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A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma

Phase 2
18 Years
Open (Enrolling)
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma


I. 6-month progression-free survival (PFS6) (Group A) II. Efficiency of neurosphere
generation after pretreatment with RO4929097. (Group B)


I. Radiographic response rate. (Group A) II. Toxicities associated with this regimen. (Group
A) III. Overall survival. (Group A) IV. Expression levels of Notch pathway components and
downstream targets. (Group B) V. Tumor propagation. An extension of lifespan by 50% in tumor
bearing mice (mice bearing fresh tumor tissue). (Group B) VI. Patient event-free survival in
correlation with expression levels of Notch pathway components and downstream targets.

VII. 6-month progression-free survival (PFS6). VIII. Toxicities associated with this
regimen. IX. Overall survival.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

Group A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3,
8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

Group B (surgical resection indicated): Patients receive oral gamma-secretase inhibitor
RO4929097 once daily on days -6 to -1. Patients undergo surgical resection on day 0. Within
30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in
group A.

After completion of study treatment, patients are followed up every 2 months.

Inclusion Criteria:

- Patients must have histologically proven glioblastoma which is progressive or
recurrent following radiation therapy and/or chemotherapy

- Patients must have measurable contrast-enhancing progressive or recurrent
glioblastoma by MRI imaging within two weeks of starting treatment; patient must be
able to tolerate MRIs

- GROUP B PATIENTS ONLY: Patients must be eligible for surgical resection according to
the following criteria:

- Expectation that the surgeon can resect >= 50% of the Gd-enhancing tumor with
low risk of inducing neurological injury

- Absence of hematologic, cardiac or other medical contraindications to surgery

- Surgery must take place Monday-Thursday with the exception of patients being
treated at Cleveland Clinic/University Hospitals: these patients may undergo
surgery Monday - Friday

- Patients must have a tumor size >= 2.5 cm in diameter in two perpendicular
planes in order to enable correlative studies

- Paraffin embedded tissue must be available from initial surgical resection at
diagnosis (prior to any treatment)

- Patients may have an unlimited number of prior therapy regimens but no prior
γ-secretase inhibitors

- Patients must have recovered from severe toxicity of prior therapy; the following
intervals from previous treatments are required to be eligible:

- 3 months from the completion of radiation

- 6 weeks from a nitrosourea chemotherapy

- 3 weeks from a non-nitrosourea chemotherapy

- 4 weeks from any investigational (not FDA-approved) agents

- 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., small
molecule targeted therapy, thalidomide, bevacizumab, etc.)

- Patients may not be on an enzyme-inducing anti-epileptic drug (EIAED); if previously
on an EIAED, patient must be off for at least 14 days prior to the first dose of

- Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be
able to care for himself/herself with occasional help from others)

- Hemoglobin >= 9 g/dL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin >= institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) =< 4.0 x institutional upper limit of normal

- Creatinine within institutional upper limit of normal OR

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

- Electrolytes - calcium, chloride, magnesium, potassium, phosphorus, sodium within
institutional normal limits

- Patients must be able to provide written informed consent

- Women of childbearing potential and men must use two forms of contraception (i.e.,
barrier contraception and one other method of contraception) starting prior to study
entry, for the duration of study participation, and for at least 12 months
post-treatment; for appropriate methods of contraception considered acceptable;
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

- PREGNANCY TESTING: 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 prior to treatment start and be required to agree to have the test
repeated within 24 hours prior to the first dose of RO4929097 (serum or urine);
a pregnancy test (serum or urine) will also be administered every 4 weeks
(within 24 hours prior to starting every cycle) if their menstrual cycles are
regular or every 2 weeks if their cycles are irregular while on study; 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 potential of RO4929097 to cause serious or
life-threatening birth defects

- 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

- Patients may not be breast-feeding

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or
bladder; patients with prior malignancies must be disease-free for >= five years

- Patients must have a Mini Mental State Exam score of >= 15

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, which would jeopardize
the ability of the patient to receive the treatment outlined in this protocol with
reasonable safety, are ineligible

- Patients with prior treatment with γ-secretase inhibitors are ineligible

- Patients may not be receiving any other investigational agents

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to RO4929097 or other agents used in the study are

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

- Patients with the following cardiovascular abnormalities are ineligible: baseline
QTcF > 450 msec (male) or QTcF > 470 msec (female)

- Patients with a requirement for antiarrhythmics or other medications known to prolong
QTc are ineligible

- Patients with a history of being serologically positive for hepatitis B or C, or who
have a history of cirrhosis are ineligible

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

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, a history of torsades de pointes or other significant cardiac arrhythmias
other than chronic stable atrial fibrillation, or psychiatric illness/social
situations that would limit compliance with study requirements, are ineligible

- Pregnant women or those who are breastfeeding are ineligible

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with RO4929097

- Patients who have not recovered to < CTCAE grade 2 toxicities related to prior
therapy are not eligible to participate in this study

Type of Study:


Study Design:

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

Outcome Measure:

Progression-free survival (PFS) (Group A)

Outcome Description:

Actual estimate of the success rate, including confidence intervals, will be provided to allow direct assessment of the strength of the evidence for efficacy. Additional analyses will include Kaplan Meier estimates of time-to-event.

Outcome Time Frame:

At 6 months

Safety Issue:


Principal Investigator

David Peereboom

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Food and Drug Administration

Study ID:




Start Date:

December 2010

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma



Adult Brain Tumor ConsortiumBaltimore, Maryland  21231-1000