bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib (2ND-STEP, JCOG1802).
Authors: Endo Makoto , Tanaka Kazuhiro , Matsumoto Yoshihiro , Hiraga Hiroaki , Iwata Shintaro , Tsukushi Satoshi , Watanuki Munenori , Akiyama Toru , Yonemoto Tsukasa , Nakayama Robert , Ae Keisuke , Kawashima Hiroyuki , Tsuchiya Hiroyuki , Katagiri Hirohisa , Nagano Akihito , Takenaka Satoshi , Kataoka Tomoko , Machida Ryunosuke , Fukuda Haruhiko , Ozaki Toshifumi ,   Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group
Published: June 2021

TPS11580

Background: Soft tissue sarcomas (STS) are a rare type of malignancy, which comprises of a variety of histologies. Chemotherapy is the standard treatment for patients with advanced STS. Doxorubicin alone or in combination with ifosfamide is widely accepted as the first-line chemotherapy for advanced STS. While a combination with gemcitabine and docetaxel is regarded as a standard regimen of the second-line chemotherapy after failure of doxorubicin-based first-line regimen, the efficacy is not sufficient. Trabectedin, eribulin, and pazopanib are the candidates of the second-line chemotherapy for advanced STS, although there is no clear evidence showing which is better among those agents. The purpose of this clinical trial conducted by Bone and Soft Tissue Tumor Study Group of Japan Clinical Oncology Group (JCOG) is to determine the most promising regimen among trabectedin, eribulin and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: The study, JCOG1802, is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 year-old or older, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy for STS other than doxorubicin-based regimen, ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. To select the most promising regimen in median PFS (3 months in the worst regimen and 4 months in the best regimen) with a probability of at least 80%, a total of 120 patients will be enrolled from 37 institutions in Japan. After JCOG1802, a subsequent phase III trial comparing the winner of this study and a combination of gemcitabine and docetaxel will be planned. The study was activated at December 5, 2019 and 22 of planned 120 patients have been enrolled as of February 15, 2021. Clinical trial information: jRCTs031190152.
Exploring the role of digital health coaching for men with prostate cancer.
Authors: Handley Nathan , Wen Kuang-Yi , Gomaa Sameh , Brassil Kelly Jean , Jackson Lindsey , Dicker Adam P.
Published: June 2021

TPS1586

Background: Toxicity leading to impaired quality of life is common among men receiving treatment for Prostate Cancer (PCa). Digital interventions may be beneficial in enhancing health self-efficacy in managing symptom burden. This study evaluates the feasibility and preliminary outcomes of digital health coaching intervention on men with PCa. Methods: This pilot study aims to recruit up to 100 adult, English-speaking men with PCa who in the last 2 years have required active treatment, defined as cancer management via active surveillance, surgery, radiation, androgen deprivation, chemotherapy, hormonal therapy, immunotherapy or a combination of these modalities. Men will be enrolled across the catchment area of Jefferson Health using social media and a variety of other outreach tools approved by the Institutional Review Board. Consented patients are enrolled in a 3-month digital health coaching program which combines weekly calls with up to 4 nudges of evidence-based content delivered via text or email weekly. The program focuses on a weekly health topic, such as physical, mental, social, or financial health, and managing symptoms, and empowers participants to set health goals of importance to them. Primary endpoints include feasibility, defined as 60% of participants completing the 3-month program. The main secondary endpoints measured are health self-efficacy as measured by the Cancer Behavior Inventory-Brief (CBI-B), quality of life, as measured by the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), financial toxicity as measured by the Comprehensive Score of Financial Toxicity (COST) and physical and mental health as measured by the Patient Reported Outcomes Measurement Information System-Global Health 10 (PROMIS-10). Outcomes are captured on enrollment and monthly through program completion for a total of 4 data points. Summary statistics will be used to describe patient demographic and clinical characteristics of the study population. Summary statistics will also be used to describe CBI, EPIC-CP, PROMIS and COST by assessment time. The change in CBI-B scores from baseline to 3 months will be calculated along with 95% confidence intervals. Additional LMMs will be created to assess the relationship between self-efficacy (CBI) and quality of life (EPIC-CP), financial toxicity (COST) and global health (PROMIS- SF10).
Phase 2 trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.
Authors: Peters Katherine B. , Villano John L. , Butowski Nicholas A. , Cohen Adam Louis , Mendez Joe Sammy , Giglio Pierre , Zhang Chi , Raza Shahzad , McGranahan Tresa , Lobbous Mina , MacLeod David , Gad Shayne , Penchev Sara , Silberstein David , Crapo James
Published: June 2021

