bluuebunny/crossref_metadata_2025 huggingface dataset:
Fragility index of trials supporting approval of anti-cancer drugs in common solid tumors.
Authors: Desnoyers Alexandra , Nadler Michelle , Saleh Ramy , Amir Eitan
Published: May 2020

2055

Background: The Fragility Index (FI) quantifies the reliability of positive trials by estimating the number of events which would change statistically significant results to non-significant results. Here, we calculate the FI of trials supporting approval of drugs for common solid tumors. Methods: We searched Drugs@FDA to identify randomized trials (RCT) supporting drug approvals by the US Food and Drug Administration between January 2009 and December 2019 in lung, breast, prostate, gastric and colon cancers. We adapted the FI framework (Walsh et al. J Clin Epidemiol 2014) to allow use of time to event data. First, we reconstructed survival tables from reported data using the Parmar Toolkit (Parmar et al. Stat Med 1998) and then calculated the number of events which would result in a non-significant effect for the primary endpoint of each trial. The FI was then compared quantitatively to the number of patients in each trial who withdrew consent or were lost to follow-up. Multivariable linear regression was used to explore association between RCT characteristics and the FI. Results: We identified 69 RCT with a median of 669 patients (range 123-4804) and 358 primary outcome events (range 56-884). The median FI was 26 (range 1-322). The FI was ≤10 in 21 trials (30%) and ≤20 in 31 trials (45%). Among the 69 RCT, the median number of patients who withdrew consent or were lost to follow up was 27 (range, 6-317). The number of patients who withdrew consent or were lost to follow-up was equal or greater than the FI in 42 trials (61%). There was statistically significant inverse association between FI and trial hazard ratio (p0,001) and a positive association with number of patients who were lost to follow-up or withdrew consent (p0,001). There was no association between trial sample size, year of approval or reported p-value and the FI. Conclusions: Statistical significance of trials supporting drug approval in common solid tumors relies often on a small number of events. In most trials the FI was lower than the number of patients lost to follow up or withdrawing consent. Post-approval randomized trials or real-world data analyses should be performed to ensure that effects observed in registration trials are robust.
Performance status restriction in phase III cancer clinical trials.
Authors: Kouzy Ramez , Abi Jaoude Joseph , Mainwaring Walker , Lin Timothy , Miller Austin B. , Jethanandani Amit , Espinoza Andres F. , Taniguchi Cullen M. , Ludmir Ethan B.
Published: May 2020

2059

Background: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We sought to characterize trial-related factors associated with the use of eligibility criteria that restrict patients by PS, and analyze patient accrual breakdown by PS. Methods: We searched ClinicalTrials.gov for phase III RCTs between 2003-2018. Randomized multi-arm trials assessing a therapeutic intervention in cancer patients were included. PS data were extracted from corresponding manuscripts. Trials with PS restriction Eastern Cooperative Oncology Group (ECOG) ≤1 were identified. Factors associated with PS restriction were determined, and trial patient accrual was analyzed. Results: Six-hundred trials were included with PS data for 238,213 patients. In total, 527 studies (87.8%) specified an upper PS restriction cutoff as part of their exclusion criteria, and 237 studies (39.5%) had a strict inclusion criterion of patients with ECOG PS ≤1. Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P< 0.001) and lung cancer trials (P < 0.001). Nearly half of trials that led to subsequent FDA approval included strict PS restrictions. Binary logistic regression revealed stable use of restrictive PS eligibility criteria between 2007-2018 (P= 0.789). The vast majority of patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of enrolled patients had a poor PS (ECOG 2 or higher).Trials of hematologic cancers had the largest proportion of patients with ECOG PS ≥2 (8.7%), while lung, breast, gastrointestinal and genitourinary trials all included less than 5% of patients with poor PS (P< 0.001). Only 4.8% of patients enrolled in trials that led to subsequent FDA approval had a poor PS. Conclusions: The use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring, to ensure generalizability of results, while maintaining patient safety.
Mobile apps: Breaking barriers to early cancer detection in underserved communities.
Authors: Munoz-Zuluaga Carlos A. , Gallo-Perez José David , Perez-Bustos Andres , Orozco-Urdaneta Mavalynne , Druffel Karen , Cordoba-Astudillo Lida Patricia , Parra Lara Luis Gabriel , Velez Carolina , El-Sharkawy Farah , Zambrano-Vera Katherin , Erazo Raul Hernando , King Mary Caitlin , Sardi Armando
Published: May 2020

