bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.
Authors: Chenard-Poirier Maxime , Ingles Garces Alvaro Henrique , Jones Robert Hugh , Quinton Amy , Plummer Elizabeth R. , Drew Yvette , Kowalski Mark Marion , Klencke Barbara J. , Banerji Udai 
Published: September 2018

TPS2607 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. SRA737 is currently being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation, monotherapy study of SRA737 (NCT02797964). Methods: Up to 40 patients with advanced cancer will receive oral SRA737 administered daily on a 28-day schedule. For dose-escalation, an accelerated titration design with 100% dose escalation and single patient cohorts is allowed until Grade 2 related toxicity is observed, followed by a rolling-6 design. Dose expansion will include 6 patients with any solid tumor treated at the recommended Phase 2 dose (RP2D). Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of monotherapy SRA737 and to establish a RP2D. The PK profile and PD biomarkers will be investigated. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of indication specific expansion cohorts of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations such as gene mutations and amplifications/deletions, has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. The dose and schedule identified in this trial will inform the design and conduct of Phase 2 studies of SRA737 as a single agent and in combination with other targeted or immunomodulatory agents. Clinical trial information: NCT02797964.
A phase 1b, open label, single institution trial of nintedanib in combination with bevacizumab in patients with advanced solid tumors.
Authors: Madan Ankit , Jones Benjamin Scott , Paluri Ravi Kumar , Jerome Mary , Miley Debi , Robert Francisco 
Published: September 2018

TPS2614 Background: Vascular endothelial growth factor (VEGF) is a potent factor in inducing angiogenesis. VEGF inhibitors have produced demonstrable but limited and transient clinical benefit for various cancers. One mechanism of resistance includes revascularization secondary to up-regulation of alternative pro-angiogenic signals such as platelet derived growth factor receptor (PDGF) and fibroblast growth factor receptor (FGFR) pathway. Nintedanib is an oral triple kinase inhibitor that blocks the VEGFR, PDGFR and FGFR pathways. Our study is using combination of Nintedanib (Nin) and Bevacizumab (Bev) which will block VEGF as well as salvage pathway of angiogenesis (PDGFR and FGFR). Phase I dose selection studies revealed that Nin is generally well tolerated (Clin Can Res 16:47, 2010). LUME-Lung 1 phase 3, international, double blind, placebo controlled trial using Nin and docetaxel in non-small cell lung cancer (NSCLC) showed significant improvement in progression free survival (PFS) regardless of histology and improvement in overall survival (OS) in lung adenocarcinoma (Lancet oncology 15:2, 2014). Methods: This is a phase 1b, open label, single institution trial with standard 3+3 design. Primary objective is to evaluate the safety and tolerability of combination of Nin and Bev. The secondary objective is to determine clinical efficacy (objective response), PFS, and evaluation of plasma levels of angiogenic and anti-angiogenic biomarkers like VEGF, PDGF, VEGF-R and FGF. Patients (pts) in cohort I will be treated with Bev 15 mg/kg day 1 intravenously every 3 weeks and Nin 150 mg orally (PO) twice daily (BID) from day 2-21. In the absence of dose limiting toxicities, Nintedanib dose will be increased to 200 mg PO BID in cohort II. Major inclusion criteria includes advanced solid tumors for which Bev has an indication (non-squamous, NSCLC, colon, ovarian, cervical and renal cancer), progression after at least 1 line of systemic treatment, and measurable disease. Pts with prior treatment with Bev can be enrolled. We will enroll 18 patients. Cohorts I has been completed without DLT (n = 3). Cohort II has enrolled 10 patients. Clinical trial information: NCT02835833.
Phase 1 study of onalespib, HSP90 inhibitor, and AT7519M, CDK9 inhibitor, in patients with advanced solid tumors.
Authors: Do Khanh Tu , Chen Alice P. , Meehan Robert S. , O'Sullivan Coyne Geraldine Helen , Supko Jeffrey G. , Trepel Jane B , Clark Jeffrey W. , Hays John L. , Lyons John F. , Keer Harold N. , Hewes Julia , Sze Cameron , Marzano Marissa , Bhushan Ketki , Muzikansky Alona , Ivy S. Percy , Doroshow James H. , Shapiro Geoffrey 
Published: September 2018

