Supplementary Figure 1. Differential expression analysis based on per-pixel adavosertib mass spectrometry imaging drug distribution (p-value = 0.115, t-test). Boxplot show the median, 25% and 75% quantiles.

Abstract Purpose: Adavosertib is an oral small-molecule inhibitor of Wee1. The Adult Brain Tumor Consortium conducted a phase I study evaluating adavosertib in combination with radiation (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM), as well as a surgical window-of-opportunity study in recurrent GBM. Patients and Methods: The MTD of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in two separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in patients with recurrent GBM undergoing surgery. Results: As separate cohorts, the MTD for concurrent adavosertib with RT/TMZ was 200 mg daily Monday through Friday × 6 weeks during RT, and the MTD for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, six of 12 patients experienced dose-limiting toxicities (DLT) in the combination cohort. The mean ratios of the intratumoral to plasma concentration of adavosertib were 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in nonenhancing tissue. Conclusions: Adavosertib at 200 mg daily Monday through Friday × 6 weeks with RT/TMZ and at 425 mg daily on a 5-day/28-day cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLT, and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5-day/28-day cycle with adjuvant TMZ is the recommended phase II dosage. Tissue pharmacokinetics in tissue homogenates and by microdialysis provided complementary information about drug penetration.

Supplementary Table 2. Estimated Pharmacokinetic values for AZD 1775.

Supplemental tables with the number of patients treated with number of cycles and the incidence of DLTs.

Supplementary Figure S2ABCDE from Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

Representative image of complete response after treatment with pelabresib.

CONSORT diagram of patient disposition throughout study

Supplementary Figures Legends 1-5, Table 1 from Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

Supplementary Figure S3AB from Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

Supplementary Figure S4ABC from Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

PK/PD Analysis of the Relationship Between Maximum Relative Change in Gene Expression and Pelabresib Exposure Metrics.

Supplementary Figure S5ABC from Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

PDGFRA has been shown to be commonly altered in high-grade gliomas (HGGs), including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analysis of 260 high-grade glioma cases, which revealed PDGFRA genomic alterations (mutations and/or amplifications) in 13% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors, and PDGFRA gene amplification resulted in even higher expression levels in H3K27M DMGs as well as H3 wild-type HGGs. We tested a panel of patient- derived pHGG/H3K27M DMG models against a range of PDGFRA inhibitors, including avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA. Avapritinib showed supra-micromolar blood-brain barrier penetration in our pre-clinical models and demonstrated significant survival impact in an aggressive patient-derived H3K27M DMG mouse xenograft model. Finally, building on this preclinical activity, we report here the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib has thus far been well tolerated with no significant acute toxicities. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib is a selective, CNS-penetrant small molecule inhibitor of PDGFRA that shows potent activity in preclinical models and produces promising clinical responses with good tolerability in patients with high-grade glioma. This suggests a promising role for avapritinib therapy in this population with previously dismal outcomes. Citation Format: Lisa Mayr, Maria Trissal, Kallen Schwark, Jenna Labelle, Andrew Groves, Julia Furtner-Srajer, Jeffrey Supko, Liesa Weiler-Wichtl, Olivia Hack, Jacob Rozowsky, Joana G. Marques, Eshini Pandatharatna, Ulrike Leiss, Verena Rosenmayr, Frank Dubois, Noah F. Greenwald, Sibylle Madlener, Armin S. Guntner, Hana Pálová, Natalia Stepien, Daniela Lötsch-Gojo, Christian Dorfer, Karin Dieckmann, Andreas Peyrl, Amedeo A. Azizi, Alicia Baumgartner, Ondřej Slabý, Petra Pokorná, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stücklin, Sabine Mueller, David T. Jones, Natalie Jäger, Jaroslav Štěrba, Leonhard Müllauer, Christine Haberler, Chandan Kumar-Sinha, Arul Chinnaiyan, Rajen Mody, Mary Skrypek, Nina Martinez, Daniel C. Bowers, Carl Koschmann, Johannes Gojo, Mariella Filbin. Clinical response to the PDGFRα inhibitor avapritinib in high-grade glioma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5719.

PDF file - 41K, Pharmacokinetic parameters of vorinostat and its major metabolites.

PDF file 196K, The Data Supplement contains Supplementary Tables 1-3, which provide additional detail about the clinical trial as well as Supplementary Methods and References

PDF file - 39K, Response by schedule and diagnosis.

PDF file - 42K, Alvocidib pharmacokinetic parameters.

PDF file, 19K, Line graph representing the mean change in eGFR for nine patients that received bardoxolone methyl treatment for at least six cycles. Error bars represent the SEM.

Supp. Fig.1. CONSORT Flow Diagram Supp. Fig.2. MRI Perfusion Parameters Supp. Fig. 3. Immunohistochemistry Supp. Fig. 4. Gene Expression Profile Supp. Table 1. Adverse Events Supp. Table 2. Pharmacokinetic Data Supp. Table 3. Molar Drug Levels Supplemental Methods