bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.
Authors: Campian Jian Li , Abraham Christopher , Luo Jingqin , Talcott Grayson , Katumba Ruth , Kim Albert H , Dunn Gavin P. , Ansstas George , Johanns Tanner Michael , Ciorba Matthew A , Chheda Milan G , Huang Jiayi 
Published: June 2021

TPS2070 Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]
A phase 1/2 study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent glioblastoma.
Authors: Odia Yazmin , Goldlust Samuel Aaron , Mehta Minesh P. , Lassman Andrew B. , Colman Howard , Kumthekar Priya , Mason Warren P. , Harrison Rebecca A. , Butowski Nicholas A. , Venur Vyshak , Plotkin Scott Randall , Schulder Michael , Boockvar John A , Duic J Paul , Li Kai , Liu Yang , Tamir Sharon , Mundy Gregory , Shacham Sharon , Wen Patrick Y. 
Published: June 2021

TPS2071 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O6-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.
Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4 expression.
Authors: McKean Meredith , Falchook Gerald Steven , Bendell Johanna C. , Bashir Babar , Palmisiano Neil , Watson Roshawn , McKenna Mary-Anne , Campbell Carly , Smethurst Dominic Paul , Jeffrey Phil , Kirui Julius , Arkenau Hendrik-Tobias , Fontana Elisa 
Published: June 2021

TPS2668 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) and nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance of Nectin-4 in several human cancers, including lung, ovarian, breast and bladder cancer; however, the precise roles and clinical relevance of Nectin-4 in tumors remain largely unknown. The Nectin-4 targeted enfortumab vedotin, linked to MMAE via a val-cit linker, is highly active in late-stage bladder cancer and demonstrates notable additional clinical activity as a single agent and in combination with pembrolizumab1. Skin toxicities, bone marrow suppression, peripheral neuropathy and diabetes have been associated with enfortumab, with some of these toxicities already noted with MMAE-bearing antibody therapies. We anticipate a similar toxicity profile for BT8009 in clinical studies. BT8009 exhibited a favorable preclinical profile and was effective in a range of cell-derived xenograph tumor models. Methods: Study BT8009-100 (NCT04561362) will evaluate safety and tolerability of weekly and every other week BT8009 administration, alone and in combination with q4w nivolumab. Determination of both a realistic phase 2 dose and a sequence will also be key to further exploration of safety and efficacy signals, along with an early examination of the role of baseline immunohistochemistry-ascertained levels of tumor Nectin-4. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression after exhausting SOC options (i.e., bladder, breast, pancreatic, head and neck, gastric, esophageal and ovarian). Patients must have available tumor tissue, acceptable hematologic and other critical organ function and be willing to participate. Appropriate ethical and regulatory approvals and advice will be in place and adhered to. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, concomitant CYP3A4 inhibitors and significant history of autoimmune disease for the nivolumab cohorts. PK serial collections will be taken on D1 through D15. Radiologic tumor assessments for response per RECIST will be taken every two months. 1. Enfortumab Vedotin. FDA_data. 761137Orig1s000MultiDiscliplineR.pdf (fda.gov). Clinical trial information: NCT04561362.
A phase 1 dose-escalation study of intravenously (IV) administered TAK-676, a novel STING agonist, alone and in combination with pembrolizumab in patients (pts) with advanced or metastatic solid tumors.
Authors: Falchook Gerald Steven , Luke Jason J. , Strauss James F. , Gao Xin , LoRusso Patricia , VOON PEI JYE , Li Cong , Shaw Michael , Gregory Richard C. , Horn Kristin , Gibbs John , Lineberry Neil , Stumpo Kate , Malek Karim , Olszanski Anthony J. 
Published: June 2021