TPS2617 Background: The 90kDa heat shock chaperone protein (HSP90) exerts housekeeping functions within cells. HSP90 participates in the folding, stabilization, activation, and proteolytic turnover of mutant or over-expressed “client proteins” that contribute to the growth and survival of cancer cells. HSP90 inhibition leads to degradation of these aberrant proteins through the ubiquitin-proteasome pathway, allowing for simultaneous targeting of multiple pathways. Inhibition of HSP90 alone stimulates a compensatory upregulation of HSP70, which is anti-apoptotic at the pre-mitochondrial, mitochondrial and post-mitochondrial levels. The transcriptional induction of HSP70 has been linked to the activity of CDK9. In vitro and in vivo studies show that disruption of HSP70 induction by CDK9 inhibition can augment HSP90 inhibitor responses. Combined inhibition of HSP90 and CDK9 may produce synergistic anti-tumor activity. Methods: We are conducting an a phase I trial of the combination of the HSP90 inhibitor onalespib, and the CDK9 inhibitor AT7519, utilizing a 3+3 trial design, with dose-limiting toxicities defined during cycle 1. Estimated enrollment: 37 patients. Onalespib and AT7519M are both administered on days 1, 4, 8, and 11 of a 21-day cycle following a 1-week lead-in of onalespib alone to facilitate PK/PD endpoints. Patients must have histologically confirmed solid tumors that have progressed on standard of care therapy or for which no standard treatment exists, with an ECOG 0-1. Exclusion criteria include a prolonged QTc interval (Fridericia formula), pre-existing retinal disease, or cardiac dysfunction with EF < 50% at study entry. Current pharmacodynamic analyses include the analysis of HSP70 expression in plasma and peripheral blood mononuclear cells after treatment with onalespib, and after the combination, as proof-of-principle of target inhibition. At this time, DL1 has completed enrollment; accrual is ongoing with measurement of HSP90 client proteins and HSP70 levels in patient plasma and PBMC samples. This trial is open through the ETCTN. Clinical trial information: NCT02503709.
An open-label, phase Ib study of NEO-PV-01 + adjuvant with nivolumab in patients with melanoma, non-small cell lung carcinoma, or transitional cell carcinoma of the bladder.
Authors: Naing Aung , Hu-Lieskovan Siwen , Govindan Ramaswamy , Margolin Kim Allyson , Moles Melissa Ann , Gaynor Richard , Goldstein Matthew Jordan , Ott Patrick Alexander 
Published: September 2018

TPS3116 Background: Cancer cells contain unique DNA mutations that result in altered amino acid sequences known as neoantigens. Growing evidence supports a central role for neoantigens as targets for tumor directed immune responses. Tumor mutational burden as well as neoantigen load have been associated with anti-tumor activity of checkpoint inhibitors. Vaccines targeting neoantigens offer a highly specific way to induce de novo T cell reactivity and to expand existing T cell responses against neoantigens. Here, we describe NEO-PV-01, a personalized, neoantigen vaccine designed specifically for the molecular profile of each individual’s tumor. Methods: NT-001 is a single-arm, phase IB study designed to evaluate the safety of administering NEO-PV-01 + adjuvant (Poly-ICLC) with nivolumab in patients with advanced melanoma, smoking-associated non-small cell lung carcinoma, or transitional cell carcinoma of the bladder who have received no more than one prior systemic treatment. Patients undergo a baseline tumor biopsy and HLA typing. DNA and RNA sequencing is performed on the tumors as well as peripheral blood to serve as normal DNA controls. On Day 1, patients begin treatment with nivolumab at a dose of 240 mg IV while their customized vaccine is being generated. Each vaccine is custom designed for the individual patient and contains up to 20 peptides 14-35 amino acids in length. The peptides are pooled into four groups and mixed with Poly-ICLC at the time of administration. Beginning at Week 12, patients receive five priming immunizations over a three-week period followed by booster vaccinations at Weeks 19 and 23. The primary endpoint is safety. Secondary endpoints are ORR, CBR, PFS, and assessment of response conversion between Week 12 and Week 24. Exploratory endpoints include extensive immune monitoring. Clinical trial information: NCT02897765.
Phase 3, open-label, randomized study of first-line pembrolizumab (pembro) vs investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC): KEYNOTE-177.
Authors: Diaz Luis A. , Le Dung T. , Yoshino Takayuki , Andre Thierry , Bendell Johanna C. , Koshiji Minori , Zhang Yinghua , Kang S. Peter , Lam Bao , Jaeger Dirk 
Published: September 2018

