bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal fluorescence-guided surgery of colorectal peritoneal metastases, a phase I/II clinical trial.
Authors: de Gooyer Jan-Marie , Elekonawo Fortuné , Bremers Andre J.A. , Boerman Otto , Rijpkema Mark , de Wilt Johannes H.W. 
Published: May 2020

TPS4119 Background: Successful treatment of patients with colorectal peritoneal carcinomatosis highly depends on complete surgical tumor resection of all tumor. Oncological outcomes can potentially be improved by intraoperative imaging using a tumor-targeting antibody conjugated to a fluorophore and a radiotracer. This enables preoperative radionuclide imaging, real-time intraoperative fluorescence imaging and gamma detection. In this study we investigate the feasibility, accuracy and safety of CEA-targeted preoperative SPECT/CT and intraoperative fluorescence imaging in patients with colorectal PC. Methods: In this phase I/II single arm protein dose escalation study patients with peritoneal metastases of colorectal origin who are scheduled for cytoreductive surgery and HIPEC will receive an intravenous injection of the CEA-targeting tracer 111In-DOTA-labetuzumab-IRDye800CW. The first 15 patients will receive a single dose of 2,10 or 50 mg 6 to 7 days prior to surgery. Four to five days after injection SPECT/CT imaging of the thorax and abdomen is performed to determine intra-abdominal tumor load and detect extra-abdominal metatases. At day 6/7 after injection, standard cytoreductive surgical resection extended with real-time near-infrared fluorescence imaging and radio guidance is performed. After surgery, the peritoneal cavity will be re-examined for residual disease with fluorescence imaging. Resected specimens are analyzed microscopically, immunohistochemically (CEA and H&E) and by gamma counting. Blood samples are drawn for farmacokinetics and safety analysis at 180 minutes, 4 days, 6 days and 3 weeks after tracer injection. In the phase II dose expansion cohort, 14 more patients will receive the optimal dose as determined in the phase I trial. The primary objectives of the trial are to assess the safety, feasibility and accuracy of preoperative SPECT/CT and intraoperative fluorescence imaging after administration of 111In- labetuzumab-IRDye800CW in patients with peritoneal carcinomatosis of colorectal origin who will undergo cytoreductive surgery and HIPEC. The secondary objectives are to assess whether additional malignant lesions can be visualized by fluorescence imaging after cytoreductive surgery, to assess the intensity of fluorescence in malignant and non-malignant tissue, to assess the correlation between localization of the dual-labeled antibody and CEA expression in tumor and healthy tissue and to determine blood concentrations of the dual labelled antibody at several time points in patients. Clinical trial information: NCT03699332 .
A phase II study of induction PD-1 blockade in subjects with locally advanced mismatch repair-deficient rectal adenocarcinoma.
Authors: Cercek Andrea , Stadler Zsofia Kinga , Cohen Jenna L. , Weiss Jill A , Lamendola-Essel Michelle F. , Krishnan Asha , Yaeger Rona , Segal Neil Howard , Connell Louise Catherine , El Dika Imane H. , Kemeny Nancy E. , Saltz Leonard B. , Smith Jesse Joshua , Nash Garrett Michael , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R. , Diaz Luis A. 
Published: May 2020

TPS4123 Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .
A phase II study of selective HDAC6 inhibition with KA2507 for second-line treatment of advanced biliary tract cancer (ABC-11).
Authors: Bridgewater John A. , Beer Philip , Bendall Jennifer , Dehbi Hakim-Moulay , Duggan Marian , Hung Michelle , King Justine , McElwaine-Johnn Hilary , White Laura 
Published: May 2020

