Sir Peter MacCallum Department of Oncology - Research Publications
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ItemA PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMOURS AND ATYPICAL TERATOID RHABDOID TUMOURS(OXFORD UNIV PRESS INC, 2022-06)Abstract BACKGROUND: Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumours (MRT) and atypical teratoid rhabdoid tumours (ATRT) in pre-clinical models. We report results of the open label, phase II study of oral panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumour activity of low dose, continuous oral panobinostat as well as its associated toxicities. To assess the biological activity of low dose panobinostat by measuring histone H4 acetylation status in peripheral mononuclear cells (PMNC), and differentiation markers. METHODS: Following primary institutional standard of care induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2/day, with a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat at different dosing levels. Patients were monitored for toxicity; dose reductions were in decrements of 2mg/m2/day. RESULTS: A total of 13 patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled. The average age at enrollment was 3.6 years (range 0.8-6.8 years). The mean treatment duration was 206 days (13-344 days). Currently, six patients (42.9%) remain on study with a mean study duration of 531 days (range 13-895 days). 6/14 patients (42.9%) were removed due to disease progression at a mean study duration of 245 days (44-560 days). 2/14 patients (14.3%) withdrew due to toxicity. 12/14 patients (85.7%) required dose reductions. The main toxicities were thrombocytopaenia and leukopaenia (Grade III-IV). Real-time pharmacodynamic assessment of panobinostat, at a dose as low as 6mg/m2/day resulted in significant acetylation of histone H4 in PMNC. CONCLUSIONS: Treatment with low dose panobinostat is well tolerated in infants and children with MRT/ATRT, with significant acetylation of histone H4 in PMNC.
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ItemPOTENTIAL MECHANISMS OF RESISTANCE IDENTIFIED THROUGH ANALYSIS OF MULTIPLE BIOMARKERS IN IMMUNE HOT NON-RESPONDERS WITH NON-SMALL CELL LUNG CANCER (NSCLC) TREATED WITH TISLELIZUMAB(BMJ PUBLISHING GROUP, 2020-11)Background Tislelizumab, an anti-PD-1 monoclonal antibody, has demonstrated clinical benefit for patients with NSCLC. The underlying response and resistance mechanisms to tislelizumab treatment remain unknown. Methods Baseline tumor samples from 59 nonsquamous (NSQ) and 41 squamous (SQ) NSCLC patients treated with tislelizumab monotherapy (NCT02407990 and NCT04068519) were tested for gene mutations using large panel next generation sequencing and RNA expression using gene expression profiling (GEP; Precision Immuno-Oncology Panel, HTG Molecular Diagnostics). GEP analyses of NSQ and SQ NSCLC were performed separately due to different gene expression patterns. Results The ORR, mPFS, and mOS in this pooled NSCLC cohort were 15.2% (95% CI: 9.0, 23.6), 4.1 months (95% CI: 2.20, 6.11), and 15.1 months (95% CI: 11.20, NE), respectively, with a median study follow-up of 15.3 months (95% CI: 14.06, 15.90). Non-responders (NRs) exhibited distinct tumor and immune gene signature profiles and could be clustered into two subgroups: NR1 and NR2. Compared with responders, NR1 had elevated cell cycle signatures in both NSQ (P=0.2) and SQ (P=0.03) cohorts, and a trend of decreased inflamed gene signature profiles. However, NR2 showed comparable or even higher tumor inflammation (18-gene), and CD8+ T-cell signature scores in both NSQ and SQ cohorts and could be classified as immune hot. To explore the resistance mechanisms of immune hot NRs, differentially expressed gene analyses between immune hot NR2 and responders were performed. M2 macrophage and Treg signature scores were higher in NR2 in both NSQ (M2, P=0.05; Treg, P=0.03) and SQ (M2, P=0.05 [subgroup of NR2]; Treg, P=0.03) cohorts; significantly higher expression of immune regulatory genes included PIK3CD, CCR2, CD244, IRAK3, and MAP4K1 (P<0.05) in NSQ and PIK3CD, CCR2, CD40, CD163, and MMP12 (P<0.05) in SQ. Significantly higher epithelial–mesenchymal transition (EMT) and angiogenesis gene expression, including SNAI1, FAP, VEGFC, and TEK (P<0.05) genes, were also observed in SQ NR2. Moreover, gene mutation analysis identified seven immune hot NR patients harboring either driver mutations (RET fusion, ROS1 fusion, BRAF, and PIK3CA amp) or well-established resistance mutations (loss of function mutation in JAK2, STK11, and MDM2 amplification). Conclusions Despite the presence of immune hot features, a subgroup of tislelizumab NRs with NSCLC were identified. High levels of immune suppressive factors, such as M2 macrophage and Treg signatures, angiogenesis, and EMT genes, as well as the existence of driver/resistance mutations, may indicate mechanisms of resistance of immune hot NRs, highlighting potential novel treatment targets. Acknowledgements Editorial assistance was provided by Agnieszka Laskowski, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago, IL), and funded by the study sponsor. Trial Registration NCT02407990 and NCT04068519
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ItemA PHASE II STUDY OF CONTINUOUS LOW DOSE PANOBINOSTAT IN PAEDIATRIC PATIENTS WITH MALIGNANT RHABDOID TUMORS/ATYPICAL TERATOID RHABDOID TUMORS(OXFORD UNIV PRESS INC, 2020-12)Abstract
BACKGROUND
Panobinostat treatment has been shown to terminally differentiate malignant rhabdoid tumor (MRT)/atypical teratoid rhabdoid tumors (ATRT) in pre-clinical models. This is an open label, phase II study of panobinostat in patients with newly diagnosed or relapsed MRT/ATRT. AIMS: To assess the anti-tumor activity of low dose, continuous panobinostat, its associated toxicities, the biological activity of low dose panobinostat by measuring histone acetylation status in peripheral mononuclear cells (PMNC), and markers of differentiation in fresh tumor tissue specimens.METHODS
Following cycles of induction and consolidation chemotherapy and/or radiation treatment, patients were enrolled and commenced on panobinostat as a continuous daily oral dose starting at 10mg/m2 following a three-week wash out period between therapies. Real-time acetylation status, measuring acetylated H4 on PMNC, was performed to determine the pharmacodynamics of panobinostat. Patients were monitored for drug toxicities with the possibility of dose reductions in decrements of 2mg/m2.RESULTS
Six patients with newly diagnosed ATRT/MRT and one patient with relapsed MRT have been enrolled to date. The average age at enrollment was 2.5 years. Currently, six patients (85.7%) remain on study with a mean treatment duration of 170 days (range 44–327 days). One patient was removed from study at day 44 due to disease progression. The main dose-limiting toxicity observed to date has been myelosuppression. Panobinostat, at a dose of 10mg/m2, caused significant acetylation of H4 in PMNC.CONCLUSIONS
Treatment with panobinostat appears to be well tolerated in infants with MRT/ATRT, with successful real-time pharmacodynamic assessment of H4 acetylation.