Phase I/II Adaptive Randomized Trial of Bevacizumab versus Bevacizumab plus Vorinostat in Adults with Recurrent Glioblastoma
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.
Disease Group: Brain,CNS
Treatment Agent: Avastin,Vorinostat
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Genentech, Inc.,Merck Sharp and Dohme Corp.,NCI BRAIN TUMOR TRIALS COLLABORATIVE (BTTC)
Primary endpoint: 1. Phase I To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult patients with malignant glioma. 2. Phase II 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. Secondary endpoint: Phase II To determine the radiological response, time-to-progression(TTP) and overall survival(OS) in the treatment arms. To determine the efficacy and safety of combination of Vorinostat and Bevacizumab including in a subset of patients whose tumors exhibit a mesenchymal-pro-angiogenic phenotype associated with poor outcome. To determine the effects of bevacizumab with and without vorinostat upon biomarkers of angiogenesis. To evaluate the occurrence of symptoms and correlate to disease progression and tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool.
IRB Review and Approval Date: 07/06/2011
Recruitment Status: Closed
Projected Accrual: 108
1) 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.
Wafer acceptable if recurrence is confirmed.
2) 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. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis using the local institutional standards for such determination including advanced imaging or surgery.
3) For the phase II portion of the study, patients may have had treatment for no more than 2 prior relapses. There is no limit to the number of relapses for the phase I portion of the study provided the functional status and other eligibility criteria for enrollment are met. Relapse is defined as progression following initial therapy (i.e. radiation+/- chemo if that was used as initial therapy). The intent therefore is that patients had no more than 3 prior therapies (initial and treatment for 2 relapses). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered as 1 relapse. For patients who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse
4) All patients must sign an informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information.
5) The baseline on-study MRI should be performed within 14 days (+ 3 working days) prior to registration but before starting treatment and on a steroid dosage that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and registration (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI, must be used throughout the period of protocol treatment for tumor measurement.
6) Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) At least 4 weeks(28 days) have elapsed from the date of surgery and the patients have recovered from the effects of surgery. b) Evaluable or measurable disease following resection of recurrent Malignant Glioma is not mandated for eligibility into the study. c) To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or at least 4 weeks post-operatively, within 14 days prior to registration. If the 96-hour scan is more than 14 days before registration, the scan needs to be repeated. If the steroid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable steroid dosage for at least 5 days.
7) Patients must be 18 years old or older.
8) Patients must have a Karnofsky performance status (KPS) equal or greater than 60.
9) At the time of registration: (1) Patients must have recovered from the toxic effects of prior therapy to < grade 2 toxicity per CTC version 4 (except deep vein thrombosis): 28 days from any investigational agent; 4 weeks (28 days) from prior cytotoxic therapy; 2 weeks (14 days) from vincristine; 6 weeks (42 days) from nitrosoureas; 3 weeks (21 days) from procarbazine administration; >1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). (2) Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
10) Patients must have adequate bone marrow function (ANC>/= 1,500/mm^3 and platelet count of >/= 100,000/mm^3), adequate liver function (SGPT </= 3 times upper limit normal and alkaline phosphatase </= 2 times upper limit normal, total bilirubin </= 1.5 mg/dl), “Patients with high bilirubin levels related to known diagnosis of benign hyperbilirubinemia (Gilbert’s syndrome) will be eligible", and adequate renal function (BUN </= 1.5 times institutional normal and Creatinine < 1.5 mg/dl) prior to registration. These tests must be performed within 14 days prior to registration.
11) Patients receiving treatment with any antiepileptic medications except valproic acid (because of its HDAC inhibitory activity) can be included in the study. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4); however, vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should preferably be treated with non-enzyme inducing anti-epileptic medications although this is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of these drug levels should be considered, as considered clinically appropriate by the treating physician.
12) Women of childbearing potential must have a negative B-HCG pregnancy test documented within 14 days prior to registration. Women of childbearing potential must not be pregnant, must not be breast-feeding and must practice adequate contraception for the duration of the study, and for 30 days after the last dose of study medication. Patients must not be pregnant because animal studies show that bevacizumab and Vorinostat are teratogenic.
13) Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study.
14) Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 12 weeks (84 days) from the completion of radiation therapy to study entry except if there is unequivocal evidence for tumor recurrence (such as histological confirmation or advanced imaging data such as PET scan) in which case at least 4 weeks (28 days) from completion of radiation therapy will suffice (Note: for patients who have undergone surgery to confirm recurrence after radiation therapy, guidelines in 4.9a should be followed).
15) Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon either PET or Thallium scanning, MR spectroscopy or surgical/pathological documentation of disease.
16) Male patients on treatment with Vorinostat must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication .
1) Inability to comply with protocol or study procedures (for example,
an inability to swallow tablets).
2) Prior treatment with bevacizumab or vorinostat.
3) Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. A 5-day wash out period is required. Patients who have failed prior treatment with other histone deacetylase inhibitors will be excluded.
4) Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent.
5) Any condition, including the presence of clinically significant laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. These would include, a) Active infection (including persistent fever) including known AIDS or Hepatitis C infection, b) Diseases or conditions that obscure toxicity or dangerously alter drug metabolism, c) Serious intercurrent medical illness (e.g. symptomatic congestive heart failure).
6) Current, recent (within 4 weeks (28 days) of the first infusion of this study), or planned participation in an experimental antitumor drug study(other than the current one).
7) Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
8) Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg).
9) Prior history of hypertensive crisis or hypertensive encephalopathy.
10) New York Heart Association (NYHA) Grade II or greater congestive heart failure.
11) History of myocardial infarction or unstable angina within 6 months prior to Day 1.
12) History of stroke or transient ischemic attack within 6 months prior to Day 1
13) Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1.
14) History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1.
15) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
16) 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.. “Patients with recent resection will be eligible for entry into the surgical arm of the study but will follow guidelines as in the protocol"
17) Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.
18) History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.
19) Serious, non-healing wound, active ulcer, or untreated bone fracture.
20) Proteinuria as demonstrated by: (a) Urine protein:creatinine (UPC) ratio >/= 1.0 at screening OR (b) 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).
21) Known hypersensitivity to any component of bevacizumab
22) Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential is required for study treatment..
23) Patients with spinal disease (metastasis) and/or leptomeningeal disease will not be allowed in the study.
Information and next steps
Phase I/Phase II
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