bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in subjects with MET amplified metastatic colorectal cancer (mCRC) detected by cell-free (cf)DNA.
Authors: Jia Jingquan , Niedzwiecki Donna , Arrowood Christy , Garett-Mead Nancy , Nagy Rebecca , Lanman Richard B. , Wright John , Nixon Andrew B. , Strickler John H. 
Published: February 2020

TPS270 Background: MET amplification (amp) is a well-described driver of acquired EGFR antibody (Ab) resistance and is found in 10-20% of pts with KRAS and NRAS wild-type mCRC treated with anti-EGFR Abs. Blood-based genomic profiling of cfDNA is a non-invasive and efficient means of identifying acquired MET amp in mCRC. Although the activity of anti-MET tyrosine kinase inhibitors (TKIs) in EGFR Ab refractory mCRC has been shown in preclinical and clinical studies, the clinical efficacy of anti-MET TKIs in pts with MET amplified mCRC is not well established. Savolitinib is a potent and highly selective oral small molecule anti-MET TKI that is currently under clinical development for MET-driven papillary renal cell carcinoma, NSCLC and gastric cancer. Methods: This single-arm phase II study will evaluate the clinical efficacy and tolerability of savolitinib in pts with MET amplified mCRC. Eligible pts include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, an anti-VEGF Ab and an anti-EGFR Ab. Pts must have MET amp detected by Guardant360 (G360) cfDNA screening assay. Up to 150 patients will be screened to identify at least 15 pts for study accrual. Prior treatment with an anti-MET TKI or monoclonal Ab against c-MET or HGF is excluded. The primary objective is to estimate the objective response rate (ORR) for savolitinib. In this heavily pre-treated cohort an observed ORR of 20% is considered clinically meaningful and worthy of further study. Secondary objectives are to evaluate the efficacy (progression-free survival, duration of response), safety and tolerability. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if savolitinib eliminates MET amp in cfDNA. Subjects will receive savolitinib at a dose of 600mg by mouth daily on 28-day cycles. Response will be assessed every 2 cycles (8 weeks) per RECIST version 1.1. This study was initiated on 1/30/2019. Recruitment is ongoing in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03592641.
NuTide: 302—A phase Ib study of the ProTide NUC-3373 in combination with standard therapies in advanced colorectal cancer.
Authors: Ciombor Kristen Keon , Graham Janet Shirley , Aroldi Francesca , Coveler Andrew L. , Schlechter Benjamin L. , Clark Jeffrey William , Graham Jill , Rodgers Lisa Jane , De Gramont Aimery , Tabernero Josep , Berlin Jordan , Blagden Sarah Patricia , Evans T.R. Jeffry 
Published: February 2020

TPS274 Background: Although 5-FU-based regimens such as FOLFOX and FOLFIRI remain the cornerstone of treatment for patients (pts) with colorectal cancer (CRC), their clinical utility is limited by resistance mechanisms and toxicity. Anti-cancer activity of 5-FU is dependent on conversion to an active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. However, due to multiple limitations including: reliance on enzymatic activation; catabolism by dihydropyrimidine dehydrogenase (DPD) and a short plasma half-life, 5-FU is not efficiently converted to FUDR-MP. NUC-3373, a phosphoramidate transformation of FUDR-MP, was designed to bypass the key resistance mechanisms that limit the clinical utility of 5-FU. NUC-3373 demonstrated a favorable PK/PD profile and promising efficacy signals in the first-in-human study (NuTide:301) in pts with advanced solid tumors. NUC-3373 has a longer plasma t1/2 (9.7 hours) than 5-FU (8-14 minutes) and generates high intracellular levels of FUDR-MP (Ghazaly et al ESMO, 2017). TS is efficiently inhibited and sequestered into TS-ternary complexes, depleting the pool of deoxythymidine monophosphate (dTMP) within 2-4 hours. Methods: NuTide:302 is a three-part, Phase Ib study in pts with advanced CRC who have relapsed after ≥2 prior lines of 5-FU-containing therapies. Primary objective is to identify a RP2D of NUC-3373 when administered weekly and q2w in combination with standard agents used in CRC treatment. Secondary objectives include safety, PK/PD and anti‐tumor activity. In Part 1, patients are receiving NUC-3373 with leucovorin (LV) to determine if LV augments TS inhibition. In Part 2, NUC-3373 (±LV) will be administered in dose escalating cohorts, in a modified 3+3 design, with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected in Part 2 will be combined with biologics targeting VEGF or EGFR pathways. To date, 22 pts have received study treatment. Recruitment is ongoing in the US and Europe. Clinical trial information: NCT03428958.
KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJc): A double-blind, randomized, placebo-controlled phase III study.
Authors: Chung Hyun Cheol , Bang Yung-Jue , Fuchs Charles S. , Qin Shukui , Satoh Taroh , Shitara Kohei , Tabernero Josep , Van Cutsem Eric , Alsina Maria , Cao Z. Alexander , Chen Xinqun , Bhagia Pooja , Shih Chie-Schin , Janjigian Yelena Yuriy 
Published: February 2020

