bluuebunny/crossref_metadata_2025_split huggingface dataset:
REPLACEMENT trial in progress: Combination therapy with atezolizumab plus bevacizumab for TACE unsuitable patients with beyond up-to-seven criteria in intermediate stage hepatocellular carcinoma: A phase II study.
Authors: Ueshima Kazuomi , Kudo Masatoshi , Yamanaka Takeharu , Aikata Hiroshi , Yamashita Tatsuya , Ikeda Masafumi , Tateishi Ryosuke , Moriguchi Michihisa , Hiraoka Atsushi , Tsuchiya Kaoru , Ogasawara Sadahisa , Mochida Satoshi , Miyayama Shiro , Hasegawa Kiyoshi , Yoshimura Kenichi , Takehara Tetsuo 
Published: June 2021

TPS4162 Background: Transarterial chemoembolization (TACE) had been developed as a standard of care in patients with intermediate-stage HCC at a time when systemic therapy was not available. This stage includes a certain TACE-unsuitable subpopulation, such as beyond up-to-seven criteria. Recently, the American Association for the Study of Liver Diseases and Asia-Pacific Primary Liver Cancer Expert Meeting have recommended systemic therapy for those patients to achieve overall survival (OS) beyond 2 years without impaired liver function in their consensus guideline. However, there is not enough data on systemic therapy for this population. Atezolizumab (Atezo), anti-PD-L1 antibody, plus Bevacizumab (Bev), anti-VEGF antibody, combination therapy has been shown to significantly improve OS, progression-free survival (PFS), and overall response rate (ORR) against sorafenib, which is a standard of care in unresectable HCC according to a phase III randomized controlled trial, IMbrave150. Therefore, we investigate the efficacy and safety of Atezo+Bev combination therapy in patients with HCC beyond up-to-seven criteria in this trial. Methods: REPLACEMENT trial is a multicenter, single-arm phase II study of Atezo+Bev combination therapy. Key eligibility criteria are age ≥20 years, ECOG performance status 0-1, Child-Pugh A, no vascular invasion, no extrahepatic metastasis, beyond up-to-seven criteria, and patients who have received neither systemic therapy nor TACE. Patients will be administrated Atezo 1200 mg/body + Bev 15 mg/kg once every 3 weeks. The primary endpoint is PFS per modified RECIST (mRECIST). The secondary endpoints include PFS, ORR, duration of response (DOR) per mRECIST; PFS, ORR, DOR per RECIST ver.1.1; OS and safety including change of liver function based on albumin-bilirubin (ALBI) score until disease progression. A total of 60 events are necessary to investigate the hypothesis that a target point estimation of PFS rate at 6 months (null population: 55%, alternative population: 73%). The estimated sample size is, therefore, 70 patients. In addition, the results of the Atezo+Bev therapy in this arm will be compared with those in approximately 600 TACE treated consecutive patients with intermediate-stage HCC, using the propensity score matching method, as an exploratory analysis of a possible replacement of TACE by the Atezo+Bev therapy. Patients’ enrollment had already started in December 2020, and 12 patients were enrolled as of 16th February ’21. Clinical trial information: jRCTs071200051.
Phase I study of CCW702, a bispecific small molecule-antibody conjugate targeting PSMA and CD3 in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Markowski Mark Christopher , Kilari Deepak , Eisenberger Mario A. , McKay Rana R. , Dreicer Robert , Trikha Mohit , Heath Elisabeth I. , Li Jing , Garzone Pamela D. , Young Travis S. 
