Sorafenib in Newly Diagnosed High Grade Glioma

Glioblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00884416
• Other study ID #: 08-122
• Secondary ID: 2009DR102913031
• Status: Completed
• Phase: Phase 1
• First received: April 17, 2009
• Last updated: October 31, 2014
• Start date: March 2009
• Est. completion date: March 2012

Study information

• Verified date: October 2014
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: SwissmedicSwitzerland: Ethikkommission
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: March 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Anaplastic Oligoastrocytoma
• Anaplastic Oligodendroglioma
• Astrocytoma
• Glioblastoma
• Gliosarcoma
• Oligodendroglioma

Intervention

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

Locations

Country	Name	City	State
Switzerland	Geneva University Hospital (Hopitaux Universitaires de Geneve), Department of Oncology	Geneva	GE

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Geneva	Bayer

Country where clinical trial is conducted

Switzerland, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy	Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy in patients with newly diagnosed high grade glioma	35 weeks	Yes
Secondary	Maximum Observed Plasma Concentration (Cmax) and Area under the curve (AUC) of sorafenib and temozolomide		0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post dose	No
Secondary	Response rate		35 weeks	No
Secondary	Time to treatment failure		20 months	No
Secondary	6 month progression-free survival		6 months	No
Secondary	Event free survival		20 months	No
Secondary	Overall survival		20 months	No