Sorafenib in Newly Diagnosed High Grade Glioma

Sponsor

University Hospital, Geneva (Other)

Overall Status

Completed

CT.gov ID

NCT00884416

Collaborator

Bayer (Industry)

Enrollment

Location

Arm

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Mar 1, 2009

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

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

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

Primary Outcome Measures

Safety and tolerability of sorafenib in combination with radiation and temozolomide chemotherapy [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

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]
Response rate [35 weeks]
Time to treatment failure [20 months]
6 month progression-free survival [6 months]
Event free survival [20 months]
Overall survival [20 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.