2065

Background: Despite being potentially curable with early detection and timely treatment, breast (BC) and cervical cancers (CC) remain leading causes of death for Colombian women. Lack of cancer screening education, tedious administrative processes, and geographical limitations hinder early cancer detection. Today, technological tools permeate all levels of society and could gather data for user risk stratification, deliver clear and customized information, and help with care coordination, tracking, and addressing communication, transportation, and financial barriers. We aimed to assess the effectiveness of a free mobile application (mApp) to reach women, understand misconceptions about cancer screening, identify users at risk for BC and CC, and coordinate screening tests in Cali, Colombia. Methods: The mApp, Ámate, was developed over 4 months and advertised to women (≥14 years) in waiting rooms of 4 healthcare facilities in Cali, Colombia for 23 months. Ámate used educational, evaluative, and risk factor questions followed by brief explanations to assess the population’s knowledge, educate users on BC and CC, and identify users in need of BC and/or CC screenings. Correct answers yielded points redeemable for cellular data. Women who required screening were subsequently navigated to a healthcare provider and enrolled in the national cancer program. Results: From August 2017-August 2019, 1,043 women from Cali downloaded Ámate and answered all questions. Misconceptions about BC included beliefs that BC can be prevented (87%), obesity does not increase the risk of BC (49%), deodorant causes BC (17%), and only women with a relative with BC can get BC (16%). For CC, misconceptions included that pap smears should not be performed while sexually active (64%), vaginal pain is an early sign of CC (44%), and only women contract HPV (33%). Overall, 31.5% (329) were identified as at-risk and needed a mammogram and/or pap smear. So far, 30% (98) were successfully navigated and completed their recommended screening test(s). Barriers to enrollment in these programs included patient unwillingness, using fake contact information, limited available appointments, and denied access due to healthcare coverage. Conclusions: Ámate is an accessible tool that identifies women at-risk for breast and cervical cancer and detects barriers to early cancer detection. Administrative obstacles exist and must be addressed to improve early cancer detection/screening. Ámate is currently being tested in other areas of Colombia and may be useful in other underserved countries.
4-miRNA signature combined with MGMT methylation status in glioblastoma: A multicentric retrospective biomarker analysis with accompanying prospective cohort study.
Authors: Niyazi Maximilian , Fleischmann Daniel F , Reifenberger Guido , Herms Jochen , Tonn Joerg , Belka Claus , Unger Kristian
Published: May 2020

2517

Background: Previously, we identified a prognostic 4-miRNA signature (built from let-7a-5p, let-7b-5p, miR-125a-5p and miR-615-5p) in glioblastoma patients treated according to the EORTC26981/22981-NCIC CE3 protocol. We present results of a novel external validation and will report on a completed prospective study on blood plasma samples of glioblastoma patients prior to chemoradiotherapy (CRT). Methods: The external validation cohort (n = 103) contained IDH1/2 wildtype tumors with known MGMT promoter methylation from the LMU-Munich (n = 37), the University Hospital Düsseldorf (n = 33) and TCGA (n = 33). Risk groups from the combination of miRNA signature with MGMT promoter methylation were analyzed for overall survival (OS) and prognostic performance using C-index. Within the prospective study (n = 52), blood samples were taken prior to RT, on d42 and d84 (22 cases analyzed up to now). Risk scores were obtained from signature miRNA expression levels in resection or biopsy specimen (retrospective, endpoint OS) and blood plasma (prospective, PFS). Results: The 4-miRNA signature was independent of sex and MGMT promoter methylation (p > 0.1) and defined high-risk (n = 47, med. OS: 16.4months) and low-risk (n = 56, med. OS: 26.9months) patients (HR: 2.08, 95%CI: 1.25-3.46, p = 0.004). Patients with methylated (med. OS: 23.7months, n = 54) compared to non-methylated MGMT promoter (med. OS: 16.8months, n = 49) had superior OS (p = 0.007, HR: 0.48, 95%-CI: 0.28-0.82). Combining the 4-miRNA signature and MGMT promoter methylation resulted in the signature-low-risk/ MGMT-promoter-methylated (med. OS: 37.4months), signature-low-risk/ MGMT-promoter-unmethylated (med. OS: 24.7months), signature-high-risk/ MGMT-promoter-methylated (med. OS: 16.4 months) and signature-high-risk/ MGMT-unmethylated groups (med. OS: 14.3months, Log-rank p = 0.002) with superior prediction performance. Conclusions: We confirmed the 4-miRNA signature as an independent prognosticator in IDH-wildtype glioblastoma while combination with MGMT promoter methylation outperformed other established prognostic factors. Our hypothesis is, that blood plasma samples will allow the risk stratification of glioblastoma patients before CRT. Phenotypic alterations driving its prognostic value remain to be determined and will allow for 1) risk stratified trials, 2) pathway analysis and targeting and 3) testing in healthy subjects to elucidate its screening potential.
The imaging substudy of the randomized ARTE trial: MRI and 18FET PET associations with overall survival benefit from bevacizumab in elderly patients with newly diagnosed IDH wildtype glioblastoma.
Authors: Wirsching Hans-Georg , Roelcke Ulrich , Weller Jonathan , Hundsberger Thomas , Hottinger Andreas Felix , Von Moos Roger Anton Fredy , Caparrotti Francesca , Conen Katrin Lisa , Remonda Luca , Roth Patrick , Ochsenbein Adrian , Tabatabai Ghazaleh , Weller Michael
Published: May 2020

