bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II study of anlotinib combined with STUPP versus STUPP alone in patients with newly diagnosed glioblastoma (GBM).
Authors: Chen Yuan yuan Yuan , Dong Baiqiang , Chen Zhongping 
Published: June 2022

TPS2079 Background: Postoperative with radiotherapy, and concomitant and up to 6 cycles of maintenance temozolomide (TMZ) chemotherapy (STUPP regimen) is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. Anlotinib is a novel, multi-kinase inhibitor against both tumor angiogenesis and tumor cell proliferation with encouraging findings in preclinical GBM models. Our previous single-arm study (NCT04119674) showed that the addition of anlotinb to STUPP exhibited promising progression-free survival (PFS) in patients with GBM. Therefore, a phase II trial was designed to assessed the efficacy and safety of anlotinib with the STUPP regimen. Methods: This is a multicenter, randomized, controlled, phase II superiority trial. Approximately 150 patients will be randomly assigned 1:1 to receive TMZ-based radiochemotherapy with anlotinib or TMZ-based radiochemotherapy with placebo. All patients will receive radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy given 5 days per week for 6 weeks, for a total of 54–60 Gy) concurrently with TMZ (75 mg/m2 QD) and anlotinib (10 mg QD, d1–14/3wks) or placebo. Anlotinib or placebo is administrated during the 28-day treatment break. Adjuvant therapy start four weeks after radiotherapy completion, including six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) or placebo. Patients who complete adjuvant therapy are administrated anlotinib or placebo continuously until the disease progressed or unacceptable toxic effects developed. Eligibility criteria include histologically confirmed newly diagnosed GBM and a World Health Organization (WHO) performance status ≤ 2. Additional inclusion criteria include patients between 18 and 75 years old with adequate wound healing of craniotomy or biopsy; adequate hematologic, hepatic, and renal function; acceptable blood coagulation levels; and the stable or decreasing usage of glucocorticoid doses within 5 days before randomization. Exclusion criteria include potentially fatal intracranial hemorrhage on magnetic resonance imaging (MRI); tumors located only in the brainstem; prior chemotherapy or radiotherapy administered for GBM; and IDH1/2 mutation. The primary objective of this study is to compare PFS accessed by Independent Review Committee in patients receiving anlotinib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include overall survival (OS), PFS accessed by investigators, overall response rate (ORR), severity and frequency of AEs (CTCAE V5.0), and quality of life (QOL). The disease control rate (DCR) and duration of response (DOR) will also be explored. Clinical trial information: NCT04959500. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd .
A phase I/IIa, open-label, multicenter, non-randomized clinical trial to assess the safety and efficacy of CYNK-001 in combination with recombinant human interleukin 2 in adults with recurrent resection eligible IDH1 wild-type glioblastoma (GBM).
Authors: Bota Daniela Annenelie , Badie Behnam , Heimberger Amy B. , Majd Nazanin , Awadalla Mark S. , Colerangle John , He Shawn , Koppisetti Sharmila , van der Touw William , Hariri Robert , Pecora Andrew L 
Published: June 2022

TPS2080 Background: CYNK-001 is a CD56+CD3- enriched, off-the-shelf, allogeneic natural killer (NK) cell product expanded from placental CD34 cells. CYNK-001 exhibits in vitro cytotoxicity against patient-derived GBM cell lines and secretes cytolytic cytokines during co-culture with cancer cells. CYNK-001 administered via the intracranial (IC) route exhibited in vivo antitumor activity in a U-87MG orthotopic mouse model. Methods: A Phase I/IIa clinical trial is enrolling IDH1 wild-type GBM patients at first or second recurrence with contrast-enhancing measurable disease (per RANO criteria) who are candidate for surgical resection. Screening MRI scans for inclusion are performed within 14 days prior to Day -5 lymphodepletion with Cyclophosphamide 900mg/m2 and fludarabine 30mg/m2 plus mesna. Using a standard 3+3 dose escalation schema, patients will receive the first cycle of CYNK-001 intravenously (IV) at an initial dose of 2.4 x109 cells on Days 1, 8 and 15 after lymphodepletion. Cell supportive IL-2 at 6M IU administered SQ on Days 1, 3, 5, 8, 10, 12, and 15 within 3 hours prior to CYNK-001 IV infusion where applicable. Cycle 2 begins with surgical resection on Day 22 in which CYNK-001 is administered directly into the tumor cavity wall at an initial dose of 100 x106 NK cells and an Ommaya catheter placement. Subsequent CYNK-001 IC administrations via the Ommaya are on days 29 and 36 with 6M IU IL-2 SQ. DLT is evaluated for all dosing cohorts from day 1 to 7 days post last dose of cycle 2. Once a maximum tolerated dose is identified, a safety lead-in cohort with an additional 3 cycles of CYNK-001 IC will be administered prior to initiating the Phase IIa portion of the study. Endpoints: The primary endpoint is dose-limiting toxicity for the Phase I analysis and 6-month progression free survival post tumor resection for the Phase IIa component. Post-resected tumor tissue will be characterized for effector immune cell function and immune suppression with assessments directed at CYNK-001 tumor distribution using methodology developed at Celularity Inc. Approximately 66 patients are planned for this Phase I/IIa study. Approximately 66 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05218408.
A combined phase I/II study of a novel bicycle tumor-targeted immune cell agonist BT7480 in patients with nectin-4 associated advanced malignancies.
Authors: Papadopoulos Kyriakos P. , Dowlati Afshin , Dickson Amy , Hirschberg Sandra , Westrup Sally , Upadhyaya Punit , Cohen Heather , Hurov Kristen , Watson Roshawn , Hazard Sebastien , Smethurst Dominic , Rodon Ahnert Jordi 
Published: June 2022

