bluuebunny/crossref_metadata_2025_split huggingface dataset:
WINTHER: An international study to select rational therapeutics based on the analysis of matched tumor and normal biopsies in subjects with advanced malignancies.
Authors: Soria Jean-Charles , Rodon Ahnert Jordi , Berger Raanan , Miller Wilson H. , Brana Irene , Loriot Yohann , Mughal Tariq I , Lazar Vladimir , Wunder Fanny , Bresson Catherine , Koscielny Serge , Afshar Mohammad , Saintigny Pierre , Tsimberidou Apostolia Maria , Richon Catherine , Batist Gerald , Onn Amir , Ackerstein Aliza , Rubin Eitan , Kurzrock Razelle 
Published: September 2018

TPS11625 Background: Today, personalized cancer medicine implies matching the patient’s tumor genomic characteristics with molecularly and immune targeted agents. Although there are an increasing number of DNA aberrations that can now be matched to a cognate therapy, some patients do not display such druggable oncogene drivers. Methods: WINTHER is an open non-randomized study involving 6 cancer centers in France, Spain, Israel, Canada and USA applying genomic and also transcriptomic assays to guide treatment decisions. The novelty of the WINTHER approach lies in the use of tumor and matched normal tissue biopsies together and an algorithm for predicting efficacy of therapies. The aim is to provide a rational therapeutic choice for all of the patients enrolled in the study whether or not they harbor actionable DNA alterations. The study endpoint is the comparison of the progression-free-survival (PFS) under the WINTHER selected therapy to the PFS of the last therapeutic line. Patients included have refractory metastatic cancer of any histological type, with at least one prior therapeutic regimen and performance status of 0 to 1. Patients who have received a matched treatment based on a molecular anomaly as their immediate prior therapy were excluded. After consent, patients undergo a tumor and histologically-matched normal tissue biopsy. Extracted DNA and RNA of both tumor and normal from frozen tissues at the local center under common standard operating procedures are sent to centralized laboratories for omics investigations. DNA is investigated at Foundation Medicine Inc. and RNA at Gustave Roussy using Agilent technology. For RNA, the WINTHER algorithm is applied on the differential RNA expression data between tumor and normal tissues and establishes the list of drugs with the presumed higher score of efficacy for each patient. Patients with actionable genomic events enter in ARM A, and patients without any druggable anomaly of the DNA enter in ARM B and are treated using the WINTHER algorithm RNA-based treatment decision tool. To date, the trial has recruited 303 patients. Clinical trial information: NCT01856296.
A phase 2 study to determine the efficacy and safety of TVB-2640 in combination with bevacizumab in patients with first relapse of high grade astrocytoma.
Authors: Diaz Duque Adolfo Enrique , De Feyter Henk , Kemble George , McCulloch William , Brenner Andrew Jacob 
Published: September 2018

TPS2080 Background: The mainstay of treatment for Glioblastoma Multiforme (GBM) remains surgical removal followed by combined chemotherapy with temozolomide and radiation therapy. Second line Bevacizumab (Bev) is indicated upon progression, but unfortunately the responses are not very long lasting, and there are no therapeutic options available at that point. We have learned that antiangiogenic resistance in GBM is promoted by hypoxia; moreover, metabolomic profile of GBM under such conditions reveals an increased presence of long chain fatty acids. On second hand, tumor cells compared to normal cells depend more on palmitate, and is Fatty Acid Synthase (FASN) the enzyme capable of catalyzing its biosynthesis. Further studies have shown how GBM overexpress FASN and how its inhibition selectively inhibits growth and viability of tumor cells by inducing tumor cell apoptosis. TVB-2640 emerges as a novel agent that selectively inhibits FASN. This study represents a phase 2 clinical investigation of TVB-2640, which is to be conducted in patients with Recurrent High Grade Astrocytoma. Methods: This is a prospective, randomized, phase 2 study of TVB-2640 in combination with Bev or Bev alone in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Patients 18 years or older, with ECOG 0 to 2 and GBM progression following standard combined modality treatment will qualify for the study. Patients will be randomized into 2 separate arms. Patients in arm number one will receive Bev every 2 weeks in combination with TVB-2640 while patients in arm number two will receive Bev alone every 2 weeks. MR-Spectroscopy will be obtained on all patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive Bev in combination with TVB-2640. A total sample size of 24 patients will provide 90% power to detect a 4 months difference in PFS (3 months for Bev alone (historic controls) versus 7 months for TVB-2640 in combination with Bev, i.e., a hazard ratio of 0.43) using a one-sided log-rank test with alpha = 0.1. The trial is open and enrollment will begin in Feb 2017. Clinical trial information: NCT03032484.
First-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-α in patients with advanced liver cancer.
Authors: Sarker Debashis , Plummer Elizabeth R. , Basu Bristi , Meyer Tim , Huang Kai-Wen , Evans T.R. Jeffry , Spalding Duncan , Ma Yuk Ting , Palmer Daniel H. , Chee Cheng Ean , Toh Han Chong , Habib Nagy A 
Published: September 2018

