High Dose Ascorbate With Preoperative Radiation in Patients With Locally Advanced Soft Tissue Sarcomas

Phase Ib:

The phase Ib portion of this study is to ensure the safety and tolerability of high dose
ascorbate in combination with external beam radiation therapy (EBRT) as assessed by incidence
of dose-limiting toxicities (DLT). EBRT will be given at the standard dose for resectable
soft tissue sarcomas according to the NCCN sarcoma guidelines.2 Patients will receive 50 Gy
over 5 weeks, during which time they will be receiving three times a week IV high dose
ascorbate. IV ascorbate infusions will be continued until the end of radiation therapy.
Surgery will be performed 4-6 weeks from the end of radiation to allow for adequate tissue
healing and resolution of acute toxicities.

Phase 2:

The phase 2 part of the study will provide an estimate of the relative treatment effect of
pharmacological ascorbate in combination with preoperative EBRT in subjects with locally
advanced, resectable, extremity or retroperitoneal high grade sarcomas, as measured by
pathological response rates.

As above, patients will receive the first dose of pharmacological ascorbate intravenously on
day 1 of week 1 provided no reactions are seen to the test dose. This will be followed by 3
times a week dosing at Dose 0 until completion of EBRT. Standard doses of radiation for
resectable soft tissue sarcomas according to the NCCN sarcoma guidelines will be
administered.2 Patients will receive preoperative radiation at a dose of 50 Gy over 5 weeks
starting on week 1 day 1. Subjects will be followed either by clinic visit or phone contact
every 12 weeks for approximately 24 months after the end of the treatment phase, at which
time the initial survival data and disease recurrence will be assessed.

Inclusion Criteria:

1. Subject or subject's legally acceptable representative has provided informed consent.

2. Histologically confirmed diagnosis of locally advanced STS of extremity or
retroperitoneum that is unresectable with clear wide margins, for which preoperative
radiotherapy is considered appropriate.

- Resectable stage IIB, III, and IV disease that are not suitable for surgically
resection alone due to inability to achieve clear margins.

- Including metastatic (stage IV) disease for which radiotherapy and surgical
resection are indicated.

- Except certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, Kaposi sarcoma,
and bone sarcomas.

3. Previous treatment: prior systemic anti-cancer treatment consisting of chemotherapy,
immunotherapy, or targeted therapy are allowed provided therapy completed at least 1
year prior to enrollment.

- No prior pharmacologic ascorbate or tumor vaccines allowed.

- No prior radiation to the same tumor bed allowed.

4. Age ≥18 years.

5. Both men and women of all races and ethnic groups are eligible for this trial.

6. ECOG performance status ≤1.

7. Tolerate one test dose (15g) of ascorbate.

8. Patient must have measurable disease:

- Tumor size at least ≥ 5 cm in the longest diameter as measured by CT scan or MRI
for which radiation is feasible and indicated.

Exclusion Criteria:

1. Certain histologic subtypes: GIST, Desmoid, Ewing sarcoma, bone sarcomas and Kaposi
sarcoma.

2. G6PD (glucose-6-phosphate dehydrogenase) deficiency.

3. Prior history of symptomatic oxalate kidney stones.

4. Patients actively receiving insulin are excluded unless approved by the IND medical
monitor, IND sponsor, and the study PI.

5. History of other malignancy within the past 3 years except treated with curative
intent and no known active disease present and has not received chemotherapy for ≥ 1
year before enrollment/randomization and low risk for recurrence.

6. Female subjects who are pregnant or breast-feeding, or planning to become pregnant
during study treatment and through 3 months after the last dose of study treatment.

7. Female subjects of childbearing potential or male subjects who are unwilling to use 2
highly effective methods of contraception during study treatment and through 3 months
after the last dose of study treatment.

8. Currently receiving treatment in another investigational device or drug study, or less
than 30 days since ending treatment on another investigational device or drug
study(s).

9. Other investigational interventional procedures while participating in this study are
excluded.

10. Subject previously has entered this study.

11. Patients who are on the following drugs and cannot have a drug substitution:
flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic
acid may affect urine acidification and, as a result, may affect clearance rates of
these drugs.

12. Evidence of uncontrolled CNS metastases.

13. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ascorbate.

14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

15. Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4
inducer, which results in lower serum levels of antiretroviral drugs.

16. Any of the following laboratory abnormalities:

- Hemoglobin < 9.0 g/dL

- Absolute neutrophil count (ANC) < 1500 per mm3

- Platelet count < 100,000 per mm3

- Total bilirubin > 1.5 × ULN

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN

- Alkaline phosphatase > 2.5 × ULN

- PT (or INR) and PTT (or aPTT) > 1.5 × ULN

- Creatinine > 2.0 × ULN