bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of mechano-microenvironment of acral melanoma and its potential impact on tumor cell invasion.
Authors: Yi Xin , Liu Jia yong , Dai Jie , Guo Jun , Wu Cong ying , Si Lu , Mao Lili , Qi Zhong Hui
Published: May 2019

e21062

Background: Acral melanoma is the main subtype in Asia, and tends to be insensitive to conventional and novel therapies compared with cutaneous melanomas. It has been proved that biomechanical alterations inside the tumor microenvironment significantly affect tumor progression in breast, pancreatic and other cancers(Hepatology. 2016 July ; 64(1): 261–275; Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXXI) . Hence, we hypothesized that the biomechanical microenvironment plays critical roles in proliferation and invasion in acral melanoma. In this study, the main purpose is to observe whether melanoma cells have the same ability called “durotaxis” as other tumors, which to respond to a gradient of extracellular stiffness and migrate in a directed fashion. Methods: In this study, the stiffness was compared between the acral melanoma tissue and the normal tissue by using the atomic force microscope (AFM) with fresh samples and the freezing microtome sectioning specimen (J. Matthew Barnes et al., Nature Cell Biology 2018.) . A stiffness gradient polyacrylamide hydrogel system was constructed to observe how the acral melanoma cells response. Using automated tracking (Curr Protoc Cell Biol. ; 76: 12.12.1–12.12.16.) of positional data for large sample size of single migrating cells to systematically analyze polarized melanoma cell migration in response to stiffness gradient. Results: The results showed that 1) all the acral melanoma cell lines tested displayed strong anti-durotactic migratory response, which was in accordance with the AFM measurement that the melanoma microenvironment gradually softened; 2) Acral melanoma cells tend to move toward softer areas on gradient gels, which is contrary to the migration behavior of most other tumor cells. Conclusions: In this study, we presented the different migratory pattern of acral melanoma cells. It may illustrate the invasion mechanism for aral melanoma cells. It could also herald that extracellular matrix may be a potential therapeutic target in acral melanomas.
Genetic relationship between pilar cysts, pilar tumors and pilar carcinomas.
Authors: Hagen Rachael , Kolodney Joanna Amy , Patterson Jessica , Kolodney Michael
Published: May 2019

e21063

Background: Pilar cysts, also known as trichilemmal cysts, are common cutaneous nodules that occur sporadically or an autosomal dominant inheritance pattern. A pilar cyst can transform into a proliferating pilar tumor (PPT) or pilar carcinoma. This study aimed to determine the genetic relationships between the malignant variants and the precursor pilar cysts. Methods: We performed whole exome (WES) and Sanger sequencing of pilar cysts and matched blood (or other non-lesional tissue representing systemic DNA) from 17 subjects with multiple familial pilar cysts and 15 with a single, apparently sporadic, pilar cyst. We then performed WES on four subjects with PPTs, one with matched blood, and one subject with a pilar carcinoma matched with blood. Results: We identified a c.2234G > A somatic mutation in phospholipase C delta 1 ( PLCD1), a tumor suppressor gene, in all 21 familial pilar cysts sequenced. In addition, 16 of the 17 subjects with familial pilar cysts were hemizygous for a c.1379G > A germline variant in PLCD1. By contrast, neither of these two mutations were found in subjects with PPTs or the subject with a pilar carcinoma. A potential loss-of-function somatic mutation of the tumor suppressor gene p53 was identified in the subject with a pilar carcinoma. Conclusions: Our results indicate that hereditary pilar cysts are an autosomal dominant tumor syndrome resulting from two hits to the PLCD1 tumor suppressor gene. However, these somatic PLCD1 mutations were not present in the four PPTs or the pilar carcinoma. This suggests that the more aggressive cyst variants originate from sporadic pilar cysts. In addition, our results are consistent with loss of p53 being a key event that causes pilar cysts to evolve into carcinomas as previously proposed.
A phase III, multicenter, randomized, open label trial of [fam-] trastuzumab deruxtecan (DS-8201a) versus investigator’s choice in HER2-low breast cancer.
Authors: Modi Shanu , Ohtani Shoichiro , Lee Caleb C. , Wang Kongming , Saxena Kapil , Cameron David A.
Published: May 2019

