bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.
Authors: Rizvi Naiyer A. , Infante Jeffrey R. , Gibney Geoffrey Thomas , Bertino Erin Marie , Cooley Sarah A. , Lekatis Kiki , Wigginton Jon M. , Gutierrez Andres A. , Gupta Ashok Kumar , Kim Su Young , Hodi F. Stephen 
Published: March 2020

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.
A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors.
Authors: Sanborn Rachel E. , Sharfman William Howard , Segal Neil Howard , Hodi F. Stephen , Wolchok Jedd D. , Urba Walter John , Fox Bernard A. , Topalian Suzanne Louise , Pardoll Drew M. , Covello Kelly L. , McDonald Dan , Kim Su Young , Gupta Ashok Kumar , Wigginton Jon M. , Gajewski Thomas 
Published: March 2020

TPS3110 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down-regulate NK and T cell activity, respectively. Lirilumab, an anti-KIR antibody that potentiates innate immunity, has demonstrated modest side effects in a phase I monotherapy trial. Nivolumab, a PD-1 receptor blocking antibody that potentiates adaptive immunity, has shown clinical activity with various solid tumors in phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity with anti-KIR and anti-PD-1 antibodies could achieve more favorable biologic and clinical activity than either agent alone. Here, we describe a phase I study of lirilumab plus nivolumab in pts with advanced solid tumors, the first collaborative clinical trial being conducted by the International Immuno-Oncology Network (II-ON). Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with any solid tumor, except primary central nervous system tumors, will be enrolled. During cohort expansion, pts (N=16/cohort) with non-small cell lung carcinoma – squamous and non-squamous histology, renal cell carcinoma, melanoma, colorectal carcinoma, or ovarian carcinoma will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity in all pts, and pharmacodynamic effect on tumor infiltrating lymphocyte subsets from melanoma pts. Exploratory objectives include a thorough assessment of innate and adaptive immunity modulation by this combination in peripheral blood and/or tumor specimens, as well as preliminary associations with clinical outcome. As of Feb 1, 2013, three pts have started therapy. Clinical trial registration number: NCT01714739. Clinical trial information: NCT01714739.
Trial proactive: A prospective, randomized, multicenter, open label phase III study of active specific immunotherapy with racotumomab plus best support treatment versus best support treatment in patients with advanced non-small cell lung cancer.
Authors: Gomez Roberto E , Macias Amparo , Crombet Tania , Vazquez Ana Maria , Perez Rolando , Ardigo Maria Laura , Lage Agustin 
Published: March 2020

TPS3123 Background: Gangliosides, especially NeuGc-GM3, are attractive targets for cancer immunotherapy. They are not expressed in normal human cells but are overexpressed and involved in tumor growth in several tumors (melanoma, neuroectodermal pediatric tumors and breast cancer). More than 70% of non-small cell lung cancers (NSCLC) express NeuGc-GM3. Racotumomab is an anti-idiotypic monoclonal antibody that mimics NeuGc gangliosides. Administered as a therapeutic vaccine it acts as an antigen, inducing a cellular and humoral immune response against NeuGc-GM3 and other gangliosides. Previous trials have shown its low toxicity and high immunogenicity. Recently, a multicenter, randomized, placebo controlled, double-blind trial in 176 NSCLC (IIIB and IV) patients with at least stable disease after first line therapy and progression free at inclusion showed a statistical significant survival benefit in favor of racotumomab. Methods: This phase III, multinational, randomized (1:1), open label trial will evaluate efficacy and safety of racotumomab plus best supportive care (BSC) versus BSC. 1,082 patients with NSCLC (stages III or IV) showing response or stable disease after standard first-line therapy (platinum-based chemotherapy and radiotherapy) are eligible if they remain free of progression and have a PS ≤ 1. Vaccination consists of an induction period (5 doses, 1 every 14 days) followed by a maintenance period (1 dose every 28 days, until worsening of the PS or unacceptable toxicity occur). Upon progression other onco-specific therapies may be used and vaccination can continue. Overall survival (OS) will be compared using a two-sided log rank test at a significance level (alpha) of 0.05 with 90% power to detect a hazard ratio of 0.79. There will be 3 interim analyses and a final analysis when 758 deaths occur. So far 190 patients have been randomized. An Independent Data Monitoring Committee oversees the study and has so far (last meeting September 2012) concluded that the trial can continue. The trial is registered in ClinicalTrials.gov under NCT01460472. Clinical trial information: NCT01460472.
FOCUS4: A prospective molecularly stratified, adaptive multicenter program of randomized controlled trials for patients with colorectal cancer (CRC).
Authors: Shiu Kai-Keen , Maughan Tim , Wilson Richard H. , Adams Richard A. , Pugh Cheryl , Brown Louise , Fisher David , Wasan Harpreet , Middleton Gary William , Steward William P. , Kaplan Richard S. 
Published: March 2020

