DM-CHOC-PEN Plus Radiation for Brain Tumors

The primary goal of this Phase I oncology clinical trial will be to evaluate the safety and
use of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) plus radiation, as
anticancer therapy for adults with advanced cancer involving the central nervous system (CNS)
involvement.

DM-CHOC-PEN is a polychlorinated pyridine cholesteryloxycarbonate that crosses the blood
brain barrier (BBB), accumulates in CNS tumor tissue in humans and has produced objective
responses, with acceptable/reversible hepatic toxicities (in patients with prior liver
disease) and no evidence of hematological, renal, neuro-toxicities with improved quality of
life and overall survival in adult Phase I/II clinical trials - IND - 68,876.

The drug recently received Orphan Drug designation for NSCLC involving the brain.

The FDA supports the proposed Phase I clinical trial designed to identify safety, toxicities
and an acceptable MTD of the drug in combination with radiation in adult cancers subjects
with CNS involvement.

Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous
system (SNS) tumors. Trends in CNS tumors have sharply increased since 1989 for individuals
with a history of cancer, who appeared to have 'beaten the odds', only to have a reoccurrence
from cancer involving the CNS after years of remission; the most common types of cancer in
AYA individuals are - from lung, breast, melanoma, and sarcoma malignancies. This group of
individuals deserves special attention.

A critical component in designing an agent that will cross the protective blood brain barrier
(BBB) is that the agent must be readily transported intracerebrally, does not produce local
irritation/neurotoxicity and is not recycled back into the general circulation. After IV
administration DM-CHOC-PEN readily penetrates the BBB, is not a substrate for the transporter
protein P-glycoprotein (P-gp) and has shown anticancer activity in CNS tumors. The effective
transport of DM-CHOC-PEN into CNS tumors in adults without neurotoxic behavioral alterations
and associated events supports the drug's use in combination with radiation in the treatment
of CNS tumors. The observed responses noted in adults with metastatic cancers involving the
CNS and cerebellum treated with DM-CHOC-PEN is encouraging. Thus, the drug's unique
properties and lack of toxicities noted in the adult studies merits the Phase I trial
proposed here in combination with radiation.

The specific objectives of this Phase I study will be to:

1. Conduct a Phase I clinical trial with DM-CHOC-PEN plus radiation in adults with advanced
cancers involving the central nervous system to document toxicities, define an
acceptable maximum tolerated dose (MTD), and identify anticancer activity for the binary
treatment DM-CHOC-PEN plus radiation. All data will be communicated through an e-RAP
program. This will be accomplished through IND - 68.876.

2. Studying the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in adults
after being treated with DM-CHOC-PEN and radiation.

3. Analyze data and prepare a Phase II clinical trial or a Designation Orphan Drug
application for FDA review.

Inclusion Criteria:: Inclusion Criteria will be as follows -

- Subjects must have histological proof of a CNS malignancy (primary or metastatic),
which has been treated with standard treatments, that may include radiation, and must
have measurable lesions.

- Subjects must have life expectancy of at least 12 weeks and a Karnofsky performance
score: > 60 % (or a Zubrod performance status of < 2).

- The age limit - a limit of 39 years of age. Gender is not a criterion.

- All subjects must be off previous chemo- and/or radiotherapy for at least three (3)
weeks prior to entrance into the study and have recovered from any toxic effects
induced by such treatment(s); no nitrosourea type drug or ipilumimab treatments are
permitted within the last six (6) weeks prior to enrollment. No major surgery within
14 days of enrollment. Subjects may continue to receive anti- estrogen/steroid therapy
that has been initiated at least eight weeks prior to enrollment in the study.

- Subjects should have adequate bone marrow function defined as a peripheral WBC
>3,000/mm3 with an ANC >1500/mm3 and a platelet count >100,000/mm3.

- Subjects should have hepatic function (alkaline phosphatase, AST and ALT) < ULN and
renal functions with serum creatinine - <1.5 x UNL. If a patient has liver metastasis
and/or a history of liver disease - they will receive a lower dose of the drug per
treatment protocol.

