WCI1837-10: Phase I Trial of Temozolomide, Bevacizumab Plus Bortezomib for Patients With Recurrent Glioblastoma Multiforme
- Each patient must meet all of the following inclusion criteria to be enrolled in the
1. Age 18 years or more.
2. Patients must have histologically confirmed diagnosis of a recurrent/progressive
WHO grade IV malignant gliomas (glioblastoma multiforme and gliosarcoma).
3. Patients must have measurable progressive or recurrent disease by MRI within 2
weeks of starting treatment.
4. No prior bortezomib is allowed.
5. An interval of at least 6 weeks between prior surgical resection, 4 weeks from
the end of prior radiotherapy.
6. Patients must be at least 10 days off any Enzyme inducing Anti-Epileptic Drugs
(EIAEDs) of the CYP-450 such as phenytoin, carbamazepine, phenobarbital.
7. Karnofsky performance status score of 60 or mre, and a MMSE > 15.
8. Patients must have recovered from toxicity of prior therapy.
9. Hematocrit > 29%, ANC > 1,500 cells/microliter, platelets > 125,000
cells/microliter for 14 days prior to enrollment.
10. Serum creatinine < 1.5 mg/dl, serum SGOT and bilirubin < 1.5 times upper limit
11. An interval of at least 3 months from the completion of most recent radiation
therapy. At least 4 weeks from a non-nitrosourea chemotherapy regimen and at
least 6 weeks from a nitrosourea containing regimen.
12. For patients on corticosteroids, they must have been on a stable dose for 1 week
prior to entry if clinically recommended.
13. May have up to three biological therapies
14. Voluntary written informed consent before performance of any study-related
procedure not part of normal medical care, with the understanding that consent
may be withdrawn by the subject at any time without prejudice to future medical
15. Female subject is either post-menopausal or surgically sterilized or willing to
use an acceptable method of birth control (i.e., a hormonal contraceptive,
intra-uterine device, diaphragm with spermicide, condom with spermicide, or
abstinence) for the duration of the study.
16. Male subject agrees to use an acceptable method for contraception for the
duration of the study.
- Patients meeting any of the following exclusion criteria are not to be enrolled in
1. Co-medication that may interfere with study results; e.g. immuno-suppressive
agents other than corticosteroids.
2. Greater than three prior recurrences.
3. Enzyme inducing Anti-Epileptic Drugs (EIAEDs) of the CYP-450 such as phenytoin,
4. Patients receiving concurrent investigational drugs.
5. Evidence of CNS hemorrhage on baseline MRI or CT scan (except for grade 1
hemorrhage that has been stable for at least 3 months).
6. History of stroke within six months.
7. Requires therapeutic anti-coagulation.
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection requiring IV antibiotics and psychiatric illness/social
situations that would limit compliance with study requirements, or disorders
associated with significant immunocompromised state.
9. Patient has a calculated or measured creatinine clearance of <20 mL/minute
within 14 days before enrollment.
10. Patient has greater or equal to Grade 2 peripheral neuropathy within 14 days
11. Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (Appendix), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic
evidence of acute ischemia or active conduction system abnormalities. Prior to
study entry, any ECG abnormality at Screening has to be documented by the
investigator as not medically relevant.
12. Patient has hypersensitivity to bortezomib, boron or mannitol.
13. Female subject is pregnant or breast-feeding. Confirmation that the subject is
not pregnant must be established by a negative serum beta-human chorionic
gonadotropin (beta-hCG) pregnancy test result obtained during screening.
Pregnancy testing is not required for post-menopausal or surgically sterilized
14. Patient has received other investigational drugs with 14 days before enrollment
15. Serious medical or psychiatric illness likely to interfere with participation in
this clinical study.
16. Diagnosed or treated for another malignancy within 3 years of enrollment, with
the exception of complete resection of basal cell carcinoma or squamous cell
carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after
curative therapy. Patients with prior malignancies must be disease free for at
least 5 years.
17. Serious, non-healing wound, active ulcer, or untreated bone fracture. Bone
fractures must be healed.