Study of 4-Demethyl-4-cholesteryloxycarbonylpenclome in Patients With Brain Tumors

DM-CHOC-PEN has been selected for Phase II intravenous studies in the treatment of patients
with advanced malignancies with central nervous system measurable disease based on the
improved PFS and objective responses seen for patients treated during the Phase I DTI-021
trial and the manageable toxicities noted. Melanoma, breast and lung cancers involving the
CNS have responded to DM-CHOC-PEN in the Phase I study, thus the basis for the choice of
tumors to be treated in the Phase II trial. Currently, the opinion is that the drug is
penetrating the blood brain barrier (BBB) attached to rbcs and released intracerebrally in
tumor masses in situ.

The trial will be carefully monitored, and if a cancer type has >3 confirmed responders in
the first 18 evaluable patients (Stage -1 enrollment); accrual will be expanded for that
tumor type with a goal of 7/43 for achieving an 80% power at the 5% level of significance
(Stage-2 enrollment) with unacceptable response rate (P0) 0.1 and desirable response rate
(P1) 0.25. Thus, each arm will have a 2-stage design. This will allow resources to be
directed to the most promising areas - selection of 1 or 2 tumor types to develop via
additional trial studies. A desirable response rate is 25% or better. The above is for each
tumor type - lung, breast, melanoma and GBM.

In summary, for any tumor type or treatment sub-group, a response rate of <15% or a rate of
"possibly treatment-related Gr-3/4 toxicities" of >25% will be considered unacceptable and
enrollment in the respective tumor type category will be discontinued.

Inclusion Criteria:

- Patients must have histological proof of a cancer - melanoma, breast, or lung cancer
- which has spread to the CNS or glioblastoma (GBM) or other primary malignant
neoplasm of the CNS which has been treated with standard treatments, which may
include radiation, and must be measurable (RECIST).

- Patients 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 - 18 or older. Gender is not a criterion.

- All patients 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. Patients may continue to receive anti-estrogen/steroid therapy
that has been initiated at least eight weeks prior to enrollment in the study.

- Patients 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.

- Patients 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.

- Patients should not be allergic to eggs or soy beans. Patients 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. Patients with a history of cardiac disease must be stable.

- Patients 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. Patients must have CNS involvement - from a
malignancy. Lung cancer may be either small cell or non-small cell.

Exclusion Criteria:

- Patients 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.

- Patients 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 - the azole antifungal -
fluconazole, erythromycin, phenobarbital, verapamil.

- Patients 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. Patients receiving these drug 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.