Gemcitabine With Ascorbate Including Adolescents
Primary Purpose
Soft Tissue Sarcoma, Bone Sarcoma, Unresectable Soft Tissue Sarcoma
Status
Withdrawn
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ascorbate
Gemcitabine
Sponsored by
About this trial
This is an interventional treatment trial for Soft Tissue Sarcoma
Eligibility Criteria
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.
Sites / Locations
- University of Iowa Hospitals & Clinics
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Ascorbate in combination with Gemcitabine
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
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
Secondary Outcome Measures
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
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04877587
Brief Title
Gemcitabine With Ascorbate Including Adolescents
Official Title
A Pilot Study of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas Including Adolescents
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Withdrawn
Why Stopped
Unable to enroll
Study Start Date
January 2023 (Anticipated)
Primary Completion Date
May 31, 2025 (Anticipated)
Study Completion Date
May 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Dickens
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Soft Tissue Sarcoma, Bone Sarcoma, Unresectable Soft Tissue Sarcoma, Metastatic Bone Sarcoma, Metastatic Soft-tissue Sarcoma, Unresectable Bone Sarcoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ascorbate in combination with Gemcitabine
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ascorbate
Other Intervention Name(s)
Vitamin C
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Gemcitabine
Other Intervention Name(s)
Gemzar®
Intervention Description
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
Primary Outcome Measure Information:
Title
Adverse Events as defined by CTCAE version 5.0
Description
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.
Time Frame
Adverse events will be followed for 4 weeks after the last pharmacologic ascorbate infusion
Title
ORR as defined by RECIST 1.1 guidelines
Description
Overall Response Rate (ORR) as defined by the percentage of patients with a complete or partial response, according to RECIST 1.1 guidelines
Time Frame
For two years following completion of treatment
Secondary Outcome Measure Information:
Title
PFS defined by RECIST 1.1 guidelines
Description
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
Time Frame
For two years following completion of treatment
Title
OS defined as the time from first day of study treatment to death due to any cause
Description
Overall Survival (OS) defined as the time from first day of study treatment to death due to any cause
Time Frame
For two years following completion of treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Dickens, MD, FAAP
Organizational Affiliation
University of Iowa Hospitals & Clinics
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Iowa Hospitals & Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
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Gemcitabine With Ascorbate Including Adolescents
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