EXHIBIT 10.38
 
MATERIAL TRANSFER AGREEMENT

This Material Transfer Agreement (“MTA”) has been adopted for use by Cellceutix
Corporation, 100 Cummings Center, Suite 151-B, Beverly, MA 01915 (“Cellceutix”)
in all transfers of research material (“Research Material”) whether Cellceutix
is identified below as its Provider or Recipient.

Provider: Cellceutix Corporation
Provider’s address: 100 Cummings Center, Suite 151-B, Beverly, MA 01915

Recipient: Beth Israel Deaconess
Recipient’s address: 330 Brookline Avenue, Boston, MA 02215

1.  Provider agrees to transfer to Recipient’s Investigator named below the
following Research Material:
_____________Kevetrin_____________________________________________

2.  THIS RESEARCH MATERIAL MAY NOT BE USED IN HUMAN SUBJECTS.  This Research
Material will only be used for research purposes by Recipient’s investigator in
his/her laboratory, for the Research Project described below under suitable
containment conditions.  This Research Material will not be used for commercial
purposes such as serving, production or sale, for which a commercialization
license may be required.  Recipient agrees to comply with all Federal rules and
regulations applicable to the Research Project and the handling of the Research
Material.

2(a).  Are Research Materials of human origin? _________yes____X____no

2(b).  If yes in 2(a), were Research Materials collected according to 45 CFR 46
“Protection of Human Subject?” __________yes__________no

Please provide Assurance Number:
________________________________________________

3.  This Research Material will be used by Recipient’s investigator solely in
connection with the following research project (“Research Project”) described
with specificity as follows (use an attachment page if necessary):

See ATTACHED Research Project entitled “Assessment of the Therapeutic Potential
of Kevetrin in Melanoma and Renal Cell Carcinoma” at end of document below

4.  Recipient shall obtain written approval on Research Project protocol and
procedures from Cellceutix before starting the Research Project. Recipient shall
not publish or disclose results of the Research Project without written consent
from Cellceutix. Recipient also agrees to include a member of the Cellceutix
team as a research collaborator and author in all Research Project publications
or publications involving the Research Material named above.
 
 
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5.  This Research Material represents a significant investment on the part of
Provider, and is considered proprietary to Provider.  Recipient’s investigator
therefore agrees to retain control over this Research Material, and further
agrees not to transfer the Research material to other people not under her or
his direct supervision without advance written approval of Provider.  Provider
reserves the right to distribute the Research Material to others and to use it
for its own purposes.  When the Research Project is completed, or three (3)
years have elapsed, whichever occurs first, the Research Material will be
destroyed by Recipient or otherwise disposed of as mutually agreed by Provider
and Recipient. Furthermore, Information regarding the Research Project, apart
from publications as mentioned above, will be considered confidential and will
be treated as such by Recipient.

6.  This Research Material is BEING SUPPLIED TO RECIPIENT WITH NO WARRANTIES,
EXPRESS OR IMPLIED, INCLUDING ANY WARRANTY OF MERCHANTABILITY OR FITNESS FOR A
PARTICULAR PURPOSE.  Provider makes no representations that the use of the
Research Material will not infringe any patent or proprietary rights of third
parties.

7.  Cellceutix shall retain title to any patent or other intellectual property
rights in inventions made by Recipient’s employees in the course of the Research
Project.  Unless prohibited by law from doing so, Recipient agrees to hold
Provider harmless and to indemnify Provider for all liabilities, demands,
damages, expenses and losses arising out of Recipient’s use for any purpose of
the Research Material.

8.  The undersigned Provider and Recipient expressly certify and affirm that the
contents of any statements made herein are truthful and accurate.

9.  The validity, interpretation, performance and enforcement of this Agreement
shall be governed by the laws of the Commonwealth of Massachusetts, without
regard to its choice of law provisions.  The parties hereto hereby irrevocably
and unconditionally consent to the exclusive jurisdiction of the courts of the
Commonwealth of Massachusetts and the United States District Court for the
District of Massachusetts for any action, suit or proceeding (other than appeals
therefrom) arising out of or relating to this Agreement, and agree not to
commence any action, suit or proceeding (other than appeals therefrom) related
thereto except in such courts.

IN WITNESS WHEREOF, we, the undersigned as duly authorized representatives,
agree to all terms and conditions stated above, and by our signatures, place
this Agreement into full effect as of the last date written below.

Beth Israel Deaconess Medical
Center                                                                                                Cellceutix
Corporation

 

 
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Assessment of the Therapeutic Potential of Kevetrin in Melanoma and Renal Cell
Carcinoma

Rationale: In most melanomas and renal cell carcinomas (RCC), the gene encoding
the tumor suppressor p53 is neither mutated, deleted, nor epigenetically
silenced. Because the p53 gene is fundamentally intact in these tumors, it may
be possible to exploit the nuclear and/or mitochondrial pro-apoptotic functions
of p53 in the treatment of these malignancies.

p53 signaling is virtually always incapacitated in tumor cells. In RCC and
melanoma – tumors with an intact p53 gene - the signaling pathways downstream of
p53 are presumably disabled by the overexpression of various antagonists that
destabilize p53 (e.g. HDM2) or interfere with its transcriptional activity (e.g.
iASPP, HDMX). This reliance on p53 antagonists – in particular, HDM2 – as a
means of limiting p53 function suggests that these tumors might be susceptible
to drugs that block HDM2. Prior work from our lab with an investigational HDM2
antagonist (1), however, has demonstrated that this approach has negligible
pro-apoptotic activity in vitro and only modest activity against melanoma and
RCC xenografts when the HDM2 antagonist is used as a single agent. Despite the
lack of single agent activity, however, the drug was highly lethal against some
melanoma cell lines when used in combination with the multikinase inhibitor
sorafenib. The pro-apoptotic activity of this drug combination was shown to be
dependent on the mitochondrial translocation of p53 and independent of its
transcriptional activity. These data suggest that an agent that activates p53
function in the mitochondria (e.g. Kevetrin) might be particularly effective in
the treatment of RCC and melanoma.

