Sorafenib in Newly Diagnosed High Grade Glioma

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Anaplastic Oligoastrocytoma; Anaplastic Oligodendroglioma	Drug: Sorafenib dose escalation	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	17 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (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
Study Start Date :	March 2009
Actual Primary Completion Date :	December 2011
Actual Study Completion Date :	March 2012

Arms and Interventions

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Arm	Intervention/treatment
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

Outcome Measures

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Primary Outcome Measures :

1. Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy [ Time Frame: 35 weeks ]
   Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy in patients with newly diagnosed high grade glioma

Secondary Outcome Measures :

1. 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 ]
2. Response rate [ Time Frame: 35 weeks ]
3. Time to treatment failure [ Time Frame: 20 months ]
4. 6 month progression-free survival [ Time Frame: 6 months ]
5. Event free survival [ Time Frame: 20 months ]
6. Overall survival [ Time Frame: 20 months ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
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

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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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Hottinger AF, Aissa AB, Espeli V, Squiban D, Dunkel N, Vargas MI, Hundsberger T, Mach N, Schaller K, Weber DC, Bodmer A, Dietrich PY. Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma. Br J Cancer. 2014 May 27;110(11):2655-61. doi: 10.1038/bjc.2014.209. Epub 2014 May 1. Erratum in: Br J Cancer. 2018 Jan 09;:.

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
First Posted:	April 20, 2009
Last Update Posted:	November 4, 2014
Last Verified:	October 2014

Keywords provided by Andreas F. Hottinger, 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:

Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Sorafenib	Temozolomide; Niacinamide; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Vitamin B Complex; Vitamins; Micronutrients; Growth Substances; Physiological Effects of Drugs; Antineoplastic Agents, Alkylating; Alkylating Agents