bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: The ARETHUSA trial.
Authors: Siena Salvatore , Sartore-Bianchi Andrea , Personeni Nicola , Pietrantonio Filippo , Germano Giovanni , Amatu Alessio , Bonoldi Emanuela , Valtorta Emanuele , Barault Ludovic , Di Nicolantonio Federica , Siravegna Giulia , Crisafulli Giovanni , Rimassa Lorenza , De Braud Filippo G. , Santoro Armando , Lazzari Luca , Luraghi Paolo , Amirouchene-Angelozzi Nabil , Bardelli Alberto , Marsoni Silvia 
Published: May 2019

TPS2659 Background: Metastatic colorectal cancer (CRC) harbouring genetic defects in the mismatch-repair pathway (MMRd) presents with a high tumor mutational burden (TMB), and is highly sensitive to anti–programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes, and consequently the increase of TMB and immunogenic neoantigens, thus suggesting that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods: Arethusa (NCT03519412) is a 2-cohorts, phase II trial consisting of three different phases. In the SCREENING, 348 mCRC RAS-mutated patients will be tested for MMR status. MMRd patients will proceed directly to TRIAL for immediate pembrolizumab treatment (expected 14). MMR-proficient (MMRp) patients will be further tested for expression of O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. IHC-negative, promoter methylation-positive MMRp patients (expected 67) will enter in the PRIMING phase and will be treated with TMZ until PD. TMB will then be assessed on tumor biopsies at resistance. Those patients that will have > 20 mutations/megabase will proceed to TRIAL (expected 20) and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated., while the MMRd cohort will be used for comparison. Tissue biopsies, longitudinal blood and stool collection will be used for discovery of predictive molecular biomarkers and assessment of tumor evolution. Clinical trial information: NCT03519412.
A multicenter, phase II study of soluble LAG-3 (Eftilagimod alpha) in combination with pembrolizumab (TACTI-002) in patients with advanced non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC).
Authors: Peguero Julio Antonio , Bajaj Pawan , Carcereny Enric , Clay Timothy Dudley , Doger Bernard , Felip Enriqueta , Krebs Matthew , Forster Martin , Ponce Aix Santiago , Roxburgh Patricia , Triebel Frederic 
Published: May 2019

TPS2667 Background: Eftilagimod alpha (efti, IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Pembrolizumab binds to the PD-1 receptor, blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help restore effector T-cell responses. The rationale to combine efti and pembrolizumab comes from their complementary mechanisms of action. Efti activates APCs and lead to an increase in activated T cells which effect potentially reduces the number of non-responders to pembrolizumab. Combining an APC activator like efti to pembrolizumab is therefore fundamentally different from many other trials combining two checkpoint inhibitors like an anti-LAG-3 mAb with an anti-PD-1 mAb. In a previous phase I study (NCT 02676869) in metastatic melanoma the combination was found to be safe and well tolerable with encouraging signs of clinical activity. Methods: In the course of this multicenter, open label, Phase II study, patients will be recruited for each of three indications: A: 1st line, PD-X (PD-1 or PD-L1) naïve non-small cell lung cancer (NSCLC); B: 2nd line, PD-X refractory NSCLC; C: 2nd line PD-X naive head and neck squamous cell carcinoma (HNSCC). The study is designed according to Simon's optimal two-stage design, with objective response rate acc to iRECIST as primary endpoint. Secondary endpoints include progression free survival and overall survival. In case there are more responses achieved than a predefined threshold (each part counted separately) in pts recruited in the initial stage (n = 58), additional pts (51) will be recruited in stage 2. Efti will be administered for a maximum of 18 cycles (1 cycle = 3 weeks) as 30 mg subcutaneous injection every 2 weeks for the first 8 and every 3 weeks for the 10 following cycles. Pembrolizumab (200 mg intravenous infusion every 3 weeks) is administered in parallel for up to 35 cycles. Patients are followed up for progression and survival. Clinical trial information: 03625323.
A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.
Authors: Pant Shubham , Mulder Imke , Shah Amishi Yogesh , Msaouel Pavlos , Altan Mehmet , Weinberg John , Stevenson Alex , Meric-Bernstam Funda , Yap Timothy A , Subbiah Vivek , Rodon Ahnert Jordi 
Published: May 2019

