tbuckley/cabot-search huggingface dataset:
Trifluridine/tipiracil plus capecitabine and bevacizumab as upfront treatment for metastatic colorectal cancer: Results of the phase 1 TriComB study.
Authors: Paolo Ciracì, Veronica Conca, Roberto Moretto, Carlotta Antoniotti, Margherita Ambrosini, Sabina Murgioni, Giovanni Gori, Alessandra Russo, Francesca Bergamo, Giovanni Randon, Vittorio Studiale, Elisabetta Fini, Federica Marmorino, Beatrice Borelli, Marco Maria Germani, Guglielmo Vetere, Martina Carullo, Chiara Boccaccio, Gianluca Masi, Chiara Cremolini
Journal: Journal of Clinical Oncology (2024)

3558 Background: Capecitabine (cap) plus Bevacizumab (bev) is a standard option for previously untreated unresectable metastatic colorectal cancer (mCRC) patients (pts) deemed not fit for upfront chemotherapy doublets. A synergistic effect of the sequential administration of cap and Trifluridine/Tipiracil (FTD/TPI) has been shown both in vitro and in vivomodels. Here, we present safety and preliminary activity results of the phase 1 TriComB study, an open-label, multicenter, phase 1/2 trial, evaluating FTD/TPI in combination with cap and bev in mCRC pts. Methods: Patients with previously untreated mCRC, ineligible for oxaliplatin- and/or irinotecan- based regimens, were enrolled. A 3 + 3 dose escalation design was used to identify the recommended dose (RD) of FTD/TPI (days 15-19 and 22-26) in combination with cap (1000 mg/sqm/BID days 1-14) and bev (5 mg/kg day 1,15) in 28-days cycles. Adverse events (AEs) were reported according to CTCAE version 5.0 and tumor response was assessed by RECIST version 1.1. Results: 11 pts (5 men, 6 women; median age: 77, range: 47-84 years) were enrolled. For the first three patients (FTD/TPI: 25mg/sqm BID) no dose limiting toxicities (DLTs) were observed. At 30 mg/sqm BID dose level, 3/5 DLTs were reported: 2 pts experienced a dose delay of &gt;7 days from the scheduled timing and 1 patient was unable to receive ≥ 75% of study drugs’ doses during the first cycle. FTD/TPI was de-escalated and 3 additional patients were treated at 25 mg/sqm BID. Since 1/6 pts experienced a DLT (grade 4 colonic perforation) that was identified as the RD. Grade 3/4 AEs are listed in the Table. As of January 2024, Overall Response Rate is 72.7% (8/11 pts) and 66.7% (4/6 pts) in the overall population and at the RD, respectively. Conclusions: The sequential combination of cap and FTD/TPI with bev is feasible. The phase 2 of the study is ongoing to evaluate antitumor activity of this regimen in the same patients' population. Clinical trial information: NCT04564898 Safety summary Clinical trial information: NCT04564898 . [Table: see text]
Pilot study of CBX-12 pharmacodynamics in patients with advanced solid tumors.
Authors: Sarah Shin, Geraldine Helen O'Sullivan Coyne, Larry V. Rubinstein, Naoko Takebe, John Joseph Wright, Deborah Wilsker, Katherine V. Ferry-Galow, Chris Alan Karlovich, Larry Anderson, Laura Kuhlmann, Ralph E. Parchment, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2024)

