bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of NEROFE and doxorubicin in KRAS-mutated ST2-positive solid tumors.
Authors: Weinberg Benjamin Adam , Wang Hongkun , Reuss Joshua E. , Boikos Sosipatros Alexandros , Walsh Elaine M. , Kim Chul , He Aiwu Ruth , Noel Marcus Smith , Gramza Ann Wild , Gibney Geoffrey Thomas , Liu Stephen V. , Macke Laura Ann , Montcalm Jennifer E. , Bouker Kerrie , Ohana Joel , Sandler Uziel , Devary Yoram 
Published: June 2023

TPS2667 Background: KRAS-mutated tumors are notoriously difficult to treat clinically with targeted therapies. Recent advances targeting KRAS G12C with sotorasib and adagrasib are encouraging but limited to a small subset of patients. NEROFE is a 14 amino acid peptide which inhibits suppression of tumorigenicity 2 (ST2; member of the interleukin 1 [IL-1] receptor family and IL-33 receptor), a novel immune checkpoint present on tumor cells and tumor-associated macrophages. ST2 blockade with NEROFE has been shown to transform an immunosuppressive tumor microenvironment into an immune-stimulatory microenvironment. NEROFE also has been shown to induce microRNA miR-217 which downregulates KRAS and MAPK1/2 gene expression in preclinical models. When combined with low-dose doxorubicin, NEROFE has a synergistic effect on inducing apoptosis in KRAS-mutated, ST2-positive cell lines and xenograft models. Methods: This is a phase I trial of NEROFE given at 48 mg/m2 (dose level [DL] -1), 96 mg/m2 (DL1), 192 mg/m2 (DL2), or 288 mg/m2 (DL3) IV weekly with doxorubicin 8 mg/m2 IV weekly. A standard 3+3 dose escalation/de-escalation is used. The primary objective is to determine the recommended phase II dose. Patients are eligible if they have an advanced solid tumor with a KRAS mutation and ST2-positivity (via immunohistochemistry [IHC], centrally confirmed with pre-screening allowed). Patients must have measurable disease amenable to serial biopsy. Patients must have had progression or intolerance to all standard therapies or must decline available standard therapy. Pharmacokinetic profiles will be analyzed from serial blood draws pre- and 1, 2, 4, 6, and 24 hours post-infusion on cycle 1 day and cycle 2 day 1. Pre- and on-treatment tumor biopsies are mandatory. Correlative studies include IHC for ST2 expression, immune cell infiltration and blood-based analyses of KRAS mRNA, miR-217, and cytokines. Enrollment to DL1 began in Q1 2023 (NCT05661201). Clinical trial information: NCT05661201 .
GNC-038, a tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale.
Authors: Wang Jianxiang , Qi Junyuan , Li Wenyu , Zhai Zhimin , Li Ping , Zou Wen , Ding Muran , Yang Xue , Wang Rong , Guo Wanjing , Xiao Sa , Khalili Jahan S. , Zhu Hai , Olivo Martin Sebastian , Zhu Yi 
Published: June 2023