TPS2069

Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.
A phase 1, first in human study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor (CAR) in subjects with HER2 overexpressing solid tumors.
Authors: Bauml Joshua , Grover Natalie Sophia , Ronczka Amy , Cushing Daniel , Klichinsky Michael , Barton Debora , Dees Elizabeth Claire
Published: June 2021

TPS2660

Background: Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into, and abundantly present in the solid tumor microenvironment (sTME). Tumor- associated macrophages typically evince immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR confers on the macrophages the ability to selectively recognize and phagocytose antigen overexpressing cancer cells. Additionally, CAR macrophages reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and immune memory. Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in many cancers, including but not limited to breast and gastroesophageal cancers (Table). CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies have shown that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden and prolonged survival in relevant models. CT-0508 cells were safe and effective in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. Methods: This is a FIH phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 in approximately 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 who have failed available therapies including anti-HER2 therapies when indicated. Filgrastim will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. The CT-0508 CAR macrophage product will be manufactured, prepared and cryopreserved from mobilized peripheral blood monocytes. The study is enrolling Group 1 subjects, who will receive CT-0508 infusion split over D1, 3 and 5. Subjects will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 subjects will follow, and will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of trafficking, persistence, TME modulation, immune response and safety. Clinical trial information: NCT04660929. [Table: see text]
Phase 1/2 study of the novel SUMOylation inhibitor TAK-981 in adult patients (pts) with advanced or metastatic solid tumors or relapsed/refractory (RR) hematologic malignancies.
Authors: Dudek Arkadiusz Z. , Juric Dejan , Dowlati Afshin , Seymour Erlene Kuizon , Rodon Ahnert Jordi , Wang Bingxia , Huszar Dennis , Berger Allison J. , Friedlander Sharon , Gomez-Pinillos Alejandro , Proscurshim Igor , Olszanski Anthony J.
Published: June 2021

TPS2667

Background: SUMOylation, a posttranslational modification analogous to ubiquitination, attaches a small, ubiquitin-like modifier (SUMO) to target proteins. SUMOylation plays a central role in regulating type I interferon (IFN-I)-dependent innate response and functions to constrain the innate immune response, which can impair tumor immune surveillance. TAK-981 is a first-in-class, small-molecule inhibitor of SUMO-activating enzyme subunit 2 (SAE2). Inhibition of SAE2 by TAK-981 disrupts SUMOylation, thereby allowing innate immune system activation. In ex vivo assays, TAK-981 increased phagocytic activity of monocyte-derived macrophages, increased natural killer cell cytotoxicity, and induced markers of dendritic cell activation and maturation via IFN-I signaling. In syngeneic mouse models, TAK-981 resulted in antitumor activity, including complete remissions, and a sustained, protective antitumor immune response. Methods: This first-in-human study of single-agent TAK-981 comprises two parts. Phase 1 primary objectives are to determine safety and tolerability, and to select a recommended phase 2 dose (RP2D); secondary objectives are to assess preliminary antitumor activity, characterize pharmacokinetics (PK), and explore pharmacodynamic (PD) biomarkers. This phase will enroll ̃70 pts with untreatable locally advanced or metastatic solid tumors or RR lymphoma. The phase 2 primary objective is to evaluate preliminary efficacy at the RP2D in ̃132 pts with non-squamous non-small cell lung cancer, cervical cancer, microsatellite-stable colorectal cancer, or CD20+ RR diffuse large B-cell lymphoma or follicular lymphoma. Pts receive TAK-981 via a 1-hour intravenous infusion on days 1, 4, 8, and 11 in 21-day cycles until unacceptable toxicity, pt withdrawal, or death. Dose escalation is proceeding from 3 mg, guided by an adaptive 3+3 design combined with Bayesian logistic regression modelling with overdose control, plus consideration of other safety, clinical, PK, and PD data. The RP2D will be based on the maximum tolerated dose (MTD) or on a biologically effective dose (BED) that is ≤MTD. The BED is defined as a dose at which there is evidence of drug-target engagement and inhibition of SUMOylation, plus: induction of cytokines/chemokines and/or IFN-I signature in tumor or blood; evidence of increased T cell infiltration in tumor; or antitumor activity. PK/PD modeling in the BED range is ongoing and will be used in RP2D determination. Clinical trial information: NCT03648372.
Tumor-agnostic precision immuno-oncology and somatic targeting rationale for you (TAPISTRY): A novel platform umbrella trial.
Authors: Drilon Alexander E. , Liu Haiying , Wu Felice , Chen David , Wilson Timothy Richard , Simmons Brian P. , Barlesi Fabrice
Published: June 2021