TPS3618 Background: About 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti-programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study designed to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy in the first-line setting for dMMR or MSI-H mCRC. Methods: Key eligibility criteria include age ≥ 18 years, locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, no active autoimmune disease or brain metastases, and no prior therapy for mCRC. Pts are to be randomized 1:1 to receive either pembro 200 mg Q3W or investigator’s choice of SOC chemotherapy, which must be chosen prior to randomization; options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab. Treatment is to continue until disease progression, unacceptable toxicity, pt/investigator decision, or completion of 35 cycles (pembro only). Response is to be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per RECIST adapted for immunotherapy response patterns. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro beyond initial RECIST-defined progression. AEs are to be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 21 countries. Clinical trial information: NCT02563002.
The CCTG CO.26 trial: A phase II randomized study of durvalumab plustremelimumab and best supportive care (BSC) vs BSC alone in patients with advanced colorectal carcinoma (CRC) refractory to standard therapies.
Authors: Chen Eric Xueyu , Jonker Derek J. , Kennecke Hagen F. , Koski Sheryl L. , Wei Alice Chia-chi , Magoski Nadine M , Tu Dongsheng , O'Callaghan Christopher J. 
Published: September 2018

TPS3621 Background: Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor (PD-1) thereby preventing reduction in the number and efficacy of activated T-cells. Tremelimumab is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) thereby resulting in enhanced T-cell activation and anti-tumour activity. Monotherapy with the anti-PD-1 agent pembrolizumab has demonstrated significant activity in CRC pts with tumours demonstrating microsatellite instability (MSI-H). Inhibiting PD-1/PD-L1 alone is likely of limited benefit in advanced CRC as only 5% of pts are MSI-H. Targeting both PD-L1 and CTLA-4 may have additive or synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition will lead to improved patient survival vs BSC alone in advanced CRC, regardless of MSI status. Methods: This randomized phase II study (ClinicalTrials.gov NCT02870920) will assess the efficacy and safety of D+T vs BSC in pts with metastatic or advanced, unresectable, refractory CRC (n = 180). Pts have failed standard chemotherapy based regimens containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor, if Ras wild type) and no other therapeutic options. Pts are randomized in a 2:1 ratio to receive D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival; secondary endpoints include progression free survival, safety, overall response rate and quality of life. Analysis will be according to randomized group stratified by ECOG PS (0 vs 1) and site of tumour (right vs transverse vs left vs rectum). In addition, blood, plasma, and archival tissue will be collected and assessed for potential prognostic and predictive biomarkers, including tumour MSI status. As of February 1 2017, 20 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02870920.
PRODIGE 34 ADAGE: Adjuvant chemotherapy in elderly patients with resected stage III colon cancer—A randomized phase III trial.
Authors: Aparicio Thomas , Etienne Pierre-Luc , Bouche Olivier , Mineur Laurent , Hiret Sandrine , Martin Jean , Desgrippes Romain , Maillard Emilie , Breysacher Gilles , Faroux Roger , Cany Laurent , Francois Eric , Cristol-Dalstein Laurence , Carola Elisabeth , Paillaud Elena , Retornaz Frédérique , Seitz Jean Francois 
Published: September 2018

TPS3628 Background: Colon cancer (CC) occurs in around 50% of the patients after 70 years. Adjuvant chemotherapy (CT) has demonstrated a benefit on disease-free survival (DFS) and overall survival after a stage III CC resection. Nevertheless, adjuvant CT is poorly used in elderly patients. There is still concern about the efficacy of doublet CT with oxaliplatin in fit elderly patients and the usefulness of fluoropyrimidine monotherapy in unfit elderly patients. The selection of patients that should be treated remains a challenge. Geriatric evaluation and tumor biology should be explored to help for patient selection. Methods: ADAGE is a multicenter, randomized phase III study comparing 3-years DFS of 2 therapeutic strategies in 2 groups of patients aged over 70 with completely resected stage III CC. Patients are included in one of the 2 groups after a multidisciplinary team evaluation; Group 1 (arm A and B) is defined as “able” to be treated with doublet CT; Group 2 (arm C and D) is defined as “unable” to be treated with doublet CT. In each group, patients are randomized according to a 1:1 ratio. Randomization is stratified according to center, gender, stage (IIIA vs IIIB vs IIIC), occlusion and/or perforation (yes vs no) and independent activity of daily living score (IADL: normal vs abnormal). Arm A and D receive LV5FU2 or capecitabine, arm B FOLFOX4 or XELOX and arm C is an observation arm. The treatment is planned for 6 months. Adjuvant CT should start within 12 weeks after surgery. Geriatric questionnaires and Lee score must be completed before randomization. Radiological assessment is performed every 6 months for 3 years after randomization and then annually for 2 years. Hypotheses (α two-sided = 5%, power = 80%) are to improve 3-years DFS from 65% (arm A) to 72% (arm B) in group 1 (756 patients required) and from 40% (arm C) to 55% (arm D) in group 2 (226 patients required). Safety is evaluated based on laboratory and clinical tests before each cycle. Exploratory analysis are planned to determine geriatric prognostic factors for DFS. A biological ancillary study is planned to allow prognostic evaluation of mismatch repair status and other molecular signatures. At the 1stof February 2017 the accrual was 246 patients. Clinical trial information: NCT02355379.
NRG-GI002: A phase II clinical trial platform for total neoadjuvant therapy (TNT) in rectal cancer.
Authors: George Thomas J. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Pogue-Geile Katherine L. , Wu Christina Sing-Ying , Vijayvergia Namrata , Wolmark Norman 
Published: September 2018

