bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy.
Authors: Pant Shubham , Mulder Imke , Shah Amishi Yogesh , Msaouel Pavlos , Altan Mehmet , Weinberg John , Stevenson Alex , Meric-Bernstam Funda , Yap Timothy A , Subbiah Vivek , Rodon Ahnert Jordi
Published: May 2019

TPS2670

Background: The gut microbiome has emerged as a new therapeutic target to augment the efficacy of immune checkpoint blockade. MRx0518 is a novel, gut microbiome-derived, oral live biotherapeutic, designed to induce a broad immunostimulatory response to re-engage PD-1 inhibitor activity. Preclinical studies showed that MRx0518 reduced tumour growth in models of kidney, lung and breast cancer. MRx0518 increased CD4 and CD8 T cell and NK cell infiltration into the tumour and decreased Tregs. Upregulation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4 and CD8 T cells. The study, one of the first oncology trials conducted with live biotherapeutics, is a single center, open label, safety and preliminary efficacy study of MRx0518 in combination with pembrolizumab in patients with solid tumors who have progressed on PD-1 inhibitors. Methods: Trial consists of 2 parts. In Part A, 12 patients receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 with a DLT period of 1 cycle (21 days). In Part B, up to 30 patients per cohort (NSCLC, Urothelial, Renal and Melanoma) will receive pembrolizumab 200 mg every 3 weeks plus 1 capsule (bid) of MRx0518 for up to 35 cycles or until disease progression per RECIST 1.1. The primary end points are safety and tolerability of MRx0518 in combination with pembrolizumab (Parts A and B) and clinical benefit of MRx0518 in combination with pembrolizumab (Part B). Secondary end points are objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory end points include biomarkers of treatment effect, effect on microbiota and overall survival. Recruitment is ongoing. Clinical trial information: NCT03637803.
An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.
Authors: Middleton Mark R. , Sacco Joseph J. , Merchan Jaime R. , Curti Brendan D. , Vanderwalde Ari M. , Olsson-Brown Anna Claire , Aroldi Francesca , Fotiadis Nicos , Baum Scott , Coffin Robert S. , Kaufman Howard , Harrington Kevin J.
Published: May 2019

TPS2671

Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.
A phase I study of [225Ac]-FPI-1434 radioimmunotherapy in patients with IGF-1R expressing solid tumors.
Authors: Juergens Rosalyn A. , Zukotynski Katherine A. , Juneau Daniel , Krnezich Lily , Simms Ryan , Forbes John , Burak Eric S. , Valliant John , Stafford Lauren , Armor Thomas , Molnar Istvan , Saad Fred
Published: May 2019

TPS3152

Background: Type I insulin-like growth factor receptor (IGF-1R) is a transmembrane protein which is overexpressed in solid tumors including non–small cell lung, prostate, and breast cancers. [225Ac]-FPI-1434 is a radioimmunoconjugate consisting of a humanized monoclonal antibody that binds to the external domain of IGF-1R, a proprietary bifunctional chelate, and an alpha-emitting radionuclide actinium-225 (Ac-225), which binds to the external domain of IGF-1R. Internalization of the conjugate and decay of Ac-225 causes tumor cell death primarily through double stranded DNA breaks. The indium-111 analog, [111In]-FPI-1547, with the identical antibody and bifunctional chelate is used for patient selection, in-vivo imaging, and quantification of IGF-1R targets prior to therapy. Based on anti-tumor activity of [225Ac]-FPI-1434 in preclinical models, favorable toxicology studies in cynomolgus monkeys, and prior human experience with the unconjugated antibody, the first in human clinical evaluation was initiated. Methods: This open-label multi-center phase I study (NCT03746431) follows a modified 3+3 dose-escalation design to characterize the safety profile, determine a maximum tolerated dose (MTD), evaluate dose-limiting toxicities (DLT), describe pharmacokinetics, derive radiation dose estimates to normal organs, and evaluate the objective response rate of [225Ac]-FPI-1434 therapy in patients with IGF-1R expressing solid tumors. Eligibility requirements for therapy include: presence of at least one measurable lesion as determined by sufficient tumor uptake using SPECT/CT of an imaging analog [111In]-FPI-1547; radiation dose estimates of the planned therapeutic activity within prespecified limits; and adequate bone marrow reserves, hepatic, and renal function. Dose cohorts begin with 10 kBq [225Ac]-FPI-1434 per kilogram (kg) patient weight and successively increase to 20, 40, 80, and 120 kBq/kg as a single intravenous injection per patient followed by an 8-week DLT evaluation period. This trial is currently enrolling patients. Clinical trial information: NCT03746431.
TiFFANY study: A multicenter phase II basket-type clinical trial to evaluate efficacy and safety of pan-FGFR inhibitor TAS-120 for advanced solid malignancies with FGFR alterations identified by circulating tumor DNA.
Authors: Jogo Tomoko , Nakamura Yoshiaki , Komatsu Yoshito , Kato Ken , Shinozaki Eiji , Bando Hideaki , Kato Takeshi , Nishina Tomohiro , Esaki Taito , Fujii Satoshi , Suzuki Mitsuko , Fuse Nozomu , Sato Akihiro , Nomura Shogo , Lefterova Martina , Odegaard Justin , Ebi Hiromichi , Yoshino Takayuki
Published: May 2019