TPS3154

Background: Actionable genomic alterations are found in many solid tumors in pediatric and adult populations. Identifying such alterations can match patients (pts) to genome-driven therapies. Although TRK and immune checkpoint inhibitor therapies have tumor-agnostic approval for NTRK-rearranged and tumor mutational burden (TMB)-high cancers, respectively, similar approvals remain an unmet need for other genome-driven cancers, limiting pt access to potentially active therapies. Platform master protocol studies leveraging comprehensive next-generation sequencing (NGS) are a pragmatic means of evaluating multiple genome-driven therapies in rare biomarker-selected populations. Contemporary study designs include adult and pediatric pts to expand care across age groups. Methods: TAPISTRY (NCT04589845) is a phase 2, global, open-label, multi-cohort study evaluating the efficacy and safety of targeted therapy or immunotherapy, as single agents or in combination, in pts with unresectable, locally advanced/metastatic solid tumors. Eligible pts have tumors that harbor genomic alterations or are TMB-high by NGS (Foundation Medicine or CLIA/equivalent-certified laboratory). General inclusion criteria: PD on prior treatment/no available acceptable treatment; measurable disease (by RECIST v1.1, RANO, INRC), adequate ECOG/equivalent PS and end organ function. Pts will be assigned to treatment according to eligibility criteria for biomarker-defined cohorts (Table). Pediatric pts may be enrolled if age-appropriate formulations/dosages are established. Samples will be taken for central NGS biomarker testing at baseline (tissue/blood), tumor assessments (blood) and at response/PD (optional tissue/blood). Tumor assessments (CT, MRI, PET) will be completed at baseline then every 6–8 weeks, depending on cohort. Primary endpoint: confirmed ORR by independent review committee (IRC; RECIST v1.1). Key secondary endpoints: ORR (by investigator [INV], per RECIST/INRC); DoR, CBR, PFS, time to CNS PD (by IRC and INV, per RECIST/INRC); intracranial efficacy (Cohorts A–D; per RANO [primary brain tumors]/RECIST [baseline CNS mets]); OS; patient-reported outcomes; safety; pharmacokinetics and immunogenicity (Cohorts D and F). Treatment will continue until PD, loss of clinical benefit, unacceptable toxicity, discontinuation or death. Target enrollment is 650 pts at 100+ sites based on screening 40,000+ pts; 3 pts enrolled as of 9 Feb 2021. Clinical trial information: NCT04589845. [Table: see text]
A phase 1/2 study with open-label, dose escalation phase followed by single-arm expansion at the maximum tolerated dose to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 injection alone and in combination with cetuximab in adults with advanced solid tumors and head and neck cancer.
Authors: Bessudo Alberto , Cohen Ezra E.W. , Gutierrez Rodolfo , Johnson Daniel H. , Rosenberg Ari , Sukari Ammar , Stemmer Salomon M. , Weinberg Benjamin Adam , Reuveni Hadas , Schickler Michael , Liang Bertrand C.
Published: June 2021

