High Dose Ascorbate and Radiation Therapy before Surgery in Treating Patients with Stage IIB-IV Soft Tissue Sarcomas of Extremity, Trunk, and Retroperitoneum
This trial studies the side effects of high dose ascorbate and how well it works in combination with external beam radiation therapy before surgery in treating patients with stage IIB-IV soft tissue sarcomas of extremity, trunk, and retroperitoneum. High dose ascorbate (Vitamin C) may kill cancer cells. External beam radiation therapy delivers high-energy beams to the tumor from outside of the body. The purpose of this study is to see if high dose ascorbate in combination with radiation therapy will reduce the size of the tumor. High doses of ascorbate together with radiation therapy may work better in killing the cancer cells than either treatment alone.
Inclusion Criteria
- Subject or subject’s legally acceptable representative has provided informed consent
- 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
- Patients with locally recurrent sarcoma after surgery alone are eligible for enrollment if other inclusion criteria are met
- Patient does not have histologic subtypes: gastrointestinal stomal tumor (GIST), Desmoid, Ewing sarcoma, bone sarcomas and Kaposi sarcoma
- Age >=18 years
- Patients with history of non-melanomatous skin cancer, in situ carcinoma, or low-risk prostate cancer can be enrolled
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Tolerate one test dose (15 g) of ascorbate
- Patient must have measurable disease: * Tumor size at least >= 5 cm in the longest diameter as measured by computed tomography (CT) scan or MRI for which radiation is feasible and indicated
Exclusion Criteria
- Hemoglobin < 9.0 g/dL (within 21 days of day 1 of study)
- Absolute neutrophil count (ANC) =< 1500 per mm^3 (within 21 days of day 1 of study)
- Platelet count =< 100,000 per mm^3 (within 21 days of day 1 of study)
- Total bilirubin >= 1.5 x ULN. Subjects with direct bilirubin < ULN with total bilirubin levels > 1.5 x ULN will not be excluded (within 21 days of day 1 of study)
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN (within 21 days of day 1 of study)
- Alkaline phosphatase > 2.5 x ULN (within 21 days of day 1 of study)
- Prothrombin time (PT) (or international normalized ratio [INR]) and partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT]) >= 1.5 x ULN (within 21 days of day 1 of study)
- Creatinine > 2.0 x ULN (within 21 days of day 1 of study)
- G6PD (glucose-6-phosphate dehydrogenase) deficiency
- Prior history of two episodes of symptomatic oxalate kidney stones within last year
- 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
- Prior history of receiving pharmacological ascorbate
- Patients actively receiving insulin therapy AND needing daily fingerstick for glucose monitoring
- Concurrent, clinically significant, active malignancies within two years of study enrollment
- 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
- 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
- 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)
- 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
- Known central nervous system (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, linear accelerator [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
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ascorbate
- 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
- Known human immunodeficiency virus (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
- Patients who are on warfarin and cannot have a drug substitution or who decline the drug substitution
Additional locations may be listed on ClinicalTrials.gov for NCT03508726.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of neoadjuvant ascorbate in combination with preoperative external beam radiation therapy (EBRT) as assessed by incidence of dose-limiting toxicities (DLT) in subjects with locally advanced high grade soft tissue sarcomas of extremity, trunk and retroperitoneum. (Phase Ib)
II. To estimate the efficacy of neoadjuvant ascorbate and radiotherapy as assessed by the pathological complete response rates (pCR) in subjects with locally advanced high grade soft tissue sarcomas. (Phase II)
SECONDARY OBJECTIVES:
I. Time to disease progression (local or distant recurrence).
II. Overall response rate (ORR) pre-operation (pre op) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or a later tool for monitoring disease progression.
III. Overall survival rate (OS) at 2 years.
IV. To grade radiation related skin toxicity overlying the tumor as compared to historical controls.
V. To measure labile iron using T2* imaging sequence on magnetic resonance imaging (MRI) pre and post ascorbate treatments and compare with serum iron measurements.
VI. To evaluate diffusion weighted imaging sequences on MRI in pre and post treatment tumors and correlate it with necrosis and survival.
OUTLINE:
Patients receive pharmacological ascorbate intravenously (IV) over 30-120 minutes thrice weekly (TIW) and beginning 1 week later, undergo EBRT over 25-28 fractions for up to 5 weeks in the absence of disease progression or unacceptable toxicity. Within 4-6 weeks after EBRT, patients undergo surgery.
After completion of study treatment, patients are followed up every 12 weeks for 24 months.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUniversity of Iowa/Holden Comprehensive Cancer Center
Principal InvestigatorMohammed M. Milhem
- Primary ID201901810
- Secondary IDsNCI-2019-04398
- ClinicalTrials.gov IDNCT03508726