bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential association of 5-hydroxymethylcytosine levels with clinical and histopathological characteristics in breast cancer tumors.
Authors: Peña-Curiel Omar , Prada Diddiera , Otero Miguel , Díaz-Chávez José , Villarreal-Garza Cynthia , Justo Montserrat , Reynoso Nancy , Castro Hernandez Clementina , Cabrera-Galeana Paula , Bargallo-Rocha Enrique , Villaseñor-Navarro Yolanda , Caro-Sánchez Claudia , De La Garza Jaime G. , Herrera Montalvo Luis Alonso
Published: September 2018

e23173

Background: Breast cancer is one of the top causes of cancer death worldwide. In Mexico, locally advanced breast cancer (LABC) comprises the majority of the breast cancer stages at diagnosis. Recent studies have suggested that 5-hydroxymethylcytosine (5hmC), could be a prognostic marker in breast cancer. However, the role of 5hmC on clinical and histopathologic characteristics in LABC has not been explored. Methods: From a cohort of locally advanced and advanced breast cancer patients treated at the National Cancer Institute in Mexico City with a 3-year follow-up, we measured 5hmC levels by immunodetection from fresh frozen tissue samples taken from the initial biopsy (N = 193). We determined the association between 5hmC levels and the most relevant clinical and histopathological characteristics. Results: From the full cohort analyzed; 42% were luminal A (n = 82), 33% were luminal B (N = 63), 9% were HER2-positive (N = 18), and 15% were triple-negative tumors. We found higher levels of global 5hmC in HER2 positive tumors vs. all other subtypes (p = 0.028, Kruskal-Wallis test). In luminal B tumors, 5hmC levels were associated with Ki67 (β = -0.04, 95%CI: -0.08, -0.01, p = 0.01 from multivariable model) but not in luminal A. Furthermore, we found that low 5hmC levels were associated with higher histological grade in HER2-positive tumors (p = 0.03, Kruskal-Wallis test). In subgroup analysis of LABC patients, we found higher 5hmC levels in non-ductal vs. ductal invasive tumors (β = 1.38, 95%CI: 0.049, 2.911, p = 0.043 from multivariable model). Also, lower 5hmC levels were associated with Ki67 (β = -2.53, 95%CI: -4.32, -0.74; p = 0.009 from multivariable model) and with histological type (p = 0.028, Kruskal-Wallis test) in LABC luminal B tumors. A borderline association with OS (p = 0.07, log-rank test) and RFS (p = 0.071, log-rank test) was observed in luminal A tumors in the LABC group. Conclusions: Our findings suggest that 5hmC levels are differentially associated with distinct clinical and histopathological characteristics in breast cancer, especially those linked to aggressiveness, including Ki67, histological type, and grade.
Evaluation of the prognostic value of the OncoMasTR RNA panel in diverse tumor types.
Authors: Moran Bruce , Lanigan Fiona , Russell Niamh , Barron Stephen , Wang Chan-Ju , Jirstrom Karin , Bracken Adrian P. , Gallagher William M.
Published: September 2018

e23201

Background: Master transcriptional regulators (MTRs) are genes that are highly connected with many other genes and which can contribute to a specific cellular phenotype. The OncoMasTR panel, a set of 10 proliferation-linked MTRs and the key regulator of senescence CDKN2A, was identified in lymph node-negative breast cancer patients using publicly available data (Lanigan et al FEBS 2015 10.1111/febs.13354). Using two prognostic gene signatures and an experimentally defined ‘proliferative’ signature, highly concordant results for the top ranking sets of MTRs were found. One advantage of this process was the distillation of gene signatures into a discrete, mechanistically anchored biomarker set shown to be prognostically relevant, particularly in ER-positive patients, and with an ability to discriminate patients into low versus high risk of recurrence. Our aim here was to determine if the OncoMasTR panel was similarly useful in multiple other cancer types using publicly available transcriptomic data. Methods: The Gene Expression Omnibus was queried for datasets with relevant overall-, disease free- and/or recurrence free-survival information alongside microarray gene expression data. Survival analysis was conducted on 34 datasets using the R statistical environment package ‘survival’. Patient samples were scored based on median or tertile expression which were summed to give a final OncoMasTR RNA score, used to divide the patient samples into two groups (low and high risk) for analysis. Results: Using all 2,047 possible combinations of genes, a total of 23 datasets had significant prognostic associations. Following appropriate correction via multiple testing, this was reduced to 4 datasets representing bladder, lung and colorectal cancers, and multiple myeloma. Hazard ratios for the top 100 combinations in each data set were 1.8 – 2.1, 1.6 – 1.9, 1.1 – 1.3, 1.3 – 1.5 (standard error ±0.2, 0.1, 0.2, 0.1) respectively. All genes were found in the top ten combinations in all 4 datasets, and no specific combination was found to be prevalent across datasets, indicating that every MTR in the OncoMasTR panel contributes to its utility. Conclusions: The OncoMasTR panel is potentially prognostically useful in multiple cancer types.
Copy number variants signature in two patients with relapsed acute promyelocytic leukemia.
Authors: Nanni Jacopo , Marconi Giovanni , Fontana Maria Chiara , Papayannidis Cristina , Lo Monaco Silvia , Baldazzi Carmen , Padella Antonella , Simonetti Giorgia , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Testoni Nicoletta , Abbenante Maria Chiara , Paolini Stefania , Franchini Eugenia , Ottaviani Emanuela , Martinelli Giovanni , Bertamini Luca
Published: September 2018