TPS463 Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH > 2.0) G/GEJ cancer; life expectancy > 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and 5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.
Margetuximab (M) combined with anti-PD-1 (MGA012) or anti-PD-1/LAG-3 (MGD013) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).
Authors: Catenacci Daniel V.T. , Rosales Minori Koshiji , Wigginton Jon M. , Chung Hyun Cheol , Yoon Harry H. , Shen Lin , Moehler Markus H. , Kang Yoon-Koo 
Published: February 2020

TPS468 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care palliative 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). M, an Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. M coordinately enhanced both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. MGA012 (INCMGA00012) is a humanized, hinge-stabilized, IgG4 κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. MGD013 is a humanized Fc-bearing bispecific tetravalent protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC pts, and induced a 30% objective response rate (ORR). This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC pts. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study. The first single arm, CTX-free cohort A evaluates M+MGA012 in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) pts. After 40 pts are evaluated for response/safety, 60 more pts will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) pts are enrolled irrespective of PD-L1 status. Part 1 randomizes pts to 1 of 4 arms (50 pts each): control arm (T+CTX) or 1 experimental arm (M+CTX; M+CTX+MGA012; M+CTX+MGD013). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either MGA012 or MGD013, depending on results from part 1; with 250 pts each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.
A pilot study of avelumab in Epstein-Barr virus-associated gastric cancer.
Authors: Mc Laughlin Ronan Andrew , Aird John , McCormack Orla , DeGascun C. , Hussein R. , Molloy B. , Malara A. , Galligan M. , Kelly Catherine Margaret , Doran Peter , Duffy Austin G. 
Published: February 2020

TPS473 Background: Gastric Cancer (GC) is the third most common cause of cancer related deaths worldwide. The median overall survival of patients with stage 4 disease is approximately 1 year. Current accepted treatment approach with chemotherapy is applied with little consideration for known genetic or biologic heterogeneity. Whilst immune-based approaches in GC look promising it is clear that single-agent PD1/PDL1 inhibition benefit a minority. We must clarify a means of identifying prospectively those patients who may benefit from this treatment. A recent landmark paper by The Cancer Genome Atlas (TCGA) proposed a classification of GC into four subtypes: Epstein-Barr-virus (EBV)-positive, microsatellite instable (MSI), chromosomal instable (CI), and genomically stable (GS). Two of the four – EBV and MSI subtypes – are likely to be immunogenic and amenable to PD1/PDL1 inhibition. Recent advances have shown EBV-positive tumors to be infiltrated by lymphocytes and be enriched for PDL1. Methods: This single centre single-arm pilot study in gastric or junctional adenocarcinoma will explore the hypothesis that administering anti-PDL1 therapy (Avelumab) in a prospectively identified population enriched for potential responders will result in improved outcomes. The anticipated frequency of EBV associated-GC (c10%) means that approximately N = 100 patients will be screened to identify N = 10 participants. If a positive signal for efficacy is seen this will provide a basis for a larger, multicentre study. Previously treated Patients with confirmation of stage 4 EBV- positive gastric or oesophago-gastric adenocarcinoma meeting eligibility criteria will be enrolled. Avelumab will be administered at a dose of 10mg/kg IV every 14days. Primary endpoint is to determine the 6-month progression free survival (PFS) of Avelumab in EBV-associated GC. Secondary endpoints include overall response rate, overall survival, median PFS time and feasibility/accrual rate at 12 months. Exploratory endpoints will be to evaluate changes in immune parameters in the peripheral blood over time. Kaplan-Meier methods for primary efficacy endpoint with two-tailed one-sample proportion test will be used to evaluate the evidence to reject the null hypothesis. Clinical trial information: 2018-002085-39.
A phase III trial in progress comparing tislelizumab plus concurrent chemoradiotherapy (cCRT) with placebo plus cCRT in patients with localized esophageal squamous cell carcinoma (ESCC).
Authors: Wang Wei-Hu , Li Jiancheng , Li Tao , Zhao Kuaile , Yu Rong , Wang Wenqing , Chen Mingqiu , Liang Long , Zou Jiyan , Wang Yidi , Shen Wei , Wu Zhe , Xiao Zefen 
Published: February 2020

