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: April 9, 2014
Last verified: April 2014
  Purpose

This phase I trial is studying the side effects and best dose of RO4929097 when given together with temozolomide and radiation therapy in treating patients with newly diagnosed malignant glioma. Enzyme inhibitors, such as 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 or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving RO4929097 together with temozolomide and radiation therapy may kill more tumor cells.


Condition Intervention Phase
Adult Anaplastic Astrocytoma
Adult Anaplastic Ependymoma
Adult Brain Stem Glioma
Adult Diffuse Astrocytoma
Adult Ependymoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Mixed Glioma
Adult Pilocytic Astrocytoma
Adult Pineal Gland Astrocytoma
Adult Subependymal Giant Cell Astrocytoma
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Procedure: therapeutic conventional surgery
Radiation: intensity-modulated radiation therapy
Radiation: 3-dimensional conformal radiation therapy
Drug: temozolomide
Other: diagnostic laboratory biomarker analysis
Other: pharmacological study
Procedure: adjuvant therapy
Procedure: neoadjuvant therapy
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 DLT is less than 33% using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ 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:
  • Pharmacokinetics analysis [ Time Frame: Pre-dose, 30 minutes, 1, 2, 4, 6, and 8 hours ] [ Designated as safety issue: No ]
    Descriptive statistics (including number, mean and/or median, standard deviation, coefficient of variation, and range) for PK parameters will be tabulated by dose level.

  • Impact of RO4929097 on the components of the Notch pathway, on cancer stem cell population and on angiogenesis [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    Analyses will include comparison of results before and after exposure to 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).

  • Effects of RO4929097 and temozolomide on MRI parameters [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    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.

  • Development of potential biomarkers for evaluation of gamma-secretase and Notch inhibitors activity [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
    A Wilcoxon test will be used to determine p value of changes in mean values of YKL-40 and HES1, with a p value of less than 0.05 considered statistically significant.


Estimated Enrollment: 24
Study Start Date: May 2010
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I

Pre-surgery treatment: Patients receive oral gamma-secretase inhibitor RO4929097 (RO4929097) once daily on days 1-7 of week 1 and day 1 of week 2.

Surgery: Patients undergo surgery 2-3 hours after administration of RO4929097 on day 1 of week 2.

Treatment concurrent with radiotherapy: Beginning 3-4 weeks after surgery, patients undergo conventional focal (intensity-modulated or 3-D conformal) radiotherapy 5 days a week for approximately 6 weeks. Patients also receive oral RO4929097 once daily for approximately 10 weeks beginning the day of radiotherapy and oral temozolomide once daily for approximately 6 weeks beginning the day before radiotherapy.

Adjuvant treatment following radiotherapy: Approximately 4 weeks after completion of radiotherapy, patients receive oral RO4929097 once daily on days 1-28 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given orally
Other Names:
  • R4733
  • RO4929097
Procedure: therapeutic conventional surgery Radiation: intensity-modulated radiation therapy
Other Name: IMRT
Radiation: 3-dimensional conformal radiation therapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Drug: temozolomide
Given orally
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: diagnostic laboratory biomarker analysis Other: pharmacological study
Other Name: pharmacological studies
Procedure: adjuvant therapy Procedure: neoadjuvant therapy

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed glioblastoma, including any of the following subtypes:

    • Glioblastoma
    • Anaplastic astrocytoma
    • Gliosarcoma
    • Other malignant gliomas

      • No pure anaplastic oligodendroglioma
  • Patients with presumed malignant glioma based on radiographic assessment may be enrolled onto the protocol without histological confirmation provided they meet the following additional eligibility criteria:

    • 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 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
    • If after the on-protocol surgery the patient is found not to meet histological criteria, the patient will be removed from the study and replaced
  • Underwent prior stereotactic biopsy or incomplete surgical resection
  • Indication for additional debulking surgery

    • No contraindication to a brain surgical procedure
    • Patients who are not candidates for surgical resection may be allowed (except brain surgery)
  • ECOG performance status 0-1 (Karnofsky 70-100%)
  • Life expectancy > 2 months
  • Leukocytes > 3,000/mm^3
  • ANC > 1,500/mm^3
  • Platelet count > 100,000/mm^3
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT < 2.5 times ULN
  • Creatinine normal OR creatinine clearance > 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use two forms of effective contraception for 4 weeks before, during, and 12 months after completion of study therapy
  • Able to swallow tablets
  • QTc ≤ 450 msec in males and a QTc ≤ 470 msec in females
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to gamma-secretase inhibitor RO4929097 or other agents used in this study
  • No malabsorption syndrome or other condition that would interfere with intestinal absorption
  • No known history of hepatitis B or C or history of liver disease or other forms of hepatitis or cirrhosis
  • No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia defined as less than the lower limit of normal for the institution, 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
    • History of torsades de pointes or other significant cardiac arrhythmias
    • Psychiatric illness and/or social situations that would limit compliance with study requirements
  • No requirement for antiarrhythmics or other medications known to prolong QTc
  • No concurrent medications or food that may interfere with the metabolism of RO4929097 including ketoconazole and grapefruit
  • Must be recovered to < grade 2 toxicities related to prior therapy
  • No prior chemotherapy, radiotherapy, biological, or experimental therapy for glioma
  • No prior radiotherapy to the brain, head, or neck
  • No combination antiretroviral therapy for HIV-positive patients
  • No other concurrent investigational agents
  • No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

    • Patients on concurrent medications that are strong inducers and/or inhibitors of CYP3A4 should switched to alternative medications to minimize any potential risk
  • No concurrent hypofractionated radiotherapy or radiosurgery
  Contacts and Locations
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: April 9, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Astrocytoma
Ependymoma
Glioblastoma
Glioma
Gliosarcoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014