bluuebunny/crossref_metadata_2025 huggingface dataset:
First-in-human phase I trial of NHS-IL12 in advanced solid tumors.
Authors: Kim Joseph W. , Heery Christopher Ryan , Bilusic Marijo , Singh Nishith K. , Madan Ravi A. , Sabzevari Helen , Schlom Jeffrey , Gulley James L.
Published: March 2020

TPS2617

Background: NHS-IL12 is an antibody-cytokine conjugate consisting of two heterodimers of interleukin (IL)-12, fused to a human monoclonal antibody specific for DNA-histone H1 complex exposed in tumor necrosis. IL12 is a proinflammatory cytokine, produced by activated phagocytes and dendritic cells, that plays a critical role in regulating the transition from innate to adaptive immunity. Early clinical trials of IL12 reported clinical responses in metastatic renal cell carcinoma, Kaposi sarcoma (50–71% response rate), T-cell lymphoma (56%), and non-Hodgkin’s lymphoma (21%). However, systemic toxicity limited further clinical development. NHS-IL12 is designed to reduce toxicity associated with systemic administration of IL12 by selectively targeting delivery to necrotic areas of tumors. A fluorescence imaging study of NHS-murine (mu)-IL12 in mice with syngeneic lung carcinoma demonstrated effective targeting by NHS-muIL12. Immunohistochemistry studies further confirmed effective targeting of tumors by NHS-muIL12. In another study in canines with spontaneously occurring solid tumors, 2 of 11 subjects achieved a partial response with a single dose. Methods: This is a phase I dose-escalation study designed to determine the maximum tolerated dose of NHS-IL12 and to define the biologically optimal dose and schedule based on immunologic (pharmacodynamic) analysis of cytokines such as interferon-g, and IL-10, at multiple times points from 4 hours up to 2 weeks following the administration of NHS-IL12. Eligible patients (pts) include those with evaluable or measurable solid tumors who have progressive disease on at least one prior line of therapy. Pts with a condition associated with significant necrosis of non-tumor bearing tissue, (e.g., ulcerative colitis), are excluded. Modified immune-related response criteria are used to assess response, the major features of these criteria being (a) imaging confirmation of both progression and response at least 4 weeks after initial imaging, and (b) no consideration of new lesions unless the total measurable tumor burden meets the criteria for progressive disease. This trial opened to accrual in Nov. 2011 and may enroll up to 78 pts.
Safety, pharmacokinetics, and antitumor activity of MEDI3617, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.
Authors: Natale Ronald B. , Rizvi Naiyer A. , Infante Jeffrey R. , Joseph Lindsay J. , Viner Jaye , McDevitt Jennifer T. , Ji Fei , Shin Soyoung , Liang Meina , Burris Howard A.
Published: March 2020

TPS2621

Background: MEDI3617 is an investigational monoclonal antibody that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 (Ang2) ligands with the Tie2 receptor. Methods: This is an ongoing phase 1 dose-escalation and dose-expansion study in patients with advanced solid tumors, Karnofsky performance status ≥70, and adequate organ function. Patients were treated with escalating IV doses of MEDI3617 on day 1 of each 21 day cycle in cohorts of 3-6 patients. The objectives are to evaluate the safety profile and determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and clinical activity of MEDI3617. Results: Preliminary data are presented for 21 patients (14M/7F), median age 65 yrs, evaluable for DLT. One DLT occurred: grade 4 neutropenia lasting more than 7 days. The most frequently reported drug-related adverse events (% of patients) were fatigue (24%), diarrhea (19%), nausea (19%), dysgeusia (14%), and headache (14%), all of which were ≤ grade 2. All monotherapy dose levels have completely enrolled patients without exceeding the maximum tolerated dose. The exposure of MEDI3617 after the first dose showed a more than dose-proportional increase. Suppression of free Ang2 was dose-dependent. Maximum accumulation of total Ang2 was observed at the lowest administered dose. No anti-MEDI3617 neutralizing antibodies were detected. Of the 21 patients, 4 continue on treatment (maximum of 6+ months in a patient with carcinoid tumor of the jejunum) as of the data cut-off date. Of the 17 patients for whom response data are available, 5 had stabilization of disease of 12 weeks or greater. Conclusions: Preliminary safety and activity signals warrant continued evaluation of MEDI3617. This study was funded by MedImmune, LLC.
A dose escalation, single arm, phase Ib/II combination study of BEZ235 with everolimus to determine the safety, pharmacodynamics, and pharmacokinetics in subjects with advanced solid malignancies including glioblastoma multiforme.
Authors: Salkeni Mohamad Adham , Beg Muhammad Shaalan , Olowokure Olugbenga Olanrele , Fathallah Hassana , Thomas Hala , Mercer Carol A , Charif Mahmoud , Chaudhary Rekha T. , Abdel Karim Nagla , Warnick Ronald , McPherson Christopher , Moorthy Ganesh , Desai Pankaj B , Kozma Sara , Thomas George , Rixe Olivier
Published: March 2020