e23207

Background: Nowadays, Acute Promyelocytic Leukemia (APL) is a disease entity with a very high rate of cure and an estimated 2-year overall survival of 97%. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure, and relapse is a very rare occurrence. Methods : We collected data of all the APL referred to our institution from 2014. Within 23 patients, we encountered 20 new diagnosis and 2 relapse of APL. We analyzed blasts in samples obtained from Bone Marrow with Single Nucleotide Polymorphisms Array Cytoscan HD. Results: We compared copy number alterations in both relapsed patients with alterations detected in the pool of 20 newly diagnosed APL and we found specific signatures of CNVs for each patient. There were several copy number alterations related to each patient: the first patient presented gain of ROBO2, GRIP1, CTNNB1, SOX6, PBX1, GRIK2, CDKAL1 and loss FAF1, CREBBP, SBF1; the second patient presented gain of ROBO1, MAPK10, CADPS2, APBA1 and loss of GRIP1 and MYB. Subsequently we focused our attention on ROBO and GRIP1genes because they were alterated in both relapsed patients: ROBO proteins are associated to K channels while GRIP1 is involved in various critical functions, for example in androgen receptor binding, beta-catenin binding, glucocorticoid receptor binding, and it is also a regulator of glutamate metabolism, a well-known pathway in Leukemic Stem Cells. Conclusions: APL relapse is a very rare entity, and it is announced to become rarer with the advances in first line therapy. Molecular characteristics are hard to analyze without an effort to collect and bank samples together from multiple institutions. Since relapses, especially relapses out of follow-up period, represent a sudden life-treating condition for patients, to predict patients at higher risk of relapse we selected two candidate genes that could be involved in pathways favoring relapse. By the analysis of ROBO 1-2 and GRIP1 at the diagnosis of APL we could establish a different and strict follow-up program for patients with these alterations. Acknowledgement: ELN,AIL,AIRC,prog. Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project,HARMONY.
Overexpression of satellite alpha transcript in breast cancer patients to impair specific chromosomes.
Authors: Ichida Kosuke , Suzuki Koichi , Kakizawa Nao , Fukui Taro , Takayama Yuji , Watanabe Fumiaki , Kato Takaharu , Saito Masaaki , Futsuhara Kazushige , Rikiyama Toshiki
Published: September 2018

e23216

Background: Impairment of stability in chromosomal structure facilitates abnormal segregation of chromosomes, increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation in the centromere region of chromosomes, which is associated with heterochromatin structures. Insufficient methylation, or demethylation, results in chromosomal instability. Satellite alpha transcript (Sat-A) is non-coding RNA transcribed from satellite alpha repetitive sequences at centromere, which is overexpressed by demethylated status of centromere. We have reported that increased levels of Sat-A were observed in patients with colorectal cancer, resulting in chromosomal instability. Difference levels of demethylation were reported in breast cancer patients but their association with Sat-A expression and chromosomal instability are not well known. In this study, we determined if Sat-A was involved in the chromosomal instability of breast cancer. Methods: We constructed lentiviral vectors expressing Sat-A and control viruses, which were infected in human mammary epithelial cells. The expression levels of Sat-A were determined by qRT-PCR and copy number alterations were evaluated by array CGH. Demethylation levels of satellite alpha sequences were determined by Methylight PCR. Then, these results were verified by using clinical specimens of 45 breast cancer patients. Results: Array CGH analysis revealed that copy number alterations were frequently seen at specific chromosomes of 8q and 20q in infected cells, despite no alteration in control, which was consistent with results in the clinical specimens. Patients with high levels of Sat-A expression showed more alterations than patients with low. Regression analysis exhibited that levels of Sat-A expression were significantly collated with demethylation levels of satellite alpha sequences. Conclusions: Overexpression of Sat-A impaired stability of chromosome 8q and 20q in human mammary epithelial cells, which was also recognized in clinical specimens of breast cancer patients. Chromosomal instability induced by Sat-A is involved in the development of breast cancer.
SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors.
Authors: Baselga Jose , Cortés Javier , DeLaurentiis Michelino , Dent Susan , Diéras Véronique , Harbeck Nadia , Hsu Jerry Y. , Jin Huan , Schimmoller Frauke , Wilson Timothy R. , Im Young-Hyuck , Jacot William , Krop Ian E , Verma Sunil
Published: September 2018