TPS3187 Background: Topoisomerase 1 (TOP1) inhibitors effectively kill a diverse range of tumor cells but have limited clinical utility due to severe off-target toxicities. Targeted therapeutic strategies have been developed to circumvent these limitations, although there remains an unmet need for antigen-agnostic tumor targeting. CBX-12 is a peptide conjugate that uses a novel pH-low insertion peptide (pHLIP) linked to TOP1 inhibitor exatecan to selectively target the low-pH tumor microenvironment and deliver the payload intracellularly. Recently published results of the first-in-human study of CBX-12 (NCT04902872) demonstrated single-agent activity in 4 patients, including a complete response in a patient with ovarian cancer. The predominant reported toxicity was myelosuppression with the most common grade 3/4 treatment-related adverse event being neutropenia in 28.6% of patients. Here we report our new pharmacodynamic (PD) biomarker-driven pilot study of CBX-12 in patients with advanced solid tumors. The primary objective of this study is to assess the effects of CBX-12 on biomarkers of DNA damage response (DDR) in biopsy specimen to establish the degree and duration of CBX-12 target engagement. The secondary objectives are to assess the effects of CBX-12 on TOP1 molecular response; determine any association between tumor TOP1 levels, DDR modulation, and plasma exatecan levels; evaluate the effect of CBX-12 on CD8+ T cell infiltration and activation in the tumor microenvironment; assess the objective response rate using RECIST v 1.1; and assess safety and tolerability of CBX-12. The planned PD endpoints aim to confirm and further enrich knowledge of the mechanisms underlying response or resistance to CBX-12 treatment, and guide future complementary treatment combination strategies. The study results may also help identify future patient populations likely to benefit from CBX-12 treatment. Methods: CBX-12 will be administered intravenously once weekly in 28-day cycles at the recommended phase 2 dose. Mandatory biopsies will be collected at baseline, 24-36 hours post first dose, and on cycle 3 day 1 to assess both short- and long-term effects of CBX-12 on the tumor. Mandatory research blood samples will be collected at specified timepoints for pharmacokinetic, circulating tumor cell, and cell-free DNA analyses. Clinical trial information: NCT05691517 .
Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in combination with gemcitabine and docetaxel in non-small cell and small cell lung cancers.
Authors: Christine Auberle, Jared Cohen, Saiama Naheed Waqar, Daniel Morgensztern, Kaitlyn Fischer, Tamara Cole, Allison Gordon, Jessica Porzel, Cynthia Fogal, Katlyn Kraft, Jingxia Liu, Sasha Haarberg, John S. Bomalaski, Ramaswamy Govindan, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2024)

TPS3189 Background: Arginine is essential to neoplastic growth and development, yet many cancer cells do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing arginine auxotrophy in cancer cells that are ASS1 negative. Preclinical data suggests that ADI-PEG 20 in combination with docetaxel (D), resulted in increased expression of hENT, the transporter for gemcitabine (G) as well upregulation of dCK to trap G inside of cancer cells. A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS). We are conducting a phase I/II trial examining the safety, tolerability, to determine the recommended phase II dose (R2PD) and evaluate the efficacy of this combination in patients with previously treated metastatic non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) with an alternative dosing regimen than that used in STS based on the mechanism of action. Methods: Eligible pts include previously treated metastatic NSCLC and SCLC with performance status 0-1 with adequate organ function. Pts are excluded if previously treated with G; however, prior use of docetaxel is permitted. Up to 12 patients will be enrolled in an open-label phase I trial with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with G and D. Primary objectives of the phase I portion are to determine the safety, tolerability and recommend phase II dose (RP2D) of combination ADI-PEG 20, G and D. Pts will be treated with ADI-PEG 20 intramuscularly at 36mg/m 2 on day -7 of cycle 1 and then on days 1, 8, and 15 of each subsequent cycle with dose-escalated G (600, 750, 900 mg/m 2 ) on day 2 and D (60, 75, 75 mg/m 2 ) on day 1 of each 21-day cycle for up to 8 cycles then will continue with combination therapy at provider discretion for up to 34 cycles. The phase II will consist of two cohorts (NSCLC and SCLC) receiving the triplet treatments at the RP2D determined during phase I. Primary objective of the phase II portion is to determine the objective response rate (ORR) in each cohort. Phase II uses a Simon optimal two-stage design per cohort for ORR with a minimum of 12 patients and a maximum of 36 patients per cohort. In the phase I, patient accrual at the maximum tolerated dose level is nearing completion and ADI-PEG in combination with G and D will be further evaluated in the phase II with separate cohorts for NSCLC and SCLC. Clinical trial information: NCT05616624 .
A first-in-human (FIH), phase 1/2, dose-escalation, dose-optimization, and dose-expansion study of PARP1-selective inhibitor IMP1734 in participants with advanced solid tumors.
Authors: Guru P. Sonpavde, Justin A Call, Gerald Steven Falchook, Benjamin Garmezy, Drew W. Rasco, Lan Liu, Tiantian Niu, Jenna He, Congcong Zhang, Jarema Kochan, Sam Rebello, Giuseppe Russo, Viola Chen, Suba Krishnan
Journal: Journal of Clinical Oncology (2024)