TPS2612 Background: saRNAs are small oligonucleotide drugs designed to selectively upregulate therapeutic proteins by recruiting endogenous transcriptional complexes to a target gene, leading to increased expression of naturally processed mRNA. Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) is a leucine zipper protein which acts as a master regulator of liver homeostasis and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis. MTL-CEBPA comprises a double stranded RNA payload formulated inside a SMARTICLES liposomal nanoparticle to specifically target the CEBPA gene and has been shown to improve liver function and inhibit hepatocellular cancer (HCC) tumor growth in preclinical models (Reebye et al, Hepatology, 2014). MTL-CEBPA is the first saRNA and the first drug targeting C/EBP-α to enter clinical trials. Methods: Pts with advanced HCC (Child-Pugh A or B7 only) or secondary liver cancer refractory to or ineligible for standard treatment, ECOG PS 0-1, acceptable haematologic, liver and renal function, are currently being enrolled in a standard 3+3 dose escalation study. Once the RP2D is defined, 12-15 patients with advanced HCC will be evaluated further in a dose expansion cohort. MTL-CEBPA is administered as a 1-hr IV infusion on Day 1, 8 and 15 of a 28-day cycle. RECIST tumor response is assessed after every 2 cycles. The primary objective is to determine safety and tolerability; secondary objectives include PK, liver function improvement and anti-tumor activity. Correlative studies include C/EBP-α mRNA levels in PBMCs and optional tumor tissue, evaluation of C/EBP-α downstream target genes (e.g.TGFβ) and distal target engagement in white blood cells (e.g.IL-6, NF-κB, IFN-γ). Recruitment to cohort 2 is shortly to be completed, with no DLTs reported to date. Clinical trial information: NCT02716012.
Phase I study of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors.
Authors: Cescon David W. , Hansen Aaron Richard , Abdul Razak Albiruni Ryan , Stayner Lee-Anne , Hilton John Frederick , Renouf Daniel John , Denny Trisha , Fletcher Graham , Mak Tak W , Bray Mark R , Bedard Philippe L 
Published: September 2018

TPS2619 Background: TTK (MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. TTK is overexpressed in several tumor types, which may contribute to survival and proliferation of aneuploid cells, and higher expression correlates with adverse outcomes. The Campbell Family Therapeutics Group at the University Health Network (UHN) has developed CFI-402257, a potent (Ki = 0.09 nM, IC50 = 1.2 nM), highly selective and orally active inhibitor of TTK, with negligible activity towards 265 other kinases. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 at tolerated doses in several cell line (breast, colorectal) and patient-derived (ovarian) xenograft models. Pharmacodynamic effects including reduction in phospho-histone H3 were observed. In syngeneic mouse colorectal cancer models, CFI-402257 + PD-1 immune checkpoint blockade demonstrated greater activity than either agent alone, and resulted in tumor regressions and immunity to rechallenge. Methods: This multi-center Phase I dose escalation study (3+3 design) will determine the safety, tolerability and maximum tolerated dose (MTD) of CFI-402257 administered as daily continuous oral treatment. Secondary and correlative endpoints include plasma PK, antitumor activity, and molecular features associated with response or clinical benefit. An expansion cohort (n = 12) will be enrolled at the MTD. Key inclusion criteria: adult patients with advanced solid tumors, measurable disease (RECIST 1.1), adequate organ function and performance status (ECOG 0-1). Exclusion criteria: uncontrolled medical illness, CNS metastases (unless stable x 3 months). CFI-402257 will be dosed once daily on a continuous schedule in 28-day cycles, beginning at 5 mg/day with planned escalation to 56 mg/day. DL1 completed enrolment 01/2017 and accrual is ongoing. Phase II studies are planned (Stand Up to Cancer Canada Breast Cancer Dream Team). Funding: UHN, CIRM. Clinical trial information: NCT02792465.
A phase 1 dose-escalation trial of intratumoral TTI-621, a novel immune checkpoint inhibitor targeting CD47, in subjects with relapsed or refractory percutaneously-accessible solid tumors and mycosis fungoides.
Authors: Thompson John A. , Akilov Oleg , Querfeld Christiane , Taylor Matthew H. , Johnson Lisa , Catalano Tina , Petrova Penka S. , Uger Robert A. , Irwin Meghan , Sievers Eric L. 
Published: September 2018