TPS3156

Background: Approximately 7% of advanced solid malignancies have FGFR gene alterations. However, standard treatment for FGFR-altered malignancies has not been established. Moreover, circulating tumor DNA (ctDNA) analysis has a potential to accurately identify FGFR alterations by assessing spatial and temporal intratumoral heterogeneity, which have shown to be associated with a poor prognosis and resistance to anti-cancer therapy. Methods: We are conducting an investigator-initiated multicenter phase II basket-type trial to investigate efficacy and safety of TAS-120, a highly selective covalent pan-FGFR inhibitor, for the patients with advanced solid malignancies with FGFR alterations identified by ctDNA analysis as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). Eligibility criteria include histologically confirmed unresectable advanced or recurrent solid tumors regardless of histology of origin; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and clonal FGFR alterations ( FGFR1-3 gain-of-function mutations, FGFR1,2 amplifications and FGFR2,3 fusions) identified by a 73-gene sequencing ctDNA panel (Guardant360). Enrolled patients will receive TAS-120 20 mg once daily, orally, in a 21 day-cycle. The primary endpoint is to clarify objective response rate (ORR) assessed by investigators per RECIST v1.1. The secondary endpoints are to evaluate progression-free survival, duration of response, time to treatment failure, disease control rate, overall survival, ORR by central determination, and incidence of adverse events. Target sample size is determined as 26 to test the null hypothesis of ORR as 5% with one-sided alpha level of 2.5% and power of 80% to detect an expected value of ORR as 25%. Furthermore, tumor tissue and ctDNA will be serially collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. Clinical trial information: 194624.
FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.
Authors: Hyman David Michael , Goyal Lipika , Grivas Petros , Meric-Bernstam Funda , Tabernero Josep , Hu Youyou , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Anne , Zanna Claudio , Flaherty Keith
Published: May 2019

TPS3157

Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.
SGNTV-001: Open label phase 2 study of tisotumab vedotin for locally advanced or metastatic disease in solid tumors.
Authors: Hong David S. , Tehrani Omid S. , Safran Howard , Steuer Conor Ernst , Lacy Jill , Taylor Matthew H. , George Thomas J. , Rangwala Reshma A. , Jain Shweta , Viana Nicacio Leonardo , Cho May Thet
Published: May 2019

TPS3160

Background: Tisotumab vedotin (TV) is being developed for patients with cervical cancer and other solid tumors known to express Tissue Factor (TF). Expression of TF on tumor cells has been associated with poor prognosis in several tumor types. Four tumor types were chosen for this study based on unmet medical need and TF expression. TV is an antibody-drug conjugate composed of a TF-targeted fully human monoclonal immunoglobulin G1 conjugated via a protease-cleavable valine citrulline linker to the drug monomethyl auristatin E (MMAE). TV-mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). In preclinical studies, TV treatment resulted in potent and long-lasting tumor regression in TF-expressing xenograft models derived from a variety of solid cancers, including patient-derived xenograft models with heterogeneous TF expression. TV has shown preliminary evidence of activity in heavily pretreated patients with many TF-expressing tumor types in the GEN701 phase 1 study. Methods: SGNTV-001 (innovaTV 207) is a global, open label, multicenter phase 2 trial designed to assess the safety, tolerability, and activity of TV for the treatment of solid tumors. (NCT03485209; EudraCT 2017-005076-26). Patients are currently enrolling in 4 cohorts: colorectal cancer (CRC), squamous non-small cell lung cancer (NSCLC), exocrine pancreatic adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN). Patients must have measureable disease per RECIST v1.1 that has progressed despite standard of care systemic treatment in the locally advanced or metastatic setting (up to 3 prior lines for CRC, 2 for squamous NSCLC and SCCHN, and 1 for pancreatic adenocarcinoma) and have an ECOG score of 0 or 1. The primary endpoint is investigator-determined confirmed ORR as measured by RECIST v1.1. Secondary objectives include DOR, PFS, OS, DCR, and TTR, as well as safety and pharmacokinetic parameters. The first patient was enrolled in July 2018 and the study is currently enrolling across 16 sites in the US (as of January 2019) with additional sites opening in EU countries. Clinical trial information: NCT03485209.
A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer.
Authors: Schoffski Patrick , Aftimos Philippe Georges , Massard Christophe , Italiano Antoine , Jungels Christiane , Andreas Karen , Keegan Mitchell , Ho Peter T.C.
Published: May 2019