TPS3156

Background: NT219 is a small molecule, dual inhibitor of insulin receptor substrates (IRS) 1/2 and signal transducer and activator of transcription 3 (STAT3), effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. Patient derived xenograft (PDX) models have shown that inhibition of both IRS and STAT3 is essential to overcome targeted epidermal growth factor receptor inhibitor (EGFRi) resistance, and NT219 has demonstrated efficacy as monotherapy and in combination with immune oncology therapies. Particularly, both pathways have been found to be relevant in resistance to cetuximab in head and neck squamous cell carcinoma (HNSCC) PDX models. Methods: This phase 1/2 study (Clinical trial: NCT04474470) began in September 2020. The phase 1 component has a dose escalation arm of NT219 as a single agent at doses ranging between 3mg/kg and 50mg/kg in adult subjects with recurrent and/or metastatic solid tumors enrolled in sequential dose cohorts of 3 to 6 subjects, in a conventional 3+3 design aiming to establish the safety of single agent NT219. Following the conclusion of follow up on the third dose cohort, an additional dose-escalation arm of NT219 in combination with standard dose cetuximab will be opened in patients with recurrent and/or metastatic HNSCC and colorectal cancer, aiming to establish the safety of NT219 when combined with cetuximab. In the expansion phase, 29 patients will be enrolled at the recommended phase 2 dose in combination with standard dose cetuximab in patients with recurrent/metastatic HNSCC. The primary objectives of the trial are safety, tolerability, MTD, and RP2D and preliminary efficacy of NT219 alone and in combination with cetuximab. Measurements of STAT3 and IRS1/2 phosphorylation in biopsy specimens and TILs will be evaluated as potential biomarkers. NT219 provides a first-in-class treatment for patients with resistant neoplastic disease. The current trial will provide important data in patients with recurrent/metastatic cancers, particularly, HNSCC on the effects of the inhibition of STAT3 and IRS1/2 pathways as a novel therapeutic approach. Clinical trial information: NCT04474470.
Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.
Authors: Lee Dae Ho , Roohullah Aflah , Cho Byoung Chul , Lemech Charlotte Rose , de Souza Paul L. , Millward Michael , Choi Jun Young , Park Kyung Eui , Lee Minseon , Kim YeongMun , Shin YOUNGKEE , Han Ji-Youn
Published: June 2021

TPS3157

Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.
Phase II/III study of Circulating tumOr DNA as a predictive BiomaRker in Adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Wolmark Norman , George Thomas J.
Published: June 2021

TPS3622

Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N = 1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint in North America. NCT#: 04068103. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.
MATTERHORN: Efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—A randomized, double-blind, placebo-controlled, phase 3 study.
Authors: Janjigian Yelena Y. , Van Cutsem Eric , Muro Kei , Wainberg Zev A. , Al-Batran Salah-Eddin , Hyung Woo Jin , Molena Daniela , Evans Brent , Ruscica Dario , Robbins Scott H. , Negro Alejandra , Tabernero Josep
Published: June 2021

TPS4151

Background: Gastric and gastroesophageal junction cancers (GC, GEJC) are the fifth most common cancer types and the third leading cause of cancer-related deaths globally (Globocan 2020). Standard of care for resectable GC/GEJC includes neoadjuvant-adjuvant FLOT chemotherapy (5-fluorouracil + leucovorin + oxaliplatin + docetaxel) combined with surgery and lymph node dissection for some regions of the world. While treatment advances have improved survival, the 5-year recurrence rate remains high and 5-year overall survival (OS) is poor for patients with resectable disease. Evidence suggests cytotoxic chemotherapy can promote antitumor immunity, thus the combination of immune checkpoint inhibitors, such as durvalumab (an anti–PD-L1 antibody), with cytotoxic chemotherapy may result in increased efficacy (Yu et al. Cancer Lett. 2019; Li et al. Mol Cancer. 2021). MATTERHORN (NCT04592913) is a phase 3, multicenter study evaluating the efficacy and safety of neoadjuvant-adjuvant durvalumab or placebo with FLOT followed by adjuvant durvalumab or placebo in patients with resectable GC/GEJC. Methods: Approximately 900 adult patients will be randomized 1:1 to Arm A or Arm B for 2 neoadjuvant and 2 adjuvant cycles (single cycle defined as durvalumab or placebo every 4 weeks [Q4W] + FLOT [Q2W × 2]); followed by durvalumab or placebo Q4W for 10 cycles. Eligible patients must have histologically confirmed, resectable, stage II or higher GC or GEJC not treated with anticancer therapy, ECOG performance status 0 or 1, and adequate organ function. Complete surgical resection of the primary tumor must be achievable. A tumor tissue sample will be taken at screening or <3 months prior to enrollment. Key exclusion criteria are any prior immune-mediated therapy, peritoneal dissemination or distant metastasis, (adeno)squamous cell carcinoma, or gastrointestinal stromal tumor. The primary endpoint is event-free survival (EFS) assessed by blinded independent central radiology review (BICR) and/or local pathology testing. Secondary endpoints include OS and pathological complete response rate (pCR). Safety and tolerability will be evaluated by adverse events, vital signs, laboratory parameters, and electrocardiogram. Enrollment is ongoing. Funding: AstraZeneca. Clinical trial information: NCT04592913.
MONEO: A phase II study of avelumab (Av) plus FLOT in the peri-operative treatment for patients (pts) with resectable gastric or gastroesophageal junction cancer (GC).
Authors: ALSINA MARIA , Ponz-Sarvise Mariano , Lopez Garcia Dario , Gonzalez Marta , De Andrea Carlos E , Gros Alena , Vivancos Ana , Jiménez-Fonseca Paula , Diez Garcia Marc , Arrazubi Virginia , Sanz-Garcia Enrique , Martínez de Castro Eva , Guardeno Raquel , Calvo Mariona , Buges Cristina , Longo Federico , Tabernero Josep , Villacampa Guillermo , Muñoz Susana , Melero Ignacio
Published: June 2021

