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…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I:
Primary: To determine the MTD of nelfinavir as an adjuvant in the
radiochemotherapy treatment in primary glioblastoma patients by assessing the
incidence of any grade 3 or higher non-haematological or grade 4 or higher
haematological acute toxicity (CTCAE v3.0), excluding toxicities that can be
expected from the standard treatment of chemoradiotherapy with temozolomide.
Phase II
Primary: PFS at 6 months
Secondary outcome
Phase I:
Secondary:
• Incidence of other acute toxicity, assessed according to CTCv3.0.
• 6- months progression free survival
• Overall survival
• Metabolic ratios of standardized uptake value (SUV) of serial 18F-FDG:
assessed by PET-CT.
• Perfusion measurements (rCBV) with Perfusion MRI
Phase II:
Secondary:
• Progression free survival at 12 months
• Overall survival
• Incidence of acute toxicity, assessed according to CTCv3.0.
• Metabolic ratios of standardized uptake value (SUV) of serial 18F-FDG:
assessed by PET-CT.
• Phosphorylation of AKT in tumour tissue before treatment
Background summary
There is a strong rationale to start a clinical trial of NFV and chemoradiation
with temozolomide in primary glioblastoma patients:
1. Preclinical work demonstrates that nelfinavir results in downregulation of
Akt signalling in cancer cells and therefore results in radiation
sensitization, antiangiogenisis and tumour cell migration.
2. There is a high frequency of Akt activation in glioblastoma patients.
3. There is no clear evidence of sensitization of normal tissues to radiation
seen in HIV patients.
4. There is evidence in vivo that nelfinavir also has a chemotherapy
sensitizing effect.
5. NFV has been safely administered to HIV+ patients over the last decade with
minimal side effects.
Study objective
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 design
A multi-centre combined phase I/II trial.
Phase I: a single arme study with a 3+3 cohort design.
Phase II: a 2-arm open randomized phase II trial based on the Simon 2-stage
design with PFS at 6 months as primary outcome measure.
Intervention
Treatment with Nelfinavir
Study burden and risks
The extra burden for the patients, including the PETs and the blood samples,
will be mentioned by the physician.
Postbus 5800
6202 AZ Maastricht
NL
Postbus 5800
6202 AZ Maastricht
NL
Listed location countries
Age
Inclusion criteria
Histological confirmed glioblastoma multiforme at primary diagnosis
Tumours which do enhance on pre-operative imaging
Age >=18-70
WHO performance status 0-2, RTOG- RPA class III-IV.
No recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
Willing and able to comply with the study prescriptions
Have given written informed consent before patient registration
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 uncontrolled infectious disease
No use of terfenadine, astemizol, cisapride, sildenafil, lovastatin or simvastatin
No 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 (lovastatin, simvastatin, atorvastatin), rifampin, rifabutin, felodipine, nifedipine, and sildenafil or St. John's wort.
Adequate haematological, renal and hepatic function
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
Exclusion criteria
the opposite of the above
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-001078-34-NL |
| ClinicalTrials.gov | NCT00694837 |
| CCMO | NL22167.068.08 |