TPS1102

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have greatly improved survival in HER2+ breast cancer (BC). However, there are many more BC patients with HER2-low expression (immunohistochemistry [IHC] 1+ or 2+/ in situ hybridization-negative), for whom no HER2-targeted therapies are approved. [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a humanized HER2 antibody, peptide-based cleavable linker, and a topoisomerase I inhibitor payload. It has a drug-to-antibody ratio of ~8 and the membrane permeability of the cleaved payload enables a cytotoxic bystander effect. In an ongoing phase 1 trial, T-DXd demonstrated an objective response rate (ORR) of 44.2% (19/43) with a manageable safety profile in heavily pretreated, advanced HER2-low BC (Oct 2018 data cutoff; Modi et al, SABCS 2018). Methods: DESTINY-Breast04 is a randomized, phase 3, 2-arm, open-label, multicenter study comparing efficacy and safety of T-DXd vs physician’s choice in HER2-low, unresectable and/or metastatic BC. Approximately 540 subjects will be randomized 2:1 to T-DXd (5.4 mg/kg intravenous every 3 weeks) or physician’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). Randomization is stratified by HER2 IHC status, number of prior treatments, and prior CDK4/6 inhibitor therapy/hormone receptor (HR) status. HER2 IHC will be assessed and confirmed by central testing based on archival samples. The primary efficacy endpoint is progression-free survival (PFS) per mRECIST v1.1 determined by blinded independent central review. Secondary efficacy endpoints are investigator-assessed PFS, overall survival, confirmed ORR, and duration of response. Safety endpoints include serious adverse events (AEs), treatment-emergent AEs, and AEs of special interest (interstitial lung disease/pneumonitis, cardiotoxicity, and infusion-related reactions). Primary PFS analysis will occur when 318 events are observed in HR+ subjects; providing 90% power to detect a hazard ratio of 0.68 with 1-sided α of 0.025. Enrollment began in Dec 2018. Clinical trial information: NCT03734029.
XENERA-1: A phase II trial of xentuzumab (Xe) in combination with everolimus (Ev) and exemestane (Ex) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and non-visceral involvement.
Authors: Schmid Peter , Rugo Hope S. , Cortes Javier , Huang Chin-Lun , Crossley Kate , Massey Dan , Burris Howard A.
Published: May 2019

TPS1103

Background: The mTOR inhibitor Ev, combined with Ex, is a mainstay in the treatment of post-menopausal women with advanced HR+/HER2- BC. However, the activity of Ev is limited by counter-regulatory feedback mechanisms in cancer cells, involving reactivation of insulin-like growth factor (IGF)/mTOR survival signaling. Combining Ev with the humanized IGF-1 and IGF-2 ligand-blocking antibody Xe abrogates this feedback, thus intensifying inhibition of tumor growth; this leads to a pronounced effect in patients with non-visceral (e.g., bone and lymph node) metastases. The phase II XENERA-1 trial evaluates the combination of Xe with Ev and Ex in post-menopausal women with HR+/HER2- BC. Methods: XENERA-1 (NCT03659136) is a double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Xe in combination with Ev and Ex, in post-menopausal women with HR+/HER2- locally advanced/mBC and non-visceral disease. The population comprises post-menopausal mBC patients who have progressed on ≤1 previous line of a non-steroidal aromatase inhibitor, with or without a CDK 4/6 inhibitor, who may have received fulvestrant. Other inclusion criteria are: an Eastern Cooperative Oncology Group Performance Status of 0 or 1; adequate organ function; and non-visceral disease (absence of brain, liver, lung, peritoneal or pleural metastases). Patients are randomized (1:1) to receive Xe (1000 mg/week, iv) or placebo (weekly, iv), in combination with Ev (10 mg/day) and Ex (25 mg/day). Treatment will continue until disease progression, unacceptable toxicity or other reasons. The primary endpoint is progression-free survival according to RECIST 1.1 criteria, by independent review. Secondary endpoints are: overall survival; disease control; duration of disease control; objective response; and time to progression of pain/intensification of palliation. Safety and pharmacokinetic endpoints, and exploratory biomarkers will also be evaluated. The first patient was enrolled in January 2019; target enrollment is 80 patients in 12 countries. Clinical trial information: NCT03659136.
CONTESSA: A multinational, multicenter, randomized, phase III registration study of tesetaxel plus a reduced dose of capecitabine in patients (pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (LA/MBC) who have previously received a taxane.
Authors: O'Shaughnessy Joyce , Piccart Martine , Schwartzberg Lee S. , Cortes Javier , Harbeck Nadia , Im Seock-Ah , Rugo Hope S. , Untch Michael , Yardley Denise A. , Bondarenko Igor , Chan Stephen , Dieras Veronique , Pegram Mark D. , Kroll Stew , O'Connell Joseph P. , Vacirca Jeff , Wei Thomas , Tang Kevin , Seidman Andrew David
Published: May 2019

