bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 study of patritumab deruxtecan (HER3-DXd; U3-1402) in combination with osimertinib in patients with advanced EGFR-mutated NSCLC.
Authors: Janne Pasi A. , Mostillo Joseph , Shrestha Pomy , Zhang Ruoyang , Fan Pang-Dian , Cantero Frédérique 
Published: June 2022

TPS3161 Background: Although first-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib improved survival in patients (pts) with advanced/metastatic EGFR-mutated ( EGFRm) non-small cell lung cancer (NSCLC), therapy after acquired resistance to osimertinib remains an unmet need. HER3 is expressed in the majority of EGFRm NSCLCs. HER3-DXd is a novel, investigational, HER3-directed antibody-drug conjugate that demonstrated preliminary single-agent clinical activity in EGFRm NSCLC. In preclinical models of EGFRm NSCLC, osimertinib increased membrane HER3 expression, improved the internalization rate of HER3-DXd, and enhanced tumor growth inhibition by HER3-DXd. Therefore, HER3-DXd with osimertinib might improve outcomes in pts with disease that progressed with osimertinib therapy. This phase 1 study (NCT04676477; U31402-A-U103) evaluates HER3-DXd in combination with osimertinib in pts with advanced EGFRm NSCLC that has progressed with first-line osimertinib therapy. Methods: This is an open-label, 2-part study of HER3-DXd in combination with osimertinib. Pts are enrolling in North America, Europe, and Asia. Dose escalation enrolls pts with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 del or L858R) and progression during or after osimertinib therapy. Pts receive HER3-DXd 1.6, 3.2, 4.8, or 5.6 mg/kg intravenously (IV) every 3 weeks (Q3W) in combination with osimertinib 40 or 80 mg orally (PO) once daily (QD). Pts are enrolled in each cohort guided by safety (dose-limiting toxicities) using a Bayesian logistic regression model. Primary objectives of dose escalation are to assess safety and tolerability of the combination and identify a recommended combination dose (RCD). In dose expansion, pts will be randomized 1:1 to receive either HER3-DXd and osimertinib at the RCD (arm 1, [≈60 pts]) or HER3-DXd 5.6 mg/kg IV Q3W (arm 2, [≈60 pts]). A third arm (arm 1b, [≈60 pts]) may be added to evaluate 2 provisional RCDs of HER3-DXd + osimertinib. The primary objective of dose expansion (arms 1, 2, and 1b) is to evaluate efficacy of the combination vs that of monotherapy. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review. Other efficacy endpoints include ORR by investigator and duration of response, disease control rate, time to response, progression-free survival, and overall survival. If the RCD includes an osimertinib dose of 80 mg PO QD, ≈30 pts with advanced EGFRm NSCLC without prior treatment will be enrolled and treated at the RCD in a separate cohort; the primary objective is to assess safety and tolerability. A tumor sample after progression with osimertinib (or prior to entry) is required for pts enrolled in dose expansion for retrospective evaluation of HER3 and biomarker analyses. Clinical trial information: NCT04676477.
Phase 1 study of KT-333, a targeted protein degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors.
Authors: Starodub Alexander , Gollerkeri Ashwin , De savi Chris , Dey Joyoti , Agarwal Sagar , Donohue Sean , Perea Rachelle , Klaus Christine , Gollob Jared 
Published: June 2022