TPS3116

Background: Downregulation of a number of signaling pathways, including the mammalian target of rapamycin (mTOR) pathway, has been demonstrated to be efficacious in a large range of solid tumors such as breast, colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we find that rapamycins lead to suppression of a negative feedback loop from S6 Kinase 1 (S6K1) to Protein Kinase B (PKB), leading to hyperactivation of PKB. In pre-clinical studies using a mouse model of carcinogen-induced HCC, we have demonstrated that combining BEZ235 (a potent and highly selective reversible ATP site competitive inhibitor of PI3K and mTOR) with everolimus (an allosteric inhibitor of mTOR) synergizes to inhibit tumor growth. BEZ235, an orally administered agent, has demonstrated preliminary antitumor activity in a first-in-human phase I study. The current study will evaluate this combination in patients with a variety of solid malignancies that includes glioblastoma multiforme (GBM). Methods: This study is divided into a phase 1b portion designed to determine safety of increasing doses of the combination, with extensive pharmacokinetics, pharmacodynamics and pharmacogenomics analysis; and a phase 2 portion that includes both solid tumors and GBM based on predominance of the mTOR and PI3K deregulation in these tumors, to determine preliminary anti-tumor activity and the recommended dose for phase 2 studies. We will also integrate biomarker assessment for gene expression products of the mTOR downstream pathway such as eukaryotic initiation factor 4E binding protein (4EBP1) and S6 kinase (S6K). The phase 1b portion has started accruing.
A randomized, double-blind, phase (Ph) III study of the irinotecan-based chemotherapy FOLFIRI plus ramucirumab (RAM) or placebo (PL) in patients (pts) with metastatic colorectal carcinoma (mCRC) progressive during or following first-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and a fluoropyrimidine (FP) (RAISE) (NCT01183780).
Authors: Grothey Axel , Tabernero Josep , Rougier Philippe , Ballal Shaila , Crane Heidi , Rutstein Mark D.
Published: March 2020

TPS3634

Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In a preclinical study, antiangiogenic and antitumor effects were observed when DC101, an antibody that targets murine VEGFR-2, was administered to mice bearing human colon cancer xenografts. Antitumor activity for RAM has been demonstrated in a Ph I study in pts with solid tumors over a wide range of RAM dose levels and in a Ph II study with RAM + mFOLFOX-6 as 1st-line therapy in pts with mCRC. Methods: This ongoing, randomized, double-blind, placebo-controlled Ph III study includes mCRC pts with measurable or nonmeasurable disease and ECOG performance status of 0-1 who have experienced disease progression during or within 6 months following 1st-line therapy with BEV, OXALI, and any FP. Randomization is stratified by geographic region, KRAS status, and time to progression after initiation of 1st-line therapy. Pts are randomized 1:1 to either RAM 8 mg/kg or PL every 14 days. Pts in both arms receive FOLFIRI (irinotecan: 180 mg/m2, folinic acid: 400 mg/m2, 5-fluorouracil: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hours). The primary endpoint is overall survival (OS). The sample-size estimate assumes 85% power to detect at least a 2.5-month median OS difference (HR = 0.8) between treatment arms with a 1-sided alpha of 0.025. Secondary endpoints include progression-free survival, tumor response, safety, pharmacokinetics, immunogenicity, and correlations between biomarkers and clinical outcome. CRC tissue and blood collection is mandatory for biomarker analyses. As of 05 January 2012, 238 of 1050 planned pts have been enrolled from 100 sites in North America, South America, Europe, Asia, and Australia.
TRICC-c: BIBF 1120 versus placebo in patients receiving oxaliplatin plus fluorouracil and leucovorin (mFOLFOX6) for advanced, chemorefractory metastatic colorectal cancer (mCRC)—A multicenter, randomized phase II trial in progress.
Authors: Berger Andreas , Ettrich Thomas , Marten Angela , Seufferlein Thomas
Published: March 2020

