Gemcitabine Plus Ascorbate for Sarcoma in Adults

• ClinicalTrials.gov Identifier: NCT03468075
• Recruitment Status: Terminated
• First Posted: March 16, 2018
• Results First Posted: December 10, 2020
• Last Update Posted: December 10, 2020
• Sponsor: Mohammed Milhem, MBBS
• Collaborators: University of Iowa Adolescent and Young Adult (AYA) Cancer Program; St. Baldrick's Foundation; University of Iowa
• Information provided by (Responsible Party): Varun Monga, MD, University of Iowa

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Sarcoma; Soft Tissue Sarcoma; Unresectable Soft Tissue Sarcoma; Metastatic Bone Tumor; Bone Sarcoma	Drug: Ascorbate; Drug: Gemcitabine	Phase 2

Detailed Description:

This study will enroll male and female patients 18 years old or older who have a 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, must have been given. 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.

During screening, subjects will receive a test dose (15g) of ascorbate. If the test dose results in any toxicity >/= CTCAE grade 3 or a significant medical event in the opinion of the principal investigator, the patient will be considered a screen failure.

Subjects who pass screening will then receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for at least 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Treatment will be terminated with progression of disease. Disease will be assessed by CT of the chest, abdomen and pelvis or MRI of the lesion every 2 cycles for progression.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas in Adults
• Actual Study Start Date: July 11, 2018
• Actual Primary Completion Date: April 16, 2019
• Actual Study Completion Date: October 19, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Gemcitabine + High-Dose Ascorbate; Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator.

Drug: Ascorbate; Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle; Other Names: Ascorbic Acid; Vitamin C; Pharmacological ascorbate; Drug: Gemcitabine; Administered on Days 1, 8 and 15, after the infusion of ascorbate; Other Name: Gemzar

Outcome Measures

Primary Outcome Measures :

1. Tumor Response [ Time Frame: Every 2 months for first 6 months, then every 3 months up to 2 years post treatment ]
   From first day of treatment to documented disease progression as described by RECIST 1.1 criteria. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: Every 2 months for first 6 months, then every 3 months up to 2 years post treatment ]
   Time from start of therapy (day 1, cycle 1) to documented disease progression or death due to any cause. Progression will be defined using the RECIST 1.1 guidelines. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.
2. Overall Survival [ Time Frame: Every 2 months for first 6 months, then every 3 months up to 2 years post treatment ]
   Time from start of therapy (day 1, cycle 1) to death.
3. Incidence of Adverse Events (AE) Per CTCAE 4.03 [ Time Frame: Up to 30 days after completion of study treatment ]
   Categorize and quantify adverse events from start of therapy (day 1, cycle 1) to end of study per (CTCAE) version 4.03.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242

Sponsors and Collaborators

Mohammed Milhem, MBBS

University of Iowa Adolescent and Young Adult (AYA) Cancer Program

St. Baldrick's Foundation

University of Iowa

Investigators

• Principal Investigator: Varun Monga, MD; University of Iowa

  Study Documents (Full-Text)

Documents provided by Varun Monga, MD, University of Iowa:

Study Protocol and Statistical Analysis Plan  [PDF] March 13, 2019

Informed Consent Form  [PDF] September 1, 2018

More Information

• Responsible Party: Varun Monga, MD, Assistant Clinical Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT03468075
• Other Study ID Numbers: 201802800 (Phase II)
• First Posted: March 16, 2018
• Results First Posted: December 10, 2020
• Last Update Posted: December 10, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Varun Monga, MD, University of Iowa:

Sarcoma; Soft tissue; Ascorbate

Additional relevant MeSH terms:

Sarcoma; Osteosarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Ascorbic Acid; Gemcitabine; Vitamins; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Antioxidants; Protective Agents