bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase 1 trial of ELI-002 immunotherapy as treatment for subjects with Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma and other solid tumors.
Authors: Pant Shubham , Furqan Muhammad , Abdul-Karim Raghad Muhsin , Chung Vincent , Devoe Craig E. , Johnson Melissa Lynne , Leal Alexis Diane , Park Haeseong , Wainberg Zev A. , Welkowsky Esther , Haqq Christopher M. , O'Reilly Eileen Mary , Weekes Colin D. 
Published: June 2022

TPS2701 Background: Mutations in KRAS and NRAS occur in one quarter of human solid tumors. The G12D allele is the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary and gallbladder cancers. ELI-002 2P is an immunotherapeutic comprised of a lymph-node targeted amphiphile (AMP)-modified G12D and G12R mutant KRAS peptides together with an AMP-modified CpG oligonucleotide adjuvant. In preclinical models, ELI-002 demonstrated increased cytotoxic KRAS-specific T cells compared to non-lymph node targeted controls using the same peptide and adjuvant. Clinical evaluation of adoptively transferred KRAS-specific T cells demonstrated objective antitumor activity (Tran 2016). Circulating tumor (ctDNA) methodology permits identification of patients with minimal residual disease (MRD) following locoregional treatment. In MRD setting, immunotherapy is anticipated to succeed as the ratio of effector T cells to target tumor cells is maximized prior to bulk visible disease. The AMPLIFY-201 study (NCT04853017) is evaluating ELI-002 in patients with KRAS mutated solid tumors with MRD. Methods: AMPLIFY-201 is an open-label, dose-escalation and expansion phase I, first in human, trial evaluating ELI-002 2P in patients with KRAS mutated tumors with MRD following standard of care therapy. The initial phase I cohort enrolls patients with colorectal and pancreatic cancer to receive multiple doses of AMP-peptides 70mcg each (1.4 mg total) admixed with AMP-CpG 0.1 mg, administered once every two weeks. Subsequent phase I cohorts will enroll patients with RAS-mutated pancreatic, colorectal, non-small cell lung, ovarian, bile duct or gallbladder cancer, who will receive a fixed dose of AMP-peptides 70 mcg each, together with escalating doses of AMP-CpG. Safety and efficacy will be summarized with descriptive statistics. The maximum tolerated dose (if any) and the recommended phase II dose (RP2D) will be determined with the dose-response activity of ELI-002 2P in eliciting functional KRAS-specific T cells. Preliminary antitumor activity will be characterized using changes from baseline in ctDNA, serum biomarkers appropriate for tumor type, and progression free survival time. Eligibility includes patients who have received standard of care locoregional treatment according to NCCN guidelines and whom have MRD persistence or relapse (ctDNA positive). Patients with colon and pancreas cancer with Stage IV oligometastatic disease (< 3 lesions in one organ) rendered surgically free of disease and with MRD, are also eligible. The dose escalation portion of the study is currently enrolling. Clinical trial information: NCT04853017.
Phase 1 study of SGN-PDL1V, a novel, investigational vedotin antibody–drug conjugate directed to PD-L1, in patients with advanced solid tumors (SGNPDL1V-001, trial in progress).
Authors: Patnaik Amita , Call Justin A , Spreafico Anna , Nabell Lisle , Yan Mingjin , Forero-Torres Andres , Gillison Maura L. 
Published: June 2022

