bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of controlled IL-12 in combination with a PD-1 inhibitor in subjects with recurrent glioblastoma.
Authors: Chiocca E. Antonio , Lukas Rimas Vincas , Rao Ganesh , Barrett John A. , Buck Jill Y. , Demars Nathan , Smith Amy , Miao John , Zhou Qiang (John) , Gelb Arnold Bruce , Cooper Laurence 
Published: May 2019

2020 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate conditionally expressing IL-12 under the control of veledimex (V) acting via the proprietary RheoSwitch Therapeutic System (RTS) gene switch with a therapeutic window. Intratumoral Ad + oral V monotherapy (Phase 1 study, NCT02026271 ) resulted in a new sustained intra-tumor influx of activated cytotoxic T cells, consistent with an immune-mediated anti-tumor effect improving median overall survival (mOS) of subjects with recurrent glioblastoma (rGBM). This correlated with an increased circulating CD8+/FoxP3+ T cell ratio (“cytoindex”), an emerging biomarker for mOS. PD-1 expression on infiltrating T cells at biopsy after Ad+V, supports combining controlled IL-12 with a PD-1 inhibitor to further augment T-cell-mediated anti-tumor effects. The rationale is also supported by increased OS (100% combo vs 63% for Ad+V vs 40% for anti-PD-1) in mice bearing GL-261 glioma. Methods: An ongoing open label, dose-escalation Phase 1 trial (NCT03636477) is evaluating safety and tolerability of local, controlled IL-12 with nivolumab (nivo) in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles, Day 0) plus V (10-20 mg) PO QD x 15 with nivo (1-3mg/kg) IV on Days -7, 15, then Q2W. Results: Safety data revealed a similar profile as Ad +V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with anti-PD-1 reports. ARs were manageable and reversible with no synergistic toxicities. Nivo alone did not alter peripheral IL-12 levels (median baseline (before anti-PD-1) 0.9 pg/mL; Day 0 1 pg/mL) increasing to 5.5 pg/mL on Day 3. Nivo alone increased peripheral T cells (CD3+CD8+ median baseline 23%; Day 0 26%) and Ad+V elevated peripheral CD3+CD8+ to 31% at Day 14. Nivo alone decreased regulatory T cells (FoxP3 baseline 1.5% vs Day 0 0.8%). Ad+V decreased these to 0.3% (Day 14). Combination therapy improved the cytoindex (baseline 15; Day 0 29; Day 14 80). Conclusions: Controlled IL-12 production using Ad + V with nivo is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile, warranting continued investigation in rGBM. Clinical trial information: NCT03636477.
Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.
Authors: Wu Jing , Yuan Ying , Cordova Christine , Aboud Orwa , Penas-Prado Marta , Theeler Brett James , Bryla Christine , Su Yu-Ting , Grajkowska Ewa , McCoy Ann , Boris Lisa , Siegel Christine , Antony Ramya , Garren Nancy , Lawhon Tracy , Armstrong Terri , Gilbert Mark R. 
Published: May 2019

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.
Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM).
Authors: Reardon David A. , Kaley Thomas Joseph , Dietrich Jorg , Clarke Jennifer Leigh , Dunn Gavin , Lim Michael , Cloughesy Timothy Francis , Gan Hui Kong , Park Andrew J. , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph 
Published: May 2019