TPS1107

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.
SGNLVA-002: Single-arm, open label phase Ib/II study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer.
Authors: Han Hyo S. , Alemany Carlos A. , Brown-Glaberman Ursa Abigail , Pluard Timothy J. , Sinha Rajni , Sterrenberg Danielle , Albain Kathy S. , Basho Reva K. , Biggs David , Boni Valentina , Diab Sami , Tsai Michaela L. , Tkaczuk Katherine Hanna , Wang Yinghui , Wang Zejing , Meisel Jane Lowe
Published: May 2019

TPS1110

Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.
Nimbus: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer.
Authors: Barroso-Sousa Romualdo , Trippa Lorenzo , Lange Paulina , Andrews Chelsea , McArthur Heather L. , Haley Barbara B. , Rugo Hope S. , Emens Leisha A. , Winer Eric P. , Mittendorf Elizabeth A. , Tolaney Sara M.
Published: May 2019

TPS1115

Background: A previous study from our group showed that approximately 9% of metastatic breast cancer (MBC) is hypermutated, defined as a tumor mutational burden (TMB) ≥10 Mutations/Megabase (Mut/Mb). The aim of this study is to evaluate if patients with hypermutated HER2-negative MBC benefit from the combination of nivolumab plus ipilimumab. Methods: This is an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of nivolumab 3 mg/Kg intravenously (IV) every 14 days plus Ipilimumab 1 mg/Kg IV every 6 weeks in subjects with hypermutated metastatic HER2-negative breast cancer. Patients with measurable HER2-negative MBC, TMB ≥10 Mut/Mb assessed by a cancer-gene panel evaluating > 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting are eligible. The primary objective is overall response rate according to RECIST 1.1. Secondary objectives include the safety and tolerability of the combination, progression-free survival, and overall survival. The study will follow a two-stage design. In the first stage 14 patients will be enrolled. If there is at least one patient with objective response, accrual will continue to the second stage where an additional 16 patients will be enrolled. If there are at least 4 patients with an objective response among the 30 patients, the regimen will be considered worthy of further study. If the true response rate is 5%, the chance the regimen is declared worthy of further study is less than 5%. If the true response rate is 25%, the chance that the regimen is declared worthy of further study is > 90%. Tumor biopsies, peripheral blood, and stool collection are mandatory and will be obtained at baseline, on treatment (end of cycle 1), and at disease progression and will be assessed for potential biomarkers of treatment response. The trial was activated in February 2019, and accrual should be completed in 18 months. Clinical trial information: NCT03789110.
A phase II study of PD-1 inhibition for the prevention of colon adenomas in patients with Lynch syndrome and a history of partial colectomy.
Authors: Jeter Joanne M. , Hampel Heather , Stanich Peter , Pearlman Rachel , Hinton Alice , Hays John L. , Goldberg Richard M.
Published: May 2019

