Avastin / Irinotecan in Patients With Recurrent or Progressive Malignant Glioma (AVIRMA01-09)

August 1, 2011 updated by: Medical University Innsbruck

An Academic Prospective Single-arm Phase II Clinical Trial for Evaluation of Advanced Functional Neuroimaging Techniques and Molecular Markers in the Course of Anti-angiogenic Therapies in Malignant Gliomas

Malignant glioma are the most common and aggressive primary brain tumors in adults. Despite advances in multimodal treatment including surgery, radiation and chemotherapy, most patients have a dismal prognosis of 9-15 months (Stupp et al., NEJM 2005).

A major reason for the aggressiveness of malignant glioma is a pronounced tumor neovascularization, mainly driven by the vascular endothelial growth factor (VEGF) and its receptors. The therapeutic monoclonal antibody Bevacizumab (Avastin®) inhibits the VEGF pathway by binding the VEGF ligand. In Magnetic Resonance Imaging (MRI) this treatment reduces contrast enhancement by restoring both, the blood-brain-barrier and the destabilized vessel integrity. Furthermore, it raises the sensitivity of co-administered chemotherapeutics such as Irinotecan. In conclusion, anti-angiogenic therapy leads to the problem that the routinely used MRI techniques cannot distinguish anti-vascular effects from true anti-tumor effects.

The study hypothesis of the clinical trial part is that in 35% of malignant glioma patients Avastin / Irinotecan chemotherapy results in objective tumor responses assessed by standard / functional MRI and FET- /FLT-PET neuroimaging. The study hypothesis for the translational study part is that the expression of the molecular targets of Avastin and Irinotecan in malignant glioma tissue ( = tumor and vascular cells) are predictive for Avastin / Irinotecan therapy induced treatment response measured by functional MRI and FET- / FLT-PET imaging.

Study Overview

Status

Unknown

Conditions

Recurrent Malignant Glioma

Intervention / Treatment

Drug: Bevacizumab / Irinotecan

Study Type

Interventional

Enrollment (Anticipated)

Phase

Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Austria
- - Innsbruck, Austria, A-6020
    - Recruiting
    - Medical University Innsbruck, Department for Neurology
    - Contact:
      
      Guenther Stockhammer, MD, Prof.
      
      Email: guenther.stockhammer@i-med.ac.at
    - Contact:
      
      Martha Nowosielski, MD
      
      Email: Martha.Nowosielski@i-med.ac.at
    - Principal Investigator:
      
      Guenther Stockhammer, MD, Prof.
    - Sub-Investigator:
      
      Martha Nowosielski, MD
    - Sub-Investigator:
      
      Markus Glatzer, MD
  - Salzburg, Austria, 5020
    - Recruiting
    - Paracelsus Medical University, Christian Doppler Klinik
    - Contact:
      
      Markus Hutterer, MD
      
      Email: m.hutterer@salk.at
    - Principal Investigator:
      
      Stefan Golaszewski, MD
    - Sub-Investigator:
      
      Markus Hutterer, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

Inclusion Criteria:

