bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma (DIRECTOR).
Authors: Tabatabai Ghazaleh , Wick Wolfgang , Reifenberger Guido , Steinbach Joachim Peter , Schnell Oliver , Hau Peter , Herrlinger Ulrich , Sabel Michael , Ketter Ralf , Schlegel Uwe S. , Marosi Christine , Goldbrunner Roland , Homicsko Krisztian , Nikkhah Guido , Pichler Josef , Vajkoczy Peter , Meixensberger Juergen , Weller Michael 
Published: March 2020

TPS2103 Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial is an open-label prospectively randomized phase II trial investigating 2 different TMZ rechallenge regimens, i.e. 1 week on/1 week off (Arm A, 120-150 mg/m2 per day for 7 days) versus 3 weeks on/1 week off (Arm B, 80-100 mg/m2 per day for 21 days) in recurrent glioblastoma. Patients were enrolled at first progression after having completed the first-line TMZ radiochemotherapy and at least 2 adjuvant TMZ cycles. At randomization, MGMT gene promoter methylation status from the primary or recurrent tumor was mandatory. The study treatment was monitored every 2 months by MRI using MacDonald criteria. Translational studies included blood biomarker (e.g. regulatory T cell counts, MGMT activity in peripheral blood). In addition, quality-of-life was evaluated by QLQ-C30 and QLQ-BN20 EORTC scores. Neurocognitive testing using the NeuroCogFx was optional. The primary endpoint is median time-to-treatment failure that was defined as progression, toxicity or death from any cause. Secondary endpoints are progression-free survival, overall survival, response and MGMT correlations. The trial was performed in 16 sites in Austria, Germany, and Switzerland. 105 of 166 patients have been enrolled (53 patients in Arm A and 52 patients in Arm B) before the enrollment was prematurely stopped on 30 June 2012. The database will be closed on 30 June 2013. Clinical trial information: NCT00941460.
Phase II trial of triple-receptor tyrosine kinase receptor inhibitor nintedanib (BIBF 1120) in recurrent high-grade gliomas.
Authors: Norden Andrew David , Schiff David , Ahluwalia Manmeet Singh , Lesser Glenn Jay , Nayak Lakshmi , Lee Eudocia Quant , Muzikansky Alona , Dietrich Jorg , Smith Katrina H. , Gaffey Sarah C. , McCluskey Christine Sceppa , Ligon Keith L. , Reardon David A. , Wen Patrick Y. 
Published: March 2020

TPS2104 Background: Bevacizumab is the standard of care for patients with recurrent high-grade glioma (HGG). However, with current treatment options the median duration of response is only approximately 4 months. Potential mechanisms of resistance include upregulation of fibroblast growth factor (FGF) and increased pericyte coverage mediated by platelet-derived growth factor (PDGF). Nintedanibis an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1/3, and vascular endothelial growth factor receptor (VEGFR) 1-3 that may overcome the problem of resistance to prior anti-VEGF therapy. Methods: This is an open-label, phase II trial in adults with first or second recurrence of HGG, stratified by prior therapy with bevacizumab. The primary endpoint is 6-month progression-free survival (PFS6) in the bevacizumab-naive arm and PFS3 in the post-bevacizumab arm. A Simon two-stage design is employed. Although the glioblastoma (GBM) comparison is the one of primary concern, 10 anaplastic glioma (AG) participants will be accrued to each arm in exploratory cohorts. Results: Nine of 40 GBM patients and 10 of 10 AG patients have been accrued in the bevacizumab-naive arm. Data in this arm are maturing. In the post-bevacizumab arm, 14 patients have been accrued, 10 of whom had GBM (71%). There were 11 men (79%), median age was 52 years (range 32-70), and median KPS was 90 (range, 60-100). One patient with anaplastic astrocytoma was not evaluable for response analysis because of early withdrawal of consent. There have been no responses. Two patients (1 with GBM and 1 with anaplastic oligodendroglioma) achieved stable disease. Median PFS was 28 days (95% CI: 27-28), and maximum PFS was 56 days. Median OS was 57 days (95% CI: 29-155). The post-bevacizumab arm was stopped after stage 1. Treatment was well tolerated, with limited Grade 3 liver function test abnormalities (n = 3), abdominal pain (n = 1), and hypertension (n = 1). Grade 1-2 adverse events also included diarrhea, nausea/vomiting, fatigue, and bleeding. Conclusions: Despite limited toxicity, nintedanibis ineffective in the cohort of recurrent HGG patients who failed bevacizumab. Updated results in the bevacizumab-naive arm will be presented. Clinical trial information: NCT01380782.
A phase Ib study of combined angiogenesis blockade with REGN910 (SAR307746), a selective monoclonal antibody (MAb) against angiopoietin-2 (Ang2) and ziv-aflibercept in patients with advanced solid tumor malignancies.
Authors: Adriaens Lieve , Papadopoulos Kyriakos P. , Graham Donna M. , Patnaik Amita , Razak Albiruni R.A. , Tolcher Anthony W. , Siu Lillian L. , Rasco Drew Warren , Trail Pamela , Brownstein Carrie M. , Lowy Israel 
Published: March 2020

