Search

Supplementary Data from CpG Oligodeoxynucleotides Alter Lymphocyte and Dendritic Cell Trafficking in Humans

Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma.Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib.Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified.Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.

Purpose: CpG oligodeoxynucleotides (CpG-ODN) are being investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (PDC) into potent antigen-presenting cells. CpG-ODN also induce PDC to secrete chemokines that alter lymphocyte migration. Whether CpG-ODN TLR signals enhance antigen-specific immunity and/or trafficking in humans is unknown.Experimental Design: We conducted a phase I study of CpG-ODN (1018 ISS) given as a vaccine adjuvant with granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce T-cell immunity to a peptide vaccine from the tumor-associated antigen hTERT.Results: The adjuvant effect was limited; only 1 of 16 patients showed a high-frequency hTERT-specific tetramer CD8+ T-cell response. However, CpG-ODN induced marked, transient peripheral blood lymphopenia. Biopsies showed dense lymphocytic infiltration at the vaccine site clustered around activated PDC. In vitro, CpG-ODN-treated PDC induced T-cell migration, showing that CpG-ODN stimulation of human PDC was sufficient to chemoattract T cells.Conclusions: Our results show that (a) CpG-ODN with GM-CSF may not be an effective adjuvant strategy for hTERT peptide vaccines but (b) GM-CSF/CpG-ODN causes a PDC-mediated chemokine response that recruits T-cell migration to the peripheral tissues. These findings suggest a novel therapeutic role for targeted injections of CpG-ODN to direct lymphocyte migration to specific sites such as the tumor bed.

Supplementary Table Legend from Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01

Supplementary Table 1 from Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01

Background: The epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in many cancers, including glioblastoma (GBM) and non-small cell lung cancer (NSCLC). EGFR tyrosine kinase activity driven by common EGFR mutations can be inhibited by small molecules, however, resistance to available agents may be driven by mutations in the EGFR active kinase site or other regions. BDTX-1535 is an orally available, highly potent, selective, irreversible inhibitor of EGFR mutations, including extracellular variants and amplifications commonly expressed in GBM and inhibits the uncommon EGFR mutations found in NSCLC, including the C797S mutation acquired following 3rd generation EGFR inhibitor therapy. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Preclinical studies suggest that BDTX-1535 has potential to be clinically active in suppressing tumor growth in patients with GBM and NSCLC with or without CNS metastases, including a potential survival benefit. Methods: BDTX-1535-101 (NCT05256290) is Phase 1, open-label, multicenter study to assess the safety, tolerability, PK, CNS penetrance, and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. The Monotherapy Dose Escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease. Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy. Once a provisional recommended Phase 2 dose (RP2D) has been established, BDTX-1535 monotherapy will be explored in the following Dose Expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy; 3) NSCLC with acquired EGFR resistance mutation following a 3rd generation EGFR inhibitor in 1L setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants. Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023. For additional information, please contact BDTX_1535_101_Study@bdtx.com Citation Format: Melissa Johnson, Jason Henry, Alex Spira, James Battiste, Iyad Alnahhas, Manmeet Ahluwalia, Minal Barve, Jeffrey Edenfield, DoHyun Nam, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Helena Yu, Patrick Wen. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT127.

Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.

Purpose: Anaplastic Lymphoma Kinase (ALK) aberrations have been identified in pediatric type infant gliomas, but their occurrence across age groups, functional effects, and treatment response have not been broadly established. Experimental Design: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly-generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric and 10 congenital) with in vitro and in vivo validation of aberrations. Results: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs, and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages and no gross effects on perinatal brain development was seen in pregnant mice treated with the ALK inhibitor ceritinib. Conclusions: These findings support expanded evaluation of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. Citation Format: Anne-Florence Blandin, Ross Giglio, Maya Srikanth Graham, Guadalupe Garcia, Seth Malinowski, Jared K. Woods, Shakti Ramkissoon, Lori Ramkissoon, Frank Dubois, Kate Schoolcraft, Jessica W. Tsai, Dayle K. Wang, Robert Jones, Jayne Vogelzang, Kristine Pelton, Sarah Becker, Fiona Watkinson, Claire Sinai, Elizabeth Cohen, Matthew Booker, Michael Tolstorukov, Veerle Haemels, Liliana Goumnerova, Karen Wright, Mark Kieran, Katie Fehnel, David Reardon, Arnault Tauziede-Espariat, Rishi Lulla, Benjamin Carcamo, Stanley Chaleff, Alain Charest, Frederik De Smet, Azra H. Ligon, Adrian Dubuc, Melanie Pagès, Pascale Varlet, Patrick Wen, Brian Alexander, Susan Chi, Sanda Alexandrescu, Ralf Kittler, Robert Bachoo, Rameen Beroukhim, Pratiti Bandopadhayay, Keith L. Ligon. ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma [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 1201.