TPS3154 Background: Programmed cell death ligand 1 (PD-L1) is a cell-surface protein involved in the programmed cell death protein 1 (PD-1)/PD-L1 immune checkpoint, which inhibits T-cell activation. Elevated PD-L1 expression is observed across a broad spectrum of solid tumor types. Expression of PD-L1 in tumors can signal through PD-1 on T cells to inhibit T-cell effector function. Blockade of the PD-1/PD-L1 signaling axis may restore antitumor immunity by reactivating T-cell effector function in the tumor microenvironment. SGN-PDL1V is a novel, investigational vedotin antibody–drug conjugate directed to PD-L1 with multiple proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, and immunogenic cell death (ICD). Even in xenograft models with low, heterogeneous PD-L1 expression, SGN-PDL1V demonstrated antitumor activity via direct cytotoxicity and the bystander effect. Cytotoxicity mediated by SGN-PDL1V also led to immune activation due to MMAE-induced ICD (Kwan et al 2021). These preclinical findings provide a rationale for evaluating SGN-PDL1V in patients (pts) with advanced solid tumors. Methods: SGNPDL1V-001 (NCT05208762) is a phase 1, first-in-human, multicenter, open-label trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-PDL1V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization cohorts (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed metastatic/unresectable solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, melanoma, or ovarian cancer, will be eligible. Pts must have ECOG PS 0–1 and have failed or are unable to tolerate standard therapies. Pts must have PD-L1 expression ≥1 by tumor proportion score or combined positive score based on historical testing. Prior treatment with an MMAE-containing agent or an anti–PD-L1 agent (within 6 months) is not permitted. Primary endpoints include adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints include rate and duration of objective response, progression-free survival, overall survival, PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamics (PD), PK/PD relationships, and patient-reported outcomes. Safety and antitumor activity endpoints will be assessed using descriptive statistics. Objective response rate will be analyzed by tumor type, dose levels, and schedules. Enrollment for Part A is ongoing at sites in North America and is planned in Europe. Clinical trial information: NCT05208762.
Efficacy of afatinib in patients with advanced/metastatic solid tumors harboring NRG1 gene fusions: A novel, prospective real-world outcomes study based on single-patient protocol data.
Authors: Liu Stephen V. , Minasi Lori Ann E. , Herpers Matthias , Frohn Claas 
Published: June 2022

TPS3180 Background: Oncogenic neuregulin 1 ( NRG1) gene fusions occur in ̃0.2% of solid tumors overall and in up to 31% of cases of invasive mucinous lung adenocarcinoma [Laskin et al. Ann Oncol. 2020;31(12):1693–1703; Cadranel et al. Oncologist. 2021;26(1):7–16]. NRG1 fusion proteins provide an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to ErbB3 (HER3), leading to HER3 heterodimerization and activation of downstream signaling pathways, resulting in oncogenesis. Afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, represents a potential treatment for NRG1-fusion positive ( NRG1+) tumors. This study aims to examine the safety and efficacy of afatinib in patients with NRG1+ solid tumors, for which no authorized targeted therapy exists. Methods: This prospective, decentralized, US study (NCT05107193) will include 40 evaluable patients aged ≥18 years. Participating molecular test providers across the USA will identify eligible fusions in the course of routine diagnostic assays. When a patient with an NRG1 fusion is identified, participating test providers will notify the treating physician of the study as a treatment option for the patient. Patients’ primary oncologists will then contact the trial sponsor to confirm patient eligibility. Once approved by the central Institutional Review Board, patients will receive afatinib on a single-patient protocol basis, until disease progression or treatment is no longer tolerated. The recommended dosage per SmPC is 40 mg orally QD. Patients will be screened and enrolled into the study at their existing point-of-care setting. Inclusion criteria include a histologically or cytologically confirmed diagnosis of an advanced, unresectable/metastatic, non-hematologic malignancy with an NRG1 fusion, evaluable per RECIST 1.1. Any coding gene as the NRG1 fusion partner is permitted. Fusion status will be confirmed prospectively by a contracted molecular test provider. Exclusion criteria include prior systemic anti-cancer therapy or investigational drug within 14 days or 5 half-lives (whichever is shorter) of the start of afatinib treatment; an actionable driver mutation other than NRG1 fusion for which FDA-approved targeted therapy is available; and prior treatment with an ErbB-targeted therapy. The primary endpoint of the study is confirmed objective response (OR) by independent central review per RECIST 1.1, defined as best overall response of either complete response or partial response and analysed as the proportion of patients with an OR. The key secondary endpoint is duration of response, defined as the time from the first documented OR to progression or death. Secondary endpoints include time to OR and disease control per investigator assessment. Safety will also be assessed. The study is open for recruitment. Clinical trial information: NCT05107193.
STOPTRAFFIC-1: A phase I/II trial of SX-682 in combination with nivolumab for refractory RAS-mutated microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Johnson Benny , Kopetz Scott , Hwang Hyunsoo , Yuan Ying , DePinho Ronald Anthony , Zebala John , Overman Michael J. 
Published: June 2022