TPS3645 Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarker-based subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.
SWOG S1115: Randomized phase II clinical trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) versus mFOLFOX in patients withmetastatic pancreatic cancer after prior chemotherapy.
Authors: Chung Vincent M. , McDonough Shannon , Philip Philip Agop , Cardin Dana Backlund , Lowy Andrew M. , Benedetti Jacqueline K. , Blanke Charles Davic 
Published: March 2020

TPS4145 Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Over 80% of pancreatic cancers are KRAS mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. Recent data has shown that blocking both the PI3K/AKT and MEK pathways simultaneously is effective in KRASmutant tumors. Our trial is a novel, molecular targeted treatment approach for patients with metastatic pancreatic cancer that has the potential to establish a new treatment paradigm. Methods: S1115 was activated in SWOG in August 2012 and is currently IRB approved at 130 institutions within SWOG and the Clinical Trials Support Unit (CTSU). Patients (performance status 0 or 1) with metastatic pancreatic cancer failing standard gemcitabine chemotherapy are randomized to MK-2206 135 mg orally weekly plus selumetinib 100 mg orally daily or mFOLFOX IV every 2 weeks. Eligibility criteria allow metastatic patients who have progressed within 6 months of receiving adjuvant gemcitabine. Patients receiving prior 5-fluorouracil (excluding radiation-sensitizing doses), capecitabine, oxaliplatin, MEK or PI3K/AKT inhibitors are not eligible. Stratification factors include duration of prior systemic therapy and presence of liver metastases. The primary endpoint of this study is overall survival (OS) in patients treated with the combination of MK-2206 and selumetinib compared with those treated with mFOLFOX. Based on previous studies, median OS in the control group is approximately 6 months. Assuming a one-sided type 1 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 120 eligible patients will be accrued to detect an improvement in median survival from 6 to 9 months (corresponding to a 1.5 hazard ratio). Prospective tumoral tissue collection will be undertaken. ClinicalTrials.gov Identifier: NCT01658943. Support: NCI grants CA32102 & CA38926 Clinical trial information: NCT01658943.
A UGT1A1 genotype-directed phase II toxicity and efficacy-finding study of irinotecan combined with S-1 as first-line treatment in advanced gastric cancer.
Authors: He Xiaofeng , Du Zedong , Wen Feng , Zhang Pengfei , Tang Ruilei , Zhou Yi , Li Qiu 
Published: March 2020

TPS4154 Background: The best chemotherapy regimen for advanced gastric cancer (AGC) is uncertain, but promising findings have been reported with Irinotecan (IRI) plus S-1. However, IRI can induce severe neutropenia or diarrhea associated with homozygosity of the UGT1A1*28 or UGT1A1*6 alleles. This trial was designed to compare the toxicity and efficacy on different doses of IRI combined with S-1 according to UGT1A1 genotype as first-line chemotherapy in AGC in Chinese patients. Methods: Previously untreated patients with histologically proven gastric or gastroesophageal junction adenocarcinoma, aged between 18 and 75 years with ECOG performance status 0-2 were classified according to UGT1A1 genotype: wild-type (none of *28 or *6 allele); heterozygous (only one of *28 or *6 allele); or homozygous (*28/*28, *6/*6, or double heterozygous for *28 and *6). Patients were randomized (1:1) to receive either low or high dose of IRI given i.v. (90 min) on day 1 in each genotype group. The low and high dose of IRI were 80mg/m2 and 200 mg/m2 in the wild-type group, 80 mg/m2 and 150 mg/m2 in the heterozygous group, 40 mg/m2 and 80 mg/m2 in the homozygous group. S-1 was administered orally at a dose level set on the basis of the body surface area (BSA): 40 (BSA<1.25 m2), 50 (BSA≥1.25 to<1.5 m2 ) or 60 mg (BSA≥1.5 m2) twice a day on day1-7. Courses were repeated every 2 weeks, unless disease progression, unacceptable toxicity or patient refusal. The primary endpoint was to explore the safety and efficacy on different doses of IRI combined with S-1 according to UGT1A1 polymorphism. Based on the frequency of UGT1A1*28 and UGT1A1*6 gene polymorphism in Asian gastrointestinal cancer patients, the chi-square test and fisher exact test were used to evaluate the planned sample size which is 100 in total: 40 for the wild-type, 40 for the heterozygous and 20 for the homozygous group. Until now, 8 patients have been enrolled. Clinical trial information: ChiCTR-OCH-12002472.
Regorafenib (REG) in patients with hepatocellular carcinoma (HCC) progressing following sorafenib: An ongoing randomized, double-blind, phase III trial.
Authors: Cheng Ann-Lii , Finn Richard S. , Kudo Masatoshi , Llovet Josep M. , Qin Shukui , Le Berre Marie-Aude , Krissel Heiko , Bruix Jordi 
Published: March 2020