TPS3171 Background: The signal transducer and activator of transcription 3 (STAT3) protein is activated by cytokines and growth factors resulting in tumor growth and promotion and hindering antitumor immunity. Approximately 70% of human cancers including both hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3). There is evidence of constitutive activation of STAT3 through genetic mutations or aberrant cellular signaling pathways in tumors such as large granular lymphocytic leukemia (LGL-L), peripheral T-cell lymphoma (PTCL), and cutaneous T-cell lymphomas (CTCL). Hyperactivation of STAT3 has been reported in a variety of solid tumors. In several of these cancers, the levels of pSTAT3 and/or activated STAT3 have been shown to correlate with poor clinical prognosis. As with other transcription factors, selective inhibition of STAT3 has been proven to be difficult with conventional therapeutic approaches. KT-333 is a potent highly selective, heterobifunctional small molecule degrader of STAT3. In preclinical studies, durable tumor regressions were seen with weekly KT-333 administration in STAT3-dependent T cell lymphomas, and antitumor activity was seen in solid tumors in combination with anti-PD1 (ASH 2021, SITC 2021). Methods: KT-333 is being evaluated in an open-label, dose escalation (Phase 1a, n = 40) study in patients with lymphomas relapsed or refractory (R/R) to at least two prior systemic treatments or for whom standard therapies are unavailable. Dose escalation will be conducted by accelerated titration followed by a 3+3 design in ascending doses of intravenous KT-333 administered once weekly in 28-day cycles to evaluate safety and define the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) in plasma and urine and preliminary pharmacodynamic effects (PD) of KT-333 using blood (peripheral blood mononuclear cells [PBMCs], plasma/serum) and tumor tissue. After confirming the MTD/RP2D in patients with lymphoma, patients with advanced solid tumors will be enrolled in a separate Phase 1a cohort at the MTD/RP2D. In Phase 1b (n = 80), patients with PTCL, CTCL, LGL-L (T-cell LGL-L or chronic lymphoproliferative disorder of natural killer-cells), or solid tumors R/R to at least one prior systemic standard of care treatment or for whom standard therapies are not available, will be enrolled in separate 20 patient cohorts. This will further characterize safety, PK, PD and evaluate the clinical activity of KT-333. Treatment with KT-333 will continue until disease progression, unacceptable toxicity, or patient refusal. KT333-TL-101 began enrolling in January 2022. Clinical trial information: NCT05225584.
Phase 2 study of trastuzumab deruxtecan in the neoadjuvant treatment for patients with HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Takahari Daisuke , Kawazoe Akihito , Machida Nozomu , Minashi Keiko , Yamagata Yukinori , Hara Hiroki , Wakabayashi Masashi , Komura Yu , Sato Akihiro , Kuwata Takeshi , Kojima Motohiro , Shitara Kohei 
Published: June 2022

TPS4161 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. DESTINY-Gastric01 study showed significantly higher objective response rate with T-DXd than physician's choice of chemotherapy (51.3%, vs. 14.3%, Shitara K, et al. NEJM 2020) as well as prolonged overall survival (median 12.5 vs. 8.4 months, hazard ratio 0.59). Considering that high response rate or major pathological response (MPR), which is defined as the proportion of subjects with < 10% residual tumor may be associated with favorable survival outcomes after preoperative chemotherapy, T-DXd could be a promising neoadjuvant treatment for patients with gastric and gastroesophageal junction (GEJ) cancer. However, to our knowledge, there is no currently ongoing study of T-DXd as a neoadjuvant setting for patients with gastric and GEJ cancers. Methods: This is an open-label, single-arm, multicenter, investigator initiated phase 2 trial to evaluate antitumor activity of T-DXd as the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma. Eligible patients should have previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort will enroll patients with HER2 overexpression defined as immunohistochemistry （IHC）3+ or IHC2+/ in situ hybridization（ISH）+ by local assessment. According to the results of exploratory biomarker analysis of DESTINY-Gastric01 study (Shitara K, et al. ESMO-GI2021), patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with HER2-extra cellular domein (ECD) higher than 11.6 ng/ml also will be enrolled into the exploratory cohort. Patients will receive 3 cycles of T-DXd (6.4mg/kg) by intravenous infusion every 3 weeks followed by surgery at 3 to 8 weeks after last T-DXd infusion.The primary endpoint is MPR rate. The threshold in the main cohort is defined as 20%, and the expected MPR rate was set at 45%. The minimum sample size of this trial is 23 patients in the main cohort (α- and β-error probabilities, 0.1 and 0.15, respectively). Total number of patients will be increased up to 27 patients depending on the enrollment. In addition, 10 patients will be recruited into the exploratory cohort. Secondary endpoints are pathologic complete response (pCR) rate, curative resection rate, and adverse event rate. Biomarker analyses including whole exome sequencing, RNA sequencing, proteomics, and ctDNA changes will also be conducted using pre- and post-treatment tumor and blood samples. Enrollment is ongoing at six sites in Japan from November 2021. Clinical trial information: NCT05034887.
GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.
Authors: Hoffe Sarah E. , Kim Dae Won , Costello James , Malafa Mokenge Peter , Aguilera Todd Anthony , Beg Shaalan Shaalan , Parikh Parag , Herman Joseph M. , Caster Joseph Michael , Ghaly Maged , Moser Elizabeth Charlotte , Terry Kara , Kurman Michael , Holmlund Jon 
Published: June 2022