Published: June 2021

TPS5094 Background: CCW702 is a novel bispecific antibody comprised of a small molecule imaging agent ligand (DUPA) with specificity for prostate specific membrane antigen (PSMA) conjugated to an anti-CD3 antibody via an unnatural amino acid. This format has the structure of an antibody drug conjugate with the activity of a CD3-engaging bispecific antibody. The design of CCW702 was leveraged to optimize the structure and function of T cell redirected cytotoxicity against PSMA-positive prostate cancer tumors in preclinical development. Methods: This is a first-in-human, open-label, multi-center phase 1 study evaluating the safety and tolerability of CCW702 when administered via subcutaneous (SC) injection in men with mCPRC. This study will be conducted in two parts: Part I, a dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD); Part II, a dose expansion to determine efficacy at the R2PD. Safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy will be evaluated. Efficacy will be assessed by change in circulating tumor cells (CTC), PSA50 response rate, and objective tumor response by RECIST v1.1. Key biomarkers include characterization of CTC, T cell phenotyping in peripheral blood, chemokines and cytokines over time, and evaluation of available tumor biopsies by IHC. Key inclusion criteria include men age ≥ 18 years with histologically or cytologically confirmed adenocarcinoma who, in the metastatic setting, have progressed on at least one novel AR-targeted therapy. Up to 1 prior chemotherapy regimen is allowed. This study will enroll 20-30 patients in Part 1 and approximately 40 patients in Part 2. The study opened in December 2019 and is currently enrolling in the dose escalation phase. Clinical trial information: NCT04077021.
AdvanTIG-202: A phase 2 study investigating anti-TIGIT monoclonal antibody ociperlimab plus anti-PD-1 monoclonal antibody tislelizumab in patients with previously treated recurrent or metastatic cervical cancer.
Authors: Wu Lingying , Wang Peng-Hui , Hsiao Sheng-Yen , Chang Chih-Long , Kim Hee Seung , LEE JUNG-YUN , Ryu Sang-Young , Zuo Yunxia , Mu Xiyan , Gao Yujuan , Yang Silu , Lee Jae-Kwan 
Published: June 2021

TPS5595 Background: Women with recurrent/metastatic cervical cancer represent a poor prognostic group with high unmet clinical needs. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor expressed on immune cells and upregulated on T-cells and natural killer cells in multiple solid tumors, inhibiting anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Tislelizumab is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-202 is a Phase 2, randomized, multicenter, open-label study (NCT04693234). Approximately 167 pts with cervical squamous cell or adenosquamous carcinoma or adenocarcinoma, recruited from 100 centers, whose disease progressed on or after ≥ 1 prior line of chemotherapy for recurrent/metastatic disease will be included in this 2-Part study. In Part 1, approximately 80 pts will be randomized (1:1) to either ociperlimab 900 mg intravenously (IV) in combination with tislelizumab 200 mg IV every 3 weeks (Q3W) (Arm 1), or tislelizumab monotherapy 200 mg IV Q3W (Arm 2), until disease progression, unacceptable toxicity, or withdrawal of consent. In Part 2, Arm 1 will be expanded by approximately 87 additional pts whose tumors are evaluable for PD-L1 expression. The primary endpoint is overall response rate (ORR) (RECIST v1.1) assessed by Independent Review Committee (IRC) in Arm 1. Secondary endpoints are investigator-assessed ORR in Arm 2, IRC-assessed and investigator-assessed ORR in Arm 1, IRC-assessed and investigator-assessed duration of response, progression-free survival, time to response, disease control rate, clinical benefit rate and overall survival, cancer-specific health-related quality of life (HRQoL), safety, pharmacokinetics and immunogenicity in Arms 1 and 2. Exploratory endpoints are generic HRQoL and the association of biomarkers with patient prognosis, response or resistance. Clinical trial information: NCT04693234.
SIENDO/ENGOT-EN5/GOG-3055: A randomized phase 3 trial of maintenance selinexor versus placebo after combination platinum-based chemotherapy in advanced or recurrent endometrial cancer.
Authors: Vergote Ignace , Perez-Fidalgo Jose Alejandro , Hamilton Erika P. , Van Gorp Toon , Valabrega Giorgio , Laenen Annouschka , Oza Amit M. , Levy Tally , Cibula David , Sehouli Jalid , Guerra Eva , Chon Hye Sook , Bergamini Alice , Romero Ignacio , Michel Dayana , Shah Jatin J. , Monk Bradley J. , Slomovitz Brian M. , Mirza Mansoor Raza , Makker Vicky 
Published: June 2021

TPS5610 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Options for advanced or recurrent EC following platinum-based therapy and/or radiotherapy are limited and prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone is approved for relapsed/refractory multiple myeloma. In addition, selinexor monotherapy has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase 2 study, 50 mg/m2 (̃80 mg) selinexor administered twice weekly demonstrated a disease control rate ( SD ≥ 12 weeks or a PR) of 35% with 2 confirmed partial responses among 23 heavily pretreated EC patients); similar results were observed in 60 pts with platinum resistant or refractory ovarian cancer (median 5 prior regimens, ORR 8%, DCR 30%) (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent EC following platinum-based chemotherapy. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase 3 study in patients in partial (PR) or complete remission (CR) after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 248 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrence at the time of taxane-platinum therapy and disease status after chemotherapy (PR vs CR). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.