TPS3101 Background: CD47 is an immune checkpoint that binds to signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. CD47 blockade promotes both innate (macrophage phagocytosis) and adaptive immunity (T cell responses). TTI-621 (SIRPαFc) is an immune checkpoint inhibitor designed to bind human CD47 and block the “do not eat” signal. The IgG1 region of TTI-621 engages Fcγ receptors on macrophages, converting the inhibitory signal to one that activates, thereby enhancing phagocytosis, and antitumor activity. A Phase 1 study is ongoing to evaluate the safety/tolerability and preliminary efficacy of IV administered TTI-621 in subjects with relapsed/refractory hematologic malignancies. It is hypothesized that employing direct intratumoral injections will result in very high local target engagement, promoting the development of innate and adaptive immune responses. Methods: A Phase 1 multicenter, open-label study was initiated to characterize the safety and tolerability of delivering TTI-621 directly into cancer lesions to achieve high local CD47 engagement to increase phagocytosis of tumor cells (NCT02890368). Subjects are being enrolled in sequential cohorts that gradually increase in dose and dosing frequency to characterize the feasibility of intratumoral TTI-621 injections and their safety, PK, pharmacodynamics, and preliminary antitumor activity. Eligible subjects are adults with relapsed or refractory percutaneously-accessible solid tumors or mycosis fungoides (MF), which have progressed on standard anticancer therapy or for which no other approved therapy exists. TTI-621 is delivered by intratumoral injection at protocol-defined doses and dosing regimens starting at 1 mg/injection. Serial biopsies are being collected to characterize local anti-tumor responses and assess the impact of TTI-621 on the tumor microenvironment. Clinical trial information: NCT02890368.
Phase 1/2 study of in situ vaccination with tremelimumab + intravenous (IV) durvalumab + poly-ICLC in patients with select relapsed, advanced cancers with measurable, biopsy-accessible tumors.
Authors: Slingluff Craig L. , Dasilva Daniel , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph , Bhardwaj Nina 
Published: September 2018

TPS3106 Background: Immunotherapy has demonstrated promising antitumor activity in various advanced cancers. Combined tumor targeting from multiple drugs with unique mechanisms may provide further improved outcomes. Tremelimumab (TRE) is a CTLA-4 antibody and durvalumab (DUR) blocks PD-L1. Poly-ICLC is a toll-like receptor 3 agonist. Intratumoral (intra-T) injection of poly-ICLC directly alters the tumor microenvironment (TME), and by creating an in situ vaccination, may trigger a clinically effective systemic anti-tumor response when also combined with DUR and TRE. Methods: This is an ongoing Phase 1/2, open-label, multicenter study (NCT02643303). The study evaluates the use of intra-T administration of TRE and IV DUR + poly-ICLC (intra-T and intramuscular [IM]) to determine the safety, preliminary efficacy and immune activity of this regimen in patients with advanced, measurable, biopsy-accessible tumors: head and neck squamous cell carcinoma, breast cancer, sarcoma, merkel cell carcinoma, cutaneous T-cell lymphoma, melanoma, genitourinary cancer, and other solid tumors. Phase 1 determines the recommended combination dosing (RCD) for the regimen with dose de-escalation based on dose limiting toxicities (DLTs) and standard 3 + 3 rules. Starting doses are: DUR, 1500 mg IV; TRE, 75 mg IV; TRE, 10 mg intra-T; poly-ICLC, 1 mg intra-T/IM. Phase 1 starts with Cohort 1A (DUR + poly-ICLC). Upon demonstration of tolerability, enrollment proceeds with Cohort 1B (DUR + IV TRE + poly-ICLC) and Cohort 1C (DUR + intra-T TRE + poly-ICLC). The RCD is the highest dose at which < 2/6 patients have DLTs. In Phase 2, up to 66 evaluable patients are treated using the RCD regimen, with enrollment of 6 patients per tumor type initially, and enrollment of 6 additional patients per 3 tumor types contingent upon at least 1 response among the initial 6 patients. Study endpoints are RCD and safety, objective response rate, progression-free survival, and overall survival. Exploratory endpoints are biological activity, including effects on the TME and immunological responses. Enrollment opened on 28 Dec 2016. Clinical trial information: NCT02643303.
A phase 1b/2 study of ARRY-382, an oral inhibitor of colony stimulating factor 1 receptor (CSF1R), in combination with pembrolizumab (Pembro) for the treatment of patients (Pts) with advanced solid tumors.
Authors: Harb Wael A. , Johnson Melissa Lynne , Goldman Jonathan Wade , Weise Amy M. , Call Justin Anthony , Dudek Arkadiusz Z. , Gonzalez Rene , Cowey C. Lance , Eves P. Taylor , Gollerkeri Ashwin , Gainor Justin F. 
Published: September 2018

