Study With Nelfinavir and Combined Radiochemotherapy for Glioblastoma

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: nelfinavir

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 Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht Radiation Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Exclusion Criteria:

The opposite from above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Maastricht Radiation Oncology
• Collaborators: Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (ACTUAL): January 1, 2013
• Study Completion (ACTUAL): January 1, 2013

Study Registration Dates

• First Submitted: June 9, 2008
• First Submitted That Met QC Criteria: June 10, 2008
• First Posted (ESTIMATE): June 11, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 10, 2015
• Last Update Submitted That Met QC Criteria: April 9, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: glioblastoma; functional imaging; nelfinavir; AKT pathway
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Nelfinavir
• Other Study ID Numbers: 07-09-04/07; EudraCT number 2008-001078-34