A Phase II Study of Subcutaneous Bevacizumab in Relapsed / Progressive Glioblastoma

1.1 Primary Aim: To describe MRI response rate as regards edema and enhancement of glioblastoma and radiation- related brain enhancement when treated with subcutaneous (SQ) bevacizumab daily. See section 11 for detail on response assessment.

1.2 Secondary Aims: 1.2.1 To characterize toxicities of SQ bevacizumab. 1.2.2 To describe response rate as per primary aim (above) in study participants who discontinue SQ bevacizumab for any reason and go on to receive treatment with standard IV bevacizumab or bevacizumab-containing combination.

2 BACKGROUND 2.1 Bevacizumab is a monoclonal antibody cancer therapeutic which targets vascular endothelial growth factor (VEGF) and which has been FDA approved for the treatment of glioblastoma. Clinical trials of bevacizumab in glioblastoma multiforme (GBM) patients documented edema and enhancement response rates between 75 and 100%, with consequent improvement in neurologic symptoms and decrease in corticosteroid requirements.(1-3) The FDA approval was based on response rate; there has not been proof that bevacizumab prolongs survival in GBM patients. The related VEGF antagonist cediranib can decrease brain edema in a manner comparable to bevacizumab(4) but failed to prolong survival in GBM patients in a recent phase III study.(5) Thus bevacizumab remains strictly palliative for GBM patients, a disease which in any case is not thought to be curable with available treatments.

2.2 Most monoclonal antibody therapeutics remain effective when given subcutaneously instead of intravenously.(6-9) Preclinical animal data show this to be true for bevacizumab as well, with 100% bioavailability for SQ as compared to IV administration.(10) In a mouse tumor model, SQ bevacizumab produced better antitumor effects than intravenous bevacizumab.(11) Some treatments are also less toxic when given subcutaneously - a recent example is bortezomib, which produces less neuropathy when given SQ instead of IV but is just as effective against myeloma.(12) This is presumably because of lower peak doses. There is no published correlation between dose of bevacizumab and incidence of the common side effects, which include hypertension and proteinuria, as well as less common but more dangerous toxicities such as gut perforation. If these toxicities relate to peak doses obtained after IV administration, it may be that they are less frequent in a dosing scheme in which SQ administration yields a low sustained and stable dose. It is not clear what SQ dose of bevacizumab is necessary to obtain benefit in GBM. Although the FDA approved dose is 10mg/kg every 14 days, earlier European GBM studies used 5mg/kg every 14 days and produced similar response rates.(1) This uncertainty about the required dose is, in fact, true for all the diseases in which bevacizumab is used; an example can be seen in two simultaneously published phase III ovarian cancer studies, one of which used bevacizumab maintenance at 15mg/kg every 3 weeks and the other half that dose at 7.5mg/kg every 3 weeks, with the lower dose study actually obtaining improved survival for participants as compared to the higher.(13, 14) It is possible that at least in GBM, lower doses might be better. Some theorize that the hypoxia produced by antiangiogenic treatments promote a more aggressive, infiltrative tumor phenotype. There is some thought that a less complete blockade of VEGF would decrease consequent hypoxia and conversion to this aggressive phenotype.(15) A recent retrospective series reported that GBM patients who encounter bevacizumab toxicity and undergo dose reduction have longer survival than contemporaneously treated GBM patients who continue at 10mg/kg every 14 days.(16) Thus it is ethical and perhaps even beneficial to explore lower doses of bevacizumab in the treatment of GBM.

2.3 The rapid and nearly universal response rate in GBM patients as regards enhancement and edema together with the direct palliative benefit of bevacizumab monotherapy makes this an excellent population to study an alternate dosing scheme. In this study the investigators propose to study subcutaneous bevacizumab for the treatment of patients with GBM and progressive edema representing tumor progression or symptomatic radiation aftereffects. All participants will receive the same dose of 25 mg SQ daily, which would translate into 350 mg over 14 days or 5mg/kg/14 days for a 70 kg patient - the same total dose used in the European GBM series and the same dose as is used to treat metastatic colon cancer. Bevacizumab solution is known to be stable in refrigerated prefilled syringes(17), and participants would take these home, injecting themselves after the manner of low molecular weight heparin. Participants would receive weekly toxicity assessment, and MRI at 3 weeks looking for evidence of response in terms of reduction of enhancement and edema; see section 11. Those participants with response would continue on SQ bevacizumab as long as they continued to experience clinical benefit. Participants not responding, progressing after initial response or encountering toxicity specific to the subcutaneous route of injection or discontinuing study participation for any reason would be offered conversion to standard IV bevacizumab as standard of care or other treatments as appropriate and available. Improvement in enhancement / edema among participants converting to standard IV bevacizumab or bevacizumab containing combinations will be followed as a secondary endpoint.