TPS4652 Background: The ABC-02 trial provided Level A evidence supporting the use of cisplatin plus gemcitabine as first-line chemotherapy for advanced biliary tract cancer (ABC) [Valle, 2010]. In second line therapy oxaliplatin and 5FU and ivosedinib for IDH1 mutated cancers are options [Lamarca, 2019; Abou-Alfa, 2019] however there remains significant unmet need for patients without actionable alterations. Histone deacetylase 6 (HDAC6) is over-expressed in cholangiocarcinoma, reducing primary cilia. This is mediated through increased resorption in normal human cholangiocytes via tubulin deacetylation in the ciliary axoneme. Inhibition of HDAC6 elicits both cell intrinsic and extrinsic anti-cancer activity. HDAC6 inhibition reversed oncogenic loss of ciliation and demonstrated preclinical efficacy in a syngeneic rat orthotopic biliary cancer model [Gradilone, 2013]. KA2507 is a potent and selective small molecule inhibitor of HDAC6. Phase I dose escalation study identified an oral dose of 800mg bid for further development, being well tolerated and showing evidence of selective target engagement. Methods: ABC-11 is a Phase II multi-centre, open-label study of KA2507 in 40 evaluable patients with advanced biliary tract cancer previously treated with standard of care chemotherapy. The study follows a single-arm single-stage design using A’Hern’s methodology. Eligible patients receive continuous 28-day cycles of fixed daily oral dose of KA2507 until death, disease progression or other pre-defined reason for study drug discontinuation. Tumour assessment is made at baseline and at 8-weekly intervals using RECIST 1.1 criteria until disease progression; primary endpoint is PFS at 4 months. Independent Data Monitoring Committee will review 4 month PFS and other data after first six patients, after a total of 17 patients (futility analysis, corresponding to cut-off of the Simon’s minimax 2-stage design; 33% was set as the target 4-month PFS rate expected with KA2507) and at least annually thereafter. Subject to availability of adequate tissue, mandatory pre-treatment and on-study tumour biopsy samples will undergo multiparameter flow cytometry of immune cell subsets, immunofluorescence analysis of immune cell subsets (activation status and topology) and T cell repertoire studies. The study received regulatory and ethical approval to proceed in January 2020 and enrolment is in progress. Clinical trial information: NCT04186156 .
Etctn 10388: A phase I trial of triapine and lutetium Lu 177 dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Chauhan Aman , Kunos Charles , El Khouli Riham , Kolesar Jill , Weiss Heidi , Carson William Edgar , Evers Mark B , Kidd Mark S. , Beumer Jan Hendrik , Arnold Susanne M. , Kohn Elise C. , Anthony Lowell Brian 
Published: May 2020

TPS4660 Background: Radiolabeled somatostatin analogues provide a means of delivering targeted radiation with a high therapeutic index to NETs that express somatostatin receptors (SSTRs). Radiolabeled somatostatin analogue Lutetium Lu 177 Dotatate (Lutathera) is a beta-emitting radionuclide, recently FDA approved for use in SSTR positive gastroenteropancreatic neuroendocrine tumors (GEPNETS) in the US based on the NETTER-1 Phase III trial. Despite favorable PFS and safety profile, the drug has limited cytoreductive capability with a 17% ORR. We hypothesize that addition of an effective radiation sensitizer could help improve antitumor activity of Lutathera. Ribonucleotide reductase (RNR) is the only enzyme responsible for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate (dNDP), the key building blocks for DNA synthesis. Radiation is a potent inducer of DNA double-strand breaks (DSBs), and RNR is the rate-limiting enzyme in the repair of DNA in this setting. Triapine is an inhibitor of RNR. This study will test the hypothesis that radiation sensitizer triapine can be safely combined with peptide receptor radionuclide therapy and ultimately may improve antitumor activity of Lutetium Lu 177 Dotatate. Methods: This study is an investigator initiated, NCI sponsored, multicenter phase 1 trial of triapine and Lutetium Lu 177 Dotatate in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment. A total of 29 patients will be enrolled in the dose escalation with help of Bayesian optimal interval design (BOIN) and dose expansion cohorts. The study will be open through the NCI ETCTN (National Cancer Institute Experimental Therapeutics Clinical Trials Network) program. Patients will be treated with 177 lutetium dotatate in combination with triapine. Triapine will be administered orally (100 mg once a day starting dose) from D1-14 with each dose of PRRT [200 mCi]. Primary endpoint is to evaluate recommended phase II dose (RP2D). Secondary endpoints are to evaluate safety, pharmacokinetics, and clinical activity (ORR and PFS). We are also evaluating NETEST, a novel blood based test that evaluates levels of 51 neuroendocrine tumor gene transcripts. In addition, the study will correlate clinical outcome with baseline somatostatin receptor density, somatic tumor mutations and germline mutations. Clinical trial information: 04234568 .
NAPOLI-3: An open-label, randomized, phase III study of first-line liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin versus nab-paclitaxel + gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Wainberg Zev A. , Bekaii-Saab Tanios S. , Hubner Richard , Macarulla Teresa , Paulson Andrew Scott , Van Cutsem Eric , Maxwell Fiona , Moore Yan , Wang Haofei Tiffany , Zhang Bin , O'Reilly Eileen Mary 
Published: May 2020

