bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
A phase Ib/II study of niraparib combination therapies for the treatment of metastatic castration-resistant prostate cancer (NCT03431350).
Authors: Subudhi Sumit Kumar , Aparicio Ana , Zurita Amado J. , Doger Bernard , Kelly William Kevin , Peer Avivit , Rathkopf Dana E. , Karsh Lawrence Ivan , Tryon Jeffrey J. , Kothari Nishi , Zhao Xin , Zhu Eugene , Ricci Deborah S. , Tran Namphuong , De Bono Johann S. 
Published: May 2019

TPS5087 Background: Assessing multiple therapies in a single clinical trial can facilitate the rapid identification of new agents for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib (Nirap) is a highly selective PARP inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. PARP inhibition may be especially lethal in tumor cells with genetic DNA damage response deficits (DRD). Based on promising preclinical and clinical data, this study is designed as a master protocol with nirap as a backbone therapy. Combination 1 assesses the safety and efficacy of nirap plus JNJ-63723283 (JNJ-283), an anti-PD-1 monoclonal antibody. Combination 2 assesses nirap plus abiraterone acetate and prednisone (AA-P). Methods: This multicenter, global, open-label study is currently open at 18 sites in 5 countries of the planned XX sites, and is enrolling patients with mCRPC who have progressed on ≥1 androgen-receptor targeted therapy for mCRPC. Enrollment at time of abstract submission was 25 for combination 1. When combined with AA-P, the RP2D has been determined to be nirap 200 mg. The recommended phase-2 dose (RP2D) of nirap plus JNJ-283 was determined in Part 1 based on the incidence of specified adverse events and PK data to be 480 mg every 4 weeks. For Part 2 of the study, patients are assigned to receive oral niraparib daily plus JNJ-283 infusions once every four weeks until disease progression, unacceptable toxicity, death, study termination. Part 2 is described in the table. Clinical trial information: NCT03431350. [Table: see text]
Prostate cancer with oligometastatic relapse: Combining stereotactic ablative radiotherapy and durvalumab, a randomized phase II trial (POSTCARD - GETUG-P13).
Authors: Supiot Stéphane , Libois Vincent , Guimas Valentine , Rio Emmanuel , Rolland Frederic , Bompas Emmanuelle , Vansteene Damien , Tigreat Marine , Lisbona Albert , Colliaux Jeremy , Campion Loic , Blanc-Lapierre Audrey 
Published: May 2019

TPS5088 Background: Following Stereotactic Body RadioTherapy (SBRT) targeting prostate cancer (PCa) oligometastasis, a tumor response assessed by PSA decrease is observed in a majority of case. To increase this tumor response, immune targeting agents can be combined with SBRT. We hypothesize that the anti-PDL1 agent Durvalumab will enhance immune response following SBRT targeting oligometastatic lesions. In this multicenter randomized phase II trial, we therefore propose to assess the comparative efficacy of SBRT with or without Durvalumab (MEDI4736) in oligometastatic recurrent hormone sensitive prostate cancer patients. Methods: Patients with PCa were eligible if they had a biochemical recurrence following treatment with curative intent, with a maximum of 5 bone or lymph node metastases, seen only on FCH-PET CT or Ga-PSMA PET CT, not seen on conventional imaging assessments (bone scan or thorax, abdomen and pelvis CT scan). Main exclusion criteria are serum testosterone level < 8.5 nmol/ml, PSA doubling time less than 6 months, lung, brain, liver or other visceral metastases, any prior immune therapy. Patients were randomly assigned (2:1) to either SBRT + Durvalumab, or SBRT alone, with a stratification by investigation center, and number of metastases (1 vs 2-5). Durvalumab (1500 mg/cycle) will be started one month prior to SBRT to be able to evaluate PSA and immune response to the drug. It will be combined with SBRT (3x 9 or 3 x 11 Gy) and then given adjuvantly until progression with a maximum of 12 months. Ninety-six patients will be recruited in 15 centers over a recruitment period of 2.5 years. The primary endpoint is two-year Progression-free survival. Secondary objectives include quality of life, androgen deprivation therapy free survival, prostate cancer specific survival, overall survival, time to first symptomatic event, acute and late toxicity. Patients in both groups will be observed for PSA progression every 3 months after random assignment, with confirming imaging at PSA progression. Clinical trial information: NCT03795207.
IMPACT: Immunotherapy in patients with metastatic cancers and CDK12 mutations.
Authors: Reimers Melissa Andrea , Abida Wassim , Chou Jonathan , George Daniel J. , Heath Elisabeth I. , McKay Rana R. , Pachynski Russell Kent , Zhang Jingsong , Choi Jae Eun , Feng Felix Y , Neshewat Gina , Cieslik Marcin , Daignault-Newton Stephanie , Small Eric Jay , Chinnaiyan Arul , Alva Ajjai Shivaram 
Published: May 2019

