SarcomaPhase 1NCT01106872
Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas
A Phase 1 study testing Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid in people with Sarcoma and Soft Tissue Sarcoma, run by Mohammed M Milhem at 1 site in United States.
Trial summary
The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine, bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma. Valproic acid is used by people who have seizures to prevent seizures from happening; however, its use in cancer is investigational. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma
- What is being tested?
- Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2010to 22 Aug 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
About this study
Official title: A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas
The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine, bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma. Valproic acid is used by people who have seizures to prevent seizures from happening; however, its use in cancer is investigational. This study will help define the proper dosing of this valproic acid. We will assess the safety of valproic acid with the combination of the above chemotherapy drugs and check for possible side effects. Valproic acid may improve the function of the chemotherapy drugs against the cancer.
Read the 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.
- Conditions
- Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma, Unresectable Sarcoma, Metastatic Sarcoma
- Being tested
- Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid
- Keywords
- Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma, Unresectable Sarcoma, Metastatic Sarcoma, Valproic Acid, Bevacizumab, Histone Deacetylase Inhibitor
- Medical subject headings
- Sarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bevacizumab, Gemcitabine, Docetaxel and Valproic AcidDrug
Also called Avastin, Gemzar, Taxotere, Depakene
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Bevacizumab Combined with Gemcitabine, Docetaxel and Valproic Acid in Advanced Sarcoma Receives: Drug: Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluate toxicities
Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.
Measured: After one cycle (3 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Apr 2010 (estimated)
- Study startSep 2010
- Primary completionJul 2017
- Study completion22 Aug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SarcomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- Mohammed M Milhem
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Sponsor-investigator, Mohammed M Milhem, University of Iowa
- Investigators
- Mohammed Milhem, MD, Principal investigator, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01106872
- Sponsor's protocol ID
- 200911736
- Other IDs
- AVF4761s
- Status last verified
- Aug 2018
- First submitted
- 22 Mar 2010
- Last updated
- 10 Aug 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas
- ClinicalTrials.gov ID
- NCT01106872
- Acronym / sponsor ID
- 200911736
- Conditions
- Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma, Unresectable Sarcoma, Metastatic Sarcoma
- Keywords
- Sarcoma, Soft Tissue Sarcoma, Locally Advanced Sarcoma, Unresectable Sarcoma, Metastatic Sarcoma, Valproic Acid, Bevacizumab, Histone Deacetylase Inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 47 participants (actual)
- Lead sponsor
- Mohammed M MilhemUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Sep 2010 (actual)
- Primary completion
- Jul 2017 (actual)
- Study completion
- 22 Aug 2017 (actual)
- First posted
- 20 Apr 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine, bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma. Valproic acid is used by people who have seizures to prevent seizures from happening; however, its use in cancer is investigational. This study will help define the proper dosing of this valproic acid. We will assess the safety of valproic acid with the combination of the above chemotherapy drugs and check for possible side effects. Valproic acid may improve the function of the chemotherapy drugs against the cancer.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: Bevacizumab, Gemcitabine, Docetaxel and Valproic AcidBevacizumab Combined with Gemcitabine, Docetaxel and Valproic Acid in Advanced Sarcoma |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (29 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bevacizumab, Gemcitabine, Docetaxel and Valproic AcidAlso: Avastin, Gemzar, Taxotere, Depakene | Drug | Treatment |
Primary outcome
Evaluate toxicities
Time frame: After one cycle (3 weeks)
Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2018.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mohammed Milhem, MD principal investigator
University of Iowa
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Bevacizumab, Gemcitabine, Docetaxel and Valproic Acid in people with Sarcoma and Soft Tissue Sarcoma, run by Mohammed M Milhem at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluate toxicities (time frame: After one cycle (3 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2018.