2520

Background: Bevacizumab failed to demonstrate overall survival benefit despite markedly prolonged progression-free survival in glioblastoma patients. Reasons for this divergence may include suboptimal patient selection and delayed diagnosis of progression on MRI scans under bevacizumab. Imaging analyses of retrospective and uncontrolled clinical trial cohorts suggest MRI diffusion mapping as a predictor of benefit from bevacizumab. Moreover, amino acid PET has been proposed by the RANO working group for the differentiation of tumor versus edema or gliosis based on proof-of-principle studies demonstrating earlier detection of progression with PET compared to MRI. Methods: ARTE (NCT01443676) was a 2:1 randomized, multi-center, open-label trial of hypofractionated radiotherapy in combination with intravenous bevacizumab every 2 weeks (BEV/RT) versus RT alone in patients with newly diagnosed glioblastoma aged 65 years or older. Patients with histologically and molecularly confirmed IDH wildtype glioblastoma aged 65 years or older were analyzed. MRI was available from 67 and serial 18FET PET from 30 patients in this post hoc analysis. 18FET PET intensity ratios and herein reported MRI parameters including tumor volumetric analyses and ADC were analyzed blinded for outcome and study arm. Results: Demographic, clinical and molecular parameters were balanced between treatment arms. Overall survival benefit from bevacizumab was observed for larger contrast-enhancing tumor volumes (hazard ratio [HR] per cm3 0.94, 95% CI 0.89-0.99, p = 0.032) and higher ADC (HR 0.18, 95% CI 0.05-0.66, p = 0.025) on pre-treatment MRI. Response in the BEV/RT arm by the standard MRI-based RANO criteria was associated with overall survival by trend (HR 0.56, 95% CI 0.30-1.10, time-dependent p = 0.094). In a multivariate model controlling for established risk factors, 18FET tumor-to-brain uptake ratios (TBR) of non-contrast-enhancing tumor portions predicted inferior overall survival specifically in the BEV/RT arm (HR [per 0.1 18FET TBR] 1.50, 95% CI 1.05-2.13, time-dependent p = 0.025). Controlling for 18FET TBR at first follow-up identified benefit from BEV/RT by trend (HR 0.41, 95% CI 0.16-1.07, p = 0.069). Conclusions: Large contrast-enhancing tumor mass and high ADC identify patients with overall survival benefit from bevacizumab. Under bevacizumab, non-contrast enhancing tumor portions can be adequately monitored by amino acid PET.
Eradication of medulloblastoma by NKG2D-specific CAR T-cells.
Authors: Dai Hong-jiu , Sun Bin , Yang Dong , Xu Hui , Zhu Jingjing , Wei Jia , Zhao Xudong
Published: May 2020

2522

Background: Medulloblastoma (MB) is a cancerous malignant brain tumor, that most often occurs in young children. Standard-of-care therapies for treating pediatric MB have long-term side effects, even in children who are cured. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in brain tumor, yet the clinical outcome is limited. It's reported that NKG2D ligands are wildly expressed in MB cells, which supports NKG2D system might play an important role in MB therapy. Here, we take advantage of NKG2D-specific CAR-T cells (KD-025) for MB treatment. Methods: HTB186, HTB185 and HTB187 MB cell lines as well as MB cancer patient samples were evaluated for NKG2D ligands expression. The KD-025 showed antigen-specific stimulation by cytokine secretion and target cell lysis. HTB186 cells, which stably express luciferase protein, were used to establish in vivo subcutaneous and xenograft models in NSG mice. Mice received a single treatment of 10 million KD-025 intravenously. Results: NKG2D ligands were detected on HTB186 and HTB187 cells and most of screened BM patient samples. The KD-025 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-025 expression was > 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-025 with HTB186 cells specifically upregulates TNF-α, IFN-γ, IL-10 and IL-2 cytokines and strongly lysis tumor cells even at low E:T ratio (70-80% at 8:1). Strikingly, KD-025 markedly eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. Regarding to T cell persistence, the CAR-T cells are barely detectable 24 days after injection, which is comparable with CD19 CAR in our experiments as well as published data. No obvious pathological changes were found in the tested organs. Conclusions: Our work with the KD-025 contributes to the growing body of research committed to discovering a novel therapy for MB. NKG2D ligands are highly expressed on human MB samples. KD-025 potently respond to MB and eliminate tumor in a xenograft mouse model with no obvious safety issues. The results support future clinical trial of KD-025 in patients with MB, where the need for effective treatment is great.
Advanced imaging to assess longitudinal vascular changes in brain metastases treated with immune checkpoint inhibition.
Authors: Kim Albert Eusik , Chang Ken , Beers Andrew , Emblem Kyrre E. , Kalpathy-Cramer Jayashree , Lee Eudocia Quant , Lin Nancy U. , Nayak Lakshmi , Chukwueke Ugonma Nnenna , Oh Kevin S. , Shih Helen Alice , White Michael , Lawrence Donald P. , Moy Beverly , Cohen Justine Vanessa , Giobbie-Hurder Anita , Cahill Daniel P. , Sullivan Ryan J. , Brastianos Priscilla Kaliopi , Gerstner Elizabeth Robins
Published: May 2020

