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

NCT01119599 | Completed Phase 1

• 6 other identifiers: NCI-2011-01410CDR000067264109-1778556P30CA008748U01CA069856
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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

  The percentage of patients who experience toxicity at each dose level will be calculated, with a 95% confidence interval.

  28 days

Secondary Outcomes (3)

• Changes in MRI parameters

  Baseline to up to 4 years

• Percent changes in serum YKL-40 levels and hair follicle HES1 levels

  Baseline to up to 4 years

• Pharmacokinetic (PK) parameters of gamma-secretase/Notch signalling pathway inhibitor RO4929097

  Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours

Other Outcomes (1)

• Expression of a variety of proteins through immunohistochemistry and/or real time quantitative polymerase chain reaction and tumor tissue culture

  Up to 4 years

Study Arms (1)

Treatment (RO4929097, surgery, radiation therapy)

EXPERIMENTAL

See Detailed Description.

Radiation: 3-Dimensional Conformal Radiation Therapy; Drug: Gamma-Secretase Inhibitor RO4929097; Radiation: Intensity-Modulated Radiation Therapy; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Procedure: Therapeutic Conventional Surgery

Interventions

3-Dimensional Conformal Radiation Therapy RADIATION

Undergo 3-D conformal radiation therapy

Also known as: 3-dimensional radiation therapy, 3D-CRT, Conformal Therapy, Radiation Conformal Therapy

Treatment (RO4929097, surgery, radiation therapy)

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Treatment (RO4929097, surgery, radiation therapy)

Intensity-Modulated Radiation Therapy RADIATION

Undergo IMRT

Also known as: IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy

Treatment (RO4929097, surgery, radiation therapy)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (RO4929097, surgery, radiation therapy)

Pharmacological Study OTHER

Correlative studies

Treatment (RO4929097, surgery, radiation therapy)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temodal, Temodar

Treatment (RO4929097, surgery, radiation therapy)

Therapeutic Conventional Surgery PROCEDURE

Undergo surgery

Treatment (RO4929097, surgery, radiation therapy)

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Conditions

Neuroma, Acoustic; Meningioma; Astrocytoma; Ependymoma; Choroid Plexus Neoplasms; Craniopharyngioma; Neuroectodermal Tumors, Primitive; Glioblastoma; Gliosarcoma; Medulloblastoma; Glioma; Oligodendroglioma; Pinealoma; Glioma, Subependymal

Interventions

Radiotherapy, Conformal; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Radiotherapy, Intensity-Modulated; Temozolomide

Condition Hierarchy (Ancestors)

Neurilemmoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Cranial Nerve Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Peripheral Nervous System Neoplasms; Vestibulocochlear Nerve Diseases; Retrocochlear Diseases; Ear Diseases; Otorhinolaryngologic Diseases; Otorhinolaryngologic Neoplasms; Cranial Nerve Diseases; Nervous System Diseases; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Neoplasms, Neuroepithelial; Neoplasms, Glandular and Epithelial; Cerebral Ventricle Neoplasms; Brain Neoplasms; Brain Diseases; Central Nervous System Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Antonio Omuro

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2010
• First Posted: May 7, 2010
• Study Start: May 1, 2010
• Primary Completion: June 1, 2013
• Last Updated: September 29, 2015

Record last verified: 2015-06

Locations

US (2)