TPS3191 Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). While several approved nonselective PARPi have provided robust anti-tumor activity, they are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1 but spare PARP2 may improve the risk-benefit profile for this class of therapies by retaining anti-tumor activity while avoiding PARP2-related toxicities. IMP1734 (EIK1003) is a potent PARP1-selective inhibitor that inhibits tumor growth in nonclinical models and may widen the therapeutic index in tumors where non-selective PARPi have demonstrated efficacy. Methods: Study EIK1003-001 (IMP1734-101) is a global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of IMP1734 in participants with advanced solid tumors. The study has 3 parts: Part 1 (FIH; Dose Escalation), Part 2 (Dose Optimization), and Part 3 (Dose Expansion at the recommended dose for expansion [RDE]). Part 1 of this study is currently enrolling and consists of dose escalation of IMP1734 in study participants with advanced/recurrent/metastatic ovarian, breast, or prostate cancer with suspected deleterious/deleterious mutations in a pre-specified panel of homologous recombination repair (HRR) genes (n = 70). Eligible participants must be ≥ 18 years of age, have histologically or cytologically confirmed tumors as indicated in each study part, and at least 1 RECIST v1.1-measurable lesion and/or pre-specified serum tumor-specific marker. All participants must have a deleterious or suspected deleterious mutation in select HRR genes. Primary endpoints include safety and tolerability (evaluation of dose-limiting toxicities and determining the maximum tolerated dose, maximum achievable dose, and RDE). Secondary endpoints include evaluation of the pharmacokinetic parameters of IMP1734 and measures of efficacy, including overall response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints include analysis of pharmacodynamic biomarkers, serial ctDNA measurements, and patient quality-of-life measures. This study opened on 11 Dec 2023. Clinical trial information: NCT06253130 .
An open-label study to assess the safety and efficacy of naporafenib (ERAS-254) administered with trametinib in previously treated patients with locally advanced unresectable or metastatic solid tumor malignancies with RAS Q61X mutations (SEACRAFT-1).
Authors: Alexander I. Spira, Meredith McKean, Adil Daud, Kyaw Zin Thein, Brian Andrew Van Tine, Judy S. Wang, Joyce Antal, Rebecca Sutton, Yue Cui, David S. Hong
Journal: Journal of Clinical Oncology (2024)

TPS3178 Background: The rat sarcoma viral oncogene (RAS)/mitogen-activated protein kinase (MAPK) pathway is a key signaling cascade that drives cell proliferation, differentiation, and survival. Inappropriate activation of this pathway drives tumorigenesis in a subset of solid tumors. There are 3 isoforms of RAS (KRAS, NRAS, and HRAS) with the most commonly mutated codons being 12, 13, and 61. While these codon mutations map to the active site of RAS, they appear to have differential impacts on pathway activation. Mutations at codon 61 (RAS Q61X) are generally thought to be the most MAPK pathway-activating relative to mutations at codons 12 and 13 and are therefore thought to be the most oncogenic. Naporafenib is a pan-RAF inhibitor that is being evaluated in combination with trametinib, which inhibits MEK, a downstream node of the RAS/MAPK pathway. Clinical proof of concept (PoC) in patients with NRASm melanoma (of which 80 to 90% have Q61X mutations) and preliminary PoC for patients with RAS Q61X NSCLC have been established for the combination. Preclinical data across tumor types suggest that RAS Q61X is a potential predictive biomarker for the combination of naporafenib with trametinib, a hypothesis being tested in this trial. Methods: SEACRAFT-1 (NCT05907304) is a Phase 1b, open-label study evaluating the clinical activity and safety of the combination of naporafenib and trametinib in pts with locally advanced, unresectable, or metastatic solid tumor malignancies that are not responsive to standard therapies or for which there are no standard therapies. Eligible pts must be ≥18 years (or ≥12 and &lt;18 years in an adolescent substudy) with documented RAS Q61X mutation by an analytically validated assay. Pts must also have ≥1 measurable lesion per RECIST (Response Evaluation Criteria in Solid Tumors, v1.1) and Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 (or Karnofsky/Lansky Performance Status ≥70 for adolescent pts). Exclusion criteria include prior therapy with an ERK, MEK, RAF, or RAS inhibitor, QTcF &gt;450 ms at baseline, and left ventricular ejection fraction (LVEF) &lt;50% at baseline. A total of up to 115 pts will be enrolled to receive naporafenib 200 mg BID and trametinib 1 mg QD continuous in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is ORR; secondary endpoints include assessment of PFS, DOR, safety, and tolerability. Clinical trial information: NCT05907304 .
Study of ELU001, a C’Dot drug conjugate (CDC) targeting folate receptor α (FRα) overexpressing solid tumors.
Authors: Wen Wee Ma, Anthony W. Tolcher, Cesar Augusto Perez, Andrea Elisabeth Wahner Hendrickson, Douglas W. Orr, Yonina R. Murciano-Goroff, Carey K. Anders, Erika P. Hamilton, Elizabeth M. Swisher, Cara Amanda Mathews, Babar Bashir, Luis Alexander Rojas-Espaillat, Gerardo Colon-Otero, Gregory Paul Adams, Catherine W. Reddick, Eliel Bayever
Journal: Journal of Clinical Oncology (2024)