2529

Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) for melanoma and lung cancer. This breakthrough has prompted interest in evaluating ICI in BM of other histologies. However, accurately assessing intracranial response in patients undergoing ICI is a challenge, as current measures cannot distinguish pseudoprogression from true tumor progression. To shed light on potential biomarkers of response, we prospectively use perfusion MRI to identify characteristic vascular signatures in a BM-specific trial of ICI. Methods: As part of an ongoing phase II study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 53 patients have been enrolled, of whom 44 have received at least baseline advanced MR imaging. Histologies include 21 with breast cancer, 5 with non-small cell lung cancer, 4 with melanoma, and 13 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 33 evaluable patients include 4 PR, 10 SD, and 19 PD. On preliminary analysis, there was a correlation between increased tumor cerebral blood volume/flow with tumor progression. Correlation of additional vascular physiologic parameters (e.g. vessel caliber, tissue oxygenation) and volumetric response to patient outcome and standardized response criteria (iRANO) are ongoing. Conclusions: Pembrolizumab likely has anti-tumor efficacy in BM. Our data provides potential evidence that effective ICI is associated with a decrease in perfusion. Ongoing analyses to uncover additional vascular changes – specifically longitudinal metrics reflecting vascular structure and function - within BM to ICI are pending. These findings have potential to illustrate mechanisms of efficacy for ICI and biomarkers of response in this patient population.
Intra-operative radiation therapy as salvage treatment option for recurrent glioblastoma multiforme.
Authors: Salim Nidal , Krivoshapkin Alexey , Zvereva Daria , Gaytan Alexey , Abdullaev Orkhan , Sergeev Gleb , Marmazeev Ilya , Krotenkova Irina , Kiselev Roman , Semin Pavel
Published: May 2020

2535

Background: Glioblastoma multiforme (GBM) is an extremely aggressive cerebral tumor with poor prognosis. The majority of patients relapse after the initial surgery plus adjuvant radiation and chemotherapy. In case of recurrence there is no established standard therapy. The optimal techniques for salvage re-irradiation are unclear, so that procedure poses a challenge. In contrast to traditional external beam radiotherapy (EBRT) intra-operative radiotherapy (IORT) may improve patient’s outcome at the cost of minimal side effects and short treatment duration. Methods: A total of 30 patients were treated with recurrent GBM between August 2016 and June 2019. All patients underwent maximal safe resection; patients were divided into IORT and EBRT groups. 15 patients were included in each group with similar clinical characteristics. All patients in IORT group underwent maximal safe microsurgical resection with subsequent intraoperative balloon electronic brachytherapy (IBEB) and no further adjuvant treatment. IBEB was performed using Axxent electronic brachytherapy device (Xoft Electronic Brachytherapy (eBx) System, USA. Patients in EBRT group underwent same surgery followed by external beam radiotherapy. Contrast-enhanced brain MRI with perfusion was performed within 24 hours of surgery +/- brain PET-CT with 18-FDOPA and then every 3 months. Both groups were also assigned to subgroups (≤ 2.5cm3 and > 2.5cm3) based on post-operative contrast-enhancing volume (POCEV). Median overall survival (OS) since diagnosis and local progression-free survival (locPFS) following the second surgery were analyzed. Possible toxicities and prognostic factors were also evaluated. Results: Median OS was 27 months in IORT group and 21 months in EBRT group. The locPFS range between 3.5 to 39 months in IORT group and only 2 to 10 months in group with EBRT. Kaplan-Meier OS curves in patients with POCEV ≤ 2.5cm3 showed more favorable outcomes for patients in the IORT group (p < 0.05). In patients with POCEV > 2.5cm3 the median OS was 17 months in IORT group and 13.5 months in EBRT group. Conclusions: IORT of recurrent GBM is feasible and provides encouraging local progression-free and overall survival; no high-grade radiation induced toxicities occur and further studies to establish this method are mandatory. The toxicity profile of additional IBEB was manageable. Maximal safe microsurgical resection is the most important prognostic factor and could determine the effectiveness of post-surgical IBEB.
Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma.
Authors: Molaie Donna , Lai Albert , Ellingson Benjamin M. , Nguyen Thien , Bahng Hye Hyun , Filka Emese , Green Stacey , Pope Whitney B. , Leng Mei , Yong William H. , Green Richard M. , Polikoff Jonathan , Spier Liz , Iwamoto Fabio Massaiti , Lassman Andrew B. , Cloughesy Timothy Francis , Nghiemphu Phioanh Leia
Published: May 2020