TPS1587

Background: Colon cancers and adenomas that are associated with Lynch syndrome (LS) often display microsatellite instability (MSI), a characteristic that is associated with increased response to treatment with PD-1 inhibitors. Because LS patients with a history of colon cancer are at increased risk of having a second primary colon cancer or high-risk adenoma, preventive measures are of particular interest in this population. We hypothesize that a maintenance schedule of nivolumab can be safely administered to LS patients with a history of treated colon cancer with remaining colon at risk in order to decrease the incidence of adenomas, advanced adenomas and second primary colon cancers. Methods: OSU 17198 is a phase II multi-center, single-arm study of nivolumab in patients with germline MLH1 or MSH2 mutations and a history of hemicolectomy for colon cancer at least one year prior to study entry. Subjects must have completed any adjuvant therapy at least 6 months prior to study participation and may not have received prior therapy with a PD-1 inhibitor. Nivolumab is given at 240mg IV every 3 months for two years, and colonoscopies will be performed prior to study entry, after the fourth dose, after the eighth dose, and one year after the eighth dose. Subjects will be monitored for auto-immune adverse effects. The primary endpoint is incidence of adenomas at three years, and secondary endpoints are safety, incidence of advanced adenomas, and incidence of colon and non-colon cancers at three years. Approximately 104 subjects will be enrolled to obtain 94 evaluable subjects. This study is currently open for enrollment at the Ohio State University and at various stages of activation at seven additional sites in the United States. Enrollment of this study is anticipated to be completed in 2020, and data collection is anticipated to be complete in 2023. This study has undergone safety review by the FDA and the Ohio State University Institutional Review Board. Clinical trial information: NCT03631641.
Oral DNA vaccination targeting VEGFR-2 combined with anti-PD-L1 avelumab in patients with progressive glioblastoma, a phase I/II study: NCT03750071.
Authors: Wick Wolfgang , Wick Antje , Platten Michael , Chinot Olivier L. , Van Den Bent Martin J. , Dhermain Frederic , Mansour Marc , Podola Lilli , Lubenau Heinz
Published: May 2019

TPS2076

Background: The vaccine (VXM01) is a VEGFR-2 coding DNA vaccine, using a Salmonella Ty21a carrier for oral application. VEGFR-2 is over-expressed in glioblastoma and serves as a promising target for VEGFR-2 primed T cells with the potential to alter tumor angiogenesis and/or eliminate VEGFR-2 expressing tumor cells. VXM01 was well tolerated in a previous phase I/II study involving 14 patients with progressive glioblastoma multiforme. Immunological correlates of vaccination and anti-tumor immunity in the blood and in the tumor were detected. At least one objective clinical response was attributed to vaccine monotherapy, with one more PR achieved in combination with nivolumab. Prolonged overall survival was associated with peripheral immune responses against VEGFR-2, J Clin Oncol 36, 2018 (suppl; abstr 2017). A combination study with the anti PD-L1 checkpoint inhibitor monoclonal antibody avelumab is currently underway. Methods: A multicentre, open-label phase I/II study ( EudraCT.gov no. 2017-003076-31), will enrol 30 patients with progressive glioblastoma, previously treated with temozolomide/radiotherapy. The primary objective is to evaluate safety and tolerability of the vaccine in combination with avelumab. In a 1+2 safety run in, two cohorts of non-reoperable patients will be vaccinated with one of 2 doses of the oral vaccine (106 or 107 CFU) with concurrent intravenous avelumab. After safety evaluation and recommendation of study continuation by the Data Safety Monitoring Board, 18 non-re-operable and 6 re-operable patients will be treated with 107 CFU of the vaccine + avelumab. Vaccinations for all patients will be on day 1, 3, 5, and 7, followed by 4-weekly boosts until progression. Avelumab 800 mg will be administered every two weeks until progression. The enrolment of cohort 1 started with inclusion of the 1st patient in November 2018. The end of study is week 60. Follow up visits will be on months 1, 3, 6, 12 and 24. Objective response rate (ORR), clinical response using iRano criteria, immunological correlates before and after treatment using ELISpot, FACS, TCR-sequencing, IF, and IHC laboratory methods. Clinical trial information: NCT03750071.
A first-in-human study of KY1044, a fully human anti-ICOS IgG1 antibody as monotherapy and in combination with atezolizumab in patients with selected advanced malignancies.
Authors: Quaratino Sonia , Sainson Richard , Thotakura Anil , Henderson Simon J , Pryke Kerstin , Newton Anthea , Brennan Nuala , Oelmann Elisabeth
Published: May 2019