TPS3110 Background: CSF1, which signals via CSF1R, regulates tumor-associated macrophages and myeloid-derived suppressor cells, both critical drivers of immune escape in the tumor microenvironment. ARRY-382 is a highly selective, oral inhibitor of the CSF1R intracellular tyrosine kinase. The first-in-human study of ARRY-382 monotherapy identified the maximum tolerated dose (MTD) of 400 mg QD, with biologic activity at doses ≥200 mg QD (Bendell JC et al. Mol Cancer Ther. 2013;12:A252). Preclinical data supports combining a PD-1 inhibitor with a CSF1R inhibitor (Zhu Y et al. Cancer Res. 2014;74:5057-69). This study is designed to evaluate ARRY-382 in combination with pembro, a potent and highly selective humanized monoclonal antibody that targets PD-1. Methods: This is an open-label, multicenter, phase 1b/2 study (NCT02880371) to determine the MTD and/or recommended phase 2 dose (RP2D) of ARRY-382 + pembro and to evaluate the activity of the combination in select indications. In phase 1b (Part A), the primary objective is to identify the MTD/RP2D. Up to 18 pts with select advanced solid tumors (Part A) will be enrolled in 2 successive cohorts evaluating ARRY-382 at doses of 200 mg QD and 400 mg QD, respectively, in combination with pembro 2 mg/kg Q3W. Once the MTD/RP2D has been determined in phase 1b, phase 2 will concurrently evaluate the combination in up to 20 pts with advanced unresectable/metastatic melanoma (Part B) and in up to 33 pts with PD-L1-positive (tumor proportion score ≥50) non-small cell lung cancer (NSCLC) (Part C). The primary objective of Part B is to assess the pharmacodynamics and antitumor activity of ARRY-382 + pembro in pts with advanced unresectable/metastatic melanoma, and the endpoints include effects of treatment on circulating growth factors and cytokines, markers of bone resorption, and objective response rate (ORR). The primary objective of Part C is to assess the efficacy of ARRY-382 + pembro in pts with PD-L1–positive NSCLC (Part C). The primary endpoint is ORR. Immune-related response rate and safety will be evaluated in all pts in the study. Clinical trial information: NCT02880371.
A phase I study of enadenotucirev (EnAd), an oncolytic Ad11/Ad3 chimeric group B adenovirus, in combination with nivolumab in tumors of epithelial origin.
Authors: Harb Wael A. , Rosen Lee S. , Wang Ding , Fakih Marwan , Mahadevan Daruka , Clemens Wendy , Selvaggi Giovanni , Bosque Suzanne , Brown Richard , Alvis Simon , Champion Brian , McElwaine-Johnn Hilary 
Published: September 2018

TPS3115 Background: EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines with little replication in normal and non-carcinoma cells. Previous studies have shown that after systemic administration there is significant uptake and replication of EnAd in various carcinomas associated with improved CD8+ T-cell tumor infiltration. These data provide the rationale for combination of EnAd with the checkpoint inhibitor (CPI), nivolumab (anti-PD-1 antibody) to potentially enhance the response to nivolumab. This is a phase I study in subjects with metastatic or advanced carcinoma. The study design has a dose escalation stage, followed by a dose expansion stage which will evaluate the ability to improve responses in tumors normally non-responsive to CPI and also to evaluate the ability to detect meaningful responses in PDL1 negative tumors that are less responsive to CPI. Methods: The dose escalation phase consists of 5 cohorts of patients with metastatic or advanced epithelial tumors in a standard "3 + 3" design. Subjects will receive increasing dose levels and/or cycles of EnAd followed by a q3w regimen of nivolumab (360mg). EnAd treatment cycles comprise 3 intravenous (IV) infusions on Days 1, 3 and 5. Nivolumab is administered as an IV infusion given every 3 weeks starting on Day 15 and continuing for up to 8 treatment cycles. The Dose Expansion phase will investigate the combination of EnAd and nivolumab in expanded cohorts of colorectal cancer, urothelial cell carcinoma, squamous cell carcinoma of the head & neck, and non-small cell lung cancer patients. The primary objectives are to establish the MTD of EnAd and nivolumab combination, to evaluate the safety and to recommend doses for future studies. Secondary endpoints include overall response, duration of response and progression free survival, assessed according to RECIST Version 1.1 and irRECIST Version 1. Enrollment to cohorts 3 & 4 began in January 2017. Clinical trial information: NCT02636036.
A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.
Authors: Hollebecque Antoine , Argiles Guillem , Andre Thierry , Cervantes Andres , Leger Catherine , Valette Aude , Amellal Nadia , Fougeray Ronan , Tabernero Josep 
Published: September 2018

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p < 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.