TPS2668 Background: Bispecific T cell engagers can mediate single antigen-specific cell cytolysis, but cannot preempt clonal relapse, or modify the immunosuppressive cancer cell surfaceome. The first-in-class octavalent, CD19xCD3x4-1BBxPD-L1 tetra-specific antibody, GNC-038, functions as a CD19-specific T cell engager by mediating direct antitumor activity, but further, GNC-038 overcomes inhibition of T cells by PD-L1 based on its 4 binding sites. The antitumor activity of GNC-038 is mediated by activating CD3 and 4-1BB signaling on T cells and targeting high expression of CD19 or PD-L1 on tumor cells. Preclinical studies showed GNC-038 has robust anti-tumor activity. Considering its favorable tolerance and pharmacokinetics in cynomolgus monkeys, we developed a phase I study to investigate GNC-038 for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) and relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: Patients diagnosed with relapsed/refractory non-Hodgkin lymphoma or acute lymphoblastic leukemia are currently being enrolled in this phase I study to evaluate the safety, tolerability and pharmacokinetics of GNC-038. This study will be conducted in two phases, dose-escalation (Ia) and dose-expansion (Ib). During the dose escalation phase, R/R-NHL patients will receive GNC-038 (0.016-6 μg/kg/d) as continuous intravenous (cIV) infusion for 8 weeks. Further escalation will be conducted with step-up dosing: cIV infusion of 3.6 μg/kg/d GNC-038 will be administered during week 1 followed by higher doses on subsequent weeks (9, 13.5, 20.25 or 30 μg/kg/d). R/R-ALL patients will receive GNC-038 by cIV infusion for 8 weeks (0.016-16 μg/kg/d). During the dose-expansion phase, one or more dosages will be chosen for further investigation in specific indications. The primary endpoints are dose limiting toxicity (DLT), maximum tolerated dose (MTD), treatment emergent adverse events (TEAE) and recommended phase 2 dose (RP2D). Secondary endpoints are adverse events (AEs), pharmacokinetics, objective response rate (ORR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Exploratory endpoints are biomarker assessment, anti-drug antibody (ADA) and pharmacodynamics. The dose expansion phase (Ib) has been initiated. Clinical trial information: NCT04606433 .
High-dose vitamin C to enhance neoadjuvant immune checkpoint therapy in mismatch repair proficient colon cancer: The ALFEO pilot study.
Authors: Sartore-Bianchi Andrea , Amatu Alessio , Di Nicolantonio Federica , Troiani Teresa , Tosi Federica , Napolitano Stefania , Martini Giulia , Bencardino Katia , Bonazzina Erica , Carnevali Pietro , Forti Edoardo , Mutignani Massimo , Vanzulli Angelo , Ghezzi Silvia , Scaglione Francesco , Marsoni Silvia , Bardelli Alberto , Ciardiello Fortunato , Ferrari Giovanni , Siena Salvatore 
Published: June 2023

TPS2675 Background: Most colon cancer (CC) patients can be treated with upfront curative surgery; however, relapse often occurs and the disease becomes deadly. Neoadjuvant chemotherapy does not jeopardize timing or quality of surgery and enhances relapse-free outcomes in proficient mismatch-repair (pMMR) CC (Morton et al, J Clin Oncol 2023). In the same setting, the use of immune checkpoint inhibitors (ICIs) with a single dose of ipilimumab (Ipi) and two doses of nivolumab (Nivo) proved to be feasible without delaying surgery and resulting in 23% major pathological responses (mPR) (Chalabi et al, ASCO 2022). We have previously shown that high dose vitamin C (HDVitC) triggers tumor infiltration and activation of CD8+ T cells in mouse tumors, enhancing efficacy of ICIs in pMMR CC preclinical models (Magrì et al, Sci Transl Med 2020). Methods: ALFEO is an open-label pilot trial of neoadjuvant CC treatment to test whether HDVitC can enhance the efficacy of ICIs in this setting. Main inclusion criteria are pMMR CC stage cT4N0/TxN1-2/[cM1 liver-limited disease with favorable oncological criteria candidate for upfront surgery on both T and M after multidisciplinary team evaluation]. Patients will receive Nivo i.v. 3 mg/kg D1 and D15, Ipi i.v. 1 mg/kg D 1 and VitC 70 g/ m2 D1-3 and 15-17. Tumor assessment will be performed at D21-28, followed by surgery within D28. Primary objective is activity of Nivo/Ipi + HDVitC; secondary objective is safety; exploratory objectives are correlation between efficacy and pharmacodynamic including tumor microenvironment changes. Primary endpoint is mPR rate. Considering the proof-of-principle nature of the trial, a design with a boundary for early stopping (both futility/utility and toxicity) and a fixed maximum sample size of 24 patients has been chosen. mPR for the Ipi/Nivo has been set at 23% (H0), while H1 at 75%. A Bayesian hypothesis test-based design (Zhou et al, Pharm Stat 2021) will be used for decision-making. Su. Clinical trial information: ECTR2022-502101-15-00 .
Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.
Authors: Jain Prantesh , Hutson Alan , Janes Cayla , Bruno Debora S. , Durm Greg Andrew , Sangal Ashish , Mehrotra Bhoomi , Crombet Ramos Tania , Leon Kalet , Dy Grace K. 
Published: June 2023