TPS3162

Background: RET gene alterations (mutations and fusions) leading to constitutive kinase activity have been identified in various tumor types including non-small cell lung cancer (NSCLC), medullary thyroid (MTC), colon, breast and ovarian cancer. The current generation of multi-kinase inhibitors approved for treatment of such tumors, do not selectively target RET and exhibit significant off-target activity especially against vascular endothelial growth factor receptor 2 (VEGFR2), resulting in dose-limiting toxicities that prevent the full inhibition of RET in those tumors. Recently, early clinical data from a class of more selective RET inhibitors have shown promising results with a more favorable safety profile in patients with RET alterations. BOS172738 is a novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2. This phase 1 study is assessing the safety and tolerability of BOS172738 in patients with advanced solid tumors with RET alterations. Methods: NCT03780517 is a phase 1, open label, multicenter, dose escalation trial to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738, an orally dosed RET kinase inhibitor, in patients with advanced solid tumors with RET gene alterations. RET gene alteration status will be assessed locally but confirmed centrally. The study is comprised of 2 parts: in Part A (dose escalation), patients with advanced solid tumors with RET gene alterations will receive BOS172738 orally once daily in each 28-day cycle. Select patients in Part A are eligible for intrapatient dose escalation. On establishing the recommended phase 2 dose (RP2D), Part B (expansion) will enroll up to an additional 60 patients to 1 of 3 tumor type-specific cohorts. The 3 expansion cohorts will each consist of up to 20 advanced cancer patients with: 1) RET gene-fusion NSCLC; 2) RET gene-mutant MTC; and 3) other RET gene-altered advanced tumors or NSCLC/MTC with prior specific RET gene-targeted therapy. Patients in expansion cohorts will receive BOS172738 daily at the RP2D until disease progression or other discontinuation criteria have been met. The study is currently open to enrollment globally with the first patient entered in 01/2019. Clinical trial information: NCT03780517.
A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.
Authors: Chong Curtis Robert , Bauer Todd Michael , Laurie Scott Andrew , Patel Manish R. , Yamamoto Noboru , Davenport Teffany , Geng Junxian , Gibson Neil , Vallaster Markus P. , LoRusso Patricia
Published: May 2019

TPS3166

Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.
A CRUK first-in-human phase I trial of a CDC7 Inhibitor, LY3143921 hydrate, in patients with advanced solid tumors.
Authors: Gallagher Peter F. , Coyle Victoria , Evans T.R. Jeffry , Plummer Elizabeth Ruth , Clive Sally , McGuigan Lesley , Roxburgh Patricia , Haris Noor Md , Symeonides Stefan N. , Naylor Gregory , Bashir Saira , Stanley Barbara , Godfrey Lisa , Elliott Moira , Halbert Gavin , Brook Sue , Dobbs Nicola , Wilson Richard H.
Published: May 2019

TPS3167

Background: CDC7 is a protein with key roles in DNA replication initiation, the intra-S-phase checkpoint and M-phase completion. CDC7 is over-expressed in malignant compared to non-malignant cells, particularly those with TP53 mutations, making it an attractive therapeutic target. LY3143921 hydrate is an orally administered ATP-competitive CDC7 inhibitor. Pre-clinical studies in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC) demonstrate favourable anti-cancer activity, particularly in squamous NSCLC and in CRC with TP53 null and missense mutations. We hypothesise that solid tumours mutated in TP53 will be sensitive to LY3143921 therapy. Methods: This is a first-in-human, phase I trial of LY3143921 hydrate (LY3143921) monotherapy given twice daily, continuously on a 21 day schedule until disease progression, patient (pt) withdrawal or unacceptable toxicity (NCT03096054). Eligible pts have histologically proven advanced/metastatic solid tumours for which no further standard therapy exists and WHO PS 0-1. Pts have regular clinical assessment and tumour imaging every 2 cycles. Phase Ia (dose escalation) is recruiting in a 3+3 design following 3 initial single patient cohorts (starting dose 30 mg OD), enriching for patients with malignancies associated with p53 mutations (CRC, sqNSCLC, high grade serous ovarian, squamous cell oesophageal, squamous cell head & neck, urothelial, pancreatic and triple negative breast cancer). Recruitment to cohort 6 (180 mg BD) is ongoing. On determination of the maximum tolerated dose (MTD) and recommended phase II dose and schedule (RP2D), 2 expansion cohorts (≤ 25 pts each) of patients with CRC and sqNSCLC will be evaluated. Primary objectives: assess safety and tolerability of LY3143921, determine MTD and RP2D. Secondary objectives: evaluate preliminary efficacy and PK profile of LY3143921. All pts will have archival tumour tissue retrospectively analysed, while patients in phase Ib will also have pre- and on-treatment tumour biopsies. Evaluation of potential predictive and pharmacodynamic biomarkers including p53 mutations, phosphorylated MCM2, cyclin B1 and molecular subgroups of target tumours will be included. Clinical trial information: NCT03096054.
POLEM: Avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III dMMR or POLE exonuclease domain mutant colon cancer—A phase III randomized study.
Authors: Lau David , Cunningham David , Gillbanks Angela , Crux Richard , Powell Rachel , Kalaitzaki Eleftheria , Annels Nicola E. , Sclafani Francesco , Gerlinger Marco , Chau Ian , Tomlinson Ian , Starling Naureen , Pandha Hardev S. , Church David N. , Dhillon Tony
Published: May 2019

