RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma

Phase 1

Terminated

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

Interventions: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study

Registration Number: NCT01189240

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 13

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase II Stage I	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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
Phase I Dose Finding	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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.
Phase I Dose Finding	bevacizumab	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.
Phase I Dose Finding	pharmacological study	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.
Phase I Dose Finding - Level 1 5mg	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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.
Phase I Dose Finding	laboratory biomarker analysis	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.
Phase II Stage I	bevacizumab	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
Phase II Stage I	laboratory biomarker analysis	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
Phase II Stage II Arm 2	bevacizumab	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
Phase I Dose Finding - Level 2 10mg	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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.
Phase I Dose Finding - Level 2 10mg	pharmacological study	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.
Phase I Dose Finding - Level 3 20mg	bevacizumab	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.
Phase I Dose Finding - Level 3 20mg	pharmacological study	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.
Phase II Stage II Arm 1	bevacizumab	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
Phase II Stage II Arm 1	laboratory biomarker analysis	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
Phase II Stage II Arm 1	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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
Phase II Stage II Arm 2	laboratory biomarker analysis	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
Phase I Dose Finding - Level 2 10mg	laboratory biomarker analysis	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.
Phase I Dose Finding - Level 1 5mg	bevacizumab	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.
Phase I Dose Finding - Level 2 10mg	bevacizumab	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.
Phase I Dose Finding - Level 3 20mg	laboratory biomarker analysis	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.
Phase I Dose Finding - Level 1 5mg	laboratory biomarker analysis	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.
Phase I Dose Finding - Level 1 5mg	pharmacological study	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.
Phase I Dose Finding - Level 3 20mg	gamma-secretase/Notch signalling pathway inhibitor RO4929097	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.

Primary Outcome Measures

Name	Time	Method
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)	28 days	Pts were treated at escalating dose levels of RO4929097 (Dose levels: 5, 10 or 20 mg) for an observed evaluation at the end of a 4week period. 3 pts treated at each cohort if less than or equal to 33% dose will be escalated. Pts must receive one dose of treatment to be evaluated for toxicity. A standard 3+3 dose escalation method will be used

Secondary Outcome Measures

Name	Time	Method
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15	24hr	all pts at all dose levels (5,10 and 20mg) will have pks collected. 10 samples will be collected at various time points over a 24 hour time point. Samples will be collected on the 15th day of treatment during cycle 1.
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1	24 hrs	all pts at all dose levels (5,10 and 20mg) will have pks collected. 10 samples will be collected at various time points over a 24 hour time point. Samples will be collected on the first day of treatment during cycle 1. For initial cycle (Cycle 1) bevacizumab was not given until 2 or 3 days after all PKs samples of initial dose of RO49290977 was collected
Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab	28 days - 1 cycle	Pts were treated at escalating dose levels of RO4929097 (Dose levels: 5, 10 or 20 mg) for an observed evaluation at the end of a 4week period. 3 pts treated at each cohort. Pts must receive one dose of treatment to be evaluated for toxicity. Toxcity description associated with combination of RO4929097 and Bevacizumab
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1	24hrs	all pts at all dose levels (5,10 and 20mg) will have pks collected. 10 samples will be collected at various time points over a 24 hour time point. Samples will be collected on the first day of treatment during cycle 1.
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15	24hr	all pts at all dose levels (5,10 and 20mg) will have pks collected. 10 samples will be collected at various time points over a 24 hour time point. Samples will be collected on the 15th day of treatment during cycle 1.

Trial Locations

Locations (4): H. Lee Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
University of California San Francisco Medical Center-Parnassus
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San Francisco, California, United States
Memorial Sloan-Kettering Cancer Center
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New York, New York, United States
University of California at Los Angeles (UCLA )
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Los Angeles, California, United States