bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma: The phase III “PREVENT” trial of the AIO /CAOGI /ACO.
Authors: Goetze Thorsten Oliver , Piso Pompiliu , Lorenzen Sylvie , Bankstahl Ulli Simone , Ostrzyzek Marcin , Pauligk Claudia , Habibzade Timursah , Reim Daniel , Bechstein Wolf Otto , Königsrainer Alfred , Mönig Stefan Paul , Rau Beate , Schwarzbach Matthias , Al-Batran Salah-Eddin
Published: June 2021

TPS4149

Background: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40- 50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since patients with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. Methods: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts with localized and locally advanced diffuse and mixed type (Laurens`s classification) adenocarcinoma of the stomach and Type II/III GEJ (i.e. ≥cT3 any N or any T N positive). All enrolled pts will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (Arm A- Control arm) or surgery + intraoperative HIPEC (cisplatin 75mg/m2 solution administered at a temperature of 42°C for 90 minutes) and postoperative FLOT (Arm B- experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, R0 resection rate, perioperative morbidity/mortality including VAS pain score and quality of life as assessed by EORTC QLQ C30 questionnaire. The trial starts with a safety run-in phase. After 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed assessing feasibility, safety, and tolerability in Arm B. First patient was randomized on 18JAN2021. Currently one patient is recruited. EudraCT: 2017-003832-35; ClinicalTrials.gov ID: NCT04447352. Clinical trial information: NCT04447352.
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.
A randomized phase II trial of adjuvant pembrolizumab versus observation following curative resection for stage I non-small cell lung cancer (NSCLC) with primary tumors between 1-4 cm: Big Ten Cancer Research Consortium BTCRC-LUN18-153.
Authors: Durm Greg Andrew , Furqan Muhammad , Feldman Lawrence Eric , Patel Malini , Hall Richard Delmar , Jalal Shadia Ibrahim , Birdas Thomas J. , Kesler Kenneth , Rieger Karen Marie , Ceppa DuyKhanh , Hanna Nasser H.
Published: June 2021

TPS8583

Background: There are approximately 35,000 cases of stage I lung cancer in the United States each year. While these patients have better 5-year overall survival (OS) rates than their counterparts with locally advanced and metastatic disease, there is still considerable room for improvement. Based on a recent publication validating the 8th edition of the TNM classification, the 5-year OS for node-negative pathologically-staged NSCLC between 1-4cm ranges from 73-86%, and recurrence rates for resected stage I NSCLC can range from 18-38%. Previous studies looking at adjuvant chemotherapy in this setting have shown no benefit for stage IA tumors, and the current standard of care is observation alone. Checkpoint blockade with PD-1/PD-L1 inhibitors has shown considerable activity in NSCLC including in metastatic disease, as consolidation in stage III disease after chemoradiation, and in studies evaluating neoadjuvant immunotherapy. Given this activity and their favorable safety profile, we designed a study of adjuvant PD-1 inhibition following resection in stage I NSCLC. Methods: This study is a randomized phase II multicenter trial of adjuvant Pembrolizumab versus observation alone following complete resection of stage I NSCLC with tumors between 1-4cm. The trial will enroll 368 patients randomized 1:1 to either Pembrolizumab 400mg IV every 6 weeks for up to 9 cycles or observation alone with scheduled CT scans and routine clinical follow-up. Stratification factors include PD-L1 ≥50% vs. < 50% and tumor size of 1-2cm vs. > 2-4cm. The lead site is Indiana University, and the trial will be conducted through the Big Ten Cancer Research Consortium. The primary endpoint is disease free survival (DFS), and secondary endpoints include OS, DFS at 1-, 2-, and 3-year time points, and toxicity. The trial opened to accrual at the lead site in May 2020, and there are currently 6 patients enrolled. Clinical trial information: NCT04317534.
Randomized phase III Trial of MEDI4736 (durvalumab) as concurrent and consolidative therapy or consolidative therapy alone for unresectable stage 3 NSCLC: A trial of the ECOG-ACRIN Cancer Research Group (EA5181).
Authors: Varlotto John M. , Sun Zhuoxin , Ramalingam Suresh S. , Wakelee Heather A. , Lovly Christine M. , Oettel Kurt R. , Masters Gregory A. , Pennell Nate
Published: June 2021

