Treatment of Radiation and Cisplatin Induced Toxicities With Tempol

One hundred and twenty (120) participants with head and neck cancer are scheduled to undergo
combined radio- and chemotherapy (n = 120).

Nearly all (90% to 97%) participants receiving radiotherapy in the head and neck will develop
some degree of mucositis. Of these participants treated with radiotherapy with or without
chemotherapy, 34% to 43% will present severe mucositis. As a result, the participant's
quality of life is affected, hospital admittance rates are higher, the use of total
parenteral nutrition is increased and interruption of treatment is more frequent, all of
which compromise tumor control. Mucositis causes 9% to 19% of chemotherapy and radiotherapy
interruption.

A common chemotherapeutic agent used in head and neck cancer is Cisplatin. Cisplatin (cis-
diamminedichloroplatinum(II), CDDP) is an antineoplastic drug used in the treatment of many
cancers including testicular cancer, ovarian cancer, bladder cancer, head and neck cancer,
esophageal cancer, small and non-small cell lung cancer, breast cancer, cervical cancer,
stomach cancer, prostate cancer, brain tumors, neuroblastoma, sarcomas, multiple myeloma,
melanoma, mesothelioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, and
thyroid cancer. While toxicities include ototoxicity, gastrotoxicity, myelosuppression, and
allergic reactions, the main dose-limiting side effect of cisplatin is nephrotoxicity
followed by ototoxicity.

Tempol is a piperidine nitroxide. Nitroxides are a class of stable free radical compounds
that have anti-oxidant activity protecting mammalian cells against numerous toxic agents
including hydrogen peroxide, superoxide, and t-butyl hydroperoxide cytotoxicity. This
anti-oxidant activity of Tempol has led to its investigation as a potential radioprotector
and chemoprotectant. In radiation and chemotherapy, Tempol protects normal cells from
radiation and cisplatin-induced damage; however, in cancerous or tumor cells, Tempol is
reduced to its hydroxylamine form that does not and cannot protect the cells from radiation
and cisplatin induced damage. This distinction is of particular importance in the setting of
cancer treatment, in which both normal and tumor tissue is exposed to radiation and
chemotherapy. Without using Tempol, both normal cells and cancer cells suffer from toxicity.
Tempol is the only known compound to possess this functional duality. Because of Tempol's
free-radical scavenging ability, this compound is able to prevent many of the toxicities
associated with cisplatin and radiation treatment including the prevention of mucositis,
nephrotoxicity, and ototoxicity.

The first group 60 participants will be randomized 1:1 to either Tempol 600 mg daily or
placebo. Assuming that treatment is well tolerated but ≥20% of the participants in the active
arm have grade 3 or 4 mucositis, a second group of 60 participants may be enrolled, and
randomized 1:1 to receive either Tempol 1000 mg daily or placebo.

Throughout the treatment period, participants will take study medication twice daily on both
chemo/radiation days and cancer treatment free days. On radiation/chemo days, participants
will be instructed to take study medication 10 minutes before each proton therapy or
radiation treatment (400 or 600 mg) and again in the evening (200 or 400 mg) no less than 6
hours following the first dose. Participants will begin to take study medication two (2) days
before their scheduled cancer treatment. When proton therapy or radiation is not
administered, participants will take the medication twice daily, 400 mg or 600 mg in the
morning and 200 mg or 400 mg in the evening. On the day of radiation therapy, study
medication will be administered within 10 minutes prior to each course of radiotherapy.
Participants will be instructed to hold the solution in their mouth swishing for
approximately 30 seconds and then swallow.

Inclusion Criteria:

1. Be ≥18 years of age with medically diagnosed squamous cell cancer of the head and neck
(SCCHN);

2. Be scheduled to receive definitive radiotherapy or proton therapy administered with a
curative intent;

3. If female and of child bearing potential, be using an effective birth-control method
with a history of reliability for the individual participant;

4. If male and of child bearing potential, adequate methods of contraception must be
employed including use of condoms with spermicide. No sperm donation for 90 days until
after the conclusion of the study;

5. Must be receiving cisplatin for chemotherapy;

6. Be properly informed of the nature and risks of the clinical investigation, comply
with all clinical investigation-related procedures, and sign an Informed Consent Form
prior to entering the clinical investigation;

7. Must have a score 2 or less on the Eastern Cooperative Oncology Group (ECOG)
performance status;

8. Participant life expectancy ≥ 6 months; and

9. Adequate baseline organ function (hematologic, liver, renal, nutritional and
metabolic):

Haematology:

Absolute neutrophil count (ANC) ≥1.5 Hemoglobin ≥ 10 g/dL Platelets ≥ 100,000 per
microliter of blood

Hepatic:

Total bilirubin ≤ 2 X (Upper limit normal) ULN Alanine amino transferase (ALT) and
Aspartate aminotransferase (AST) ≤5 x ULN

Renal:

Serum creatinine ≤ ULN or, if > ULN calculated creatinine clearance (CrCl) ≥ 60 mL/min.

Nutritional and metabolic:

Urine Albumin > 3.0 mg/dl

Exclusion Criteria:

1. Prior radiotherapy of the head and neck;

2. Have a clinically significant infection defined as any acute viral, bacterial or
fungal infection, which requires specific therapy. Anti-infectious therapy must have
been completed within 14 days of starting study treatment;

3. Be taking any non-approved therapy for oral mucositis, including β-carotene,
tocopherol, laser irradiation, brushing the oral mucosa with silver-nitrate
prophylactically, systemic TGF-β (transforming growth factor beta), or systemic KGF
(keratinocyte growth factor) during or within 14 days of starting treatment;

4. Be taking mugard;

5. Be taking prostaglandins, pentoxifylline or leucovorin during or within 14 days of
starting treatment;

6. Be rinsing with allopurinol, hydrogen peroxide, sucralfate, or chlorhexidine
mouthwashes during or within 14 days of starting treatment;

7. Have had a recent, serious, non-malignant medical complication that, in the opinion of
the investigator, makes the individual unsuitable for study participation;

8. Have used an investigational drug within 28 days of the initiation of study treatment;

9. Have a history of a positive blood test for HIV;

10. At the time of screening, having a significant active medical illness which, in the
opinion of the investigator, would preclude completion of the study;

11. Participants with a treatment plan consisting of chemoradiation followed by further
chemotherapy;

12. Participants with body weight less than 35 kg, 77 lbs;

13. Women who are pregnant or who are breastfeeding;

14. Participants with known hearing loss;

15. Participants with known intolerance to platin drugs;

16. History of insulin-dependent Diabetes Mellitus; and

17. Participants with Hepatitis B/C.