- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01269411
RO4929097 in Treating Patients With Recurrent Invasive Gliomas
Phase I Pharmacodynamic and "High Content" Study of the Gamma-Secretase Inhibitor RO4929097 in Patients With Recurrent Malignant Gliomas (MGs) Targeting p75NTR to Inhibit Brain Tumor Initiating Cells (BTICs) and Recurrent Invasive Gliomas
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVES:
I. Determine, in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer), the safety and maximum-tolerated dose of RO4909297 administered at 2 dose levels.
II. Determine the pharmacokinetics, intratumoral drug concentration, target modulation, and evidence of any treatment effect in the malignant glioma tumor tissue by R04929097 administered at the dose found in Part A.
SECONDARY OBJECTIVES:
I. Determine the pharmacokinetic (PK) profile of RO4909297 in patients with recurrent MGs (many of whom receive dexamethasone, a moderate CYP3A4 inducer).
II. Determine the progression-free survival of patients with recurrent malignant glioma following treatment with R04929097.
III. Determine if the RPTD dose of RO4929097 significantly inhibits p75^NTR cleavage and processing.
IV. Determine the effects of RO4929097 on the establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways.
V. Determine the ability of RO4929097 to inhibit Notch signaling, by assessing downstream target activation, in glioma tissue of patients with recurrent MG.
VI. Determine the association between a number of serum, tumor, and BTIC markers and response to R04929097.
OUTLINE: This is a multicenter, dose-escalation (part A) study followed by an open-label (part B) study.
PART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8. Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Post resection tumor specimens are collected for correlative studies, including pharmacokinetic and biomarker assays.
After completion of study therapy, patients are followed up at 30 days and then every 3 month for up to 6-12 months.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Ontario
-
Toronto, Ontario, Canada, M5G 2M9
- University Health Network-Princess Margaret Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Patients must have radiographic progression of a histologically confirmed glioblastoma, high-grade astrocytoma, NOS, anaplastic mixed oligo-astrocytoma, or anaplastic oligodendroglioma
- In patients that present radiographic evidence of progression after concurrent treatment with radiation and low-dose temozolomide, diagnosis of progression should be made after at least 2 cycles of monthly temozolomide in order to rule out pseudoprogression
- Secondary MGs (evolving from a prior low-grade glioma) can be included as long as they are considered malignant in the latest resection
- Patients must have at least one enhancing lesion that can be accurately measured as > 1 X 1 cm on a MRI
Prior treatment must include radiotherapy (with or without temozolomide)
- No limit to the number of prior recurrences or surgeries
For Part B only, surgical resection should be considered a reasonable therapeutic option for a patient that can tolerate surgical resection
- Patients with multifocal disease can be included as long as resection is considered a reasonable option to manage the nodule that is progressing
- There must be sufficient tissue available (minimum from a 1 X 1 cm lesion) for a biopsy to be taken during surgery
- There must be sufficient tissue available for evaluation of p75^NTR status from a prior surgery (using immunohistochemistry on fixed tissue or, in uncommon cases in which frozen tissue is available from a prior surgery, western blot) (part B)
- ECOG performance status < 2 (Karnofsky > 50%)
- Life expectancy of greater than 4 weeks
- Absolute neutrophil count > 1,500/mcL
- Platelets > 100,000/mcL
- Hemoglobin > 90 g/L (or > 9 g/dL)
- Total bilirubin < 2.0 mg/dL
- BUN < 25 mg/dL
- AST/ALT < 3 X institutional upper limit of normal
- Creatinine within institutional normal limits OR creatinine clearance > 60 mL/min
- No major medical illnesses or psychiatric impairments that, in the investigator's opinion, would prevent administration or completion of protocol therapy
- Not pregnant or nursing
- Negative serum pregnancy test
- Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, during, and for 12 months after completion of study therapy
- Able to swallow pills
- Patients with a history of seizures need to have had no generalized seizures in the last month prior to entering the study
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097
- No malabsorption syndrome or other condition that would interfere with intestinal absorption