TPS4155

Background: GC represents a worldwide problem; radical surgery remaining the gold standard of curative treatment. In the West, even with peri-operative chemotherapy, 5-year survival rate is approximately 40%. GC is a heterogeneous disease, well characterized by different molecular classifications, all having in common the role of the immune system and a T-cell inflamed phenotype across all subtypes. The anti-PD-L1 Av antibody has demonstrated efficacy in GC with response rates of around 10% in the refractory setting. The addition of other immune checkpoint inhibitors to chemotherapy have demonstrated efficacy in the metastatic setting. The combination of Av to perioperative chemotherapy may increase pathological responses by a synergistic effect, and then improving the survival (OS). Methods: The MONEO is an open-label, non-randomized, multicentric, phase II study that explores the combination of Av plus peri-operative FLOT (docetaxel, oxaliplatin, fluorouracil/leucovorin) in resectable GC pts. EudraCT 2019-000782-21; ClinicalTrials NCT03979131. Main inclusion criteria require pts with histologically proven GC, stage Ib (T1N1 only) - IIIC (7th AJCC Ed), available paraffin block from diagnosis and surgery, evaluable disease (RECIST 1.1) amenable to radical surgery. Significant comorbidities and active autoimmune diseases are excluded. Treatment consists of surgery with 4 peri-operatory cycles of FLOT + Av, followed by Av up to one year. The primary objective is the pathological complete response (pCR) rate, compared to historical data. Secondary objectives include OS, disease-free survival, R0 resection rate, tolerability and biomarker analysis. Key point is the comprehensive biomarker analysis from tissue and blood samples (pathological immune response, TCR clonality, immune contexture characterization, immunodynamic monitoring). Statistics for an estimated 33% pCR (historical 16%), 82% power, 0.1 one-side type I error. 37 pts will be recruited from 10 Spanish centers. The sponsor is Vall d'Hebron Institute of Oncology (VHIO), principal investigators Dr. Melero and Dr. Alsina. In compliance with the Helsinki Declaration. At a data cut-off day of 5th of February 2021, 38 patients have been enrolled, 27 of them have had the surgery. Although the difficulties during the COVID19 pandemia, only two patients had been withdrawn from the study. Clinical trial information: NCT03979131.
Phase III study of NUC-1031 + cisplatin versus gemcitabine + cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).
Authors: Knox Jennifer J. , McNamara Mairead Geraldine , Goyal Lipika , Cosgrove David , Springfeld Christoph , Sjoquist Katrin Marie , Park Joon Oh , Verdaguer Helena , Braconi Chiara , Ross Paul J. , Oh Do-Youn , De Gramont Aimery , Zalcberg John Raymond , Palmer Daniel H. , Valle Juan W.
Published: June 2021

TPS4164

Background: Biliary tract cancer (BTC) is an aggressive disease with a poor prognosis. Gemcitabine + cisplatin (GemCis) is the accepted global standard of care (SoC), however key cancer resistance mechanisms associated with the transport, activation and breakdown of gemcitabine are known to limit its clinical activity across a range of tumor types, including BTC. NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome these key resistance mechanisms and generate much higher levels of the active anti-cancer metabolite, dFdCTP, in cells. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 21 patients enrolled in 2 dose cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 16 were considered to be efficacy evaluable. In this population, 1 patient had a CR and 6 patients had PRs, resulting in an ORR of 44% (7/16). This compares favorably to the 26% ORR reported for the SoC regimen. In addition, 6 patients had SD, resulting in a DCR of 81% (13/16). The combination was well tolerated with no unexpected AEs or DLTs. The recommended dose of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy led to initiation of a global registrational study. Methods: NuTide:121 is a phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on Days 1 and 8 of 21-day cycles. Primary endpoints are OS and ORR. Secondary endpoints include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific. Clinical trial information: NCT04163900.
A phase 3, multicenter, randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy in participants with muscle-invasive urothelial carcinoma of the bladder.
Authors: Williams Stephen B. , Cutie Christopher , Keegan Kirk A , Raybold Bradley , Acharya Milin , Zhu Wei , Li Xiang , O'Dondi Lang A , Beeharry Neil , Spratt Daniel Eidelberg
Published: June 2021