TPS2618 Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Ziv-aflibercept (ZAFL) is a recombinant human fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF), thereby preventing the interaction of these ligands with their receptors. In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients. Methods: This phase 1b study employs a standard 3+3 dose escalation design exploring 5 different combination treatment dose levels of REGN910 and ZAFL. Once the recommended phase 2 dose (RD) of the combination treatment is determined, additional patients will be enrolled in a safety expansion cohort, for a planned total enrollment of up to 40 patients. The primary study objectives are to evaluate the safety and determine the RD of the 2 drugs in combination when both are administered IV every 2 weeks in patients with advanced solid tumors. Secondary endpoints include characterization of the PK and potential immunogenicity of REGN910 and ZAFL when given in combination, evaluation of correlative PD biomarkers related to REGN910 and ZAFL, and identification of antitumor activity. Enrollment to cohorts 1 and 2 has been completed without DLT. Enrollment to cohort 3 opened in December 2012. Updated enrollment status will be presented. Reference: ClinicalTrials.gov Identifier: NCT01688960. Clinical trial information: NCT01688960.
Phase I study of pazopanib (PAZ) in combination with PCI-24781 (PCI) in patients (pts) with metastatic solid tumors with new tumor proliferation imaging correlates in renal cell carcinoma (RCC) and sarcoma.
Authors: Truong Thach-Giao , Grabowsky Jennifer A. , Chen Stephanie , Ea Roth , Ko Andrew H. , Friedlander Terence W. , Bergsland Emily K. , Harzstark Andrea Lynne , Reinert Anne , Fung Gordon , Daud Adil , Munster Pamela N. 
Published: March 2020

TPS2623 Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (pan-HDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.
Evesor: The first phase I trial combining multiple dose/dosing schedules—Pharmacodynamic assessments and mathematical modeling to optimize the benefit/toxicity ratio of everolimus and sorafenib association.
Authors: You Benoit , Freyer Gilles , Tod Michel , Rodriguez Claire , Cassier Philippe Alexandre , Hommel-Fontaine Juliette , Valette Pierre-Jean , Guitton Jerome , Henin Emilie 
Published: March 2020

TPS2625 Background: In 2004, FDA declared the abandon rate of new oncology drugs was too high and new trial designs should be developed. The combination of everolimus (EVE) and sorafenib (SOR) is rational, and has been studied in 11 phase I studies, where approved monotherapy regimens have been used (EVE qd and SOR bid). Although promising efficacy outcomes were found, the combination may be abandoned due to metabolical and skin toxicity. The best doses and dosing schedules of EVE and SOR associated with the optimal benefit/toxicity ratio may be identified using mathematical modeling of data from an adequately designed multiparameter trial. Methods: This academic study is composed of 4 arms with different dosing schedules of EVE and SOR (qd; 1 week/2; 3 days-on …), and dose escalations. Patients with different tumor types potentially sensitive to the combination are enrolled. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies & repetitive PBMC assays; kinetics of circulating tumor DNA kinetics & angiogenesis markers; tumor angiogenesis changes using repeated DCE-ultrasounds; and radiological/clinical effects. These data enrich a translational multiscale model meant to quantify the relationships between drug dosing modalities, PK, PD, radiological and clinical effects, developed in parallel. The doses and dosing schedules of EVE and SOR which enable maximization of benefit/toxicity ratio (utility function) will be searched using simulations, and then tested. The protocol was approved by ethic committee in 2012. Two patients a month have been enrolled in 2 centers since January 2013. Expected results: Mathematical modeling of the relationships between dosing modalities; PK; PD; radiological and clinical effects based on the data from an adequately designed trial may help determine the optimal doses and dosing schedules of EVE and SOR (with the best benefit/toxicity ratio), and avoid the combination abandon. EVESOR study may embody the proof of concept of this new model-based trial design. Clinical trial information: 2012-002818-39.
Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis.
Authors: Sangro Bruno , Crocenzi Todd S. , Welling Theodore Hobart , Iñarrairaegui Mercedes , Prieto Jesús , Fuertes Carmen , Delanty Laurie , Feely William , Anderson Jeffrey , Grasela Dennis M. , Wigginton Jon M. , Gupta Ashok Kumar , Melero Ignacio 
Published: March 2020