- Patients who are serologically positive for hepatitis A, B, or C, and have a resulting positive serological test, or have a history of liver disease, other forms of hepatitis, or cirrhosis are ineligible
- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia (within 7 days prior to study treatment), despite adequate electrolyte supplementation
- No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements
- HIV-positive patients on combination antiretroviral therapy are ineligible
- Baseline QTc ≤ 450 msec (male) or QTc ≤ 470 msec (female)
- No history of risk factors for QT interval prolongation, including, but not limited to, family or personal history of long QT syndrome, recurrent syncope without known etiology, or sudden unexpected death
- No history of torsades de pointes or other significant cardiac arrhythmias or the need for concomitant meds with known potential to prolong QT interval or antiarrhythmics
- Use of food that may interfere with the metabolism of RO4929097 is prohibited, including grapefruit or grapefruit juice
- Patients must have recovered from the effects of any prior treatment (systemic chemotherapy/radiotherapy) or surgery (<CTCAE grade 2 toxicities related to prior therapy)
- Patients who have had chemotherapy, surgery, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study are not eligible
- Patients may not be receiving any other investigational agents
Patients cannot be receiving enzyme-inducing anti-epileptic drugs (EIAEDs)
- If previously treated with EIAEDs, patients must have been switched to non-EIAEDs 4 weeks prior to starting RO4929097
- Enzyme-inducing antiepileptic drugs (EIAEDs) include: carbamazepine (Tegretol); oxcarbazepine (Trileptal); phenobarbital (or derivatives); phenytoin (Dilantin)
- 3.1.10.2 Non enzyme-inducing Antiepileptic Drugs (Non-EIAEDs) include: clobazam (Frisium); clonazepam (Rivotril); gabapentin (Neurontin); levetiracetam (Keppra); lamotrigine (Lamictal); topiramate (Topamax)
No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
- Even though dexamethasone is a moderate inducer of CYP3A4, patients may remain on dexamethasone at the lowest dose possible
- Stable or decreasing steroid dose within 5 days prior to registration required
- No medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
- No other investigational or commercial agents or therapies may be administered with the intent to treat the patient's malignancy
- No re-irradiation (any technique) is allowed
- If a patient elects to have a new resection of his/her tumor in the absence of progression of the disease, treatment will be discontinued and no re-challenge will be allowed after this additional surgery
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Treatment (RO4929097 and surgery)
PART A: Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PART B: Patients receive oral RO4929097 once daily on days 1-7 and undergo surgery on day 8. Beginning 28 days later, patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. |
Correlative studies
Other Names:
Undergo surgery
Given orally
Other Names:
Correlative
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Maximum-tolerated dose (MTD) defined as the dose level in which less than or equal to 1 out of 6 patients experience dose limiting toxicity (DLT) assessed using NCI CTCAE version 4.0
Time Frame: 21 days
|
21 days
|
Pharmacokinetic (PK) profile of RO4909297
Time Frame: Pre-dose, 1, 2, 4, 8, and 24 hours
|
Pre-dose, 1, 2, 4, 8, and 24 hours
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression-free survival following treatment with R04929097
Time Frame: From registration to time of progression or death, whichever occurs first, assessed up to 12 months
|
The Kaplan-Meier method will be used.
|
From registration to time of progression or death, whichever occurs first, assessed up to 12 months
|
Inhibition of p75NTR cleavage and processing
Time Frame: Up to 12 months
|
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients.
The Wilcoxon signed-rank and rank sum tests will be used.
|
Up to 12 months
|
Establishment and growth of BTIC cultures in neurosphere growth conditions, effects on proliferation, ability to self-renewal, and ability to differentiate along lineage-specific pathways
Time Frame: Up to 12 months
|
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients.
The Wilcoxon signed-rank and rank sum tests will be used.
|
Up to 12 months
|
Inhibition of Notch signaling, by assessing downstream target activation
Time Frame: Up to 12 months
|
Descriptive statistics, such as the mean, median and range, will be used to summarize the marker across patients.
The Wilcoxon signed-rank and rank sum tests will be used.
