bluuebunny/crossref_metadata_2025_split huggingface dataset:
An exploratory study to investigate the immunomodulatory activity of BMS-936558 in patients with metastatic clear-cell renal cell carcinoma.
Authors: Drake Charles G. , Fishman Mayer N. , Curti Brendan D. , Kim Jenny J. , Stadler Walter Michael , McNeel Douglas G. , Choueiri Toni K. , Redman Bruce , Hudes Gary R. , Jure-Kunkel Maria , McDonald Dan , Gupta Ashok Kumar , Pathak Ashutosh Kumar , Wigginton Jon , Sznol Mario 
Published: March 2020

TPS2613 Background: With the enhanced understanding of the immune response to a tumor, new immunotherapeutic agents may expand treatment options for metastatic renal cell carcinoma (mRCC). The programmed death-1 (PD-1) receptor is upregulated by activated lymphocytes, and upon binding to its ligands, inhibits lymphocyte function. In a phase 1 study of the anti-PD-1 monoclonal antibody BMS-936558, encouraging antitumor activity has been observed in patients with previously treated mRCC. Responses occurred in extensive mRCC and were durable in many patients. Here we describe an exploratory study to investigate the immune-regulatory activity of various doses of BMS-936558 in patients with metastatic clear-cell RCC. Methods: Eighty patients with metastatic clear-cell RCC will be enrolled in this open-label, parallel group, randomized study. Patients who have received prior treatment with ≥3 therapies, including ≥1 anti-angiogenic therapy, will be enrolled in Arms 1-3 (~20 patients per arm); 20 treatment-naïve patients will be enrolled in Arm 4. BMS-936558 will be administered every 3 weeks until disease progression or unacceptable toxicity at 0.3 mg/kg (Arm 1), 2 mg/kg (Arm 2), and 10 mg/kg (Arms 3 and 4). Patients in the 0.3-mg/kg group may escalate to 2 mg/kg if not responding. Tumor assessments will occur every 6 weeks for the first 12 months then every 12 weeks for the remainder of the study. The primary objective is to evaluate the effects of BMS-936558 on the frequency of circulating immune cell subsets, levels of soluble factors associated with immune responses, and tumor infiltrating lymphocyte populations (based on pre-treatment and week 5 paired biopsies). Secondary objectives are to assess the safety, tolerability, antitumor activity, and immunogenicity of BMS-936558. Exploratory objectives include the association of clinical activity and safety with selected biomarkers in peripheral blood and tumor microenvironment and the characterization of the pharmacokinetics of BMS-936558. As of February 1, 2012, 30 patients were enrolled.
A phase I study of BMS-936558 in combination with gemcitabine/cisplatin, pemetrexed/cisplatin, or carboplatin/paclitaxel in patients with treatment-naive, stage IIIB/IV non-small-cell lung cancer.
Authors: Gettinger Scott N. , Rizvi Naiyer A. , Shepherd Frances A. , Chow Laura Q. , Laurie Scott Andrew , Spigel David R. , Sbar Eric , Shen Yun , Brahmer Julie R. 
Published: March 2020

TPS2615 Background: Lung cancer is the leading cause of cancer-related mortality worldwide and non-small-cell lung cancer (NSCLC) accounts for ~85% of all cases. Platinum-based chemotherapy alone or in combination with bevacizumab is considered first-line standard of care for advanced NSCLC. Despite such therapy, most patients (pts) will experience disease progression within 6 months and die from their disease within 1 year. Programmed death-1 (PD-1) is a coinhibitory receptor that negatively regulates T-cell activation; PD-1 expression by tumor infiltrating lymphocytes is associated with poor prognosis in NSCLC. BMS-936558 is a fully human anti-PD-1 monoclonal antibody that blocks ligand interaction with PD-L1 and PD-L2. In a phase 1 trial, BMS-936558 had antitumor activity at doses of 1-10 mg/kg in pts with advanced tumors, and impressive tumor responses in heavily pre-treated pts with NSCLC. Here we describe a phase 1 study planned to evaluate the safety and tolerability of BMS-936558 in combination with 3 standard, platinum-based doublet chemotherapy regimens in pts with NSCLC. Methods: Treatment-naïve pts with stage IIIB/IV NSCLC will be enrolled. Treatment arms will include: A) gemcitabine 1250 mg/M2 on day 1 (D1) and day 8 (D8)/cisplatin 75 mg/M2 D1/BMS-936558 D1; B) pemetrexed 500 mg/M2 D1/cisplatin 75 mg/M2 D1/BMS-936558 D1; and C) carboplatin AUC 6 D1/paclitaxel 200 mg/M2 D1/BMS-936558 D1. The starting dose of BMS-936558 will be 10 mg/kg for each treatment arm. A decision to de-escalate to a lower dose (2 or 0.3 mg/kg) will be guided by the number of dose-limiting toxicities reported per treatment arm. Chemotherapy will be given for 4 cycles (1 cycle = 3 weeks). BMS-936558 will be administered every 3 weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary objectives are to assess safety and tolerability by measuring the frequency of adverse events (AEs), serious AEs, and laboratory abnormalities; secondary objectives are to determine the overall response rate and disease control rates based on RECIST 1.1. As of February 1, 2012, 2 patients were enrolled.
Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational monoclonal antibody that targets IGF-I and IGF-II, in adult patients with advanced solid tumors.
Authors: Haluska Paul , Menefee Michael E. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Northfelt Donald W. , LaVallee Theresa , Huang Wenmei , Yu Xiang-Qing , Viner Jaye , LoRusso Patricia 
Published: March 2020