TPS2670 Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803.
An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.
Authors: Middleton Mark R. , Sacco Joseph J. , Merchan Jaime R. , Curti Brendan D. , Vanderwalde Ari M. , Olsson-Brown Anna Claire , Aroldi Francesca , Fotiadis Nicos , Baum Scott , Coffin Robert S. , Kaufman Howard , Harrington Kevin J. 
Published: May 2019

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.
A phase I study of [225Ac]-FPI-1434 radioimmunotherapy in patients with IGF-1R expressing solid tumors.
Authors: Juergens Rosalyn A. , Zukotynski Katherine A. , Juneau Daniel , Krnezich Lily , Simms Ryan , Forbes John , Burak Eric S. , Valliant John , Stafford Lauren , Armor Thomas , Molnar Istvan , Saad Fred 
Published: May 2019

TPS3152 Background: Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors including non–small cell lung, prostate, and breast cancers. [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and an alpha-emitting radionuclide actinium-225 (Ac-225), which binds to the external domain of IGF-1R. Internalization of the conjugate and decay of Ac-225 causes tumor cell death primarily through double stranded DNA breaks. The indium-111 analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection, in-vivo imaging, and quantification of IGF-1R targets prior to therapy. Based on anti-tumor activity of [225Ac]-FPI-1434 in preclinical models, favorable toxicology studies in cynomolgus monkeys, and prior human experience with the unconjugated antibody, the first in human clinical evaluation was initiated. Methods: This open-label multi-center phase I study (NCT03746431) follows a modified 3+3 dose-escalation design to characterize the safety profile, determine a maximum tolerated dose (MTD), evaluate dose-limiting toxicities (DLT), describe pharmacokinetics, derive radiation dose estimates to normal organs, and evaluate the objective response rate of [225Ac]-FPI-1434 therapy in patients with IGF-1R expressing solid tumors. Eligibility requirements for therapy include: presence of at least one measurable lesion as determined by sufficient tumor uptake using SPECT/CT of an imaging analog [111In]-FPI-1547; radiation dose estimates of the planned therapeutic activity within prespecified limits; and adequate bone marrow reserves, hepatic, and renal function. Dose cohorts begin with 10 kBq [225Ac]-FPI-1434 per kilogram (kg) patient weight and successively increase to 20, 40, 80, and 120 kBq/kg as a single intravenous injection per patient followed by an 8-week DLT evaluation period. This trial is currently enrolling patients. Clinical trial information: NCT03746431.
TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with FGFR alterations identified by circulating tumor DNA.
Authors: Jogo Tomoko , Nakamura Yoshiaki , Komatsu Yoshito , Kato Ken , Shinozaki Eiji , Bando Hideaki , Kato Takeshi , Nishina Tomohiro , Esaki Taito , Fujii Satoshi , Suzuki Mitsuko , Fuse Nozomu , Sato Akihiro , Nomura Shogo , Lefterova Martina , Odegaard Justin , Ebi Hiromichi , Yoshino Takayuki 
Published: May 2019

TPS3156 Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.
FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.
Authors: Hyman David Michael , Goyal Lipika , Grivas Petros , Meric-Bernstam Funda , Tabernero Josep , Hu Youyou , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Anne , Zanna Claudio , Flaherty Keith 
Published: May 2019

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.
SGNTV-001: Open label phase 2 study of tisotumab vedotin for locally advanced or metastatic disease in solid tumors.
Authors: Hong David S. , Tehrani Omid S. , Safran Howard , Steuer Conor Ernst , Lacy Jill , Taylor Matthew H. , George Thomas J. , Rangwala Reshma A. , Jain Shweta , Viana Nicacio Leonardo , Cho May Thet 
Published: May 2019

