bluuebunny/crossref_metadata_2025_split huggingface dataset:
SKYSCRAPER-07: A phase III, randomized, double-blind, placebo-controlled study of atezolizumab with or without tiragolumab in patients with unresectable ESCC who have not progressed following definitive concurrent chemoradiotherapy.
Authors: Goodman Karyn A. , Xu Rui-hua , Chau Ian , Chen Ming Huang , Cho Byoung Chul , Shah Manish A. , Muro Kei , Wang Yifan , Ichimaru Mari , Liu Qingyuan , Wang Luhua 
Published: January 2022

TPS374 Background: The current standard of care for patients (pts) diagnosed with unresectable, locally advanced esophageal squamous-cell carcinoma (ESCC) is definitive platinum-based concurrent chemoradiotherapy (dCRT). However, ESCC has poor prognosis, with more than half of tumors reoccurring after dCRT (Smyth et al. Nat Rev Dis Primers 2017), highlighting the need for additional therapy options in this setting. Cancer immunotherapies have demonstrated activity in ESCC, and targeted inhibition of the PD-L1/PD-1 pathway may be further amplified using novel anti-TIGIT agents such as tiragolumab. In preclinical mouse models, concomitant blockade of PD-L1/PD-1 and TIGIT pathways demonstrated prolonged survival over the respective single-agents. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) resulted in a clinically meaningful improvement in PFS and higher ORR vs atezolizumab alone (31.3 vs 16.2%) in first-line pts with PD-L1+ (TPS ≥1%) metastatic NSCLC. SKYSCRAPER-07 (NCT04543617) will determine if tiragolumab plus atezolizumab combination therapy provides superior clinical benefit to atezolizumab monotherapy or placebo in pts with unresectable ESCC whose cancers have not progressed following dCRT. We hypothesize that combination therapy will prolong PFS and OS compared with placebo in this setting. Methods: Eligible pts (≥18 years) must have unresectable ESCC, without progressive disease (PD) after platinum-based dCRT (according to regional oncology guidelines for ESCC); ECOG PS 0–1; no prior treatment with any immune checkpoint inhibitor. Approximately 750 pts will be randomized 1:1:1 to either Arm A (tiragolumab 600mg + atezolizumab 1200mg IV Q3W), Arm B (atezolizumab 1200mg + placebo IV Q3W) or Arm C (double placebo IV Q3W). Treatment will continue for up to 17 cycles of 21 days, or until unacceptable toxicity or investigator-assessed radiographic PD (per RECIST v1.1). Stratification factors include geographic region (Asia vs rest of world), PD-L1 expression and staging prior to dCRT (II vs III vs IV). Co-primary efficacy endpoints are investigator-assessed PFS and OS; key secondary endpoints include independent review facility-assessed PFS and DoR. Safety, pharmacokinetic, biomarker and immunogenicity analyses will be performed. Recruitment is ongoing. Clinical trial information: NCT04543617.
CA209-8YD: A phase I/II trial of rucaparib in combination with ramucirumab with or without nivolumab in previously treated advanced gastroesophageal adenocarcinoma (GEA) (RiME).
Authors: Saeed Anwaar , Park Robin , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Saeed Azhar , Ng Elizabeth , Thompson Kayra , Moya Stephanie , Barbosa Lori , Phadnis Milind , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Catenacci Daniel V.T. 
Published: January 2022

