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RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01119599
First received: May 6, 2010
Last updated: November 21, 2014
Last verified: June 2014
  Purpose

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as gamma-secretase/Notch signalling pathway inhibitor RO4929097, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.


Condition Intervention Phase
Acoustic Schwannoma
Adult Anaplastic (Malignant) Meningioma
Adult Anaplastic Astrocytoma
Adult Anaplastic Ependymoma
Adult Brain Stem Glioma
Adult Choroid Plexus Neoplasm
Adult Craniopharyngioma
Adult Diffuse Astrocytoma
Adult Ependymoblastoma
Adult Ependymoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Grade I Meningioma
Adult Grade II Meningioma
Adult Medulloblastoma
Adult Mixed Glioma
Adult Myxopapillary Ependymoma
Adult Oligodendroglioma
Adult Papillary Meningioma
Adult Pilocytic Astrocytoma
Adult Pineal Gland Astrocytoma
Adult Pineoblastoma
Adult Pineocytoma
Adult Primary Melanocytic Lesion of Meninges
Adult Subependymal Giant Cell Astrocytoma
Adult Subependymoma
Adult Supratentorial Primitive Neuroectodermal Tumor
Malignant Adult Intracranial Hemangiopericytoma
Drug: Gamma-Secretase Inhibitor RO4929097
Procedure: Therapeutic Conventional Surgery
Radiation: Intensity-Modulated Radiation Therapy
Radiation: 3-Dimensional Conformal Radiation Therapy
Drug: Temozolomide
Other: Pharmacological Study
Other: Laboratory Biomarker Analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 Trial of RO4929097 in Combination With Standard Radiotherapy and Temozolomide for Newly Diagnosed Malignant Glioma: A Pharmacokinetic and Pharmacodynamic Study

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum-tolerated dose defined as the highest dose studied for which the incidence of dose limiting toxicity is less than 33% using National Cancer Institute Common Toxicity Criteria [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.


Secondary Outcome Measures:
  • Pharmacokinetic (PK) parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097 [ Time Frame: Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours ] [ Designated as safety issue: No ]
    Noncompartmental and/or compartmental methods will be used to calculate PK parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide from the plasma concentration-time data collected from each individual. Descriptive statistics (including number, mean and/or median, standard deviation, coefficient of variation, and range) for PK parameters will be tabulated by dose level.

  • Changes in MRI parameters [ Time Frame: Baseline to up to 4 years ] [ Designated as safety issue: No ]
    Perfusion and diffusion-based MRI parameters including but not restricted to blood volume, mean and median apparent diffusion coefficient and structural volumes will be analyzed. Results will be summarized, and mean and median values at different time points will be tabulated. Changes in such parameters will be checked for statistical significance and correlated with the disease status.

  • Percent changes in serum YKL-40 levels and hair follicle HES1 levels [ Time Frame: Baseline to up to 4 years ] [ Designated as safety issue: No ]
    Means and medians of all patients together will be calculated and tabulated for each time point, with depiction of standard deviations. A Wilcoxon test will be used to determine p value of changes in mean values of YKL-40 and hairy and enhancer of split 1, (Drosophila) (HES1), with a p value of less than 0.05 considered statistically significant.


Other Outcome Measures:
  • Expression of a variety of proteins through immunohistochemistry and/or real time quantitative polymerase chain reaction and tumor tissue culture [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Analyses will include comparison of results before and after exposure to gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Wilcoxon rank sum test), as well as status of the Notch pathway and cancer stem cells in a control population of 20 untreated patients (Mann Whitney test).