2032 Background: Durvalumab (durva), a human IgG1 monoclonal Ab against PD-L1, is FDA-approved for selected patients with bladder and non-small cell lung cancers. PD-L1 is expressed by some GBM tumors, while GBM infiltrating T lymphocytes often express PD-1. Radiation induced cell death releases tumor antigens and could potentiate anti-PD-(L)1 therapy. Methods: This ongoing Phase 2 open-label study (NCT02336165) evaluates the safety and efficacy of durva (10 mg/kg every 2 weeks) in 5 GBM cohorts. Results are presented for Cohort A, which evaluates durva + standard radiotherapy (RT, 60 Gy over 30 fractions) followed by durva monotherapy in patients with new unmeth GBM after maximum safe resection. The primary efficacy endpoint for Cohort A is overall survival at 12 months (OS12); secondary endpoints include safety/tolerability, tumor response rate, and progression-free survival (PFS). Historical benchmarks of median OS and OS12 for patients with new unmeth GBM following standard therapy are 12.7 months and 50%, respectively (EORTC 26981-22981/NCIC CE.3). Results: Median follow-up of 40 enrolled patients is 24.5 months (data cutoff = 05 Nov 2018). Baseline characteristics: male, 70%; median age, 57.0 [22 to 77] years; ECOG PS0, 60.0%; ECOG PS1, 40.0%; measurable disease, 80.0%; and dexamethasone use, 32.5%. Treatment-related adverse events with maximum CTCAE grade ≥ 3 occurred in 14 (35.0%) patients; the most common were asymptomatic increased lipase (n = 6) and increased amylase (n = 2). Twenty-four of 40 patients were alive at 12 months (Kaplan-Meier for OS12, 60.0% [90% CI: 46.1, 71.4]). Median OS was 15.1 (95% CI: 12.0, 18.4) months. As of 05 Nov 2018, 8 (20%) patients remain alive, with ongoing survival ranging from 15.7 to 34.9 months. Tumor immunocorrelative and systemic studies are pending. Conclusions: This is the first study report of anti-PD-L1 for new GBM. Durva was well tolerated when combined with RT and seemed to have efficacy among patients with new unmeth GBM. Further studies may be warranted. Clinical trial information: NCT02336165.
A TITE-CRM phase I/II study of disulfiram and copper with concurrent radiation therapy and temozolomide for newly diagnosed glioblastoma.
Authors: Huang Jiayi , DeWees Todd , Campian Jian Li , Chheda Milan G , Ansstas George , Tsien Christina , Zipfel Gregory J. , Dunn Gavin P. , Ippolito Jospeh E , Cairncross J. Gregory , Easaw Jacob C. , Rubin Josh , Kim Albert H 
Published: May 2019

2033 Background: Disulfiram (DSF) has shown promising activity against glioblastoma in preclinical studies and is more effective when combined with copper (Cu). Our previous phase I study established the maximum tolerated dose (MTD) of DSF when combined with adjuvant temozolomide (TMZ). This phase I/II study aims to establish the MTD when disulfiram and copper are combined with concurrent radiation therapy (RT) and TMZ for newly diagnosed glioblastoma and to explore preliminary efficacy. Methods: Eligible patients were treated with standard RT and TMZ plus escalating doses of DSF (250 mg - 375 mg PO QD) and Cu (2 mg PO TID), followed by adjuvant TMZ plus DSF (500 mg/day) and Cu. The time-to-event continual reassessment method (TITE-CRM) was used to continuously estimate the probability of dose-limiting toxicity (DLT) and to assign patients to doses with an estimated DLT probability of approximately 20% with a margin of 5%. Tumor mutations were evaluated with next-generation sequencing for all patients. Results: Eighteen glioblastoma patients were treated with the study therapy: 8 with DSF of 250 mg/day and 10 with 375 mg/day. Three DLTs were observed: 1 with 250 mg/day (grade 2 urinary incontinence and ataxia), and 2 with 375 mg/day (both grade 3 elevated liver enzymes). DSF had an estimated DLT probability of 10% (95% CI: 3-29%) at 250 mg/day, and 21% (95% CI: 7-42%) at 375 mg/day. After a median follow-up of 12.3 months, 1-year progression-free survival (PFS) was 57%, and 1-year overall survival (OS) was 69%. There was no significant difference in PFS/OS when stratified by DSF doses, surgical extent, or MGMT methylation status. However, glioblastomas with IDH1 (n = 6), BRAF (n = 2), or NF1 (n = 1) mutations had significantly better PFS and OS than those without the mutations: 1-year PFS: 100% vs 22%, respectively, p = 0.001; 1-year OS: 100% vs 42%, respectively, p = 0.006. Conclusions: The MTD of DSF with RT/TMZ/Cu for glioblastoma is 375 mg/day, and the recommended phase II dose is 250 mg/day. Although confirmation with larger sample size is needed, the combination demonstrates promising preliminary efficacy for the subset of glioblastoma with IDH1, BRAF, and NF1 mutations. Clinical trial information: NCT02715609.
Correlation of systemic and local inflammation with survival prognosis in glioma patients.
Authors: Mir Seyed Nazari Pegah , Ay Cihan , Marosi Christine , Moik Florian , Riedl Julia , Ricken Gerda , Hainfellner Johannes A. , Preusser Matthias , Pabinger Ingrid , Berghoff Anna Sophie 
Published: May 2019