TPS2689 Background: BT7480 is a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist ( Bicycle TICA) that co-ligates cluster of differentiation (CD)137 (on immune cells) and Nectin-4 (on tumor cells). BT7480 comprises 3 bicyclic peptides ( Bicycles), 1 that binds to Nectin-4 and 2 that bind to CD137. The Bicycles are conjugated via a branched trimeric polyethylene glycol linker. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137 resulting in a tumor-localized costimulatory signal that leads to an antitumor response in preclinical studies. Nectin-4 is reported to be highly expressed in numerous tumors with unmet medical need including bladder, pancreas, breast, ovary, esophagus, head and neck, stomach, and lung cancers. Many of these tumor types also contain CD137 expressing cells. BT7480 exhibited a favorable preclinical profile supporting initiation of a first-in-human study to investigate safety and efficacy in indications with evidence of Nectin-4 expression. Methods: BT7480-100 (NCT05163041) is a PhI/II study to evaluate safety and tolerability of BT7480 administered as an intravenous infusion QW in a 28-day cycle, and to determine a recommended Phase 2 dose to further explore efficacy and safety. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression including urothelial; head and neck squamous cell; non-small cell lung; ovarian, breast, gastric or esophageal carcinoma after exhausting standard of care options. Patients must have available tumor tissue, acceptable hematologic and other critical organ function. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, significant history of autoimmune disease and prior CD137 targeted therapy. Pharmacokinetic and pharmacodynamic analyses will be performed to support dose escalation decisions and increase the understanding of safety and clinical activity signals observed during the study. Tumor response will be assessed per RECIST every 8 weeks. Cohorts 1 and 2 have been completed without DLT. Enrollment in cohort 3 began in January 2022. Clinical trial information: NCT05163041.
IL believe: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab or standard-of-care chemotherapy in patients with locally advanced or metastatic solid tumors.
Authors: Starodub Alexander , Gabrail Nashat Y. , Zhang Ying , Torrejon Castro Davis Y , Slavsky Sibel , Singel Stina Mui , Powderly John D. 
Published: June 2022

TPS2695 Background: Advances in immunotherapy have led to significantly improved survival and quality of life in some cancer patients, but many with less immunogenic tumor types derive suboptimal clinical benefit. Recombinant human interleukin-2 (IL-2, aldesleukin) can induce a response rate of ̃15% in metastatic renal cell carcinoma and metastatic melanoma, yet toxicities (vascular leak syndrome, cytokine storm) have limited its use. TransCon IL-2 β/γ, a novel prodrug with sustained release of a receptor-selective IL-2 (IL-2 β/γ), was designed to optimally address drawbacks of aldesleukin: potent activation of undesired IL-2Rα+ cell types and high Cmax with rapid clearance. TransCon IL-2 β/γ comprises 3 main components: IL-2 β/γ, a methoxy polyethylene glycol (mPEG) carrier molecule, and a linker connecting the two. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the mPEG carrier through cleavage of the TransCon Linker. This results in a lower Cmax and much longer effective t½ of free IL-2 β/γ compared to aldesleukin. PD-1 expression at the cell surface of activated cytotoxic T cells and natural killer cells provides a clear rationale to study TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: IL Believe is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced or metastatic solid tumors. All patients need ≥1 measurable lesion per RECIST 1.1 and an ECOG score of ≤ 2. The primary objectives are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of intravenous (IV) TransCon IL-2 b/g alone (Part 1) or with 200 mg IV pembrolizumab in solid tumors where pembrolizumab monotherapy may have clinical activity (Part 2). Each part will enroll ̃15 patients. Part 3, Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon IL-2 β/γ at the RP2D determined in Part 2, combined with chemotherapy. Platinum Resistant Ovarian Cancer is currently planned for dose expansion with other indication specific cohorts to be included in a subsequent amendment. Each cohort will be analyzed using a Simon 2-stage design and will enroll ̃56 patients. Other key objectives include the evaluation of pharmacokinetics, pharmacodynamic biomarkers, and antitumor activity according to RECIST 1.1. Recruitment started in January 2022 and is ongoing (NCT05081609). Clinical trial information: NCT05081609.
An open-label, multicenter, phase 1 study of RP3 as a single agent and in combination with nivolumab in patients (pts) with solid tumors.
Authors: Harrington Kevin Joseph , Rullan Antonio , Deighton Louise , Barata Joao , Castro Henry , Ahlers Christoph Matthias , McRae John , Bommareddy Praveen , Coffin Robert S. , Middleton Mark R. 
Published: June 2022

