RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01189240
First received: August 25, 2010
Last updated: March 19, 2014
Last verified: March 2014

August 25, 2010
March 19, 2014
December 2010
January 2013   (final data collection date for primary outcome measure)
  • Maximum-tolerated dose and the recommended phase II dose of gamma-secretase inhibitor RO4929097 in combination with bevacizumab determined by dose-limiting toxicity rate (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Overall survival (Phase II) [ Time Frame: From treatment start date to date of death, assessed up to 30 days ] [ Designated as safety issue: No ]
    A one-sided Logrank test will be used to assess the two survival distributions, which under the null are the same. The hazard ratio will be estimated along with 80% confidence interval. Kaplan-Meier survival plots will be used to depict the overall survival in each treatment group.
  • Maximum-tolerated dose and the recommended phase II dose of gamma-secretase inhibitor RO4929097 in combination with bevacizumab (Phase I) [ Designated as safety issue: Yes ]
  • Overall survival (Phase II) [ Designated as safety issue: No ]
  • Safety and efficacy (Phase I and II) [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01189240 on ClinicalTrials.gov Archive Site
Proportion of patients who are progression-free at 6 months (Phase I) [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
A one-sided Logrank test will be used to assess the two survival distributions, which under the null are the same. The hazard ratio will be estimated along with 80% confidence interval.
  • Progression-free survival at 6 months (Phase I) [ Designated as safety issue: No ]
  • Pharmacokinetics (Phase I) [ Designated as safety issue: No ]
  • Proportion of patients alive and progression-free survival at 6 months (Phase II) [ Designated as safety issue: No ]
  • Frequency of toxicity (Phase II) [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma
Phase I/II Study of R04929097 With Bevacizumab in Patients With Recurrent Malignant Glioma

This phase I/II trial is studying the side effects and the best dose of RO4929097 to see how well it works when given together with bevacizumab compared to bevacizumab alone in treating patients with progressive or recurrent malignant glioma. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving RO4929097 together with bevacizumab may kill more tumor cells.

PRIMARY OBJECTIVES:

I. Assess the safety profile and the recommended phase II dose of gamma-secretase inhibitor RO4929097 (RO4929097) in combination with bevacizumab in patients with recurrent malignant glioma.

II. Assess the progression-free survival at 6 months of patients treated with this regimen.

III. Compare the overall survival of patients with recurrent glioblastoma treated with RO4929097 and bevacizumab versus bevacizumab alone.

SECONDARY OBJECTIVES:

I. Describe the toxicity associated with this regimen in these patients. II. Assess the pharmacokinetics of this regimen in these patients. III. Estimate the proportion of patients alive and progression-free survival at 6 months in patients treated with RO4929097 and bevacizumab versus bevacizumab alone.

IV. Evaluate the safety and tolerability of these regimens in these patients. V. Explore potential prognostic biomarkers from glioma tissue at baseline and potential association with Notch pathway inhibition.

OUTLINE: This is a multicenter, phase I, dose-escalation study of gamma-secretase inhibitor RO4929097 (RO4929097) followed by a randomized phase II study.

PHASE I: Patients receive oral RO4929097 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15 (days 2 or 3 and 15 of course 1 only). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized* to 1 of 2 treatment arms.

ARM I: Patients receive oral RO4929097 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.

ARM II: Patients receive bevacizumab as in arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *If phase II single-arm study demonstrates effectiveness, it will proceed to the phase II randomized study.

Some patients undergo blood sample collection for pharmacokinetic studies. Archived tumor tissue samples are analyzed for potential biomarkers and Notch pathway inhibition.

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

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Recurrent Adult Brain Tumor
  • Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
    Given orally
    Other Names:
    • R4733
    • RO4929097
  • Biological: bevacizumab
    Given IV
    Other Names:
    • anti-VEGF humanized monoclonal antibody
    • anti-VEGF monoclonal antibody
    • Avastin
    • rhuMAb VEGF
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Experimental: Arm I (Phase II)
    Patients receive oral RO4929097 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.
    Interventions:
    • Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
  • Experimental: Arm II (Phase II)
    Patients receive bevacizumab IV as in arm I.
    Interventions:
    • Biological: bevacizumab
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
13
Not Provided
January 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed malignant glioma (phase I)

    • Glioblastoma
    • Anaplastic astrocytoma
    • Anaplastic oligodendroglioma
    • Mixed anaplastic oligoastrocytoma
  • Histologically confirmed glioblastoma following radiotherapy and temozolomide (phase II)
  • Progressive or recurrent disease after conformal external-beam radiation therapy and concurrent temozolomide, followed by ≥ 1 adjuvant course of temozolomide
  • Measurable disease by MRI within the past 2 weeks
  • Tumor tissue form indicating availability of archived tissue from initial resection at diagnosis of malignant glioma completed and signed by a pathologist
  • Karnofsky performance status 60-100%
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin normal
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min

    • Urine protein: If proteinuria ≥ +2 protein, a protein level should be < 1,000 mg by a 24-hour urine collection
  • Electrolytes (calcium, chloride, magnesium, potassium, phosphorus, sodium) within institutional normal limits
  • Fertile patients must use 2 forms of effective contraception before, during, and for ≥ 12 months (6 months phase II, bevacizumab arm only) after treatment
  • Negative pregnancy test
  • Not pregnant or nursing
  • At least 5 years since prior malignancy except nonmelanoma skin cancer, or carcinoma in situ of the cervix, breast, or bladder
  • Mini Mental State Exam score of ≥ 15
  • Must be able to tolerate MRI
  • No serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive the treatment outline in this protocol with reasonable safety
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to gamma-secretase inhibitor RO4929097 or bevacizumab
  • Must be able to swallow capsules
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
  • Not history of being serologically positive for hepatitis A, B, or C
  • No history of cirrhosis
  • No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia despite adequate electrolyte supplementation
  • No uncontrolled intercurrent illness including, but not limited to, any of the following:

    • 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
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • No serious or non-healing wound, ulcer, or bone fracture
  • No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
  • No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within the past 6 months
  • No clinically significant cardiovascular disease, including any of the following:

    • Inadequately controlled hypertension (systolic BP > 160 mm Hg and/or diastolic BP > 90 mm Hg) despite antihypertensive medication
    • History of cerebrovascular accident or transient ischemic attack at any time
    • Myocardial infarction or unstable angina within the past 12 months
    • NYHA grade II-IV congestive heart failure
    • Serious and inadequately controlled cardiac arrhythmia
    • Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)
    • Clinically significant peripheral vascular disease
  • No evidence of bleeding diathesis or coagulopathy
  • No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • No requirement for antiarrhythmics or other medications known to prolong QTc
  • One or 2 prior treatment regimens allowed
  • Recovered from severe toxicity of prior therapy
  • At least 3 months since prior radiotherapy
  • At least 6 weeks since prior nitrosourea
  • At least 3 weeks since prior chemotherapy
  • At least 4 weeks since prior and no other concurrent investigational agents
  • At least 2 weeks since prior non-cytotoxic, FDA-approved agent (e.g., Tarceva [erlotinib hydrochloride], hydroxychloroquine, bevacizumab, etc.)
  • At least 28 days since any prior surgery
  • No prior γ-secretase inhibitors and/or bevacizumab
  • At least 10 days since prior and no concurrent enzyme-inducing anti-epileptic drug
  • No concurrent combination antiretroviral therapy for HIV-positive patients
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01189240
NCI-2011-02509, NCI-2011-02509, CDR0000683099, ABTC-1002, ABTC-1002, U01CA137443
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Edward Pan National Cancer Institute (NCI)
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP