bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors.
Authors: Shapiro Geoffrey , Supko Jeffrey G , Cho Daniel C. , Hilton John Frederick , Hadfield Matthew , Pruitt-Thompson Solida , Bordoli-Trachsela Eveline , Zvereva Nela , Wolanski Andrew , Sato-DiLorenzo Aya , Gotthardt Susan , Fox Edward A. , Verselis Sigitas Jonas , Kumar Ashok , Holden Sylvia A. , Ram Siya , Chafai-Fadela Karima , Harding Kimberly , Menon Krishna E. 
Published: March 2020

TPS2627 Background: Thioureidobutyronitrile, kevetrin, has demonstrated anti-tumor activity in several wild type and mutant p53 human tumor xenografts without evidence of genotoxicity. In wild type p53 models, kevetrin induces cell cycle arrest and apoptosis through activation and stabilization of wild type p53, resulting in increased expression of p53 target genes p21 and PUMA. Kevetrin also alters processivity of MDM2, and induces monoubiquitination of wild type p53, enhancing its stability (AACR 2011 abstract 4470). Mutant p53 is a complex target since it is an array of mutant proteins with oncogenic properties. Kevetrin induces degradation of oncogenic mutant p53 and induces apoptosis (AACR 2012 abstract 2874). Kevetrin therefore has the unique ability to target both wild type and mutant p53 tumors thereby controlling tumor growth in a wide range of preclinical tumor models. Methods: Adults with refractory locally advanced or metastatic solid tumors, acceptable liver and kidney function, and hematological status were eligible. Objectives include determination of DLT, MTD, recommended phase 2 dose, pharmacokinetics (PK), pharmacodynamics (PD), and evaluating preliminary evidence of antitumor activity. Kevetrin is given as a 1-hour intravenous infusion once weekly for 3 weeks in 28-day cycles. The starting dose was 10 mg/m2. In a 3+3 design, groups of 3-6 patients are evaluated for toxicity at each dose level. Dose escalation is based upon the number and intensity of adverse events in cycle 1. Kevetrin PK is characterized for the first and last doses given in cycle 1. Kevetrin induced expression of p21 in lymphocytes in preclinical studies; therefore p21 expression in peripheral blood mononuclear cells will be measured as a PD biomarker. Antitumor activity by RECIST 1.1 criteria and serum tumor markers will be assessed. The p53 status of tumors of selected patients will be determined. The second cohort is currently under evaluation. Conclusion: In preclinical models, Kevetrin has activity against tumors harboring both wild type and mutant p53 by diverse mechanisms. A first-in-human dose escalation trial is underway. Clinical trial information: NCT01664000.
Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM).
Authors: Bhatia Shailender , Curti Brendan D. , Gordon Michael S. , Chesney Jason , Logan Theodore , Thompson John A. , Royer Nels , Bittner Rachel , Fontana David , Grosso Joseph , Clemens Pamela L. , Cohen Lewis J. , Ahlers Christoph Matthias , Wigginton Jon M. , Hwu Patrick 
Published: March 2020

TPS3109 Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.
Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145).
Authors: Slingluff Craig L. , Petroni Gina R. , Dengel Lynn , Mullins David W. , Grosh William W. , Weiss Geoffrey R. , Strieter Robert M , Neese Patrice , Nail Carmel , Patterson James W , Olson Walter C. , Chianese-Bullock Kimberly A. 
Published: March 2020

TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8+ CXCR3+ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3+T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8+ CXCR3+ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3+ CD25hi CD4+(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.
Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases.
Authors: Janosky Maxwell Dale , Demaria Sandra , Novik Yelena , Oratz Ruth , Tiersten Amy , Goldberg Judith D , Wang Ena , Marincola Francesco , Formenti Silvia , Adams Sylvia 
Published: March 2020

TPS3122 Background: To assess the local and systemic effects of the novel combination of local radiotherapy (RT) with imiquimod (IMQ) applied topically to breast cancer metastatic to skin, and measure immunologic correlates (clinicaltrials.gov NCT01421017). Breast cancer is the 2nd most common tumor to metastasize to the skin. Current therapies for unresectable skin lesions are rarely curative. Patients ultimately die of visceral metastases, necessitating more effective therapies. IMQ, a synthetic TLR-7 agonist has profound effects on the tumor immune microenvironment and can lead to regression of cutaneous breast cancer metastases (Adams, Clin Ca Res, 2012). The trial was designed based on accumulated data supporting the synergy of combined RT/immunotherapy (Formenti, JNCI, 2013), and pre-clinical data demonstrating the synergy of topical IMQ and local RT in a mouse model of mammary adenocarcinoma which ulcerates through the skin, and mimics a chest wall recurrence. In the mouse model, the combination was superior with complete regressions of the treated tumors, responses at untreated sites and improved survival (Dewan, Clin Ca Res, 2012). Methods: Eligibility: patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. RT is delivered to 1 area of skin metastases in 5 fractions of 6 Gy (days 1, 3, 5, 8, 10). IMQ cream is applied topically 5 nights/week for 8 weeks, beginning on day 1. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with 25 additional patients planned. Primary endpoint is the response rate in untreated distant metastases, assessed by immune-related response criteria. The local tumor responses and safety of the combination will also be determined; tumor biopsies will be studied for immune-mediated rejection signatures and peripheral lymphocytes for antigen-specific T and B cell responses. To date, 10 patients have been enrolled. The phase I portion has been successfully completed with 6 patients without DLT. Phase II enrollment has begun. Clinical trial information: NCT01421017.
A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial immunotherapy with L-BLP25 (tecemotide) in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.
Authors: Kasper Stefan , Overkamp Friedrich , Moehler Markus Hermann , Kullmann Frank , Lang Hauke , Schoen Michael , Smith-Machnow Victoria , Hegewisch-Becker Susanna , Seehofer Daniel , Bechstein Wolf , Heike Michael , Voehringer Matthias , Heinemann Volker , Greil Richard , Geissler Michael , Lordick Florian , Peeters Marc , Van Cutsem Eric , Galle Peter Robert , Schimanski Carl Christoph 
Published: March 2020

TPS3124^ Background: 15-20% of all patients (pts) diagnosed with colorectal cancer (crc) develop metastases (mets) surgical resection remains the only potentially curative treatment available. Current 5-year survival rate following R0 resection of liver mets lies between 28-39%, recurrence occurs in up to 70% of pts. To date, adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active MUC1-specific cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in crc pts following R0/R1 resection of liver mets known to highly express MUC1 glycoprotein. Phase III data from L-BLP25 in NSCLC will be reported at this meeting. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver mets. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous mets, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. L-BLP25 arm receives a single dose of 300 mg/m2 cyclophosphamide (CPA) 3 d before 1st L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg weekly for 8 weeks, followed by sc L-BLP25 930 μg maintenance doses at 6-week (year 1 and 2) and 12-week (year 3) intervals until recurrence. Control arm: CPA is replaced by saline solution and L-BLP25 by placebo. Primary endpoint (PE) is RFS time. Secondary endpoints: Overall survival (OS), safety, tolerance, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. Study start was in Q3 2011. 19 centers were initialized and 36 patients recruited, no SUSARs occurred. Study recruitment will end Q3 2013: follow-up until Q3 2017. PE assessment is in Q3 2016. Interim analyses are not planned.No major practical issues were identified during setup and early conduct of the study. Clinical trial information: 2011-000218-20.
Pilot, proof-of-concept studies for determining the feasibility of the use of FLT-PET in patients with pancreatic adenocarcinoma.
Authors: Lamarca Angela , Manoharan Prakash , Asselin Marie-Claude , Trigonis Ioannis , Hindmarsh Pamela , Wood Sarah , McMahon Ray , Rao Madhu , Hubner Richard , Mahbubunnabi Tamal , O'Reilly Derek , Deshpande Rahul , Valle Juan W. , Saleem Azeem 
Published: March 2020