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .
EndoTAG-1 plus gemcitabine versus gemcitabine alone in patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FOLFIRINOX treatment (NCT03126435).
Authors: Chen Li-Tzong , Su Muh-Hwan 
Published: May 2020

TPS4669 Background: Pancreatic cancer (PC) is the 3rd deadliest cancer in the United State surpassing breast cancer in 2016, with the overall survival rate of - 9% for those newly diagnosed individuals. The notorious disease is set to become the 2nd leading cause of death from cancer by 2020 in US (National Cancer Institute, NIH). FOLFIRINOX regimen is one of the standard 1st-line treatments for PC patients with good performance status; however, there is currently no standard of care in 2nd-line therapy after FOLFIRINOX failure. EndoTAG-1 is a novel formulation of cationic liposomes embedded with Paclitaxel, which specifically displays antivascular and antiangiogenic activities. By binding and internalizing at tumor endothelial cells after intravenous administration, the cytostatic activity of paclitaxel will be targeted to the activated tumor endothelial cells. Methods: Eligible patients with measurable locally advanced and/or metastatic adenocarcinoma of the pancreas failed on FILFIRINOX treatment will be screened and randomized (1:1) into one of the two arms in the study (n=218). The primary endpoint of the study is overall survival (OS), with secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and quality of life (QoL). Arm A: EndoTAG-1 plus Gemcitabine: Patients will receive intravenous injection with EndoTAG-1 (22 mg/m2) twice weekly plus gemcitabine (1,000 mg/m2) once weekly for consecutively 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. Arm B: Gemcitabine: Patients will receive gemcitabine (1,000 mg/m2) once weekly for consecutive 3 weeks followed by 1 week rest. The treatment will be repeated every 4 weeks, with 8 weeks per cycle. The treatment will be kept until any one of the following occurs: progressive disease or unacceptable toxicity or withdrawal of consent. The phase III trial began enrollment since November 2018. The trial will continue as planned from the last review in January 2020. Clinical trial information: NCT03126435 .
Phase I study of AMG 509, a STEAP1 x CD3 T cell-recruiting XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kelly W. Kevin , Danila Daniel Costin , Edenfield William Jeffery , Aggarwal Rahul Raj , Petrylak Daniel Peter , Sartor A. Oliver , Sumey Christopher Joseph , Dorff Tanya B. , Yu Evan Y. , Adra Nabil , Waterhouse David Michael , Armstrong Andrew J. , Horvath Lisa , Pook David William , Appleman Leonard Joseph , Lau Aubrey , Salvati Mark , Kouros-Mehr Hosein 
Published: May 2020

TPS5589 Background: Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen that is highly expressed in prostate cancer. AMG 509 is a potent bispecific XmAb 2+1 immune therapy designed to direct T-effector cells to STEAP1-expressing cells. AMG 509 contains two identical humanized anti-STEAP1 Fab domains that bind STEAP1-expressing cells, an anti-CD3 scFv domain that binds T cells, and an Fc domain, engineered to lack effector function, that extends serum half-life. In preclinical studies, AMG 509 induced potent and specific T-cell-mediated lysis of STEAP1-expressing cancer models. Methods: This open-label, phase I, first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 509 in patients with relapsed/refractory mCRPC. The dose exploration phase (n=40) will estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) using a Bayesian logistic regression model. The dose expansion phase (n=30) will confirm safety, PK, and pharmacodynamics at the MTD or RP2D and collect further safety, efficacy, and biomarker data. Efficacy will be assessed by prostate-specific antigen response, circulating tumor cell response, and objective tumor response per RECIST 1.1 with Prostate Cancer Working Group 3 modifications. Key inclusion criteria: men ≥18 years with histologically/cytologically confirmed mCRPC who are refractory to novel hormonal therapy (e.g., abiraterone and/or enzalutamide) and have failed 1–2 taxane regimens or are medically unsuitable for or have refused taxanes; ongoing castration with total serum testosterone ≤50 ng/dL; evidence of progressive disease; ECOG performance status 0–1; life expectancy ≥3 months; and adequate hematologic, renal, hepatic, and cardiac function. In the dose exploration phase, novel antiandrogen therapy must have been given in the metastatic setting. Key exclusion criteria: pure small-cell or neuroendocrine carcinoma of the prostate; untreated CNS metastases or leptomeningeal disease; any anticancer therapy or immunotherapy, radiation therapy, or major surgery <4 weeks from first dose; history of or current autoimmune disease or any disease requiring immunosuppressive therapy (≤10 mg/d prednisone permitted); prior STEAP1-targeted therapy; infection requiring IV antimicrobials <7 days from first dose. The study opened in January 2020 and is recruiting patients. Clinical trial information: NCT04221542 .
A phase Ib trial of enzalutamide with venetoclax in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Gopalakrishnan Dharmesh , Kirk Jason , Davis John , George Saby , Levine Ellis Glenn , Beumer Jan Hendrik , Appleman Leonard Joseph , Tang Dean , Chatta Gurkamal S. 
Published: May 2020

