A multi-centre, open-label, single-arm, dose-finding phase I/II study to evaluate safety, tolerability, dosing schedule, and preliminary efficacy of carrier-added 4-L-[131I]iodo-phenylalanine (131I-IPA), administered as single or repetitive injections in patients with recurrent glioblastoma multiforme (GBM), concomitantly to 2nd line external radiation therapy (XRT) - IPAX-1Study

Cancer cells have a considerably larger nutrient consumption than non-malignant
cells. This is also the case for malignant gliomas which show a higher uptake
of amino acids in comparison with normal brain tissue. The uptake typically
increases with the malignancy grade, and is particularly high in GBM. Amino
acid transporter proteins actively transport amino acids across the blood-brain
barrier (BBB) into tumour cells. Thus, they are prime targets for radio-imaging
and targeted radiotherapy of gliomas in general and for GBM in particular.

4-iodo-L-phenylalanine (IPA) is a derivative of the naturally occurring
essential amino acid L- phenylalanine, containing an iodine atom in position 4
(para-position) of the phenyl ring. Due to its mode of beta decay, 131I is
known to cause mutation and death in cells that it penetrates, and other cells
up to several millimetres away, making it an ideal candidate for imaging and
treating inoperable GBM lesions. In addition to this physical effect, an
intrinsic cytostatic effect on GBM cells of IPA was demonstrated in
pre-clinical studies, as well as a radio-sensitising activity, synergistic to
both, the intramolecular radiolabel, and external field radiation therapy (XRT).

(see also study protocol chapter 1.1 Background, page 26)

Primary objective
To assess the safety and tolerability of intravenous 131I-IPA administered
concomitantly to 2nd line XRT in recurrent GBM

Secondary objectives:
- To assess the maximum tolerated dose (MTD) of 131I -IPA administered
concomitantly to 2nd line XRT in recurrent GBM
- To evaluate the feasibility of a fractionated administration of 131IIPA
- To evaluate the radiation absorbed dose to tumour from 131I-IPA
- To explore the antineoplastic effect of 131I-IPA + XRT combination therapy
- To explore a possible influence of MGMT promoter methylation status on the
biological response to 131I-IPA + XRT combination therapy
- To explore the occurrence and frequency of pseudo-progression (PsPD) in
response to 131I-IPA + XRT combination therapy
- To explore the cognitive function before, during and after therapy

Open-label, single-arm, randomised, parallel-group, multicentre dose-finding
study.

IV administration of [131I]-L-4-iodophenylalanine
(see the information provided in section J)

A physical examination, including measurement of bloodpressure, heartrate,
temperature, weight and an ECG, collection of blood- and urine samples and
completion of two questionnaires will take place at screening, treatment visits
and end of study visit. In addition CT and MRI scans will be performed at
several visits. Depending on the treatment group, SPECT imaging and whole body
planar imaging will be done.
During study visits, the patient will be asked about his wellbeing and
potential adverse events. The patient will need to follow guidelines after
radiation for 7 days. The study patient may experience adverse reactions
related to radiation therapy.

The Patient Information Leaflet & Informed Consent Form provides information on
the possible adverse events and other inconveniences in chapter 4

The study protocol contains a chapter on risks and benefit: chapter 1.3
Benefit-Risk Assessment, page 26.