TPS3636

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in western countries. With advances in the treatment of metastatic CRC (mCRC) in the last decade using combination chemotherapy and bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), progression free survival (PFS) in first and second line setting was substantially improved. Tumour angiogenesis is also driven by other factors but VEGF including Platelet Derived Growth Factor (PDGF) and Fibroblast Growth Factor (FGF). BIBF1120 is a potent, orally available triple angiokinase inhibitor that blocks the receptor tyrosine kinase activity of human VEGFR1-3, FGFR1 and -3 and PDGFRα and -β. Thus, BIBF1120 could be an exciting addition to the treatment of patients with chemorefractory CRC. Methods: Randomized, double-blind, placebo-controlled, multicentre, phase II trial of BIBF1120 (orally, 200 mg, bid, d1-d14, Arm A) vs. placebo (Arm B) in patients receiving mFOLFOX6 (oxaliplatin, 85 mg/m2, fluorouracil, 400 mg/m2 bolus and 2400 mg/m2 over 46 h, leucovorin, 200 mg/m2) q14 d for patients (ECOG performance status 0-1) with chemorefractory mCRC who received one prior line of chemotherapy. Scheduled are 90 patients per treatment arm. Primary endpoint: PFS, Secondary endpoints: objective response, overall survival, duration of overall response, safety. Additionally there will be an explorative analysis of predictive biomarkers for BIBF1120. 4 of planned 180 patients have been enrolled. We expect the last patient out in June 2013. (Trial identifier: NCT01362361.)
Sequential first-line treatment for metastatic colorectal cancer with capecitabine, irinotecan, and bevacizumab: Capecitabine plus bevacizumab (Cape-Bev) versus capecitabine, irinotecan plus bevacizumab (CAPIRI-Bev): The AIO KRK 0110/ML22011 randomized, phase III trial.
Authors: Giessen Clemens Albrecht , Modest Dominik Paul , Stintzing Sebastian , Fischer von Weikersthal Ludwig , Vehling-Kaiser Ursula , Spaeth-Schwalbe Ernst , Freiberg-Richter Jens , Mayerle Julia , Bangerter Markus , Denzlinger Claudio , Sieber Markus , Teschendorf Christian , Peuser Bettina , Heinemann Volker
Published: March 2020

TPS3639

Background: Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question in bevacizumab-based first-line treatment including escalation- and de-escalation strategies. Methods: The AIO KRK 0110/ML22011 trial (ClinicalTrials.gov NCT01249638) is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of Cape-Bev versus CAPIRI-Bev in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, ECOG PS 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumor tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are ORR, OS, PFS, safety and quality of life. Conclusion: The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with CAPIRI-Bev and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary. By January 2012, 79 of planned 516 patients have been enrolled.
A randomized, multicenter, double-blind, placebo (PBO)-controlled phase III study of paclitaxel (PTX) with or without ramucirumab (IMC-1121B; RAM) in patients (pts) with metastatic gastric adenocarcinoma, refractory to or progressive after first-line therapy with platinum (PLT) and fluoropyrimidine (FP).
Authors: Wilke Hansjochen , Cunningham David , Ohtsu Atsushi , Nuber Ulrike , Bruns Rolf , Schmitt-Bormann Beate
Published: March 2020

TPS4139

Background: Vascular endothelial growth factor (VEGF) expression in gastric cancer (GC) is associated with more aggressive clinical disease. VEGF expression in resected GC is associated with tumor recurrence and shorter survival. Data from Phase 2 and 3 studies suggest that agents targeting the VEGF pathway improve the efficacy of some chemotherapy regimens in 1st- and 2nd-line treatment of patients with gastric or gastroesophageal carcinomas. RAM, a fully human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2), potently blocks the binding of VEGF to VEGFR-2, inhibits VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced mitogenesis of human endothelial cells. Methods: Pts are randomized 1:1 to receive PTX + RAM or PTX + PBO until disease progression or intolerable toxicity (28-day cycle; RAM/PBO 8 mg/kg Days 1, 15; PTX 80 mg/m2 Days 1, 8, 15). Eligibility includes metastatic or locally advanced, unresectable gastric or gastroesophageal junction adenocarcinoma; prior first-line therapy with any PLT/FP doublet with or without anthracycline; progressive disease during or following first-line therapy; ECOG PS 0-1; bilirubin ≤ 1.5 × upper limit of normal (ULN), transaminases ≤ 3 × ULN for ALAT/ASAT if no liver metastases, < 5 × ULN if liver metastases; creatinine ≤ 1.5 × ULN; absolute neutrophil count ≥ 1.5 × 109/L, hemoglobin ≥ 9 g/dL; platelets ≥ 100 × 109/L. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival, time to progression, best overall response, objective response rate, safety, patient-reported outcome measures, pharmacodynamics, immunogenicity, and pharmacokinetics. This study, powered at 90% to show an increase in OS (mdn: 7 m PTX + PBO, 9.33 m PTX + RAM) at a 1-sided 2.5% significance level, will randomize 663 pts. As of 18 January 2012, approximately 58% of planned pts were randomized. The IDMC reviewed this study 23 June and 01 December 2011 and recommended the study continue unmodified.
Lapatinib in combination with ECF/x in EGFR1 positive first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071).
Authors: Moehler Markus Hermann , Schad Arno , Mauer Murielle E. , Praet Michel , Sapunar Francisco J. , Briggs Kathryn Jane , Lutz Manfred P. , Roth Arnaud
Published: March 2020

