VERTU clinical trial
Veliparib, radiotherapy and Temozolomide trial in newly-diagnosed unmethylated MGMT glioblastoma.
Principal: A/Prof Mustafa Khasraw, NHMRC Clinical Trials Centre, NSW
To evaluate using the PARP inhibitor (PARPi) veliparib with radiotherapy and later with adjuvant temozolomide chemotherapy to ultimately improve progression-free and survival outcomes of GBM patients with unmethylated O (6)-methylguanine-DNA methyltransferase (MGMT) status. There is a robust biological rationale to use PARPi, known to kill cancer cells that are already DNA damaged – by radiotherapy, alkylating agents or underlying gene mutations.
This trial proposes a novel approach to the treatment of patients with the most aggressive form of glioblastoma, who have the worst outcome with current standard treatment
Most GBM patients with the biomarker of unmethylated MGMT do not survive beyond one year. The MGMT gene is a DNA repair enzyme that overcomes effects of alkylating chemotherapy such as temozolamide (TMZ). If MGMT is active (unmethylated), chemotherapy damage is repaired. In approx 30% of GBM patients, the MGMT gene is inactivated due to methylation of its promoter region. DNA methylation is a well-known mechanism for controlling gene expression. By methylating the MGMT gene there is better response to chemotherapy (the tumour will have inefficient DNA repair). A better response to radiotherapy and chemotherapy is anticipated with PARPi prior to DNA repair.
PARPi used in combination with cytotoxic agents (chemotherapies) or radiotherapy can increase effectiveness of DNA damage. When PARP is inactivated, cells become genomically unstable and die. There is evidence of synergy when PARPi is administered with radiotherapy. Veliparip is a PARP inhibitor, when given with temozolomide acts synergistically in xenograft models. The team’s preclinical work demonstrated synergy of the combination of veliparib with both or either radiation and TMZ, in TMZ resistant patient derived cell lines. They are proposing the first clinical trial to test this combination.
"We know that radiation is effective in treating brain cancer but unfortunately the cancer comes back in most of the patients. So by adding this drug to the radiation we are hoping to improve the outcome of patients by increasing the damage to the tumours."
- A/Prof Mustafa Khasraw
Despite recent randomised trials, there has been minimal shift in the average survival for GBM patients of 15 months. Patients with unmethylated MGMT status have shorter life expectancy and any benefit of TMZ in this group is questionable. Veliparib is a PARPi that demonstrated safety in combination with TMZ and radiotherapy. The study team has preclinical evidence of synergy of veliparib given with TMZ or radiotherapy. The benefit is striking in the presence of a DNA repair signature. This trial is proposed to replace the TMZ during concurrent radiotherapy with veliparib and add veliparib to TMZ during adjuvant therapy.
This project will bring us one step closer to personalised treatments, facilitating effective management. If study results are promising a second stage study followed by a randomised phase III clinical trial in collaboration with international investigators and/ or research groups will be planned. A larger trial is currently being considered by NRG Oncology. This study will contribute to the total randomised evidence of radiotherapy/PARPi combination (in a potential subsequent meta-analysis), thereby providing direct experience in an Australian context and additional insights of this approach via linked biological studies.
The impact of GBM on patients, their families and society is far-reaching. This study will test the potential effect of veliparib in patients with unmethylated GBM who currently have a dismal prognosis. This study will explore a promising set of biomarkers that may revolutionise GBM treatment paradigms. Importantly, if they observe a signal with veliparib, the team plans a subsequent study to confirm findings with international partners including NRG Oncology. This research project has potential to provide a fundamental shift in the current evidence-base by informing clinical practice regarding the role of PARPi in patients with unmethylated MGMT.
Team & Partners
The study team consists of national leaders with proven track records in trials recruitment and conduct; including investigators from the Cooperative Trials Group for Neuro-oncology (COGNO) from high volume neuro-oncology units and utilisation of trials expertise at the NHMRC Clinical Trials Centre (CTC). This project will involve input from consumer representatives, Cure Brain Cancer Neuro-oncology Group (headed by A/Prof Kerrie McDonald), COGNO members and other Australian investigators. Cure Brain Cancer funds will enable completion of the initial project phase, assessing feasibility and safety of treatment and providing initial evidence on efficacy of the combination.
- Prof John Simes, NHMRC Clinical Trials Centre
- Prof Mark Rosenthal, Royal Melbourne Hospital
- A/Prof Kerrie McDonald, University of NSW
- Dr Eng Siew Koh, Liverpool Hospital
- A/Prof Hui Gan, Austin Health
- A/Prof Kate Drummond, Royal Melbourne Hospital
- Dr Zarnie Lwin, Royal Brisbane & Women’s Hospital
- Dr Elizabeth Hovey, Prince of Wales Hospital
- Dr Matthew Foote, Princess Alexandra Hospital
- Dr Helen Wheeler, Royal North Shore Hospital
- Ms Liz Barnes and Ms Ann Livingstone NHMRC Clinical Trials Centre
- Ms Robyn Leonard, Cooperative Trials Group for Neuro-oncology (COGNO)
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