TPS2618 Background: MEDI-573 is an investigational dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF‑1R and insulin receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid receptors, MEDI-573 may achieve antitumor activity without perturbing glucose homeostasis. Objectives of this phase 1 dose-escalation and expansion study are to evaluate safety and determine the maximum tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI-573 in adult patients with solid tumors. Methods: Patients with advanced solid tumors, Karnofsky status ≥60, and adequate organ function were treated with escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 weeks (30 or 45 mg/kg q3w) using a 3+3 design. Three patients per dose level were evaluated for safety. A biomarker-rich dose-expansion arm tested weekly 5 or 15 mg/kg MEDI‑573 in patients with advanced bladder cancer. Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in ≥10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were ≤ grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45 mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF‑I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI‑573 were detected. Of 43 patients, 8 (19%) had stable disease ≥12 weeks. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development.
A phase I clinical trial of autologous, anti-CD19 gene targeted T cells for adults with B cell acute lymphoblastic leukemia (B-ALL).
Authors: Davila Marco L. , Riviere Isabelle , Wang Xiuyan , Bartido Shirley , Stefanski Jolanta , Taylor Clare , Olszewska Malgorzata , Borquez-Ojeda Oriana , Qu Jinrong , Wasielewska Teresa , Frattini Mark G. , Sadelain Michel , Brentjens Renier J. 
Published: March 2020

TPS2619 Background: Complete remission (CR) rates for B-ALL in adults is high (>80%), but overall survival remains low (approximately 30%). Patients with relapsed disease have a very poor prognosis with a median survival measured in months. Therefore, there is a dire need for novel therapies for adults with relapsed or minimal residual B-ALL. To this end we have developed a novel T cell therapy for B cell malignancies using patient derived T cells genetically modified to express the 19-28z chimeric antigen receptor (CAR), an artificial T cell receptor specific to the CD19 antigen expressed on most B cell tumors. Human T cells retrovirally modified to express the 19-28z CAR successfully targets and eradicates B cell tumors in vitro and systemic human B cell cancers in mice. We have recently published the results of our initial Phase I clinical trial experience (Brentjens, Rivière et al., Blood 2011) utilizing this technology in adults with chronic lymphocytic leukemia. These results suggest clinical activity and demonstrate a persistence of 19-28z+ T cells that is inversely associated with tumor burden. These studies suggest that 19-28z+ T cells may be particularly effective in relapsed B-ALL because these tumors retain a degree of chemotherapy sensitivity, which will allow the infusion of T cells after salvage chemotherapy when patients have low tumor burdens. To our knowledge, this is the first clinical trial using autologous CD19 targeted T cells in adults with B-ALL. Methods: We are enrolling patients to a Phase I T cell dose escalation trial (NCT01044069). Adults with CD19+ B-ALL classified as a CR, relapsed, or refractory are eligible for enrollment. After patients are enrolled they are leukapheresed to obtain peripheral blood T cells, which are then retrovirally transduced to express the 19-28z CAR and expanded in our GMP gene transfer facility. Enrolled patients with relapsed or refractory B-ALL undergo a cycle of re-induction chemotherapy and conditioning cyclophosphamide followed by infusion of autologous 19-28z+ T cells. To date, 11 patients have been enrolled and 2 patients have been infused with 19-28z+ T cells.
Design of a phase I clinical trial with PNT2258, a novel DNA interference oligonucleotide (DNAi), in patients with advanced solid tumors.
Authors: Rasco Drew Warren , Tolcher Anthony W. , Patnaik Amita , Papadopoulos Kyriakos P. , Amaya Alex , Gaylor Shari , Moore Timothy David , Forgey Robert , Goodwin Neal , Bisgaier Charles L. , Rodrigueza Wendi V. 
Published: March 2020