2540

Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m2/day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .
MRI changes in patients with newly diagnosed glioblastoma treated as part of a phase II trial with bavituximab, radiation, and temozolomide.
Authors: Ly Ina , Cardona Jonathan , Lou Kevin , Beers Andrew , Chang Ken , Brown James , Reardon David A. , Arrillaga-Romany Isabel , Forst Deborah Anne , Jordan Justin T , Lee Eudocia Quant , Dietrich Jorg , Nayak Lakshmi , Wen Patrick Y. , Chukwueke Ugonma Nnenna , Batchelor Tracy , Curry William T. , Kalpathy-Cramer Jayashree , Gerstner Elizabeth Robins
Published: May 2020

2546

Background: Glioblastoma and tumor endothelial cells express phosphatidylserine (PS), a highly immunosuppressive membrane phospholipid. Bavituximab – a chimeric monoclonal antibody – binds to β2-glycoprotein 1 (β2-GP1) to form a complex of β2-GP1 with PS, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers demonstrated response rates up to 75% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of PS blockade, radiation, and temozolomide. Methods: 33 adult patients with IDH-wild-type, MGMT-methylated or -unmethylated newly diagnosed glioblastoma were enrolled in this phase II trial (NCT03139916) and received 6 weeks of chemoradiation, followed by 6 cycles of adjuvant temozolomide (C1-C6 aTMZ). Bavituximab (3 mg/kg) was given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs were performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood flow (rCBF) were measured. Median percent changes during treatment were compared to pre-treatment values. Results: Median progression-free survival (mPFS) was 8 months. Based on a median overall survival (mOS) of 17.1 months, patients were categorized into above-median survivors (AMS) and below-median survivors (BMS). All patients had pre-treatment scans. 31 had evaluable pre-C1, 25 had pre-C3, and 7 had pre-C5 scans. Compared to BMS, AMS had a greater reuction in enhancing tumor volume and rCBF, and a greater increase in Ktrans during treatment (table). One patient remains on study; 23 patients have died. Bavituximab was well tolerated. Conclusions: mPFS and mOS in patients treated with bavituximab, radiation and temozolomide were comparable to standard chemoradiation and aTMZ. Lower rCBF in AMS may reflect decreased tumor perfusion while higher Ktrans could imply enhanced drug delivery to the tumor. Bavituximab induces changes in tumor vasculature that may improve survival in a subset of patients. Clinical trial information: NCT03139916 . [Table: see text]
Association of peripheral blood CD4+ T-cell depletion under temozolomide with inferior survival of patients with IDH wildtype glioblastoma.
Authors: Weller Michael , Terksikh Ekaterina , Silginer Manuela , Krieg Carsten , Roth Patrick , Becher Burkhard , Wirsching Hans-Georg
Published: May 2020

2548

Background: Standard first line chemoirradiation with temozolomide is associated with distinctive peripheral blood immune cell profiles in IDH wildtype glioblastoma. Whether such profiles at recurrence are associated with survival has not been studied in detail. Methods: Peripheral blood mononuclear cells of 21 healthy donors and of 91 patients with IDH wildtype glioblastoma were analyzed by flow cytometry at 1st recurrence. Patients received either (i) standard chemoirradiation with temozolomide (TMZ) followed by dose-intensified TMZ at first recurrence within the phase II trial DIRECTOR (N = 52) or (ii) hypofractionated radiotherapy with or without bevacizumab (N = 39) followed by investigators’ choice within the phase II trial ARTE. Patients were classified based on unsupervised analyses of PBMC profiles at 1st recurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors. Results: At 1st recurrence, two patient clusters were identified in the DIRECTOR cohort which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase ( MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vs CD4low 2.1 vs 2.4 months, p = 0.19), whereas post-recurrence overall survival was longer among the CD4high cluster (12.7 vs 8.7 months, p = 0.004). At 2nd recurrence after dose-intensified TMZ re-challenge, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p = 0.004). The reported associations were retained in multivariate Cox models controlling for established prognostic factors. In the ARTE cohort, CD4+ T cell fractions at 1st recurrence did not differ compared to diagnosis (p = 0.91) and there were no associations with bevacizumab (p = 0.28) or survival (p = 0.74), supporting that the effects observed in the DIRECTOR cohort were driven by TMZ. Conclusions: We conclude that TMZ-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.
Lymphocyte-activation gene 3 (LAG-3) expression in the inflammatory microenvironment of glioma.
Authors: Mair Maximilian , Kiesel Barbara , Feldmann Katharina , Widhalm Georg , Dieckmann Karin , Woehrer Adelheid , Muellauer Leonhard , Preusser Matthias , Berghoff Anna Sophie
Published: May 2020