TPS2670 Background: Immuno-oncology therapies, including immune checkpoint inhibitors (CPIs), are revolutionizing cancer treatment. However, primary and secondary resistance to CPIs remains a significant challenge. CPI resistance has been associated with reduced interferon (IFN) signaling, altered antigen presentation, and an immunosuppressive tumor phenotype. Stimulating innate immune cells to develop a proinflammatory tumor environment that activates IFN signaling and downstream adaptive antitumor immune mechanisms is predicted to overcome such resistance. Stimulator of Interferon Genes (STING) is a key mediator of type 1 IFN-dependent innate immune modulation. Most STING agonists evaluated clinically have required intratumoral administration, which has significant logistical challenges and excludes many pts whose tumors are not accessible for injection. TAK-676 is a novel STING agonist under clinical investigation as an IV administered systemic therapy in pts with solid tumors. Methods: The primary objective of this study is to determine the safety and tolerability of TAK-676 alone and in combination with pembrolizumab. Secondary objectives are to: determine the pharmacologically active dose and recommended phase 2 dose; characterize TAK-676 pharmacokinetics; assess preliminary antitumor activity; and assess STING agonism gene signature induction. An exploratory objective is to assess immune cell activation and clinical response. The study comprises a single-pt safety lead-in with single-agent (SA) TAK-676 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation will start in the combination arm when ≥2 dose levels in the SA arm have been evaluated and considered safe. In both arms, pts will receive TAK-676 on days 1, 8, and 15 in 21-day cycles for up to 1 year. In the combination arm, pts will also receive pembrolizumab 200 mg IV on day 1 of each cycle. Adult pts with histologically confirmed advanced or metastatic solid tumors who have no standard therapeutic options or are intolerant to them, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and ≥1 Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1- evaluable lesion are eligible; pts with tumors that have relapsed, are refractory or naïve to anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy are eligible for the combination arm. Planned enrollment is ̃76 pts; recruitment is ongoing. Clinical trial information: NCT04420884.
A phase 1, multicenter, open-label, dose-escalation, safety, pharmacodynamic, pharmacokinetic study of Q702 with a cohort expansion at the RP2D in patients with advanced solid tumors.
Authors: Alistar Angela Tatiana , El-Khoueiry Anthony B. , Mahalingam Devalingam , Mita Monica M. , Kang Hwankyu , Yang Yeong-In , Ahn Jiye , Kim Jeongjun , Choi Baejung , Jeon Yeejin , Jung Chunwon , Jeon Borami , Kim Jaeseung , Nam Kiyean 
Published: June 2021

TPS2673 Background: Immune checkpoint inhibitors directly targeting T cell activation have been successfully used in the treatment of various malignancies, nevertheless, the durable ORRs are low for certain indications. The low ORRs have been attributed to the immune suppressive tumor microenvironment (TME), composed of innate immune suppressive components such as tumor associated macrophages (TAM) and myeloid-derived suppression cells (MDSC). The potential contributions of innate immune modulation to anti-tumor immunity, suggest the need for the novel strategies to elicit a more efficient/robust immune response against the targeted malignant cells. Axl, Mer and CSF1R receptor tyrosine kinases play vital roles in promoting an immune suppressive TME by affecting TAM and MDSC populations and by decreasing antigen presentation on tumor cells. Q702 is a novel Axl/Mer/CSF1R inhibitor, able to modulate the TAM and MDSC population leading to CD8+ T cell activation and to increase antigen presentation of the tumor cells in syngeneic animal models. Q702, as a monotherapy, shows significant tumor growth inhibition in multiple syngeneic tumor models, and demonstrates synergistic effects with anti-PD-1 treatment particularly in high myeloid containing tumor models. Interestingly, intermittent administration of Q702 monotherapy demonstrates a more favorable immune cell population changes, possibly through preventing immune exhaustion secondary to negative feedback with continuous activation. These results suggest that Q702 monotherapy or in combination with existing therapies have a good potential to become a novel treatment strategy for patients with advanced solid tumors. Methods: “A Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the RP2D in Patients with Advanced Solid Tumors. (NCT04648254)” is open and recruiting patients at 4 US investigative sites. Patients with histologically or cytologically confirmed advanced or metastatic solid tumors, that have progressed following SOC or for which there is no SOC which confers clinical benefit are being enrolled in this study. The study follows a standard dose escalation. The study will enroll up to 78 patients. The primary endpoint is to establish safety, PK profile and define the recommended phase 2 dose. The secondary and exploratory endpoints include establishing pharmacokinetic/pharmacodynamic relationship, potential biomarkers and preliminary anti-tumor activity. Clinical trial information: NCT04648254.
First-in-man phase I clinical trial evaluating TTI-101, an orally bioavailable, small molecule inhibitor of STAT3, in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , de Achaval Sofia , Alibhai Imran , Kaseb Ahmed Omar 
Published: June 2021

