bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II, multicenter, open-label, proof of concept study of tasquinimod in patients with advanced/metastatic hepatocellular (HCC), ovarian (OC), renal cell (RCC) and gastric (GC) carcinomas.
Authors: Escudier Bernard J. , Faivre Sandrine J. , Oza Amit M. , Van Cutsem Eric , Agnes Geniaux , Baton Frederique 
Published: March 2020

TPS2622 Background: Treatment resistance and disease progression are common in HCC, OC, RCC and GC. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, resulting in immunomodulatory, anti-angiogenic and anti-metastatic effects involving downregulation of chemokine receptor type 4 and hypoxia-inducible factor. Tasquinimod significantly improves PFS (7.6 v 3.3 mo) in patients with metastatic hormone-resistant prostate cancer (Pili, R. et al. 2011. JCO 29:4022-8) and is in an ongoing phase III program. Its unique mode of action (MOA) makes tasquinimod attractive for other indications. The primary study objective is to determine the clinical activity of tasquinimod in advanced/metastatic HCC, OC, RCC and GC. Tasquinimod has been shown to delay disease progression with limited tumor shrinkage, therefore an innovative design was proposed, with PFS rate as the main endpoint. Methods: Design: Phase II, multinational, exploratory proof of concept study to evaluate tasquinimod activity in 4 independent cohorts of patients (HCC, OC, RCC and GC) with progressive disease after standard therapy. An innovative design (Litwin S. 2007. Stat Med 26:4400-15) based on the proportion of patients who have not progressed nor died at predefined timepoints (PFS rate) will be used in each cohort independently. Patients: 110–200 patients (dependent on outcome of futility analyses) aged ≥18 yr, ECOG performance status 0 or 1 will be enrolled. Patients must have histologically confirmed and documented HCC, OC, RCC or GC and demonstrable disease progression on standard therapy. Recruitment is ongoing. Dosage: Tasquinimod will be administered as a starting dose of 0.5 mg/day, in each cohort. After 2 wks, the dose will be increased to 1 mg/day based on individual safety and tolerability. Primary endpoint: PFS rate, defined as the proportion of patients who have neither progressed nor died at 12 wks (GC), 16 wks (HCC, RCC) or 24 wks (OC). Secondary endpoints: Include OS, response rate, safety, pharmacokinetics, inflammatory and specific target biomarkers to explore comprehensively the MOA according to each disease type. Clinical trial information: NCT01743469.
Clinical and preclinical activity of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk of hematologic malignancies, against blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Authors: Frankel Arthur E. , Woo Jung Hee , Mauldin Jeremy Preston , Carraway Hetty Eileen , Frankfurt Olga , Forman Stephen J. , Brooks Christopher , Bergstein Ivan , Cirrito Thomas , Rowinsky Eric K. 
Published: March 2020

TPS3105^ Background: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), a rare and aggressive dendritic cell-derived hematologic malignancy that typically involves the skin and invariably progresses to a leukemic phase, has a dismal prognosis with a median survival of approximately 14 months. Since BPDCN cells express high levels of the interleukin-3 receptor (IL-3R), SL-401, a novel targeted therapy directed to IL-3R, is being developed to treat BPDCN and other IL-3R-expressing hematologic malignancies. SL-401 is a recombinant biologic comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis (Frankel et al, Prot Eng 13, 575, 2000). SL-401 is cytotoxic in vitro to IL-3R-expressing leukemia blasts (Frankel et al, Leukemia 14, 576, 2000) and inhibits tumor growth in vivo (Black et al, Leukemia 17, 155, 2003). Recently, SL-401 demonstrated ultra-high anti-tumor potency against BPDCN cells in the femtomolar (10-15 M) range (Angelot-Delettre et al, Blood 118 Suppl 2588, 2011). Methods: In a Phase I/II trial of SL-401 in patients with IL-3R-expressing advanced hematologic malignancies, 4 patients with heavily pretreated BPDCN received a single cycle of SL-401 as a 15-minute infusion daily for 5 days. Results: All patients had CD4+/CD56+/CD123+ (IL-3Ralpha) expressing blasts and had failed previous combination chemotherapy regimens and allogeneic bone marrow transplantation. There were no serious adverse events. Three patients treated with SL-401 at 12.5 μg/kg/day (the planned pivotal Phase IIb trial dose) experienced complete responses (CRs). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen and lymph nodes. CR durations are 5, 3+, and 1+ months to date. Conclusions: Given these robust clinical responses, as well as the mechanistic rationale for SL-401 in BPDCN, additional BPDCN patients are being evaluated in the study and a pivotal Phase IIb multi-cycle trial in this ultra-orphan indication is being planned. Clinical trial information: NCT00397579.
A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).
Authors: Melero Ignacio , Gangadhar Tara C. , Kohrt Holbrook Edwin , Segal Neil Howard , Logan Theodore , Urba Walter John , Hodi F. Stephen , Ott Patrick Alexander , Perez-Gracia Jose Luis , Wolchok Jedd D. , Shah Aadhar , Kurland John F. , Cohen Lewis J. , Levy Ronald , Wigginton Jon M. , Goldberg Stacie M. 
Published: March 2020

