bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRUST-II: A global phase II study for taletrectinib in ROS1 fusion–positive lung cancer and other solid tumors.
Authors: Nagasaka Misako , Sugawara Shunichi , Choi Chang-Min , Okamoto Tatsuro , Yanagitani Noriko , Nosaki Kaname , Takahashi Toshiaki , Fujiwara Yutaka , Hayashi Hidetoshi , Khoury John , Nieva Jorge J. , Gabayan A. Eli , Raez Luis E. , Chen Hongbin , Dimou Anastasios , Pennell Nathan A. , Liu Geoffrey , Ou Sai-Hong Ignatius , Seto Takashi , Ohe Yuichiro 
Published: June 2022

TPS8601 Background: Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK positive solid tumors in an ongoing phase 2 study (NCT04617054). Methods: TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N = 53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N = 46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N = 10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1 positive solid tumor other than NSCLC (N = 10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. Clinical trial information: NCT04919811.
Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).
Authors: Zhang Fan , Hu Yi , Han Xiao , Hu ZhiSong 
Published: June 2022

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.
A randomized, controlled, open-label, phase 2 study of cemiplimab ± RP1 in patients with advanced cutaneous squamous cell carcinoma (CERPASS).
Authors: Haydon Andrew Mark , Khushalani Nikhil I. , Robert Caroline , Brungs Daniel , Collichio Frances A. , Colevas A. Dimitrios , Lim Annette May Ling , Kudchadkar Ragini Reiney , Chai-Ho Wanxing , Daniels Gregory A. , Lutzky Jose , Lee Jenny HJ , Silk Ann W. , Lebbe Celeste , Grob Jean-Jacques , Smith Margaret , Fury Matthew G. , Alamgeer Muhammad , Hill Andrew Graham , Migden Michael Robert 
Published: June 2022

TPS9593 Background: RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy. The prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients despite the adoption of cemiplimab and pembrolizumab as a standard treatment. Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC. This study is evaluating the efficacy and safety of cemiplimab ± RP1 versus cemiplimab alone in advanced CSCC. Methods: This global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiation therapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial is enrolling approximately 180 pts from centers in the EU, Australia, Canada, and USA. Pts are randomized in a 2:1 ratio to receive combination therapy or monotherapy respectively. Pts receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 is injected intratumorally at a starting RP1 dose of 1 × 106 plaque-forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 107 PFU/mL Q3W together with the same dose of cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses if protocol specific criteria are met. No crossover is allowed. Pts are stratified by disease status (nodal or distant metastatic or locally advanced CSCC) and prior systemic therapy. Tumor assessments are performed every 9 weeks. The dual independent primary endpoints are overall response rate and complete response rate, both by a blinded independent review. Secondary endpoints include safety, progression-free survival, duration of response, and overall survival. Exploratory endpoints include quality of life, and immune biomarker analyses. This trial is currently enrolling pts. Clinical trial information: NCT04050436.
Early together: A randomized phase III study of early palliative care in metastatic uveal melanoma (MUM).
Authors: Piperno-Neumann Sophie , Rodrigues Manuel , Marchal Timothee , Gastaud Lauris , Fogliarini Anne , Bouleuc Carole , Libert Yves , de Koning Leanne , Bredart Anne , Savignoni Alexia , Dolbeault Sylvie , Burnod Alexis 
Published: June 2022

TPS9598 Background: Uveal melanoma is a rare cancer. Up to 50% of patients (pts) develop metastasis, mainly hepatic. Overall survival in metastatic pts is 12 months (mo), contrasting with a good overall condition until death. To evaluate the impact of integrating early palliative care on patient needs and self-efficacy, we designed a comparative randomized trial in MUM pts. Methods: 162 pts will be randomized (1:2) between the control and the experimental groups in two French centres (Institut Curie-Paris and Centre Antoine Lacassagne-Nice). In the control group, palliative care is introduced according to international guidelines. In the experimental group, it is added earlier, concomitant to the announcement of metastases by the medical oncologist. The main objective is to assess if early supportive care impacts on patient psychological needs at 6 mo, versus standard of care, based on the SCNS-SF34 questionnaire. Secondary objectives include patient’s other needs at 6 and 12 mo, quality of life (QLQ-C30), progression-free and overall survival, and partners’ needs (SCNS-P&C). MUM pts, suitable for a treatment with no curative intent, ECOG PS 0-1, with no physical or biological sign of disease, and capable of filling questionnaires are eligible. Questionnaires are completed by all pts at each oncological visit (baseline, 3, 6, 9 and 12 mo). Supportive care visits take place every 6 weeks if needed and address patient’s information needs, disease and treatment understanding, social and psychological status, symptoms, and partners’ involvement. Prognostic uncertainty and disease seriousness in the absence of symptom is addressed depending on pts’ expressed needs. Medical oncologists and supportive care physicians from both centres attend communication skill training provided by an expert during the study. Analyses: SCNS-SF34 psychological needs scale scores at 6-mo will be compared with a Student’s t-test, in an ITT analysis. For 10 points mean score difference expected between groups (within standard deviation of 20 points) and a two-sided type 1 error of 5%, inclusion of 54 pts (control group) and 108 pts (experimental group) provides the study 85% of power. The planned inclusion period is 3 years, pts will be followed for one year, for a total study duration of 4 years. From July 2020 to January 2022, 63 pts have been enrolled in the trial; 2 pts declined. Five pts were removed early from the study: one for consent retrieval, 4 for early death due to metastasis. COVID-19 delayed enrollment for 5 months. We plan to complete the study Q4 2023 and to analyze the data Q4 2024. Clinical trial information: NCT04728113. [Table: see text]
Tocilizumab in combination with ipilimumab and nivolumab in solid tumors.
Authors: Abdel-Wahab Noha , Montazari Emma , Spillson Christine , Bentebibel Salah-Eddine , Awiwi Muhammad , Elsayes Khaled M. , Gao Jianjun , Altan Mehmet , Wong Michael K.K. , Glitza Isabella Claudia , Amaria Rodabe Navroze , McQuade Jennifer Leigh , Patel Sapna Pradyuman , Tawbi Hussein A. , Davies Michael A. , Yee Cassian , Sharma Padmanee , Allison James Patrick , Ekmekcioglu Suhendan , Diab Adi 
Published: June 2022

TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.
Design and rationale of a first-in-human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible (irrev), pan-FGFR inhibitor (FGFRi), in adult patients with solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822).
Authors: Goyal Lipika , Perez Cesar Augusto , Kato Shumei , Sharma Manish , Garmezy Benjamin , Kobayashi Ken , Franovic Aleksandra , Tam Betty , Voong Cynthia 
Published: June 2022

TPS9601 Background: FGFR1-4 gene alterations are observed in approximately 7% of all human cancers. There are currently 3 FDA-approved, reversible FGFRi for treatment of patients w/previously treated, locally advanced or metastatic (met) cholangiocarcinoma (CCA) harboring FGFR2 gene fusions/rearrangements (pemigatinib and infigratinib) or met urothelial carcinoma (UC) w/susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib). A major limitation of approved and clinical-stage FGFRi is emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. Up to 67% of CCA patients treated with either reversible or irrev FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irrev, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated w/disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in 28d GLP toxicology studies in rats and beagle dogs and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models in vitro and in vivo. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced & metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given po qd continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 120 pts: Part A is a dose-escalation to MTD for pts w/AMST having either FGFR2 and/or FGFR3 alterations. Part A assesses single agent KIN-3248; Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (ICC, UC, or other AMST), each driven by specified FGFR alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-1, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. FGFRi-naïve & -pretreated patients are both eligible. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Enrollment is expected to commence in April 2022. Clinical trial information: NCT05242822.
A first-in-human, phase 1b study to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of neoadjuvant use of ph-762 administered intratumorally in subjects with advanced melanoma.
Authors: Robert Caroline , Roy Severine , Cuiffo Benjamin , Cardia James , Fricker Simon Paul 
Published: June 2022

TPS9608 Background: Antibodies targeting immune checkpoints such as PD-1 and CTLA-4 has shown significant benefit in late-stage melanoma. But further improvements in therapeutic options are still required. Two approaches for improving the outcome of immunotherapy with checkpoint inhibitors are neoadjuvant treatment and local intratumoral (IT) injection. IT immunotherapy uses the tumor as its own vaccine to activate the immune system, priming an anti-tumor immune response and generating systemic tumor responses, whilst minimizing systemic exposure and off-target toxicities. Neoadjuvant therapy provides the opportunity for preoperative disease shrinkage with the potential to improve surgical morbidity. There is currently no neoadjuvant standard of care for resectable, advanced melanoma patients. PH-762 is a potent RNAi molecule targeting PD-1 with structural and chemical modifications conferring properties suitable for IT administration, including an optimized cell and tissue uptake profile. Pharmacology studies show potent in vitro silencing of PD-1 associated with T cell activation, and robust, dose-dependent in vivo inhibition of tumor growth in syngeneic tumor models. Methods: The purpose of this study is to evaluate the safety of neoadjuvant use of PH-762 administered by IT injection in subjects with resectable stage IIIB/IIIC/IIID or IV melanoma, to determine the recommended Phase 2 dose, PK after IT injection, and potential immunologic and pathologic tumor responses. Study treatment constitutes of once weekly injections with PH-762 into one designated tumor lesion for 4 weeks prior to surgical excision at 5-6 weeks after the initial injection, with up to 5 dose levels tested in a serial fashion in cohorts of 3 or more subjects. Eligible subjects will have at least one resectable melanoma deposit that is large enough to allow IT injection, and that can undergo repeated biopsy. Subjects with active brain metastases, leptomeningeal disease, uveal melanoma, and auto-immune disease are excluded. The dose of PH-762 will be normalized to tumor volume to ensure an equivalent local dose (tumor tissue concentration). Post tumor excision, subjects will be followed-up for 6 weeks. Primary endpoint is to determine a safe dose of PH-762 assessed by incidence of Dose Limiting Toxicities (DLT) prior to tumor resection. Bayesian optimal interval (BOIN) design will be employed to evaluate escalating doses of PH-762 to determine the Maximum Tolerated Dose based on occurrence of DLT. Tumor changes will be evaluated per RECIST criteria (version 1.1 and iRECIST version adapted for use with IT therapy) and pathological response. Immunological response in tumor tissue and blood samples will be assessed as secondary endpoints. Enrollment commenced in February 2022. Clinical trial information: 2021-002859-10.
High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma
Authors: Bertamini Luca , Oliva Stefania , Rota-Scalabrini Delia , Paris Laura , Morè Sonia , Corradini Paolo , Ledda Antonio , Gentile Massimo , De Sabbata Giovanni , Pietrantuono Giuseppe , Pascarella Anna , Tosi Patrizia , Curci Paola , Gilestro Milena , Capra Andrea , Galieni Piero , Pisani Francesco , Annibali Ombretta , Monaco Federico , Liberati Anna Marina , Palmieri Salvatore , Luppi Mario , Zambello Renato , Fazio Francesca , Belotti Angelo , Tacchetti Paola , Musto Pellegrino , Boccadoro Mario , Gay Francesca 
Published: June 2022

PURPOSEHigh levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement.METHODSCTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10–5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643 ). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10–5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity.RESULTSCTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039).CONCLUSIONIn multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.