Gemcitabine With Ascorbate Including Adolescents

Study Overview
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Brief Summary
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The purpose of this research study is to see if a high dose of ascorbate (Vitamin C), in combination with the chemotherapy drug gemcitabine, is safe and effective in adolescents with locally advanced unresectable or metastatic soft tissue and bone sarcomas

Detailed Description
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The primary objective of the expansion cohort of this pilot study is to evaluate preliminary evidence of anti-tumor activity of intravenous ascorbate in combination with gemcitabine as assessed by overall response rate to inform a subsequent Phase II trial.

Official Title
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A Pilot Study of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas Including Adolescents

Conditions
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Soft Tissue Sarcoma, Bone Sarcoma, Unresectable Soft Tissue Sarcoma, Metastatic Bone Sarcoma, Metastatic Soft-tissue Sarcoma, Unresectable Bone Sarcoma

Intervention / Treatment
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* Drug: Ascorbate
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged ≥ 13 years to 17 years ECOG Performance Status of ≤ 2 Ability to provide written informed consent from patient guardian and informed assent from patient; obtained prior to participation in the study and any related procedures being performed Tolerate a 10g ascorbate infusion (screening dose). 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 or 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. 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. 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. 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: Inadequate organ function as defined by: Hematology: Neutrophil count of </=1,000/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 G6PD (glucose-6-phosphate dehydrogenase) deficiency Baseline MUGA or ECHO < than the lower limit of the institutional normal. ECHO or MUGA only done on patients with prior doxorubicin exposure. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E) History of myocardial infarction or unstable angina within 6 months prior to Day 1 History of stroke or transient ischemic attack within 6 months prior to Day 1 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 Actively receiving insulin or requiring finger stick glucose monitoring at time of ascorbate infusion (unless an exception is granted by the IND sponsor, medical monitor, and the PI). Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) Pregnancy (positive pregnancy test) or lactation. Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, warfarin and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs. Other concurrent severe and/or uncontrolled medical conditions 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. 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. Concomitant use of any anti-cancer therapy or radiation therapy. Palliative radiation therapy to non-target lesions is permitted. Females of childbearing potential (FOCBP) who are unwilling 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 Male patients whose sexual partners are FOCBP 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. 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 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.37 Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent Patients with GIST tumors and Kaposi sarcoma are excluded 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.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ascorbate in combination with Gemcitabine<br>The study will begin with a safety run-in. A patient-individualized pharmacokinetically-guided dose escalation design will be used for Ascorbate. Gemcitabine is administered following standard fixed dose infusion practice adopted at The University of Iowa Hospitals & Clinics. Ascorbate is infused prior to gemcitabine. Cycles are 28 days. Patients will be treated for a total of 6 cycles and assessed every 2 cycles for disease response. | Drug: Ascorbate<br>* A patient-individualized pharmacokinetically-guided dose escalation design will be used for Ascorbate. The goal of the within-patient dose escalation is to achieve a target plasma ascorbate level between 20mM and 30mM. The administered dose levels under consideration are listed below. Dose Level Ascorbate 2 60 g/m2 IV Days (1,2,8,9,15,16) 1 50 g/m2 IV Days (1,2,8,9,15,16) 0 (Starting dose) 40 g/m2 IV Days (1,2,8,9,15,16) 1 30 g/m2 IV Days (1,2,8,9,15,16)<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* Gemcitabine 900 mg/m2 given at a fixed dose rate of 10 mg/m2/min on D1, D8 and D15 to be given over 90 min every 28 days<br>* Other names: Gemzar®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events as defined by CTCAE version 5.0 | Occurrence of adverse events as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The number and severity of all adverse events will be summarized by simple descriptive statistics. | Adverse events will be followed for 4 weeks after the last pharmacologic ascorbate infusion | 
| ORR as defined by RECIST 1.1 guidelines | Overall Response Rate (ORR) as defined by the percentage of patients with a complete or partial response, according to RECIST 1.1 guidelines | For two years following completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS defined by RECIST 1.1 guidelines | Progression Free Survival (PFS) defined as the time from first day of study treatment to the first documented disease progression or death due to any cause, RECIST 1.1 guidelines | For two years following completion of treatment | 
| OS defined as the time from first day of study treatment to death due to any cause | Overall Survival (OS) defined as the time from first day of study treatment to death due to any cause | For two years following completion of treatment |