TPS5091 Background: Tumors with biallelic CDK12 loss have been identified as a distinct subtype in metastatic castration resistant prostate cancer (mCRPC) and other cancer types. The CDK12 biallelic loss mCRPC genomic signature, distinct from homologous recombination deficient (HRD) and ETS fusion signatures, is characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens, and increased tumor T cell infiltration. Early clinical experience with anti-PD-1 immunotherapy in CDK12 loss mCRPC patients (pts) is notable for deep and sustained PSA as well as radiographic responses. We hypothesize that CDK12 biallelic loss is a potential biomarker of immune checkpoint immunotherapy (ICI) efficacy in mCRPC and other cancers. Methods: IMPACT (NCT03570619) is a multi-center, open label, phase 2 study of pts with metastatic cancers that harbor CDK12 biallelic loss. mCRPC pts will be enrolled in cohort A (n = 25) in a Mini-Max Simon Two-Stage design, and all other pts in single-stage cohort B (n = 15). All pts will receive induction therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks (up to 52 weeks in total). Eligible pts must have identified biallelic CDK12 loss on any CLIA/CAP approved next generation sequencing assay and a histologic diagnosis of metastatic prostate adenocarcinoma or other metastatic carcinoma. No prior ICI is allowed. The primary endpoint is the overall response rate (ORR) in cohort A per PCWG3 criteria. An ORR of 30% is targeted in cohort A. Secondary endpoints include safety, secondary efficacy measures, quality of life, and survival measures. Exploratory objectives include tumor whole exome analysis and changes in immune profiles with therapy. Comprehensive and serial monitoring of peripheral blood immune cell populations will be performed via T cell clonal diversity assessment and multi-parametric flow cytometry. Changes in myeloid and lymphoid populations will be assessed from whole blood. Polarization and effector function of T cells and activation of antigen presenting cells will be further characterized from isolated peripheral blood mononuclear cells. Study accrual is ongoing. Clinical trial information: NCT03570619.
BEATcc (ENGOT-Cx10/GEICO 68-C/GOG3030/JGOG1084): A randomized, open label, phase III study of cisplatin and paclitaxel chemotherapy with bevacizumab (CTx plus B) with or without atezolizumab (Atz) as first-line treatment for metastatic, persistent, or recurrent (m/r) carcinoma of the cervix (CCx).
Authors: Oaknin Ana , Gladieff Laurence , Colombo Nicoletta , Villacampa Guillermo , Mirza Mansoor Raza , De Giorgi Ugo , Randall Leslie M. , Takekuma Munetaka , González-Martín Antonio 
Published: May 2019

TPS5594 Background: The combination of CTx plus B is first line treatment for most patients (pts) with m/r CCx not amenable for local therapy based on GOG240 results. GOG240 regimen showed an improvement in overall survival (OS) compared to CTx alone: 16.8 vs. 13.3 months (HR 0.77, 95% CI 0.62–0.95, p = 0.007). However, further improvement in first line therapy outcomes is an unmet need. Immune-checkpoint inhibitors are breakthrough therapies in several tumor types, and their development in CCx is supported by a strong scientific rationale. Human papillomavirus infection (HPV) causes more than 90% of CCx cases. PD-L1 is a HPV biomarker and is found frequently up-regulated in CCx. Nivolumab and pembrolizumab (Pb) (anti-PD-1 antibodies) have shown response rates of 26.3% and 14.3%, respectively, in pretreated m/r CCx. This has led to the recent FDA approval of Pb in pretreated PD-L1+ m/r CCx. The BEATcc trial (NCT03556839) evaluates the addition of the anti-PD-L1 agent Atz to GOG240 regimen as first line treatment for m/r CCx, following the synergistic rationale between anti-VEGF agents and PD-1/PD-L1 blockade. Methods: Eligible pts: m/r CC with adequate organ function. Pts will be randomized 1:1 to either Arm A (control): C 50 mg/m2 + Tx 175mg/m2 + B 15 mg/kg (CTx plus B) i.v. D1 Q3W or Arm B (experimental): CTx plus B + Atz 1200 mg i.v. D1 Q3W. Stratification factors: prior chemo-radiation, histology and Chemotherapy backbone (CTx vs carboplatin-Tx). Treatment is planned until disease progression, unacceptable toxicity or withdrawal of consent. Pts with a complete response after ≥6 cycles or those with unacceptable CTx toxicity may be allowed to continue only on biologics therapy. An Independent Data Monitoring Committee will analyze the safety of the first 12 pts in the experimental arm completing 2 treatment cycles. The primary endpoint is OS. The study started enrolling in October 2018 and will enroll approximately 404 pts across Europe, Japan, and the US. Clinical trial information: NCT03556839.
Phase 2 trial of tisotumab vedotin in platinum-resistant ovarian cancer (innovaTV 208).
Authors: Mahdi Haider , Schuster Steven Robert , O'Malley David M. , McNamara Donna M. , Rangwala Reshma A. , Liang Shang-Ying , Jain Shweta , Nicacio Leonardo , Chon Hye Sook 
Published: May 2019