TPS4163 Background: Sorafenib is the accepted first-line systemic therapy for HCC, but no standard option is available for patients with tumor progression following sorafenib. An open-label phase II study suggested that REG, a multikinase inhibitor, had an acceptable safety profile and showed evidence of antitumor activity in patients with progressive HCC (Bolondi et al. Eur J Cancer 2011; 47 [Suppl 1]: abstract 6.576): disease control was achieved in 26/36 patients (72%) and median time to progression (TTP) was 4.3 months; median overall survival (OS) was 13.8 months. On the basis of these promising data, a phase III trial was designed. Methods: This randomized, double-blind, placebo (PBO)-controlled, multinational study (ClinicalTrials.gov identifier NCT01774344) will assess the efficacy and tolerability of REG vs PBO in patients with HCC that has progressed following sorafenib treatment (target n=530). Inclusion criteria include Barcelona Clinic Liver Cancer stage B or C disease, Child–Pugh A liver function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Patients who discontinued sorafenib ≥8 weeks before study entry or who received other previous systemic therapy for HCC will be excluded. Patients will be randomized in a 2:1 ratio to receive REG 160 mg or matching PBO OD for weeks 1–3 of each 4-week cycle; all patients will also receive best supportive care. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. The primary endpoint is OS; secondary endpoints are TTP, progression-free survival, tumor response, and safety. Analysis will be according to randomized group, stratified by geographic region (Asia vs rest of world), ECOG PS (0 vs 1), alfa-fetoprotein level (<400 vs ≥400 ng/ml), extrahepatic disease (yes vs no), and macrovascular invasion (yes vs no). In addition, blood, plasma, and archival tissue will be assessed for pharmacokinetic and biomarker analyses, and health-related quality of life and health utility will be measured. Clinical trial information: NCT01774344.
A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma.
Authors: Apolo Andrea Borghese , Parnes Howard L. , Madan Ravi Amrit , Gulley James L. , Wright John Joseph , Khadar Kattie , Trepel Jane B. , Schlom Jeffrey , Arlen Philip M. , Merino Maria , Steinberg Seth M. , Choyke Peter L. , Lindenberg Maria Liza , Kurdziel Karen A. , Folio Les , Figg William Douglas , Agarwal Piyush K. , Bottaro Donald P. , Dahut William L. 
Published: March 2020

TPS4589 Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.
A phase II trial of cabozantinib (Cabo) in patients (pts) with castrate-resistant prostate cancer (CRPC) metastatic to bone (NCT01428219).
Authors: Grivas Petros , Daignault Stephanie , Cooney Kathleen A. , Jacobson Jon , Yablon Corrie , Ross Brian Dale , Chenevert Thomas L , Galbán Craig J , Rehemtulla Alnawaz , Keller Evan T. , Kunju Priya , Mehra Rohit , Escara-Wilke June , Shelley Greg , Pienta Kenneth James , Hussain Maha , Smith David C. 
Published: March 2020

TPS5094 Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone micro-environment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/duration, PSA response, PSA time-to-progression. A Simon's two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is <0.45; it would be of definite clinical interest if the 12-week PF proportion is >0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.