2052 Background: Immune modulating therapies have been a long withstanding treatment approach in glioma. However, gliomas are characterized by a particular absence of tumor infiltrating lymphocytes in the local tumor microenvironment. We aimed to gain insight on the distinct patterns of inflammation associated with survival prognosis in glioma. Methods: Patients were recruited at time of glioma diagnosis or progression in the prospective observational Vienna Cancer and Thrombosis Study (CATS). A single blood draw was performed at study inclusion. PD-L1 expression in the tumor tissue was investigated via immunohistochemistry. Optimal cut-off according to ROC curve was used to assess cut off values for survival analysis. Results: 193 patients with glioma (75.6% glioblastoma (WHO grade IV), 19.7% anaplastic glioma (WHO grade III), and 4.7% diffuse glioma (WHO grade II)) were included. 40/193 (20.7%) glioma had an IDH1 mutation. Membranous PDL1 expression in the tumor tissue was observed in 20/193 (10.4%) patients. 1/20 patient presented with PD-L1 expression and IDH1 mutation ( p = 0.082). PD-L1 significantly correlated with increased monocyte count (median: 0.657 vs. 0.450 [G/L], p = 0.008), higher C-reactive protein (CRP) (0.43 vs. 0.1 [mg/dL], p = 0.005) and higher fibrinogen (379 vs. 303 [mg/dL], p = 0.001). Presence of IDH1 mutation significantly correlated with increased platelet count (303 vs. 232 [G/L], p = 0.001) and lower Neutrophil/Lymphocyte (N/L) ratio (3.34 vs. 5.13, p = 0.016). Higher lymphocyte count ( > 1.484 [G/L], log-rank: p = 0.011), higher platelet count ( > 245.5 [G/L], p = 0.0001), as well as decreased N/L ratio ( < 5.13, p = 0.001) were significantly associated with increased survival prognosis. Conclusions: PD-L1 expression in tumor tissue was associated with markers of systemic inflammation in glioma patients. Systemic inflammation markers furthermore predicted improved survival. Immune modulating therapy approaches might be a promising approach in subgroups of glioma associated with increased baseline interaction of immune system and glioma.
Carbon ion reirradiaton for patients with malignant gliomas: Toxicity and first results of the prospective dose-escalation phase I/II CINDERELLA trial.
Authors: Combs Stephanie E , Bernhardt Denise , Adeberg Sebastian , Herfarth Klaus K , Unterberg Andreas , Wick Wolfgang , Debus Juergen , Rieken Stefan 
Published: May 2019