TPS3107 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell non-Hodgkin’s lymphoma (B-NHL). Methods: This phase I study (n=70) will include dose escalation (Part 1) using a 6+9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 +2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.
A phase Ib, open-label, multicenter study of urelumab (BMS-663513) in combination with rituximab in subjects with relapsed/refractory B-cell malignancies.
Authors: Kohrt Holbrook Edwin , Godwin John E. , Lossos Izidore S. , Williams Michael E. , Timmerman John , Link Brian K. , Goldberg Stacie M. , McGirr Analia , Kurland John F. , Wigginton Jon M. , Cohen Lewis J. , Levy Ronald 
Published: March 2020

TPS3108 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.
Chimeric antigen receptor (CAR+) modified T cells targeting prostate specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC).
Authors: Slovin Susan F. , Wang Xiuyan , Hullings Melanie , Arauz Gabrielle , Bartido Shirley , Lewis Jason Stuart , Schöder Heiko , Zanzonico Pat , Scher Howard I. , Riviere Isabelle 
Published: March 2020

TPS3115 Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated anti-tumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 107 to 3 x 107 CAR+ T cells/kg.All 7 pts received 300mg/m2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 107 CAR+ T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for > 6 months; a second pt has stable scans for > 20 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 107 CAR+ T cells/kg and 2 received 3 x 107 CAR+ cell/kg. All 3 had intermittent fever spikes up to 39oC associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR+ cells persisted in the circulation for up to 2 weeks. Scans with 18F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safely treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests in vivo activation and persistence of T cells in blood for up to 2 weeks. Ongoing imaging with 18F may be suboptimal; a second cohort of pts will be studied with 124I-FIAU. Clinical trial information: NCTO1140373.
Intergroup ALFA/GOELAMS randomized phase II trial of lirilumab anti-KIR monoclonal antibody (IPH2102/BMS986015) as maintenance treatment in elderly patients with acute myeloid leukemia (EFFIKIR trial).
Authors: Vey Norbert , Dombret Hervé , Ifrah Norbert , Pigneux Arnaud , Gardin Claude , Buyse Marc E. , Andre Pascale , Tirouvanziam-Martin Anne , Zerbib Robert Albert , Buffet Renaud , Rozencweig Marcel 
Published: March 2020

TPS3117^ Background: Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I–expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK cell-mediated antitumor efficacy and increased survival in patients with acute myeloid leukemia (AML) upon haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). Anti-KIR antibody treatment resulted in long-term survival in SCID mice inoculated with lethal autologous AML cells (Romagne, Blood 2009). Lirilumab is a second generation fully human monoclonal antibody targeting the major inhibitory KIR on NK cells. The objectives of this study are to determine if maintenance therapy with lirilumab can improve leukemia-free survival (LFS) of elderly patients in first complete remission (CR1) of AML and to assess two dose schedules leading to either intermittent or continuous KIR occupancy. Methods: EFFIKIR is a randomized double-blind 3-arm placebo controlled trial of lirilumab in elderly patients in CR1 of AML. Patients aged 60 to 80 in CR1 of AML following standard induction and consolidation programs are randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks or 1 mg/kg q 4 weeks according to a minimization algorithm adjusting for center, primary vs. secondary AML, no. of consolidation cycles (1 vs. 2) and cytogenetics (intermediate vs. high risk). Patients are to receive up to 2 yrs of therapy. ECOG performance status of 0-1, adequate hematologic, liver and renal function, and recovery from toxicities of prior chemotherapies are required. Patients are excluded if they are eligible for bone marrow transplantation and if the time interval since last consolidation exceeds 3 mos. The primary endpoint is LFS based on independent central review. The trial will accrue 50 patients in each arm and is powered (80%) to detect an improvement in LFS with a hazard ratio of 0.60 and a one-sided alpha of 0.05. Each dose schedule will be compared to placebo using a Hochberg procedure. The first patient was randomized on 12/11/2012. Clinical trial information: NCT01687387.
Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept.
Authors: Moehler Markus Hermann , Kim Yeul Hong , Tan Iain B. , Balogh Agnes , Sanchez Teresa Kong , Bang Yung-Jue 
Published: March 2020

