Overview

RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

Status:
Completed
Trial end date:
1969-12-31
Target enrollment:
0
Participant gender:
All
Summary
This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as gamma-secretase/Notch signalling pathway inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Treatments:
Dacarbazine
R04929097
Temozolomide
Criteria
Inclusion Criteria:

- Patients must have newly diagnosed glioblastoma, anaplastic astrocytoma, gliosarcoma
or other malignant gliomas with the exception of pure anaplastic oligodendroglioma;
note: patients with presumed malignant glioma based on radiographic assessment may be
enrolled onto Arm A of the study without histological confirmation provided they meet
the following additional eligibility criteria:

- The MRI of the brain shows typical findings of a malignant glioma or glioblastoma
(single ring-enhancing mass with necrotic portions)

- To exclude brain abscess, diffusion-weighted MRI must show absence of restricted
diffusion corresponding to the necrotic center of the lesion

- To confirm the diagnosis of neoplastic disease, MR perfusion must show that the
lesion has increased perfusion

- To exclude pilocytic astrocytoma, the patient's age must be over 25

- To exclude brain metastasis, a computed tomography (CT) of the chest, abdomen and
pelvis must demonstrate absence of other malignancy

- The principal investigator must review MRI and CT findings and agree with
diagnosis of presumed malignant glioma

- Note: If after the on-protocol surgery the patient is found not to meet
histological criteria described (diagnosis of glioblastoma, anaplastic
astrocytoma, gliosarcoma or other malignant gliomas with the exception of
pure anaplastic oligodendroglioma), the patient will be removed from the
study and replaced

- ARM A ONLY: Patients must have an indication for additional debulking surgery as part
of their initial treatment

- Life expectancy of greater than 2 months

- Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)

- Hemoglobin >= 9 g/dL

- Leukocytes > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Total bilirubin < 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73
m^2 for patients with creatinine levels above institutional normal

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) at least 4 weeks prior to
study entry, for the duration of study participation, and for at least 12 months
post-treatment; should a woman become pregnant or suspect she is pregnant while she or
her partner are participating in this study and for 12 months after study
participation, the patient should inform the treating physician immediately

- Women of childbearing potential are required to have a negative serum pregnancy test
(with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior
to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine)
will be administered every 4 weeks if their menstrual cycles are regular or every 2
weeks if their cycles are irregular while on study within the 24-hour period prior to
the administration of RO4929097; a positive urine test must be confirmed by a serum
pregnancy test; prior to dispensing RO4929097, the investigator must confirm and
document the patient's use of two contraceptive methods, dates of negative pregnancy
test, and confirm the patient's understanding of the teratogenic potential of
RO4929097

- Female patients of childbearing potential are defined as follows:

- Patients with regular menses

- Patients, after menarche with amenorrhea, irregular cycles, or using a
contraceptive method that precludes withdrawal bleeding

- Women who have had tubal ligation

- Female patients may be considered to NOT be of childbearing potential for the
following reasons:

- The patient has undergone total abdominal hysterectomy with bilateral
salpingo-oophorectomy or bilateral oophorectomy

- The patient is medically confirmed to be menopausal (no menstrual period) for 24
consecutive months

- Pre-pubertal females; the parent or guardian of young female patients who have
not yet started menstruation should verify that menstruation has not begun. If a
young female patient reaches menarche during the study, then she is to be
considered as a woman of childbearing potential from that time forward

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior chemotherapy, radiotherapy, biological or experimental therapy for glioma

- Prior history of radiotherapy to the brain, head or neck

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to RO4929097 or other agents used in the study

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible

- Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of
CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently
with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are
taking concurrent medications that are strong inducers/inhibitors or substrates of
CYP3A4 should be switched to alternative medications to minimize any potential risk;
if such patients cannot be switched to alternative medications, they will be
ineligible to participate in this study

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow tablets

- Patients with known history of hepatitis B or C, or who have a history of liver
disease, other forms of hepatitis or cirrhosis are ineligible; (hepatitis B and C
serology should be obtained as part of pre-treatment evaluation but are not required
for eligibility)

- Patients with uncontrolled electrolyte abnormalities including hypocalcemia,
hypomagnesemia, hyponatremia, hypophosphatemia, and hypokalemia defined as less than
the lower limit of normal for the institution, despite adequate electrolyte
supplementation are excluded from this study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, history of
torsades de pointes or other significant cardiac arrhythmias, or psychiatric
illness/social situations that would limit compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with RO4929097 or temozolomide; these potential risks may also
apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated

- A corrected QT (QTc) > 450 msec in males and a QTc > 470 msec in females

- Patients who have not recovered to < Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in
this study

- ARM A ONLY: Patients with contraindication to a brain surgical procedure

- A requirement for antiarrhythmics or other medications known to prolong QTc