TPS3615

Background: Colon cancer with deficient mismatch repair (dMMR) and POLE mutations are characterised by a high tumor mutational burden (TMB) and an immunogenic lymphocyte infiltrate. Approximately 12% of stage III colon cancer have dMMR. POLE mutations occur in 1% of colon cancers, but is enriched in patients <50 years of age. Colon cancer with high TMB have demonstrated to be sensitive to immune checkpoint inhibition in the metastatic setting. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody, avelumab following adjuvant chemotherapy can improve disease free survival (DFS) in patients with stage III colon cancer with dMMR or POLE mutations. Methods: We are recruiting patients with curatively resected, stage III colon cancer which are dMMR or have a centrally confirmed POLE exonuclease domain mutation. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (CAPOX [capecitabine, oxaliplatin] for 12 weeks or capecitabine for 24 weeks) or chemotherapy followed by avelumab (10mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life, and health resource use. Exploratory objectives will investigate circulating, tumor and stool based biomarkers of avelumab benefit. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (i.e. 87%). Target accrual is 402 patients which provides 80% power to detect a hazard ratio of 0.48 for DFS at a two–sided alpha of 0.05. This trial is a national, multi-centre phase III trial and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. Clinical trial information: NCT03827044.
Clinical verification of circulating tumor RNA (ctRNA) as novel pretreatment predictor and tool for quantitative monitoring of treatment response in metastatic colorectal cancer (mCRC): A biomarker study of the DEEPER trial.
Authors: Sunakawa Yu , Usher Joshua L. , Jaimes Yolanda S , Tsuji Akihito , Shiozawa Manabu , Watanabe Takanori , Satake Hironaga , Ota Hirofumi , Kochi Mitsugu , Ohori Hisatsugu , Manaka Dai , Matsuura Masato , Takeuchi Masahiro , Danenberg Peter V. , Fujii Masashi , Ichikawa Wataru , Lenz Heinz-Josef , DANENBERG KATHLEEN
Published: May 2019

TPS3621

Background: A randomized phase II trial, DEEPER (JACCRO CC-13) [NCT02515734], is on-going to evaluate FOLFOXIRI plus cetuximab (cet) vs. FOLFOXIRI plus bevacizumab (bev) in terms of depth of response as primary endpoint in 360 mCRC patients (pts) with RAS wild-type tumors, PS0-1, and no previous chemotherapy. This is a head-to-head comparative trial of 2 key monoclonal antibodies in mCRC treatment; therefore, it would be of interest to perform the biomarker study for developing novel predictors of cet or bev. The clinical utility of circulating tumor DNA (ctDNA) analysis has been largely validated for monitoring during treatment and companion diagnostics after chemotherapy. However, there are few published results regarding ctRNA in cancer treatment. Use of ctRNA from liquid biopsies would enhance tumor profiling through the trending of actionable biomarkers not found in ctDNA, and allow for patient monitoring by measuring dynamic changes in levels of gene expressions. Methods: This study will enroll pts with willing to undergo biopsies of both tissue and blood among participants of the DEEPER trial. The estimated number is 250. The main purpose is to find novel predictors for efficacy of cet or bev in mCRC using liquid biopsies, which are performed to obtain ctDNA and ctRNA at 6 time points: pre-treatment, 8 weeks after treatment start, beginning of maintenance phase in FOLFOXIRI-regimen, progression, before and 8 weeks after 2nd-line treatment. The tissue samples collected before chemotherapy will be used for analyzing intra-tumoral genetic alterations. Associations between analytes in blood/tissue and the clinical outcomes of each treatment (with cet or bev) will be assessed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests in univariate analyses. We will evaluate on whether transcriptomic analysis in ctRNA could predict treatment efficacy more accurately compared to genomic analysis in ctDNA, and verify the clinical utility of ctRNA testing in mCRC treatment. Accrual will continue until the DEEPER trial is completed. Clinical trial information: UMIN000018412.
Phase II trial PD-L1/PD-1 blockade avelumab with chemoradiotherapy for locally advanced resectable T3B-4/N1-2 rectal cancer: The Ave-Rec trial.
Authors: Michael Michael , Wong Rachel , Gill Sanjeev Singh , Goldstein David , Ngan Sam , Heriot Alexander Graham , Link Emma , Farrell Maria , Neeson Paul J , Ramsay Robert George , Wilson Kasmira , Mitchell Catherine , Tie Jeanne , Pavlakis Nick , Zalcberg John Raymond , Segelov Eva
Published: May 2019

