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

This is a single-arm open-label phase Ib/II clinical study assessing the efficacy of concurrent high dose ascorbate in combination with radiotherapy in patients with locally advanced, resectable, high grade 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, trunk 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.

Eligibility Criteria:
Inclusion Criteria:

1. Subject or subject's legally acceptable representative has provided informed consent.
2. Histologically confirmed diagnosis of locally advanced soft tissue sarcoma of extremity, trunk or retroperitoneum that is unresectable with clear wide margins, for which preoperative radiotherapy is considered appropriate

   - Including metastatic (stage IV) disease for which radiotherapy and surgical resection of the primary tumor are indicated.
3. Patients with locally recurrent sarcoma after surgery alone are eligible for enrollment if other inclusion criteria are met.
4. Patients do not have histologic subtypes: GIST, Desmoid, Ewing sarcoma, bone sarcomas and Kaposi sarcoma.
5. Age ≥18 years.
6. Patients with a history of non-melanomatous skin cancer, in situ carcinoma, or low-risk prostate cancer can be enrolled.
7. ECOG performance status \</=1.
8. Tolerate one test dose (15g) of ascorbate.
9. 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. Inadequate organ function within 21 days of Day 1 of study as defined by:

   * Hemoglobin \< 9.0 g/dL
   * Absolute neutrophil count (ANC) \</= 1500 per mm3
   * Platelet count \</= 100,000 per mm3
   * Total bilirubin \>/= 1.5 × ULN. Subjects with direct bilirubin \< ULN with total bilirubin levels \> 1.5 X ULN will not be excluded.
   * 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
2. G6PD (glucose-6-phosphate dehydrogenase) deficiency.
3. Prior history of symptomatic oxalate kidney stones within the last year.
4. Prior radiation therapy in excess of 20 Gy to the site of the current diagnosis of sarcoma. No overlap with prior radiation fields in excess of 20 Gy is allowed.
5. Prior history of receiving pharmacological ascorbate.
6. Patients actively receiving insulin therapy and needing daily fingerstick for glucose monitoring.
7. Concurrent, clinically significant, active malignancies within two years of study enrollment.
8. 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.
9. 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.
10. Currently receiving treatment in another invasive investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s).
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. Known CNS disease, except for treated brain metastasis: Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
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 and hepatitis B \& C individuals. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs.
16. Patients who are on warfarin and cannot have a drug substitution or who decline the drug substitution.