TPS475 Background: In China, esophageal cancer (EC) ranks as the eigth most common cancer and the sixth most common cause of cancer related death. The predominant histological subtype of EC is ESCC. At first diagnosis, more than half of patients (pts) with ESCC are unfit for surgery. An alternative to surgery is cCRT; however, many pts experience local failure or distant metastasis after cCRT. As such, innovative therapies are needed. Tislelizumab, an investigational humanized monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. In previous studies, tislelizumab, as a monotherapy and in combination with chemotherapy, was generally well tolerated and had antitumor activity in pts with ESCC. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT03957590) is designed to compare the efficacy of tislelizumab versus placebo in combination with cCRT. Patients with histologically confirmed localized ESCC for whom cCRT is suitable and surgery is unsuitable/declined are being enrolled. Approximately 316 Chinese pts will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo (IV Q3W) in combination with cisplatin (25 mg/m2 IV on Days 1-3 of each 3-week cycle) plus paclitaxel (135 mg/m2 IV Q3W) and radiotherapy at a total dose of 50.4 Gy. An Independent Data Monitoring Committee will be established to assess the safety/tolerability of tislelizumab plus cCRT in the first 20 enrolled pts; monitoring across the study will occur at regular intervals thereafter. Progression-free survival (PFS), assessed by a Blinded Independent Review Committee per RECIST v1.1, is the primary endpoint. Secondary efficacy endpoints include overall response rate, duration of response, and overall survival. Incidence and severity of adverse events (CTCAE V5.0) and HRQoL are additional secondary endpoints. Exploratory endpoints include PFS rate at Years 1 and 2, pharmacokinetic profile, and predictive biomarker analyses. Clinical trial information: NCT03957590.
Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.
Authors: George Thomas J. , DeRemer David L. , Parekh Hiral D. , Lee Ji-Hyun , Markham Merry Jennifer , Daily Karen Colleen , Kaye Frederic J. , Staal Stephen , Jones Dennie V. , Stechmiller Bruce K. , Allegra Carmen Joseph , Hromas Robert A. 
Published: February 2020

TPS591 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks on treatment. Enrollment continues to a maximum of 47 evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]
Phase I study of a new concept cancer vaccine composed artificial intelligence (AI)-designed shared-antigen peptides plus combined synergistically activating antigen-specific CTL reaction (CYT001) in patients with advanced hepatocellular carcinoma (CRESCENT 1).
Authors: Ogasawara Sadahisa , Kanzaki Hiroaki , Koroki Keisuke , Kanayama Kengo , Maruta Susumu , Kobayashi Kazufumi , Kiyono Souichiro , Nakamura Masato , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Tawada Akinobu , Chiba Tetsuhiro , Arai Makoto , Nakada Hiroyuki , Yamaguchi Nobuko , Hanaoka Hideki , Kato Naoya 
Published: February 2020

