bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the benefit of adaptive randomization in the CC-115 arm of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A phase II randomized Bayesian adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma.
Authors: Rahman Rifaquat , Trippa Lorenzo , Fell Geoffrey , Lee Eudocia Quant , Arrillaga-Romany Isabel , Touat Mehdi , Drappatz Jan , Galanis Evanthia , Ahluwalia Manmeet Singh , Colman Howard , Nabors Louis B. , Hepel Jaroslaw T. , Schiff David , Welch Mary Roberta , Meredith David M. , Chiocca E. Antonio , Reardon David A. , Ligon Keith L. , Alexander Brian Michael , Wen Patrick Y. 
Published: June 2021

2006 Background: Adaptive randomization adjusts enrollment rates based upon early trial results, which can allow for decreased enrollment for therapies less likely to meet the primary endpoint of a trial. CC-115, a CNS-penetrant, oral inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK), was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. As CC-115 was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio, we sought to investigate the impact of adaptive randomization in its testing. Methods: In INSIGhT, adults with newly diagnosed MGMT-unmethylated glioblastoma and available genomic data are adaptively randomized to an experimental arm or the control arm of standard radiotherapy with concurrent and adjuvant temozolomide. Patients randomized to CC-115 received it (10mg po BID) with radiotherapy and as adjuvant monotherapy, and a safety lead-in 3+3 design was used for this arm. By simulating the INSIGhT trial with standard uniform randomization, we estimated the reduction of enrollment rate and sample size of the CC-115 arm that was attributable to adaptive randomization. Results: Twelve patients were randomized to CC-115; 58% (n = 7) patients had possible treatment-related CTCAE grade > 3 toxicity. Compared to the control arm, there was no significant difference in progression-free survival (PFS, HR 0.66, 95% CI 0.32-1.36, p = 0.3) or overall survival (OS, HR 0.93, 95% CI 0.43-2.03, p = 0.8). Based on early PFS results, randomization probability to CC-115 decreased from 25% to 16%. At the time of the CC-115 arm closure, 14% of enrolled INSIGhT patients had been randomized to this arm. Compared to average expected enrollment by standard randomization, the use of adaptive randomization decreased the number of patients randomized to CC-115 by 50% (12 patients vs. 18 patients [95% CI 11-25 patients]). Conclusions: The INSIGhT trial, designed with adaptive randomization, facilitated more efficient testing of CC-115 and decreased the number of patients allocated to the CC-115 arm relative to a standard randomization design. Clinical trial information: NCT02977780.
Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI).
Authors: Ducray Francois , Sanson Marc , Chinot Olivier L. , Fontanilles Maxime , Rivoirard Romain , Thomas-Maisonneuve Laure , Cartalat Stephanie , Tabouret Emeline , Bonneville-Levard Alice , Darlix Amelie , Ameli Roxana , Meyronet David , Gueyffier Francois , Remontet Laurent , Maucort-Boulch Delphine , Dehais Caroline , Honnorat Jerôme ,   POLA Network
Published: June 2021

2007 Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies. Clinical trial information: NCT03561870.
The efficacy and clinical survival outcome of different first-line treatments in EGFR-mutant non-small cell lung cancer with brain metastases.
Authors: Wang Huijuan , Xing Ruyue , Zhang Mina , Zhang Xiaojuan , Yang Jinpo , Li Mengmeng , Ma Zhiyong 
Published: June 2021

2028 Background: Brain metastasis is one of the most important factors for poor prognosis of lung cancer, and the incidence of brain metastasis in EGFR-mutant(m+) advanced NSCLC is more common. The first-generation EGFR TKI is a standard first-line treatment. The purpose of this study is to explore the best method for EGFRm+ NSCLC with brain lesions, and to find out correlative factors influencing survival outcome. Methods: The clinical data of NSCLC with brain metastases was retrospectively analyzed. All patients had received 1st generation EGFR TKI, and patients were divided into 4 group, group A : EGFR TKI monotherapy, group B: EGFR TKI plus chemotheapy(CT),Group C:EGFR TKI plus bevacizumab, group D :EGFR TKI plus CT plus bevacizumab.The efficacy of intracranial and extracranial lesions and survival outcome were analyzed. Results: A total of 584 EGFRm+ advanced NSCLC patients from December 2017 to May 2020 were screened,and 228(39%) had brain metastasis at baseline in the treatment-naive. Among them, 194pts had complete medical record and follow-up data. At the follow-up date (January 1, 2021), 147pts had disease progressed and 78pts had died. Intracranial PFS of group A,B,C,D were 11.1m(n = 97), 11.3m(n = 59)，21.2m(n = 19), and 18.9m(n = 19), respectively. No difference was found between A and B group (P = 0.745), so as C and D group (P = 0.684).But, the intracranial PFS of group C+D(with bevacizumab) was significantly longer than group A+B(11.3m (95%CI 12.2-14.8) vs 21.0m (95%CI 15.2-22.7), P = 0.007).The extracranial PFS of groups A, B, C, and D were 11.0m, 14.3m, 21.7m, and 18.9m, respectively,and the P value were 0.006, 0.002, and 0.011, respectively when compared with group A. The mOS of groups A,B were 27.8m and 24.2m,respectively, but group C and D had not yet reached. The intracranial ORR of group A, B, C, and D were 17.9% (14/78), 37.3% (19/51), 60.0% (9/15), and 66.7% (10/15), respectively. The extracranial ORR were 48.5% (47/97), 81.1% (43/53), 73.7% (14/19), and 73.7% (14/19),respectively. Conclusions: For EGFR-mutant NSCLC with brain metastases, the first-generation EGFR-TKI plus bevacizumab can significantly improve the efficacy of intracranial lesions, delay the progression of intracranial lesions, and prolong suvival time, Although the first-generation EGFR-TKI plus CT could improve extracranial ORR when compared with ERGF-TKI monotherapy, it has limited efficacy on intracranial lesions and could not increase survival time.
ATRXLoss to impair glioma stem cell viability and self-renewal via proton radiotherapy induced necrosis.
Authors: Garces Angel Adrian , Bronk Lawrence , Bhat Krishna , Grosshans David R 
Published: June 2021