TPS3629 Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy (tx) and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC. The experimental arms are not intended for direct comparison, but to test a variety of sensitizers or hypotheses in a consistent and relatively homogenous high-risk patient (pt) population with correlative biomarkers. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC as defined by any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. Based on promising phase I results, the first experimental arm will assess the activity of veliparib added to standard chemoRT (capecitabine + RT). Primary endpoint is to demonstrate improvement in Neoadjuvant Rectal Cancer (NAR) score for the experimental arm vs control representing 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, tx completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional arms added through rolling protocol amendments. NCT02921256. Support: U10 CA-180868, -20, 21, -22; UG-189867; AbbVie. Clinical trial information: NCT02921256.
Transanal versus laparoscopic total mesorectal excision for low rectal cancer: A multicenter randomized phase III clinical trial (TaLaR trial) protocol.
Authors: Luo Shuangling , Wang Jianping , Kang Liang , Chen Wenhao 
Published: September 2018

TPS3631 Background: Since 1982, Total Mesorectum Excision (TME) was regarded as a golden standard for radical resection of rectal cancer. Current evidences have proved that both open and laparoscopic TME could achieve the comparative oncological safety. However, for low rectal cancer, it remains a challenge to achieve complete TME with safe resections margin by the conventional transabdominal approach, especially in cases such as bulky mesorectum, enlarged prostate, narrow pelvic floor, etc. Transanal TME (TaTME) is a new approach for rectal cancer. Several retrospective studies have showed its advantage of providing better resection quality for low rectal cancer compared with transabdominal approach, but its long-term effect still needs to be explored. Methods: TaLaR trial is an open-label multicenter randomized controlled phase III trial with a non-inferiority design, aiming to compare the short and long term effect between TaTME and laparoscopic TME (lapTME) for low rectal cancer. Patients diagnosed with clinical stage no more than T3N0 or ycT3N2 rectal cancer, inferior border of the tumor from anal verge less than 7cm, are eligible for the present study. A total of 1114 patients (557 per group) will be randomized to either TaTME or lapTME. The primary end-points are 3-year disease-free survival (DFS) and 5-year overall survival (OS). The secondary endpoints include resection quality, postoperative morbidity and mortality, pelvic function and quality of life. Clinical trial information: NCT 02966483.
A randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).
Authors: Zhu Ji , Sun Xinchen , Zhang Tao , Liu Anwen , Zhu Yuan , Jia Jianhui , Zhu Yaqun , Tan Shisheng , Zhou Juying , Zhang Chen , Wang Xin , Cai Gang , Luo Bo , Wu Junxin , Yang Jialin , Zhang Zhen 
Published: September 2018

TPS3632 Background: Irinotecan is an effective drug for rectal cancer. Early small sample size trials have assessed the addition of irinotecan to standard CRT with fluoropyrimidines in neoadjuvant phase of locally advanced rectal cancer, in which pCR rates varied from 13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete recruitment in autumn 2016. However, all patients in case group were prescribed with weekly irinotecan dose of 60mg/m2 guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation. Therefore, this phase III trial was designed to confirm the potential improvement in outcomes seen with the addition of irinotecan to CRT. Methods: Eligible patients are randomly allocated to either radiotherapy 50 Gy with concurrent capecitabine, followed by a cycle of capecitabine and oxaliplatin two weeks after the end of CRT (Control arm) or radiotherapy 50 Gy with concurrent capecitabine and irinotecan, followed by a cycle of capecitabine and irinotecan (Case arm). Capecitabine is prescribed with 825mg/m2 The primary end point is ypCR. The hypothesis is to increase ypCR from 12% in the control group to 25% in the case group. To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360 randomly assigned patients are required. Secondary end points are toxicities, surgical complications, local control, progression-free survival and overall survival. Clinical trial information: NCT02605265.