Safety Evaluation of a Combination of Brain Radiation Therapy and Bevacizumab (Avastin®) for Treatment of Brain Metastasis
Condition: Metastatic Malignant Neoplasm to Brain
MeSH terms: Neoplasm Metastasis; Brain Neoplasms; Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      This phase I pilot study aims to define the safety of a combined treatment of bevacizumab and
      whole brain radiation therapy for the treatment of patients with brain metastasis of solid
      tumors. If this therapeutic scheme confirms it's safety profile, the investigators can
      expect:

        -  first, to allow that all patients can receive bevacizumab for their advanced and/or
           metastatic cancer if necessary, even in case of brain metastasis.

        -  Secondly, if this trial confirm a synergic effect of the combination of angiogenesis
           inhibitors and brain radiotherapy for local control of brain metastasis, an improvement
           of the therapeutic results for these patients which have a poor hope of survival and for
           which none innovative approach is currently suggested.

      Moreover, the investigators hope that the analysis of the different data of MRI evaluation -
      morphological and functional - will allow better definition of radiological evaluation of the
      therapeutic effect of angiogenesis inhibitors on brain metastasis.
    

Detailed description: 
      Brain metastasis remain a common complication of many solid tumors, occurring from 10 to 20%
      of patients with cancer, and the incidence may arise up to 20-40% in autopsy series. Despite
      the treatment, the patient outcome is poor and brain metastasis become a major cause of death
      from cancer.

      Some recent studies showed an increase incidence of brain metastasis; several explanations
      are evocated:

        -  The increased efficacy of brain imaging in screening of brain metastasis.

        -  The relative longer life expectancy of cancer patients in correlation with more
           efficient therapies (new chemotherapy drugs, targeted therapies) for visceral and bone
           metastasis, but without effect on the risk of brain metastasis (sanctuary effect),

      Therapeutic management of brain metastasis: standards of care and improvement strategies

      For patients with a poor survival hope, the treatment is limited to best supportive care with
      a palliative intent. At the opposite, a specific treatment of brain metastasis must be
      proposed when a real benefit may be expected.

      Surgery or radiosurgery are indicated for limited brain involvement (1 to 3 metastasis).

      In case of multiple localisations, whole brain radiation therapy (WBRT) is the most common
      approach; however this treatment is realized with a palliative intent: control of
      neurological symptoms and brain oedema.

      In the literature, an objective response rate of 50-60 % is expected from WBRT, but the
      majority of these patients will relapse and died from brain metastasis, with a median
      survival time of 4 to 6 months.

      Considering these poor results, it seems crucial to develop some innovative strategies, in
      order to improve the survival hope for these patients.

      Different concomitant approaches were tested in association with WBRT (cytotoxics such as
      temozolomide, radio-sensitizers such as efaproxiral), and more recently combination of
      radiation therapy with therapy targeting different signalling pathway were developed, for
      example with lapatinib for HER2 pathway. Targeted therapies acting on neoangiogenesis seem
      also may be considered as an interesting axis of research.

      Rationale utilisation of angiogenesis inhibitors for treatment of brain metastasis

      Neo-angiogenesis plays an important role in the growth of brain metastasis, acting on
      different mechanisms such as tumor neo-angiogenesis (by development of new blood vessels),
      co-option with existing blood vessels and increased vascular permeability. Therefore,
      angiogenesis inhibitors, particularly agents targeting VEGF/VEGFR pathway, could be
      interesting in the treatment of brain metastasis.

      In pre-clinical models, VEGF is the best characterized mediator of angiogenesis, and its role
      was pointed in the development of brain metastasis: increased transmigration of tumor cells
      through the blood-brain barrier by a VEGF-dependent disrupting effect, anti-apoptotic effect
      of VEGF by a paracrine action.

      This data suggest a therapeutic effect of VEGF targeting agents on brain metastasis and a
      decrease of brain metastasis development has been observed in some anti-VEGF anti-sens
      therapy.

      Moreover, VEGF involves vascular permeability and this mechanism is important in the
      development of peri-tumoral oedema.

      Anti-angiogenic treatments are divided in two groups: on one hand, angiogenesis inhibitors
      (acting by normalization of the existing tumor vascularisation and through a decreased
      formation of new blood vessels) and on the other hand, vascular disrupting agents (which can
      destroy pathologic vessels).