TPS5599 Background: Androgen receptor (AR) signaling plays an important role in prostate cancer (PCa) cell survival and proliferation. Xenograft and PDX models demonstrate that untreated PCa harbors AR−/lo stem cells not critically dependent on androgens for survival.1 Furthermore, castration and enzalutamide (enza) leads to expansion of both AR−/lo and AR+/hi resistant clones in xenograft tumors, resulting in two distinct CRPC-propagating populations.2 However, most current CRPC treatments are directed towards AR+/hi cells. RNAseq revealed that BCL-2 is highly up-regulated in AR−/lo tumors post-castration and in AR+/hi CRPC tumors post-enza.2 Strikingly, BCL-2, but not BCL-XL and MCL-1, was selectively up-regulated in these xenograft tumors. These results were subsequently validated in patient CRPC datasets.2,3 Venetoclax (ven), a potent and selective BCL-2 inhibitor, inhibits enza resistance in AR+/hi CRPC and tumor growth in AR−/lo xenograft models.2 A recent phase I trial of ven combined with tamoxifen showed promising activity in ER+ and BCL2+ metastatic breast cancer.4 We hypothesize that co-targeting AR−/lo and AR+/hi PCa clones with ven and enza will prevent the emergence of enza resistance in human mCRPC. Methods: This is a phase Ib, single-center, single-arm trial of enza (160mg/d) with ven in patients with mCRPC that has progressed on previous therapies which may include anti-androgens. Three dose-levels of ven (400mg, 600mg and 800mg/d q28d) will be evaluated using a 3+3 study design. Fifteen to 18 patients will be enrolled in this phase to assess dose-limiting toxicities, maximum tolerated dose, and recommended phase II dose. Aims of correlative studies include (1) assessing the pharmacokinetic interaction between enza and ven, (2) identification of potentially predictive blood and tissue biomarkers (including pre- and post-treatment CTC levels, expression of BCL2, AR, ARv7 in pre-and post-treatment biopsies and CTCs), (3) measurement of pre- and post-treatment BCL2 expression in peripheral blood mononuclear cells as a surrogate for ven activity, and (4) the development of 3D organoid models from CTCs and biopsies. The trial is open with 3 patients enrolled to dose-level 1, and 2 patients currently at dose-level 2. Correlative studies are ongoing. References: (1) Qin J, et al. Cell Stem Cell. 10(5): 556-69, 2012 (2) Li Q, et al. Nat Commun. 9(1): 3600, 2018 (3) Rajan P, et al. Eur Urol. 66 (1):32-9, 2014 (4) Lok SW, et al. Cancer Discov. 9(3):354-69, 2019. Clinical trial information: NCT03751436 .
PREDIX II HER2: Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC).
Authors: Kornalijnslijper-Altena Renske , Andersson Anne , Brandberg Yvonne , Kessler Luisa Edman , Elinder Ellinor , Hartman Johan , Hellstrom Mats , Johansson Hemming , Killander Fredrika , Linderholm Barbro Kristina , Lindman Henrik , Valachis Antonios , Wennstig Anna Karin , Xie Hanjing , Hatschek Thomas , Bergh Jonas C. S. 
Published: May 2020

TPS605 Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy. Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007. Clinical trial information: NCT03894007 .