TPS3111 Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA <100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.
A phase I/II study of multiple peptides cocktail vaccine for advanced/recurrent ovarian cancer.
Authors: Takeuchi Satoshi , Shoji Tadahiro , Kagabu Masahiro , Honda Tatsuya , Miura Fumiharu , Omi Hideo , Takada Anna , Sugiyama Toru 
Published: March 2020

TPS3116 Background: Despite improvement in chemotherapy including the molecular targeting agents, advanced or recurrent ovarian cancer (A/ROC) are still incurable. Some tumor associated proteins, hypoxia-inducible protein 2 (HIG2), and tumor related vascular endothelial growth factor receptor 1,2 (VEGFR1,VEGFR2) were found to be candidates as new targets, and their epitope peptides have been shown to have the ability to induce specific cytotoxic T lymphocyte ( CTL) responses. We conducted a phase I/II study of these peptides cocktail vaccine (PCV) in patients with A/ROC in order to evaluate toxicity, immunological response, and tumor response. Methods: 23 patients positive for human leukocyte antigen (HLA)-A2402 (A24) and 15 patients with HLA-A0201(A02) were enrolled in this study. Enrollment is still on going up to 30 evaluable patients in each group. PCV for A24 comprises FOXM1(Forkhead Box M1), MELK(maternal embryonic leucine zipper kinase), HJURP(Holliday junction recognition protein), VEGFR1 and VEGFR2. As for A02- PCV comprises HIG2, VEGFR1and VEGFR2. Cocktails were made at a dose of 1mg of each peptide with GMP grade-adjuvant, MONTANIDE ISA51. Vaccination schedule included weekly subcutaneous administration for first 12 weeks, then bi-weekly administration for next 16 weeks, then further vaccination was done monthly for 8 times and 3-6 months as a maintenance step according to patient’s need. Pre- and post-vaccination blood samples were obtained from the patients for toxicity assessment and immunological evaluation. Clinical responses were evaluated every three months by RECIST v 1.1. Results: PCV were generally well tolerated with no major adverse events, and most of the patients developed specific CTL responses. One patient showed complete response, two showed partial response and 10 showed stable disease in 22 evaluable patients. At the time of the analysis, median overall survival was 5 months (from 30 to 623 days) and 9 months(from 54 to 921 days),in A24 and A02, respectively. 11 patients remained alive with median follow up of 9 months. Conclusions: These findings suggest these peptides cocktail vaccines are safe and applicable for advanced/recurrent ovarian cancer. Clinical trial information: UMIN000003862, UMIN000003860.
Results of the CARMA study to investigate catumaxomab therapy for ascites related to peritoneal carcinomatosis in clinical practice.
Authors: Kurbacher Christian M. , Sehouli Jalid , Welslau Manfred , Tempelhoff G.-F. , Kufahl J. , Marth Christian , Oettle Helmut , Schmalfeldt Barbara , Urban Elisabeth , Kunzmann Volker 
Published: March 2020