TPS2644

Background: The Inducible T-cell costimulator (ICOS/CD278) is related to the CD28 superfamily and is induced upon T cell activation. There is a hierarchical order of ICOS expression level, in which highly immunosuppressive TReg (CD4+Foxp3+) present in the tumor microenvironment (TME) are at the top level of expression and CD8 TEff cells are at the bottom level. In addition, ICOS expression on TRegs is higher in the TME than in the blood or spleen. Methods: KY1044, a fully human anti-ICOS IgG1 kappa monoclonal antibody, selectively binds to ICOS with high affinity (which is maintained at intratumoral acidic pH) and has a dual mechanism of action: it promotes the preferential depletion of intratumoral ICOSHigh TRegs resulting in an increase in the TEff:TReg ratio in the TME; and it stimulates ICOSLow TEff cells. Preclinical data demonstrate that KY1044 monotherapy or in combination with anti-PD-L1 is associated with immune cell activation and anti-tumor response. In order to validate the dual mechanism of action in vivo, studies in mice and cynomolgus monkeys were conducted. Firstly, KY1044 injected i.v. at doses up to 100 mg/kg weekly were well tolerated in non-human primates. In addition, pharmacodynamic studies in mice and cynomolgus monkey confirm preferential depletion of ICOSHigh cells. KY1044-CT01 is an open-labelled first in human Phase I/II study assessing the safety, tolerability, PK, PD and anti-tumor activity of KY1044 administered every 3 weeks (Q3W) as an i.v. single agent infusion and in combination with atezolizumab (1200 mg, Q3W IV) in adult patients with advanced/metastatic malignancies. The primary endpoint of the Phase I dose escalations, designed as sequential but overlapping arms of KY1044 monotherapy and combination with atezolizumab, is safety and tolerability. Secondary endpoints are the characterization of pharmacokinetic, pharmacodynamic and efficacy profiles in all patients. In the Phase II part, the primary endpoint is overall response rate (ORR), and the measure of clinical efficacy will be confirmed as per RECIST 1.1. and immune-related (ir)RECIST. An intensive biomarker plan is integral to the study design to underpin the phenotypic and molecular changes in both peripheral blood and tumor. Clinical trial information: NCT03829501.
Phase 1 with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
Authors: Morelli Maria Pia , David Justin M. , Houston Nicole D. , Lipkowitz Stan , Lee Jung-min , Zimmer Alexandra Dos Santos , Zia Farah Z. , Ekwede Irene , Nichols Erin , Pavelova Mira , Trupp Rebecca , Hewitt Stephen M. , Fantini Massimo , Arlen Philip M. , Tsang Kwong Y. , Annunziata Christina M.
Published: May 2019

TPS2645

Background: NEO-201 is a novel humanized IgG1 monoclonal antibody (mAb) generated against the Hollinshead allogenic colorectal cancer vaccine platform. Briefly, tumor-associated antigens (TAA) derived from tumor membrane fractions pooled from colorectal cancer surgical specimens were screened for delayed-type hypersensitivity and evaluated in clinical trials. The original vaccine was used to generate monoclonal antibodies, one of which is NEO-201. In preclinical data generated in our laboratory, we have demonstrated that NEO-201 exert anti-tumor activity by natural killer (NK)-mediated antibody-dependent cytotoxicity (ADCC) against several tumor type including colorectal and pancreatic cancer models (Fantini, et al. 2018). We have identified NEO-201 antigen as a glycosylated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue (David, et al. 2018). This could result in a specific anti-tumor activity without significant normal tissue toxicity. Nevertheless, toxicity was further assessed in non-human primates and transient neutropenia was the only adverse event observed. Based on this data we designed a first in human phase I trial to evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized monoclonal antibody NEO-201. Methods: This is a first-in-human phase 1 study with expansion cohort to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood pof expression NEO201 antigen and have progressed to standard of treatments and have a PS0-2 ECOG. Study design is a classic Fibonacci (3+3) dose escalation, with a cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and four different dose levels will be explored (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). No intra-patient dose escalation is allowed. Patients will be evaluated for safety every two weeks, with weekly laboratory testing, according to CTCAEv4.0. and with a DLT window of 28 days (cycle 1). Response will be assessed every 8 weeks (2 cycles of treatment) according to RECISTv1.1. Additionally, biological samples will be collected to understand NEO-201 pharmacokinetic, the effect on the immune process and their correlation with treatment toxicity and response. As of February 2019 we have completed enrollment in the first DL and are evaluating for DLT. Clinical trial information: NCT03476681.
A phase I/Ib multicenter study to evaluate the humanized anti-CD73 antibody, CPI-006, as a single agent, in combination with CPI-444, and in combination with pembrolizumab in adult patients with advanced cancers.
Authors: Mobasher Mehrdad , Miller Richard A. , Kwei Long , Strahs Deborah , Das Vaijayanti , Luciano Gabriel , Powderly John D. , Merchan Jaime R. , Barve Minal A. , LoRusso Patricia , Tripathi Abhishek , Luke Jason J.
Published: May 2019

