bluuebunny/crossref_metadata_2025_split huggingface dataset:
An open-label, randomized phase II study comparing first-line treatment with dovitinib (TKI258) versus sorafenib in patients with advanced hepatocellular carcinoma.
Authors: Cheng Ann-Lii , Lim Ho Yeong , Poon Ronnie Tung Ping , Throngprasert Sumitra , Reddick Cathy , Zhang Yong , Shi Michael , Tan Eugene , Wang Yongyu 
Published: March 2020

TPS4147 Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor that may rely on tumor angiogenesis for growth, invasion, and metastasis. Inhibition of the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) pathways temporarily prevents HCC tumor progression. However, because the fibroblast growth factor receptor (FGFR) pathway can serve as an escape pathway for these tumors, simultaneous inhibition of FGFR may be required to provide a sustainable antitumor response. Dovitinib (TKI258) has been shown to be a potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic factors, including FGFR, VEGFR, and PDGFR, with IC50 values of < 20 nM. Preclinical studies in HCC xenograft models have demonstrated that the antitumor effects of dovitinib are superior to those of the kinase inhibitor sorafenib, which is approved for use in advanced HCC. These data support additional testing of dovitinib in advanced HCC patients. Methods: This study (NCT01232296) is an open-label, randomized phase II trial being conducted at multiple centers in the Asia-Pacific region. Adult patients are eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C) with Child-Pugh class A cirrhotic status. Patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and cannot be eligible for (or have had disease progression after) surgical or locoregional therapies. Patients are randomized 1:1 to receive dovitinib (500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400 mg twice daily). Patients will be treated until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover will be permitted. The primary end point of this trial is overall survival. Secondary end points include time to tumor progression, disease control rate, time to definitive deterioration in ECOG status, safety, and pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib on plasma/serum biomarkers will also be explored. As of 30 January 2012, 93 of the planned 150 patients have been enrolled.
Sorafenib in combination with local microtherapy guided by gadolinium-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma (HCC) (SORAMIC).
Authors: Ricke Jens , Schuette Kerstin , Rosmorduc Olivier , Jakob Augustinus , Verslype Chris , Sangro Bruno , Walecki Jerzy , Klumpen Heinz-Josef , Peynircioglu Bora , Yalcin Bulent , Bartolozzi Carlo , Amthauer Holger , Malfertheiner Peter 
Published: March 2020

TPS4148 Background: HCC is a leading cause of cancer-related mortality in both men and women. It represents the fifth most common cancer worldwide with an increasing incidence. For the individual patient tumor stage at diagnosis (number and size of nodules, presence or absence of vascular invasion, presence or absence of extrahepatic spread), liver function and general health status are the principal prognostic factors. The clinical management of HCC requires a comprehensive, multidisciplinary approach. In early HCC curative treatment can be achieved by local ablation, resection or liver transplantation. In intermediate stages patients (pts) are offered locoregional treatment with palliative intent (transarterial chemoembolisation (TACE), Yttrium-90-radioembolisation (SIRT)). In advanced disease systemic therapy with sorafenib (sor) has the potential to prolong survival of pts and is standard of care in pts with preserved liver function. Studies on the combined use of locoregional and systemic therapy with their potential of a beneficial synergism are few and conducted in a small number of pts. Methods: This phase II-study is composed of three substudies with the following primary objectives: 1. In pts in whom local ablation is appropriate to determine if sor in combination with RFA prolongs the time-to-recurrence in comparison with RFA plus placebo. Primary endpoint (PEP): time to recurrence, n = 290 pts 2. In pts in whom RFA is not appropriate (palliative treatment group) to determine if the combination of SIRT and sor improves the overall survival in comparison to sor alone. PEP: overall survival, n = 375 pts 3. To confirm in a 2-step procedure that Gd-EOB-DTPA enhanced MRI is non-inferior or superior compared with contrast-enhanced multislice CT for stratification of pts to a palliative or a local ablation treatment strategy. PEP: correct stratification of pts to a palliative versus local ablation treatment strategy; n = 830 pts The trial has started in December 2010 as a multinational and multicentric study. 90 pts have been enrolled until January 31st 2012 with 51 pts randomized in the palliative arm and 14 pts treated in the curative arm.
Randomized phase II trial of TACE plus everolimus as first-line therapy in localized unresectable hepatocellular carcinoma (HCC): The TRACER trial.
Authors: Poon Ronnie Tung Ping , Chen Li-Tzong , Xue Hong-Ling , Tannir Bayane , Wang Jia Hua , Tanwandee Tawesak , Paik Seung-Woon 
Published: March 2020