2059 Background: The prospective phase I/II CINDERELLA trial investigates toxicity and effectiveness of a dose escalated reirradiation with carbon ions in patients with recurrent gliomas. Methods: Following a dose escalating protocol, 52 patients with WHO°II-IV gliomas were irradiated with carbon ions with doses of 3 Gy (RBE) in 10 – 16 fractions in 7 dose leels. Median age was 42 years (range: 28 - 69) with 19 female and 33 male participants. Forty-one patients were diagnosed with WHO°III/IV gliomas and 11 patients with WHO°II gliomas. At the time of reirradiation, all patients showed contrast-enhancing recurrences. MRI-based treatment planning encompassed the contrast enhancing lesion (GTV) with additional safety margins of 5 mm (CTV) and 3 mm (PTV). Clinical follow-up visits including contrast-enhanced MRI were scheduled every two months. We used RANO-criteria for diagnosis of progression. Survival rates were analyzed with Kaplan-Meier estimator. Relevant prognostic factors were determined with log rank-test, and toxicity was classified according to CTCAE v4.0. Results: Median time between first irradiation and reirradiation was 9 months (range: 7 – 228). PTV size was 12 – 310 ml. During follow-up ≥°3 toxicities were not observed. Follow-up MRI suggested radiation necrosis in 4 patients. Median overall survival was 352 days and was not influenced by age, gender or radiation dose. A significant trend for improved survival rates was seen in patients with small target volumes (480 days [PTV < 75ml] vs. 322 days [PTV > 75ml], p = 0.06) and initial low grade histology (497 days [WHO °II] vs. 322 days [WHO°III/IV], p = 0.069). During follow-up, 45 patients had local progression, while clinical deterioration was not seen. Median local progression-free survival was 138 days. Twenty-eight patients received chemo-/immunotherapy after reirradiation. Of those, 14 patients were treated with bevacizumab. Progression after reirradiation did not influence overall survival significantly. Conclusions: Carbon ion re-irradiation with 10-16 fractions of 3 Gy for patients with recurrent gliomas is safe; no dose limiting toxicities were observed. Median overall survival with approximately one year is high in comparison to other treatment options. It remains unclear if RANO-criteria is securing the diagnosis of therapy failure after carbon ion reirradiation. Further randomized controlled trials must be awaited to evaluate the effectiveness of reirradiation of carbon ions compared to other treatment options. Clinical trial information: NCT01166308.
Stereotactic radiosurgery for resected brain metastases: Does the surgical corridor need to be treated?
Authors: Shi Siyu , Jaoude Joseph Abi , Sandhu Navjot , Wang Elyn , Schofield Kirsten , Jin Michael C. , Zhang Carrie , Liu Elisa , Pollom Erqi L. , Soltys Scott G. 
Published: May 2019

2068 Background: Post-operative stereotactic radiosurgery (SRS) is the standard of care for resected brain metastases, but SRS techniques are not standardized. Although expert consensus guidelines recommend that the surgical corridor leading to the resection cavity be included in the SRS plan, this statement is not based on data. We analyzed the patterns of failure and toxicity with post-resection SRS, with the hypothesis that the corridor needs not be targeted with SRS. Methods: In this IRB-approved retrospective review, from 428 lesions treated from 2005-2018 with post-resection SRS, 58 lesions (57 patients) had evaluable data and a ‘deep’ tumor with a surgical corridor defined as ≥ 1.0 cm from the surface pre-operatively. SRS targeted the surgical corridor, defined as the surgical tract uninvolved by tumor on pre-operative imaging, in 33(57%). Brain failure was defined as local (LF) if within the surgical cavity involved with tumor pre-resection, corridor (CF) if within the surgical tract leading to the surgical cavity, distant (DF) if a new parenchymal tumor, or leptomeningeal (LMD) for new nodular/classical leptomeningeal enhancement. The cumulative incidences of failure and adverse radiation effect (ARE) were analyzed with death and whole brain radiation therapy as competing risks. Results: The median follow-up was 14 months. Not targeting surgical corridor was associated with prior SRS/resection for other brain metastases (23% vs. 0%, p=0.01), deeper tumors (median 2.1 cm vs. 1.4 cm, p<0.01), and systemic treatment within 3 months (p =0.01), but not other factors (p>0.10). The 12-month failure rates, if surgical corridor was not treated vs. treated, respectively, were: CF 8% (1-24%) vs. 0% (p=0.12), LF 4% (0-17%) vs. 13% (4-27%) (p=0.32), LMD 40% (19-61%) vs. 10% (2-23%) (p=0.03), DF 65% (43-81%) vs. 35% (19-52%) (p=0.02), and ARE 8% (1-22%) vs. 13% (4-28%) (p=0.35). After adjusting for systemic treatment, differences were not statistically significant (p>0.05). Conclusions: Omitting the surgical corridor in post-operative SRS for resected brain metastases was not associated with statistically significant differences in recurrences or adverse radiation effect. Surgical corridor does not need to be included in all post-resection SRS.
A phase II study of pembrolizumab for HPV-associated papilloma patients with laryngeal, tracheal, and/or pulmonary involvement.
Authors: Pai Sara I. , Friedman Aaron D , Franco Ramon , Muniappan Ashok , Park Jong Chul , Campbell Nicholas Paul , Krantz Seth B. , Song Phillip C , Bove Michiel , Carroll Thomas L , Faquin William C , O'Neill Anne M. , Wirth Lori J. 
Published: May 2019

