Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)

Abstract

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

Keywords: Bayesian; Bone neoplasm; Muramyl tripeptide; Osteosarcoma; Phase II trial; Rare cancer; Sarcoma.

Fig. 1

a. Flow diagram of the study design with three arms A, B and C. Randomisation is between arm B and C in the deemed un-resectable cohort. b. Consort flow diagram of the study participants. A total of 18 patients assessed, 10 were excluded and 8 registered. Of the latter, 5 were randomised. c. Planned and actual recruitment during the study period

Fig. 2

a. Summary of treatments administered and major patient events for each patient in all arms. b. Summary of the timing and of worst adverse events for each patient in all arms

Fig. 3

Circos plots of chromosomal rearrangements in all patient tumour core biopsy samples with adequate quality RNA. Fusion genes were identified by carrying out FusionCatcher analysis on RNA-Seq data. Patient B2 and C2 had data from three separate core biopsies, whereas C3 had two and C1 had one core biopsy sample. Patient B2 had two core samples post treatment

Fig. 4

Heatmap of the top 50 most differentially expressed genes amongst the patient biopsy samples. Expression values were calculated using Kallisto. Top and left-hand side dendograms indicate hierarchical clustering of columns (patients) and rows (genes). Note similarity of all three B2 core samples, C2 and C3 samples. Expression changes were identified post treatment in patient B2 (B2-PT)

Fig. 5

Cytokine activation in peripheral blood samples in different patients (A1 to C3, legend). Results from the Bio-Plex multiplex assay are shown as concentration against time (days) for all collected blood samples for all patients’ available post-randomisation. Samples from specific timepoints are missing either because of failed sample collection or results were below the detection limit of the specific assay