Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma

Phase 1

Completed

Conditions: Malignant Glioma
Recurrent Glioblastoma

Interventions: Drug: bevacizumab
Drug: vorinostat

Registration Number: NCT01266031

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: The goal of this Phase I portion of this clinical research study is to find the highest tolerable dose of bevacizumab with or without vorinostat, that can be given to patients with malignant gliomas. The safety of these drug combinations will also be studied.

The goal of this Phase II part of this clinical research study is to learn if bevacizumab when given with or without vorinostat can help to control malignant gliomas. The safety of these drug combinations will also be studied.

Detailed Description: Background

* Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment, consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective.

* Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved against cancer by FDA based on improved survival of advanced colon cancer patient, has recently been studied in the GBM.

* The present study aims to determine the potential of vorinostat, an HDAC inhibitor plus bevacizumab, versus bevacizumab alone, in an attempt to increase the anti-angiogenic effects of VEGF by blocking the evasive resistance by combination with vorinostat and to also not only provide the potential of the independent effects of both agents but also the potential for synergy.

Objectives

* To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult patients with malignant glioma.

* To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as determined by progression free survival (PFS) using an adaptive randomization phase II trial design.

Eligibility

* Patients must have histologically proven glioblastoma, gliosarcoma or anaplastic glioma to be eligible for the Phase I component of this protocol. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma NOS (not otherwise specified). Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a malignant glioma is made. Only patients with histologically proven or imaging proven recurrent glioblastoma or gliosarcoma will be eligible for the Phase II component.

* Patients must have shown unequivocal evidence for tumor progression as determined by an MRI scan done prior to study entry which will be reviewed by the treating physician to confirm and document recurrence.

* No prior treatment with bevacizumab or Vorinostat

Design

The phase I component will assess the MTD of Vorinostat in combination with Bevacizumab. A conventional phase I design will be used and the MTD will be selected using a 3+3 accrual design at each dose level until MTD is determined. A maximum of 18 patients will be recruited to this component of the study.

The phase II component of the trial compares Bevacizumab to Vorinostat+ Bevacizumab in patients with recurrent GBM. The primary outcome is progression free survival. Patients will be randomized between the two arms using a Bayesian adaptive algorithm. Patients will be randomized fairly between the two arms at the start of the trial (for the first 20 patients). Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in favor of the treatment that, on average, has better results in terms of failure time. Therefore, each successive patient is more likely to receive the treatment with better results, on average. A minimum of 20 and a maximum of 90 patients will be accrued.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 96

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bevacizumab	bevacizumab	10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.
Vorinostat and Bevacizumab	bevacizumab	Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle. Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.
Vorinostat and Bevacizumab	vorinostat	Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle. Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS) at 6 Months	Baseline until disease progression or death due to any cause, up to six months	PFS is time measured in months to disease progression as assessed at six months from participant registration. Assessments continue every 8 weeks up to 28 days after last dose (follow-up), anticipated trial length one year. Participants must be assessed at least 4 weeks after surgery to begin treatment in the adaptive randomized Phase 2 portion of the trial. PFS in participants in the surgical arm determined from the date of randomization to the treatment arms and not from the date of registration in the trial. Study outcome measure period ended June 2015.
Maximum Tolerated Dose (MTD) of Oral Vorinostat Used With Bevacizumab	28 day, cycle 1	MTD defined as the dose level at which 1/6 patients experience dose limiting toxicity (DLT), using conventional Phase I design where the MTD was selected using a 3+3 accrual design at each dose level until MTD was determined. Toxicities will be graded according to the Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.

Secondary Outcome Measures

Name	Time	Method
Mean Symptom Interference at the Time of Clinical Evaluation	Baseline, (cycle 2), week 8 (cycle 4), and end of therapy, approximately week 52 (cycle 12)	Overall mean interference severity of 6 interference items. Interference is rated 0-10, zero is "did not interfere" and 10 is "as bad as you can imagine". All patients with at least one valid questionnaire will be included in the analyses.
Time to Progression (TTP)	3, 6, and 12 months from patient registration	Progression defined by the Modified MacDonald criteria is 25% increase in the sum of products, of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any lesion/site, OR failure to return for evaluation due to health or deteriorating condition (unless clearly unrelated to this cancer).
Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PIGF), and Basic Fibroblast Growth Factor (bFGF)	Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion)	About 5cc of blood was collected to measure plasma angiogenic proteins vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and basic fibroblast growth factor (bFGF) by enzyme-linked immunosorbent assay (ELISA).
Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Stromal Cell-derived Factor α (SDF1α), and Angiopoietin 1 (Ang 1) and 2 (Ang 2) by Enzyme-linked Immunosorbent Assay (ELISA)	Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion)	About 5cc of blood was collected to measure plasma angiogenic proteins stromal cell-derived factor α (SDF1α), angiopoietin 1 and 2 by enzyme-linked immunosorbent assay (ELISA).
Percentage of Patients Rating Their Symptoms to be 7 or Greater on a 0-10 Scale Using the Mean Severity of the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT) Self Reporting Tool	Baseline, week 4, week 8, and end of therapy, approximately week 52 (cycle 12)	Percentage of patients rating their symptoms to be 7 or greater on a 0-10 scale using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Self Reporting Tool. Zero is "not present" and 10 is "as bad as you can imagine. All patients with at least one valid questionnaire will be included in the analyses. Differences of at least 2 points will be classified as the minimum clinically meaningful change in the symptom severity and symptom interference measures.
Number of Participants With Serious and Non-Serious Adverse Events	Phase I adverse events collected within 4 week (28 day) cycle. Phase II evaluated for adverse events after each cycle for first 2 cycles and subsequently after each 2 cycles of treatment prior to initiating the next cycle.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Overall Survival (OS)	up to 30 months.	OS was computed using the number of months from the date of randomization to the date of death, up to 30 months. Participants still alive were censored at the last follow-up date.
Mean Symptom Severity Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Self Reporting Tool	Baseline, week 4 (cycle 2), week 8 (cycle 4), and end of therapy, approximately week 52 (cycle 12)	Overall mean severity of 22 symptoms. Symptoms are rated 0-10, zero is "not present" and 10 is "as bad as you can imagine". All patients with at least one valid questionnaire will be included in the analyses.
Radiological Response	End of therapy, approximately	Magnetic resonance imaging (MRI) and contrast-enhanced (CE) MRI was used to evaluate tumor response. Response is defined by the Modified MacDonald criteria. Complete Response (CR) is complete disappearance of all measurable and evaluable disease. Partial response (PR) is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. Partial Response, Non-Measurable (PRNM) is not applicable. Stable/No Response does not qualify for CR, PR or progression. Progression is 25% increase in the sum of products, of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any lesion/site, OR failure to return for evaluation due to health or deteriorating condition (unless clearly unrelated to this cancer).