TPS4140

Background: Survival of HER2+ metastatic GC is prolonged by trastuzumab when administered with CF/X (VanCutsem, ASCO 2009). Lapatinib inhibits both EGFR1 and HER2, is active in HER2+ GC lines, and has shown clinical activity in uncontrolled phase II GC trials. A phase III trial of lapatinib with X + oxaliplatin in HER2+ (FISH) GC is closed to recruitment. Additional unaddressed questions include the efficacy and safety of lapatinib with ECF/X (epirubicin + cisplatin + 5-FU or capecitabine (X), which is a preferred chemotherapy (CT) regimen in GC), and its activity in patients (pts) with discordant FISH or IHC HER2 status or EGFR1+. Methods: This is a phase II, randomized, double- blind, placebo controlled, multicenter trial sponsored by the EORTC. About 480 pts with adenocarcinoma of the stomach or esophagogastric junction not amenable to curative surgery and without prior palliative CT are screened centrally for HER2/EGFR1 by FISH and IHC. Patients are enrolled into one of two strata: 1) HER2 FISH- and IHC 2/3+, or 2) HER2 IHC 0/+ and EGFR1 FISH+ or IHC 2/3+. Pts HER2 FISH+/IHC 2/3+ and pts without HER2/EGFR1 by FISH/IHC will be excluded. 168 pts are anticipated to be randomized to lapatinib 1,250 mg cont. until progression or placebo, administered 6 cycles of ECF or ECX (72/96 in stratum 1/2, respectively).The primary endpoint is progression-free survival (PFS) in stratum 2 and 77 events are needed for 80% power to detect an increase in PFS from 4 to 6.5 months with lapatinib (HR=0.615, one-sided alpha 10%). Secondary endpoints include PFS, toxicity, response rate, overall survival, and correlation of HER2/EGFR1 status with response. Currently, half of all screened patients (19/38) have been randomized. So far, 8/38 (21%) pts were HER2+ according TOGA criteria. By FISH or IHC, 14/38 were EGFR1+, with 4/14 pts double HER2/EGFR+. Enrolment continues in 5 centers with about 4-10 patients per month. A safety cohort analysis will be performed in the first 15 pts receiving lapatinib. Conclusions: This is the first trial to analyze prospectively and separately the role of lapatinib combined with chemotherapy in EGFR1+ GC pts stratified by FISH/ IHC.
DOCTOR: A randomized phase II trial of preoperative cisplatin, 5-fluorouracil, and docetaxel with or without radiotherapy based on poor early response to standard chemotherapy for resectable adenocarcinoma of the esophagus and/or OG junction.
Authors: Barbour Andrew , Smithers Bernard Mark , Burmeister Bryan , Zalcberg John Raymond , Spry Nigel , Smith Garrett , Wilson Kate , Roff Kate , Yip Sonia , Walpole Euan Thomas ,   Australasian Gastro-Intestinal Trials Groups (AGITG)
Published: March 2020

TPS4145

Background: Surgery forms the mainstay of curative treatment for oesophageal and gastro-oesophageal junction adenocarcinoma (OAC). Preoperative chemotherapy (CTX) with or without concurrent radiotherapy (CRT) have resulted in modest improvements in outcome. Patients who demonstrate a histological response in the resected specimen following pre-operative therapy (CTX or CRT) have consistently better survival than non-responders. Recent data suggests that early metabolic response, assessed by FDG-PET scan performed 14+/-1 days after the start of CTX compared with a baseline PET scan, is predictive of a histological response and improved survival. Increasing the proportion of responders to pre-operative therapy remains one of the major challenges facing patients with localised OAC. Methods: 150 patients with resectable adenocarcinona of the oesophagus or GOJ will be registered and given 1 cycle of cisplatin and 5FU (CF). Patients will undergo a series of baseline tests including endoscopy, endoscopic ultrasound and 18FDG-PET. At Day 15 of the initial CF cycle the PET will be repeated. Patients with a PET response (≥ 35% reduction in SUVmax) to initial treatment will continue with CF as standard treatment prior to surgery. PET non-responders (< 35% reduction in SUVmax) will be randomized equally to receive either docetaxel, cisplatin and 5FU (DCF) or DCF plus radiatiotherapy. Following completion of the preoperative chemotherapy /chemoradiotherapy patients will have their cancer surgically removed. The primary end point is major histological response (<10% residual viable tumour) and secondary endpoints of progression-free and overall survival, toxicity, quality of life and feasibility of response-based therapy. Eligibility: T2 or greater tumours (by EUS or CT), or T1 tumours that are poorly differentiated, or T1 node positive, histologically proven invasive adenocarcinoma of the oesophagus or GOJ, technically resectable tumour which is sufficiently FDG avid on the initial PET staging scan. Status: Opened to accural 2009.
TACE 2: A randomized placebo-controlled, double-blinded, phase III trial evaluating sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma (HCC).
Authors: Meyer Tim , Fox Richard , Bird Deborah , Watkinson Anthony , Hacking Nigel , Stocken Deborah , Johnson Philip James , Palmer Daniel H.
Published: March 2020