The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.

O manejo de tumores cerebrais avançados ou recidivantes requer uma cooperação e um trabalho conjunto de uma equipe multidisciplinar. Não há um consenso sobre a jornada de tratamento dos tumores cerebrais recorrentes ou progressivos, e as opções terapêuticas existentes são limitadas. Neste capítulo, abordamos as descobertas mais recentes no perfil molecular dos tumores do SNC e nos estudos que vêm explorando esses avanços.

The following questions and recommendations are pertinent to the following:Target PopulationThese recommendations apply to adults with progressive GBM who have undergone standard primary treatment with surgery and/or chemoradiation.Question 1In adults with progressive glioblastoma is the use of bevacizumab as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationLevel III: Treatment with bevacizumab is suggested in the treatment of progressive GBM, as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months, while not providing evidence for improvement in overall survival. Question 2In adults with progressive glioblastoma is the use of bevacizumab as combination therapy with cytotoxic agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationLevel III: There is insufficient evidence to show benefit or harm of bevacizumab in combination with cytotoxic therapies in progressive glioblastoma due to a lack of evidence supporting a clearly defined benefit without significant toxicity.Question 3In adults with progressive glioblastoma is the use of bevacizumab as a combination therapy with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 4In adults with progressive glioblastoma is the use of targeted agents as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.Question 5In adults with progressive glioblastoma is the use of targeted agents in combination with cytotoxic therapies superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 6In adults with progressive glioblastoma is the use of immunotherapy monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.Question 7In adults with progressive glioblastoma is the use of immunotherapy in combination with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?Recommendation There is insufficient evidence to support a recommendation regarding this question.Question 8In adults with progressive glioblastoma is the use of immunotherapy in combination with bevacizumab superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival?RecommendationThere is insufficient evidence to support a recommendation regarding this question.

These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). QUESTION (Q1): In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy?Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5 months of TMZ-treatment free interval.Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. QUESTION (Q2): In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy?Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. QUESTION (Q3): In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy?Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM.Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. QUESTION (Q4): In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy?Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. QUESTION (Q5): In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy?Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

BACKGROUND Astrocytomas are a subset of diffuse gliomas defined by intact 1p and 19q arms. Isocitrate dehydrogenase 1 mutations (mIDH-1) occur in ~70% of grade 2/3 gliomas, leading to accumulation of 2-hydroxyglutarate (2-HG). Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mIDH1/2 enzymes being investigated in a phase 3 study in non-enhancing gliomas. In an ongoing perioperative study in grade 2/3 gliomas, treatment with VOR was associated with interferon (IFN) signaling activation and increased T-cell infiltration, suggesting adequate 2-HG suppression renders the tumor immune microenvironment for immune checkpoint blockade, and supporting investigation of VOR in combination with an anti-programmed cell death (PD-1) antibody such as pembrolizumab in recurrent IDH-mutant gliomas treatment. This study will evaluate the safety and tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) of VOR, and evaluate CD3+ T-cell infiltration in tumors following preoperative treatment with the combination or VOR. METHODS This study will enroll ~70 patients with recurrent or progressive Grade 2/3 mIDH-1 astrocytoma. Key eligibility: enhancing disease, mIDH1-R132H, Karnofsky Performance Status ≥70, eligible for resection (perioperative phase only). Safety lead-in: Cohort 1 (Nf~6): VOR 40 mg QD plus pembrolizumab 200 mg Q3W in 21-day cycles. Based on DLT evaluation, cohort 2 may enroll an additional ~6 patients at VOR 20 mg QD plus pembrolizumab 200 mg Q3W. Randomized, perioperative phase (Nf~60): randomized 1:1:1 to the combination, VOR 40 mg QD, or untreated for 4 weeks preoperatively; all patients can opt to receive the combination postoperatively. Primary objectives: safety and tolerability, and VOR RCD with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with the combination compared to untreated tumors. Secondary objectives include clinical activity, VOR PK in tumor and blood, 2-HG concentration in tumors, and overall survival. This study will be active in the United States.