Proposed Study Design: We propose to assess the effects of Kevetrin alone and in
combination with two FDA-approved multikinase (primarily VEGFR2) inhibitors.
Prior data from our laboratory indicate that agents of this class can augment
the pro-apoptotic and antitumor effects of HDM2 antagonists and will presumably
have a similar effect with Kevetrin.

RCC:  Kevetrin will be first evaluated as a single agent for its ability to
induce apoptosis in the human RCC cell lines 786-0 and A498 in vitro. These
assays will involve exposure of the cells to the drug followed by flow cytometry
to assess staining with propidium iodide (PI) and Annexin-FITC. In the event
that the drug induces apoptosis as determined by flow cytometry, we will
investigate the apoptotic mechanism by examining cell lysates for caspase
activation and PARP cleavage. Subcellular fractions of treated cells will be
examined for mitochondrial translocation of p53 and nuclear translocation of
AIF. We will also determine the extent to which the apoptotic activity of the
drug is inhibited by caspase inhibitors (e.g. ZVAD) and agents known to
selectively block p53 function in the nucleus (pifithrin-a) and in the
mitochondria (e.g. pifithrin-µ).

To assess the effects of Kevetrin in vivo, the drug will be studied as a single
agent and in conjunction with the FDA-approved VEGFR antagonist sunitinib. In
these xenograft studies, 1.0 x 107 786-0 or A498 human RCC cells will be
implanted subcutaneously into the flanks of 40 nude/beige mice.  Once tumors
have reached the diameter of 7 mm, the tumor-bearing mice will be divided into 4
treatment groups and treated with Kevetrin alone (200 mg/kg IP MWF ), sunitinib
alone (50 mg/kg by gavage), saline (control), or both sunitinib + Kevetrin. Mice
will be treated for 21 days.  Tumor size will be measured thrice weekly.  On day
#10, three mice from each treatment group will be sacrificed and their tumors
excised and divided into two halves. One half will be frozen for subsequent
biochemical analysis and the other half fixed in formalin for paraffin
embedding. At the end of the study (Day #21 or when the control tumors reach a
diameter of 20mm, whichever comes first), the remaining mice will be sacrificed
and their tumors excised and processed as described above for the Day #10
tumors. Study endpoints include:

1.
Serial tumor measurements to show the antitumor activity of single agent
Kevetrin and that of a Kevetrin/sunitinib combination in RCC xenografts

2.
Analysis of tumor vascularity as determined by IHC (microvessel density with
anti-CD31 antibody). It is expected that p53 activation and VEGFR inhibition
would act in synergy to suppress tumor angiogenesis.

3.
IHC and western blot analysis to determine the effects of each agent
individually and in combination on a). p53 levels and subcellular localization;
b). expression of p53-dependent genes such as p21; c). induction of tumor cell
apoptosis as determined by caspase 3 activation and TUNEL assay. If increased
apoptosis is detected in the tumors from treated mice, we will also assess the
ability of the drug(s) to induce AIF nuclear translocation.

 
 
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Melanoma: Kevetrin will be evaluated as a single agent for its ability to induce
apoptosis in melanoma cell lines A375, SKMel5 (both of which have the BRAFV600E
mutation), SKMel2 (which has an NRAS mutation), and SKMEL31, (which has wild
type BRAF and NRAS genes). The methods by which apoptosis will be assessed are
identical to those proposed above for the RCC studies.

To determine the activity of Kevetrin against melanoma xenografts, the drug will
be studied alone and in combination with the VEGFR antagonist Axitinib. The
rationale for this plan is based on our previous work with an HDM2 antagonist
which demonstrated limited antitumor activity when used as a single agent but
sustained tumor non-progression when used in combination with the multikinase
inhibitor sorafenib. The decision to substitute Axitinib for sorafenib is based
on its more potent VEGFR inhibitory activity.

For these xenograft studies, 1 x 107 A375, SKMel2, and SKMEL31 melanoma cells
will be implanted subcutaneously into the flanks of 40 nude/beige mice.  Once
tumors have reached the diameter of 7 mm, the tumor-bearing mice will be divided
into 4 treatment groups and treated with Kevetrin alone, axitinib alone (30
mg/kg daily), saline (control), or both Kevetrin + axitinib. Mice are treated
daily by gavage for 21 days. Tumor size is measured thrice weekly.  On day #10,
three mice from each treatment group will be sacrificed and their tumors excised
and divided into two halves. One half will be frozen for subsequent biochemical
analysis and the other half fixed in formalin for paraffin embedding. At the end
of the study (Day #21 or when the control tumors reach a diameter of 20mm,
whichever comes first), the remaining mice will be sacrificed and their tumors
excised and processed as described above for the Day #10 tumors. Study endpoints
will be the same as those proposed above in the RCC analyses.

Drugs: The sunitinib used in these studies will be unused clinical grade
material provided to us by patients who are no longer receiving the drug. The
investigational VEGFR2 antagonist axitinib will be purchased from LC
Laboratories.
 
References:
1. Liu Q, Mier JW, Panka DJ. Differential modulatory effects of GSK-3b and HDM2
on sorafenib-induced AIF nuclear translocation (programmed necrosis) in
melanoma. Mol Cancer 2011; 10:115.

 
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