TPS2646

Background: CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. CPI-006 is a humanized IgG1 FcγR binding-deficient anti-CD73 antibody now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA) or combination with CPI-444, an oral, small molecule, selective A2aR antagonist or in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods: Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients must have: non-small cell lung, renal cell carcinoma, urothelial bladder, cervical, colorectal, ovarian, pancreatic, prostate, head and neck, triple-negative breast, endometrial, select sarcomas and non-Hodgkin lymphoma malignancies relapsed, refractory or intolerant to 1 to 5 standard therapies; aged ≥ 18 yo; adequate organ function and measurable disease. The objectives of the study are 1) evaluate the safety and tolerability of SA CPI-006, in combination with CPI-444 and in combination with pembrolizumab, 2) evaluate the pharmacokinetics of each regimen and 3) identify potential biomarker signals predictive of response. Study design in table. Study Design. Clinical trial information: NCT03454451. [Table: see text]
Intravenous administration of ALKS 4230 as monotherapy and in combination with pembrolizumab in a phase I study of patients with advanced solid tumors.
Authors: Vaishampayan Ulka N. , Fishman Mayer N. , Cho Daniel C. , Hoimes Christopher J. , Velcheti Vamsidhar , McDermott David F. , Slichenmyer William J. , Putiri Emily , Losey Heather , Rossi Sean , Ernstoff Marc S.
Published: May 2019

TPS2649

Background: ALKS 4230 is a fusion protein of circularly permuted IL-2 and IL-2 Receptor (IL-2R) α designed to selectively bind the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γc, for activation of CD8+ T cells and NK cells, which drive antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of immunosuppressive CD4+ regulatory T cells (Tregs) at concentrations below those that activate iaIL-2R expressing cells. Binding of IL-2 to haIL-2R on endothelial cells may contribute to capillary leak syndrome seen with high-dose IL-2. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to enhance tumor killing and improve tolerability. ALKS 4230 has previously been shown to improve antitumor activity relative to IL-2 in murine models. In this clinical study, ALKS 4230 will be assessed as monotherapy and in combination with anti-PD-1 therapy. Methods: ALKS 4230 is being studied in adults with advanced solid tumors in a phase I first-in-human trial designed primarily to assess the safety of ALKS 4230 alone and with pembrolizumab. The study will also determine a monotherapy recommended phase 2 dose (RP2D) and characterize pharmacokinetics, pharmacodynamics (PD), immunogenicity, and evidence of anti-tumor activity. It will be conducted in 3 parts: monotherapy dose escalation (Part A), monotherapy dose expansion at the RP2D (Part B), and combination therapy with pembrolizumab (Part C). ALKS 4230 is administered as a 30 minute IV infusion once daily for five days in each 14 or 21 day cycle. Part A is inpatient. Eligibility requires ECOG PS 0-1 and adequate bone marrow, liver and kidney function. Part B will enroll 21 patients each in renal cell carcinoma and melanoma cohorts. Part C will enroll up to 79 patients total into 3 cohorts based on tumor type and prior anti-PD-1 therapy; a 4th cohort will enroll patients from Part A or B who received at least 4 cycles of ALKS 4230 or experienced disease progression on monotherapy. The primary PD endpoint is change from baseline in CD8+ T, NK, and Treg cell counts. Inflammatory cytokine levels will also be measured. Parts A and C are currently enrolling. Clinical trial information: NCT02799095.
A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy.
Authors: Yap Timothy A , Papadopoulos Kyriakos P. , LoRusso Patricia , Wong Deborah J.L. , Hu-Lieskovan Siwen , Holz Josefin-Beate ,   FS118-17101 Study Team
Published: May 2019