TPS4184 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks (Zhong 2017). Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide (Riley 2006). Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells (Doskey 2016). As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety (El-Mahdy 2020, Sishc 2021). In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Materials/Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial is now enrolling. Clinical trial information: NCT04698915.
A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186—Trials in progress.
Authors: Dotan Efrat , Catalano Paul J. , Lenchik Leon , Boutin Robert , Yao Xin , Beg Shaalan Shaalan , Vijayvergia Namrata , Gatsonis Constantine , Zhen David Bing , Li Daneng , Wagner Lynne I. , Simon Melissa A. , Wong Terence Z. , O'Dwyer Peter J. 
Published: June 2022

TPS4185 Background: Evidence-based data is lacking to guide the care of older adults with newly diagnosed metastatic pancreatic cancer (mPCA). As a result, treatment approach and the selection of chemotherapy regimens are often extrapolated from data from younger patients. Furthermore, vulnerable older adults are often treated with dose adjusted regimens with limited data to support this practice. EA2186 is a phase II randomized controlled trial, and the first prospective study aiming to define the optimal treatment approach of vulnerable older adults with newly diagnosed mPCA. Methods: Patients aged 70 years and over with histologically confirmed pancreatic adenocarcinoma, evidence of metastatic disease, ECOG PS 0-2 and adequate organ function, who are considered vulnerable are eligible for this trial (accrual target 184). This study utilizes a screening geriatric assessment which characterize patients as fit, vulnerable or frail by evaluating functional status, cognition and co-morbidities. Vulnerable patients according to this screening assessment are those with mild abnormalities in functional status, comorbidities and/or cognition, or older than 80 years of age. Those patients will be randomized to receive either modified Gemcitabine/Nab-Paclitaxel or dose-reduced 5-Fluorouracil Leucovorin and Liposomal Irinotecan every 2 weeks. A comprehensive geriatric assessment (GA) and quality of life (QOL) evaluation are completed prior to initiation of therapy for all randomized patients. Follow up will continue until disease progression or withdrawal, with repeated GA and QOL assessments at each disease evaluation. Overall survival is the primary objective, with secondary objectives including progression free survival, and response rate. Enrolled patients will be stratified by age 70-74 vs ≥75, and ECOG PS 0-1 vs 2. Additional endpoints of interest for older adults include: evaluation of risk factors identified through GA, and capturing toxicities of interest for this patient population (i.e. hospitalization, deterioration in PS, and falls). Correlative studies include assessment of pro-inflammatory biomarkers or aging in the blood (IL-6 and CRP) as well as imaging evaluation of sarcopenia and body composition as predictors of treatment tolerance. Clinical trial information: NCT04233866.
Precision Promise (PrP): An adaptive, multi-arm registration trial in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Picozzi Vincent J. , Duliege Anne-Marie , Collisson Eric Andrew , Maitra Anirban , Hidalgo Manuel , Hendifar Andrew Eugene , Beatty Gregory Lawrence , Doss Sudheer , Matrisian Lynn McCormick , Herena Pamela S , Fleshman Julie , Detry Michelle A. , Berry Donald A. , Simeone Diane M. 
Published: June 2022

