Clinical trial NCT04634227: Gemcitabine Plus Ascorbate for Sarcoma in Adults (Pilot)
Official title: A Pilot Study of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas in Adults
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Sarcoma
Soft Tissue Sarcoma
Unresectable Soft Tissue Sarcoma
Metastatic Bone Tumor
Bone Sarcoma
Keywords: Sarcoma
Soft tissue
Ascorbate
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: Mohammed Milhem, MBBS
First posted: 2020-11-18
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: The primary objectives of this pilot study are to assess the feasibility of pharmacokinetically-guided, patient-individualized dosing and to obtain preliminary evidence of anti-tumor activity of intravenous ascorbate in combination with gemcitabine to inform a subsequent Phase II trial. Soft tissue and bone sarcomas will be studied as different cohorts given the differences in biology and historical responses to single agent gemcitabine in these disease types. As such, 10 evaluable patients per disease cohort will be included.

Eligibility criteria: Inclusion Criteria:

* Male or female patients aged ≥ 18 years old
* ECOG Performance Status of ≤ 2
* Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
* Tolerate a 15g 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.
* 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.
* Patients with NO 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

Exclusion Criteria:

* Lab values in the below ranges:

  * Neutrophil count of \</=1500/mm3
  * Platelet count of \</= 100,000/mm3L
  * Hemoglobin \< 9 g/dL (transfusion to meet eligibility allowed)
  * 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 without known bony metastases
  * 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 \< 3.0
  * Serum sodium \< 130
  * Serum albumin \<2.5g/dl
* G6PD (glucose-6-phosphate dehydrogenase) deficiency
* Prior exposure to gemcitabine for metastatic disease
* Subjects with prior doxorubicin exposure with a MUGA or ECHO demonstrating LVEF \< the lower limit of the institutional normal.
* 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
* Actively receiving insulin or requiring fingerstick glucose monitoring at time of ascorbate infusion
* Patients on warfarin and unable to be substituted to another anticoagulant
* 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.
* Women of childbearing potential (WOCBP) who are not 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
* 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.
* 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 other anti-cancer therapy or radiation therapy. Palliative radiation therapy to non-target lesions is permitted.
* 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.
* 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 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.

Primary outcomes:
measure: Determine the 12 weeks progression free survival (PFS 12) at 12 weeks post treatment initiation
timeFrame: 12 weeks post-treatment
Secondary outcomes:
measure: Assess overall survival of patients with unresectable or metastatic soft tissue and bone sarcoma treated with high dose ascorbate when administered intravenously concurrently with gemcitabine
timeFrame: Every 2 months for first 6 months, then every 3 months up to 2 years post treatment
measure: Determine the tumor response as per RECIST 1.1 criteria
timeFrame: 12 weeks post-treatment
measure: Incidence of Adverse Events (AE) Per CTCAE 4.03
timeFrame: Up to 30 days after completion of study treatment
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: John
state: Iowa
Study officials:
affiliation: University of Iowa Hospitals & Clinics
name: John Rieth, MD
role: PRINCIPAL_INVESTIGATOR
References: