DM-CHOC-PEN for Brain Tumors in AYA Subjects

The primary goal of this Phase II AYA oncology clinical trial will be to evaluate the safety
and efficacy of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN), as anticancer
therapy in AYA individuals with advanced cancer involving the central or spinal nervous
system (CNS & SNS).

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 adolescent, young adult and adult Phase I/II clinical trials -
IND - 68,876.

The FDA supports the proposed Phase II clinical trial designed to identify safety and
efficacy in AYA cancers subjects now that the Phase I AYA trial has been completed with
acceptable toxicity and MTDs identified.

Almost 700,000 people in the US are living with tumors involving the CNS or spinal nervous
system (SNS) tumors. Nearly 15% of these tumors involve the adolescent/young adult (AYA)
population, aged 15-39 years of age. It is predicted that 10,617 AYA individuals will be
diagnosed with brain or CNS tumors resulting in 434 deaths this year in the US. Trends in CNS
tumors have sharply increased since 1989 for AYA individuals with a history of cancer, who
appeared to have 'beaten the odds', only to have a re-occurrence from cancer involving the
CNS after years of remission; the most common types of cancer in AYA individuals are -
melanoma, leukemia and sarcomas. This group of individuals deserves special attention.

For males and female individuals <20 years of age, primary brain and secondary cancers of the
CNS and spinal nervous system (SNS) are the most common causes of death from cancer and in
the 20-39 year age group the first cause of cancer-related deaths in males and the fifth
cause of cancer-related deaths in females. The incidence and histology of cancer types does
vary according to subject age.

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 neurotic behavioral alterations
and associated events supports the drug's use in children with CNS tumors at an age in which
brain development and maturation is still very active with cognitive lability. The observed
responses noted in adults with metastatic cancers involving the CNS and cerebellum treated
with DM-CHOC-PEN may also occur in medulloblastoma in AYA. Thus, the drug's unique properties
and lack of toxicities noted in the adult studies merits the Phase I trial proposed here in
children.

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

1. Conduct a Phase II clinical trial with DM-CHOC-PEN in AYA individuals that have advanced
cancers with central or spinal nervous systems involvements and monitor safety and
document anticancer activity for the drug. All data will be communicated through an
e-RAP program. This will be accomplished through IND - 68.876.

2. Verify the pharmacokinetic/dynamic profiles of DM-CHOC-PEN and metabolites in AYA
subjects with advanced cancers involving the central nervous system.

3. Analyze data and prepare an Orphan Drug Designated package for FDA submission for AYA
subjects with CNS involvement from cancer for review.

Inclusion Criteria: will be as follows -

- Subjects must have histological proof of a malignancy, which has been treated with
standard treatments, which may include radiation, and measurable lesions are not
required but must have evidence that the disease is advanced.

- 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: 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 included.