TPS595 Background: CYT001 (CYTLIMIC Inc.) is a novel cancer vaccine involving artificial intelligence (AI)-designed shared-antigen peptides and optimal combined adjuvants that boost the cancer-immunity cycle. The two multi-HLA reactive peptides heat shock protein 70 (HSP70) and glypican 3 (GPC3) were screened by an AI-based prediction system according to the proteome, mRNA, and histopathology data fromhuman samples. These immunogenic peptides were confirmed to show cross-reactivity to HLA-A 24:02, 02:01, and 02:06. Poly-ICLC (Oncovir Inc.) binds to Toll-like receptor 3 (TLR3) and melanoma differentiation antigen 5 (MDA5) on antigen-presenting cells (APCs)and activates APCs. LAG-3Ig (Immutep Inc.) binds to the major histocompatibility complex (MHC) class II molecules of APCs and activates APCs. Both poly-ICLC and LAG-3Ig synergistically activate antigen-specific CTL reactions as effective combination adjuvants. The present study aims to evaluate the safety and tolerability of CYT001 (mixture of HSP70 peptide [2.0 mg], GPC3 peptide [2.0 mg], poly-ICLC [1.0 mg], and LAG-3Ig [1.4 mg]) in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single-center, phase 1, open-label, single-arm, investigator-initiated clinical trial of CYT001 for advanced HCC patients with no eligible standard systemic therapy, Child–Pugh A liver disease, and HLA-A 24:02, 02:01, or 02:06. Enrolled patients will receive CYT001 as a subcutaneous injection on days 1, 8, 15, and 21 in the 1st and 2nd cycles, days 1 and 15 in the 3rd and 4th cycles, and day 1 in the 5th cycle or later of 28-day cycles. The primary endpoint is dose-limiting toxicity, and the secondary endpoints are safety and the response rate. The transition of the CTL reactions of both the HSP70 and GPC3 peptides will be evaluated using blood samples of the subjects. Exploratory analyses include investigation of candidate biomarkers for treatment efficacy using liver tumor biopsy samples (baseline and after the 1st cycle) and blood samples (baseline and every days of administration). Clinical trial information: jRCT2031190072.
FIDES-01, a phase II study of derazantinib in patients with unresectable intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions and mutations or amplifications (M/A).
Authors: Javle Milind M. , Shaib Walid Labib , Braun Stephan , Engelhardt Marc , Borad Mitesh J. , Abou-Alfa Ghassan K. , Boncompagni Andrea , Friedmann Silke , Gahlemann Christoph Georg 
Published: February 2020

TPS597 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In iCCA, FGFR genetic aberrations include FGFR2 fusions and, less commonly, FGFR2 M/A. iCCA prognosis is poor, and chemotherapeutic and targeted treatment options are limited. While FGFR2 fusions are acknowledged oncogenic drivers, the oncogenic potential of FGFR2 M/A is less well defined. Derazantinib (DZB) is an investigational, oral small-molecule kinase inhibitor with activity against FGFR1, 2 and 3, which demonstrated antitumor activity in patients with unresectable iCCA with FGFR2 fusions. Based on preliminary efficacy data demonstrating durable responses of > 6 months and a clinically meaningful progression-free survival in a subset of iCCA patients harboring FGFR2 M/A (NCT01752920), the multicenter, multicohort open-label phase 2 study FIDES-01 is evaluating the effect of DZB in separate cohorts of iCCA patients with FGFR2 fusions or FGFR2 M/A. Methods: The new cohort evaluates 300 mg once daily dosing of DZB in patients with unresectable iCCA with FGFR2 M/A per liquid or tissue biopsy-based next generation sequencing and at least one previous systemic therapy. Treatment will continue until progressive disease, intolerance, withdrawal of informed consent, or death. Using a Simon’s two-stage design, the primary endpoint to assess the antitumor activity of DZB is the proportion of patients with PFS at 3 months (PFS3; per RECIST 1.1 central review). Secondary objectives are evaluation of median PFS, objective response rate, duration of response, safety profile, quality of life (incl., QLQ-C30, QLQ-BIL21, EQ-5D), and symptom response from baseline. Current status: The study was initiated in July 2019 with planned enrollment of 43 patients with confirmed FGFR2 M/A. Clinical trial information: NCT03230318.