2046 Background: Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15 month median survival time. Although IDH1R132H is traditionally associated with improved glioma patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients also harbor ATRXLoss, an inactivation of the ATRX chromatin remodeling protein shown to impair DNA damage repair via non-homologous end joining. The recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which ATRXLoss contributes to GSC proton radiotherapy (PRT) sensitivity, a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), are not well understood. We hypothesize that ATRXLoss impairs GSC post-radiation viability and self-renewal capacity by promoting necrosis to a higher extent after PRT than XRT. Methods: Isogenic TS543-ATRXWT and TS543-ATRXLoss patient derived glioma cells were cultured as neurospheres and treated with 2-8 Gy XRT or PRT. GSC viability was quantified using the CellTiterGlo 3D assay 12 days after irradiation. The Annexin V apoptosis and necrosis assay was conducted every 8 hours up to 72 hours after irradiation. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA). Results: ATRXLoss significantly decreased TS543 GSC viability after 2-8 Gy radiation therapy compared to ATRXWT (Unpaired t-test with Welsh’s correction and Holm-Sidak’s Multiple Comparisons Test p<0.0001). TS543-ATRXLoss also significantly inhibited GSC self-renewal over TS543-ATRXWT when subject to either 6 Gy PRT or XRT (Pairwise Pr(>χ2)<0.01). Interestingly, PRT significantly reduced GSC viability to a higher extent than XRT in both TS543-ATRXWT and TS543-ATRXLoss, which demonstrates the effectiveness of PRT to treat ATRXLoss gliomas. Follow up studies confirmed that ATRXLoss sensitizes TS543 GSCs more extensively to the cytotoxic effects of PRT compared to XRT via the upregulation of necrosis at 72 hours post-irradiation (Two-way ANOVA with Tukey’s post-hoc Multiple Comparisons Test p<0.0001). Conclusions: We conclude that ATRXLoss substantially contributes to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRXLoss confers PRT sensitivity, especially via dsDNA damage.
Evaluation of GM-CSF and AS01B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM).
Authors: Wen Patrick Y. , Reardon David A. , Forst Deborah Anne , Lee Eudocia Quant , Iwamoto Fabio Massaiti , Diaz-Mitoma Francisco , Anderson David E , Lassman Andrew B. 
Published: June 2021

2047 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We enrolled a total of 20 patients with KPS at least 70 and first recurrence of GBM into 2 arms of the Phase IIa extension of gB/pp65 enveloped virus-like particles (eVLPs) adjuvanted with either GM-CSF given intradermally or with AS01B given intramuscularly (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Results: 10 patients (6 women, 4 men) with a median age of 58 (33-67 yrs) were enrolled into the GM-CSF arm and 10 patients (3 women, 7 men) with a median age of 65 (40-67) enrolled into the AS01B arm. Disease control rates of 40% and 50% were observed in the GM-CSF and AS01B arms, respectively, with 2 sustained PRs in the GM-CSF arm. The 6-month OS rate for the GM-CSF arm is 80% and is estimated to be comparable for the AS01B arm. CMV-specific CD4+ effector memory T cells may correlate with tumor responses in both arms of the study, with AS01B boosting higher frequencies of these cells regardless of baseline CD4/CD8 ratio. Conclusions: These encouraging results from both arms of the trial justify further clinical evaluation in a randomized, controlled trial expected to begin later in 2021. Clinical trial information: NCT03382977.
Impact of circulating tumor DNA (ctDNA) detection on survival outcomes of patients (pts) treated with immune-checkpoint inhibitors (ICIs) in early clinical trials.
Authors: Galvao Vladimir , Matos Ignacio , Moreno Ana , Alonso Guzman , Brana Irene , Villar Maria , Saavedra Santa Gadea Omar , Oberoi Honey Kumar , Ros Javier , Berche Roger , Ann Wornham Natassia , Arenillas Carlota , Saura Cristina , Oaknin Ana , Felip Enriqueta , Muñoz-Couselo Eva , Elez Elena , Tabernero Josep , Toledo Rodrigo , Garralda Elena 
Published: June 2021