TPS3622

Background: Standard neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate of 10-30%: but 20-40% of patients (pts) are non-responders, 10-15% have local recurrence. Tumoural immune infiltrates are predictive of response. Preclinical studies show that radiotherapy (RT) via interferon signaling is immuno-stimulatory, enhancing local/distant tumour cell death. RT also stimulates PDL1 production and the immunosuppressive activity of myeloid derived suppressor cells. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab post LCCRT may enhance the pathological/imaging response rates whilst potentially reducing local/distant relapse rates. Methods: (1) Trial Design: Phase II single arm trial, across 6 Australian sites (2) Endpoints: (a) Primary; Pathological response rate post-LCCRT, as documented by central pathologist, (b) Secondary; MRI/FDG PET imaging responses at 8 weeks post LCCRT (pre-surgery). Toxicity. (c) Exploratory; Tumoural immune cell subsets/checkpoint expression (by multiplex immunohistochemistry and in-vitro functional assays) and ctDNA analysis at baseline and during treatment. Distant relapse-free survival and the documentation of sites of relapse. (3) Sample size: An increase in the proportion of pathological complete responses by > 25% (from 10% to 35%) will be considered clinically important. Power = 90%, α = 0.05, 41 pts are required– an additional 4 pts to allow for drop-out. Total sample size = 45pts. Treatment: All pts to receive standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on RT days] over 5.5 weeks). Post LCCRT (prior to surgery), pts receive 4 cycles Avelumab (10mg/kg, q2 weeks). Surgical resection 10-12 weeks post LCCRT. Fresh tumour biopsy and ctDNA sampling pre LCCRT, pre Cycle 1 Avelumab and at surgery. Response by FDG PET and pelvic MRI pre surgery. Pts to be followed up for 2 years. Major Inclusion Criteria: Pts with LARC, MRI stage T3b-4/N1-2/M0, planned for LCCRT followed by curative resection, tumoural lower border within 12cm from the anal verge, measurable disease (RECIST1.1), ECOG 0-1, adequate organ function and no contraindications to Avelumab therapy. Current Enrolment: 11 of the planned 45 patients enrolled. Clinical trial information: NCT03299660.
Modified FOLFOX versus modified FOLFOX plus nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Moonlight, a randomized phase 2 trial of the German Gastric Group of the AIO.
Authors: Al-Batran Salah-Eddin , Pauligk Claudia , Goetze Thorsten Oliver , Riera-Knorrenschild Jorge , Goekkurt Eray , Angermeier Stefan , Kullmann Frank , Thuss-Patience Peter C. , Homann Nils , Ettrich Thomas Jens , Junge Sabine , Hofheinz Ralf , Lorenzen Sylvie
Published: May 2019