- Subjects should not be allergic to eggs or soy beans.

- Subjects must be medically, psychologically and neurologically stable and have
triplicate baseline ECG's with a mean QTc interval <500 ms and >300 ms and neither a
history of congenital prolonged or short QT syndrome. Subjects with a history of
cardiac disease must be stable.

- Subjects and/or legal guardian must understand the nature of the study and be willing
to sign an informed consent that complies with the investigator/DEKK-TEC policies and
approved by the Human Investigation Review Committee.

Exclusion Criteria:Criteria: Inclusion Criteria: Inclusion Criteria will be as follows -

- Subjects must have histological proof of a CNS malignancy (primary or metastatic),
which has been treated with standard treatments, that may include radiation, and must
have measurable lesions.

- Subjects must have life expectancy of at least 12 weeks and a Karnofsky performance
score: > 60 % (or a Zubrod performance status of < 2).

- The age limit - a limit of 39 years of age. Gender is not a criterion.

- All subjects must be off previous chemo- and/or radiotherapy for at least three (3)
weeks prior to entrance into the study and have recovered from any toxic effects
induced by such treatment(s); no nitrosourea type drug or ipilumimab treatments are
permitted within the last six (6) weeks prior to enrollment. No major surgery within
14 days of enrollment. Subjects may continue to receive anti- estrogen/steroid therapy
that has been initiated at least eight weeks prior to enrollment in the study.

- Subjects should have adequate bone marrow function defined as a peripheral WBC
>3,000/mm3 with an ANC >1500/mm3 and a platelet count >100,000/mm3.

- Subjects should have hepatic function (alkaline phosphatase, AST and ALT) < ULN and
renal functions with serum creatinine - <1.5 x UNL. If a patient has liver metastasis
and/or a history of liver disease - they will receive a lower dose of the drug per
treatment protocol.

- Subjects should not be allergic to eggs or soy beans.

- Subjects must be medically, psychologically and neurologically stable and have
triplicate baseline ECG's with a mean QTc interval <500 ms and >300 ms and neither a
history of congenital prolonged or short QT syndrome. Subjects with a history of
cardiac disease must be stable.

- Subjects and/or legal guardian must understand the nature of the study and be willing
to sign an informed consent that complies with the investigator/DEKK-TEC policies and
approved by the Human Investigation Review Committee.

Exclusion Criteria: Exclusion criteria will be as follows:

- Subjects with concurrent severe and/or uncontrolled medical co-morbidities - including
active infections, unstable uncontrolled diabetes, cardiovascular and pulmonary,
renal, psychiatric or social conditions that could compromise the safety or compliance
of treatment are not eligible.

- Concomitant chemotherapy or radiotherapy is not permitted.

- Pregnant or lactating females are excluded. Women of childbearing age, and their
sexual partners, must use an effective contraception program. Males who are having
sexual relations with women capable of child bearing must use the barrier birth
control while on the study and for 3-months after the last dose of the study drug.

- Subjects taking CYP3A4 inducers or inhibitors are not eligible since it is not known
whether the study drug is metabolized through this pathway. The following CYP3A4
inhibitors/inducers are not permitted during the trial - phenobarbital, fluconazole,
erythromycin, verapamil; the latter 3-drugs are moderate CYP3A4 inhibitors.

- Subjects taking the following medications may experience QT/QTc interval prolongation
and are not eligible for the trial - most anti-arrhythmia drugs (incl. amiodarone),
erythromycin, quinolone antibiotics, ketoconazole, Zithromax, and phenothiazine and
will be denied enrollment in the study. The possible interactions of these drugs and
DM-CHOC-PEN have not been established. Subjects receiving these drugs will only be
eligible if they discontinue the drugs and have an acceptable ECG.

- Coagulopathies - patients requiring full dose anticoagulation with warfarin are
excluded. However, patients stable and on other anticoagulants can be incl