Estimated Enrollment: 34
Study Start Date: May 2010
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (RO4929097, surgery, radiation therapy)
See Detailed Description.
Drug: Gamma-Secretase Inhibitor RO4929097
Given PO
Other Name: RO4929097
Procedure: Therapeutic Conventional Surgery
Undergo surgery
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3-D conformal radiation therapy
Other Names:
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy
Drug: Temozolomide
Given PO
Other Name: TMZ
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies
Other: Laboratory Biomarker Analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have newly diagnosed glioblastoma, anaplastic astrocytoma, gliosarcoma or other malignant gliomas with the exception of pure anaplastic oligodendroglioma; note: patients with presumed malignant glioma based on radiographic assessment may be enrolled onto Arm A of the study without histological confirmation provided they meet the following additional eligibility criteria:

    • The MRI of the brain shows typical findings of a malignant glioma or glioblastoma (single ring-enhancing mass with necrotic portions)
    • To exclude brain abscess, diffusion-weighted MRI must show absence of restricted diffusion corresponding to the necrotic center of the lesion
    • To confirm the diagnosis of neoplastic disease, MR perfusion must show that the lesion has increased perfusion
    • To exclude pilocytic astrocytoma, the patient's age must be over 25
    • To exclude brain metastasis, a computed tomography (CT) of the chest, abdomen and pelvis must demonstrate absence of other malignancy
    • The principal investigator must review MRI and CT findings and agree with diagnosis of presumed malignant glioma

      • Note: If after the on-protocol surgery the patient is found not to meet histological criteria described (diagnosis of glioblastoma, anaplastic astrocytoma, gliosarcoma or other malignant gliomas with the exception of pure anaplastic oligodendroglioma), the patient will be removed from the study and replaced
  • ARM A ONLY: Patients must have an indication for additional debulking surgery as part of their initial treatment
  • Life expectancy of greater than 2 months
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%)
  • Hemoglobin >= 9 g/dL
  • Leukocytes > 3,000/mcL
  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 100,000/mcL
  • Total bilirubin < 1.5 X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately
  • Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
  • Female patients of childbearing potential are defined as follows:

    • Patients with regular menses
    • Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
    • Women who have had tubal ligation
  • Female patients may be considered to NOT be of childbearing potential for the following reasons:

    • The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy
    • The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months
    • Pre-pubertal females; the parent or guardian of young female patients who have not yet started menstruation should verify that menstruation has not begun. If a young female patient reaches menarche during the study, then she is to be considered as a woman of childbearing potential from that time forward
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Prior chemotherapy, radiotherapy, biological or experimental therapy for glioma
  • Prior history of radiotherapy to the brain, head or neck
  • Patients may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study
  • Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
  • Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; if such patients cannot be switched to alternative medications, they will be ineligible to participate in this study
  • Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets
  • Patients with known history of hepatitis B or C, or who have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible; (hepatitis B and C serology should be obtained as part of pre-treatment evaluation but are not required for eligibility)
  • Patients with uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, and hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, history of torsades de pointes or other significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097 or temozolomide; these potential risks may also apply to other agents used in this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • A corrected QT (QTc) > 450 msec in males and a QTc > 470 msec in females
  • Patients who have not recovered to < Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study
  • ARM A ONLY: Patients with contraindication to a brain surgical procedure
  • A requirement for antiarrhythmics or other medications known to prolong QTc
  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: NCT01119599

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio Omuro Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01119599     History of Changes
Other Study ID Numbers: NCI-2011-01410, NCI-2011-01410, CDR0000672641, 09-177, 8556, U01CA069856, P30CA008748
Study First Received: May 6, 2010
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adamantinoma
Astrocytoma
Choroid Plexus Neoplasms
Craniopharyngioma
Ependymoma
Glioblastoma
Glioma
Glioma, Subependymal
Gliosarcoma
Hemangiopericytoma
Medulloblastoma
Meningioma
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Neuroma, Acoustic
Oligodendroglioma
Bone Diseases
Bone Neoplasms
Brain Diseases
Brain Neoplasms
Central Nervous System Diseases
Central Nervous System Neoplasms
Cerebral Ventricle Neoplasms
Cranial Nerve Diseases
Cranial Nerve Neoplasms
Ear Diseases
Meningeal Neoplasms
Musculoskeletal Diseases
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on November 27, 2014