Status and phase
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About
The purpose of this research study is to determine the amount of LBH589 that can be given to people safely when LBH589 is given in combination with bevacizumab. LBH589 in combination with bevacizumab is a drug combination that may stop cancer cells from growing abnormally. LBH589 has been used alone in other trials for solid tumor malignancies. Bevacizumab is FDA approved for use in patients with colorectal cancer and has been studied extensively in other types of solid tumors. The combination of LBH589 and bevacizumab has not yet been studied but information from other studies suggests that the combination may help prevent the growth of the participant's tumor.
Full description
Phase I
Primary Objective
• To determine the maximum tolerated dose (MTD) of LBH589 in combination with bevacizumab given at 10 mg/kg every 2 weeks in patients with recurrent glioblastoma (GBM), gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma or mixed anaplastic oligoastrocytoma.
Secondary Objective
• To define safety.
Phase II
Primary Objective
• To determine the efficacy of LBH589 in combination with bevacizumab in patients with recurrent GBM or gliosarcoma as measured by 6-month progression-free survival (PFS6).
Secondary Objectives
To measure overall survival, time-to-tumor progression and objective tumor response. To further evaluate safety.
Exploratory Objectives
To provide preliminary data on the efficacy in patients with recurrent anaplastic astrocytoma, anaplastic oligodendroglioma or mixed anaplastic oligoastrocytoma. To explore the relationship of the molecular phenotype of the tumor with survival. To investigate correlation of treatment response with laboratory correlates including, plasma angiogenic proteins and perfusion MRI.
Statistical Design
The Phase I study follows a standard 3+3 dose escalation design. Three potential dose levels of oral LBH589 3x per week days 1, 3 and 5 are under evaluation including a starting dose 0 on a weekly schedule as well as dose level 2 and a de-escalation dose level 1 on a weekly schedule. [Note: The study was amended to revise the starting dose due to concerns for thrombocytopenia with the weekly dosing regimen.] The DLT observation period is the first 30 days of treatment. For the Phase II study, based on prior research of bevacizumab monotherapy, a PFS6 rate of 35% does not justify further utilization of LBH589 in combination with bevacizumab while a PFS6 rate of 55% is worthy of further study. With 41 GBM eligible participants in the Phase II study, the treatment would be deemed promising if at least 20 GBM participants achieve 6-month progression-free survival. This design has at least 85% power and a 0.07 significance level to predict the difference between the null hypothesis of 35% PFS6 rate and the alternative hypothesis of 55% PFS6 rate. The protocol specifies a planned interim analysis after the first 21 participants have been accrued. If 12 or more of those participants have died or experienced disease progression/ relapse within 6 months of initiating treatment, accrual will be suspended and the data carefully reviewed before proceeding with additional patient accrual. Participants who are removed from active treatment for toxicity prior to reaching 6 months on treatment are not included in this interim analysis. Participants with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (ie, the phase II dose) are eligible for inclusion in the interim analysis.
Enrollment
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Inclusion criteria
PHASE I Inclusion Criteria (the following modifications to the general eligibility criteria apply to Phase I patients only):
• Patients may have been treated for any number of prior relapses. Relapse is defined as progression following initial therapy
PHASE II Inclusion Criteria (phase II patients must meet the general eligibility criteria as well as the following):
Exclusion criteria
Subject has received previous therapy with anti-VEGF targeted agents or with any histone deacetylase inhibitors. (Prior treatment with valproic acid for seizures is allowed but requires a washout of at least 14 days prior to starting LBH589.) Although concomitant use of the following drugs is not allowed on study, previous use is allowed, provided patients meet the following mandatory washout periods:
i. Drugs w/ risk of causing TdP = 72 hrs; ii. Warfarin = 7 days.
History of grade 2 thrombocytopenia or grade 3 neutropenia on any prior regimen.
Presence of ≥ grade 2 peripheral neuropathy.
Bleeding diathesis or coagulopathy
History of intratumoral or peritumoral hemorrhage if deemed significant by the treating physician
Treatment with warfarin. (For patients requiring anticoagulation therapy, only therapeutic low molecular weight heparin or factor Xa inhibitors are permitted.)
Patients who have received any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
Any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
Patients with any disease that will obscure toxicity or dangerously alter drug metabolism
Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and has not received treatment for that particular disease for a minimum of 3 years
Impaired cardiac function as detailed in the protocol
Uncontrolled hypertension (systolic blood pressure >/= 140 mmHg and/or diastolic blood pressure >/= 90 mmHg) and/or prior history of hypertensive crisis or hypertensive encephalopathy
Significant vascular disease within 6 months prior to Day 1
History of stroke or transient ischemic attack within 6 months prior to Day 1
Patients with unresolved diarrhea > CTCAE grade 1
Patients with INR > 1.5
Patients with major surgery or a significant traumatic injury within 28 days prior to Day 1
Patients with any condition that impairs their ability to swallow and/or absorb pills
Concomitant use of drugs with a risk of causing torsades de pointes
Concomitant use of CYP3A4 inhibitors during the treatment phase of the study and within 72 hours prior to starting treatment
Concomitant use of potent CYP3A4/5 inducers during the treatment phase of the study and within 2 weeks prior to starting treatment
Concomitant use of any anti-cancer therapy or radiation therapy, or any other investigational agent
Patients has known human immunodeficiency virus (HIV) of hepatitis C infection (baseline testing for HIV or hepatitis C is not required)
History of allergic reactions attributed to compounds of similar chemical or biologic composition to LBH589 or bevacizumab, or their excipients
Patient is in a situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study
Patient has a significant history of non-compliance to medical regimens
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 of 1.0 or greater at screening
Subject is pregnant or intends to become pregnant during the study
Primary purpose
Allocation
Interventional model
Masking
51 participants in 7 patient groups
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Data sourced from clinicaltrials.gov
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