Patients present with a first or second tumor recurrence / progression of a histological confirmed supratentorial malignant glioma WHO Grade III-IV (Classification following WHO criteria).
Patients with surgical resection of tumor recurrence / progression: Following standard therapy(first recurrence) or standard therapy / second line chemotherapy (second recurrence, excepting antiangiogenic approaches) patients must have evidence of further tumor progression measured by standard MRI sequences (MacDonald criteria). If possible, patients may have prior surgical resection of the tumor progression and will be eligible if the following conditions apply:
- Patients must have recovered from the effects of surgery
- To adequately asses the malignant glioma before surgery and the extent of residual disease postoperatively, two MRIs scans have to be performed:
- A first standard MRI scan has to be done within 1 week before surgery to document a progressed or recurrent malignant glioma.
- A second standard / functional MRI scan has to be done between 24 and 48 hours after surgery to document the postoperative malignant glioma (Baseline MRI scan).
- FET- / FLT-PET scans have to be done within 2 weeks after surgery to document the postoperative malignant glioma (Baseline PET scans).
Patients without surgical resection of the tumor recurrence / progression: Patients must have evidence of tumor progression measured by standard MRI sequences (MacDonald criteria).
- Additional functional MRI sequences have to be done within 1 week prior to study enrollment.
- FET- / FLT-PET scans have to be done within 2 weeks after surgery to document the postoperative malignant glioma (Baseline PET scans).
Resolution of all acute toxic effects of prior therapy to grade ≤ 1 (except alopecia)
Patients must have an ECOG performance status of 0-2
Patients must be ≥ 18 years and ≤ 80 years of age, with a life expectancy of greater than 8 weeks
Patients must have adequate organ function as defined by the following criteria:
Bone Marrow Reserve
- Platelets ≥ 75.000/μL
- Absolute Neutrophil Count ≥ 1500/μL
- Hemoglobin ≥ 10.0 g/dL Blood Coagulation
- aPTT ≤ 1.5 times upper limit of normal (ULN) Hepatic Function
- ASAT and ALAT ≤ 2.5 times ULN
- ALP ≤ 2.5 times ULN
- Total SERUM Bilirubin < 1.5 times ULN Renal Function
- SERUM Creatinine ≤ 1.5 times ULN Metabolism
- SERUM Albumin ≥ 3.0 g/dL All tests must be performed ≤ 3 days prior to study enrollment. Eligibility for hemoglobin count may be reached by transfusion.
Signed and dated informed consent document by the patient, indicating that the patient has been informed of all the pertinent aspects of the trial prior to study enrollment.
Willingness and ability of the patient to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
The patient is active participant in another clinical trial, which investigates substances with antiangiogenic effectiveness
Exclusion of patients in the event of
- surgery of a recurrent / progressed malignant glioma within 2 weeks prior to study enrollment
- chemotherapy (Standard therapy o Second Line Chemotherapy) within 2 weeks prior to study enrollment
- radiation therapy (Standard therapy) within4 weeks to study enrollment
- evidence in baseline MRI of intratumoral or peritumoral hemorrhage deemed clinically significant by the treating physician (area of hemorrhage > 25% of tumor area)
Significant Co-Morbidities within 12 months prior to study enrollment
- myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure
- cerebrovascular accident including transient ischemic attack
Significant Co-Morbidities at Baseline Evaluation
- Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
- Pulmonary embolism within 4 weeks before study enrollment
- A known HIV (human immunodeficiency virus) or Hepatitis B/C infection or severe acute infection
Anticoagulation: Current treatment with therapeutic doses of Marcoumar / Sintrom excluding thrombosis prophylaxis with low dose Heparin
Pregnancy, Breastfeeding and Non-Contraception
- Female patients who are pregnant or nursing
- Patients who are sexually active and unwilling or unable to use a medically acceptable method of contraception during the trial
Evidence of increased intracranial pressure
- midline shift > 5 mm
- headache, distinct nausea and vomiting
Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart excess risk associated with study participation or study drug administration, or which would make the patient inappropriate for entry into this study. The decision to enroll the patient in this study is in the judgment of the investigator.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Diagnostic
Allocation: N/A
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the objective tumor response criteria (RR, ORR, ORD) assessed by Standard MRI and FET-/FLT-PET during Avastin / Irinotecan chemotherapy. Time Frame: three years	three years

Secondary Outcome Measures

Outcome Measure	Time Frame
Evaluation of the predictive / prognostic value of the VEGF pathway and tumor cell proliferation rate in tumor and vascular cells of malignant gliomas treated with Avastin / Irinotecan Chemotherapy Time Frame: three years	three years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University Innsbruck

Collaborators

Roche, Austria

Investigators

Principal Investigator: Guenther Stockhammer, MD, Prof., Department for Neurology, Medical University Innsbruck

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

homepage Medical University Innsbruck

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2010

Primary Completion (Anticipated)

March 1, 2013

Study Completion (Anticipated)