2502 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the respiratory tract impacting breathing, swallowing, and voice and carries a 1-4% risk of malignant transformation. There is no curative therapy for RRP. Given the tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts > 12 years of age were treated with pembro 200mg every 3 weeks. Adjuvant surgical debridement of RRP was permitted for airway obstruction but not dysphonia. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease in response out of 21 (assuming > 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). Serial biopsies (up to 8 biopsies/patient over the 24 months of treatment) to identify biomarkers of response and mechanisms of immune resistance (PD-L1 expression, mutations in HLA class I antigen presentation machinery, and tumor mutational burden) are underway. Results: Accrual is complete (n = 21 pts accrued between May 2016 and Jan 2019). Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. As of February 1, 2019, ORR is 43% (9/21) (.95 two-stage CI: 22%-66%) (4 of 11 with juvenile-onset RRP and 5 of 10 with adult-onset RRP disease responded). No complete responses have been observed. Fatigue was the most frequent treatment related adverse event (TRAEs); Grade 3 TRAEs included uveitis and hypophysitis, both were reversible upon pembro discontinuation. The frequency of surgical interventions was reduced in all pts undergoing surgery for airway palliation prior to study entry. Conclusions: Pembro reduces the need for routine surgical interventions based on the response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.
Results from a first-in-man, open label, safety and tolerability trial of CAN04 (nidanilimab), a fully humanized monoclonal antibody against the novel antitumor target, IL1RAP, in patients with solid tumor malignancies.
Authors: Awada Ahmad , Eskens Ferry , Robbrecht Debbie , Lassen Ulrik Niels , Soerensen Morten Mau , Steeghs Neeltje , Jungels Christiane , Aftimos Philippe Georges , Fretland Signe Øien , Thorsson Lars , Guren Tormod Kyrre 
Published: May 2019

2504 Background: Interleukin 1 receptor Accessory protein, IL1RAP, is expressed in several solid tumors, both on cancer cells and tumor-associated inflammatory cells. CAN04 is a first-in-class fully humanized monoclonal antibody targeting IL1RAP blocking IL-1 alpha and beta signaling and triggering antibody dependent cellular cytotoxicity. Methods: The primary objective was to assess safety and tolerability of weekly CAN04 in order to define the Recommended Phase 2 Dose (RP2D). Patients (pts) with relapsed or refractory non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), breast or colorectal cancer were included using a 3+3 dose escalation design. Key eligibility criteria were ECOG ≤1, normal organ function and no bleeding disorder/coagulopathy. Tumor responses were evaluated according to irRC every 8 weeks. PK and biomarkers were analyzed in serum. Results: 22 pts were enrolled across 5 cohorts (1-10 mg/kg). Demography: mean age 62 yrs (39-81); gender 14 M and 8 F; median number of prior lines of therapy 3 (range 1-11). AEs occurred mainly following the first dose and the most common AEs were: infusion related reaction (IRR) (41%), pyrexia (27%), fatigue (23%), chills (23%) and nausea (23%). AE grade 3 or 4: one IRR, one neutropenia/leukopenia and one hypokalemia, all of them grade 3. Serum CRP and IL-6 were reduced after two weeks of treatment. There were linear increases of AUC and Cmax (1-10 mg/kg) and CAN04 exposure at 10mg/kg was above levels associated with signs of efficacy in preclinical models. In pts receiving at least one dose of CAN04, 9/20 (45%) had SD by irRC (7/20 had SD by RECIST 1.1) at 8 weeks follow up. Two pts, one with NSCLC and one with PDAC, had SD for 6 and 4 months (latter still on therapy). Conclusions: CAN04 demonstrated a manageable safety profile and a RP2D of 10 mg/kg has been established. The dose expansion phase of the trial will evaluate CAN04 as monotherapy as well as in combination with relevant chemotherapy regimens in NSCLC and PDAC in separate arms. Clinical trial information: NCT03267316.