TPS377 Background: GEA is one of the leading causes of cancer-related deaths worldwide and in the US. In chemo refractory GEA, therapeutic options are limited with modest efficacy. About 35% of GC have DNA damage response (DDR) gene alterations and PARP inhibitors have shown to induce synthetic lethality and reduce tumor burden in in vitro and in vivo models of GEA. DDR deficient tumors have increased tumor mutational load, tumor infiltrating lymphocytes, and increased chemokines and PD-L1 expression in the tumor microenvironment. PARP inhibitors like rucaparib enhance antigen presentation, induce pro-inflammatory cytokines, influence PD-1/PD-L1 expression, and modulate T- and B- cell activity. Furthermore, results from multiple GEA early phase trials have supported the immune modulatory impact of VEGF targeted agents like ramucirumab. We hypothesize that modulation of the tumor microenvironment via PARP and VEGF inhibition will enhance anti-tumor immunity and lead to clinical synergy when combined with immune checkpoint inhibitors like nivolumab in this population. Methods: A safety lead in phase of 6-9 patients will be followed by an open label, two parallel cohorts phase II study. A total of 52 patients (26 in each cohort) will be enrolled. A starting rucaparib dose of 600 mg BID in combination with the standard doses of ramucirumab and flat doses of nivolumab will be used for the safety lead in. Rucaparib dose will be lowered for phase II if > 1/6 patients experienced DLTs. Participants enrolled to cohort A will receive rucaparib at the recommended phase II dose (RP2D) PO twice daily + ramucirumab 8mg/kg IV q2w + nivolumab 480mg IV q4w (28-day cycles). Participants in cohort B will receive rucaparib at RP2D PO twice daily + ramucirumab 8mg/kg IV q2w (28-day cycles). Assessment of tumor response using modified RECIST v1.1 will be done every 2 cycles. 50% of Pts who will be enrolled in each of the 2 cohorts must have a deleterious tumor gene alteration in at least 1 gene in a screening 17-gene homologous recombination deficient (HRD) panel. Eligible Pts received ≥1 line of therapy, ECOG PS 0-1, adequate organ function, no prior PARP inhibitors, and have mismatch repair (MMR) proficient tumors with measurable disease. Primary objectives are to determine the RP2D and overall response rate (ORR) in phase I and II respectively. Secondary objectives include safety, overall benefit rate (OBR), median PFS, OS, and ORR in HRD positive and negative cohorts. Enrollment to the RiME trial is currently ongoing. The study is funded by research grants from Bristol Myers Squibb and Clovis. Clinical trial information: NCT03995017.
A multicenter, observational, phase 4 study (STELLAR) to evaluate the safety and tolerability of lenvatinib (LEN) in patients with advanced or unresectable hepatocellular carcinoma (uHCC).
Authors: Peck-Radosavljevic Markus , Goyal Lipika , Strasser Simone , Matilla Peña Ana Maria , Marinho Rui , Granito Alessandro , Roderburg Christoph , Marsico Mark , Christou Vanessa C , Xie Ran , Saraf Pankhoori , Meyer Tim 
Published: January 2022

TPS485 Background: HCC is a leading cause of cancer-related deaths worldwide. LEN is now a first-line treatment option for patients with uHCC, based on the REFLECT study in which LEN was established as noninferior to sorafenib (SOR) for overall survival (OS); LEN also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time-to-progression, and objective response rate vs SOR. The safety profile of LEN was consistent with its known side-effect profile. This postauthorization safety study aims to better characterize the safety of LEN, including hepatotoxicity, in real-life conditions in a Western population. Methods: This prospective, open-label, observational study (NCT04763408) will enroll patients with advanced or uHCC in routine clinical practice whom the treating physician has decided to treat with LEN (n = 500) or SOR (n = 500) according to the product labels. Enrollment is planned for 60 sites across Europe, Australia, USA, and Russia. The primary endpoint is the safety of LEN (hepatic-related toxicity and overall safety profile with regard to serious adverse events, grade ≥3 adverse events, and dose modifications and discontinuations due to adverse events). Secondary endpoints include treatment patterns (duration of treatment, incidence of dose interruptions and dose reductions, relative dose intensity, and subsequent treatments) and OS with LEN. Similar efficacy and safety data will be collected with SOR as an internal control for the population. Additionally, associations will be explored between patients’ baseline characteristics and treatment decisions as well as clinical and safety outcomes. Visits will be scheduled according to routine practice. Patients will be followed from initiation of treatment until the end of observation (whichever occurs first: withdrawal of consent, loss to follow-up, death, or end of the study [ie, 6 months after the last patient is enrolled]). Safety will be collected from initiation of LEN or SOR until the earlier of: 28 days after LEN/SOR discontinuation or the end of observation for patients who did not discontinue. Patients will be followed for survival and subsequent anticancer treatments until the end of observation, irrespective of length of treatment. Clinical trial information: NCT04763408.
Randomized phase II trial of postoperative adjuvant capecitabine and temozolomide versus observation in high-risk pancreatic neuroendocrine tumors: SWOG S2104.
Authors: Soares Heloisa P. , Guthrie Katherine A , Ahmad Syed A. , Washington Mary Kay , Ramnaraign Brian Hemendra , Raj Nitya Prabhakar , Seigel Carole , Bellasea Shay , Chiorean E. Gabriela , Dasari Arvind , Strosberg Jonathan R. , Eng Cathy , Philip Philip Agop 
Published: January 2022