TPS4586

Background: The standard of care for patients with muscle-invasive bladder cancer (MIBC) consists of neoadjuvant chemotherapy and radical cystectomy (RC) or chemoradiotherapy (CRT). However, RC is associated with potential morbidity or mortality from the procedure. TAR-200 is an intravesical drug-delivery system designed for the local continuous release of gemcitabine within the bladder. Cetrelimab is an investigational immunoglobulin G4 anti–programmed cell death protein-1 antibody. In patients with MIBC, this clinical trial will evaluate whether combination treatment with intravesical TAR-200 and systemic cetrelimab will result in enhanced local and systemic antitumor activity versus concurrent CRT. Methods: SunRISe-2 (NCT04658862) is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus CRT in participants with MIBC. Eligible participants are aged ³18 years with an ECOG performance status of 0, 1, or 2, and histologically proven, cT2-T4a, N0, M0 urothelial carcinoma of the bladder diagnosed within 90 days of the randomization date, and who refuse or are ineligible for RC. Approximately 550 participants will be randomized in a 1:1 ratio and with stratification by 2 factors: transurethral resection of bladder tumor screening results (visibly complete vs incomplete) and screening tumor stage (T0 vs Ta/T1/Tis vs T2-T4a). Participants in Arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks on study; and, beginning at week 24, every 12 weeks through study year 3. Cetrelimab will be dosed every 3 weeks until month 18. Participants in Arm 2 will receive standard of care CRT (with either cisplatin or gemcitabine, for up to 6 weeks). A primary disease assessment will be performed at week 18 to evaluate treatment response in both arms. Subsequent assessments (axial imaging and cystoscopy) will occur at week 24 and every 12 weeks thereafter through study year 2, and then every 24 weeks through study year 5. The primary endpoint is bladder intact event-free survival. Key secondary endpoints include metastasis-free survival, overall survival, overall response rate (at week 18), and safety and tolerability. Other/exploratory end points include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, healthcare resource utilization, and biomarkers. Participants are being enrolled at approximately 272 study sites worldwide. The study opened for enrollment in December 2020. Clinical trial information: NCT04658862.
Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) (CaNI) for advanced renal cell carcinoma with variant histology (aRCCVH).
Authors: McGregor Bradley Alexander , Xie Wanling , Bilen Mehmet Asim , Braun David A. , Xu Wenxin , Ravi Praful , Heath Elisabeth I. , McDermott David F. , McKay Rana R. , Hammers Hans J. , Choueiri Toni K.
Published: June 2021

TPS4592

Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment naïve or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Database Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1-sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123.
PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).
Authors: Allaf Mohamad E. , Kim Se Eun , Master Viraj A. , McDermott David F. , Signoretti Sabina , Cella David , Gupta Rajan T. , Cole Suzanne , Shuch Brian M. , Lara Primo "Lucky" N. , Kapoor Anil , Heng Daniel Yick Chin , Leibovich Bradley C. , Michaelson M. Dror , Choueiri Toni K. , Jewett Michael A.S. , Maskens Deb , Harshman Lauren C , Carducci Michael Anthony , Haas Naomi B.
Published: June 2021

TPS4596

Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
Authors: Ahrens Marit , Escudier Bernard , Haanen John B. A. G. , Boleti Ekaterini , Gross Goupil Marine , Grimm Marc-Oliver , Negrier Sylvie , Barthelemy Philippe , Gravis Gwenaelle , Ivanyi Philipp , Bedke Jens , Castellano Daniel , Panic Andrej , Mellado Begona , Maroto-Rey Pablo , Rottey Sylvie , Zschaebitz Stefanie , Deckbar Dorothee , Hartmann Arndt , Bergmann Lothar
Published: June 2021

TPS4597

Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky >70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ̃306 pts. stratified for papillary or non-papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423.
Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH).
Authors: Chi Kim N. , Metser Ur , Czernin Johannes , Calais Jeremie , Prasad Vikas , Eiber Matthias , Shore Neal D. , Jensen Jessica , Fleshner Neil Eric , Tagawa Scott T. , Sartor A. Oliver
Published: June 2021

TPS5087

Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Clinical trial information: NCT04647526.