TPS4144

Background: The majority of patients (pts) with gastroesophageal cancer present with inoperable or metastatic disease and there is a strong need for efficient and tolerable first-line (1L) treatment. Oxaliplatin-based regimens like FOLFOX have become one standard of care. However, median survival is still below 12 months. Results from trials using nivolumab plus ipilimumab treatment of subjects with advanced/metastatic GC and GEJ cancers demonstrated clinical activity, in pts whose tumors did or did not express PD-L1; in addition, nivolumab alone and in combination with ipilimumab demonstrated clinical benefits in various other tumor types. Based on this clinical experience, the AIO-STO-0417 trial (Moonlight) has been designed to evaluate the combination of chemotherapy with two checkpoint inhibitors in first-line therapy of pts with gastroesophageal adenocarcinoma. Methods: This is a prospective, multicenter, randomized, investigator-initiated phase II trial. Pts with Her2-negative, inoperable, advanced or metastatic gastric or esophagogastric junction cancer will be randomized 1:1 to 1L treatment with FOLFOX (Oxaliplatin 85 mg/m²; Leucovorin 400 mg/m²; 5FU 400 mg/m² on d1 of each treatment cycle and 5FU 1200 mg/m² continuous infusion over 24 hrs d1 and d2) every 2 weeks plus Nivolumab 240 mg every 2 weeks and Ipilimumab 1mg/kg every 6 weeks (Arm A) or FOLFOX alone (Arm B). Primary endpoint of the trial is progression-free survival based on the ITT population. Main secondary endpoints are overall survival, objective response rate, Safety and Quality of life (EORTC QLQ-C30). 118 pts (59 per arm) will be enrolled to provide 80% power for detecting an average HR of 0.68 using the log rank test at a one-sided type I error of 10%. At the date of submission, (Feb 2019), 28 of planned 118 pts are randomized. Clinical trial information: NCT03647969.
KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer (mG/GEJC): A double-blind, randomized, placebo-controlled phase 3 study.
Authors: Janjigian Yelena Yuriy , Bang Yung-Jue , Fuchs Charles S. , Qin Shukui , Satoh Taroh , Shitara Kohei , Tabernero Josep , Van Cutsem Eric , Cao Z. Alexander , Chen Xinqun , Kang S. Peter , Shih Chie-Schin , Chung Hyun Cheol
Published: May 2019

TPS4146

Background: Combination therapy with the anti-HER2 antibody trastuzumab with fluoropyrimidine and platinum is the current standard for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment ADCC, and potentiate antitumor immune response in HER2+ patients. This phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the overall response rate was 87%, and the disease control rate was 100% Janjigian YY, ASCO GI 2019). KEYNOTE 811, a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH >2.0) G/GEJ adenocarcinoma; life expectancy >6 months with RECIST v1.1 measurable disease; adequate organ function and performance status. Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg IV flat dose or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) Q3W up to 2 years or until intolerable toxicity or disease progression. Investigator choice chemotherapy will include day 1 cisplatin 80 mg/m2 IV and /5-fluorouracil 800 mg/m2/day IV (days 1-5) or oxaliplatin 130 mg/m2 IV and capecitabine 1000 mg/m2 BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per NCI CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326.
Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study.
Authors: Llovet Josep M , Kudo Masatoshi , Cheng Ann-Lii , Finn Richard S. , Galle Peter R. , Kaneko Shuichi , Meyer Tim , Qin Shukui , Dutcus Corina E. , Chen Erluo , Dubrovsky Leonid , Zhu Andrew X.
Published: May 2019

TPS4152

Background: Len, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, is approved for first-line treatment of unresectable HCC (uHCC) based on the open-label phase 3 REFLECT study in which len showed noninferior overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time-to-progression (TTP) vs sorafenib. In the phase 2 KEYNOTE-224 study of pembro (a PD-1 inhibitor) as second-line treatment of advanced HCC, pembro showed meaningful clinical efficacy in pts previously treated with sorafenib, with median PFS 4.9 mo, median OS 12.9 mo, and a manageable safety profile. In results from the phase 1b KEYNOTE-524 trial, len+pembro was well-tolerated, with promising antitumor activity in pts with uHCC. LEAP-002 is a phase 3 study to evaluate the safety and efficacy of len+pembro vs len+placebo as first-line therapy for advanced HCC. Methods: Eligible pts are ≥18 y and have HCC confirmed by radiology, histology, or cytology; ECOG PS 0/1; BCLC stage C or stage B disease not amenable to locoregional therapy or curative treatment approach; CP class A liver score within 7 days before study; and ≥1 measurable lesion by RECIST v1.1. Pts with past or ongoing HCV infection and those with controlled HBV are eligible. 750 pts will be randomized 1:1 to receive len 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) orally once daily plus pembro 200 mg or placebo IV Q3W. Pembro and len will be administered until disease progression or unacceptable toxicity, with a maximum 35 cycles for pembro. Stratification will be by geographic region (Asia vs Japan and Western regions); macroscopic portal vein invasion or extrahepatic spread or both (yes or no); alpha fetoprotein ≤400 ng/mL vs >400 ng/mL; and ECOG PS 0/1. Primary end points are PFS per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary end points are ORR, duration of response, disease control rate, and TTP per RECIST v1.1 by BICR, efficacy per modified RECIST, pharmacokinetics, and safety. Imaging assessments will be performed Q9W on study. AEs will be graded per CTCAE v4.0 and monitored up to 90 days after last dose. Clinical trial information: NCT03713593.
A multicenter phase II trial of rucaparib in combination with nivolumab as maintenance therapy for patients with advanced biliary tract cancer.
Authors: Sahai Vaibhav , Tran Nguyen H. , Griffith Kent A. , Zalupski Mark
Published: May 2019