TPS2705 Background: RP3 is a genetically modified herpes simplex virus 1 (HSV-1) that contains insertions for the gibbon ape leukemia virus surface glycoprotein (GALV-GP) with the R- sequence deleted (R-), an anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule, CD40 ligand, and 4-1BB ligand. Together, these insertions are expected to increase oncolytic potency, cell-to-cell spread, immunogenic cell death, and systemic immune activation. RP3 has demonstrated antitumor activity in preclinical models using viruses similar to RP3 expressing murine versions of anti-CTLA-4, CD40L, and 4-1BBL both alone and in combination with PD1-1 blockade. Methods: This is an open-label, multicenter, Phase 1 study evaluating RP3 as monotherapy or in combination with nivolumab (nivo) in patients (pts) with solid tumors (NCT04735978). Part 1 evaluated escalating doses of RP3. Pts in Part 1 received IT injections of up to 10 mL RP3 into superficial, nodal, or visceral lesions Q2W x 5 across two dose levels (DL1: 105 plaque-forming units (PFU)/mL once, then 106 PFU/mL x 4; DL2: 106 PFU/mL once, then 107 PFU/mL x4). The RP2D is 106 PFU/mL once, followed by 107 PFU/mL IT Q2W. In Part 2, pts are being enrolled into expansion cohorts of 45 patients with GI (including HCC), lung, breast, and squamous cell carcinoma of the head and neck treated with RP1 combined with nivo. Additional cohorts will enroll patients treated with RP3 followed by nivo, RP3 monotherapy to further explore biomarkers in injected and uninjected tumors, and with the potential to also open a cohort in melanoma. Pts in both Part 1 and Part 2 may receive up to 8 additional doses of RP3 if protocol-specified criteria are met. Key inclusion criteria: confirmed advanced or metastatic non-neurological solid tumors, at least one measurable tumor ≥ 1 cm and injectable tumors ≥ 1 cm in aggregate, ECOG ≤1, and adequate hematologic, hepatic, and renal function. In Cohorts 1, 2, and 4, approximately 50% of the pts with lung, breast, and GI cancer must have liver lesions intended for injection. Exclusion criteria include prior oncolytic virus treatment, need for immunosuppressive therapy, an autoimmune disease requiring systemic therapy, active significant herpetic infections or prior complications of HSV-1 infection, active or chronic HBV or HCV infection, known HIV infection, or prior active malignancy within 3 years. Clinical trial information: NCT04735978.
Phase 1 study of C019199, an oral CSF-1R/DDRs/VEGFR2 multiple kinase inhibitor, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced solid tumors, including tenosynovial giant cell tumor.
Authors: Shen Lin , Ye Feng , Gong Jifang 
Published: June 2022