TPS8584

Background: Platinum-based concurrent chemoradiation(CRT) followed by one year of the human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, durvalumab, which blocks the interaction of PD-L1 with its receptors PD-1 and CD80, is the standard of care for locally advanced, unresectable non-small cell lung cancer (NSCLC). Early studies have noted the feasibility of concomitant administration of radiotherapy and immune checkpoint inhibition in NSCLC. EA5181 will evaluate the use of concomitant durvalumab with chemo-radiotherapy for locally advanced NSCLC. Methods: EA5181 is a randomized, multi-center, phase III study for patients with unresectable Stage III NSCLC comparing the efficacy of CRT with concomitant durvalumab to CRT, followed by one year of durvalumab. Eligibility criteria include: an ECOG PS of 0-1, adequate pulmonary function (FEV1 and DLCO both > 40%), no history of auto-immune disease and no past chemotherapy or RT for this lung cancer. Stratification factors include age, sex, stage, and planned concurrent chemotherapy type. Eligible patients with be randomized 1:1 to receive 60Gy RT (2Gy fractions) CRT and durvalumab (Arm A) or 60Gy CRT (Arm B). Investigators will be allowed to choose from three different chemotherapy options: cisplatin/etoposide q 28 days, Pemetrexed/cisplatin q 21 days, and weekly paclitaxel/Carboplatin. Arm A will use 750mg fixed of durvalumab (considered equivalent to 10mg/kg) on days 1, 11, and 21 of RT. Assuming no disease progression, patients in both arms will be followed by monthly (q28 days) fixed dose of 1500mg durvalumab for one year which will be given optimally within 14 days of radiation or when (non)hematologic toxicity is < Grade 2. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, incidence of local/distant progression and toxicity. The target sample size is 660 patients, anticipated to recruit over 55 months, with follow up for an additional 42 months. This provides approximately 82% power if the true hazard ratio for overall survival was 0.75 or less, with 2-sided alpha of 0.05, and assuming a median survival of 42.5 months in the control arm. The study was activated on 04/09/20 and has currently accrued 90 patients on 02/03/21. Clinical trial information: NCT04092283.
AdvanTIG-302: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (OCI) plus tislelizumab (TIS) versus pembrolizumab (PEM) in programmed death ligand-1 (PD-L1) selected, previously untreated, locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC).
Authors: Socinski Mark A. , Spira Alexander I. , Paz-Ares Luis G. , Reck Martin , Lu Shun , Nishio Makoto , Li Jiang , Zhou Yunfei , Rhee Joon Whan , Chica Duque Sandra , Yu Xinmin
Published: June 2021