2553

Background: The blockade of lymphocyte-activation gene 3 (LAG-3), an inhibitory receptor on tumor-infiltrating lymphocytes, is currently under investigation in many extracranial tumor entities. Methods: 54 patients with diffuse glioma were included: 35 patients with glioblastoma (GBM, median age at diagnosis: 61 years) as well as 14 with WHO grade II and 5 with WHO grade III glioma (lower-grade glioma, LGG, median age at diagnosis: 45 years). Isocitrate dehydrogenase 1/2 mutations (IDH-mt) were present in 17/54 patients and 37/54 patients had IDH wildtype (IDH-wt) tumors. LAG-3 expression on tumor-infiltrating lymphocytes (TILs) was analyzed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4, LSBio Inc.). Results: LAG-3+ TILs could be observed in 5/54 (9.3%) samples, while CD3+ TILs were present in 32/54 (59.3%) and CD8+ TILs in 24/54 (44.4%) samples. Only IDH-wt glioma presented with LAG-3+ TILs (p = 0.168). Samples with LAG-3+ TILs presented with a numerical trend towards higher presence of CD3+ (5/27 CD3+ vs. 0/22 CD3−, p = 0.072) and CD8+ TILs (4/24 CD8+ vs. 1/30 CD8−, p = 0.159). 4/7 (57.1%) samples presenting with PD-1+ TILs also presented with LAG-3+ TILs (p = 0.001). Furthermore, glioma samples with LAG3+ TILs presented with higher expression of PD-L1 (median: 1% vs. 0%; p = 0.166). There was no difference in overall survival (OS) according to LAG-3+ TIL infiltration (median OS in LAG-3+: 21.7 months vs. LAG-3−: 41.4 months, p > 0.05). Conclusions: LAG-3+ TILs are rarely observed in IDH-wt and absent in IDH-mt glioma. Gliomas with an active inflammatory microenvironment present more frequently with LAG3+ TILs. The diverse composition of the inflammatory microenvironment and particular inflammatory subgroups should be considered in future clinical trials on immune-modulating therapies in glioma.
Ibrutinib-based combination therapy exhibited therapeutic benefit in newly diagnosed primary central nervous system lymphoma.
Authors: Chen Feili , Pang Diwen , Guo Hanguo , Ou Qiuxiang , Wu Xue , Jiang Xinmiao , Wei Xiaojuan , Liu Sichu , Huang Ling , Liang Zhanli , Li Wenyu
Published: May 2020

2556

Background: Ibrutinib has shown single-agent activity in relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL), and the high dose methotrexate (HD-MTX) has been the backbone of treatment of de-novo PCNSLs. Combination therapy of HD-MTX and ibrutinib has recently shown activity in R/R PCNSLs. Methods: Eleven newly diagnosed PCNSL patients who underwent combination therapy of HD-MTX and ibrutinib were analyzed for treatment response and safety profile. HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses. Ibrutinib was held on days of HD-MTX infusion until HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. Patients’ clinicopathologic characteristics were retrospectively reviewed and genomic traits were further analyzed. Results: Nine out of 11 patients have completed the induction phase of ibrutinib-based combination therapy and received ibrutinib maintenance in addition to two patients whose disease progressed during the therapy. An objective response rate (ORR) of 82% (9/11) was observed, including 7 patients with complete response (CR, 64%) and 2 patients with partial response (PR, 18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The combination therapy of HD-MTX and ibrutinib was well tolerated and has acceptable safety. In addition, the presence of ctDNA in cerebrospinal fluid (CSF) samples closely correlated with tumor response. Sustained tumor responses were associated with the clearance of ctDNA from the CSF. Conclusions: Combination of ibrutinib and HD-MTX has acceptable safety and has demonstrated anti-tumor activity in newly diagnosed de-novo PCNSL patients. The detection of ctDNA in CSF is feasible for monitoring tumor burden in PCNSL patients.
Clinical, radiologic & prognostic profile of IDH wild type diffuse astrocytic glioma with molecular features of glioblastoma.
Authors: Akintola Oluwatosin , Samore Wesley , Martinez-Lage Alvarez Maria , Gerstner Elizabeth Robins
Published: May 2020

