Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.
BACKGROUND
Oncolytic viruses represent a novel treatment approach in GBM through oncolytic targeting as well as local immune activation. We designed a phase Ib, open-label study of intravenous reovirus (pelareorep) with GM-CSF alongside standard chemoradiotherapy to assess safety and tolerability.
METHODS
15 patients with newly diagnosed GBM were treated with GM-CSF 50mg subcutaneously (days 1–3) and pelareorep (days 4–5) in weeks 1 and 4 of chemoradiotherapy, and week 1 of adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Secondary objectives were to gain preliminary assessment of the activity of the combination and assess treatment compliance.
RESULTS
1 dose limiting toxicity (DLT) and 20 SAEs were experienced overall; median number of SAEs per patient was 2. Commonest SAEs were nervous system disorders, predominantly seizures. SARs included fever/flu-like episodes (n=5), fall (n=1) and headache (n=1). Two SUSARs occurred in dose level 2, classed as vascular disorders manifesting as hypotension episodes – one was a DLT. Suspected relationship of SARs: pelareorep (n=6); temozolomide (n=1); radiotherapy (n=1); all study drugs (n=1). 87% of patients (n=13) completed chemoradiotherapy without unplanned delays. Adjuvant treatment was delayed in 21% of cycles overall, with the majority due to inadequate haematology/biochemistry values (44% of delays). Pelareorep was omitted in 4 instances in 4 patients during chemoradiotherapy and omitted in 4 instances in 3 patients during adjuvant treatment.
CONCLUSION
We present the first clinical data using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM, suggesting that the combination is tolerable. Further analysis is underway and efficacy results will be ready for presentation at the conference. This work was supported by CRUK, The Brain Tumour Charity, Yorkshire Cancer Research and Oncolytics Biotech Inc.
PURPOSE CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non–small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial. METHODS Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm. RESULTS The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology. CONCLUSION The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.
Background: Oncolytic viruses are of increasing interest as an immunologic approach to treating glioma. We previously reported safety data from a phase Ib, open-label study of intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed glioblastoma and confirmed that the combination is tolerable. Following agreement from the relevant ethics authorities we have now completed long term follow up data on all patients treated in the study to investigate whether there is a signal of impact on survival. METHODS: 15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following end of study patients were followed up as per institutional practice. Ethical approval was granted to collect survival data in all patients who survived beyond study closure up to June 2021.
Results: We showed that using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM was tolerable with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months for patients in dose level 1 and 16.1 months in dose level 2, giving median OS for all patients 13.1 months. It was notable however that a small number of patients survived beyond 24 months. The 24-month survival estimate for all patients was 33%, 16.7% for dose level 1 and 50% for dose level 2. One patient in dose level 2 remains alive at 42 months.
Conclusion: We previously reported that intravenous delivery of pelareorep with standard chemoradiotherapy is tolerable in newly diagnosed GBM. Although based on small numbers, these long-term follow up data suggest that this may be an active combination in a subset of GBM patients and further randomized studies are warranted.
Citation Format: Susan C. Short, Jessica Kendall, Anthony Chalmers, Catherine McBain, Alan Melcher, Adel Samson, Rachel Phillip, Sarah Brown. Combination of reovirus (pelareorep) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alongside standard chemoradiotherapy and adjuvant chemotherapy (temozolomide) for patients with glioblastoma multiforme (GBM): Long term follow up results of the ReoGlio phase Ib trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT569.
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