TPS9128

Background: Monotherapy with programmed death 1 (PD-1)/PD-L1 antibodies has improved clinical outcomes for patients (pts) with non-oncogenic driven NSCLC but clinical responses are limited by primary and secondary resistance, and improvements in durability of response are required. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a co-inhibitory, immune checkpoint receptor upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. OCI (BGB-A1217) is a novel, humanized mAb that binds to TIGIT with high affinity and specificity, which has demonstrated competent binding with C1q and all Fcγ receptors while inducing antibody-dependent cellular cytotoxicity. 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-302 is a Phase 3, multicenter, international, randomized, double-blind study (NCT04746924) investigating OCI in combination with TIS compared with PEM in adult pts (≥ 18 years of age) with PD-L1 selected, previously untreated, locally advanced, unresectable or metastatic NSCLC without oncogenic EGFR or ALK mutation. Approximately 605 pts will be randomized 5:5:1 to receive: OCI 900 mg intravenously (IV) plus TIS 200 mg IV every three weeks (Q3W; Arm A), PEM 200 mg IV plus placebo IV Q3W (Arm B) or TIS 200 mg IV plus placebo IV Q3W (Arm C). Pts will be treated until disease progression, loss of clinical benefit, intolerable toxicity or withdrawal of consent. Stratification factors include histology (squamous vs non-squamous) and region (Asian vs non-Asian). Cross-over is not permitted. Key eligibility criteria include histologically confirmed disease, PD-L1 expression ≥ 50%, no known EGFR or ALK mutations and no prior checkpoint inhibitor therapy. Dual primary endpoints are investigator-assessed progression-free survival (PFS; RECIST v1.1) and overall survival (Arms A and B) in the Intention-to-Treat population. Secondary endpoints include PFS (assessed by Blinded Independent Review Committee), investigator-assessed overall response rate and duration of response, safety and tolerability, and patient-reported health-related quality of life (EORTC-QLQ-C30, QLQ-LC13 and EQ-5D-5L; Arms A and B). Exploratory endpoints include disease control rate, clinical benefit rate and time to response. This study will also evaluate the association between biomarkers and response or resistance. Study enrollment has begun and recruitment is ongoing. Clinical trial information: NCT04746924.
A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).
Authors: Zhang Li , Fang Wenfeng , Yang Yunpeng , Yu Qitao , Wu Di , Lin Yingcheng , Zhang Hua , Zhu Junfei , Wu Guowu , Lan Bin , Zhou Zeqiang , WANG Zibing , Lei Xiaolin , Lin Haifeng , HU Xiaohua , Pan Suming
Published: June 2021

TPS9131

Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.
Multicenter phase I/II trial of encorafenib with and without binimetinib in combination with nivolumab and low-dose ipilimumab in metastatic BRAF-mutant melanoma.
Authors: Jameson-Lee Max , Ott Patrick Alexander , Luke Jason J. , Postow Michael A. , Poklepovic Andrew Stewart
Published: June 2021

TPS9596

Background: Targeted therapy (BRAF + MEK inhibitors) and immunotherapy (anti-PD1 + anti-CTLA4) have improved overall survival for metastatic or unresectable BRAFV600E/Kmutant melanoma. Whereas targeted therapy has a high response rate, immunotherapy may deliver longer term disease control for a larger number of patients. Despite these treatments, patients with high risk metastatic melanoma such as those with brain or liver metastases, elevated lactate dehydrogenase (LDH) and bulky disease have inferior treatment outcomes with current therapies. A BRAF+MEK+PDL1 regimen has recently emerged however the role for this treatment remains unclear. Several recent trials combining MEK inhibition and immunotherapy have failed possibly because MEK inhibition can compromise T cell activation. Meanwhile the addition of CTLA4 blockade to PD1 inhibition appears to disproportionately benefit patients with non-T cell-inflamed tumors and potentially high-risk disease. For patients with high risk BRAF-mutant metastatic melanoma, further investigation of BRAF/MEK targeted and PD-1/CTLA-4 directed immunotherapy combination strategies remains a priority. Methods: This is an open label, multi-site, Phase 1/2 study of encorafenib (Enco) +/- binimetinib (Bini) + nivolumab (Nivo) + ipilimumab (Ipi) for the treatment of patients with unresectable or metastatic BRAF-mutated melanoma in high-risk cohorts (NCT04655157). An initial regimen confirming Phase I approach will be pursued on two schedules concurrently, with patients accruing equally to each group. Group 1 will receive 3mg/kg Nivo, and 1 mg/kg Ipi and 300mg Enco (12 participants, triple therapy) and Group 2 will receive 3mg/kg Nivo and 1mg/kg Ipi and 450mg Enco and 45mg Bini, (12 participants, quadruple therapy). Dose limiting toxicity (DLT) will be evaluated weeks 1-6. A recommended Phase II regimen (RP2R) [either triple or quadruple therapy] will be carried forward into two high risk metastatic disease cohort expansions of 30 participants each. Cohort 1 will include patients with symptomatic brain metastases, while cohort 2 will include patients with elevated LDH as well as either liver metastases OR bulky visceral disease (sum of longest diameters > 44mm). Patients meeting criteria for cohorts 1 and 2 will be placed in cohort 1. Patients with symptomatic brain metastases will be included with an ECOG up to 2 and on ≤ 4mg of dexamethasone or equivalent. Continuous Bayesian toxicity monitoring will be used throughout to monitor DLT. Pre and on-treatment tumor biopsies will assess changes in the tumor microenvironment while peripheral blood ctDNA and T cell Ki67% changes will assess early response and immune activation during triplet and quadruplet therapy. Clinical trial information: NCT04655157.
Physical and Reported Subjective Health Status in 222 Individuals with XY Disorder of Sex Development
Authors: Gong Xin Li , Raile Klemens , Slowikowska-Hilczer Jolanta , Pienkowski Catherine , Quinkler Marcus , Roehle Robert , Nordenström Anna , Neumann Uta
Published: June 2021