TPS4153

Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with a median overall survival (OS) less than 12 months. Using whole exome NGS, 26 (49%) pts in a 53 pt cohort had either DNA damage repair (DDR) pathway mutations (somatic and/or germline, n = 18), or isocitrate dehydrogenase 1 (IDH1) mutations (n = 8), and may have potentially benefited from PARP inhibition. Further, disruption of the mutated DDR pathways with a PARP inhibitor may result in increased mutational burden and neoantigens leading to immunogenicity, thus providing the rationale for combination with a PD-1 antibody. This phase 2 trial is designed to investigate the role of a PARP inhibitor in combination with a PD-1 antibody in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intra- or extra-hepatic, and gallbladder) without progression after 4-6 months of 1st line platinum-based systemic chemotherapy, measurable disease per RECIST v1.1, ECOG PS 0-1, Child-Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective is to evaluate progression-free survival (PFS) rate at 4 months. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST criteria, median PFS and OS, and safety in this patient population. Exploratory objectives include identification of predictive biomarkers of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis with immune cell subset analysis. Treatment includes rucaparib 600 mg PO BID on days 1-28 with nivolumab 240 mg on days 1, 15 Q4 weeks. In absence of disease progression, pts may continue therapy up to 2 years. Accrual goal is 32 evaluable pts. Using a null hypothesis value of a 63% PFS rate at 4 months, and an 85% alternative hypothesis, this ongoing study has 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in the study arm. Clinical trial information: NCT03639935.
A phase I/II study of GSK3145095 alone and in combination with anticancer agents including pembrolizumab in adults with selected solid tumors.
Authors: Cohen Deirdre Jill , Pant Shubham , O'Neil Bert , Marinis Jill , Winnberg James , Ahlers Christoph Matthias , Callaway Justin , Rathi Chetan , Acusta Andre , Verticelli Adeline , Bertin John , Smothers James F .
Published: May 2019

TPS4165

Background: The immunosuppressive myeloid infiltrate characteristic of the tumor microenvironment in pancreatic cancer represents a major therapeutic barrier in this disease. Modulation of this infiltrate may increase sensitivity to immune checkpoint blockade in this and other tumors with a similar phenotype. The receptor interacting protein 1 (RIP1) is a serine/threonine kinase that becomes active upon homeostatic disruptions. Bound to RIP3 and mixed lineage kinase domain-like protein (MLKL), RIP1 kinase activity drives necroptosis. However, RIP1 also signals in response to inflammatory stimuli independently of its association with RIP3. A correlation between increased RIP1 protein expression and a worse prognosis has been reported in a variety of solid tumors. Furthermore, in an unbiased screen RIP1 was identified as a top gene contributing to resistance to immunotherapy (Manguso 2017). In murine models, RIP1 kinase activity has been reported to drive pancreatic oncogenesis. Inhibition of RIP1 in the pancreatic TME leads to the replacement of tumor-permissive myeloid infiltrates with innate cells promoting an anti-tumor response by the adaptive immune system (Seifert 2016; Wang 2018) and synergized with anti-PD-1 treatment. These data suggest that the small molecule RIP1 inhibitor GSK3145095 may have therapeutic potential in multiple tumor types. Methods: This is a four-part phase 1/2 study designed to evaluate the safety, PK, PD, and preliminary activity of GSK3145095 given orally to participants with selected advanced or recurrent solid tumors. Part 1 will be conducted in approximately 30 adults with pancreatic cancer with escalating doses of GSK3145095. Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab and may be conducted in a broader population of selected solid tumors. Part 3 represents a cohort expansion of Part 2. Part 4 may investigate the combination of additional anticancer agent(s) with one or more doses of GSK3145095 identified as safe in Part 1. References: Manguso RT. Nature. 2017;547(7664):413-418. Seifert L. Nature. 2016;532(7598):245-249. Wang W. Cancer Cell 2018; 34: 757-774. Clinical trial information: NCT03681951.
DUTRENEO Trial: A phase II randomized trial of DUrvalumab and TREmelimumab as NEOadjuvant approach in muscle-invasive urothelial bladder cancer (MIBC) patients prospectively selected by immune signature scores.
Authors: Grande Enrique , Guerrero Félix , Puente Javier , Galante Isabel , Duran Ignacio , Fuentes Javier , Alonso-Gordoa Teresa , Burgos Javier , Font Pous Albert , Buisan Oscar , Pinto Alvaro , Alvarez-Maestro Mario , Reig Torras Oscar , Maroto Pablo , Garcia del Muro Xavier , Galvan Patricia , Malats Nuria , Prat Aleix , Real Francisco X. , Castellano Daniel E.
Published: May 2019