TPS1119

Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.
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.
Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502).
Authors: Sinicrope Frank A. , Ou Fang-Shu , Shi Qian , Nixon Andrew B. , Mody Kabir , Levasseur Alexandra , Dueck Amylou C. , Dhanarajan Asha R. , Lieu Christopher Hanyoung , Cohen Deirdre Jill , Innocenti Federico , Behrens Robert J. , Peters Walter , Sargent Daniel J. , Sommer Nicolas , O'Reilly Eileen Mary , Meyerhardt Jeffrey
Published: September 2018

TPS3630

Background: In metastatic colorectal cancer with deficient DNA mismatch repair (MMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for proficient MMR tumors (Le, M, et al, NEJM 2016). We propose a phase III randomized trial to determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech™), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR or microsatellite instability (MSI). By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that may serve as ‘immune priming.’ Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR or MSI will be randomized to modified FOLFOX6 for 6 months (12 cycles) alone or combined with atezolizumab (840 mg IV q2 wk) continued as monotherapy for an additional 6 months (total duration of 12 months). Patients will be stratified by T, N stage and tumor sidedness. Local testing for MSI or MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. The targeted accrual goal of 700 patients provides 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. This study will be conducted by the Alliance for Clinical Trials in Oncology. The protocol has been approved by NCI CTEP and is expected to be activated in mid 2017. Clinical trial information: NCT02912559.
CheckMate 577: A randomized, double-blind, phase 3 study of adjuvant nivolumab (nivo) or placebo in pts with resected esophageal (E) or gastroesophageal junction (GEJ) cancer.
Authors: Kelly Ronan Joseph , Lockhart Albert C. , Jonker Derek J. , Melichar Bohuslav , Andre Thierry , Chau Ian , Clarke Stephen John , Cleary James M. , Doki Yuichiro , Franke Fabio A. , Kitagawa Yuko , Mariette Christophe , Montenegro Paola Catherine , Mendez Guillermo Ariel , Ciprotti Marika , Moehler Markus H.
Published: September 2018

TPS4131

Background: Expression of the PD-1 ligands PD-L1 and PD-L2 has been reported in ≈ 40% of pts with E/GEJ cancer and is associated with a poor prognosis. In a phase 3 trial, the PD-1 inhibitor nivo demonstrated an OS benefit vs placebo (HR, 0.63; P < 0.0001), resulting in a 37% reduction in the risk of death and double the OS rate at 12 mo (27% vs 11%) in pts with advanced gastric (G)/GEJ cancer refractory to ≥ 2 lines of chemotherapy (Kang YK, et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). In this study, nivo was well tolerated, with a safety profile comparable with that of the placebo arm. These results indicate that nivo could be a new standard of care (SOC) for pts with heavily pretreated advanced G/GEJ cancer and provide a strong rationale to explore nivo in earlier lines of treatment for G/E/GEJ cancer. Currently, no effective adjuvant SOC is available after chemoradiotherapy (CRT) followed by resection for pts with E/GEJ cancer. This multinational, double-blind, phase 3 trial will evaluate nivo as an adjuvant therapy for pts with resected E/GEJ cancer (CheckMate 577; NCT02743494). Methods: In this study, an estimated 760 pts aged ≥ 18 years with stage II/III E/GEJ cancer are randomized to receive nivo or placebo. Prior to randomization, pts must have completed preoperative CRT followed by surgery and been diagnosed with residual pathologic disease after being surgically rendered free of disease with negative margins following complete resection. Pts with stage 4 resectable disease, cervical esophageal cancer, or those who have not received concurrent CRT prior to surgery are not eligible for study enrollment. Primary endpoints are OS and disease-free survival. Other key endpoints include the OS rate at 1, 2, and 3 years and safety. Clinical trial information: NCT02743494.
FRACTION (Fast Real-time Assessment of Combination Therapies in Immuno-Oncology)-gastric cancer (GC): A randomized, open-label, adaptive, phase 2 study of nivolumab in combination with other immuno-oncology (IO) agents in patients with advanced GC.
Authors: Aanur Praveen , Gutierrez Martin , Kelly Ronan Joseph , Ajani Jaffer A. , Ku Geoffrey Yuyat , Denlinger Crystal Shereen , George Thomas J. , Wind-Rotolo Megan , Guan Xiaowei , Gupta Manish , Reilly Timothy P. , Fracasso Paula M.
Published: September 2018