TPS3110 Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.
A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3 antibody fusion protein, in combination with multiple treatment regimens in patients with advanced HER2-positive solid tumors.
Authors: Richards Donald A. , Braiteh Fadi S. , Anthony Stephen Patrick , Edenfield Jeff , Hellerstedt Beth A. , Raju Robert N. , Conkling Paul , Smith David A. , Becerra Carlos , Cohn Allen Lee , Denlinger Crystal Shereen , Garbo Lawrence E. , Wu Hillary H. , Garcia Agustin , McDonagh Charlotte , Frye Sasha , Agresta Samuel V. , Moyo Victor M. 
Published: March 2020

TPS3111 Background: The HER2/HER3 oncogenic heterodimer is a potent HER receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel bispecific antibody fusion protein that inhibits ligand activated HER3 signaling through abrogation of ligand binding specifically in HER2 overexpressing tumors. In preclinical models of HER2+ solid tumors, MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression, and tumor growth. HER2 is a well-established target of anticancer agents such as trastuzumab and lapatinib, specifically in breast and gastric tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor activity of both trastuzumab and lapatinib and this phase I study seeks to determine if MM-111 can be safely used in combination with various standard of care HER2 targeting regimens, namely; (1) trastuzumab, cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3) trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open label, multicenter, dose-escalation study of MM-111 in an add-on design that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of MM-111 in combination. Each arm is designed to run as a separate phase I study to address safety and tolerability of each combination. For eligibility, patients are required to have documented advanced HER2-positive cancer, with adequate bone marrow, hepato-renal and cardiac function. The dose escalation for each arm utilizes a standard “3 + 3” design with MM-111 dosed initially at a moderate dose of 10 mg/kg and escalated up to 20 mg/kg to identify a phase II dose in combination with each regimen. Once the maximum tolerated dose or phase II dose is identified, expansion cohorts will accrue to further evaluate these combinations. The flexibility of the design allows additional combinations arms to be added. Key exploratory analyses will include an evaluation of safety, PK, and efficacy as evidenced by best overall response and duration of response.
Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced or metastatic solid tumors.
Authors: Infante Jeffrey R. , Gandhi Leena , Shapiro Geoffrey , Burris Howard A. , Bendell Johanna C. , Baselga José , Hsu Karl , Faivre Théa , Asatiani Ekatherine , Heist Rebecca Suk 
Published: March 2020

TPS3118 Background: The PI3K/mTOR and MAPK signaling pathways are frequently aberrantly activated in tumors and interact to promote growth and resistance to treatment. Simultaneous inhibition of both pathways may enhance antitumor activity. This trial investigates the combination of pimasertib, a highly selective MEK1/2 inhibitor, and SAR245409, a dual PI3K/mTOR inhibitor (ClinicalTrials.gov NCT01390818). Maximum tolerated dose (MTD) when administered once daily (qd) as a single agent to solid tumor patients (pts) is 90 mg for both compounds. Methods: Pts with advanced solid tumors characterized by frequent alterations of the MAPK or PI3K/mTOR pathways (pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian and melanoma) and/or with identified alterations in genes activating these pathways, adequate performance status and organ function, and no retinal disease are eligible for entry. The primary objective of the trial is to determine the MTD of the combination therapy. Secondary objectives include: safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker identification and antitumor efficacy (response rate via RECIST v1.1). Both compounds are dosed together qd continuously in 21 day cycles. The study uses a classical 3 + 3 design, with modified Fibonacci (decreasing increments) dose escalation based on occurrence of dose-limiting toxicities (DLTs). In parallel with dose escalation, more pts may be enrolled in already tested lower dose level (DL) cohorts to further evaluate PK, PD, safety and antitumor activity. After MTD confirmation, additional pts may be enrolled in up to 4 disease-specific cohorts based on scientific rationale, and observed preclinical and clinical activity signals. As of January 25th 2012, 20 pts have been treated. No DLTs have been reported.
The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC).
Authors: Cervantes-Ruiperez Andres , Markman Ben , Siena Salvatore , Pericay Carles , Aprile Giuseppe , Bridgewater John A. , Cubillo Antonio , Waterston Ashita Marie , Garcia-Carbonero Rocio , Kozloff Mark , McKendrick Joseph James , Samuel Leslie M. , Perez-Fidalgo Jose Alejandro , Strickland Andrew H. , Bencardino Katia , Moya Irene , Lutrino Stefania Eufemia , Mancao Christoph , Manenti Luigi , Tabernero Josep 
Published: March 2020