TPS4588

Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by cystectomy improves overall survival in patients (pts) with MIBC. Immune checkpoint inhibitors as single agents are approved in pts with advanced UC. Combination of both programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoints might be synergistic. Durvalumab (DU) is a selective, engineered, human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (TRE) is an anti-CTLA-4 mAb of the lgG2 isotype. Pembrolizumab and atezolizumab, have shown a promising activity (including significant pathologic complete responses (pT0)) in MIBC pts candidate to cistectomy, with better results in those pts with PD-L1 overexpression. It is expected that the dual targeting of the immune system with an anti-PDL1 + antiCTLA4 such as DU and TRE in the neoadjuvant setting may improve these outcomes. In addition, the most precise selection of pts according to a molecular INF-gamma signature is intended to increase the efficacy. Methods: This is a prospective and randomized phase II, open-label study conducted in urothelial MIBC pts diagnosed of T2-T4 and/or N+ candidates to cystectomy, ECOG 0-1 and adequate organ function. Pts will be treated according to the score of a pro-inflammatory signature (PIS) determined with Nanostring technology. Pts with a low PIS will receive standard cisplatin-based neoadjuvant therapy (22 pt). Pts with a high PIS will be randomized 1:1 to receive cisplatin-based neoadjuvant therapy (22 pt) or DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles (22 pt). If more than 8 responses (pT0) are observed in first 22 pts included in DU+TRE arm, 24 additional pts will be recruited in this arm. Primary objective is to assess the antitumor activity of DU+TRE measured as pT0 rate in pts with a positive PIS. Disease free survival and safety profile will be also evaluated. Tissue, plasma and urine samples will be collected for translational studies. Clinical trial information: NCT03472274.
PrE0807 phase Ib feasibility trial of neoadjuvant nivolumab (N)/lirilumab (L) in cisplatin-ineligible muscle-invasive bladder cancer (BC).
Authors: Grivas Petros , Puligandla Maneka , Cole Suzanne , Courtney Kevin Dale , Dreicer Robert , Gartrell Benjamin Adam , Cetnar Jeremy Paul , Dall'era Marc , Galsky Matt D. , Jain Rohit K. , Maughan Benjamin Louis , Agarwal Neeraj , Koshkin Vadim S , Hahn Noah M. , Carducci Michael Anthony
Published: May 2019

TPS4594

Background: Neoadjuvant cisplatin-based chemotherapy before radical cystectomy (RC) improves outcomes but ~50% of patients (pts) are cisplatin-unfit. Anti-PD(L)1 agents can prolong overall survival (OS) in platinum-resistant advanced BC and have shown high pathologic complete response rate (pCR) and safety as single agent in phase II trials in the neoadjuvant setting. The combination of anti-PD-1 and anti-KIR agents is feasible and very attractive based on complementary and non-overlapping roles in regulating adaptive and innate immune response as well as impacting the function CD8+ T and NK-cells. Higher CD8+ T cell density (TCD) at RC tissue correlates with longer OS. We hypothesize, that combining anti-PD1 (N) with anti-KIR (L) is safe and feasible as neoadjuvant therapy in cisplatin-unfit pts and results in high CD8+ TCD at RC. Methods: Phase Ib multi-institutional trial evaluating 2 doses (4 weeks apart) of N alone or N+L in 2 cohorts; pts will be assigned sequentially to N (Cohort 1), and if there is no negative safety signal after the first 12 pts, subsequent pts will be assigned to N+L (Cohort 2). Key eligibility: cT2-4aN0-1M0 stage, ≥20% tumor at TURBT, adequate organ function, no autoimmune disease within 2 years, no concurrent invasive upper urinary tract carcinoma or other active cancer. Primary endpoint: safety based on CTCAE v5.0 measured as the rate of ≥G3 treatment related adverse events (AE). Key secondary endpoints: CD8+ TCD absolute and % change between TURBT and RC, % of pts who do not get RC within 6 weeks after neoadjuvant treatment due to treatment-related AE, % pCR, recurrence-free survival, and evaluation of biomarkers in tumor tissue, blood, urine. Rates of ≥Grade 3 AE with neoadjuvant treatment will be reported along with 90% exact binomial CI. In Cohort 1, maximum CI width is 0.51; in Cohort 2, it is 0.36. Our hypothesis is that the change in CD8+ TCD between TURBT and RC will be about 3 CD8+ T cells / 100 tumor cells within HPF. Up to 43 pts will be enrolled for 36 eligible, treated pts (12:N, 24:N+L). Cohort 1 and 2 have 81% and 98% power, respectively, to detect the hypothesized difference with 1-sided type I error rate of 0.05. Trial is open to accrual in US. Clinical trial information: NCT03532451.