TPS3119^ Background: The trifunctional antibody CATU (catumaxomab) is approved in the EU for intraperitoneal (IP) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive carcinomas. Clinical data for CATU are based on 2 phase III and several phase I/II trials. However, the routine use of CATU has not been evaluated systematically. Therefore, a prospective observational study (CARMA) was started in 2010 investigating the administration of CATU in a total of 160 pts with MA under routine conditions. Participating centers were hospitals and oncologic practices in Germany and Austria. Hereby, we report on the results of the 2nd interim CARMA analysis. Methods: This analysis included 103 pts with MA due to EpCAM-positive carcinomas: ovarian, n=37; gastric, n=13; pancreatic, n=10; colorectal, n=6, miscellaneous, n=37. Pts were treated with CATU at a routine setting at 4 increasing dosages over a 2-week interval. The primary endpoint was puncture-free interval (PFI), secondary endpoints included safety and overall survival (OS). Results: The study population mainly comprised pts with advanced-stage disease. In 65% distant metastases were present. Therapy was given in 24 hospitals (73 %) and 9 outpatient facilities (27 %). Pts suffered from typical MA related symptoms such as abdominal swelling (77%), pain (56%), dyspnea (27%), anorexia (31%), constipation (13%). In 67 pts (65%), CATU was given as planned, 36 pts (35%) received <4 infusions. Most frequent adverse events (AE) were fever (20%), nausea (14%) and diarrhea (6%).The median PFI was 57 days (d), the median OS was 100 d. For the subgroups ovar/non-ovar, a median PFI of 93/41 d and a median OS of 115/72 d was observed. Conclusion: CARMA represents the first systematic evaluation of CATU therapy given for MA under routine conditions. In accordance to previous prospective trials, the presented 2nd interim-analysis was able to demonstrate a clinically meaningful benefit of CATU, particularly impressive in ovarian cancer pts. CATU showed an acceptable safety profile, thus allowing for treatment at an outpatient setting in an adequately selected group of pts. The final CARMA analysis after including 160 pts is thus eagerly awaited. Clinical trial information: DRKS00000458.
A multipeptide vaccine plus toll-like receptor agonists in melanoma patients, with evaluation of the vaccine site microenvironment and sentinel immunized node (Mel58; NCT01585350).
Authors: Slingluff Craig L. , Petroni Gina R. , Chianese-Bullock Kimberly A. , Grosh William W. , Weiss Geoffrey R. 
Published: March 2020

TPS3125 Background: Recent data show clinical activity of cancer vaccines containing a defined cancer antigen, and a peptide vaccine for melanoma. However, immune responses to peptide vaccines are often transient and of low magnitude. The most common adjuvant for peptide vaccines for melanoma has been an incomplete Freund’s adjuvant (IFA), which may have suboptimal adjuvant properties. Toll-like receptor (TLR) agonists offer the potential to improve the magnitude and persistence of antitumor T cell responses, either in combination with IFA or alone. CD40 ligation at the vaccine site microenvironment (VSME) may also improve adjuvant activity of TLR agonists and may be provided by CD4 T cell activation. We report a clinical trial of a multipeptide vaccine using TLR agonists and IFA, with correlative studies in 3 immunologic compartments. Methods: This trial is enrolling patients with resected stage IIB-IV melanoma (n=48) and is designed to evaluate the safety and immunogenicity of vaccination with peptides and either of 2 toll-like receptor agonists (TLR3 agonist polyICLC; TLR4 agonist endotoxin), with or without IFA. Patients are vaccinated 6 times over 12 weeks with 12 Class I MHC-restricted nonamer peptides. An immunogenic tetanus helper peptide is included to activate CD4 T cells in the VSME and secondarily to ligate CD40. Goals include safety assessment, measures of CD8 T cell responses, and characterization of cellular and molecular events induced in the blood, VSME and vaccine-draining node (sentinel immunized node, SIN), as well as a preliminary assessment of whether vaccination with TLR agonists improves the persistence of CD8 and CD4 T cell responses to melanoma antigens compared to prior studies with IFA. This includes a first-in-humans evaluation of the safety and immunogenicity of LPS, a classic TLR4 agonist, as a vaccine adjuvant. Thus, there is a novel dose-escalation phase with this adjuvant, which has been safely administered in other settings by intravenous and inhalation routes. An aim of this study is to identify an improved adjuvant for use in future trials combining peptides with other immune therapies. Clinical trial information: NCT01585350.