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A Phase I Trial of Vorinostat in Combination With Bevacizumab and Irinotecan in Recurrent Glioblastoma

Phase 1
18 Years
Open (Enrolling)

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Trial Information

A Phase I Trial of Vorinostat in Combination With Bevacizumab and Irinotecan in Recurrent Glioblastoma

Drug Administration: (A cycle is 28 days) Irinotecan and bevacizumab are given IV on days 1
and 15 of each cycle. Vorinostat is given orally on days 1-7 and 15-21 of each cycle.

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

Irinotecan is given at a dose of 125mg/m². Bevacizumab is given at a dose of 10mg/kg.

Maximum tolerated dose (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 dose limiting toxicities (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 magnetic resonance imaging (MRI) scans with intravenous

- Radiographic evidence for tumor progression by MRI within 14 days prior to

- Karnofsky performance status ≥ 60

- Complete blood count (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:
serum glutamic oxaloacetic transaminase (SGOT)[aspartic transaminase (AST)]/serum
glutamic pyruvic transaminase (SGPT) [alanine transaminase (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 (PT) 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
international normalized ratio (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 (WOCBP) must have a negative β-HCG pregnancy test
documented within 14 days prior to registration.

- WOCBP must agree to use 2 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

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 electrocardiogram (EKG) performed within 14 days of
registration; New York Heart Association (NYHA) 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 Centers for Disease Control and Prevention (CDC);
cannot be receiving highly active antiretroviral therapy (HAART); 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 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD)

Outcome Description:

Define MTD of vorinostat when combined with bevacizumab and irinotecan

Outcome Time Frame:

25 months

Safety Issue:


Principal Investigator

Prakash Chinnaiyan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center & Research Institute, Inc.


United States: Institutional Review Board

Study ID:




Start Date:

September 2008

Completion Date:

December 2013

Related Keywords:

  • Glioblastoma
  • recurrent glioblastoma
  • multiple agents
  • immunotherapy
  • chemotherapy
  • brain and nervous system
  • Glioblastoma



H. Lee Moffitt Cancer Center & Research Institute, Inc. Tampa, Florida  33612