be determined by
assessing adverse events according to CTCAE 4.03 and they will be used as a rule
for escalating or diminishing dose levels regarding the dose-limiting toxicities
detailed in the protocol.

 

    Secondary clinic.al study objectives

 

    ● Safety profile of the trial treatments, through assessment of adverse
event type, incidence, severity, time of appearance, related causes, as well as
physical explorations and laboratory tests. Toxicity will be grad- ed and
tabulated by using CTCAE 4.03.             ● Activity will be measured as ORR,
median PFS and media OS.             ● Pharmacodynamic changes will be checked
in order to analyze the impact of combination of these compounds in cell-cycle
control and apoptosis signaling.

 

   

PHASE II

 

Primary clinical study endpoint

 

    ● Progression-free survival (PFS): Efficacy measured by median PFS according
to RECIST 1.1. PFS for each patient is defined as the time measured in months
from registry to progression or to death due to any cause, whatever occurs
first.

 

    Secondary clinical study endpoints

 

    ● Objective Response Rate (ORR): ORR is defined as the number of subjects
with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response
(PR) divided by the number of response evaluable subjects (according to RECIST
1.1 criteria).             ● Overall survival (OS): OS is defined as the time
between the date of first dose and the date of death due to any cause. OS will
be censored on the last date a subject was known to be alive. Median of OS      
      ● Safety profile of the trial treatments, through assessment of adverse
event type, incidence , severity, time of appearance, related causes, as well as
physical explorations and laboratory tests. Toxicity will be graded and
tabulated by using CTCAE 4.03.             ● Quality of life measured by QLQ-C30
EORTC questionnaire.

 

 Appendix 5 - Page 3 

 

 

Population  

Adult patients with confirmed diagnosis of advanced undifferentiated pleomorphic
sarcoma, leiomyosarcoma, myxoid/and hypercellular myxoid liposarcoma,
myxofibrosarcoma, NOS sarcoma, synovial sarcoma, fibrosarcoma and malignant
peripheral nerve sheath tumors (MPNST).

 

Number of Patients  

Phase I: 9-18 patients

 

Phase II: 150 patients

 

Total study: 168 (including 14% of losses)

 

Sample Size Calculation  

An enrollment of 150 patients is planned (75 per arm), of whom at least 130 are
expected to be considered eligible (including external pathological review),
recruited during 24 months. A maximum of 14% patients is assumed not reaching
progression or death during the study because of follow-up losses, protocol
violations, and patient refusal or not having progressed at the time of the
statistical analysis of study endpoints.

 

The primary endpoint, progression free survival (PFS) will be measured from the
date of randomization until there is radiological evidence of disease
progression or death of any cause. The main analysis will be conducted when 102
events occur. Assuming a control group median PFS of 4.5 months (HO) and an
alternative mPFS of 7.5 months for the experimental arm (Hl ), this design will
allow for the demonstration of a statistically significant decrease in the
relative risk of progression or death with a Hazard Ratio of 0.72 in the
experimental arm (alpha=0.05, beta=0.2).

 

 Appendix 5 - Page 4 

 

 

Treatment  

Phase I: Dose-finding stage

 

A dose-finding stage is planned for an initial set of 9-18 patients (21-day
cycles):

 

    ● Starting at Dose Level 1: LB-100 1.75 mg/m2/d dl-3 followed on day 1 by
Doxorubicin 60 mg/m2 /d (d1 only)     ● Dose Level 2: LB-100 1.75 mg/m2/d dl-3
followed on day 1 by Doxorubicin 75 mg/m2 /d (d1 only)     ● Dose Level 3:
LB-100 2.33 g/m2/d dl-3 followed on day 1 by Doxorubicin 75 mg/m2 /d (dl only)  
  ● Dose Level -1: LB-100 1.25 mg/m2 /d d1-3 followed on day 1 by Doxorubicin 60
mg/m2 /d (dl only)     ● (If Dose Level -1 needs to be tested, a new scalation
dose level would be LB-100 1.25 mg/m2/d dl-3 followed on day 1 by Doxorubicin 75
mg/m2/d (d1 only)

 

   

After 6 cycles (in absence of progression or intolerance), LB-100 will be
administered as maintenance phase, until disease progression or intolerance, in
cycles every 3 weeks.