|
Up to 12 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Peter Forsyth, University Health Network-Princess Margaret Hospital
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Disease Attributes
- Astrocytoma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Central Nervous System Neoplasms
- Nervous System Neoplasms
- Glioblastoma
- Recurrence
- Glioma
- Brain Neoplasms
- Gliosarcoma
- Oligodendroglioma
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- R04929097
Other Study ID Numbers
- NCI-2011-02565
- N01CM00032 (U.S. NIH Grant/Contract)
- PHL-075
- CDR0000691784 (REGISTRY: PDQ (Physician Data Query))
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Adult Anaplastic Oligodendroglioma
-
Northwestern UniversityTerminatedAdult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma | Adult Giant Cell Glioblastoma | Adult GlioblastomaUnited States
-
National Cancer Institute (NCI)TerminatedAdult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma | Adult Diffuse Astrocytoma | Adult Ependymoma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Adult Mixed Glioma | Adult Myxopapillary Ependymoma | Adult Oligodendroglioma | Adult Pilocytic... and other conditionsUnited States
-
Vanderbilt-Ingram Cancer CenterNational Cancer Institute (NCI)TerminatedAdult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Recurrent Adult Brain TumorUnited States
-
Mayo ClinicNational Cancer Institute (NCI)Active, not recruitingAdult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma | Adult Diffuse Astrocytoma | Adult Ependymoma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Adult Mixed Glioma | Adult Myxopapillary Ependymoma | Adult Oligodendroglioma | Adult Pilocytic... and other conditionsUnited States
-
Wake Forest University Health SciencesNational Cancer Institute (NCI)TerminatedAdult Anaplastic Astrocytoma | Adult Anaplastic Oligodendroglioma | Adult Diffuse Astrocytoma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Adult Mixed Glioma | Adult Oligodendroglioma | Recurrent Adult Brain TumorUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)CompletedAnaplastic Oligoastrocytoma | Adult Anaplastic Astrocytoma | Adult Anaplastic Oligodendroglioma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Recurrent Adult Brain TumorUnited States
-
National Cancer Institute (NCI)CompletedAdult Anaplastic Astrocytoma | Adult Anaplastic Oligodendroglioma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Adult Mixed Glioma | Recurrent Adult Brain TumorUnited States
-
James ElderCompletedAdult Anaplastic Astrocytoma | Adult Anaplastic Oligodendroglioma | Recurrent Adult Brain TumorUnited States
-
Sidney Kimmel Cancer Center at Thomas Jefferson...Millennium Pharmaceuticals, Inc.CompletedAdult Anaplastic Astrocytoma | Adult Anaplastic Ependymoma | Adult Anaplastic Oligodendroglioma | Adult Diffuse Astrocytoma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Adult Mixed Glioma | Adult Oligodendroglioma | Adult Pilocytic Astrocytoma | Adult Pineal Gland Astrocytoma | Recurrent... and other conditionsUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)WithdrawnAdult Anaplastic Astrocytoma | Adult Anaplastic Oligodendroglioma | Adult Giant Cell Glioblastoma | Adult Glioblastoma | Adult Gliosarcoma | Recurrent Adult Brain TumorUnited States
Clinical Trials on pharmacological study
-
National Cancer Institute (NCI)TerminatedUnspecified Adult Solid Tumor, Protocol SpecificUnited States
-
National Cancer Institute (NCI)CompletedExtranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue | Nodal Marginal Zone B-cell Lymphoma | Recurrent Adult Burkitt Lymphoma | Recurrent Adult Diffuse Large Cell Lymphoma | Recurrent Adult Diffuse Mixed Cell Lymphoma | Recurrent Adult Diffuse Small Cleaved Cell Lymphoma and other conditionsUnited States
-
Universitätsmedizin MannheimHeidelberg UniversityUnknownLung Cancer | Brain and Central Nervous System TumorsGermany
-
Sidney Kimmel Comprehensive Cancer Center at Johns...National Cancer Institute (NCI); Peloton Therapeutics, Inc.CompletedRecurrent GlioblastomaUnited States
-
National Cancer Institute (NCI)TerminatedUnspecified Adult Solid Tumor, Protocol SpecificUnited States
-
National Cancer Institute (NCI)CompletedUnspecified Childhood Solid Tumor, Protocol Specific | Recurrent Childhood Soft Tissue Sarcoma | Recurrent Childhood Brain Stem Glioma | Recurrent Childhood Visual Pathway Glioma | Childhood Central Nervous System Germ Cell Tumor | Childhood Central Nervous System Choriocarcinoma | Childhood Central... and other conditionsUnited States
-
National Cancer Institute (NCI)CompletedUnspecified Adult Solid Tumor, Protocol SpecificUnited States
-
National Cancer Institute (NCI)TerminatedRecurrent Cutaneous T-cell Non-Hodgkin Lymphoma | Recurrent Mycosis Fungoides/Sezary SyndromeUnited States
-
National Cancer Institute (NCI)CompletedUnspecified Adult Solid Tumor, Protocol Specific | Male Breast Cancer | Stage IV Breast Cancer | Stage IV Ovarian Epithelial Cancer | Stage IV Renal Cell Cancer | Recurrent Renal Cell Cancer | Recurrent Breast Cancer | Recurrent Ovarian Epithelial Cancer | Recurrent Primary Peritoneal Cavity Cancer | Stage...United States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedMyeloid Proliferations Associated With Down SyndromeUnited States, Canada, Australia, Puerto Rico