TVB- 2640 in Combination With Bevacizumab in Patients With First Relapse of High Grade Astrocytoma

Study Overview
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Brief Summary
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Randomized phase 2 study TVB-2640 in combination with Bevacizumab versus Bevacizumab alone.

Detailed Description
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Eligible patients will be randomized into 2 separate arms: Arm number one will receive Bevacizumab every 2 weeks in combination with TVB-2640 from day 1 until day 28 of the first cycle. Arm number two will receive Bevacizumab alone every 2 weeks, from on days 1 and 15 of the first until day 28 of the first cycle. MR-Spectroscopy will be obtained on all patients (both arms) at day 28 of first cycle. Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive bevacizumab every 2 weeks in combination with TVB-2640. Every cycle will last 28 days.

Official Title
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A Phase 2 Investigator Initiated Study to Determine the Efficacy and Safety of TVB- 2640 in Combination With Bevacizumab in Patients With First Relapse of High Grade Astrocytoma

Conditions
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Astrocytoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: TVB-2640


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee Histologically confirmed high-grade astrocytoma Progression following standard combined modality treatment with radiation and temozolomide chemotherapy Recovered from reversible toxicities of prior therapy to Grade 0 or Grade 1 ECOG Performance Status of 0 to 2 Life expectancy of at least 3 months Adequate renal and liver function: AST/ALT ≤ 3 x ULN, Bilirubin ≤ 1.5 times ULN, Creatinine ≤ ULN Adequate hematologic status (without hematologic support): Hemoglobin ≥ 9 g/dL, ANC ≥ 1500 cells/ml, Platelets ≥ 100,000 cells/ml All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (for example, surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through six months after the last dose. Exclusion Criteria: Receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug Evidence of acute intracranial or intratumoral hemorrhage either by MRI or CT scan. Subjects with resolving hemorrhage changes punctuate hemorrhage, or hemosiderin are eligible Unable to undergo MRI scan (e.g., pacemaker) Received enzyme-inducing anti-epileptic agents within 14 days of study drug (e.g., carbamazepine, phenytoin, phenobarbital, primidone) Not recovered to a NCI CTCAE v.4.03 Grade ≤ 1 from AEs (except alopecia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug Evidence of wound dehiscence Pregnant or breast-feeding Clinically significant Dry Eye or necessary contact lens use Serious intercurrent illness such as: Hypertension (two or more blood pressure readings performed at screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment, Non-healing wound or ulcer, Uncontrolled life threatening cardiac arrhythmias, Untreated hypothyroidism, Uncontrolled active infection, Symptomatic congestive heart failure or unstable angina pectoris within 3 months prior to study drug, Gastrointestinal perforation, abdominal fistula, intra-abdominal abscess within 1 year Inherited bleeding diathesis or coagulopathy with the risk of bleeding HIV , Hepatitis B or C documented infections Received any of the following prior anticancer therapy: Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed, Non-antiangiogenic therapy (including investigational agents and small molecular kinase inhibitors) within 7 days or 5 half-lives, whichever is shorter, prior to the first dose of study drug, Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug, Nitrosoureas or mitomycin C within 42 days or metronomic/protracted

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab and TVB-2640<br>Bevacizumab every 2 weeks in combination with TVB-2640 dosed at 100mg/m2 daily (rounded to 50mg tab dose), from day 1 until day 28 of the first cycle. | Drug: Bevacizumab<br>* Bevacizumab is FDA approved as a treatment for recurrent Glioblastoma following failure of radiation therapy and temozolomide.<br>* Other names: Avastin;Drug: TVB-2640<br>* TVB-2640 is a potent and reversible inhibitor of the FASN enzyme. TVB-2640 inhibits the β-ketoacyl reductase (KR) enzymatic activity of the FASN enzyme.<br>|
| Experimental: Bevacizumab for Cycle 1, then Bevacizumab and TVB-2640<br>Bevacizumab alone every 2 weeks, on days 1 and 15 until day 28 of the first cycle, and then receive both Bevacizumab and TVB-2640 for the remainder of their participation in this study. | Drug: Bevacizumab<br>* Bevacizumab is FDA approved as a treatment for recurrent Glioblastoma following failure of radiation therapy and temozolomide.<br>* Other names: Avastin;Drug: TVB-2640<br>* TVB-2640 is a potent and reversible inhibitor of the FASN enzyme. TVB-2640 inhibits the β-ketoacyl reductase (KR) enzymatic activity of the FASN enzyme.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival at 6 Months (PFS6) | Survival of participants at 6 months after the start of treatment without their condition becoming any worse. Brain magnetic resonance imaging (MRI) was performed after every even cycle (e.g., C2, C4) during treatment, with tumor response assessed by the investigator for complete response (CR), partial response (PR) and PD according to the Response Assessment in Neuro-oncology (RANO) criteria. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, Nature and Severity of Adverse Events and Serious Adverse Events, Graded According to NCI - Common Toxicity Criteria for Adverse Events Version (4.03) | Number of adverse of any nature are reported as well as the number of adverse events that were classed as grade 3-5 on the NCI - Common Toxicity Criteria for Adverse Events | Up to 6 28-day cycles |