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A Phase 1 and biodistribution study of KB004 (an anti-EphA3 antibody) in patients with glioblastoma  

Lead PI: A/Prof Hui Gan, Ludwig Institute for Cancer Research, Austin Health, VIC

 A/Prof Hui Gan

Research idea

This study will determine the safety, optimal dose and efficacy of KB004 (an antibody against proteins on the cancer cell surface and cancer blood vessels called Eph receptors) in patients with GBM and generate important data regarding the blood levels and brain penetration of this antibody; these results will advance the field of Eph research and also provide vital information for future trials of KB004, or drugs based on KB004 (such as antibody drug conjugates), either alone or in combination with other drugs.

Problem

The team seek to develop a new class of agents for the treatment of patients with GBM by testing their EphA3 antibody, KB004. The tumour-specific nature of EphA3 in GBM means that KB004 is likely to be well tolerated. This study could immediately and directly benefit the participants if their tumour responds as they will be provided with on-going antibody therapy. Furthermore, they will generate scientific data that will allow further research into Eph in GBM and facilitate development of a companion diagnostic (which is vital to the goal of precision medicine approach to KB004 in GBM).

Solution

This study will be the first study of an antibody against EphA3 in any solid tumour and will specifically focus on GBM patients. The team have unique access to this drug through collaborations with Kalobios, which owns the rights to KB004. Furthermore, this study will be a world-class collaboration between clinicians and trialists (HG, ZL, PI, LJ,MK, MR, MF), imaging specialists (AS, SR, DM, PT) and scientific leaders in Eph biology (BD, BS, AB, AS). Hence, this represents an opportunity to pioneer a whole new field of GBM therapeutics and research whilst immediately helping patients.

"It has all the characteristics of a great anti-cancer drug; it's going to kill the cancer, not harm the healthy cells and not make people unwell."  

- Dr Hui Gan

Why now?

One key advance is that KB004 development has now reached the point where human testing is possible. This coincides with a time when the need for more innovative therapies for GBM is starkly apparent, with the disappointing results of most new drugs tested to date, including anti-angiogenic and anti-integrin agents. Lastly, the ability for innovative Australian neuro-oncology trials has come from the growth of truly collaborative organisations such as COGNO and CTA.

Approach

If KB004 is tolerable and shows high brain penetration (especially if one or more patients with objective responses are also seen in the proposed study), then a Phase 2 study at the recommended Phase 2 dose would be undertaken in Australia in collaboration with overseas collaborators. Subsequent studies are likely to involve biomarker-enriched groups depending on the data generated from this phase 1 study. In parallel, KB004 is likely to be a good candidate for antibody-drug conjugate (ADC) development and for combination therapy with other Eph targeting agents, conventional treatments (chemo and/or radiotherapy), or other targeted agents.

Impact

This study will have an immediate impact on Australian patients because it will give them immediate access to an innovative agent with a strong rationale as a therapeutic vehicle against GBM. Realistically, only a minority (if any) of these heavily pre-treated patients will respond but they will provide study drug for as long as they benefit. The correlative science component of this study means that, regardless of study outcome, significant and novel knowledge will be added to the efforts to find effective treatments for GBM. 

Team & Partners

The clinicians and trialists are key opinion leaders in the Australian and international neuro-oncology sphere, having participated in multiple clinical trials (Phase 1-3) of all recent major therapeutic agents for GBM. Our imaging specialists are known for their molecular imaging expertise in particular biodistribution of labelled antibodies such as KB004. The ongoing development of KB004, for GBM and other malignancies, has been pioneered by the scientific leaders in Eph biology. This study will be undertaken at two large oncology centres with suitable infra-structure and trial staff for Phase 1 studies. 

  • Prof Andrew Scott, Ludwig Institute for Cancer Research Melbourne
  • Dr Bryan Day, Prof Andrew Boyd and Dr Brett Stringer, QIMR Berghofer Medical Research Institute
  • Dr Zarnie Lwin and Dr Po Inglis, Royal Brisbane and Women's Hospital 

 

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