The purpose of the this study is to see if an investigations cancer treatment called
vorinostat can be combined with the irinotecan/bevacizumab regimen safely.
Vorinostat (provided in 100mg capsules) begins at a dose of 200mg/day, escalating to
300mg/day and then to a maximum of 400mg/day. Vorinostat will be taken prior to irinotecan
and bevacizumab on days 1 and 15. The drug should be administered at the same time every day
for days 2-7 and 16-21. Patients will be treated prophylactically with compazine 30 minutes
prior to vorinostat which, in turn, should be taken 30 minutes prior to a meal whenever
possible.
Irinotecan is given at a dose of 125mg/m2. Bevacizumab is given at a dose of 10mg/kg.
MTD will be defined by toxicities occurring during the first 4 weeks of therapy. Three
patients will be treated at dose level one and can be enrolled simultaneously. They must be
observed for DLT for at least 4 weeks from treatment day 1. Page 15 of the protocol outlines
the dose escalation parameters. At least 9 patients will be treated at the MTD. If DLT is not
achieved in any cohort of up to a dose level of 400mg/day of vorinostat, further dose
escalations will not be made. This dose will then become the recommended dose.
Patients demonstrating evidence of benefit may be treated up to a maximum of 24 cycles, at
the investigator's discretion.
Inclusion Criteria:
- Histologically proven intracranial glioblastoma or gliosarcoma with pathologic or
radiographic confirmation of tumor progression or regrowth following standard
front-line therapy. Patients will be eligible if original histology was low-grade
glioma and a subsequent diagnosis of glioblastoma or gliosarcoma was made.
- History and physical examination, including neurologic examination and performance
status, within 1 week prior to registration.
- Systolic blood pressure ≤ 160 mmHg and diastolic pressure ≤ 90 mmHg
- Able to undergo brain MRI scans with intravenous gadolinium.
- Radiographic evidence for tumor progression by MRI within 14 days prior to
registration.
- Karnofsky performance status ≥ 60
- CBC/differential obtained 14 days prior to registration, with adequate bone marrow
function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500/microL; Platelets
≥ 100,000 cells/microL; Hemoglobin ≥ 10. 0 gm/dL (use of transfusion or other
intervention to achieve Hgb ≥ 10. 0 is acceptable)
- Adequate liver function within 14 days prior to registration, defined as follows:
SGOT[AST] / SGPT[ALT] < 2. 5 times the upper limit of normal; Bilirubin ≤ 1. 6 mg/dL
- Adequate renal function within 14 days prior to registration, defined as: Creatinine ≤
1. 5 mg/dL; Urine protein screened by urine analysis for urine protein creatinine (UPC)
ratio. For UPC ratio > 0. 5, 24-hour urine protein should be obtained and the level
should be <1000 mg.
- If not on stable anticoagulation, prothrombin time must be within normal limits within
14 days prior to registration.
- If on full-dose anticoagulants (e. g., warfarin or LMW heparin) must meet both of the
following criteria: No active bleeding or pathological condition that carries a high
risk of bleeding (e. g., tumor involving major vessels or known varices); In-range INR
(usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose
of low molecular weight heparin
- Have received prior concurrent and/or adjuvant temozolomide.
- Have recovered from toxic effects of prior therapy, and there must be a minimum time
of 28 days from the administration of any prior cytotoxicity or investigational agent,
except for nitrosureas (>42 days).
- Should not have been previously treated with any other histone deacetylase (HDAC)
inhibitors (other than valproic acid for management of seizures). If they have been
treated with valproic acid as treatment for seizures, the drug should be stopped at
least 30 days before exposure to vorinostat.
- Should not have been previously treated with bevacizumab and/or irinotecan.
- Should not have undergone more than 3 prior therapies.
- Patients having undergone recent resection of recurrent or progressive tumor must meet
all of the following conditions: Patients must have recovered from the effects of
surgery and a minimum of 28 days must have elapsed from the day of surgery to the day
of registration; If a core or needle biopsy was performed, a minimum of 7 days must
have elapsed prior to registration.
- Residual disease following resection of recurrent glioblastoma is not mandated for
eligibility into the study.
- Have failed prior radiation therapy and must have an interval of ≥ 42 days (6 weeks)
from the completion of initial radiation therapy to registration.
- Must sign study-specific informed consent prior to registration.
- Women of childbearing potential must have a negative β-HCG pregnancy test documented
within 14 days prior to registration.
- Women of childbearing potential must agree to use two forms of adequate contraceptive
methods. These include (1) oral, injectable, or implantable hormonal contraceptive;
(2) tubal ligation; (3) intra-uterine device; (4) barrier contraceptive with
spermicide; or (5) vasectomized partner. Men must also protect their partner from
becoming pregnant through use of condoms with spermicide or vasectomy. Patient must
agree to have standard of care MRIs.
Exclusion Criteria:
- Prior invasive malignancy that is not the glioblastoma or gliosarcoma (except
nonmelanomatous skin cancer or carcinoma in situ of the cervix) unless patient has
been disease free and off therapy for that disease for at least 3 years.
- Acute intratumoral hemorrhage on MR imaging. Patients with MR imaging demonstrating
old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection)
will be eligible for treatment.
- Must not have any significant medical illness that in the investigator's opinion
cannot be adequately controlled with appropriate therapy or would compromise the
patient's ability to tolerate this therapy.
- Must not have any severe, active comorbidity, defined as: Transmural myocardial
infarction or unstable angina within 6 months prior to study Registration; Evidence of
recent myocardial infarction or ischemia by the findings of S-T elevations of ≥2 mm
using the analysis of an EKG performed within 14 days of registration; New York Heart
Association grade II or greater or congestive heart failure requiring hospitalization
within 12 months prior to registration; History of stroke or transient ischemic attack
within 6 months; Inadequately controlled hypertension despite antihypertensive
medication; Serious and inadequately controlled cardiac arrhythmia; Significant
vascular disease; Clinically significant peripheral vascular disease; Evidence of
bleeding diathesis or coagulopathy; Patients on dialysis; Serious or non-healing
wound, ulcer, or bone fracture; History of abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 28 days prior to registration; Acute
bacterial or fungal infection requiring intravenous antibiotics at the time of
registration; Chronic obstructive pulmonary disease exacerbation or other respiratory
illness requiring hospitalization or precluding study therapy within 14 days prior to
registration; Acquired immune deficiency syndrome (AIDS) based upon current CDC;
Cannot be receiving HAART therapy; Must not be diagnosed with hepatitis B or hepatitis
C.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to registration.
- Anticipation of need for major surgical procedures during the course of the study.
- Core biopsy within 7 days prior to registration.
- Pregnant or nursing women; breastfeeding should be discontinued prior to enrollment.
- Fertile men and women who are sexually active and not willing/able to use medically
acceptable forms of contraception during therapy and for at least 6 months after the
completion of therapy.
- Known hypersensitivity of Chinese hamster ovary cell products or other recombinant
human antibodies.
- Any condition that impairs ability to swallow pills.
- The clearance and metabolism of irinotecan is markedly enhanced in patients receiving
drugs that induce the hepatic cytochrome p450 system. In brain tumor patients, these
are typically certain types of anticonvulsants, termed enzyme-inducing anti-epileptic
drugs (EIAEDs). Patients cannot be receiving EIAEDs or any CYP3A4 inhibitors; patients
previously receiving these agents must have discontinued their use at least 2 weeks
prior to registration.