A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) endometrial cancer (EC).
Authors: Porter Rebecca L. , Veneris Jennifer Taylor , Tayob Nabihah , West Gabriela , Polak Madeline , Gardner Jeanette , Campos Susana M. , Krasner Carolyn N. , Lee Elizabeth Katherine , Liu Joyce F. , Stover Elizabeth , Wright Alexi A. , Matulonis Ursula A. , Konstantinopoulos Panagiotis A. 
Published: June 2021

TPS5611 Background: Folate receptor-alpha (FRα) is expressed on endometrial cancer (EC) cells and is associated with poor prognosis. Mirvetuximab soravtansine (ImmunoGen), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 study with dose expansion in FRα+ advanced/recurrent EC (NCT01609556) and also when combined with chemotherapy, bevacizumab as well as pembrolizumab (NCT02606305). In addition to having direct target-mediated cytotoxicity, ADCs also stimulate the local tumor immune microenvironment. Mirvetuximab soravtansine has been shown to activate monocytes and promote phagocytosis of mirvetuximab-treated FRα-positive tumor cells through a mechanism of Fc-FcγR interaction. Further, the combination of ADCs with immune checkpoint inhibitors (ICI) can overcome primary resistance to immunotherapy in murine models. Given the low response of MSS endometrial cancers to PD-1 blockade, we hypothesized that addition of mirvetuximab may enhance response of these tumors to immunotherapy. Methods: This is a Phase 2, single cohort study of mirvetuximab soravtansine with pembrolizumab in recurrent or persistent EC. Patients must have advanced or recurrent MSS serous endometrial cancer with at least 1 and up to 3 prior lines of therapy. Confirmation of FRα expression (with PS2+ staining intensity in ≥ 50% of cells, performed centrally at Ventana Medical Systems, Inc) is required. Prior receipt of ICI is excluded. Patients will receive the combination of mirvetuximab soravtansine 6 mg/kg AIBW IV and pembrolizumab 200 mg IV administered every 21 days. The co-primary endpoint is progression-free survival at 6 months (PFS6) and objective response rate (ORR) by RECIST 1.1. Translational objectives include assessment of tumor infiltrating lymphocytes (TILs), expression of immune checkpoint markers, and whole exome sequencing (WES) for DNA repair pathway mutations, neoantigens, and polymorphisms in immunologically relevant genes. Statistical considerations are for a Simon two-stage optimal design with 16 patients in Stage 1 and 19 patients in Stage 2, to a total of 35. Prespecified activity for the first stage of accrual was met, and second stage accrual began November 2020. Clinical trial information: NCT03835819.
The BURAN study of buparlisib (AN2025) in combination with paclitaxel compared to paclitaxel alone, in patients with recurrent or metastatic head and neck squamous cell carcinoma.
Authors: Soulieres Denis , Faivre Sandrine J. , Dreyer Kevin , Licitra Lisa F. 
