- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01106872
Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas
A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Soft tissue sarcomas (STS) are a heterogeneous group of benign and malignant tumors of various supportive tissues arising from the mesoderm. There are 56 known subtypes classified by the tissue of origin. Soft tissue sarcomas account for 1% of all human malignancies. These tumors share a common mesenchymal origin with the vasculature. Many of the signaling pathways involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF) - and platelet-derived growth factor (PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes1. Despite promising preclinical data supporting a role for angiogenesis inhibition in sarcoma, relatively few clinical trials have evaluated antiangiogenic therapy in sarcoma.
Most of the studies for the use of anti-angiogenic drugs have been taken from phase I trials of refractory solid tumors showing a lack of response in sarcomas. This may be due to an inadequate dose, wrong sequence of the treatment or lack of studies with combination treatments. Given the heterogeneity of sarcomas there may be a benefit in certain subgroups that can easily be missed. A recent clinical trial has shown improved cytotoxic cell kill and response rates by epigenetically modifying the tumor environment prior to chemotherapy. It is believed that the efficacy of angiogenesis inhibitors has been shown to be greatly improved when they are combined with other anticancer drugs.
Tumor metastasis is highly dependent on angiogenesis progressing through a metastatic cascade that includes primary tumor growth, modification of tumor cell growth and behavior and formation of new blood vessels. This angiogenic switch is believed to be the result of changes in the balance of angiogenesis stimulators, inhibitors and modulators present at the site of the tumor growth. These changes are due to both genetic alterations involving RAS, RAF, MYC, SRC, EGFR and HER-2 and tumor suppressor genes and epigenetic circumstances such as hypoxia, inflammation or hormonal stimulation. It is clear that vascular endothelial growth factor (VEGF) has emerged as the key stimulatory molecule for promoting angiogenesis in a variety of human malignancies. Other pro-angiogenic factors can be induced or amplified in the presence of hypoxia hypoglycemia, inflammatory cytokines and altered cell-cell contact. Thus it would be of interest to combine epigenetic modifiers like Valproic acid, a histone deacetylase inhibitor, with Bevacizumab, an anti-angiogenic agent against VEGF and standard chemotherapy (Gemcitabine /docetaxel) to better modulate the cytotoxic effects against sarcomas.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Iowa
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Iowa City, Iowa, United States, 52242
- University of Iowa Hospitals and Clinics
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Patients must meet the following laboratory criteria:
Hematology: Neutrophil count of > 1500/mm3; Platelet count of >100,000/mm3L; Hemoglobin ≥ 9 g/dL 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; Serum bilirubin ≤ 1.5 x ULN; Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min; Total serum calcium (corrected for serum albumin) or ionized calcium ≥ LLN; Serum potassium ≥ LLN; Serum sodium ≥ LLN; Serum albumin ≥ LLN or 3g/dl; Patients with any elevated alkaline phosphatase due to bone metastasis can be enrolled
- Screening EKG with a QTc less than 450 msec confirmed by central laboratory prior to enrollment to the study.
- Baseline MUGA or ECHO done only in subjects with prior doxorubicin exposure. The test must demonstrate LVEF ≥ the lower limit of the institutional normal.
- 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
- Any patient with the diagnosis of locally advanced, unresectable or metastatic sarcoma from any site. These include untreated patients or those treated with chemotherapy 1st line, 2nd line and 3rd line. Patients must have measurable disease defined as at least 1 lesion ≥ 1cm in the greatest dimension.
- Previous exposure to Gemcitabine and Taxotere 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.
1.All subtypes of sarcoma are eligible for the trial.
Exclusion Criteria:
- Prior use of Bevacizumab for the treatment of cancer.
- Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer.
- Patients who will need valproic acid for any medical condition .
- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg).
- Prior history of hypertensive crisis or hypertensive encephalopathy.
- New York Heart Association (NYHA) Grade II or greater congestive heart failure.
- 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.
- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
- History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) wit hin 1 month prior to Day 1
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
- Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
- History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
- Serious, non-healing wound, active ulcer, or untreated bone fracture
- Proteinuria as demonstrated by a UPC ratio >/= 1.0 at screening
- Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential
- Concomitant use of drugs with a risk of causing torsades de pointes
- Concomitant use of CYP3A4 inhibitors
- 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.
- 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
- Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
- Bone sarcoma is excluded
- Patients who are on drugs that prolong QT-interval on EKG (many antiarrhythmics, tricyclics, phenothiazines, and others)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment
Bevacizumab Combined with Gemcitabine, Docetaxel and Valproic Acid in Advanced Sarcoma
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Evaluate toxicities
Time Frame: After one cycle (3 weeks)
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Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.
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After one cycle (3 weeks)
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Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Sarcoma
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Central Nervous System Depressants
- Antiviral Agents
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Immunological
- Angiogenesis Inhibitors
- Angiogenesis Modulating Agents
- Growth Substances
- Growth Inhibitors
- Tranquilizing Agents
- Psychotropic Drugs
- GABA Agents
- Anticonvulsants
- Antimanic Agents
- Gemcitabine
- Docetaxel
- Bevacizumab
- Valproic Acid
Other Study ID Numbers
- 200911736
- AVF4761s (Other Identifier: UIowa IRB 01)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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