TPS3158 Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is a key signaling node and a master regulator of the key hallmarks of cancer, including tumor angiogenesis, resistance to apoptosis, metastasis, and immune evasion. STAT3 activation is observed in ̃70% of all cancers and up to 95% of hepatocellular carcinomas (HCC). Thus, inhibition of STAT3 signaling is expected to have a therapeutic effect against a wide range of cancers. TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds STAT3 and prevents phosphorylation, homodimerization, nuclear translocation, and ultimately, STAT3-mediated transcriptional activity. TTI-101 has demonstrated anti-tumor activity across a broad range of preclinical cancer models, including a Hep Pten- (hepatocyte-specific deletion of Pten) murine model of liver cancer, which recapitulates the pathogenesis of HCC in non-alcoholic fatty liver disease (NAFLD) with chronic inflammation and liver fibrosis leading to cancer at 11 months. TTI-101 treatment starting at 11 months arrested tumor growth as well as reversed liver injury and fibrosis (1). Given these findings, a clinical trial is being conducted examining the effect of this novel, targeted therapeutic agent in patients with advanced solid malignancies. Methods: This single-site Phase I trial (NCT03195699) is evaluating TTI-101 as monotherapy in patients with advanced solid tumors who are refractory to prior therapies. The primary objectives of this dose-escalation study include establishing tolerability and safety at each dose level, pharmacokinetics (PK), and establishing the recommended phase 2 dose (RP2D). The secondary and exploratory objectives include assessing clinical outcomes of patients and pharmacodynamics (PD) of TTI-101 via timed, paired tumor biopsies. The initial dose-escalation study is stratified by disease type (HCC and non-HCC) with independent dose-escalation schemas and will be followed by dose expansion cohorts where safety, PK and PD will be evaluated. TTI-101 is administered orally, twice daily for a 28-day cycle. Key eligibility criteria include: 18 years of age or older, having metastatic or unresectable solid tumor refractory to standard therapies, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group (ECOG) score of 0-2, and normal organ function. Additional criteria are specified for patients with HCC including Child-Pugh class A. HCC cohorts 1-4 and non-HCC cohorts 1-3 have been completed without dose limiting toxicities (DLTs). Enrollment to the HCC dose expansion began in February 2021. 1. Jung KH, et al. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res. 2017;23(18):5537-46. Clinical trial information: NCT03195699.
Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.
Authors: Overman Michael J. , Yothers Greg , Jacobs Samuel A. , Sanoff Hanna Kelly , Cohen Deirdre Jill , Guthrie Katherine A , Henry Norah Lynn , Ganz Patricia A. , Kopetz Scott , Lucas Peter C. , Blanke Charles David , Wolmark Norman , Hochster Howard S. , George Thomas J. , Rocha Lima Caio Max Sao Pedro 
Published: June 2021

TPS3618 Background: The superiority of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H over chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti- epithelial growth factor receptor (EGFr) antibodies in mCRC has been demonstrated in a phase III trial (N Engl J Med 2020; 383:2207). However, more patients had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean progression-free survival (PFS) of 13.7 months. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC patients may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT trial was reactivated on 1/29/2021 as a prospective phase III open-label trial that randomizes (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is PFS as assessed by site investigator. Secondary endpoints include overall survival (OS), objective response rate (RECIST v1.1), safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.
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.