TPS4150

Background: TACE is regarded as the standard of care for patients with intermediate stage HCC (BCLC B), while sorafenib (S) is the current standard for advanced disease (BCLC C). The combination of S with TACE for intermediate disease is rational since sorafenib inhibits the action of VEGF which may be induced by tumour hypoxia following TACE, and S also has direct anti-tumour effect. The combination has been shown to be safe in and active in phase I and II studies. Phase III trials are now required to determine whether TACE + S is superior to TACE alone in terms of survival. Methods: We are conducting a double blind multicentre trial to determine if the addition of S to TACE is superior to TACE alone. This is a UK NCRI trial sponsored by University College London (UCL) (EudraCT 2008-005073-36). Patients with intermediate stage HCC are randomised 1:1 to continuous S (400mg BD) or placebo (P). Key inclusion criteria include unresectable HCC confined to the liver, patent main portal vein, ECOG PS ≤1 and Child Pugh A liver score. After randomisation patients commence study drug and TACE is performed at 2-5 weeks using drug eluting beads loaded with 150mg doxorubicin (Biocompatibles UK Ltd) according to a standard protocol. Further TACE is performed at the discretion of the investigator based on radiological response and patient tolerance. The primary outcome measure is progression free survival and central, external, real time radiology review is required to confirm progression. Secondary outcome measures are overall survival, time to progression, toxicity, disease control, quality of life and number of TACE procedures performed in 12 months. The target recruitment is 412 in order to detect a hazard ratio of 0.72 using a 2-sided level of significance of α=0.05 with 85% power. The trial was reviewed by the IDMC after the presentation of the SPACE trial (Lencioni et al J Clin Oncol 30, 2012). The IDMC concurred with the conclusion of the SPACE investigators that the combination is tolerated and results required confirmation in a phase III trial. Thus recruitment into the TACE2 trial will continue as planned.
A randomized phase III trial comparing sorafenib plus best supportive care (BSC) versus BSC alone in Child-Pugh B patients (pts) with advanced hepatocellular carcinoma (HCC): The BOOST study.
Authors: Daniele Bruno , Di Maio Massimo , Gallo Ciro , Gasbarrini Antonio , Carteni Giacomo , Di Costanzo Giovan Giuseppe , Craxi Antonio , Cabibbo Giuseppe , Bolondi Luigi , Granito Alessandro , Missale Gabriele , Frassoldati Antonio , Angelico Mario , Roselli Mario , Daniele Gennaro , Perrone Francesco
Published: March 2020

TPS4151

Background: The efficacy of sorafenib in pts with advanced HCC has been demonstrated in two randomized phase III trials (Llovet JM, NEJM 2008;359:378; Cheng AL, Lancet Oncol 2009;10:25), both restricted to pts with well-preserved liver function (Child-Pugh A). Child-Pugh B (CPB) pts, that represent a relevant proportion of pts with advanced HCC in clinical practice, were not eligible. Despite this limitation, the marketing authorization of sorafenib by the main regulatory agencies was not restricted to Child A pts. CPB pts are different in terms of prognosis, and are potentially different in terms of balance between treatment efficacy and toxicity. Large observational studies [Marrero JA, ASCO 2011 (abstr 4001)] are producing quite reassuring data about sorafenib tolerability in CPB pts, but the real efficacy of the drug in this setting remains substantially unknown, due to the lack of randomized trials. Methods: BOOST (B Child HCC patients – Optimization Of Sorafenib Treatment) is a randomized phase III trial comparing sorafenib + best supportive care (BSC) vs. BSC alone in CPB pts with advanced HCC. Pts are eligible if older than 18, with ECOG performance status 0-2. Pts assigned to experimental arm receive sorafenib 400 mg twice daily, with dose reductions and interruptions according to toxicity. Overall survival (OS) is the primary endpoint. In order to demonstrate a Hazard Ratio of death 0.70 in favor of sorafenib (2-month improvement in median OS, from 4.5 to 6.5 months), with 80% power and α 0.05, 320 pts have to be randomized, 160 per arm. The BOOST trial (ClinicalTrials.gov Identifier NCT01405573; Eudract number 2009-013870-42) is approved by the Ethical Committee of the National Cancer Institute, Napoli, Italy, as coordinating centre, and is currently under evaluation by several other Institutions. BOOST is a non-profit, academic trial. The trial has received a financial support by Italian Ministry of Health (FARM84SA2X), although the support is not enough to supply sorafenib to participating centers. BOOST is partially supported by AIRC (grant IG2009-9316). The study is open to all international Centers wishing to participate.
Phase IIb randomized trial of JX-594, a targeted multimechanistic oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE).
Authors: Burke James M. , Breitbach Caroline , Patt Richard H. , Lencioni Riccardo , Homerin Michel , Limacher Jean-Marc , Lusky Monika , Hickman Theresa , Longpre Lara , Kirn David H.
Published: March 2020

