Study With Nelfinavir and Combined Radiochemotherapy for Glioblastoma

Sponsor

Maastricht Radiation Oncology (Other)

Overall Status

Completed

CT.gov ID

NCT00694837

Collaborator

Maastricht University Medical Center (Other)

Enrollment

Location

Arm

46.1

Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objectives of the trial are:

To assess safety, tolerability and activity of nelfinavir given neo-adjuvant and concomitant to chemoradiotherapy with temozolomide in patients with a newly diagnosed glioblastoma multiforme.

To describe the possible effect of nelfinavir on functional imaging To describe the activity of nelfinavir in vivo on blocking the AKT pathway.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: nelfinavir	Phase 1

Detailed Description

Glioblastoma multiforme is the most malignant and common, about 50%, variant of all primary brain tumours. The treatment strategies for this disease have not changed appreciably for many years consisting of a surgical intervention (biopsy or tumour resection) and post-operative local radiotherapy until several years ago. Combined chemoradiotherapy with temozolomide is at the moment the standard medical practice after results of the joint EORTC-NCIC phase III study randomizing between radiotherapy alone and combined chemoradiotherapy with temozolomide showed a significant improvement in 2-years survival from 8% to 24% for the combined treatment arm (Stupp 2005). Given the poor prognosis of these patients and the still poor treatment response, further therapeutic improvement will remain the most challenging topic for the future. The next step to further improve survival for this patient group would be the addition of biological modifying and/or antiangiogenic therapies. These strategies are motivated by the fact that glioblastomas often express very high levels of vascular endothelial growth factor which is a key mediator of blood vessel growth as high expression of EGFR, which upregulates the downstream PI3K-AKTpathway. (Fischer I, Carmeliet P, Koul D) One possible candidate is nelfinavir, a protease inhibitor interfering with Akt activity downstream of EGFR and upstream of VEGF. (Geng L, Gorski D, HLu B)

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I/II Study for Patients With Newly Diagnosed Glioblastoma Testing Nelfinavir in Combination With Concomitant Temozolomide and Radiotherapy.

Study Start Date :

Mar 1, 2009

Actual Primary Completion Date :

Jan 1, 2013

Actual Study Completion Date :

Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: B	Drug: nelfinavir The start dose of nelfinavir in phase 1 is 1000mg BID. The maximum administered dose, if no DLT occurs, will be1250 mg BID (2500mg). Nelfinavir will be administered 1 week before start of the chemoradiotherapy until the last day of chemoradiotherapy.

Arm

Intervention/Treatment

Experimental: B

Drug: nelfinavir

The start dose of nelfinavir in phase 1 is 1000mg BID. The maximum administered dose, if no DLT occurs, will be1250 mg BID (2500mg). Nelfinavir will be administered 1 week before start of the chemoradiotherapy until the last day of chemoradiotherapy.

Outcome Measures

Primary Outcome Measures

Fase I: To determine the MTD of nelfinavir as an adjuvant in the radiochemotherapy treatment in primary glioblastoma patients. Fase 2: Progression free survival at 6 months [Fase 1: after treatment; fase 2: 6 months after treatment]

Secondary Outcome Measures

Fase 1/2: Incidence of acute toxicity; OS; Metabolic ratios of SUV of serial 18F-FDG: assessed by PET-CT.Fase 1:6-months PFS; Relative blood flow measurement by perfusion MRI. Fase 2: PFS at 12 months; Phosphorylation of AKT in tumour tissue. [fase 1: 6 months after treatment; fase 2: 12 months after treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed glioblastoma multiforme at primary diagnosis
Tumours which do enhance on pre-operative imaging
Age >=18-65 years
WHO performance status 0-2, RTOG- RPA class III-IV.
No recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
Patient able to tolerate full course of radiotherapy
No previous radiotherapy to the head and neck area.
Prior neurosurgery within 6 weeks of treatment
No previous irradiation of the brain.
No previous chemotherapy
No prior or concurrent medical condition which would make treatment difficult to complete. Medication with steroids is allowed.
No use of terfenadine, astemizol, cisapride, sildenafil, lovastatin or simvastatin and other concurrent medication that is metabolized by the CYP3A4 isoenzyme and cannot be replaced with other equivalent medications for the period of the study: antiarrhythmics (amiodarone, quinidine), neuroleptics (pimozide), sedative/hypnotic agents (midazolam, triazolam), ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (atorvastatin), rifampin, rifabutin, felodipine, nifedipine, and sildenafil or St. John's wort.
Adequate haematological, renal and hepatic function
No uncontrolled infectious disease, absence of known HIV infection, chronic hepatitis B or hepatitis C infection
Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction)
All patients of reproductive potential (male and female) must use effective contraception for the whole duration of the treatment and until 6 months thereafter. Females must not be pregnant or lactating
Willing and able to comply with the study prescriptions
Written informed consent before patient registration