TPS3638 Background: Refractory RAS mutated MSS mCRC represents a critical unmet need with minimal response to immune checkpoint blockade (ICB). Preclinical CRC models reveal that KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019; Grover et al, Cancer Discovery, 2022). SX-682 is a novel oral small-molecule inhibitor of the CXCR1/2 chemokine receptors involved in MDSC-recruitment to the TME. This proof-of-concept study investigates whether de novo immunotherapy resistance in MSS RAS mutated mCRC can be overcome by treatment with a small molecule CXCR1/2 antagonist in combination with anti-PD-1 therapy. Methods: STOPTRAFFIC-1 (NCT04599140, enrolling) is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 in combination with nivolumab to evaluate safety and clinical activity for patients (pts) with refractory RAS ( KRAS and NRAS) mutated MSS mCRC. Key eligibility criteria: patients (pts) with MSS mCRC with measurable disease, progression or intolerance to at least 2 prior lines of standard therapy, and ECOG 0 or 1. Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg by mouth twice daily) administered in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29 of each cycle. Adverse events are assessed according to CTCAE v5.0. Response assessments (per RECIST) occur every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to cohort 5 began in January 2022. Following determination of maximum tolerated dose (MTD), dose expansion design is a Simon's optimal two-stage design. Efficacy will be assessed in the first 15 pts with a requirement of at least 2 responses in order to enroll 14 additional pts (N=29) in the second stage. Pre- and on-treatment tissue biopsies will be collected in the expansion phase. The primary objectives are to determine the safety profile of SX-682 alone and in combination with nivolumab, including the MTD, recommended phase 2 dose, and the DLT. The secondary objectives include overall response rate, progression-free survival, overall survival, and pharmacokinetic profiles of SX-682. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140.
EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors.
Authors: Ciombor Kristen Keon , Hong Sung Chul , Eng Cathy , Yao Xin , Cho May Thet , You Y. Nancy , Das Prajnan , Chakravarthy Anuradha Bapsi , O'Dwyer Peter J. 
Published: June 2022

TPS3644 Background: Trimodality therapy including chemoradiation, chemotherapy and surgical resection is standard for patients with T3-4 and/or node-positive (N+) rectal adenocarcinomas. Pathologic complete response (pCR) rates after neoadjuvant chemoradiation approach 15% in all-comers and 27% in patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) rectal cancer. Additionally, preclinical data suggest that hypofractionated radiation (large dose per fraction) may enhance immunogenicity. Given high response rates to immunotherapy in MSI-H/dMMR early stage and metastatic colorectal cancer (CRC), we hypothesized that neoadjuvant nivolumab plus ipilimumab and short course radiation in locally advanced MSI-H/dMMR rectal cancer (LARC) would result in increased pCR rates. Methods: EA2201 (NCT04751370) is an NCTN phase II clinical trial for patients with treatment-naïve locally advanced (T3-4Nx or TxN+) rectal adenocarcinoma that is dMMR or MSI-H. Patients receive nivolumab (480 mg) and ipilimumab (1 mg/kg) every 28 days for 2 cycles, followed by short course radiation (5 Gy x 5 fractions; total 25 Gy) and an additional 2 cycles of nivolumab and ipilimumab prior to disease reassessment and TME. The primary endpoint is pCR at TME. Secondary endpoints include 5-year disease-free survival, overall survival, treatment-related toxicities, and sphincter preservation rate for low-lying tumors. This study has a single-arm, two-stage design; a pCR rate of 50% or more will be taken as evidence of promising activity in this patient population. We plan to enroll 31 patients, with accrual currently ongoing. Clinical trial information: NCT04751370.
Anti-PD1, capecitabine, and oxaliplatin for the first-line treatment of dMMR esophagogastric cancer (AuspiCiOus-dMMR): A proof-of-principle study (AuspiCiOus).
Authors: Bos Joris , Haj Mohammad Nadia , Derks Sarah , Van Laarhoven Hanneke W.M. 
Published: June 2022