TPS4188 Background: The success rate of drug development in PDAC is disappointingly low.PrP is a transformative, adaptive platform clinical trial designed to continuously evaluate many novel therapeutic options while increasing the probability that patients (pts) are randomized to effective experimental therapies. It cultivates enhanced cooperation among groups representing pts advocacy, pharmaceutical companies, academia, and the FDA. This patient-centric study aims to become the largest Phase 3 registrational study in PDAC and represents a fundamental shift in drug development for PDAC in the United States (US). Methods: PrP (NCT04229004) is a platform clinical trial sponsored by the Pancreatic Cancer Action Network (PanCAN), developed based on the FDA 2020 guidance document regarding "complex innovative designs" in registration trials https://www.fda.gov/media/130897/download . It utilizes adaptive randomization and other Bayesian statistical innovations provided by Berry Consultants LLC, including the “time machine” which uses all previously randomized controls for each arm, suitably adjusted for line of therapy and the time period of the arm. Focused on 1st and 2nd line treatment of mPDAC, PrP uses an adaptive platform design with randomization to one of 2 control arms (gemcitabine + nab-paclitaxel (GA) or mFOLFIRINOX, 30% of pts) or experimental therapy (70% of pts). Candidate experimental arms are reviewed by an Arm Selection Committee based on validity of the treatment target and strength of the pre-clinical and clinical data. The primary endpoint is overall survival (OS). Pts undergo pre- and on-treatment biopsies with state-of-the-art genomic, transcriptomic, and immune analysis, along with a serial collection of blood-based research samples. Pts are managed using novel supportive care techniques; PrP contains 3 sub-protocols evaluating quality of life, sarcopenia, and actigraphy. PrP launched in 2020 and has enrolled > 130 pts; 30 US sites have been selected with 17 currently active. Current experimental arms include: (i) GA + Pamrevlumab, an anti-CTGF Ab, (ii) Racemetyrosine monotherapy, a cancer metabolism-based therapy (for follow-up of patients) and (iii) an immuno-oncology arm in activation. Other arms are in the planning stages. Compared to traditional designs, PrP offers several advantages: multiple investigational treatments evaluated in parallel over time; ̃175 pts per experimental arm required to initiate a regulatory registration; and continuous learning from every patient, resulting in significant savings of time and resources. PrP has created an entirely new learning environment for accelerating drug development in PDAC. Clinical trial information: NCT04229004.
Sequential first-line treatment with gemcitabine plus nab-paclitaxel (GA) followed by FOLFIRINOX (FFX) versus FFX alone in patients with metastatic pancreatic cancer (PC): GABRINOX-2 randomized phase 2 trial.
Authors: Portales Fabienne , Assenat Eric , Samalin Emmanuelle , Mazard Thibault , Adenis Antoine , Suchet Gallet Blandine , Fiess Catherine , Moussion Aurore , Delaine Stephanie , Grigorescu Florin , Gourgou Sophie , Ychou Marc 
Published: June 2022

TPS4190 Background: PC is a major health concern worldwide and a deadly disease due to its high metastatic behavior. In recent years, incremental progresses have been made with the use of new chemotherapy (CT) regimen in the metastatic setting. Thus, both PRODIGE 4/ACCORD11 (Conroy T, et al. 2011) and MPACT (Von Hoff D, et al. 2013) phase III trials established 2 new standard-of-care in the first line treatment of metastatic PC (mPC), demonstrating a survival benefit over gemcitabine monotherapy, with the use of FFX or GA. In the phase I/II GABRINOX trial (Assenat E, et al. ESMO Open 2021), we reported that sequential GA followed by FFX provided a high overall response rate (ORR) (64.9%) and a promising median progression-free survival (PFS, 10.5 months) and median overall survival (OS, 15.1 months), together with acceptable toxicity and remarkably low severe neurotoxicity rate (gr.3: 5.3%). To follow up these encouraging results in a controlled study, we aimed at comparing our experimental GABRINOX regimen to control FFX in the GABRINOX-2 randomized phase 2 trial (NCT05065801). Our primary objective is PFS, and our secondary objectives are tolerance, ORR, disease-control rate, OS, and Quality-of-life. Methods: Main inclusion criteria were as follows: Patients (pts) in good condition (ECOG PS ≤ 1), aged from 18 to 75 yo, with histologically or cytological proven mPC and at least one measurable metastatic target. Pts should have not been treated with (adjuvant) chemotherapy in the last 6 months. Eligible pts are randomized (ratio 1:1) either in the standard FFX group or in the experimental GABRINOX group where a GA (gemcitabine 1000 mg/m² and Nab-paclitaxel 125 mg/m², day 1-8-15) cycle alternates after a 2-weeks rest with a FFX cycle. To detect an increase in median PFS from 6.4 to 10.5 months (HR = 0.61) with a 80% power and a 5% α risk, 130 events are required among a total population of 210 pts. PFS was defined as the length of time between randomization and the onset of 1st documented progression (RECIST 1.1 criteria) or death. The study of quality of life will use the EORTC QLQ-C30 and QLQ-PAN26 self-reported questionnaires at baseline and every 2 months up to 12 months and then at 16, 20 and 24 months. Circulating DNA tests will be carried out at baseline and every 2 months until progression. All numerical variables will be expressed as medians and 95% CI, while PFS and OS will be estimated using Kaplan-Meier method. Multivariate analyses will use Cox proportional hazard model. Enrolment started in late 2021 and 3 patients were included so far. Clinical trial information: NCT05065801.
A phase II, open-label, pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
Authors: Rogers Sherise C. , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Lee Ji-Hyun , Turk Anita Ahmed , Russell Karen Bullock , Nassour Ibrahim , El-Far Ahmad , Fabregas Jesus C. , Thomas Ryan M. , Sahin Ilyas , Allegra Carmen Joseph , DeRemer David L. , George Thomas J. 
Published: June 2022

TPS4196 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]