BACKGROUND H3 K27M-mutant DMG predominantly affects children and young adults; no effective therapy is known. ONC201 is a first-in-class, anti-cancer DRD2 antagonist and ClpP agonist. METHODS Fifty pediatric and adult patients with recurrent H3 K27M DMG who received oral ONC201 monotherapy in clinical trials and expanded access were selected for a planned efficacy analysis. Eligibility criteria included measurable contrast-enhancing disease by RANO-HGG criteria (excluding pontine and spinal cord tumors), KPS/LPS≥60, ≥90 days from prior radiation, and adequate washout from prior anti-cancer therapy. The primary endpoint was overall response rate (ORR) by RANO-HGG criteria. Secondary endpoints included duration of response, time to response, progression-free survival (PFS), overall survival (OS), corticosteroid response rate, performance status response rate, and ORR by RANO-LGG criteria. Radiographic endpoints were assessed by dual-reader blinded independent central review. Data cutoff was May 31, 2021. RESULTS ORR was 20.0% (95%CI, 10.0–33.7) by RANO-HGG criteria. Median duration of response was 11.2 months (95%CI, 3.8–not reached) and median time to response was 8.3 months (range, 1.9–15.9). PFS at 6 months was 35.1% (95%CI, 21.2–49.3). The ORR was 26.0% (95%CI, 14.6–40.3) by RANO-LGG criteria. Fifteen patients (30.0%; 95%CI, 17.9–44.6) achieved an objective response by RANO-HGG and/or RANO-LGG criteria. Of 15 patients receiving ≥4 mg daily dexamethasone at baseline, 7 (46.7%; 95%CI, 21.3–73.4) achieved ≥50% confirmed reduction in dose. Of 34 patients with baseline KPS/LPS CONCLUSIONS ONC201 monotherapy exhibits durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Patients with diffuse midline glioma (DMG) harboring H3 K27M mutation have no proven therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has induced early responses in patients with H3 K27M-mutant DMG. We performed an integrated pre-clinical and clinical assessment of ONC201 treatment, in order to define response rates in H3 K27M-mutant DMG patients and to clarify predictors of response. ONC201 was effective in murine H3 K27M-mutant gliomas with excellent CNS penetration and survival benefit. H3 K27M-mutant DMG patients treated with ONC201 on active clinical trials (n=50) showed significant survival benefit in recurrent and non-recurrent settings, with multiple sustained responses. Tumor sequencing from treated patients demonstrates an EGFR/FOXG1-driven telencephalic gene regulatory network that imparts a critical resistance phenotype to ONC201. Genetic and pharmacologic knockdown of EGFR in H3 K27M-mutant cell cultures results in improved sensitivity to ONC201 and reduced FOXG1 enhancer binding, suggesting possible future combinatorial opportunities.

Raman spectroscopy has long been considered a gold standard for optically based chemical identification, but has not been adopted in non-laboratory operational settings due to limited sensitivity and slow acquisition times. Ultraviolet (UV) Raman spectroscopy has the potential to address these challenges through the reduction of fluorescence from background materials and increased Raman scattering due to the shorter wavelength (relative to visible or near-infrared excitation) and resonant enhancement effects. However, the benefits of UV Raman must be evaluated against specific operational situations: the actual realized fluorescence reduction and Raman enhancement depend on the specific target materials, target morphology, and operational constraints. In this paper, the wavelength trade-space in UV Raman spectroscopy is evaluated for one specific application: checkpoint screening for trace explosive residues. The optimal UV wavelength is evaluated at 244, 266, and 355 nm for realistic trace explosive and explosive-related compound (ERC) residues on common checkpoint materials: we perform semi-empirical analysis that includes the UV penetration depth of common explosive and ERCs, realistic explosive and ERC residue particle sizes, and the fluorescence signal of common checkpoint materials. We find that while generally lower UV wavelength provides superior performance, the benefits may be significantly reduced depending on the specific explosive and substrate. Further, logistical requirements (size, weight, power, and cost) likely limit the adoption of optimal wavelengths. Graphical abstract.

BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

BACKGROUND H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti- cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. METHODS We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). RESULTS Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. CONCLUSIONS These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.

This chapter takes a long view of the dynamic role played by the image of Carin Fock-Goering within the Nazi imagination before, during and after the Third Reich. Exploring and interrogating various constructions of imagined Swedishness and Aryanness within the Nazi propaganda machine, the chapter sheds light on the problematic, multivalent, mythologizing discourses surrounding the creation of the Fock “legend.” Her public image first functions as a paragon of total fealty to the Fuehrer and as a quasi-First Lady of the regime in the absence of a Mrs. Hitler. Fock’s curious posthumous legacy as an elevated and almost saintly ideal of womanhood within the Reich reveals much about how Sweden and Swedishness were imagined by the Third Reich. The postwar trajectory of the Fock “legend” signals a more overt expression of Sontag’s notion of “fascinating fascism” as seen through the macabre and highly fetishized fascination with and itinerary of her remains.

BACKGROUND: The outcome for glioblastoma (GBM) remains dismal with a median survival of 15 months. Vascular endothelial growth factor (VEGF) is a highly upregulated proangiogenic growth factor in GBM that contributes to tumor-associated immunosuppression by inhibition of dendritic cell maturation and antigen presentation, induction of apoptosis of CD8+ T cells and enhancing Treg activity. Hence, a combination of anti PD1 and anti VEGF is promising approach in recurrent GBM. Lower anti-VEGF therapy dosing can lead to enhanced immune infiltrate and improved survival following co-administration with an anti-tumor immunotherapeutic in preclinical studies. METHODS: This is a 90 patient randomized phase 2 open label study of nivolumab plus standard dose bevacizumab versus nivolumab plus low dose bevacizumab in recurrent GBM. Primary endpoint is to evaluate the efficacy of nivolumab when administered with standard and reduced dose bevacizumab as measured by overall survival (OS) at twelve months (OS-12). Secondary endpoint include safety, Progression free survival at 6 months, OS and overall response rate. Exploratory endpoints include circulating immunologic biomarkers, cytokines, archival tumor PD-L1 expression and inflammatory gene expression signature and perfusion and diffusion weighted imaging with response (RANO and iRANO). Eligibility Criteria include Age ≥ 18 years, first recurrence of GBM, normal organ function, KPS ≥ 70. Key exclusion criteria include active, known or suspected autoimmune disease, contraindications for bevacizumab therapy and decadron > 4 mg/ day or equivalent of steroids. STATISTICAL ANALYSIS: The one-sample log-rank test will be applied to outcomes observed for each arm individually to test the hypothesis that OS has been improved beyond the null 12-month survival rate of 45%. With N=45 patients per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 12-months following treatment at the 0.10 significance level. RESULTS: The study (NCT03452579) is ongoing and enrolling GBM patients in first recurrence.

BACKGROUND: Approximately 9%-18% of LGGs possess BRAF V600E mutations. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma, lung cancer, and anaplastic thyroid cancer. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) was evaluated as treatment for patients with recurrent/refractory BRAF V600E–mutated LGG. METHODS: In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including LGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the LGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 1 or 2 glioma that was refractory to standard-of-care therapies. The primary endpoint was investigator-assessed overall response rate (ORR) by RANO criteria. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Nine patients with LGG had enrolled at data cutoff (3 January 2018). Eight of 9 patients were evaluable for response. Median age was 33 years. Eight of 9 patients had received prior surgery. Investigator-assessed confirmed ORR was 50% (4/8; 95% CI, 16%-84%), with 3 of 4 responses ongoing at data cutoff. Two of 4 patients had a DOR of ≥ 18 months. The PFS and OS Kaplan-Meier estimates at 18 months were 50% (95% CI, 15%-78%) and 86% (95% CI, 33%-98%), respectively. Adverse events (AEs) in patients with LGG included fatigue (67%), headache (67%), arthralgia, nausea, and pyrexia (56% each). Grade 3/4 AEs included fatigue (22%), arthralgia, headache, and diarrhea (11% each). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with recurrent/refractory BRAF V600E-mutated LGG, with manageable AEs and no new safety signals

Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.

