Clinical trial NCT01738646: Ph II SAHA and Bevacizumab for Recurrent Malignant Glioma Patients
Official title: Phase II Study of Bevacizumab and Vorinostat for Recurrent WHO Grade IV Malignant Glioma Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent Glioblastoma Multiforme
Malignant Glioma
Adult Brain Tumor
Keywords: vorinostat
SAHA
bevacizumab
AVASTIN
malignant glioma
GBM
glioblastoma multiforme
brain tumor
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
name: Merck Sharp & Dohme LLC
First posted: 2012-11-30
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: It has been shown that bevacizumab has significant anti-tumor activity in patients with recurrent glioblastoma multiforme. Vorinostat has modest anti-tumor activity against malignant glioma and can enhance the action of both chemotherapy and anti-angiogenics. Patients will be treated with a combination of bevacizumab and vorinostat.

Detailed description: There is no effective therapy for patients with recurrent glioblastoma multiforme (GBM) hence such patients remain a major unmet need in oncology. The investigators have recently demonstrated that bevacizumab (BV), a humanized monoclonal antibody against vascular endothelial growth factor, has significant anti-tumor activity among recurrent glioblastoma multiforme patients. Vorinostat has modest anti-tumor activity against malignant glioma and can potentiate the action of both chemotherapy and anti-angiogenics. The current study is designed to evaluate the anti-tumor activity of vorinostat when combined with BV among recurrent glioblastoma multiforme patients.

Eligibility criteria: Inclusion Criteria:

* Age \> 18 years.
* An interval of at least 4 weeks between prior surgical resection or one week from stereotactic biopsy.
* An interval of at least 12 weeks from the end of prior radiotherapy unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven tumor progression
* An interval of at least 4 weeks from prior chemotherapy \[6 weeks for nitrosoureas, 1 week for daily administered chemotherapy (metronomic dosing)\] or investigational agent unless the patient has recovered from all anticipated toxicities associated with that therapy.
* Eastern Cooperative Oncology Group (ECOG) 0-1.
* Hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil ≥1,500 cells/microliter, platelets ≥ 100,000 cells/microliters.
* Serum creatinine, serum glutamic oxaloacetic transaminase(SGOT) and bilirubin \< 1.5 times upper limit of normal.
* Signed informed consent approved by the Institutional Review Board prior to patient entry.
* No evidence of hemorrhage on the baseline MRI or CT scan other than those that are stable grade 1.
* If sexually active, patients will take contraceptive measures for the duration of the treatments. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, hysterectomy, vasectomy), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine device (IUD).

Exclusion Criteria:

Disease-specific exclusions

* More than 2 prior episodes of disease progression
* Prior therapy with histone deacetylase inhibitors; valproic acid is not permitted and patients previously treated with valproic acid must be off valproic acid for at least 30 days prior to initiation of study medication
* Prior bevacizumab therapy
* Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
* Active infection requiring intravenous antibiotics
* Severe hepatic insufficiency, active viral hepatitis or HIV infection
* Requires therapeutic anti-coagulation with warfarin

General medical exclusions

Subjects meeting the following criteria are ineligible for study entry:

* Inability to comply with study and/or follow-up procedures

Bevacizumab-specific exclusions

* Inadequately controlled hypertension (defined as systolic blood pressure \> 150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
* Any prior history of hypertensive crisis or hypertensive encephalopathy
* New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
* History of myocardial infarction or unstable angina within 6 months prior to study enrollment
* History of stroke or transient ischemic attack within 6 months prior to study enrollment
* Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
* Symptomatic peripheral vascular disease
* Evidence of bleeding diathesis or coagulopathy
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment
* Serious, non-healing wound, ulcer, or bone fracture
* Proteinuria at screening as demonstrated by either:

  * Urine protein:creatinine (UPC) ratio \>= 1.0 at screening OR
  * Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
* Known hypersensitivity to any component of bevacizumab
* Pregnant (positive pregnancy test) or lactating. Refuse the use of effective means of contraception (men and women) in subjects of child-bearing potential

Primary outcomes:
measure: Six-month Progression-free Survival (PFS6)
timeFrame: 6 months
Secondary outcomes:
measure: Radiographic Response
timeFrame: 3 Years
measure: Percentage of Participants Who Experience Grade 3 or Greater, Treatment Related, Non-hematologic Toxicities.
timeFrame: 2.7 Years
measure: Median Progression-free Survival (PFS)
timeFrame: 3 Years
measure: Median Overall Survival (OS)
timeFrame: 3 Years
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Katherine Peters, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ghiaseddin A, Reardon D, Massey W, Mannerino A, Lipp ES, Herndon JE 2nd, McSherry F, Desjardins A, Randazzo D, Friedman HS, Peters KB. Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma. Oncologist. 2018 Feb;23(2):157-e21. doi: 10.1634/theoncologist.2017-0501. Epub 2017 Nov 13.