TPS4149 Background: Transcatheter Arterial Chemoembolization (TACE) has shown benefit in improving survival and is a widely used treatment for unresectable HCC. However, TACE induces hypoxia leading to up-regulation of HIF-1α and VEGF signaling, and tumor progression. Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR) and its downstream signaling including HIF-1α. Everolimus has also been shown to increase chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9). Combining everolimus with TACE may delay tumor progression. TRACER (Tace with Rad001 in Asian Centers for Evaluation and Research) aims to evaluate the efficacy and safety of everolimus plus TACE in patients with localised unresectable HCC. Methods: TRACER is a multinational, randomized, double-blind, placebo-controlled phase II trial. Patients aged ≥18 years newly diagnosed with localized unresectable Child A HCC; ECOG PS of <2; ≥1 unidimensional lesion measurable according to RECIST; and adequate bone marrow, liver, and renal function. Exclusion criteria include main portal vein invasion and/or extrahepatic spread; prior local or systemic treatment for HCC, or contraindications to TACE. Eligible patients who have successfully undergone the first TACE are randomized 1:1 to oral everolimus 7.5mg or matching placebo daily. TACE is repeated every 10 weeks or so. A short everolimus dose interruption of 48 hours before and after each TACE has been designed to allow recovery from complications of TACE. For standardization, doxorubicin-eluting beads are being used in every TACE. Patients shall exit the trial upon tumor progression, unacceptable toxicity, death, or trial discontinuation. All endpoints will be assessed on an ITT basis. The primary endpoint is time to progression base on Modified RECIST Criteria. Secondary endpoints include objective response rate, overall survival, and incidence of extrahepatic spread, safety and exploratory biomarkers. An independent data monitoring committee has been established to safeguard the trial subjects. Estimated total enrollment is 80, of which 12 subjects have been enrolled. (Clinical Trial Registry Number: NCT01379521.)
The CLARINET study: Assessing the effect of lanreotide autogel on tumor progression-free survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors.
Authors: Delavault Patrick , Caplin Martyn E , Liyange Nilani , Blumberg Joelle ,   UK and Ireland Neuroendocrine Tumour Society/European Neuroendocrine Tumor Society
Published: March 2020

TPS4153 Background: Somatostatin analogs (SSAs) provide good symptom control in patients with neuroendrocine tumors (NETs). Clinical studies suggest SSAs also stabilize tumor growth. In a previous double-blind study (PROMID) in a mixed functioning and non-functioning gastroenteroNET population (n=85), octreotide LAR significantly increased time to tumor progression compared with placebo. The CLARINET study is being undertaken to explore the antiproliferative effects of SSAs in a more homogeneous population. Specifically, the CLARINET study is a double-blind, placebo-controlled trial assessing the effect of 120 mg of lanreotide Autogel (lanreotide Depot in the USA) on progression-free survival in patients with non-functioning gastroenteropancreatic NETs (GEP-NETs). Methods: CLARINET is a 96-week, multinational study being conducted in collaboration with UKI NETS and ENETS in patients with well or moderately differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of <10%. Patients are stratified by prior tumor progression status and presence/absence of previous therapies, and treated with lanreotide Autogel 120 mg or placebo. The primary endpoint is time to either disease progression (using Response Evaluation Criteria In Solid Tumors) or death. Two baseline computed tomography scans (≥12 weeks apart) are being performed, followed by additional scans at intervals up to 96 weeks. Secondary endpoints include proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, safety, quality of life, plasma chromogranin A levels, tumor markers, and pharmacokinetic parameters. The primary study population for the analysis will be the intention-to-treat population. Recruitment is now complete (n=204) and, thus far, the drug safety monitoring committee has identified no safety concerns. The trial is registered with ClinicalTrials.gov (NCT NCT00353496).
Randomized phase II study of docetaxel with or without ramucirumab (IMC-1121B) or icrucumab (IMC-18F1) in patients with urothelial transitional cell carcinoma (TCC) following progression on first-line platinum-based therapy.
Authors: Petrylak Daniel Peter , Chi Kim N. , Vogelzang Nicholas J. , Sonpavde Guru , Rutstein Mark D. , Schwartz Jonathan D. , Fox Floyd E. , Wang Weigang , Abad Leslie W , Cosaert Jan , Grebennik Dmitri O. 
Published: March 2020