TPS4151 Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2+ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immune-related PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.
Metiv-HCC: A phase III clinical trial evaluating tivantinib (ARQ 197), a MET inhibitor, versus placebo as second-line in patients (pts) with MET-high inoperable hepatocellular carcinoma (HCC).
Authors: Santoro Armando , Porta Camillo , Rimassa Lorenza , Borbath Ivan , Daniele Bruno , Finn Richard S. , Raoul Jean-Luc , Schwartz Lawrence H. , He Aiwu Ruth , Trojan Jorg , Peck-Radosavljevic Markus , Abbadessa Giovanni , Goldberg Terri Robin , Bruix Jordi 
Published: March 2020

TPS4159 Background: Tivantinibis a selective, non-ATP competitive, oral inhibitor of MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET over-expression is associated with poor prognosis in HCC patients. A phase Ib study (Santoro et al, Br J Cancer, 2013) with tivantinib 360mg BID revealed no worsening of liver function in cirrhotic HCC pts. A randomized, placebo-controlled phase 2 study identified HCC patients with high tumor MET expression at immunohistochemistry (IHC) as the target population for tivantinib in second line (overall survival: 7.2 months on tivantinib, 3.8 months on placebo, HR: 0.38, p=0.01), and selected 240mg BID as the appropriate dose for HCC patients (Santoro et al, Lancet Oncol, 2013). Methods: Enrollment forthis phase III clinical trial (ARQ 197-A-U303, NCT01755767) has begun.Eligible pts must present with Child Pugh A; ECOG performance score <1; inoperable RECIST 1.1 measurable disease; adequate bone marrow, liver and kidney functions; no prior liver transplant. Pts must have progressed after or not tolerated one prior line of systemic therapy including sorafenib and their tumor samples must be deemed MET-High by IHC at a central laboratory to be eligible. Approximately 303 pts are randomized 2:1 to receive tivantinib 240mg PO twice daily or placebo. Pts are stratified by vascular invasion, metastases, and alphafetoprotein level, and they are evaluated by CT or MRI scan at 8-week intervals. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival and safety. Treatment continues until confirmed disease progression or unacceptable toxicity. Pts discontinued from study treatment will be followed for survival. Participating centers are located in Europe, Australia, New Zealand, and the Americas. This trial is expected to complete enrollment by mid-2015, and an interim analysis is planned when approximately 60% of OS events are reached. Clinical trial information: NCT01755767.
A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Amin Asim , Ernstoff Marc S. , Infante Jeffrey R. , Heng Daniel Yick Chin , Rini Brian I. , Plimack Elizabeth R. , McDermott David F. , Kollmannsberger Christian K. , Reaume Martin Neil , Spratlin Jennifer L. , Knox Jennifer J. , Voss Martin Henner , Pal Sumanta Kumar , Shen Yun , Dhar Arindam , Hammers Hans J. 
Published: March 2020

TPS4593 Background: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors are established therapies for mRCC. However, sunitinib and pazopanib rarely elicit durable responses. Programmed death-1 receptor (PD-1) is an immune checkpoint modulator that suppresses T-cell activation by interacting with its ligands (PD-L1/2) on antigen presenting cells and some tumor cells. Nivolumab, a PD-1 receptor blocking antibody, has shown durable responses in previously treated pts with mRCC in Phase 1 and 2 trials. Ipilimumab is an immune checkpoint inhibitor (anti-CTLA-4 antibody) already approved for the treatment of advanced melanoma. We describe an ongoing Phase 1 dose-escalation and expansion study evaluating combination of nivolumab with sunitinib, pazopanib or ipilimumab in pts with mRCC. Methods: Patients with histologically confirmed mRCC are treated on 4 parallel arms: nivolumab 2.0 or 5.0 mg/kg + sunitinib standard dosing (Arm S), nivolumab 2.0 or 5.0 mg/kg + pazopanib standard dosing (Arm P), nivolumab 3 mg/kg + ipilimumab 1 mg/kg as induction (Arm I-1), and nivolumab 1 mg/kg + ipilimumab 3 mg/kg as induction (Arm I-3) with nivolumab 3 mg/kg maintenance for both arms. Arms S and P are being conducted in 2 phases: nivolumab dose-escalation phase for previously treated pts (≤18 pts/arm) and then dose-expansion phase for treatment-naïve pts (20 pts/arm) if the maximum tolerated dose is ≥5 mg/kg. Arms I-1 and I-3 are fixed-dose cohorts (20 pts/arm) including both treatment-naïve and previously treated pts. Most of the study population consists of pts with clear-cell histology; non-clear cell mRCC pts are allowed in the dose-escalation cohorts of Arms S and P. The primary objectives are to assess safety and tolerability, and to determine the recommended Phase 2 dose in pts with mRCC. The secondary objective is to assess preliminary antitumor activity (objective response rate and response duration per RECIST 1.1). Exploratory objectives are to evaluate overall survival, pharmacodynamics, and predictive biomarkers for the combinations, and pharmacokinetics and immunogenicity of nivolumab. Clinical trial information: NCT01472081.