2542 Background: Detection of ctDNA is a promising tool for managing pts in oncology. Most methods require whole-genome sequencing of tumor samples followed by the design of personalized panels for tracking purposes. In this work, we evaluated the prognostic and predictive value of total ctDNA quantification, using shallow whole-genome sequencing (shWGS) exclusively from plasma samples, in a prospective cohort of pts treated with ICIs in early clinical trials. Methods: IchorCNA pipeline was used to quantify ctDNA of shWGS from plasma ctDNA samples of pts treated with ICIs in phase 1 trials, collected at baseline and prior to cycle 2 (prec2). We investigated the association and correlation of ctDNA levels with surrogate markers for tumor burden (LDH levels, summatory of target lesions (TL), liver metastasis) using Spearman and Kruskal-Wallis tests. Kaplan-Meier estimates of overall survival (OS) of pts with baseline detectable ctDNA levels versus undetectable ctDNA were calculated. A multivariate Cox proportional hazards model, including continuous classical prognostic factors (LDH, albumin, hemoglobin, derived Neutrophil-to-Lymphocyte ratio (dNLR), platelets, number of metastases sites, ECOG PS) and ctDNA was performed. An estimate of progression free survival (PFS) of pts with ctDNA increase levels in preC2 versus a non-increase group was evaluated. Results: Since January 2018, 113 pts with no standard-treatment options were included. Median (m) follow up was 14.8 months (mo). Baseline ctDNA levels correlated significantly with baseline TL (R = 0.4, p < 0.001) and LDH levels (R = 0.61, p < 0.001). Pts with liver metastasis had higher levels of ctDNA (11,68 ng/ml) versus pts with no liver disease (2,31 ng/ml) (p < 0,001). In the survival analysis pts with detectable baseline ctDNA (74 pts) had significantly shorter OS compared with pts with undetectable ctDNA (39 pts); median 9.6 m (8.4 – 16.4) and NA m (13.6-NA), respectively (HR = 2.25 [1.18-4.29] p < 0.01). In the multivariate analysis, only ctDNA and albumin levels maintained the impact in OS (HR = 1.03, p < 0.05 and HR = 0.22, p < 0.05, respectively). Pts with early increases in ctDNA had a shorter PFS compared with those with a stabilization or decrease, median 1.9 m (1.6 – 4.0) and 3.0 m (2.6 – 3.8), respectively (HR = 2.19 [1.31-3.67], p < 0.01). Conclusions: Quantification of baseline ctDNA using shWGS is a strong independent prognostic factor. Early dynamic changes of ctDNA could be a useful tool to predict PFS outcomes.
Phase 1A clinical trial of the first-in-class fascin inhibitor NP-G2-044 evaluating safety and anti-tumor activity in patients with advanced and metastatic solid tumors.
Authors: Chung Vincent , Jhaveri Komal L. , Von Hoff Daniel D. , Huang Xin-Yun , Garmey Edward Graeme , Zhang Jillian , Tsai Frank Yung-Chin 
Published: June 2021

2548 Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]
Targeting innate immunity with BXCL701 in combination with pembrolizumab in patients with advanced solid cancers: Phase 2 basket study.
Authors: Karakuzu Ozgur , Tsimberidou Apostolia Maria , Holley Veronica R. , Adat Abha , Patel Sapna Pradyuman , Sood Anil K. , Conley Anthony Paul , Urschel Gabriele E , Healey Diane I. , O'Neill Vincent , Janku Filip 
Published: June 2021

2558 Background: BXCL701 is an oral competitive inhibitor of dipeptidyl peptidases (DPPs), primarily DPP8/9, which triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods: This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1-14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to an immune checkpoint inhibitors (iCPI) naïve cohort and iCPI pretreated cohort. Each cohort is planned to enroll 9 patients in the first stage, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients in the second stage. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results: As of February 11, 2021, 16 patients were treated; 5 patients (prostate cancer, endometrial cancer, liposarcoma, basal cell carcinoma, squamous cell carcinoma of unknown primary) were enrolled in the iCPI naïve cohort and 11 patients (leiomyosarcoma [2], squamous cell carcinoma of unknown primary, triple negative breast cancer, uveal melanoma, melanoma, uterine myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to iCPI pretreated cohort. Among all 16 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701, which resulted in implementation of risk-mitigation strategies such as gradual dose escalation and blood pressure monitoring. In the CPI naïve cohort, of 4 patients with available imaging, 1 had a PR (microsatellite stable endometrial cancer [-62%]) and 1 durable stable disease (SD -10%, basal cell carcinoma on therapy for 6+ months). In the CPI pretreated cohort, of 9 patients with available imaging, 1 had a PR (-31%, uveal melanoma) and 3 durable SD (-22%, pleomorphic sarcoma on therapy for 8+ months; +4%, squamous cell carcinoma of unknown primary on therapy for 6 months; +5%, uterine myxoid sarcoma on therapy for 6 months). Conclusions: BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Prespecified efficacy endpoints were met in the first stage and both cohorts will proceed to second-stage of the study Clinical trial information: NCT04171219.