TPS4675^ Background: The vascular endothelial growth factor (VEGF) pathway may play an important role in the pathogenesis of bladder cancer. Two antibodies (ramucirumab or icrucumab) in combination with docetaxel are being tested in this clinical study. Ramucirumab is a fully human IgG1 monoclonal antibody (MAb) that specifically binds with high affinity to VEGF receptor-2 (VEGFR-2), thereby blocking the interaction of VEGF ligands. Ramucirumab inhibits VEGF-mediated proliferation of human endothelial cells and migration of human leukemia cells. Icrucumab is a fully human IgG1 MAb that specifically binds with high affinity to VEGFR-1 and blocks the binding of VEGF-A, VEGF-B, and placental growth factor (PlGF) to the receptor, thereby inhibiting subsequent signaling. Blockage of VEGFR-1 and VEGFR-2 by antibodies demonstrates antiangiogenic and antitumor activity and prevents dissemination and growth of lung metastases in several tumor xenograft models. Methods: This study includes patients (pts) with TCC with progressive disease after prior platinum-based therapy. Pts are randomized equally to 1 of 3 open-label treatments given on a 21-day cycle: docetaxel (75 mg/m2) on Day 1 (Arm A); docetaxel on Day 1 and ramucirumab (10 mg/kg) on Day 1 (Arm B); or docetaxel on Day 1 and icrucumab (12 mg/kg) on Days 1 and 8 (Arm C). Randomization is stratified by the absence/presence of visceral metastases and receipt of prior antiangiogenic therapy. The primary endpoint is progression-free survival (PFS). Secondary outcome measures include response rate and duration of response, overall survival, and pharmacodynamic markers, including circulating levels of PlGF, VEGF-A, VEGF-B, soluble VEGFR-1, and soluble VEGFR-2. Exploratory analyses of VEGF, VEGFR-1, and VEGFR-2 genetic polymorphisms will be performed. As of 12 January 2012, approximately 20% of 138 planned pts were randomized in the US and Canada. The sample size will allow differentiation of an expected increase in median PFS from 3.0 months to 4.5 months with a one-sided alpha of 0.1 and a power of 71%. ClinicalTrials.gov identifier: NCT01282463.
A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC).
Authors: Singer Eric A. , Friend Julia C. , Hawks Geri , Vocke Cathy , Metwalli Adam R. , Pinto Peter A. , Bratslavsky Gennady , Linehan W. Marston , Srinivasan Ramaprasad 
Published: March 2020

TPS4680 Background: There are currently no treatment options of proven efficacy for patients with advanced papillary RCC. The evaluation of families with inherited forms of RCC has allowed for the identification of genetic alterations associated with papillary RCC. HLRCC is one such familial condition with a propensity for the development of a clinically aggressive variant of papillary RCC characterized by unique histopathologic features. Germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation of FH leads to von Hippel-Lindau-independent upregulation of hypoxia inducible factors (HIF) and their downstream transcriptional targets such as vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-α) / epidermal growth factor receptor (EGFR). Upregulation of the HIF pathway may also be important in sporadic papillary RCC, although the prevalence of FH inactivation in these patients is unknown. We propose to evaluate the activity of dual VEGF/EGFR blockade with bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic papillary RCC. Methods: This is a single arm phase II study based on an open label Simon two-stage minmax design with a maximum accrual of 20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 2- patients with sporadic papillary RCC. The primary endpoint is RECIST overall response rate, assessed independently in each cohort. Patients will receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO daily). Dose reductions and drug interruptions for toxicity are allowed. Patients will be evaluated for response every 8 weeks. Major eligibility criteria include: advanced RCC associated with HLRCC or sporadic papillary RCC; age >18 years; ECOG 0-2; measurable disease by RECIST; no brain metastases; no more than 2 prior regimens containing a VEGF inhibitor; and no prior therapy with bevacizumab. The prespecified activity goal for the first stage of accrual has been met for both cohorts. NCT01130519.
A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.
Authors: Dreicer Robert , Agus David B. , Bellmunt Joaquim , De Bono Johann Sebastian , Petrylak Daniel Peter , Tejura Bindu , Shi Yuanjun , Fizazi Karim 
Published: March 2020