TPS3177 Background: C019199 was designed to be a tumor immune microenvironment (TME) modulator in order to improve the efficacy against tumor growth when combined with immune checkpoint inhibitors, like anti-PD1 or anti-PD-L1. It was shown to have a specific inhibition profile against CSF-1R, DDR1 and VEGFR2 with IC50 of 14nM, 40nM and 79nM, respectively. CSF-1R’s inhibition may deplete Tumor-associated macrophages (TAMs) in TME, help the infiltration of T cells and enhance T cell responses. But a single modulating mechanism may not be strong enough or may be vulnerable and easily overcome by tumors. C019199 can reshape the TME by additionally inhibiting DDRs and VEGFR2, which may remove the "physical barrier" of tumor extracellular matrix and further increase T cell infiltration on top of inducing tumor blood vessels normalization. As a single agent with the appropriate combination of multiple modulation effects, it will potentially turn "cold" tumors into "hot" tumors. Preclinical studies have shown that C019199 inhibits tumor growth in multiple animal tumor models and has better antitumor efficacy when combined with immune checkpoint blockades. Methods: A first-in-human, open label, multicenter, dose-escalation/expansion study of C019199 is currently enrolling. Eligible subjects (age ≥ 18 years and <76 years) with histologically or cytologically confirmed relapsed, refractory, or progressive metastatic solid tumors will be enrolled in. In Part A, the safety and tolerability of C019199 will be assessed in about 25 subjects to identify the maximum tolerated dose and recommended phase Ⅱ dose (PR2D). In Part B, the safety and antitumor activity of the RP2D will be assessed in about 60 subjects in disease-specific expansion cohorts. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities. Secondary endpoints will include pharmacokinetics, objective response rate, progression-free survival, and disease control rate. Exploratory biomarker analyses include CSF-1 and VEGF. Clinical trial information: CTR20202045.
Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US): NRG-GI008.
Authors: Dasari Arvind , Lin Yan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Rojas-Khalil Yesenia , Wolmark Norman , Yothers Greg , George Thomas J. , Lieu Christopher Hanyoung 
Published: June 2022

TPS3643 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor informed assay (SignateraTM, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs . serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs . more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs . delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/normal blood samples will be collected for exploratory correlative research. Active enrollment across the NCTN started in early 2022. Support: U10-CA-180868, -180822; UG1CA-189867; Clinical trial information: NCT05174169.
Trial in progress: Phase 3 study of bemarituzumab + mFOLFOX6 versus placebo + mFOLFOX6 in previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer with FGFR2b overexpression (FORTITUDE-101).
Authors: Smyth Elizabeth Catherine , Chao Joseph , Muro Kei , Yen Priscilla , Yanes Rolando Eduardo , Zahlten-Kumeli Anita , Rha Sun Young 
Published: June 2022

TPS4164 Background: Fibroblast growth factor receptor 2b (FGFR2b) is overexpressed in approximately 30% of non-human epidermal growth factor receptor 2 (non-HER2) positive gastric cancer (Wainberg, 2021). Bemarituzumab is a first-in-class monoclonal antibody that specifically blocks FGFR2b, inhibiting downstream tumor proliferation and enhancing antibody-dependent cellular cytotoxicity (Catenacci, 2020; Xiang, 2021). In the phase 2 FIGHT study (Wainberg, 2021; Catenacci, 2021), bemarituzumab + mFOLFOX6 improved progression-free survival (PFS; HR, 0.68; 95% CI, 0.44‒1.04; p = 0.07) and led to a 5.7 month longer median overall survival (OS; 19.2 months vs 13.5 months; HR, 0.60; 95% CI, 0.38-0.94) compared with placebo + mFOLFOX6. Methods: FORTITUDE-101 (NCT05052801) is a double-blind, placebo-controlled phase 3 study in patients with untreated, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma not amenable to curative therapy. Approximately 516 patients aged ≥18 years with IHC-confirmed FGFR2b overexpression by central testing will be enrolled and randomized 1:1 to bemarituzumab + mFOLFOX6 or placebo + mFOLFOX6. Additional key eligibility criteria include Eastern Cooperative Oncology Group performance status 0-1, evaluable disease per RECIST v1.1, adequate hematologic and organ function, and no contraindication to receive mFOLFOX6 chemotherapy. Key exclusion criteria include prior treatment for metastatic or unresectable disease except one dose of mFOLFOX6 during screening, positive HER2 status, untreated or symptomatic CNS metastasis and leptomeningeal disease, history or evidence of ongoing ophthalmologic abnormalities, and prior treatment with any FGF-FGFR pathway inhibitor. Patients randomized to bemarituzumab will receive 15 mg/kg every 2 weeks (Q2W) with an additional 7.5 mg/kg dose on cycle 1 day 8. mFOLFOX6 will be administered at a fixed dose Q2W. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint is OS; secondary endpoints include PFS, objective response (defined as best overall response of complete or partial response), and treatment-emergent adverse events. Tumor responses and PFS will be assessed locally per RECIST v1.1. The concurrent phase 1b/3 FORTITUDE-102 study (NCT05111626) will evaluate the efficacy and safety of bemarituzumab + mFOLFOX6 + nivolumab versus placebo + mFOLFOX6 + nivolumab. Clinical trial information: NCT05052801.