TPS4152

Background: JX-594 is a first-in-class targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with epidermal growth factor receptor (EGFR)/ ras pathway activation. Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer 2009). JX-594 was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol 2008 and Nature 2011). A randomized dose-finding Phase 2 trial has been completed with JX-594 in 30 patients with advanced HCC. Treatment with high-dose JX-594 was associated with prolonged survival vs low-dose JX-594 (median survival 14.1 mo vs 6.7 mo; Hazard Ratio 0.39, p=0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial of JX-594 plus BSC versus BSC in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to experimental and control arm respectively. Randomization will be stratified by region (Asian vs non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival in the 2 arms. Assuming a control median overall survival of 4.0 months and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha = 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to JX-594 will receive a dose of 109 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or < 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Enrollment has begun on this study with clinical trial registry number of NCT01387555.
Phase II trial of cabazitaxel in patients with advanced or metastatic transitional cell carcinoma of the urothelial tract who have progressed within less than 12 months after cisplatin-based chemotherapy: A Spanish Oncology Genitourinary Group (SOGUG) study.
Authors: Arranz Arija Jose Angel , Climent Duran Miguel Angel , Font Pous Albert , Garcia Alonso Mirta , Diaz Enrique Gallardo , Garcia del Muro Xavier , Gonzalez del Alba Aranzazu , Lainez Milagro Nuria , Lázaro Quintela Martin , López-Brea Marta F. , Lopez Criado M Pilar , Luque Caro Raquel , Martin Lorente Cristina , Mendez Vidal Maria Jose , Pinto Marin Alvaro , Saez M.I. , Santander Lobera Carmen , Vazquez Estévez Sergio , Echaburu Juan Virizuela , Duran Ignacio ,   Spanish Oncology Genitourinary Group (SOGUG)
Published: March 2020

TPS4672

Background: Advanced transitional cell carcinoma of the urothelium (TCCU) on progression after previous cisplatin-based combination is generally an incurable disease. The appropriate management of these patients is still an unmet need. Many drugs have shown modest or no activity in previous phase 2 trials. Population heterogeneity in these studies emerges as one of the key determinants that could explain the variable outcomes. Recently, in a phase III study in this setting, prognostic factors (PF) for overall survival were identified (Bellmunt J et al, JCO 2010). Taxanes are active drugs in 2nd-line metastatic TCCU. Cabazitaxel (C) is a semi-synthetic taxane that is a poor substrate for the multidrug resistance system. C could be a valid alternative in this patient population. Methods: This is an open label phase II study of C in patients (pts) with advanced or metastatic TCCU who have progressed within 12 months after receiving a 1st-line platinum based chemotherapy. There are three treatment arms as patients will be assigned to one of three groups previously defined based on the presence of 0, 1 or 2-3 PFs as defined by Bellmunt et al. The activity of C will be assessed separately in each group and overall. The primary endpoint is response rate (RR) evaluated according to RECIST 1.1, a maximum of 35 pts are needed in each subgroup (maximum number of pts required: 105). Secondary objectives are RR in the whole population, toxicity, progression-free survival and overall survival. In addition, an external validation of the prognostic model proposed by Bellmunt will be conducted, as well as a pharmacogenomic study in order to better define the toxicity profile of the drug and the potential responders.
Vinflunine maintenance therapy versus best supportive care (BSC) after platinum combination in advanced bladder cancer: A phase II, randomized, open-label study (MAJA study)—SOGUG 2011-02.
Authors: Maciá Sonia , Garcia-Donas Jesus , Font Pous Albert , Domenech Montserrat , Garcia del Muro Xavier , Mellado Begoña , Puente Javier , Arranz Arija Jose Angel , Climent Duran Miguel Angel , Lainez Milagro Nuria , Perez-Gracia Jose Luis , Gonzalez del Alba Aranzazu , Villa Guzman José Carlos , Pérez-Valderrama Begoña , Echaburu Juan Virizuela , Bonfill Teresa , Leon Mateos Luis , Morales-Barrera Rafael , Castellano Daniel E. , Bellmunt Joaquim ,   Spanish Oncology Genitourinary Group (SOGUG)
Published: March 2020

TPS4674

Background: Vinflunine is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. It is distinguished from the other vinca-alkaloids because it binds relatively weakly to tubulin, suggesting an improved tolerance profile as a result of less neuropathy. Based on the fact that no cumulative toxicity is expected and the results reported in second-line, we aim to test the role of vinflunine in first line therapy, as maintenance treatment for patients who obtain clinical benefit after platinum. Methods: This is a multicenter, randomized, open label, proof-of-concept study that will be performed in 20 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine 320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression. Vinflunine dose will be 280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min. Stratification factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2) 2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease with radiological response or stabilization after 6 cycles of a platinum containing doublet for metastasic/advanced disease. Primary objective will be progression free survival (PFS), considering as clinically relevant 6 months in experimental arm. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to start by February 2012. A pharmacogenomic translational study will also be conducted.
Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).
Authors: Mego Michal , Svetlovska Daniela , Obertova Jana , Reckova Maria , Miskovska Viera , Rajec Jan , Sycova-Mila Zuzana , Palacka Patrik , Liskova Stefania , Chovanec Michal , Salek Tomas , Mardiak Jozef
Published: March 2020

TPS4677

Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If <4 responses will be observed, the study will be terminated, otherwise, it will be continued with a second cohort of 20 pts.
A phase II study of intermittent sunitinib in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Wood Laura S. , Dreicer Robert , Garcia Jorge A. , Gilligan Timothy D. , Ali Khaled B. , Haddad Housam , Shah Shetal N. , Elson Paul , Rini Brian I.
Published: March 2020