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Background: In 2018, The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommended that IDH-wildtype diffuse astrocytic glioma Grade II/III with either EGFR amplification, combined whole chromosome 7 gain and whole chromosome 10 loss (+7/−10), or TERT promoter mutation should receive an integrated histological and molecular grade classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The natural history, radiologic characteristics and standard management for these patients has not been well described. They are typically excluded from clinical trials for WHO Grade IV gliomas. Methods: Adults diagnosed at Massachusetts General Hospital with IDH wildtype diffuse astrocytoma and EGFR amplification or TERT promoter mutation from 2011-2019 were identified. Demographics, functional status, radiologic features, MGMT promoter methylation status, time to progression, and overall survival were collected retrospectively. Qualitative MRI data was analyzed using the VASARI feature set. Response assessment was performed using the RANO criteria. Results: 50 patients were identified (table). 37/50 patients received standard Stupp protocol, 2/50 received hypofractionated radiotherapy with temozolomide, 6/50 received radiotherapy alone, and 1 patient received a MEK inhibitor. None were enrolled in clinical trials at diagnosis. mPFS was 10 months in the 47/50 with confirmed progression and mOS in the patients with confirmed deaths (40/50) was 17.5 months (4-47). 9/50 patients are alive with survival ranging 6-52 months. Conclusions: Outcomes for patients with molecularly defined GBM were variable. Analysis of the cohort to characterize factors that led to the observed variability is in progress. More studies on molecularly defined glioblastomas are required to better understand their behavior and to provide guidance for their inclusion or exclusion in clinical trials. [Table: see text]
A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
Authors: Kim Chae-Yong , Hwang Kihwan , Chang Jong Hee , Kang Seok-Gu , Jung Tae-Young , Kim Jeong Hoon , Kim Se-Hyuk , Kang Shin-Hyuk , Hong Yong-Kil , Kim Tae Min , Choi Byung Se , Kim YuJung , Choe Ghee Young
Published: May 2020

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Background: We evaluated the survival benefit of levetiracetam as a chemosensitizer of temozolomide for patients with newly diagnosed glioblastoma. Methods: This was an open-label, multicenter, phase II study (NCT02815410). Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2. All patients received radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles). The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation. This prospective study was designed to test whether levetiracetam in conjunction with temozolomide improved survival. The historical control group was based on data from a study by Gwak et al. for Korean patients with newly diagnosed glioblastoma with a median overall survival(OS) of 17.5 months and a median progression-free survival (PFS) of 10.1 months. Results: Forty-six patients were enrolled between August 2016 and January 2019. The median follow-up duration was 24.9 months (range, 7.9-35.5). All patients completed standard radiation therapy with temozolomide, and 39 (84.8%) patients completed six cycles of adjuvant temozolomide. Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months. OS at 6, 12, and 24 months was 100%, 91.3%, and 60.7%, respectively. PFS at 6, 12, and 24 months was 93.2%, 65.3%, and 22.6%, respectively. Conclusions: Addition of levetiracetam during concurrent and adjuvant temozolomide along with radiotherapy in patients with newly diagnosed glioblastoma may result in improved outcomes compared to historical data and merits further study. Clinical trial information: NCT02815410 .
Survival of subjects with recurrent glioblastoma receiving intratumoral administration of controlled IL-12 with limited exposure to dexamethasone.
Authors: Lukas Rimas Vincas , Kurz Sylvia Christine , Yu John , Landolfi Joseph C. , Rao Ganesh , Amidei Christina , Buck Jill Yannetti , Hadar Nira , Estupinan Taylor , Miao John , Loewy John W. , Wang Yunxia , Demars Nathan A. , Gelb Arnold Bruce , Cooper Laurence JN
Published: May 2020

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Background: Interleukin-12 (IL-12) results in anti-tumor responses in preclinical models but requires tightly controlled production to achieve safety and elicit immune system activation to realize efficacy. A phase 1 “main study” (NCT02026271) enrolled subjects with Grade III or IV gliomas who at the time of resection received intratumoral administration of a replication-deficient adenovirus expressing IL-12 under control of a transcriptional switch (Ad-RTS-hIL-12, Ad) regulated by veledimex (V), referred to as “Controlled IL-12”. It was anticipated that dexamethasone (dex), a lymphocytotoxic corticosteroid used to control edema, might diminish response to immunotherapies. We report updated findings from a substudy of subjects who were dex-free during the 4 weeks prior to Ad administration. Methods: Multicenter, phase 1 substudy (NCT03679754) that assesses safety and tolerability of Controlled IL-12 by local injection (Day 0, time of resection) of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses, Days 0-14) in subjects that were bevacizumab naïve and not receiving dex 4 weeks prior to Ad. Results: 36 subjects were treated. Of the 36, a majority received low-dose corticosteroids (≤ 20 mg dex total during V) as compared with the main study (75% vs 40%). More subjects in the substudy as compared with the main study had multifocal vs. unifocal disease (39% vs 7%). The safety profile was similar for both. Adverse reactions were mild to moderate and were manageable and reversable upon withholding V. Activation of the switch in both the main study and substudy (V 20 mg; n = 51) resulted in increased mean peak values (Day 0-28) of serum IL-12 (25.8 vs. 20.4 pg/mL) and IFN-g (57.0 vs. 39.5 pg/mL). Initial median overall survival (mOS) (unifocal, ≤ 20 mg dex cumulative, n = 20) was 16.2 (8.9, 18.5) mons (mean follow-up 12.3 mons) (Neuro Oncol 2019; 21 [suppl_6]:vi5). mOS including the impact of dex and key subject characteristics from the two studies (n = 51) will be updated and tumor response data will be provided. Conclusions: Monotherapy with Controlled IL-12 resulted in sustained increase in serum recombinant IL-12 and downstream endogenous IFN-g. There is evidence of immune-mediated anti-tumor effects which is associated with increased mOS as compared with historical controls. Follow up will investigate the adverse impact of dex, as well as the effect of additional subject characteristics ( e.g., unifocal vs. multifocal disease) on mOS. Clinical trial information: NCT03679754 .
Molecular predictors of response to selinexor in recurrent glioblastoma (GBM).
Authors: Walker Christopher James , Shen Yao , Mau-Sørensen Morten , Wen Patrick Y. , Van Den Bent Martin J. , Plotkin Scott Randall , Walenkamp Anna Maria Elisabeth , Green Adam , Califano Andrea , Chang Hua , Henegar Leah , Shacham Sharon , Alvarez Mariano J , Landesman Yosef , Lassman Andrew B.
Published: May 2020

