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

RO4929097, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Malignant Glioma
This study is ongoing, but not recruiting participants.

First Received on May 6, 2010.  
Last Updated on July 29, 2012  
History of Changes
Sponsor: Memorial Sloan-Kettering Cancer Center
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01119599
  Purpose

RATIONALE: 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.

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.

Condition Intervention Phase
Brain and Central Nervous System Tumors Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Drug: temozolomide
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: adjuvant therapy
Procedure: neoadjuvant therapy
Procedure: therapeutic conventional surgery
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
Phase 1

Study Type: Interventional
Study Design: 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 and/or recommended phase II dose [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

  • Pharmacokinetics [ Designated as safety issue: No ]

Estimated Enrollment: 34
Study Start Date: May 2010
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

  • To establish the maximum-tolerated dose and the recommended phase II dose of gamma-secretase inhibitor RO4929097 (RO4929097) in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme, anaplastic astrocytoma, gliosarcoma, or other malignant gliomas.

Secondary

  • To evaluate the pharmacokinetics of RO4929097 and temozolomide in these patients.
  • To evaluate brain and tumor penetration by this regimen, including radiotherapy, in these patients.

Tertiary

  • To evaluate pharmacodynamic effects of RO4929097 in the resected specimens from these patients in comparison with specimens obtained from untreated patients.
  • To evaluate the effects of RO4929097 on the cancer stem cells of these patients.
  • To evaluate the effects of RO4929097 on angiogenesis (microvascular density and expression of tumor vascular markers, including vascular E-cadherin, CD146, CD31, VEGF ligands and receptors, and pericyte markers).
  • To evaluate the combined effects of this regimen in explants established from tumor specimens of these patients and controls.
  • To evaluate the effects of RO4929097 on MRI parameters, including DCE-MRI perfusion, diffusion-weighted imaging, and volumetric analysis.
  • To evaluate, preliminarily, the efficacy of this regimen at 6 months in these patients.
  • To determine, preliminarily, the median progression-free survival and overall survival of patients treated with this regimen.
  • To evaluate potential biomarkers of RO4929097and Notch inhibition activity in plasma and hair follicle samples.

OUTLINE: This is a multicenter, dose-escalation study of gamma-secretase inhibitor RO4929097.

  • Pre-surgery treatment (arm A [surgical patients] only): 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 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 adjuvant courses, RO4929097is discontinued and temozolomide is continued for an additional 6 courses.

Blood and tumor tissue samples are analyzed for pharmacokinetics on days 0-2 of week 1 and day 1 of week 5. Other biomarker studies are conducted on blood and hair follicle samples.

After completion of study therapy, patients are followed up for 4 weeks and periodically thereafter.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • 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
  • Pprior stereotactic biopsy or incomplete surgical resection allowed
  • Arm A only: Patients must have an indication for additional debulking surgery as part of their initial treatment

    • No patients with contraindication to a brain surgical procedure
  • As of amendment 8 (Version date: 11/30/2011), in order to expedite completion of the study, the dose-escalation portion will be restricted to non-surgical candidates (arm B)

    • Surgical candidates may be enrolled at any time, at the previously completed dose level

PATIENT CHARACTERISTICS:

  • 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

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • 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
  • No concurrent medications or food that may interfere with the metabolism of RO4929097 including ketoconazole and grapefruit
  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 Cancer Center
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Antonio Omuro, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:

No publications provided

Responsible Party: Antonio Omuro, Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01119599    
History of Changes
Other Study ID Numbers: CDR0000672641, MSKCC-09177
Study First Received: May 6, 2010
Last Updated: July 29, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

adult anaplastic astrocytoma
adult diffuse astrocytoma
adult pilocytic astrocytoma
adult pineal gland astrocytoma
adult subependymal giant cell astrocytoma
adult giant cell glioblastoma
adult glioblastoma
adult gliosarcoma
adult mixed glioma
adult brain stem glioma
adult anaplastic ependymoma
adult ependymoma

Additional relevant MeSH terms:

Glioma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Dacarbazine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2012

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