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Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study

Phase 1
18 Years
Open (Enrolling)
Adult Anaplastic Astrocytoma, Adult Anaplastic Ependymoma, Adult Brain Stem Glioma, Adult Diffuse Astrocytoma, Adult Ependymoma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Adult Pilocytic Astrocytoma, Adult Pineal Gland Astrocytoma, Adult Subependymal Giant Cell Astrocytoma

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Trial Information

Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study


I. To establish the maximum-tolerated dose and the recommended phase II dose of
gamma-secretase inhibitor RO4929097 (RO4929097) in combination with temozolomide and
radiotherapy in patients with newly diagnosed glioblastoma multiforme, anaplastic
astrocytoma, gliosarcoma, or other malignant gliomas.


I. To evaluate the pharmacokinetics of RO4929097 and temozolomide in these patients.

II. To evaluate brain and tumor penetration by this regimen, including radiotherapy, in
these patients.


I. To evaluate pharmacodynamic effects of RO4929097 in the resected specimens from these
patients in comparison with specimens obtained from untreated patients.

II. To evaluate the effects of RO4929097 on the cancer stem cells of these patients.

III. To evaluate the effects of RO4929097 on angiogenesis (microvascular density and
expression of tumor vascular markers, including vascular E-cadherin, CD146, CD31, VEGF
ligands and receptors, and pericyte markers).

IV. To evaluate the combined effects of this regimen in explants established from tumor
specimens of these patients and controls.

V. To evaluate the effects of RO4929097 on MRI parameters, including DCE-MRI perfusion,
diffusion-weighted imaging, and volumetric analysis.

VI. To evaluate, preliminarily, the efficacy of this regimen at 6 months in these patients.

VII. To determine, preliminarily, the median progression-free survival and overall survival
of patients treated with this regimen.

VIII. To evaluate potential biomarkers of RO4929097and Notch inhibition activity in plasma
and hair follicle samples.

OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor

Pre-surgery treatment: Patients receive oral gamma-secretase inhibitor RO4929097 (RO4929097)
once daily on days 1-7 of week 1 and day 1 of week 2.

Surgery: Patients undergo surgery 2-3 hours after administration of RO4929097 on day 1 of
week 2.

Treatment concurrent with radiotherapy: Beginning 3-4 weeks after surgery, patients undergo
conventional focal (intensity-modulated or 3-D conformal) radiotherapy 5 days a week for
approximately 6 weeks. Patients also receive oral RO4929097 once daily for approximately 10
weeks beginning the day of radiotherapy and oral temozolomide once daily for approximately 6
weeks beginning the day before radiotherapy.

Adjuvant treatment following radiotherapy: Approximately 4 weeks after completion of
radiotherapy, patients receive oral RO4929097 once daily on days 1-28 and oral temozolomide
once daily on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of
disease progression or unacceptable toxicity.

Blood and tumor tissue samples are analyzed for pharmacokinetics on days 0-2 of week 1 and
day 1 of week 5. Other biomarker studies are conducted on blood and hair follicle samples.

After completion of study therapy, patients are followed up for 4 weeks and periodically

Inclusion Criteria:

- Newly diagnosed glioblastoma, including any of the following subtypes:

- Glioblastoma

- Anaplastic astrocytoma

- Gliosarcoma

- Other malignant gliomas

- No pure anaplastic oligodendroglioma

- Patients with presumed malignant glioma based on radiographic assessment may be
enrolled onto the protocol without histological confirmation provided they meet the
following additional eligibility criteria:

- 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 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

- If after the on-protocol surgery the patient is found not to meet histological
criteria, the patient will be removed from the study and replaced

- Underwent prior stereotactic biopsy or incomplete surgical resection

- Indication for additional debulking surgery

- No contraindication to a brain surgical procedure

- Patients who are not candidates for surgical resection may be allowed (except
brain surgery)

- ECOG performance status 0-1 (Karnofsky 70-100%)

- Life expectancy > 2 months

- Leukocytes > 3,000/mm^3

- ANC > 1,500/mm^3

- Platelet count > 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT < 2.5 times ULN

- Creatinine normal OR creatinine clearance > 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use two forms of effective contraception for 4 weeks before,
during, and 12 months after completion of study therapy

- Able to swallow tablets

- QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to gamma-secretase inhibitor RO4929097 or other agents used in
this study

- No malabsorption syndrome or other condition that would interfere with intestinal

- No known history of hepatitis B or C or history of liver disease or other forms of
hepatitis or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia defined as less than the lower limit
of normal for the institution, despite adequate electrolyte supplementation

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- History of torsades de pointes or other significant cardiac arrhythmias

- Psychiatric illness and/or social situations that would limit compliance with
study requirements

- No requirement for antiarrhythmics or other medications known to prolong QTc

- No concurrent medications or food that may interfere with the metabolism of RO4929097
including ketoconazole and grapefruit

- Must be recovered to < grade 2 toxicities related to prior therapy

- No prior chemotherapy, radiotherapy, biological, or experimental therapy for glioma

- No prior radiotherapy to the brain, head, or neck

- No combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- Patients on concurrent medications that are strong inducers and/or inhibitors of
CYP3A4 should switched to alternative medications to minimize any potential risk

- No concurrent hypofractionated radiotherapy or radiosurgery

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose defined as the highest dose studied for which the incidence of DLT is less than 33% using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Description:

The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Antonio Omuro

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Ependymoma
  • Adult Brain Stem Glioma
  • Adult Diffuse Astrocytoma
  • Adult Ependymoma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Adult Pilocytic Astrocytoma
  • Adult Pineal Gland Astrocytoma
  • Adult Subependymal Giant Cell Astrocytoma
  • Astrocytoma
  • Ependymoma
  • Glioblastoma
  • Glioma
  • Gliosarcoma



Memorial Sloan Kettering Cancer Center New York, New York  10021
University of Virginia Charlottesville, Virginia  22908