Context

Little is known about the physical health of individuals with 46,XY disorders of sex development (DSD).

Objective

To assess physical and reported subjective health of individuals with XY DSD.

Methods

As part of the dsd-LIFE study, patients with an XY DSD condition were analyzed in different diagnosis groups for metabolic parameters, comorbidities, metabolic syndrome, bone outcomes, and reported subjective health. Findings were evaluated by descriptive statistics.

Results

A total of 222 patients with XY DSD were included with a mean age of 28.8 ± 12.2 years, mean height of 175.3 ± 7.7 cm, mean weight of 74.3 ± 20.0 kg, and mean body mass index of 24.1 ± 6.0 kg/m2. Obesity rate was not increased when descriptively compared with Eurostat data. Fourteen patients had metabolic syndrome (14/175; 8.0%). In descriptive comparison with data from the DECODE study and World Health Organization, subjects fared better in the categories waist circumference, glucose, triglyceride, cholesterol, and high-density lipoprotein. Of participants with available bone health data, 19/122 (15.6%) patients had a Z-score ≤ –2.0 at lumbar spine indicating lowered bone mineral density (BMD). Mostly gonadectomized individuals with complete androgen insensitivity syndrome (CAIS) and no estrogen therapy had lowered BMD at lumbar spine. Individuals with XY DSD performed poorly in the category subjective health in descriptive comparison with Eurostat data.

Conclusion

Participants reported a lower subjective health status than Eurostat data but their overall metabolic health status was good. Decreased BMD at lumbar spine was especially present in gonadectomized individuals with CAIS and no estrogen therapy.
Technically Accessible, Practically Ineligible: The Effects of Medicaid Expansion Implementation on Chronic Homelessness
Authors: Willison Charley E. , Lillvis Denise , Mauri Amanda , Singer Phillip M.
Published: June 2021

Context: Homeless policy advocates viewed Medicaid expansion as an opportunity to enhance health care access for this vulnerable population. We studied Medicaid expansion implementation to assess the extent to which broadening insurance eligibility affected the functioning of municipal homelessness programs targeting chronic homelessness in the context of two separate governance systems.

Methods: We employed a comparative case study of San Francisco, California, and Shreveport, Louisiana, which were selected as exemplar cases from a national sample of cities across the United States. We conducted elite interviews with a range of local-level stakeholders and combined this data with primary-source documentation.

Findings: Medicaid expansion did not substantially enhance the functioning of homelessness programs and policies because of Medicaid access challenges and governance conflicts. Administrative burden and funding limitations contributed to limited provider networks, inadequate service coverage, and lack of linkages between Medicaid enrollment and homelessness programming. Governance conflicts reinforced these functional challenges, with homelessness under the administration of local municipalities and nongovernmental organizations while states administer Medicaid.