 

The procedure in the Phase I part is the classical 3+3 design. The dose
escalation rules are as follows: escalating in cohorts of 3-6 patients per dose
level. Three patients are treated at a given dose level. If at least 2 patients
are observed to have dose-limiting toxicity (DLT), the prior dose level is
defined as the maximum tolerable dosage (MTD) (unless only 3 patients have been
treated at that level, in which case it is the tentative MTD). If 0 of the 3
patients are observed to have DLT, the dose level is escalated one step for the
next cohort of 3 patients, and the process continues as above. If exactly 1 of
the 3 patients treated show DLT, 3 additional patients are treated at the
current dose level. If none of these additional 3 patients show DLT, the dose
level is escalated for the next cohort of 3 patients, and the process continues
as above; otherwise, the prior dose level is defined as the MTD.

         

Phase II

 

In the phase II part, the dose of doxorubicin in the control arm will be 75
mg/m2/d dl intravenously by 20 minute infusion every 3 weeks and in the
experimental arm, doxorubicin, at recommended dose derived from phase I part,
will be administered intravenously by 20 minute infusion after completion of the
administration of LB-100 by 2-hour intravenous infusion at the recommended dose
derived from phase I part. LB-100 is administered during each of the first 3
days of each cycle and doxorubicin is administered on day 1 only of each 3-week
cycle.

 

After 6 cycles (in absence of progression or intolerance), LB-100 will be
administered as maintenance phase, until disease progression or intolerance, in
cycles every 3 weeks.

 

Treatment will continue until disease progression, development of unacceptable·
toxicity, non-compliance, withdrawal of consent by the patient or investigator
decision.

 

 Appendix 5 - Page 5 

 

 

Drug Information  

LB-100

 

Pharmaceutical form: Sterile solution for injection.

 

Route of administration: Intravenous use.

 

Doxorubicin

 

Pharmaceutical form: Powder for injection.

 

Route of administration: Intravenous use.

 

Inclusion Criteria   1. Patients must provide written informed consent prior to
performance of study-specific procedures and must be willing to comply with
treatment and follow-up. Informed consent must be obtained prior to start of the
screening process. Procedures conducted as part of the patient’s routine
clinical management (e.g. blood count, imaging tests, etc.) and obtained prior
to signature of informed consent may be used for screening or baseline purposes
as long as these procedures are conducted as specified in the protocol.     2.
Age ≥ 18 years     3. Histologic diagnosis of soft tissue sarcoma
(undifferentiated plea- morphic sarcoma, leiomyosarcoma, myxoid and
hypercellular myxoid liposarcoma, myxofibrosarcoma, NOS sarcoma, synovial
sarcoma, fibrosarcoma, and malignant nerve sheath tumor) confirmed by central
pathology review.     4. Mandatory pre-treatment formalin-fixed paraffin
embedded (FFPE) tumor tissue must be provided for all subjects without exception
for central pathology review and translational research. If archive biopsy is
not available or this achived tuor sample is older than 3 months, the patient
must be willing to have a pre-treatment re-biopsy of primary or meta- static
tumor (baseline biopsy). In the phase I part, there will be a second mandatory
biopsy just before the 3rd cycle.     5. Metastatic/advanced disease in
progression in the last 6 months, and not suitable for metastasectomy or
surgical resection.

