α-TEA in Advanced Cancer

This is a dose-escalation study in which doses ranging from 2.4 mg/kg to 26.8 mg/kg of α-TEA
will be tested.

The main clinical objectives of this phase I two-stage dose-escalation trial will be to
characterize α-TEA related toxicity, determine the maximum tolerated dose, and
pharmacokinetics of α-TEA in humans. Tumor response and exploratory immunological monitoring
will also be performed. Specifically, we will determine the frequency of circulating
peripheral T cell subset populations including CD4+, CD8+ T cells and their activation status
(central memory, effector cells) and regulatory T cells (CD4/CD25/Foxp3). Exploratory
monitoring to assess tumor apoptosis and serum cytokine levels will also be performed to gain
additional insight on the influence of α-TEA on the immune response and tumor. An assessment
of the immunoscore in patients with tumor amenable to biopsy will also provide
hypothesis-generating data on the influence of α-TEA on the tumor microenvironment.

Inclusion Criteria:

- Patients with measurable or evaluable metastatic carcinoma, sarcoma or lymphoma who
have malignancy refractory or progressed after therapy and for whom no other standard
(non-experimental) therapy exists or who have declined available standard therapy,
with potential to induce cure, remission or enhanced survival. Either histologic or
cytologic diagnosis is acceptable of the primary cancer, or clinical evidence of
metastasis.

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

- Age 18 years or above.

- Laboratory values (performed within 28 days prior to enrollment) within protocol
specified range.

- Confirmed radiographic and/or serum marker showing cancer progression after at least
one systemic therapy for metastatic disease.

- Ability to give informed consent and comply with the protocol. Patients with a history
of psychiatric illness must be judged able to understand the investigational nature of
the study and the risks associated with the therapy.

- No active bleeding.

- No coagulopathy (INR <1.5, PT <16 seconds, PTT < 38 seconds) at baseline.

- Anticipated lifespan greater than 12 weeks.

- Ability to swallow capsules

- Women of childbearing potential must have a negative pregnancy test and must avoid
becoming pregnant while on α-TEA and for 4 weeks after the last dose of α-TEA. Men
must avoid fathering a child while on α-TEA and for 4 weeks after the last dose of
α-TEA.

Exclusion Criteria:

- Active serious infection that could affect treatment.

- Coagulopathy or need for anti-coagulation therapy.

- Malabsorbtion state such as ulcerative colitis, previous surgical resection of > 20%
of intestine or stomach.

- History of or active atrial fibrilliationfibrillation or supraventricular tachycardia

- Cardiac ejection fraction less than the lower limit of normal on echocardiography

- Right atrial enlargement on echocardiography

- Active cardiac ischemia. Patients with a history of ischemia ameliorated with stent
placement or coronary artery bypass grafting and who have no evidence of ischemia by
exercise or physiological stress testing are eligible.

- History of or active congestive heart failure

- Patients with tumor that has invaded vagal nerve, carotid bodies, mediastinal
structures, pericardium or myocardium.

- Abnormal thyroid function, or euthyroid, but are on medication for thyroid disorders

- Need for chronic high dose maintenance oral steroids. Stable treatment with prednisone
≤ 10 mg daily (or a biologically-equivalent dose of another steroid) is allowed.
Patients who require brief courses of steroids to manage allergic reaction to
intravenous contrast used in radiographic studies are eligible. Patients requiring
steroids for management of CNS metastatic disease are not eligible.

- Surgery or severe trauma within 4 weeks of study entry (minimally invasive procedures
acceptable).

- Active brain metastatic disease. Patients with brain metastases who have been treated
with surgery, gamma-knife radiosurgery or radiation and no radiographic progression
for at least 4 weeks and off steroids are eligible.

- Any medical or psychiatric condition that in the opinion of the PI would preclude
compliance with study procedures.

- Vitamin E supplements

- QTc greater than 450 msec at baseline (calculated using Bazett's formula), sick-sinus
syndrome or other active cardiac disease.