Published: June 2021

TPS6090 Background: Buparlisib (AN2025) is a 2,6-dimorpholino pyrimidine derivative oral pan-class I PI3K inhibitor. The PI3K signaling pathway is one of the most frequently altered pathways in HNSCC. A previous randomized, double-blind, placebo-controlled phase II study (BERIL-1)assessed patients with recurrent/metastatic HNSCC after PD on or after platinum-based chemotherapy in the metastatic setting. Patients assigned 1:1 to receive second-line oral buparlisib or placebo, plus intravenous weekly paclitaxel in 28-day cycles. Median PFS 4.6 months buparlisib arm, 3.5 months placebo arm (hazard ratio 0.65 [95% CI: 0.45–0.95], nominal one-sided p=0.011). Median OS 10.4 months buparlisib arm, 6.5 months placebo arm (hazard ratio 0.72 [95% CI: 0.49-1.04], nominal one-sided p=0.041). Best ORR buparlisib arm 39%, placebo arm 14%. Safety in buparlisib arm was manageable and comparable to placebo arm. (Soulieres, Lancet Oncology). Results suggest that buparlisib in combination with paclitaxel could be effective treatment following failure of platinum-based chemotherapy. Methods: The treatment algorithm for HNSCC was recently modified with inclusion of anti-PD-1/PD-L1 agents that provide a survival advantage, defining an unmet need after their use. The BURAN study is initiated as a confirmatory study to define activity in this setting. Methods: A multicenter, randomized, open-label phase III trial evaluating efficacy and safety of daily buparlisib (100 mg) in combination with weekly paclitaxel (80 mg/m2), compared to weekly paclitaxel alone, in patients with refractory, recurrent, or metastatic HNSCC, progressing after prior anti PD-1/anti PDL-1 therapy either as monotherapy or with a platinum-based regimen (in combination or sequence), and no more than two prior lines of treatment. 483 patients will be randomized 2:1, to receive either buparlisib in combination with paclitaxel or paclitaxel alone, stratified according to historical HPV status. Primary Objective: OS of buparlisib in combination with paclitaxel compared to paclitaxel alone. Secondary Objectives: Comparative PFS, ORR, and DoR, by Investigator and Independent Radiological Review Committee. Efficacy in subgroups of patients by randomization strata. Effect on symptoms and health related QOL. Efficacy related to biomarkers, microbiome analysis. Pharmacokinetics (PK) of buparlisib in combination with paclitaxel. Safety Objective: Comparative safety and tolerability. Primary analysis is OS in the ITT population, once 383 events have occurred, to demonstrate a 20% reduction in risk of death. Survival follow-up is to a maximum of five years. Trial opened December 12, 2020; X patients currently enrolled. Clinical Trial registry number: NCT04338399. Clinical trial information: NCT04338399.
ESCALADE: A phase 3 study of acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for patients ≤65y with untreated non-germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).
Authors: Sehn Laurie Helen , Kahl Brad S. , Matasar Matthew J. , Lenz Georg , Izutsu Koji , Zhao Weili , Tao Lin , Calvo Roser , Zinzani Pier Luigi 
Published: June 2021

TPS7572 Background: R-CHOP remains the standard of care for DLBCL. Although most patients (pts) can be cured, 3540% will experience relapsed/refractory disease, leading to poor outcomes in the majority of pts. Covalent irreversible Bruton tyrosine kinase inhibitors (BTKi) have shown higher responses in pts with non-GCB DLBCL than with GCB DLBCL. In untreated non-GCB DLBCL pts, the phase 3 PHOENIX study (Younes et al. J Clin Oncol. 2019;37:1285-95) showed that addition of the BTKi ibrutinib to R-CHOP (R-CHOP-I) did not improve outcomes in the intent-to-treat population. However, pts age < 60y treated with R-CHOP-I had significantly improved progression-free survival (PFS) and overall survival (OS) compared with those receiving R-CHOP alone. Acalabrutinib (A) is a second-generation BTKi with enhanced kinase selectivity and potential for better efficacy and tolerability than first-generation BTKis. There is a strong rationale for combining A with R-CHOP in pts with untreated DLBCL, and safety of A + R-CHOP has been shown in a phase 1b/2 study (Davies et al. ASH 2020). The aim of this study is to determine if the addition of A to R-CHOP leads to improved PFS in pts age ≤65y with untreated non-GCB DLBCL. Methods: ESCALADE (ACE-LY-312; NCT04529772) is a phase 3, randomized, global, double-blind study of A vs placebo