TPS4684

Background: Sunitinib is a standard of care initial treatment in mRCC. One challenge is balancing the acute and chronic toxicity of therapy with clinical benefit. Pre-clinical and retrospective clinical data support the concept that treatment breaks are feasible and not associated with a reduction in efficacy of sunitinib. It is hypothesized that an intermittent dosing regimen of sunitinib in mRCC pts is feasible, and may lead to prolonged duration of disease control with improved tolerance. Methods: Eligibility criteria include treatment-naïve clear cell mRCC, measurable disease, and adequate organ function. Pts will be treated for 4 cycles of sunitinib (50 mg 4/2) in the absence of unacceptable toxicity or RECIST-defined progression. Pts with ≥ 10% reduction in tumor burden per RECIST following 4 cycles will have sunitinib held, with re-staging CT scans approximately every 10 weeks thereafter to assess tumor burden. Sunitinib will be re-initiated in those patients with an increase in tumor burden of 10% or greater (per RECIST) compared to the scan obtained just prior to holding sunitinib. Pts who have RECIST tumor burden reduction of 10% or more compared to scans at the start of the most recent treatment period will again have sunitinib held. This intermittent sunitinib dosing will continue until RECIST-defined disease progression while on sunitinib. Patients not initially achieving at least a 10% reduction in tumor burden will continue sunitinib. The primary objective is the feasibility of intermittent sunitinib, defined as the proportion of patients eligible for and who undergo intermittent therapy. The alternative hypothesis is a feasibility rate of > 80% vs. the null hypothesis of < 50%. Thirty pts provides 80% power based on a two-sided exact test with a .05 type I error. Secondary endpoints include PFS and toxicity. Twenty five of planned 30 patients have been enrolled.
Prospective assessment of circulating endothelial cells (CECs) as early markers of clear cell renal cell carcinoma (CCRCC) progression in first line setting: The Circles study (SOGUG 2011-01).
Authors: Castellano Daniel E. , Esteban Emilio , Leon Luis , Basterretxea Laura , Gonzalez Arancha , Mendez Maria Jose , Jimenez Paula , Maroto Pablo , Garcia del Muro Xavier , Arranz Jose Angel , Climent Miguel Angel , Garcia-Donas Jesus
Published: March 2020

TPS4685

Background: Since the identification of Von Hippel Lindau (VHL) gene mutations as a critical step in the development of most Clear Cell Renal Cell Carcinomas (CCRCC), neoangionesis inhibition has become a cornerstone in their treatment. Despite the proven efficacy of antiangiogenic drugs, most patients will not achieve partial response by RECIST criteria. Thus, to accurately determine tumor progression is a challenging question incompletely answered by traditional radiological assessment. In recent years CECs counts have been proposed as surrogate biomarkers of angiogenesis that could be used for monitoring tumor evolution while on targeted therapies. We aim to figure out if CECs elevations could anticipate radiological progression in CCRCC. Methods: An observational prospective study is being performed in 10 institutions members of the Spanish Oncology Genitourinary group (SOGUG). Patients older than 18 years with histologically proven CCRCC on first line treatment with any targeted drug who have not progressed after 3 months of therapy are considered elegible. Recruitment begun on August the 1st 2011 and 15 of the 75 scheduled patients have been included so far. CECs are periodically collected in peripheral blood every 6 weeks for 15 months or radiological tumor progression, whatever occurs first. Median CEC values will be calculated and stated by descriptive statistics (Cellsearch, VERIDEX). To explore the evolution of CECs counts along treatment a linear model will be constructed. An association among CECs counts changes and time to progression will be analyzed with Cox model.
TERRAIN: A randomized, double-blind, phase II study comparing MDV3100 with bicalutamide (Bic) in men with metastatic castrate-resistant prostate cancer (CRPC).
Authors: Baskin-Bey Edwina S. , Shore Neal D. , Barber Kenya , Ouatas Taoufik , Heidenreich Axel
Published: March 2020