TPS4163 Background: Doublet cytotoxic treatment demonstrates survival benefit over single drug therapies in patients with advanced esophagogastric cancer (EGC). Previous clinical data suggests an improved survival outcome in patients with microsatellite instability (MSI) treated with PD-1 inhibitor monotherapy or in combination with chemotherapy in first line palliative treatment. The positive effect of immunotherapy was only seen after a couple of months of treatment. This suggests that the patient might benefit from a short course of chemotherapy at the start of treatment. However, reports on the effects of cytotoxic treatment in MSI-high tumors range from beneficial to detrimental. Thus, the value of cytotoxic treatment, as well as the effect on the tumor immune microenvironment (TME) in MSI-high tumors is unclear. Therefore, in AuspiCious-dMMR we will study the effect of sequential treatment in patients with mismatch repair deficient (dMMR) EGC on the tumor immune microenvironment and, more specifically, the impact on the infiltration of cytotoxic T cells, before and after a short course of chemotherapy, and during treatment with PD-1 inhibition. Methods: AuspiCiOus is a multi-center, open-label, single arm (phase 2) study in patients with dMMR irresectable or metastatic EGC adenocarcinoma (NCT05177133). Patients are treated with Capecitabine and Oxaliplatin for two 3-weekly cycles, after which treatment is continued with retifanlimab (PD-1 inhibitor) for 4-weekly cycles up to progression or unacceptable toxicity, with a maximum of two years. Before treatment, after chemotherapy and after two cycles of immunotherapy fresh tumor biopsies are collected to study the primary outcome (T cell infiltration and the interferon-γ signature) as well as for translational research purposes (flow cytometry, nanostring profiling, (multicolor) immunohistochemistry and organoid culturing). Blood is collected at the same time points and on day 3 after the first course of immunotherapy for isolation of peripheral blood mononuclear cell, and determination of cytokine/chemokine profile, circulating stromal markers, and circulating tumor DNA. Also, fecal samples are collected to determine changes in the intestinal microbiome and patient reported outcome measures are used to determine quality of life. (s)AEs are assessed according to CTCAE v5 and tumor response is determined according to (i)RECIST 1.1. Key eligibility criteria are 1) histological confirmed diagnosis of untreated metastatic or irresectable HER2- adenocarcinoma of stomach or junction and 2) dMMR determination by IHC. Study is open for inclusion and three of planned 25 patients have been enrolled. Clinical trial information: NCT05177133.
TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.
Authors: Choueiri Toni K. , Albiges Laurence , McKay Rana R. , Pal Sumanta K. , Hammers Hans J. , Heng Daniel Yick Chin , Beckermann Katy , Kasturi Vijay , Motzer Robert J. 
Published: June 2022

TPS4605 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al Lancet Oncol 2020). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior systemic therapies. Tivozanib was combined with Nivolumab in the phase 1b/2 TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a tolerable safety profile (Albiges et al Ann Oncol. 2021). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age >18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. Subjects will receive tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off, on the monotherapy arm, and tivozanib 0.89 mg at the same schedule in addition to nivolumab 480mg intravenously every 4 weeks on the combination arm. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review (IRR). The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.
Phase 1a/b safety study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer (ADVANCED-1).
Authors: Bandari Jathin , Zummo Jacqueline , Belani Khushboo , Brown Eppie , Metcalf McKenna , Nanayakkara Nuwan 
Published: June 2022

TPS4620 Background: Bladder cancer is the most common malignancy involving the urinary system, resulting in approximately 18,000 deaths each year in the US. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guérin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for the treatment of high-grade (HG) NMIBC (consisting of HG Ta, T1, and carcinoma in situ [CIS]). TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. TARA-002 is manufactured using the same master cell bank as OK-432 (Picibanil) and is approved in Japan and Taiwan for the treatment of several oncology indications. Nonclinical toxicology studies with TARA-002 and nonclinical and clinical studies with OK-432 (a comparable product to TARA-002) support the starting dose for the planned Phase 1a/b study. Methods: ADVANCED-1 is a Phase 1a/b, dose finding, open-label study of intravesical instillation of TARA-002 in adults with HG NMIBC. The study includes a dose escalation phase (Phase 1a) and a dose expansion phase (Phase 1b). The objective of the study is to evaluate the safety and tolerability of TARA-002, to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) in the treatment of subjects with HG Ta or CIS ± Ta NMIBC during Phase 1a, and to further assess the safety and preliminary efficacy of TARA-002 in the treatment of subjects with CIS NMIBC with active disease during Phase 1b. For this first-in-human study, stage T1 is excluded. The study includes eligible male and female subjects ≥ 18 years of age who are unable to obtain BCG or have received at least one dose of intravesical BCG or chemotherapy. Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration for each subject includes 28 days of screening period, 6-week treatment period, and 6-week follow-up period. During the dose escalation phase (1a), up to 18 subjects with HG Ta or CIS ± Ta NMIBC are enrolled. Up to 3 dose levels are tested sequentially with 6 weekly intravesical doses, starting with the lowest dose using a 3+3 design in a dose escalation manner. At the established RP2D, the dose expansion phase (1b) will enroll approximately 12 new subjects with CIS ± Ta NMIBC with active disease and treat in the same manner to further assess the safety and preliminary efficacy of TARA-002. Phase 1a is currently open for enrollment. Clinical trial information: NCT05085977; NCT05085990.