Adult Anaplastic AstrocytomaPhase 1/2NCT01189240
RO4929097and Bevacizumab in Treating Patients With Progressive or Recurrent Malignant Glioma
A Phase 1/2 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, bevacizumab and laboratory biomarker analysis in people with Adult Anaplastic Astrocytoma and Adult Anaplastic Oligodendroglioma, run by National Cancer Institute (NCI) at 4 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma
- What is being tested?
- gamma-secretase/Notch signalling pathway inhibitor RO4929097, bevacizumab and laboratory biomarker analysis
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 4 sitesUnited States
- Study dates
- Dec 2010to Feb 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed malignant glioma (phase I)
- Glioblastoma
- Anaplastic astrocytoma
- Anaplastic oligodendroglioma
- Mixed anaplastic oligoastrocytoma
- Histologically confirmed glioblastoma following radiotherapy and temozolomide (phase II)
Show all 24Show fewer
- 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
Who cannot join
- 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
Show all 39Show fewer
- 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
Trial locations and contacts
4 sites in 1 country.
United States4 sites
University of California at Los Angeles (UCLA )
Los Angeles, California, 90095
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
University of California San Francisco Medical Center-Parnassus
San Francisco, California, 94143
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, 33612
About this study
Official title: 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.
Read the detailed description
Phase I
Primary Objective:
- 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:
- To describe the toxicity associated with this combination regimen
- 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:
- 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
- Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
- Being tested
- gamma-secretase/Notch signalling pathway inhibitor RO4929097, bevacizumab, laboratory biomarker analysis, pharmacological study
- Medical subject headings
- Astrocytoma, Oligodendroglioma, Glioblastoma, Gliosarcoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
gamma-secretase/Notch signalling pathway inhibitor RO4929097Drug
Also called R4733, RO4929097
Given orally
bevacizumabBiological
Also called anti-VEGF humanized monoclonal antibody, anti-VEGF monoclonal antibody, Avastin, rhuMAb VEGF
Given IV
laboratory biomarker analysisOther
Correlative studies
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Phase I Dose Finding | Experimental | 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. Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study |
| Phase II Stage I | Experimental | 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 Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis |
| Phase II Stage II Arm 1 | Experimental | 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 Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis |
| Phase II Stage II Arm 2 | Active comparator | 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 Receives: Biological: bevacizumab; Other: laboratory biomarker analysis |
| Phase I Dose Finding - Level 1 5mg | Experimental | 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. Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study |
| Phase I Dose Finding - Level 2 10mg | Experimental | 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. Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study |
| Phase I Dose Finding - Level 3 20mg | Experimental | 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. Receives: Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097; Biological: bevacizumab; Other: laboratory biomarker analysis; Other: pharmacological study |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 28 days
Secondary outcomes (5)
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
Measured: 28 days - 1 cycle
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
Measured: 24 hrs
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.
Measured: 24hr
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.
Measured: 24hrs
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.
Measured: 24hr
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2010 (estimated)
- Study startDec 2010
- Primary completionJan 2013
- Study completionFeb 2015
Why it stopped: Company decided to stop development of drug - 7/31/12
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Adult Anaplastic AstrocytomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Edward Pan, MD, Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01189240
- Sponsor's protocol ID
- NCI-2011-02509
- Other IDs
- NCI-2011-02509, CDR0000683099, ABTC-1002, ABTC-1002, U01CA137443
- Status last verified
- Oct 2015
- First submitted
- 25 Aug 2010
- Last updated
- 14 Dec 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Study of R04929097 With Bevacizumab in Patients With Recurrent Malignant Glioma
- ClinicalTrials.gov ID
- NCT01189240
- Acronym / sponsor ID
- NCI-2011-02509
- Conditions
- Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Company decided to stop development of drug - 7/31/12
- Enrolment
- 13 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Dec 2010
- Primary completion
- Jan 2013 (actual)
- Study completion
- Feb 2015 (actual)
- First posted
- 26 Aug 2010 (estimated)
- Results
- Posted 14 Jul 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- To describe the toxicity associated with this combination regimen
- 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:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Phase I Dose Finding | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysis, Other: pharmacological studyPatients 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 | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysisPatients 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 | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysisPatients 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 | Active comparator | Biological: bevacizumab, Other: laboratory biomarker analysisPatients 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 1 5mg | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysis, Other: pharmacological studyPatients 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 | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysis, Other: pharmacological studyPatients 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 | Experimental | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097, Biological: bevacizumab, Other: laboratory biomarker analysis, Other: pharmacological studyPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Histologically confirmed malignant glioma (phase I)
- 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
Key exclusion criteria (39 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| gamma-secretase/Notch signalling pathway inhibitor RO4929097Also: R4733, RO4929097Given orally | Drug | Phase I Dose Finding, Phase I Dose Finding - Level 1 5mg, Phase I Dose Finding - Level 2 10mg, Phase I Dose Finding - Level 3 20mg, Phase II Stage I, Phase II Stage II Arm 1 |
| bevacizumabAlso: anti-VEGF humanized monoclonal antibody, anti-VEGF monoclonal antibody, Avastin, rhuMAb VEGFGiven IV | Biological | Phase I Dose Finding, Phase I Dose Finding - Level 1 5mg, Phase I Dose Finding - Level 2 10mg, Phase I Dose Finding - Level 3 20mg, Phase II Stage I, Phase II Stage II Arm 1, Phase II Stage II Arm 2 |
| laboratory biomarker analysisCorrelative studies | Other | Phase I Dose Finding, Phase I Dose Finding - Level 1 5mg, Phase I Dose Finding - Level 2 10mg, Phase I Dose Finding - Level 3 20mg, Phase II Stage I, Phase II Stage II Arm 1, Phase II Stage II Arm 2 |
| pharmacological studyCorrelative studies | Other | Phase I Dose Finding, Phase I Dose Finding - Level 1 5mg, Phase I Dose Finding - Level 2 10mg, Phase I Dose Finding - Level 3 20mg |
Primary outcome
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
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
5 secondary outcomes
Toxicity Description (Dose Limiting Toxicity-DLT) of Gamma-secretase Inhibitor RO4929097 in Combination With Bevacizumab
Time frame: 28 days - 1 cycle
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1
Time frame: 24 hrs
Measurement of Cmax to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15
Time frame: 24hr
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 1
Time frame: 24hrs
Measurement of AUC24 to Determine the Effect of Bevacizumab on the Plasma Pharmacokinetics of RO4929097 Day 15
Time frame: 24hr
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Adult Anaplastic Astrocytoma
RecruitingPhase 1
Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
Central Nervous System Neoplasms, Glioblastoma
Active, not recruitingPhase 1
Vorinostat and Temozolomide in Treating Patients With Malignant Gliomas
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Edward Pan, MD principal investigator
National Cancer Institute (NCI)
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing gamma-secretase/Notch signalling pathway inhibitor RO4929097, bevacizumab and laboratory biomarker analysis in people with Adult Anaplastic Astrocytoma and Adult Anaplastic Oligodendroglioma, run by National Cancer Institute (NCI) at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 14 Dec 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jul 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2015.