TPS515 Background: Pancreatic neuroendocrine tumors (pNETS) account for about 1-2% of all the pancreas tumors for which resection is the only curative intent modality, however, despite surgery, many patients will experience recurrence. Tumor size, positive lymph nodes and higher grade are prognostic factors for recurrence. The U.S. Neuroendocrine Tumor Study Group published a predictive score (Zaidi score, see table) demonstrating that tumors with a score≥6 had a 33% likelihood of recurrence by 24 months. Furthermore, it is known that that patients with metastatic disease who undergo curative intent resection also have a great risk of recurrence. Despite these known risk factors for recurrence, to date, no prospective study exploring the role of adjuvant cytotoxic chemotherapy has ever been performed in this population. Supported by the E2211 results using capecitabine and temozolomide (CAPTEM) in the metastatic setting, S2104 investigates the role of CAPTEM in the adjuvant setting. Methods: S2104 is a randomized phase II trial designed to evaluate recurrence-free survival (RFS) in participants with resected pNETs randomized on a 2:1 fashion to CAPTEM or observation. Patient are eligible if they had resected well-differentiated grade 2 or 3 (ki-67 up to 55%) pNETS with a Zaidi score of ≥ 3. Patients may have received resection/ablation of liver oligo-metastatic disease (up to 5 liver metastases) at the time of well-differentiated pNET resection. Key eligibility criteria: age ≥18 years, Zubrod performance status of 0-2, adequate organ and marrow function. Stratification factors include 1) Disease status prior to resection (metastatic vs. non-metastatic disease) and 2) Zaidi score (≥ 6 vs. < 6). Participants will be followed with imaging for 5 years. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180868. Clinical trial information: NCT05040360. [Table: see text]
Phase 1b study of vactosertib in combination with nal-IRI plus 5FU/LV in patients with metastatic pancreatic ductal adenocarcinoma who have failed first-line gemcitabine/nab-paclitaxel.
Authors: Park Joon Oh , Kim Seung Tae , Hong Jung Yong , Kim Seong-Jin , Park Young Suk 
Published: January 2022

TPS632 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. TGF-β is strongly involved in the tumor microenvironment of PDAC, and dysregulation of TGF-β signaling is a frequent molecular disturbance in PDAC progression and metastasis. Vactosertib is an orally bioavailable TGF-β signaling inhibitor that targets the TGF-β type I receptor kinase. In in vivo studies, vactosertib reduces cancer cell migration, invasion, and metastasis of various cancers, and combination of vactosertib with nal-IRI/5-FU/LV improves pancreatic cancer survival by suppressing cell migration, invasion, and epithelial-mesenchymal transition (EMT), highlighting a potential clinical application of this approach for PDAC patients (Hong et al, 2020). Based on this preclinical study, we develop a phase 1b study to determine the recommended phase 2 dose (RP2D) and to evaluate the safety of vactosertib in combination with nal-IRI/5FU/LV in patients with metastatic PDAC who have failed first-line gemcitabine/ nab-paclitaxel. Methods: Eligible patients have histologically confirmed PDAC who have failed first-line gemcitabine/ nab-paclitaxel with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of vactosertib (100 mg bid, 200 mg bid, and 300 mg bid) for escalation will be tested, starting with dose level 0 (DL 0, 200 mg bid) with 3 to 6 subjects recruited in each cohort. DL -1 is only tested when DL 0 is unacceptable. In the dose expansion part, one or two additional backfill cohorts among DL -1 through DL 2 will be opened for determination of the final RP2D. For each cohort, a maximum of 12 patients can be enrolled including the dose escalation and dose expansion phase. Patients in each cohort will receive vactosertib 100-300 mg orally twice per day 1-5 & day 8-12 with nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48 hours every 2 weeks. The primary endpoint is to determine RP2D and to evaluate safety of this combination. The key secondary endpoints are progression free survival, overall response rate, disease control rate based on RECIST 1.1 and overall survival. As of September 2021, 5 patients have been enrolled in DL 0 and 1 DLT has been reported in DL 0. This study is prospectively registered on ClinicalTrials.gov, NCT04258072. Clinical trial information: NCT04258072.
Phase I study of hydroxychloroquine plus binimetinib in patients with metastatic pancreatic cancer (the HOPE trial).
Authors: Surana Rishi , Lee J. Jack , Smaglo Brandon George , Zhao Dan , Lee Michael Sangmin , Wolff Robert A. , Overman Michael J. , Willis Jason , Der Channing J. , Pant Shubham 
Published: January 2022