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 > 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 < 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression <50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .
A phase I trial of diphencyprone for cutaneous neurofibromas in adult patients with neurofibromatosis type 1.
Authors: Poplausky Dina , Young Jade N , Block Brandon , Cabral Patricia , Rivera-Oyola Ryan , Estrada Yeriel , Singer Giselle K , Wong Vicky K. , Correa Da Rosa Joel , Brown Rebecca M , Gulati Nicholas 
Published: June 2023

TPS2678 Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic tumor predisposition syndrome affecting about 1 in 2500 people. Affected patients develop a variety of skin findings including café-au-lait macules, axillary freckling, and cutaneous neurofibromas (cNFs). These patients also have an increased risk of malignant tumors including gliomas and soft tissue sarcomas. However, the cNFs, of which a patient can have thousands, are often cited as the most burdensome sign. Despite their benign nature, these tumors can be physically bothersome and cause significant emotional distress. To date, there are no effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten that induces a delayed-type hypersensitivity skin reaction, for the treatment of cNFs in adults with NF1. Methods: This trial is enrolling NF1 patients aged 18 and older with at least four cNFs greater than 4mm. Subjects taking systemic immunosuppressants, those with underlying immunodeficiency or uncontrolled intercurrent illnesses, and those who are pregnant or nursing are excluded from the study. DPCP 0.04% ointment is administered topically once weekly to up to 20 cNFs in a localized area for 10 weeks. The primary endpoint is to determine the safety and tolerability of DPCP ointment in the treatment of cNFs. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. To assess subjective tolerability, subjects score their symptoms, including pain, stinging, burning, and pruritus from 0 (none) to 3 (severe). Efficacy and tumor regression are assessed using the Response Evaluation Criteria in Solid Tumors guidelines in conjunction with photographs and manual tri-axial tumor measurements. Additionally, qualitative assessments are made by the study team using 3D whole-body photography. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a cNF and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints. Quantitative RT-PCR and single-cell RNA sequencing studies will assess gene expression changes in immune and tumor cell-related genes pre- and post-treatment with DPCP. Immunohistochemistry and proteomic profiling will be performed to characterize changes in the tumor microenvironment. Genetic testing for the NF1 germline mutation will be correlated with treatment response. Enrollment is ongoing with a target of 20 participants. Since September 2022, the study has enrolled 12 patients and five have completed the study. Clinical trial information: NCT05438290 .
XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers.
Authors: Hamilton Erika P. , Chaudhry Arvind , Spira Alexander I. , Adams Sylvia , Abuhadra Nour , Giordano Antonio , Parajuli Ritesh , Han Hyo S. , Weise Amy M. , Marchesani Aubri , Gupta Divya , Josephs Kate , Kalinsky Kevin 
Published: June 2023

TPS3154 Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. High B7-H4 expression has been observed in several cancers including breast, endometrial, and ovarian, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in preclinical models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In parallel with DES, optional backfill cohorts will enroll patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a selected dose level from DES and can be initiated at multiple dose levels simultaneously. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and assessment of antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996. Clinical trial information: NCT05377996 .
Phase 1/2 study of PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, in patients with locally advanced and/or metastatic solid tumors.
Authors: Call Justin A , Orr Douglas W. , Anderson Ian Churchill , Richardson Debra L. , Chen Zhu , Ma Sharon , Hunder Naomi N. H. , Hamilton Erika P. 
Published: June 2023