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Background: The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Selinexor is FDA approved for treatment of patients (pts) with refractory multiple myeloma and is under evaluation for GBM. Methods: We previously reported encouraging results from a phase II clinical trial of selinexor for molecularly unselected pts with recurrent GBM (ASCO 2019). On available pre-treatment archival tumor tissue from 57 cases, we performed DNA exome and RNA transcriptome sequencing to use both gene mutations and expressions for exploring molecular correlates of response in selinexor treated pts, in a hypothesis generating, post-hoc, exploratory analysis. Pts with inadequate drug exposure were excluded ( < 21 days or < 3 doses). We compared OS and PFS between mutated and wild-type patients for genes mutated in at least 5 cases. RNAseq data were used to infer differential protein activities between patients with selinexor sensitive disease (defined as best response of partial or complete response, n = 7) vs. resistant disease (defined as progressive disease as best response, n = 23). Results: Two mutated genes were associated with longer survival in selinexor treated pts: DOCK8 (n = 7; progression free survival [PFS], P = 0.013, hazard ratio [HR] = 3.75 [1.32-10.62]; overall survival, P = 0.009, HR = 15.39 [2.00-118.34]) and PDX1 (n = 5, PFS, P = 0.014, HR = 4.468 [1.361-14.670]). Other commonly mutated genes in glioma, including IDH1 (n = 9) were observed but not associated with survival. Protein activities inferred from RNA sequencing data were also correlated with response to selinexor. In a machine learning model, ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling and repress innate immunity, predicted clinical benefit from selinexor (area under the ROC curve from leave one out cross validation = 0.89, permutation test P < 0.04). Conclusions: DOCK8 and PDX1 mutations were favorable prognostic factors in selinexor treated pts. Activity of three proteins (ZC3H12A, RAB43, and SOCS3) predicted clinical benefit from selinexor. Further studies with more pts are required to validate our findings. ClinicalTrials.gov: NCT01986348
A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms.
Authors: Luke Jason J. , Patel Manish R. , Hamilton Erika Paige , Chmielowski Bartosz , Ulahannan Susanna Varkey , Kindler Hedy L. , Bahadur Shakeela Wazeen , Clingan Philip R. , Mallesara Girish , Weickhardt Andrew James , Currence Scott , Xu Linzhi , Kaul Sanjeev , Chen Francine , Moore Paul A. , Bonvini Ezio , Sumrow Brad , Blumenschein George
Published: May 2020

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Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells. MGD013 demonstrates ligand blocking properties consistent with anti-PD-1 and anti-LAG-3 benchmark molecules, and improves T cell responses beyond that observed with benchmark or component antibodies alone or in combination. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and antitumor activity of MGD013 in patients (pts) with advanced solid and hematologic malignancies. Sequential single-pt cohorts were treated with escalating flat doses of MGD013 (1-1200 mg IV every 2 weeks), followed by a 3+3 design. Tumor-specific expansion cohorts are being treated at the recommended Phase 2 dose of 600 mg. Results: At data-cutoff, 50 pts (46% checkpoint-experienced) were treated in Dose Escalation, and 157 pts (32% checkpoint-experienced) in Cohort Expansion. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 146/207 (70.5%) pts, most commonly fatigue (19%) and nausea (11%). The rate of Grade ≥ 3 TRAEs was 23.2%. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies. Mean half-life was 11 days; peripheral blood flow cytometry analyses confirmed full and sustained on-target binding during treatment at doses ≥ 120 mg. Among 41 response-evaluable [RE] dose escalation pts, 3 confirmed partial responses [cPRs] (triple negative breast cancer [TNBC], mesothelioma, gastric cancer) per RECIST 1.1 were observed, while 21 pts had stable disease [SD]. Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2; both cPRs, and 7 with SD among 15 RE pts) and TNBC (n=2; 1 cPR, 1 unconfirmed PR [uPR], and 5 with SD among 14 RE pts). In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2], colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. Objective responses have been observed in several pts after prior anti-PD-1 therapy. Investigations into potential correlative biomarkers including LAG-3 and PD-1 are ongoing. Conclusions: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial information: NCT03219268 .