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
  Purpose

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.


Condition Intervention Phase
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
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of R04929097 With Bevacizumab in Patients With Recurrent Malignant Glioma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 13
Study Start Date: December 2010
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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 II (Phase II)
Patients receive bevacizumab IV as in arm I.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01189240

Locations
United States, California
University of California at Los Angeles (UCLA )
Los Angeles, California, United States, 90095
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Maryland
Adult Brain Tumor Consortium
Baltimore, Maryland, United States, 21231-1000
Johns Hopkins University-Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: Edward Pan National Cancer Institute (NCI)
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01189240     History of Changes
Other Study ID Numbers: NCI-2011-02509, NCI-2011-02509, CDR0000683099, ABTC-1002, ABTC-1002, U01CA137443
Study First Received: August 25, 2010
Last Updated: March 19, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Gliosarcoma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Antibodies
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors

ClinicalTrials.gov processed this record on October 01, 2014