TPS3160 Background: Tisotumab vedotin (TV) is being developed for patients with cervical cancer and other solid tumors known to express Tissue Factor (TF). Expression of TF on tumor cells has been associated with poor prognosis in several tumor types. Four tumor types were chosen for this study based on unmet medical need and TF expression. TV is an antibody-drug conjugate composed of a TF-targeted fully human monoclonal immunoglobulin G1 conjugated via a protease-cleavable valine citrulline linker to the drug monomethyl auristatin E (MMAE). TV-mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). In preclinical studies, TV treatment resulted in potent and long-lasting tumor regression in TF-expressing xenograft models derived from a variety of solid cancers, including patient-derived xenograft models with heterogeneous TF expression. TV has shown preliminary evidence of activity in heavily pretreated patients with many TF-expressing tumor types in the GEN701 phase 1 study. Methods: SGNTV-001 (innovaTV 207) is a global, open label, multicenter phase 2 trial designed to assess the safety, tolerability, and activity of TV for the treatment of solid tumors. (NCT03485209; EudraCT 2017-005076-26). Patients are currently enrolling in 4 cohorts: colorectal cancer (CRC), squamous non-small cell lung cancer (NSCLC), exocrine pancreatic adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN). Patients must have measureable disease per RECIST v1.1 that has progressed despite standard of care systemic treatment in the locally advanced or metastatic setting (up to 3 prior lines for CRC, 2 for squamous NSCLC and SCCHN, and 1 for pancreatic adenocarcinoma) and have an ECOG score of 0 or 1. The primary endpoint is investigator-determined confirmed ORR as measured by RECIST v1.1. Secondary objectives include DOR, PFS, OS, DCR, and TTR, as well as safety and pharmacokinetic parameters. The first patient was enrolled in July 2018 and the study is currently enrolling across 16 sites in the US (as of January 2019) with additional sites opening in EU countries. Clinical trial information: NCT03485209.
A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer.
Authors: Schoffski Patrick , Aftimos Philippe Georges , Massard Christophe , Italiano Antoine , Jungels Christiane , Andreas Karen , Keegan Mitchell , Ho Peter T.C. 
Published: May 2019

TPS3162 Background: RET gene alterations (mutations and fusions) leading to constitutive kinase activity have been identified in various tumor types including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), colon, breast and ovarian cancer. The current generation of multi-kinase inhibitors approved for treatment of such tumors, do not selectively target RET and exhibit significant off-target activity especially against vascular endothelial growth factor receptor 2 (VEGFR2), resulting in dose-limiting toxicities that prevent the full inhibition of RET in those tumors. Recently, early clinical data from a class of more selective RET inhibitors have shown promising results with a more favorable safety profile in patients with RET alterations. BOS172738 is a novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2. This phase 1 study is assessing the safety and tolerability of BOS172738 in patients with advanced solid tumors with RET alterations. Methods: NCT03780517 is a phase 1, open label, multicenter, dose escalation trial to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738, an orally dosed RET kinase inhibitor, in patients with advanced solid tumors with RET gene alterations. RET gene alteration status will be assessed locally but confirmed centrally. The study is comprised of 2 parts: in Part A (dose escalation), patients with advanced solid tumors with RET gene alterations will receive BOS172738 orally once daily in each 28-day cycle. Select patients in Part A are eligible for intrapatient dose escalation. On establishing the recommended phase 2 dose (RP2D), Part B (expansion) will enroll up to an additional 60 patients to 1 of 3 tumor type-specific cohorts. The 3 expansion cohorts will each consist of up to 20 advanced cancer patients with: 1) RET gene-fusion NSCLC; 2) RET gene-mutant MTC; and 3) other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy. Patients in expansion cohorts will receive BOS172738 daily at the RP2D until disease progression or other discontinuation criteria have been met. The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517.