      For brain tumors, most of studies were focused on the role of angiogenesis inhibitors. Of
      special interest, anti-VEGF therapies, particularly the bevacizumab, were tested in clinical
      setting. Bevacizumab, a monoclonal recombinant antibody targeting VEGF, prevents the fixation
      of VEGF to VEGF receptors 1 and 2 on the endothelial cells, with a neutralizing effect on
      VEGF action.

      In clinic, recent studies showed a significant benefit of bevacizumab (Avastin®) in the
      treatment of primary brain tumors, as shown by Vredenburgh et al. for patients with recurrent
      gliomas; these data confirm a synergic effect with chemotherapy. Similarly, a potential
      synergic action in a combined approach with radiation therapy seems to be an interesting
      therapeutic way.

      Rationale for combining angiogenesis inhibitors with radiation therapy

      In the tumor, the pathologic neo-angiogenesis reduces the diffusion of oxygen, and
      consequently promotes hypoxia. Hypoxia is one of the most causes of radio-resistance.

      Ionizing radiations induce transient hypoxia in the central area of the tumor, increasing the
      production of VEGF and consequently the neo-angiogenesis. This "vicious circle" allows the
      development of optimal conditions for radio-resistance.

      The normalization of pathologic vessels induced by angiogenesis inhibitors leads to a
      decrease of hypoxia and thus enhance the radio-sensitivity of tumor cells and endothelial
      cells.

      In clinical setting, some studies were published about treatments combining radiation therapy
      and angiogenic inhibitors. The main study was conducted for rectal carcinoma (9), showing a
      safety profile of a combined scheme of bevacizumab and capecitabine in association with
      pre-operative pelvic irradiation. Efficacy data are encouraging (downstaging for 9 /11
      patients, histological regression for 5 patients). Similar conclusions may be drawn from
      another study performed in patients with unresectable pancreatic carcinoma treated with a
      radio-chemotherapy including bevacizumab, leading to an objective response for 9 patients (20
      %), 4 of them were operable at the end of radio-chemotherapy.

      Interestingly, this combined approach seems interesting for brain tumors, as shown by a
      recent published trial conducted by Narayana in first-line treatment of gliomas. This phase 2
      study combined temozolomide chemotherapy with bevacizumab administration for a dose of 10
      m/kg at D14 and D28 during the course of radiotherapy (total dose of 59,40 Gy delivered to
      the tumor volume). An promising response rate was observed: 7% of complete response and 93%
      of partial response, the 1-year progression-free survival was 59,3%. The authors confirm the
      feasibility of this combined approach (13/15 patients completed their treatment). Three grade
      3-4 haematological toxicities and 4 non-haematological toxicities (thrombo-embolism and HTA)
      are related. None intracerebral hemorrhage or death related to the treatment was reported.

      These results indicate a possible way of innovative strategies in the therapeutic management
      of brain metastasis, by association of bevacizumab and whole brain radiation therapy.
      Furthermore, bevacizumab is now indicated for several advanced and/or metastatic cancer but
      its administration remains theorically contra-indicated for patients with brain metastasis,
      due to the fear of potential cerebral hemorrhage. However, this risk remains low, as shown by
      several studies.

      Safety data were recorded with glioblastomas are reassuring, however, it is essential to
      determine the optimal dose level of bevacizumab when combined with irradiation of the entire
      brain at a dose of 30 Gy Thus for the phase 1 pilot study that we plan to carry, it is
      important to test several dose levels of bevacizumab in combination with irradiation of the
      brain: a precaution we have decided to use a conventional fractionation of 15 Gy in 2
      fractions three weeks. Secondarily, given the good tolerability of this modality in
      combination with three levels of dose of bevacizumab used, we propose to continue the phase 1
      according to the scheme commonly used in palliative situation (30 Gy in 10 fractions and 2
      weeks) in combination with Avastin at a dose of 15 mg / kg, at which a maximum limiting
      toxicity has been observed.
    

Intervention name(s): Bevacizumab
Intervention type(s): Drug
Intervention description(s): 5, 10 or 15 mg/kg, IV, on day 1, 15 and 29 plus radiation therapy of the whole brain.
For level 0,1 and 2, a total dose of 30 Gy will be administered in 15 fractions of 2 Gy, from D15 to D33 with 5 fractions a week.
For level 3,a total dose of 30 Gy will be administered in 10 fractions of 3 Gy, from D15 to D26 with 5 fractions a week.
Intervention MeSH terms: Bevacizumab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: brain radiation therapy; Bevacizumab; brain metastasis; solid tumor