TPS3157 Background: PRO1184 is an antibody-drug conjugate (ADC) directed to folate receptor alpha (FRα), a cell surface antigen overexpressed in multiple cancers including ovarian, endometrial, lung, mesothelioma, and breast cancer. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetic (PK) profiles across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance efflux pumps. It may thus lend a robust bystander effect and induce deeper or more durable responses in refractory tumors. Preclinical studies further established that PRO1184 exerts potent antitumor activity in mouse xenograft models with high, moderate, and low FRα expression, consistent with the inherent potency and expected bystander activity of the exatecan payload. PRO1184 is stable in plasma and retains the excellent PK properties and bioactivity of the unconjugated parent antibody. The preliminary safety profile of PRO1184 was more favorable than a benchmarking deruxtecan-based ADC in cynomolgus monkeys. PRO1184 is thus a promising development candidate with a potentially large therapeutic index to benefit a broad population of patients with FRα-expressing solid tumors. Methods: PRO1184-001 is an ongoing, phase 1/2, open-label dose escalation and expansion study. Eligible patients are adults with metastatic or unresectable solid tumors, including ovarian, endometrial, non-small cell lung, breast cancer, or mesothelioma. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or mRECIST 1.1 for pleural mesothelioma. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1184 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1184 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). Part A of the study consists of a dose escalation phase and Part B consists of 4 FRα-expressing tumor specific expansion cohorts treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Clinical trial information: NCT05579366 .
FRONTIER: FAPi radioligand open-label, phase 1 study to evaluate safety, tolerability and dosimetry of [Lu-177]-PNT6555—A dose escalation study for treatment of patients with select solid tumors.
Authors: Bodei Lisa , Kavan Petr , Liberman Moishe , Taunk Neil , Metser Ur , Juneau Daniel , O'Reilly Eileen Mary , Ma Junsheng , Cioci Richard , Abdul Razak Albiruni Ryan 
Published: June 2023

TPS3161 Background: Fibroblast activation protein alpha (FAP) is a 170 kDa transmembrane glycoprotein expressed during development, active tissue remodeling, and cancer. Overexpression on cancer-associated fibroblasts in the tumor microenvironment, and on some cancer cells of mesenchymal origin, leads to the presence of FAP in > 90% of epithelial tumors, making FAP a compelling anti-cancer target. PNT6555, a potent FAP-targeting compound with rapid clearance from normal tissues and prolonged tumor retention in preclinical models1, is a radioligand consisting of a DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) and a FAP-targeting moiety (Bz-D-Ala-boroPro) connected via an aminomethyl linker. The corresponding gallium-68 and lutetium-177 chelates constitute the imaging and therapeutic theranostic pair of PNT6555 under evaluation in this phase I study. Methods: FRONTIER (NCT05432193) is a multicenter, open-label, multi-dose phase I study of PNT6555 in participants with pancreatic ductal adenocarcinoma, esophageal cancer, colorectal cancer, melanoma skin cancer, cholangiocarcinoma, or soft tissue sarcoma solid tumors with FAP over-expression. The primary aim is to evaluate the safety and tolerability of [Lu-177]-PNT6555 in order to determine a recommended phase II dose (RP2D). Dosimetry, pharmacokinetics, and tumor and immune responses will also be assessed for [Lu-177]-PNT6555, as well as safety, tolerability, and diagnostic performance of [Ga-68]-PNT6555 PET/CT. Key eligibility criteria include being refractory to prior treatment with no alternative available therapeutic options, having adequate organ function, and being FAP-positive on [Ga-68]-PNT6555 PET/CT scan, defined as ≥50% of lesions with an SUVmax of ≥1.5x the liver SUVmean. [Ga-68]-PNT6555 will be dosed at 120 - 220 MBq (3.2 - 5.9 mCi), with PET/CT initiated 90 (±30) min later. FAP-positive participants will receive [Lu-177]-PNT6555 once every 6 weeks for up to 6 cycles. Starting at 4 GBq (108 mCi) ±10%, [Lu-177]-PNT6555 may be escalated by 4 GBq, with a maximum planned dose of 12 GBq. De-escalation by 2 GBq may also occur. Dose finding will be guided by the modified toxicity probability interval (mTPI-2) statistical design with a targeted toxicity rate of 30%. The planned total sample size is 30, with targets of 3-12 DLT evaluable patients per dose level. Cohort 1 has been completed without a DLT. Enrollment to cohort 2 began in January 2023. 1. Hallet R, et al. Pre-clinical characterization of the novel fibroblast activation protein (FAP) targeting ligand PNT6555 for the imaging and therapy of cancer. Presented at SNMMI Annual Meeting April 2022; Vancouver, BC, Canada. Clinical trial information: NCT05432193 .