The scandalous Parker/Hulme murder case that rippled through New Zealand's mass media in 1954 garnered a new-found interest from an even wider audience after the release of Peter Jackson's 1994 fil...

Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 occur in a spectrum of solid and hematologic malignancies. Mutant IDH1/2 in cancer cells results in the neomorphic production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which impairs cellular differentiation via an epigenetic mechanism. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, phase 1, open-label, single-arm study of AG-120 (NCT02073994). Aims: Key objectives are to evaluate the safety, tolerability, and maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity. Key exploratory objectives include an analysis of tumor tissue samples in non-glioma subjects and magnetic resonance imagining/spectroscopy (MRI/MRS) in glioma subjects, pre and on AG-120 treatment. Methods: Patients with advanced, IDH1-mutant solid tumors, including glioma, who have recurred or progressed following standard therapy, or who have not responded to standard therapy, are eligible to receive continuous, single-agent, oral AG-120 dosed daily in 28-day cycles. Informed consent is obtained prior to entry. Sequential dose cohorts are being enrolled, with expansion cohorts planned. Blood and tumor biopsies are collected for PK/PD assessment. Objective responses are investigator assessed using either RECIST or RANO criteria for subjects with solid tumors and gliomas, respectively. Results: As of 1 July 2015, 55 patients (glioma: 20, non-glioma: 35) were treated with AG-120. Median age was 54 years (range, 23-88) and median number of prior systemic regimens 3 (range, 1-6). Doses administered were 100 mg BID (n = 4), 300 mg QD (n = 9), 400 mg QD (n = 5), 500 mg QD (n = 17), 600 mg QD (n = 5), 800 mg QD (n = 6), 900 mg QD (n = 4), and 1200 mg QD (n = 5). Median treatment duration was 1.9 months (range, 0.1-12.5). The MTD was not reached. PK analyses showed high plasma exposure and drug accumulation following oral administration and a mean half-life of 73.1 ± 66.6 hr. Overall, treatment was well tolerated: 49 patients experienced treatment-emergent adverse events (AEs), regardless of causality. Most frequently occurring AEs (%) were nausea (21.8), diarrhea (16.4), vomiting (14.5), anemia (12.7), and abdominal pain (10.9). There were no treatment-related serious AEs. Summary/Conclusion: AG-120 is a first-in-class, oral, potent, selective inhibitor of mutant IDH1 in development for solid and liquid tumors. Updated safety and clinical activity, as well as exploratory PD analyses will be presented. Future development plans for AG-120 in solid tumors will also be highlighted. Citation Format: Howard Burris, Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Murali Beeram, Mehdi Touat, Jason Faris, Nilofer Azad, Timothy Cloughesy, Lia Gore, Jonathan Trent, Daniel Von Hoff, Meredith Goldwasser, Bin Fan, Sam Agresta. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-05.

BACKGROUND: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated for patients with recurrent Glioblastoma (rGBM) in this phase 1-2 dose-escalation study. METHODS: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 1x1013 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013 every 2 months. The protocol was amended to add-on BEV 10mg/Kg every 2 weeks upon further progression. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). RESULTS: Forty-six patients at 4 recruiting medical centers in the US and Israel received up to 13 repeat doses of VB-111. Of these 30 received the high dose (1x1013). There were 22 related adverse events, 19 CTCAE grade 1-2. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one high dose vs. subjects who received lower doses, respectively (p NS). Progression free survival was 63 vs. 55 days for patients who received high vs. lower doses, respectively (p = 0.01). Median follow-up was 232 days. Six patients had a partial response and/or prolonged disease stability (≥180 days). Tumor growth rates showed a statistically significant dose response. Eleven patients received combination therapy of VB-111 with BEV after progression on VB-111 alone. Median time to second progression was 93 days. VB-111 was safe and well tolerated both as monotherapy and combined therapy. CONCLUSIONS: VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with recurrent glioblastoma. Encouraging tumor growth attenuation and responses were seen. Overall survival was about 3 months longer than historical rGBM data.