TPS4137

Background: Nivolumab, a fully human IgG4 mAb that targets programmed death-1, alone and in combination with ipilimumab, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte antigen 4, has demonstrated encouraging clinical activity in patients with advanced GC. These data support the rationale that nivolumab in combination with other IO agents or targeted therapies may improve treatment outcomes in patients with advanced GC. Given the rapid development of novel IO agents, traditional studies cannot efficiently evaluate all possible IO-IO and IO-targeted therapy combinations. FRACTION is an innovative clinical trial program with a rolling, adaptive platform design that allows for the addition of new combination regimens, as well as withdrawal of ineffective regimens. Here we describe the study concept, key design components, and the first IO treatment combinations of FRACTION-GC, a phase 2, randomized, open-label, adaptive study in advanced GC (NCT02935634). Methods: Patients with advanced GC or gastroesophageal junction (GEJ) cancer will be enrolled based on prior IO treatment and randomized to receive nivolumab plus BMS-986016 (fully human IgG4 mAb that targets lymphocyte activation gene 3) or nivolumab plus ipilimumab. Enrollment is continuous and may offer patients consecutive treatment options based on their treatment exposure and response. The primary endpoints are objective response rate, duration of response, and progression-free survival rate at 24 weeks. The secondary endpoint is safety. Comprehensive biomarker analyses will also be performed. New treatment combinations will be added over time to explore their potential benefits and to provide a continuous flow of treatment options for patients whose cancer progresses on existing treatments. In this way, FRACTION-GC is envisioned to accelerate the development of the next generation of IO combinations for patients with metastatic GC and GEJ cancer. Clinical trial information: NCT02935634.
A prospective, randomized, double-blinded, placebo-controlled, phase III study to evaluate the efficacy and safety of apatinib plus best supportive care (BSC) compared to placebo plus BSC in patients with advanced or metastatic gastric cancer: The ANGEL study.
Authors: Kang Yoon-Koo , Boku Narikazu , Kang Won Ki , Yoon Harry H. , Cascinu Stefano , Al-Batran Salah-Eddin , Houston Scott , Park Cheol Hee , McGinn Arlo N. , Chau Ian
Published: September 2018

TPS4138

Background: Apatinib is an orally administered, highly selective tyrosine kinase inhibitor of VEGFR-2 that has been studied in many clinical trials, primarily in China, treating various solid tumors. Based on the results of the Chinese Phase 3 study, apatinib was approved in China for the treatment of advanced gastric cancer (GC), but apatinib has yet to be evaluated in a randomized placebo-controlled study in the rest of the world. ANGEL is a multinational, placebo controlled, Phase 3 study investigating the efficacy and safety of apatinib in advanced GC patients in North America, Europe, and Asia Pacific. Methods: Main eligibility criteria include patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction for whom at least 2 prior lines of standard chemotherapy had failed, ECOG performance status ≤ 1, and disease progression < 6 months after last chemotherapy treatment. Approximately 459 patients will be randomized in a 2:1 ratio to receive continuous 28-day cycles of apatinib 700 mg or a matched placebo daily with best supportive care until disease progression, intolerable toxicity or withdrawal of consent. Stratification factors include geographic region (Asia vs. North America/Europe), disease measurability, prior ramucirumab treatment, and treatment therapy line (3rd or 4th). Primary endpoint is overall survival (OS) in the intent-to-treat population, and secondary endpoints are progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. The primary analysis of OS will be conducted in intention-to-treat population using a stratified log-rank test at the two-sided alpha = 0.05 level of significance. If the primary analysis of OS is statistically significant, then PFS and ORR will be analyzed. All other secondary efficacy endpoints will be analyzed using two-sided tests at the alpha = 0.05 level of significance. Enrollment opened Feb 2017. Clinical trial information: NCT03042611.
ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation.
Authors: Lowery Maeve Aine , Abou-Alfa Ghassan K. , Valle Juan W. , Kelley Robin Kate , Goyal Lipika , Shroff Rachna T. , Javle Milind M. , Borad Mitesh J. , Cleary James M. , El-Khoueiry Anthony B. , Bendell Johanna C. , Macarulla Teresa , Vogel Arndt , Korth Christopher , Jiang Liewen , Gliser Camelia , Wu Bin , Agresta Samuel V. , Pandya Shuchi Sumant , Zhu Andrew X.
Published: September 2018

TPS4142

Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.