Conclusions: Improving access to health care services for persons experiencing homelessness cannot occur without intentional coordination between sectors and levels of government and thus necessitates the development of targeted policies and programs to overcome these challenges.
Passerine birds supporting cross pollination in Erythrina stricta Roxb.
Authors: Khanduri Vinod Prasad , Kumar Kewat Sanjay , Sharma Chandra Mohan , Riyal Manoj Kumar , Kar Kalpataru , Singh Bhupendra , Sukumaran Arun
Published: June 2021

Erythina stricta is an ecologically important tree species in the rainforests of India and its nectar within the flowers contributes to birds’ diet and survival. Reports on the pollination of this species have not been published so far. We therefore explore the reproductive system of this tree species which has great significance to its ecosystem. Birds have an important role in the reproduction of trees through pollination particularly in tropical areas where reproductive success mostly depends on animal pollinator interactions. Study of visitation and nectar feeding behaviour of birds along with breeding system assessment of Erythina stricta. Birds visiting and foraging behaviour was observed during Erythrina stricta flowering season in an indian tropical rainforest. Reproductive system was assessed through controlled pollination experiments. Thirteen bird species were recorded visiting and foraging nectar from the flowers of Erythrina stricta. The maximum numbers of visits recorded were from the Red-vented Bulbul (Pycnonotus cafer, Pycnonotidae). The nectar feeding birds were, either (i) potential pollinator with long bills (e.g. Pycnonotus spp., Chloropsis aurifrons, and Dicrurus spp.) or (ii) nectar robbers with comparatively shorter bills (e.g. Zosterops palpebrosa, Stachyris ruficeps, Macronous gularis, Heterophasia glaciris). Controlled pollination experiments revealed high degree of cross pollination (xenogamy) and self-incompatibility in E. stricta. Birds were more frequent in early mornings and their foraging activity was also observed during evening hours; the frequency however, declined with respect to nectar availability. Long corolla tubes of E. stricta could restrict access to nectar collecting bees.
Efficient Steady-State Simulation of High-Dimensional Stochastic Networks
Authors: Blanchet Jose , Chen Xinyun , Si Nian , Glynn Peter W.
Published: June 2021

We propose and study an asymptotically optimal Monte Carlo estimator for steady-state expectations of a d-dimensional reflected Brownian motion (RBM). Our estimator is asymptotically optimal in the sense that it requires [Formula: see text] (up to logarithmic factors in d) independent and identically distributed scalar Gaussian random variables in order to output an estimate with a controlled error. Our construction is based on the analysis of a suitable multilevel Monte Carlo strategy which, we believe, can be applied widely. This is the first algorithm with linear complexity (under suitable regularity conditions) for a steady-state estimation of RBM as the dimension increases.
Research on Demand Side Response System of Electricity Price Under Electricity Market Incentive Mechanism
Authors: Xianyu Fu , Hongmei Zhou , Jiang Qi-jie Jiang , Fan Ke
Published: June 2021

Aiming at the traditional day-ahead dispatching scheme of power generation,the paper proposes a power system security optimization dispatching modelthat considers the demand response of electricity prices under the electricitymarket incentive mechanism. Based on the peak and valley time-of-use elec-tricity price, the paper establishes an incentive compensation mechanism toencourage users to be active. Participating in demand-side resource schedul-ing makes the effect of “peak shaving and valley filling” more pronounced.Simultaneously, to rationally configure the reserve capacity of grid operation,the system incorporates the expected power outage loss into the proposedmodel to ensure the grid operation safety. The analysis of calculation exam-ples based on IEEE24 nodes shows that the power optimal dispatch modelproposed in the paper considering demand response and expected outage loss can reduce the operating cost of the power grid under the premise of ensuringa certain level of reliability and realize the economy of the power system inthe market environment and safe operation.