TPS4146 Background: Pancreatic cancer (PC) has one of the lowest 5-year survival rates. Gemcitabine (G)-based chemotherapy is standard-of-care first-line systemic therapy. Fluorine-18 radiolabelled 3-deoxy-3-fluorothymidine (FLT), a thymidine analogue, is a substrate for thymidine kinase 1 (TK1), which is highly expressed in proliferating cells in late G1/S phase. FLT uptake (imaged and quantified by positron emission tomography (PET)) correlates with pathology-based proliferation markers and with decreases with therapy in a number of cancers. G, a nucleoside analogue, decreases proliferation by inhibiting DNA synthesis, primarily acting on S and G1/S phase thus decreasing tumour FLT uptake. Human equilibrative nucleoside transporter (hENT1) transports G and FLT into cells, making hENT1 activity a key determinant of both FLT uptake and G efficacy. Methods: Two parallel proof-of-concept studies are designed to explore the feasibility of assessing proliferation, nucleoside transport, magnitude of treatment-related FLT uptake changes and understanding the pathophysiological basis of FLT-PET imaging in patients (pts) with (1) localized or (2) advanced PC. Up to 24 PC pts with ECOG PS 0-2, able to undergo imaging and with at least one potentially evaluable lesion larger than 2cm on CT/MRI are eligible. Pts with localized disease (study 1) will have dynamic FLT-PET pre-operatively preceded by a radiolabelled H2O PET scan to assess tumour perfusion. These pts will also undergo 2-deoxy-2-fluoro-D-glucose (FDG)-PET and diffusion-weighted MR scans. For pts with metastatic disease (study 2), dynamic FLT-PET will be performed before and after G-based chemotherapy. FLT uptake expressed as a standardized uptake value (SUV), will be determined. Tumour pathological markers from the surgical samples and imaging parameters will be correlated; hENT1 status will be assessed (by immunohistochemistry) after surgery (study 1) and before treatment (study 2). Reproducibility FLT-PET studies will be performed in a cohort of subjects to assess the variability in uptake quantification.
INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced esophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG).
Authors: Pavlakis Nick , Goldstein David , Sjoquist Katrin Marie , Martin Andrew , Tsobanis Eric , Yip Sonia , Shannon Jenny , Burge Matthew E. , Cronk Michelle F. , Tebbutt Niall C. , Strickland Andrew , Lipton Lara Rachel , Price Timothy Jay , Nott Louise M. , Harris Dean Laurence , Burnell Margot J. , Alcindor Thierry , Bang Yung-Jue , Kang Yoon-Koo , O'Callaghan Christopher J. 
Published: March 2020

TPS4157 Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has a poor prognosis, and there is no established standard treatment following failure of first or second line chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor which targets kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT), and has shown activity in other solid tumours. Following promising results in colon cancer and GIST, this study will determine if regorafenib has sufficient activity and safety to warrant further evaluation in a phase III trial as a second or third line therapy for AOGC. Methods: International (Australia & New Zealand (ANZ); Canada (NCIC CTG), Korea) randomised phase II, double-blind, placebo-controlled trial with 2:1 (REG:placebo) randomisation and stratification by: (1) Lines of prior chemotherapy for advanced disease (1 vs. 2). (2) Geographic region. Eligible patients with histological confirmation of OGC, with measurable metastatic or locally advanced disease that is refractory to, or relapsed following, first or second line CT, will receive best supportive care plus 160mg REG or matching placebo orally on days 1-21 of each 28 day treatment cycle until disease progression or prohibitive adverse events. Primary endpoint is progression free survival (PFS). Secondary endpoints: PFS by baseline VEGF, response rate, overall survival, safety, quality of life and exploratory plasma angiogenesis and tissue growth factor biomarkers. 150 patients will be randomized in a 2:1 (REG:PBO) ratio. This will provide 90% power to detect a PFS rate at 2 months in the REG arm ≥ 66% versus < 50%. If 16 of 33 (evaluable) REG participants have progressed by 2 months, then the study will be reassessed or stopped. Results: As of January 2013, 19 of 29 planned ANZ sites are open, with 10 patients enrolled. Regulatory approval has been received for 16 sites in Canada and 7 sites in Korea. 4 Korean sites have received ethics approval with recruitment expected to commence in early April 2013. Clinical trial information: ACTRN12612000239864.
A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) previously treated with antiangiogenic therapy.
Authors: Motzer Robert John , Bono Petri , Hudes Gary R. , Tomita Yoshihiko , Ravaud Alain , Waxman Ian , Gore Martin Eric 
Published: March 2020

TPS4592 Background: Standard approved treatments for pts with mRCC include interleukin-2 as well as therapies that target the vascular endothelial growth factor (eg, sunitinib, pazopanib) or mammalian target of rapamycin (eg, temsirolimus, everolimus) pathways. However, most pts may develop resistance, and overall survival (OS) improvement has only been shown in one phase 3 trial in poor-risk pts. Everolimus demonstrated a 3-month improvement in median progression-free survival (PFS) vs placebo, with no OS improvement (Motzer RJ, et al. Lancet. 2008;372:449-56). A phase 1 study of the fully human programmed death-1 (PD-1) receptor blocking monoclonal antibody nivolumab showed encouraging antitumor activity with previously treated mRCC (objective response rate [ORR], 29% (10/34); stable disease at ≥24 weeks [wks], 27% [9/34]). PD-1 is an immune checkpoint receptor that negatively regulates T-cell activation and PD-1 overexpression by tumor infiltrating lymphocytes has been associated with poor prognosis in multiple tumor types. Therefore, an ongoing, randomized, open-label, global phase 3 trial was developed to evaluate the clinical benefit of nivolumab in mRCC pts previously treated with anti-angiogenic therapy. Methods: Approximately 822 pts with advanced or metastatic clear-cell mRCC who have received ≤2 prior anti-angiogenic therapies and ≤3 total prior systemic regimens will be randomized 1:1 to receive nivolumab 3 mg/kg IV every 2 wks (Arm A) or everolimus 10 mg PO daily (Arm B). Pts will be stratified by region, MSKCC risk group, and number of prior anti-angiogenic therapy regimens. Tumor response will be assessed using RECIST 1.1 every 8 wks following randomization for the first year and then every 12 wks until disease progression or treatment discontinuation, whichever occurs later. The primary endpoint is OS. Secondary endpoints include PFS, ORR, OR duration, adverse events, OS in PD ligand 1 (PD-L1) positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling pts. Clinical trial information: NCT01668784.
PROSELICA study update: Comparison of two doses of cabazitaxel (Cbz) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.
Authors: Eisenberger Mario A. , Hardy-Bessard Anne-Claire , Ford Daniel , Mourey Loic , Parente Phillip , Mainwaring Paul N. , Ng Siobhan , Alekseev Boris , Matveev Vsevolod , Carles Joan , Shapiro Jeremy , Latorzeff Igor , Bodrogi Istvan , Kim Choung-Soo , Font Albert , Segal Roanne , Berg Hendrik Pieter Van Den , Zhang Wenping (Wendy) , Chadjaa Mustapha , De Bono Johann Sebastian 
Published: March 2020

TPS5099 Background: Cbz 25 mg/m2 IV Q3W + P 10 mg PO QD has an established safety profile and significantly improves overall survival (OS) vs mitoxantrone + P in pts with mCRPC previously treated with a D-containing regimen (phase III TROPIC study; NCT00417079; median OS: 15.1 vs 12.7 mos; HR: 0.70; P < 0.0001). Pooled data on file suggest that lower Grade 3–4 neutropenia rates are observed with Cbz < 25 vs ≥ 25 mg/m2 (61% vs 74%). In an attempt to further improve the therapeutic index of Cbz in the second-line treatment of mCRPC, PROSELICA (NCT01308580) was designed to assess whether Cbz 20 mg/m2 is associated with lower hematologic toxicity and has non-inferior efficacy compared with the standard 25 mg/m2dose. Methods: PROSELICA is a randomized, open-label, multinational, phase III study comparing the efficacy and tolerability of IV Cbz 20 with 25 mg/m2, Q3W. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, confirmed mCRPC and prior therapy with a D-containing regimen are eligible. Pts are randomized 1:1 to Cbz dosing arms; all pts receive P 10 mg PO QD and are treated until disease progression, unacceptable toxicity or consent withdrawal (max. 10 cycles). Pts are stratified by ECOG PS, measurable disease and region of the world. The primary endpoint is OS (non-inferiority). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in subgroups. Planned enrollment is 1200 pts. The study started in May 2011; by 31 Dec 2012, 851 pts had been enrolled. 158 sites are enrolling pts. Based on a review of safety and efficacy endpoints, the last Data Monitoring Committee meeting (Dec 2012) recommended continuing the study without change. Clinical trial information: NCT01308580. [Table: see text]