in combination with R-CHOP for treatment of newly diagnosed non-GCB DLBCL. The study is recruiting adults ≥18y and ≤65y with previously untreated DLBCL stage IIIV disease with a Revised International Prognostic Index (R-IPI) score of 25. Prior to randomization, all pts will receive an initial R-CHOP cycle (cycle 1) as standard-of-care treatment to prevent delays in therapy initiation. Based on central Gene Expression Profile (GEP) testing performed after enrollment, pts with non-GCB DLBCL (activated B-cell like or unclassified) will be randomized into 2 arms to receive A 100 mg twice daily plus R-CHOP or placebo plus R-CHOP from cycle 2 to cycle 6 followed by 2 additional cycles of rituximab + A or placebo (cycles 7 and 8). All pts will receive primary prophylaxis with granulocyte colony-stimulating factors accompanying all R-CHOP cycles. The study aims to randomize 600 pts (̃300 per arm). The primary objective is to evaluate whether the addition of A to R-CHOP will prolong PFS. Secondary endpoints include event-free survival, complete response rate, OS, pharmacokinetics, and safety. Key exclusion criteria are central nervous system involvement, primary mediastinal lymphoma, high-grade B-cell lymphoma, diagnosis or treatment of malignancy other than DLBCL, and history of indolent lymphoma. Approximately 250 sites globally will enroll pts. Enrollment began in Q3 of 2020. Clinical trial information: NCT04529772.
A phase III trial evaluating glofitamab in combination with gemcitabine plus oxaliplatin versus rituximab in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Hertzberg Mark , Ku Matthew , Catalani Olivier , Althaus Betsy , Simko Stephen , Gregory Gareth P. 
Published: June 2021

TPS7575 Background: Prognosis is poor for patients with R/R DLBCL, particularly those who are ineligible for autologous stem cell transplant (ASCT) or who relapse after second-line therapy (Gisselbrecht C, et al. Br J Haematol 2018). While chimeric antigen receptor therapies have shown favorable response rates in R/R DLBCL, convenient off-the-shelf options are needed, especially for patients with rapidly progressing disease (Sermer D, et al. Blood Adv 2020). Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with two regions that bind to CD20 (B cells) and one region that binds to CD3 (T cells). In an ongoing Phase I study in patients with R/R non-Hodgkin lymphoma, glofitamab monotherapy has induced high response rates with a manageable safety profile (NCT03075696; Hutchings M, et al. ASH 2020). Rituximab in combination with gemcitabine and oxaliplatin (R-GemOx) is widely used for patients with R/R DLBCL who are not eligible for ASCT (Mounier N, et al. Haematologica 2013). Methods: GO41944 (NCT04408638) is a Phase III, open-label, randomized trial designed to evaluate the safety and efficacy of glofitamab plus gemcitabine and oxaliplatin (glofit-GemOx) vs R-GemOx in patients with R/R DLBCL. Eligible patients must be aged ≥ 18 years, have histologically confirmed DLBCL (excluding transformed indolent disease, and high-grade B-cell lymphoma (BCL) with MYC and BCL2 and/or BCL6 rearrangements), and have received ≥ 1 prior systemic therapies; patients who have failed only one prior line of therapy must not be eligible for high-dose chemotherapy followed by ASCT. Prior treatment with GemOx, R-GemOx or a CD20xCD3 bispecific antibody is not permitted. Patients are randomized 2:1 to receive up to eight 21-day cycles of either glofit-GemOx (intravenous [IV], followed by up to four cycles of glofitamab monotherapy) or R-GemOx (IV). A single dose of obinutuzumab is administered seven days prior to the first glofitamab administration. Randomization is stratified by number of prior lines of therapy and outcome of last systemic therapy (relapsed vs refractory). The primary objective is overall survival from time of randomization. Secondary efficacy objectives include progression-free survival, complete and overall response rates, duration of response, and time to deterioration in physical functioning and fatigue, and in lymphoma symptoms. Safety objectives comprise rate of adverse events, change from baseline in targeted vital signs and clinical laboratory test results, and tolerability. Pharmacokinetic, immunogenicity and biomarker endpoints will also be explored. The study started on February 17, 2021; an estimated enrollment of 270 patients by the study completion date of March 2022 is anticipated. Clinical trial information: NCT04408638.