TPS3637 Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are progression on 1L containing oxaliplatin, ECOG 0-1, and adequate hematological and liver function. Main exclusion criteria: prior anti-EGFR treatment. A total of 160 patients in 2L mCRC (stratified for EGFR expression, disease progression before or after 6 months after starting 1L, prior treatment with bevacizumab Y vs N) will be randomized to receive either GA201 (day 1, 8 of cycle 1 then q2W) or cet (qW) + FOLFIRI q2W (KRAS WT) or to receive GA201+ FOLFIRI or FOLFIRI alone (KRAS mutant). Collection of archival tumor plus a mandatory fresh tumor biopsy at baseline were implemented because ph I data showed that EGFR expression is not concordant between the two specimen types and to optimize assessment of potential immune related biomarkers. The fresh tumor biopsy will be centrally analyzed for EGFR (immunohistochemistry) and KRAS status. Primary objective is progression free survival; secondary endpoints are to define objective response rates, the safety profile, pharmacokinetics and pharmacodynamics. A comprehensive biomarker program (blood and tumor), mainly immune-phenotyping, immunohistochemistry in tumor samples (Ventana) and immune functional tests (including adaptive responses) were set up to investigate potential predictive biomarkers and the mode of action of GA201. Study is ongoing worldwide in 9 countries with the safety run-in phase completed in Nov 2011. Recruitment is planned to be completed by end of April 2012.
A pilot trial of a combination of therapeutic vaccines (GI-4000 and GI-6207) as adjunctive therapy with first-line therapy with bevacizumab plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed Ras-mutant positive or negative metastatic colorectal cancer.
Authors: Marshall John , Hwang Jimmy J. , Pishvaian Michael J. , He Aiwu Ruth , Weiner Louis M. , Sandene Erin K. , Gulley James L. , Heery Christopher Ryan , Schlom Jeffrey , Speyer Sue , Richman Joni , Ferraro John , Coeshott Claire , Cohn Allen , Apelian David , Rodell Timothy C. 
Published: March 2020

TPS3638 Background: A promising approach for the treatment of cancer is the development of vaccines that target specific tumor antigens. In the metastatic CRC patient population, targeted and active immunotherapy may inhibit cancer progression and improve survival. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus standard therapy in patients with metastatic colorectal cancer. GI-4000 is a proprietary immunotherapy that uses whole, heat-killed recombinant Saccharomyces cerevisiae yeast (called Tarmogens = Targeted Molecular Immunogens). GI-4000 is designed to activate a cellular immune response to target cells with activating ras mutations. Tarmogens have been shown to elicit selective killing of target cells that express a number of cancer antigens, including mutated Ras, by activation of antigenspecific T cell mediated responses. Methods: The study population consists of subjects with metastatic colorectal cancer with an activating mutation in ras. Newly diagnosed subjects receive FOLFOX (or FOLFIRI) + bevacizumab (Bev) + GI- 4000; 3 weekly injections of GI-4000 are followed by 8 cycles of Bev + FOLFOX (or FOLFIRI); day 1 and 2 every 14 days. Doses of GI-4000 are administered on day 8 of each cycle. Upon completion of chemotherapy, GI-4000 continues along with Bev maintenance every 2 weeks for up to 5 years or until subjects experience intolerance, disease recurrence, or death. If Bev is stopped, GI-4000 may continue on the same maintenance schedule alone. Subjects that have already completed standard chemotherapy (FOLFOX or FOLFIRI) may enter the study and receive Bev + GI-4000 every 2 weeks for up to 5 years. Enrollment is ongoing and will continue up to 52 subjects.