TPS2652

Background:PD-1/PD-L1 checkpoint inhibitors demonstrated remarkable anti-tumor activity, but only a minority of patients achieve full clinical benefit with deep and durable responses. Translational studies suggest resistance to cancer immunotherapy can be mediated by additional immune checkpoints e.g. lymphocyte-activation gene 3 (LAG-3). The combination of LAG-3 and PD-1 mAbs synergistically improved anti-tumor response in murine models and early clinical trials. In a small cohort, TIL LAG-3 expression enriched for responsiveness in PD-1/PD-L1 relapsed/refractory patients. FS118 is a novel bispecific antibody incorporating a LAG-3 binding Fc-region into a PD-L1-specific IgG1 antibody to potentially deliver superior anti-tumor efficacy while limiting immunotherapy-related adverse effects by dual targeting. Methods: The FiH study (NCT03440437) is being conducted in adult patients with solid tumors who failed prior PD-1/PD-L1 treatment. Primary objectives of the study are to determine safety, PK and the maximum tolerated/recommended Phase 2 dose of FS118. Secondary objectives include preliminary evidence of efficacy, immunogenicity, PD profile and exposure/response correlation. 50 subjects from four study sites in the USA are planned to enrol in dose escalation initiated with accelerated titration (5 single subject cohorts) followed by 3+3 design and expansion cohorts. FS118 is administered weekly IV in 21-day treatment cycles until progression, unacceptable toxicity, withdrawal, or death. Patients are followed for safety, overall survival and initiation of subsequent therapy. DLT clearance, dose escalation and cohort expansion (to further characterise safety, PK/PD or clinical efficacy) are supervised by a safety review committee (SRC). Translational studies assess PD-L1/LAG-3 receptor occupancy, soluble PD-L1/LAG-3 levels and the correlation of FS118 exposure with selected PD markers of target engagement and response. Translational endpoints include TIL analysis, transcriptomic profiles and target expression analyses on tumor tissues. Cohorts 1 through 6 have been completed, enrollment in cohort 7 began December 2018. Clinical trial information: NCT03440437.
A first-in-human, multicenter, open label, phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of intravenously administered ATOR-1015.
Authors: Yachnin Jeffrey , Ullenhag Gustav J , Carneiro Ana , Nielsen Dorte , Rohrberg Kristoffer Staal , Kvarnhammar Anne Månsson , Dahlman Anna , Bågeman Erika , Wennersten Camilla , Russell Charlotte Astrid
Published: May 2019

TPS2653

Background: ATOR-1015 is a human bispecific IgG1 antibody targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and the tumor necrosis factor receptor superfamily member 4, OX40 (also known as CD134). Both in vitro and in vivo, ATOR-1015 induces activation of cytotoxic T cells and depletion of regulatory T cells (1). In syngeneic tumor models, using human OX40 transgenic mice cross-reacting with both targets, ATOR-1015 is demonstrated to localize to the tumor. Further, the effects of ATOR-1015 are shown to occur in the tumor area and not in the spleen (1). Treatment with ATOR-1015 also reduces tumor growth and improves survival in several tumor models in mice, including bladder, colon and pancreatic cancer (1). The non-clinical safety profile and the pharmacokinetics were established in cynomolgus monkeys and the data were used for the dosing schedule. Methods: This is a multicenter, open-label, dose escalation study enrolling patients with advanced and/or refractory solid malignancies (NCT03782467). The primary objective of the study is to determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) and to establish the safety profile of ATOR-1015. ATOR-1015 is administered intravenously biweekly as a single agent until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The study will start with single patient cohorts until grade 2 toxicities are observed, thereafter the study follows a modified 3+3 design. At the MTD/RP2D, or a lower dose, up to 20 patients are planned for additional safety and efficacy evaluation. Study enrollment was initiated in January 2019. A total of up to 53 patients are estimated to be enrolled in the study. (1) Månsson Kvarnhammar et al. Journal for ImmunoTherapy of Cancer 2018; 6(Suppl 1):115. Abstract P683. Clinical trial information: NCT03782467.
A phase Ia/b study of TIM-3/PD-L1 bispecific antibody in patients with advanced solid tumors.
Authors: Hellmann Matthew David , Shimizu Toshio , Doi Toshihiko , Hodi F. Stephen , Rottey Sylvie , Aftimos Philippe Georges , Tina Liu Zhuqing , Velez de Mendizabal Nieves , Szpurka Anna M. , Piao Yongzhe , Vangerow Burkhard , Gandhi Leena , Leow Ching Ching
Published: May 2019