TPS634 Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a dearth of effective therapeutic options. Over 90% of PDAC harbor activating mutations in the KRAS oncoprotein, which in turn leads to activation of downstream effector proteins in the the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade serving to promote tumor cell survival, growth and metastasis. Unfortunately, single agent treatment with MAPK-inhibitors have had limited therapeutic efficacy in patients with PDAC owing to development of various tumor-cell intrinsic resistance mechanisms, including upregulation of autophagy. Hydroxychloroquine is an antimalarial drug that functions to inhibit autophagy by inhibiting acidification of lysosomes. Previously published preclinical data suggest combination therapy with binimetinib, a MEK 1/2 inhibitor, and hydroxychloroquine leads to enhanced killing of PDAC cells in vitro and in vivo. Methods: This is a single arm, single center phase I trial of binimetinib plus hydroxychloroquine in patients with metastatic pancreatic cancer harboring a KRAS mutation. All patients will receive binimetinib at a fixed dose of 45mg PO twice daily (14-day cycles) while hydroxychloroquine will be dosed at 400mg PO twice daily (14-day cycles) and dose escalated using a Bayesian optimal interval design with a target toxicity rate of 0.3. Key eligibility criteria include histologically confirmed metastatic pancreatic adenocarcinoma, prior treatment with at least one line of systemic therapy and a documented KRAS mutation. An estimated 24 patients will be enrolled in the first phase of this study and up to 15 patients in the dose expansion cohort. The primary endpoint of this study is to determine the maximum tolerated dose (MTD) of hydroxychloroquine when combined with a fixed dose of binimetinib. Key secondary endpoints include safety and toxicity profile, response rate, progression free survival (PFS) and overall survival (OS). This study is ongoing and has enrolled 10 patients at the time of submission. Clinical trial information: NCT04132505.
A phase I study of first-line L-glutamine (Gln) with gemcitabine (gem) and nab-paclitaxel (nab-p) in advanced pancreatic cancer (GlutaPanc).
Authors: Davelaar John , Tighiouart Mourad , Hendifar Andrew Eugene , Osipov Arsen , Moshayedi Natalie , Placencio-Hickok Veronica , Bhowmick Neil , Gong Jun 
Published: January 2022

TPS636 Background: Cytotoxic chemotherapy remains the preferred first-line treatment for advanced or unresectable pancreatic cancer with combination regimens including 5-fluoruracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), or gem and nab-p. The use and response of second- and third-line therapies remains dismal, thus the optimization of first-line treatment is critical. Our previous work investigating Gln metabolism in pancreatic ductal adenocarcinoma (PDAC) through glutaminase inhibition indicates that Gln deprivation in PDAC increases cancer cell survival and resistance to chemotherapy. However, when PDAC cell were treated with Gln supplementation, there was an increase in PDAC cell death with increasing concentrations of gem. In this present study we aim to test the feasibility and safety of combining L-Gln with gem and nab-p in treatment-naïve patients with unresectable or metastatic PDAC. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the recommended phase II dose (RP2D) of L-Gln in combination with gem and nab-p. The RP2D will be assessed by escalation of overdose control (EWOC), an adaptive Bayesian design, through determination of the maximum tolerated dose (MTD) across 3 doses of gem, nab-p, and L-Gln. The MTD is defined as the dose such that the probability of dose-limiting toxicities (DLTs) at the MTD is θ = 0.33. The first patient will receive 1000 mg/m2 gem, 125 mg/m2 nab-p, and 0.1 g/kg L-Gln and the subsequent doses will be determined by the EWOC algorithm. We plan to enroll a maximum of 16 patients. L-Gln is administered orally BID throughout the 28-day cycle with a one-week lead-in prior to the beginning of the first cycle where gem and nab-p are administered on days 1, 8, and 15 of each cycle. Key inclusion criteria include: advanced or unresectable, histologically confirmed pancreatic cancer that is either new or recurrent (if recurrent, prior neoadjuvant or adjuvant chemotherapy or chemoradiation is allowed but must have been completed >12 months prior to recurrence), ECOG PS ≤ 2 or KP ≥ 60%, and normal organ and marrow function. Secondary objectives are to describe any preliminary evidence of antitumor activity by assessment of objective response rate, progression-free survival, and overall survival. Since October 2020, 3 patients have been screened and 3 enrolled. Clinical trial information: NCT04634539.
Randomized phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer.
Authors: Hanna Diana L. , Jameson Gayle S. , Rasco Drew W. , Alistar Angela Tatiana , Frank Richard C. , El-Khoueiry Anthony B. , Wiedmeier Julia , Roberts Caroline , Fell Brandon , Hallberg Sarah , Roe Denise , Cridebring Derek , Rabinowitz Joshua D , Gately Stephen , Von Hoff Daniel D. 
Published: January 2022

TPS637 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A ketogenic diet defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies and has been evaluated in patients with a variety of solid tumors (Weber et al, 2020). Recently, a ketogenic diet combined with triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and significantly prolong animal survival over chemotherapy alone. Tumor growth inhibition was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Clinical trial information: NCT04631445.