Gemcitabine Plus Ascorbate for Sarcoma in Adults
Condition: Sarcoma; Soft Tissue Sarcoma; Unresectable Soft Tissue Sarcoma; Metastatic Bone Tumor; Bone Sarcoma
MeSH terms: Sarcoma; Osteosarcoma
Intervention: Ascorbate; Gemcitabine
Intervention description: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle; Administered on Days 1, 8 and 15, after the infusion of ascorbate
Intervention MeSH terms: Ascorbic Acid; Gemcitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sarcoma; Soft tissue; Ascorbate

Summary:

      This study will enroll patients who have a diagnosis of locally advanced, unresectable or
      metastatic soft tissue or bone sarcoma (except gastrointestinal stromal tumors and Kaposi's
      sarcoma) from any site.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients aged ≥ 18 years old

          2. ECOG Performance Status of ≤ 2

          3. Ability to provide written informed consent obtained prior to participation in the
             study and any related procedures being performed

               -  Patients must meet the following laboratory criteria:

               -  Hematology:

               -  Neutrophil count of >1500/mm3

               -  Platelet count of > 100,000/mm3L

               -  Hemoglobin ≥ 9 g/dL (transfusion to meet eligibility allowed)

               -  Biochemistry:

               -  AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the
                  transaminase elevation is due to disease involvement

               -  Alkaline phosphatase < 5 x ULN

               -  Serum bilirubin ≤ 1.5 x ULN

               -  Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min

               -  Total serum calcium >/= LLN or if calcium is below LLN then corrected calcium for
                  serum albumin should be >/= LLN

               -  Serum potassium ≥ LLN

               -  Serum sodium ≥ LLN

               -  Serum albumin ≥ LLN or 3g/dl

          4. Tolerate a 15g ascorbate infusion (screening dose)

          5. Baseline MUGA or ECHO done only in subjects with prior doxorubicin exposure. The test
             must demonstrate LVEF ≥ the lower limit of the institutional normal.

          6. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 7 days of the first administration of study treatment and must be willing to
             use two methods of contraception one of them being a barrier method during the study
             and for 3 months after last study drug administration

          7. Any patient with the diagnosis of locally advanced, unresectable or metastatic soft
             tissue or bone sarcoma (except GIST and Kaposi's) from any site. A minimum of 1 prior
             chemotherapy regimen, including adjuvant and neo-adjuvant therapy for the treatment of
             sarcoma. Patients eligible for an anthracycline should have received a prior
             anthracycline containing regimen. Patients who decline or are not eligible for
             anthracycline treatment may be considered for this protocol as a first line treatment.
             Patients with a diagnosis of liposarcoma should also have received eribulin if they
             received anthracycline-based therapy prior to eribulin. Patients with a diagnosis of
             myxoid liposarcoma should have received trabectedin. Patients with angiosarcoma should
             have received either taxol or docetaxel. Patients must have measurable disease defined
             as at least 1 lesion ≥ 1cm in the greatest dimension.

          8. Patients with metastatic bone sarcomas who have failed all available therapies that
             have demonstrated clinical benefit. Available therapies include but not limited to
             methotrexate, adriamycin and cisplatin for osteosarcoma and vincristine, adriamycin
             and Cytoxan, ifosfamide, etoposide (VAC/IE)for Ewing's sarcoma.

          9. Previous exposure to Gemcitabine will only be allowed if there is no residual toxicity
             from previous treatments. Toxicity must be graded as 0 or 1 prior to study.

         10. Patients must have had disease progression on or following their most recent treatment
             regimen or on presentation for the first time with locally advanced unresectable or
             metastatic disease.

        Exclusion Criteria:

          1. G6PD (glucose-6-phosphate dehydrogenase) deficiency

          2. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
             Appendix E)

          3. History of myocardial infarction or unstable angina within 6 months prior to Day 1

          4. History of stroke or transient ischemic attack within 6 months prior to Day 1

          5. 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

          6. Actively receiving insulin or requiring fingerstick glucose monitoring at time of
             ascorbate infusion (unless an exception is granted by the IND sponsor, medical
             monitor, and the PI).

          7. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Day 1

          8. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

          9. Pregnancy (positive pregnancy test) or lactation. Use of effective means of
             contraception (men and women) in subjects of child-bearing potential

         10. 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.

         11. Other concurrent severe and/or uncontrolled medical conditions

         12. Patients who have received chemotherapy or any investigational drug < 2 weeks prior to
             starting study drug or who have not recovered from side effects of such therapy.

         13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 or anticipation of need for major surgical procedure during the course
             of the study.

         14. Concomitant use of any anti-cancer therapy or radiation therapy. Palliative radiation
             therapy to non-target lesions is permitted.

         15. Male patients whose sexual partners are WOCBP not using a double method of
             contraception during the study and 3 months after the end of treatment. One of these
             methods must be a condom.

         16. Patients with a history of another primary malignancy within 2 years other than
             curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin

         17. Patients with known positivity for human immunodeficiency virus (HIV); baseline
             testing for HIV is not required. High-dose ascorbate acid is a known CYP450 3A4
             inducer, which results in lower serum levels of antiretroviral drugs.

         18. Patients with any significant history of non-compliance to medical regimens or with
             inability to grant a reliable informed consent.

         19. Patients with GIST tumors and Kaposi's Sarcoma are excluded.

         20. Patients with history of more than one symptomatic oxalate stone in the last 6 months
             or visible stone in the kidney or ureter on screening CT scan.