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).
A phase I/IIa study of the safety and efficacy of radium-223 chloride (Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC) patients with bone metastases.
Authors: Morris Michael J. , Hammers Hans J. , Sweeney Christopher , Bloma Marianne , Aksnes Anne-Kirsti , O'Bryan-Tear C. Gillies , Carrasquillo Jorge A. 
Published: March 2020

TPS4694 Background: Ra-223is a first-in-class alpha-pharmaceutical that targets bone metastases (mets) with high energy alpha-particles of short range (< 100 μm). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC) significantly improved OS vs placebo plus BSC in CRPC patients (pts) with bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an excellent safety profile. Since D is an approved chemotherapy with demonstrated survival benefit for pts progressing after castrating hormone therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC and bone mets. This study is being conducted in the Prostate Cancer Clinical Trials Consortium with an aim to establish the safe dose of Ra-223 and D when used in combination in pts with bone mets with CRPC. Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts with bone mets from CRPC intended for treatment with D. D naïve pts are preferred, although up to 10 previous infusions of D are acceptable if D was well tolerated and the patient is in good condition and fulfills all eligibility criteria at study entry. Phase I dose-escalation study: minimum of 9 pts (max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed. Dose escalation will follow a ‘3+3’ design, with no intra-patient dose escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50 kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75 mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are available after 1st Ra-223 +D inj. Phase IIa open-label expanded safety study: pts will be randomized 2:1 to the recommended dose of Ra‑223 to be used with D or to treatment with D alone (approx. 42 pts will be included). Primary endpoint is to assess safety of combining Ra-223 with D. Exploratory efficacy endpoints for the open-label expanded safety portion of the study include change in disease-related biomarkers, time to 1st radiological or clinical progression, CTC and pain assessment. Enrollment in dose-escalation portion of the study is complete; expanded safety cohort to begin enrolling in March 2012.
Targeting castration resistant prostate cancer (CRPC) with autologous PSMA-directed CAR+ T cells.
Authors: Slovin Susan F. , Wang Xiuyan , Borquez-Ojeda Oriana , Stefanski Jolanta , Olszewska Malgorzata , Taylor Clare , Bartido Shirley , Scher Howard I. , Sadelain Michel , Riviere Isabelle 
Published: March 2020

TPS4700 Background: Based on our preclinical animal models, we initiated a phase I dose-escalating study to assess safety, dose requirement and targeting efficiency of genetically directed autologous human T cells targeted to Prostate Specific Membrane Antigen (PSMA). Our approach is based on the infusion of autologous PSMA-targeted T cells utilizing the P28z second generation chimeric antigen receptor (CAR) in patients (pts) with metastatic CRPC, following iv cyclophosphamide (Cy) (trial NCT01140373). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, and renders T cells sensitive to ganciclovir for immediate T cell elimination if needed. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize adoptively transferred T cells. The aims of the trial are to assess: (1) safety of PSMA-targeted T cells; (2) biologic and anti-tumor effects; (3) T cell persistence at tumor site; and (4) immune response. 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 will be treated at 3 dose levels from 107 to 108 CAR+ T cells/kg. Four patients have been enrolled; 3 have been treated with 300mg/m2 of Cy one day before infusion of 107 CAR+ T cells/kg. Pts underwent baseline and post treatment CT, bone and PET scans. Pts are followed weekly, then monthly with blood work including immune and vector sequence monitoring. Results: The first 3 pts within the first cohort were successfully treated without toxicity. Two had stable disease for greater than 6 months with the third patient having disease progression. There were no acute adverse events. Conclusion: We have established an ex vivo transduction, expansion and therapeutic protocol for the generation and testing of safe, clinical-grade, PSMA targeted T cells. Pts enrolled at the next dose level of 3 x 107 CAR+ T cells/kg will be assessed as described and by imaging the transduced T cell population using 18F-FIAU as a radiotracer. The data pertaining to the planned T cell imaging will be presented as well.