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had &gt;1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to &lt; 75%, low = 25% to &lt; 50%, negative = &lt;25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m 2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m 2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .
A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.
Authors: Kyriakos P. Papadopoulos, Jordi Rodon Ahnert, Moh'd M. Khushman, Sunil Sharma, Meredith Pelster, Michael Cecchini, Shivaani Kummar, Minjung Choi, Lalith V Akella, Amanda Garofalo, Ziyang Yu, Varsha Iyer, Marie Huong Nguyen, Keith W. Orford, Samuel J. Klempner
Journal: Journal of Clinical Oncology (2024)

TPS3175 Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .
<sup>177</sup>Lu-edotreotide versus everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin: The phase 3 randomized LEVEL, GETNE-T2217 trial.
Authors: Alejandro Garcia-Alvarez, Rocio Garcia-Carbonero, Beatriz Anton-Pascual, Paula Jimenez-Fonseca, Belen Llana, Virginia Pubul, Urbano Anido, Javier Molina-Cerrillo, Maribel del Olmo-García, Alex Teule, Marta Benavent Viñuales, David Taieb, Come Lepage, Amandine Beron, Catherine Ansquer, Emmanuel Deshayes, Eric Baudin, Magalie Haissaguerre, Thomas Walter, Jaume Capdevila
Journal: Journal of Clinical Oncology (2024)

TPS3177 Background: Everolimus is the only approved drug for the treatment of patients with neuroendocrine tumors (NETs) of lung and thymic origin, showing a median progression-free survival (PFS) of 11 months. Retrospective data for peptide receptor radionuclide therapy (PRRT) have demonstrated promising activity in somatostatin receptor (SSTR)-positive lung NETs. This study aims to compare the efficacy, safety, and patient-reported outcomes of 177 Lu-edotreotide versus the standard of care everolimus in patients with advanced lung and thymic NETs. Methods: The LEVEL trial is a randomized, open-label, phase 3 international trial of 177 Lu-edotreotide versus everolimus in patients with progressive, advanced, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment naïve or have progressed (PD) on somatostatin analogues or ≤2 additional systemic treatments. Prior PRRT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177 Lu-edotreotide (7.5±0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is PFS according to RECIST v1.1. Secondary endpoints include overall response rate, duration of response, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30). The expected sample size is 120 patients using a two-sided group sequential Lan-DeMets with O’Brien-Fleming-like boundaries test to demonstrate statistically significant risk reduction of 46.4% (HR= 0.536) in PFS between arms (α=0.05, β=0.2). The study has received institutional review board/ethics committee approval. Recruitment started in Oct 2023. Thirteen patients are already included. Clinical trial information: NCT05918302 .