Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
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.
Interventions
Given orally
BIOLOGICALbevacizumab
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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 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. |
Countries
United States
Participant flow
Recruitment details
Phase I trial started 8/2011 and enrollment closed 7/31/12. 13 total patients treated by RO4929097 (5, 10, 20mg/kg) in combo with bevacizumab. 1 treated pt ineligible for study. Analysis data for toxicity included 13 treated pts. Analytical dataset results other than toxicity included 12 eligible pts only. Pts enrolled from outpt medical clinics
Pre-assignment details
A decision was made from the company, Roche, the owner and developer of RO4929097, that as of 7/31/12 there would be no further supply of RO4929097 and all clinical trials using this drug must stop accruing and treating patients. Hence our ABTC 1002 study was stopped during the phase 1 with 13 pt accrued and the Phase 2 was unable to begin.
Participants by arm
| Arm | Count |
|---|---|
| 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: blood samples for pharmacological study; archived tumor tissue slides for laboratory biomarker analysis.
gamma-secretase/Notch signalling pathway inhibitor RO4929097: Given orally
bevacizumab: Given IV
laboratory biomarker analysis: Correlative studies
pharmacological study: Correlative studies | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Phase I Dose Finding |
|---|---|
| Age, Continuous | 56 years |
| Initial Histological Diagnosis Glioblastoma | 10 participants |
| Initial Histological Diagnosis Other | 2 participants |
| Initial Procedure biopsy | 1 participants |
| Initial Procedure Resection | 11 participants |
| Karnofsky Performance Status 60 | 1 participants |
| Karnofsky Performance Status 70 | 0 participants |
| Karnofsky Performance Status 80 | 5 participants |
| Karnofsky Performance Status 90 | 6 participants |
| Mini Mental State Examination (MMSE) | 29 units on a scale |
| Prior Relapses 1 relapse | 8 participants |
| Prior Relapses 2 relapes | 3 participants |
| Prior Relapses 3 relapses | 1 participants |
| Race/Ethnicity, Customized African American | 2 participants |
| Race/Ethnicity, Customized White | 10 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 1 / 13 |
Outcome results
Primary
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)
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
Time frame: 28 days
Population: RO4929097 Days 1-3 weekly (doses 5,10, 20 mg) + Bev 10mg/kg IV q2 wks - cycle 28 days. 3+3 dose escalation method will be used. Target DLT is \> or equal to 33%
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | 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) | 10 mg |
Secondary
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1
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.
Time frame: 24hrs
Population: Day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Finding | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 1,215 ng*h/mL | Standard Deviation 361 |
| Phase I Dose Finding Level 2 10mg | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 2,385 ng*h/mL | Standard Deviation 606 |
| Phase I Dose Finding Level 3 20mg | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 2,232 ng*h/mL | Standard Deviation 781 |
Secondary
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15
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.
Time frame: 24hr
Population: Day 15. Only 4 pts samples were evaluable for AUC 24 at the10mg dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Finding | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 1,212 ng*h/mL | Standard Deviation 355 |
| Phase I Dose Finding Level 2 10mg | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 2,351 ng*h/mL | — |
| Phase I Dose Finding Level 3 20mg | Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 2,555 ng*h/mL | — |
Secondary
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1
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
Time frame: 24 hrs
Population: Day One only
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Finding | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 129 ng/mL | Standard Deviation 41 |
| Phase I Dose Finding Level 2 10mg | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 177 ng/mL | Standard Deviation 32 |
| Phase I Dose Finding Level 3 20mg | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1 | 241 ng/mL | Standard Deviation 172 |
Secondary
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15
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.
Time frame: 24hr
Population: Day 15 only. Level 2 10mg only had 5pts with evaluable PKs at day 15
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase I Dose Finding | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 117 ng/mL | Standard Deviation 37 |
| Phase I Dose Finding Level 2 10mg | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 189 ng/mL | Standard Deviation 49 |
| Phase I Dose Finding Level 3 20mg | Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15 | 245 ng/mL | Standard Deviation 192 |
Secondary
Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab
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
Time frame: 28 days - 1 cycle
Population: DLT Defintion, must be related to RO and/or Bev: ANC \</= 500/μL or second time ANC \<1,000/μL; PLTs \</= 25,000/μL or second time platelets \<50,000/μL; Febrile neutropenia;Thrombocytopenic bleeding (platelets \<50,000/μL and with clinically significant bleeding); Delay of treatment \> 14 days ;grade 3 or 4 non-hematological toxicity (some exceptions)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Finding | Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab | 0 participants |
| Phase I Dose Finding Level 2 10mg | Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab | 1 participants |
| Phase I Dose Finding Level 3 20mg | Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab | 0 participants |