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

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.

- INCLUSION CRITERIA:

Patients will be included in the study based on the following criteria.

- 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.

- 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.

- Patients must be 18 years old or older.

- Patients must have a Karnofsky performance status (KPS) equal or greater than 60

- At the time of registration:

- Patients must have recovered from the toxic effects of prior therapy to < grade 2
toxicity per CTC version 4 (except deep vein thrombosis )

1. 28 days from any investigational agent,

2. 4 weeks (28 days) from prior cytotoxic therapy,

3. 2 weeks (14 days) from vincristine,

4. 6 weeks (42 days) from nitrosoureas,

5. 3 weeks (21 days) from procarbazine administration,

6. greater than or equal to1 week (7 days) for non-cytotoxic agents, e.g.,
interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer
does not count).

- 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 noncytotoxic agents should be
directed to the Study Chair.

- Patients must have adequate bone marrow function (ANC greater than or equal to
1,500/mm3, platelet count of greater than or equal to 100,000/mm3), adequate liver
function (SGPT less than or equal to 3 times upper limit normal and alkaline
phosphatase less than or equal to 2 times upper limit normal, total bilirubin less
than or equal to 1.5mg/dl, Patients with high bilirubin levels related to known
diagnosis of benign hyperbilirubinemia (Gilbert s syndrome) will be eligible ., and
adequate renal function (BUN less than or equal to 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.

- 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.

- The baseline on-study MRI scan should be performed within 14 days (+ 3 working days)
prior to registration but before starting treatment and on a steroid dose 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.

- Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

1. At least 4 weeks (28 days ) have elapsed from the date of surgery and the
patients have recovered from the effects of surgery.

2. Evaluable or measureable disease following resection of recurrent Malignant
Glioma is not mandated for eligibility into the study.

3. To best assess the extent of residual 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.

- 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.

- 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.

- 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.

- 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.

- 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.

- 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
nonenzyme 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.

- 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

EXCLUSION CRITERIA:

General Exclusion Criteria

- Inability to comply with protocol or study procedures (for example, an inability to
swallow tablets).

- Prior treatment with bevacizumab or Vorinostat.

- 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.

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from providing informed consent.

- 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

1. Active infection (including persistent fever) including known AIDS or Hepatitis C
infection

2. Diseases or conditions that obscure toxicity or dangerously alter drug metabolism

3. Serious intercurrent medical illness (e.g. symptomatic congestive heart failure).

- 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).

- 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.

- Patients with spinal disease (metastasis) and/or leptomeningeal disease will not be
allowed in the study.

Bevacizumab-Specific Exclusion Criteria

- Inadequately controlled hypertension (defined as systolic blood pressure > 140 mmHg
and/or diastolic blood pressure > 90 mmHg).

- Prior history of hypertensive encephalopathy.

- New York Heart Association (NYHA) Grade II or greater congestive heart failure.

- History of myocardial infarction or unstable angina within 6 months prior to Day 1.

- History of stroke or transient ischemic attack within 6 months prior to Day1.

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1.

- History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per
episode) within 1 month prior to Day 1.

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).

- 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 section 4.9 .

- 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:

- Urine protein: creatinine (UPC) ratio greater than or equal to 1.0 at screening
OR

- Urine dipstick for proteinuria greater than or equal to 2+ (patients discovered
to have greater than or equal to 2+ proteinuria on dipstick urinalysis at
baseline should undergo a 24 hour urine collection and must demonstrate less than
or equal to 1g of protein in 24 hours to be eligible).

- Known hypersensitivity to any component of bevacizumab.

- 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.