RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

13 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-12-31

Study Completion Date

2015-02-28

Brief Summary

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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.

Detailed Description

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Phase I

Primary Objective:

1. To assess the safety profile of R04929097 in combination with bevacizumab and to determine a recommended Phase II dose of R04929097 in combination with bevacizumab in patients with recurrent malignant glioma

Secondary Objectives:
2. To describe the toxicity associated with this combination regimen
3. To assess pharmacokinetics of R04929097 in combination with bevacizumab

Phase II 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.

Conditions

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Adult Anaplastic Astrocytoma Adult Anaplastic Oligodendroglioma Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Recurrent Adult Brain Tumor

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Phase I Dose Finding

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

pharmacological study

Intervention Type OTHER

Correlative studies

Phase II Stage I

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15.Other: laboratory biomarker analysis: correlative studies.

Phase 2 - not implemented due to drug supply from company

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

Phase II Stage II Arm 1

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: laboratory biomarker analysis: correlative studies.

Phase 2 - not implemented due to drug supply from company

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

Phase II Stage II Arm 2

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15. Other: laboratory biomarker analysis: correlative studies.

Phase 2 - not implemented due to drug supply from company

Group Type ACTIVE_COMPARATOR

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

Phase I Dose Finding - Level 1 5mg

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 5mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

pharmacological study

Intervention Type OTHER

Correlative studies

Phase I Dose Finding - Level 2 10mg

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 10mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

pharmacological study

Intervention Type OTHER

Correlative studies

Phase I Dose Finding - Level 3 20mg

Patients receive oral gamma-secretase/Notch signalling pathway inhibitor RO49290977 20mg on days 1-3, 8-10, 15-17, and 22-24, and bevacizumab IV over 30-90 minutes on days 1 and 15. Other: pharmacological study: correlative studies; laboratory biomarker analysis: correlative studies.

Group Type EXPERIMENTAL

gamma-secretase/Notch signalling pathway inhibitor RO4929097

Intervention Type DRUG

Given orally

bevacizumab

Intervention Type BIOLOGICAL

Given IV

laboratory biomarker analysis

Intervention Type OTHER

Correlative studies

pharmacological study

Intervention Type OTHER

Correlative studies

Interventions

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gamma-secretase/Notch signalling pathway inhibitor RO4929097

Given orally

Intervention Type DRUG

bevacizumab

Given IV

Intervention Type BIOLOGICAL

laboratory biomarker analysis

Correlative studies

Intervention Type OTHER

pharmacological study

Correlative studies

Intervention Type OTHER

Other Intervention Names

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R4733 RO4929097 anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF

Eligibility Criteria

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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

Exclusion Criteria

* 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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Edward Pan, MD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Locations

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University of California at Los Angeles (UCLA )

Los Angeles, California, United States

Site Status

University of California San Francisco Medical Center-Parnassus

San Francisco, California, United States

Site Status

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Site Status

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Site Status

Countries

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United States