 

 Appendix 5 - Page 6 

 

 

    6. Measurable disease according to RECIST 1.1 criteria.     7. Eastern
Cooperative Oncology Group (ECOG) Performance Status of 0-1.     8. The patient
is naive of any previous treatment with anthracyclines.     9. Adequate organ,
hepatic, renal, cardiac, and hematologic function.     10. Laboratory tests as
follows:

 

    Absolute neutrophil count ≥ 1,200/mm3           Platelet count ≥ 100,000/mm3
          Hg > 9 g/dl           Bilirubin ≤ 1.5 mg/dL           PT and INR ≤ 1.5
          AST and ALT ≤ 2.5 times ULN           Creatinine ≤ 1.5 mg/dL or
estimated C1Creatinine ≥ 90 ml/min           Calcium ≤ 12 mg/dL           Blood
glucose < 150 mg/dL

 

    11. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan
assessed within 28 days before randomization.             12. Females of
childbearing potential must have a negative serum or urine pregnancy test within
24 hours prior to study treatment initiation and agree to use birth control
measures during study treatment and for 7 months after its completion. Patients
must not be pregnant or nursing at study entry. Women/men of reproductive
potential must have agreed to use an effective contraceptive method.            
13. Men or women of child bearing potential should be using an effective method
of contraception before entry into the study and throughout the same and for 6
months after ending the study. Women of childbearing potential must have a
negative urine pregnancy test before study treatment initiation.             14.
Patient must have a Central Venous Catheter for treatment.

 

 Appendix 5 - Page 7 

 

 

Exclusion Criteria   1. Previous treatment with doxorubicin, epirubicin,
idarubicin, and/or other anthracyclines or any other systemic therapy.     2.
Uncontrolled intercurrent illness including (not limited to): symptomatic
congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV),
unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks
prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias
of NCI CTCAE version 4.03 Grade >= 2), known psychiatric illness that would
limit study compliance, intra- cardiac defibrillators, known cardiac metastases,
or abnormal cardiac valve morphology(>= Grade 3).     3. It should be performed
HBV and HCV serologies prior to inclusion. If HbsAg is positive it is
recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If
these were positives the inclusion is not recommended, remaining at
investigators’ discretion the preventive treatment with lamivudine. If a
potential patient is positive for antiHCV antibodies, presence of the virus
should be ruled out with a qualitative PCR, or the patient should NOT be
included in the study (if a qualitative PCR cannot be performed then patient
will not be able to enter the study)     4. Other disease or illness within the
past 6 months, including any of the following:

 

    ● Myocardial infarction     ● Severe or unstable angina     ● Coronary or
peripheral artery bypass graft     ● Symptomatic congestive heart failure     ●
Cerebrovascular accident or transient ischemic attack     ● Pulmonary embolism

 

    5. Plasma bilirubin > ULN.     6. Creatinine > 1.6 mg/dL.     7. Evidence of
a bleeding diathesis.     8. Ongoing cardiac dysrhythmias > Grade 2.     9.
Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for
females) on baseline ECG.     10. History of allergy to study drug components.  
  11. History of another cancer with the exception of adequately treated basal
cell carcinoma or in situ cervical cancer, or with a relapse-free interval
longer than 5 years after treatment of the primary cancer with no substantial
risk of recurrence.     12. Presence of brain or central nervous system
metastases at the time of randomization .     13. Patient is unwilling to
provide translational tumor sample/s or biopsies (if required) are not easy to
be taken.         Translational Study Objectives   1. To determine predictive
biomarkers, or predictive gene signatures, of LB-100 plus doxorubicin, in
formalin-fixed paraffin-embedded (FFPE) tumor samples collected before
treatment.     2. To study the cell signaling pathways relevant in the potential
clinical benefit induced by the combination of LB-100 plus doxorubicin.     3.
To evaluate the immune-phenotype induced by LB-100 plus doxorubicin, in
peripheral blood samples collected at several time points during patient
treatment.     4. To assess potential soluble predictive biomarkers of LB-100
plus doxorubicin in plasma samples collected during patient treatment.

 

 Appendix 5 - Page 8