Know Cancer

forgot password

Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas

Phase 1
18 Years
Not Enrolling
Adult Anaplastic Oligodendroglioma, Adult Brain Stem Glioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Recurrent Adult Brain Tumor

Thank you

Trial Information

Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas


I. Determine, in patients with recurrent MGs (many of whom receive dexamethasone, a moderate
CYP3A4 inducer), the safety and maximum-tolerated dose of RO4909297 administered at 2 dose

II. Determine the pharmacokinetics, intratumoral drug concentration, target modulation, and
evidence of any treatment effect in the malignant glioma tumor tissue by R04929097
administered at the dose found in Part A.


I. Determine the pharmacokinetic (PK) profile of RO4909297 in patients with recurrent MGs
(many of whom receive dexamethasone, a moderate CYP3A4 inducer).

II. Determine the progression-free survival of patients with recurrent malignant glioma
following treatment with R04929097.

III. Determine if the RPTD dose of RO4929097 significantly inhibits p75^NTR cleavage and

IV. Determine the effects of RO4929097 on the establishment and growth of BTIC cultures in
neurosphere growth conditions, effects on proliferation, ability to self-renewal, and
ability to differentiate along lineage-specific pathways.

V. Determine the ability of RO4929097 to inhibit Notch signaling, by assessing downstream
target activation, in glioma tissue of patients with recurrent MG.

VI. Determine the association between a number of serum, tumor, and BTIC markers and
response to R04929097.

OUTLINE: This is a multicenter, dose-escalation (part A) study followed by an open-label
(part B) study.

PART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8.
Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and
15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable

Post resection tumor specimens are collected for correlative studies, including
pharmacokinetic and biomarker assays.

After completion of study therapy, patients are followed up at 30 days and then every 3
month for up to 6-12 months.

Inclusion Criteria:

- Patients must have radiographic progression of a histologically confirmed
glioblastoma, high-grade astrocytoma, NOS, anaplastic mixed oligo-astrocytoma, or
anaplastic oligodendroglioma

- In patients that present radiographic evidence of progression after concurrent
treatment with radiation and low-dose temozolomide, diagnosis of progression
should be made after at least 2 cycles of monthly temozolomide in order to rule
out pseudoprogression

- Secondary MGs (evolving from a prior low-grade glioma) can be included as long
as they are considered malignant in the latest resection

- Patients must have at least one enhancing lesion that can be accurately measured as >
1 X 1 cm on a MRI

- Prior treatment must include radiotherapy (with or without temozolomide)

- No limit to the number of prior recurrences or surgeries

- For Part B only, surgical resection should be considered a reasonable therapeutic
option for a patient that can tolerate surgical resection

- Patients with multifocal disease can be included as long as resection is
considered a reasonable option to manage the nodule that is progressing

- There must be sufficient tissue available (minimum from a 1 X 1 cm lesion) for a
biopsy to be taken during surgery

- There must be sufficient tissue available for evaluation of p75^NTR status from a
prior surgery (using immunohistochemistry on fixed tissue or, in uncommon cases in
which frozen tissue is available from a prior surgery, western blot) (part B)

- ECOG performance status < 2 (Karnofsky > 50%)

- Life expectancy of greater than 4 weeks

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Hemoglobin > 90 g/L (or > 9 g/dL)

- Total bilirubin < 2.0 mg/dL

- BUN < 25 mg/dL

- AST/ALT < 3 X institutional upper limit of normal

- Creatinine within institutional normal limits OR creatinine clearance > 60 mL/min

- No major medical illnesses or psychiatric impairments that, in the investigator's
opinion, would prevent administration or completion of protocol therapy

- Not pregnant or nursing

- Negative serum pregnancy test

- Fertile patients must use two forms of contraception (i.e., barrier contraception and
one other method of contraception) at least 4 weeks prior to study entry, during, and
for 12 months after completion of study therapy

- Able to swallow pills

- Patients with a history of seizures need to have had no generalized seizures in the
last month prior to entering the study

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to RO4929097

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

- Patients who are serologically positive for hepatitis A, B, or C, and have a
resulting positive serological test, or have a history of liver disease, other forms
of hepatitis, or cirrhosis are ineligible

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or
hypokalemia (within 7 days prior to study treatment), despite adequate electrolyte

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia other than chronic, stable atrial fibrillation, or psychiatric
illness/social situations that would limit compliance with study requirements

- HIV-positive patients on combination antiretroviral therapy are ineligible

- Baseline QTc ≤ 450 msec (male) or QTc ≤ 470 msec (female)

- No history of risk factors for QT interval prolongation, including, but not limited
to, family or personal history of long QT syndrome, recurrent syncope without known
etiology, or sudden unexpected death

- No history of torsades de pointes or other significant cardiac arrhythmias or the
need for concomitant meds with known potential to prolong QT interval or

- Use of food that may interfere with the metabolism of RO4929097 is prohibited,
including grapefruit or grapefruit juice

- Patients must have recovered from the effects of any prior treatment (systemic
chemotherapy/radiotherapy) or surgery ( therapy)

- Patients who have had chemotherapy, surgery, or radiotherapy within 4 weeks (6 weeks
for nitrosoureas or mitomycin C) prior to entering the study are not eligible

- Patients may not be receiving any other investigational agents

- Patients cannot be receiving enzyme-inducing anti-epileptic drugs (EIAEDs)

- If previously treated with EIAEDs, patients must have been switched to
non-EIAEDs 4 weeks prior to starting RO4929097

- Enzyme-inducing antiepileptic drugs (EIAEDs) include: carbamazepine (Tegretol);
oxcarbazepine (Trileptal); phenobarbital (or derivatives); phenytoin (Dilantin)

- Non enzyme-inducing Antiepileptic Drugs (Non-EIAEDs) include: clobazam
(Frisium); clonazepam (Rivotril); gabapentin (Neurontin); levetiracetam
(Keppra); lamotrigine (Lamictal); topiramate (Topamax)

- No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4

- Even though dexamethasone is a moderate inducer of CYP3A4, patients may remain
on dexamethasone at the lowest dose possible

- Stable or decreasing steroid dose within 5 days prior to registration required

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

- No other investigational or commercial agents or therapies may be administered with
the intent to treat the patient's malignancy

- No re-irradiation (any technique) is allowed

- If a patient elects to have a new resection of his/her tumor in the absence of
progression of the disease, treatment will be discontinued and no re-challenge will
be allowed after this additional surgery

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 (MTD) defined as the dose level in which less than or equal to 1 out of 6 patients experience dose limiting toxicity (DLT) assessed using NCI CTCAE version 4.0

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Peter Forsyth

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network-Princess Margaret Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

July 2011

Completion Date:

Related Keywords:

  • Adult Anaplastic Oligodendroglioma
  • Adult Brain Stem Glioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma