Sorafenib in Newly Diagnosed High Grade Glioma - Full Text View

Purpose

This is a phase I study to evaluate the safety and tolerability of Sorafenib in combination with Temodar and radiation therapy in patients with newly diagnosed high grade glioma (glioblastoma, gliosarcoma, anaplastic astrocytoma and anaplastic oligodendroglioma or oligoastrocytoma). The mechanism of action of sorafenib, an oral multikinase inhibitor, makes it an interesting drug to investigate in the treatment of patients with high grade glioma as this agent has anti-angiogenic activity and inhibits other pathways such as Ras, Platelet-derived growth factor (PDGF) and fms-like tyrosine kinase receptor-3 (Flt-3), which are potential targets against gliomas.

Condition	Intervention	Phase
Glioblastoma Gliosarcoma Anaplastic Astrocytoma Anaplastic Oligoastrocytoma Anaplastic Oligodendroglioma	Drug: Sorafenib dose escalation	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I Dose Finding Study of Sorafenib in Combination With Radiation Therapy and Temozolomide as a First Line Treatment of Patients With High Grade Glioma

Resource links provided by NLM:

Drug Information available for: Temozolomide Sorafenib Sorafenib tosylate

U.S. FDA Resources

Further study details as provided by University Hospital, Geneva:

Primary Outcome Measures:

Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy [ Time Frame: 35 weeks ] [ Designated as safety issue: Yes ]
Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy in patients with newly diagnosed high grade glioma

Secondary Outcome Measures:

Maximum Observed Plasma Concentration (Cmax) and Area under the curve (AUC) of sorafenib and temozolomide [ Time Frame: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post dose ] [ Designated as safety issue: No ]
Response rate [ Time Frame: 35 weeks ] [ Designated as safety issue: No ]
Time to treatment failure [ Time Frame: 20 months ] [ Designated as safety issue: No ]
6 month progression-free survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Event free survival [ Time Frame: 20 months ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: 20 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	18
Study Start Date:	March 2009
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Sorafenib dose titration	Drug: Sorafenib dose escalation Sorafenib dose escalation scheme: 3 first patients: 200 mg/d, if dose limiting toxicities (DLT) not reached: 3 patients at 200 mg BID, if no DLT reached: 3 patients at 400 mg bid

Detailed Description:

Up to 18 patients will be included in this phase I study. The primary goal of this study will be to establish the maximum tolerated dose of sorafenib when used in combination with temozolomide and radiation therapy. Secondary goals of this study include: response rate, time to treatment failure, 6 month progression-free survival, event free survival and overall survival. A correlative study will investigate the pharmacokinetics of sorafenib used in combination with radiation therapy and temozolomide.

Eligibility

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

Criteria

Inclusion Criteria:

Histological documentation of newly diagnosed malignant glioma
ECOG performance status of 0 or 1
Age ≥18
Life expectancy of at least 12 weeks
Hemoglobin ≥ 9.0 g/dl
Granulocyte count ≥1.5 X 10^9/L
Platelet count ≥100 X 10^9/L
SGOT ≤ 2.5X upper limit of normal (ULN)
SGPT ≤ 2.5X upper limit of normal (ULN)
Alkaline phosphatase ≤4x ULN
Serum creatinine ≤1.5X ULN
Bilirubin ≤1.5X ULN
Spontaneous PT-INR/PTT < 1.5x upper limit of normal (patients on therapeutic anticoagulation will be allowed to participate.
Patients must be on a stable or decreasing dose of corticosteroids for at least 2 weeks
Patient for whom a first line treatment with temozolomide and radiotherapy is adequate
Prophylactic anti-emetic, pentamidine inhalation / co-trimoxazole and anticonvulsants are allowed
All patients must sign written informed consent.

Exclusion Criteria:

Prior treatment for high grade glioma
Previous exposure to Ras pathway inhibitors
Other concurrent active malignancy (with the exception of cervical carcinoma in situ or non melanoma carcinoma of the skin, superficial bladder tumor [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry).
Serious medical or psychiatric illness that would, in the opinion of the investigator, interfere with the prescribed treatment, including but not limited to: Congestive heart failure > NYHA class 2, active CAD, cardiac arrythmias requiring anti-arrythmic therapy or uncontrolled hypertension within the last 12 months
Any condition limiting the patient's judgment capacity
History of HIV infection, chronic hepatitis C or B as well as clinically active infections (> grade 2 NCI-CTC version 3.0)
History of organ allograft
Renal dialysis
Evidence or history of bleeding diathesis
Major surgery within 4 weeks of start of study treatment, except for neurosurgical resection
Autologous bone marrow transplant or stem cell rescue within 4 months of study
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results.
Medical condition that prevents the patient from swallowing pills
Use of biologic response modifiers, such as G-CSF within 3 week of study entry.
Pregnant or breast-feeding women.
Refusal to use effective contraception. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and for at least 3 months after administration of study medication.
Known or suspected allergy to the investigational agent or any agent given in association with this trial.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00884416

Locations

Switzerland
Geneva University Hospital (Hopitaux Universitaires de Geneve), Department of Oncology
Geneva, GE, Switzerland, 1211

Sponsors and Collaborators

University Hospital, Geneva

Bayer

Investigators

Principal Investigator:

Pierre-Yves Dietrich, MD

Department of oncology, Geneva University hospital

More Information

No publications provided

Responsible Party:	Andreas F. Hottinger, Principal Investigator, University Hospital, Geneva
ClinicalTrials.gov Identifier:	NCT00884416 History of Changes
Other Study ID Numbers:	08-122, 2009DR1029, 13031
Study First Received:	April 17, 2009
Last Updated:	August 25, 2011
Health Authority:	Switzerland: Swissmedic Switzerland: Ethikkommission

Keywords provided by University Hospital, Geneva:

anaplastic oligodendroglioma
high grade glioma
glioblastoma
gliosarcoma
anaplastic astrocytoma
anaplastic oligoastrocytoma
phase I

first line treatment
sorafenib
temozolomide
radiation therapy
safety
tolerability
protein kinase inhibitors

Additional relevant MeSH terms:

Oligodendroglioma
Astrocytoma
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
Sorafenib
Protein Kinase Inhibitors
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on May 19, 2013