TPS5602 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer, accounting for ≈185,000 deaths worldwide in 2018. Most patients (pts) initially respond to platinum-based chemotherapy (chemo), but more than 50% of pts recur. Pts who recur in ≤6 months have platinum-resistant OC (PROC), which is associated with poor prognosis. Standard therapy for PROC includes chemo ± bevacizumab (bev). However, many pts receive single-agent chemo, which demonstrates limited response and survival (≈12% ORR, 3-4 mo PFS, ≈12 mo OS). Therefore, there is an urgent need for novel therapeutic strategies. Tissue factor (TF) is a novel oncogenic target expressed in OC. Tisotumab vedotin (TV) is a first-in-class antibody drug conjugate comprising a TF-targeted fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. TV has shown encouraging antitumor activity and a manageable safety profile in PROC in the multicohort phase 1/2 innovaTV 201 study. innovaTV 208 is a multicenter, open-label, phase 2 trial with a safety run-in phase for a dose-dense regimen (DDR) evaluating the efficacy and safety of TV in pts with PROC. Methods: innovaTV 208 will enroll ≈142 adult pts with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable disease by RECIST v1.1; and ECOG score 0-1. Eligible pts must have received bev-containing treatment for OC. Pts with platinum-refractory disease, increased risk of bleeding, active ocular surface disease, or grade > 1 peripheral neuropathy will be excluded. A safety run-in phase for the DDR will be performed in up to 12 pts who received ≤5 prior treatment regimens for PROC. In the DDR, TV will be given at previously decided lower doses IV 3Q4W for the same dose intensity as the standard 1Q3W dose; the primary endpoint is incidence of DLTs. In phase 2, pts who received ≤1 prior cytotoxic chemo regimen for PROC will be randomized to receive TV administered as IV 1Q3W or as IV 3Q4W, if shown to be tolerable. The primary endpoint for phase 2 is confirmed ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, DCR, CA-125 response rate by GCIG criteria, PFS, OS, pharmacokinetics, and safety. Clinical trial information: NCT03657043.
A phase 3 trial evaluating efficacy and safety of lenvatinib in combination with pembrolizumab in patients with advanced endometrial cancer.
Authors: Makker Vicky , Casado Herraez Antonio , Aghajanian Carol , Fujiwara Keiichi , Pignata Sandro , Penson Richard T. , Dutcus Corina E. , Guo Matthew , Dutta Lea , Orlowski Robert , Smith Alan , Miller David S. 
Published: May 2019

TPS5607 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT. Pembrolizumab (PEMBRO) is a monoclonal antibody targeting programmed cell death receptor 1 (PD-1). Preliminary analyses of a phase 1b/2 study of LEN + PEMBRO showed promising antitumor activity and a manageable safety profile in advanced endometrial cancer (EC). Methods: A multicenter, randomized, open-label, phase 3 study (KEYNOTE-775/E7080-G000-309; clinicaltrials.gov NCT03517449) will evaluate efficacy and safety of LEN + PEMBRO vs treatment of physician’s choice (TPC) in patients with advanced EC. Patients must be aged ≥ 18 years, have advanced EC that progressed after 1 prior platinum-based therapy, have measurable disease per RECIST v1.1, and an Eastern Cooperative Oncology Group performance status ≤ 1. Patients must have mismatch repair (MMR) status confirmed by central laboratory via immunohistochemistry on archived or fresh tumor biopsy. ~780 patients (~120 MMR-deficient; ~660 MMR-proficient) will be randomized to receive LEN 20 mg orally once daily and PEMBRO 200 mg intravenously (IV) every 3 weeks (Q3W) or TPC. Patients will be randomized first according to MMR status; MMR-proficient patients will be further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. TPC is either doxorubicin 60 mg/m2 by IV Q3W or paclitaxel 80 mg/m2 by 1-hour IV infusion weekly (3 weeks on/1 week off). The dual primary endpoints are progression-free survival (PFS; per RECIST v1.1 by blinded independent central review) and overall survival (OS). The PFS analysis will occur at the planned interim analysis (~363 OS events in MMR-proficient patients; ~524 PFS events), and the study will have 99% power to detect a hazard ratio (HR) of 0.55 with a 1-sided 0.0005 significance level. A final OS analysis will occur at 518 OS events, when the study will have 90% power to detect a HR of 0.75 with a 1-sided 0.0245 significance level. Secondary endpoints include objective response rate, health-related quality of life, safety and tolerability, and pharmacokinetics. Clinical trial information: NCT03517449.