TPS4698^

Background: MDV3100 is a novel androgen receptor (AR) signaling inhibitor (ARSI) in clinical development for treatment of prostate cancer (PCa). Compared with Bic in nonclinical CRPC models, MDV3100 showed higher affinity AR binding, inhibited nuclear translocation and AR-DNA binding, showed no evidence of AR agonism, and caused tumor regression in Bic-resistant xenografts. MDV3100 has shown antitumor activity in men with advanced PCa. We present the study design of a trial comparing MDV3100 and Bic in men with progressive metastatic PCa. Methods: Multinational study (Table) with planned enrollment of 370 patients (randomized 1:1 to MDV3100 160 mg/d or Bic 50 mg/d). Inclusion criteria include metastatic (≥2 bone lesions or soft tissue disease at screening) progressive CRPC (≥3 rising prostate-specific antigen [PSA] levels or new bone/soft tissue disease), ongoing stable gonadotropin-releasing hormone (GnRH) analog therapy or surgical castration (serum testosterone <50 ng/dL), Eastern Cooperative Oncology Group performance status 0–1, and life expectancy ≥1 year. Exclusion criteria include previous chemotherapy, current/prior antiandrogens (except if administered for <12 wk and discontinued no less than 6 mo before study). Patients will be stratified by time of bilateral orchiectomy or GnRH analog initiation (before/after diagnosis of metastases) and will receive treatment until occurrence of radiographic progression/skeletal-related event, start of new antineoplastic therapy, or development of an adverse event requiring discontinuation. Results: The primary endpoint is progression-free survival; secondary endpoints are safety, PSA response, and time to PSA progression. Exploratory endpoints include circulating tumor cell conversion rate and quality of life. Patients are currently enrolling. Conclusions: This ongoing, head-to-head, phase II trial is the first to prospectively assess whether MDV3100 can provide improved antitumor effects vs Bic in men with metastatic CRPC. [Table: see text]
A phase II study of live-attenuated listeria monocytogenes immunotherapy (ADXS11-001) in the treatment of persistent or recurrent cancer of the cervix (GOG-0265).
Authors: Huh Warner King
Published: March 2020

TPS5115

Background: This is a GOG/NCI sponsored phase II study (NCT01266460, GOG 0265) of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. ADXS11-001 is a live attenuated Listeria monocytogenes (Lm) immunotherapy bioengineered to secret a HPV E7 fusion protein targeting HPV-E7 transformed cells. A previous phase I dose escalation study determined the safety of ADXS11-001 in patients with late stage cervical cancer (Maciag PA. Vaccine. 2009 Jun 18;27(30):3975-83). The primary objectives of this study are: to evaluate the tolerability and safety of ADXS11-001; and to assess the activity of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. Secondary objectives are progression-free survival, overall survival and objective tumor response. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent squamous or non-squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy). Patients must have measurable disease as defined by RECIST 1.1; at least one “target lesion” as defined by RECIST 1.1; have had one prior systemic chemotherapeutic regimen for management of their disease; have adequate organ function and must be free of active infection and not on antibiotics. This protocol is a Simon 2-stage design with a planned sample size of up to 67 patients. Patients will receive ADXS11-001 at a dose of 1x109 CFU on Day 1 and repeat every 28 days for 3 total doses in the absence of disease progression or unacceptable toxicity, with each dose followed at 72 hours by a 7 day course of ampicillin, 500 mg QID. Tumor tissue and serum samples may be collected periodically for translational research. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. This phase II study just began enrolling and as of January 27, 2012, 2 patients have been enrolled.
LUX-H&N 1: A phase III, randomized trial of afatinib versus methotrexate (MTX) in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who progressed after platinum-based therapy.
Authors: Machiels Jean-Pascal H. , Licitra Lisa F. , Haddad Robert I. , Tahara Makoto , Svensson Liz , Cong Xiuyu Julie , Ehrnrooth Eva , Cohen Ezra E. W. ,   LUX-H&N1 Study Group
Published: March 2020

TPS5598

Background: EGFR (ErbB1) is expressed in 90% of HNSCC and associated with poor prognosis. Despite clinical benefit (CB) of EGFR-targeted treatments such as cetuximab treatment resistance will occur resulting in a need for novel targeted treatments to improve prognosis. Afatinib is an ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers and may overcome limitations of current EGFR-targeted treatments in HNSCC. In a randomized, proof-of-concept, Phase II trial, afatinib demonstrated comparable anti-tumor activity to cetuximab in pts with R/M HNSCC progressing after platinum-based therapy (Seiwert TY, et al; THNO, November 2011; Abs 40). Methods: LUX-H&N 1 is a phase III, randomized, open-label trial (NCT01345682) evaluating efficacy and safety of afatinib vs. MTX in pts with R/M HNSCC who have progressed after platinum-based therapy. Key eligibility criteria: confirmed R/M HNSCC not amenable to salvage surgery/radiotherapy; documented PD after cisplatin and/or carboplatin for R/M disease; any other than 1 previous platinum-based regimen for R/M disease; ECOG status 0 or 1; no PD ≤3 months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC; and no prior EGFR-targeted small molecules treatment. Eligible pts are stratified into four strata: ECOG performance score (0 vs. 1) and prior use of EGFR-targeted antibody therapy (Yes/No) given in the R/M setting. Pts are randomized 2:1 to: afatinib (40mg/d orally) or MTX (40mg/m2 IV weekly). Dose changes are permitted according to absence/presence of drug-related AEs (afatinib: escalation to 50mg/d and/or reduction to 40, 30 then 20mg/d; MTX: escalation to 50mg/m2 and/or reduction to 40, 30 then 20mg/m2). Pts receive continuous treatment until PD or AEs requiring withdrawal. Randomized treatment may continue beyond PD in case of CB as judged by the investigator. The primary endpoint is PFS and secondary endpoints include OS, OR, health-related QOL and safety. Target enrolment is 474 pts and completion of pt recruitment and data analyses are awaited.