TPS2654

Background: Programmed cell death 1 immune checkpoint inhibitors (anti-PD-1, anti-PD-L1) have demonstrated clinical benefit in a subset of patients with manageable safety across a variety of tumor types. T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) can be co-expressed with PD-1 on exhausted T-cells and may be upregulated in tumors refractory to anti-PD-1 therapy (Koyama et al. 2016). Pre-clinical studies demonstrated that blockade of both PD-1 and TIM-3 improved survival of tumor-bearing mice compared to blocking anti-PD-1 only (Koyama et al. 2016). LY3415244 is a TIM-3/PD-L1 bispecific antibody that has the ability to target and inhibit both TIM-3 and PD-L1 and the potential to overcome primary and acquired anti-PD-(L)1 resistance by a novel mechanism to bridge TIM-3- and PD-L1-expressing cells. Methods: Study JZDA is a multicenter, nonrandomized, open-label, Phase 1a/1b study of LY3415244 in patients with advanced solid tumors. In Phase 1a, subjects with any tumor type who are either PD-(L)1 inhibitor-naïve or exposed are eligible. In Phase 1b, expansion cohorts are planned in subjects with PD-(L)1-experienced NSCLC, urothelial carcinoma, and melanoma. Patients with malignant mesothelioma are not required to have received prior anti-PD-(L)1 therapy. The primary objective is to assess safety and tolerability of LY3415244 and identify the recommended Phase 2 dose (RP2D) in Phase 1a (dose escalation). Safety and tolerability of the RP2D will be assessed in Phase 1b (dose expansion). The secondary objectives are to assess the pharmacokinetics of LY3415244 in Phase 1a/1b and assess early antitumor activity of LY3415244 in Phase 1b cohorts. Pre- and on-treatment biopsies will be obtained to explore potential biomarkers of response. During Phase 1a, dose escalation cohorts will proceed via a modified toxicity probability interval-2 (mTPI-2) design with a 1-cycle (28-day) dose-limiting toxicity (DLT) observation period. LY3415244 will be dosed intravenously every 2 weeks. Data from Phase 1a will determine the RP2D, which will be used for all cohorts in Phase 1b. The study is currently open to enrollment. Clinical trial information: NCT03752177.
A randomized, placebo-controlled, phase III trial-in-progress to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Xu Jian-Ming , Kato Ken , Hubner Richard , Raymond Eric , Xu Yihuan , Liu Sumei , Qazi Ibrahim , Yoon Harry H.
Published: May 2019

TPS2656

Background: ESCC remains the predominant histological subtype of, and accounts for most deaths from, esophageal cancer. PD-1 inhibition has demonstrated antitumor activity and was generally well tolerated in patients (pts) with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest single-agent tislelizumab was generally well tolerated and had antitumor activity in pts with solid tumors, including ESCC. Methods: This phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult pts with histologically confirmed ESCC that had metastatic disease either at first diagnosis or with a ≥6 month treatment-free interval will be eligible. Additional eligibility criteria include measurable/evaluable disease, ECOG performance score ≤1, and no prior anti-PD-(L)-1, PD-L2, or other first-line therapy or palliative radiation treatment ≤4 weeks before treatment. Approximately 480 pts will be randomized 1:1 to receive investigator-chosen chemotherapy (ICC) plus tislelizumab 200 mg IV Q3W or ICC plus placebo. Chemotherapy options include: platinum (cisplatin 60–80 mg/m2 or oxaliplatin 130 mg/m2 IV Q3W) plus 5-FU 750–800 mg/m2 IV daily for 5 days Q3W; or platinum plus capecitabine 1000 mg/m2 orally BID for 14 days Q3W; or platinum + paclitaxel 175 mg/m2 IV Q3W. Progression-free survival and overall survival are coprimary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality-of-life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.
A phase I study evaluating COM701 in patients with advanced solid tumors.
Authors: Rasco Drew W. , Vaena Daniel A. , Sullivan Ryan J. , Luke Jason J. , ElNaggar Adam , Hunter John , Adewoye Adeboye H. , Olweny Judy , Patnaik Amita , Hamilton Erika Paige
Published: May 2019

TPS2657

Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.
A phase I, first-in-human, open label, dose-escalation and cohort expansion study of MGD019, a bispecific DART protein binding PD-1 and CTLA-4 in patients with unresectable or metastatic neoplasms.
Authors: Luke Jason J. , Sharma Manish , Sanborn Rachel E. , Cote Gregory Michael , Bendell Johanna C. , Weiss Glen J. , Berezhnoy Alexey , Sharma Sharad , Moore Paul A. , Bonvini Ezio , Cali Kerri , Baughman Jan E. , Wigginton Jon M. , Sumrow Brad
Published: May 2019

TPS2661

Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.