bluuebunny/crossref_metadata_2025 huggingface dataset:
Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer.
Authors: Bajetta Emilio , Floriani Irene , Di Bartolomeo Maria , Labianca Roberto , Landi Lorenza , Santoro Armando , Casaretti Rossanna , Pasquini Enzo , Di Fabio Francesca , Rondini Ermanno , Pinotti Graziella , Bidoli Paolo , Rosati Gerado , Mambrini Andrea , Ciarlo Andrea , Cordio Stefano Sergio , Ricci Sergio , Frassineti Luca , Di Costanzo Francesco , Bochicchio Anna Maria ,   on behalf of ITACA-S Study Group
Published: March 2020

LBA4001

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Evaluation of lapatinib as a component of neoadjuvant therapy for HER2+ operable breast cancer: NSABP protocol B-41.
Authors: Robidoux Andre , Tang Gong , Rastogi Priya , Geyer Charles E. , Azar Catherine A. , Atkins James Norman , Fehrenbacher Louis , Bear Harry Douglas , Baez-Diaz Luis , Kuebler J. Phillip , Margolese Richard G. , Farrar William Blair , Brufsky Adam , Shibata Henry R. , Bandos Hanna , Paik Soonmyung , Costantino Joseph P. , Swain Sandra M. , Mamounas Eleftherios P. , Wolmark Norman
Published: March 2020

LBA506

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Randomized multicenter phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy as first-line therapy in patients with translocation-related sarcoma (TRS).
Authors: Blay Jean-Yves , Leahy Michael Gordon , Bui Nguyen Binh , Patel Shreyaskumar , Santoro Armando , Hohenberger Peter , Demetri George D. , Lardelli Pilar , Perez Iratxe , Chawla Sant P.
Published: March 2020

TPS10101

Background: One third of sarcoma histotypes have specific chromosomal translocations which result in abnormal transcription factors, integral to the change to a malignant phenotype. T is the first of a new class of anti-tumor agents with a transcription-targeted mechanism of action. In vitro evidence exists of the ability of T to interfere with the aberrant transcription factor’s binding to DNA promoters in TRS. Patients with TRS, such as myxoid/round cell liposarcomas (MRCL) have benefited from long-lasting tumor control in response to T. Methods: A randomized, phase III study of T (1.5 mg/m2 in 24-h intravenous infusion every 3 weeks [q3wk]) vs doxorubicin 75 mg/m2 q3wk, or doxorubicin 60 mg/m2 with ifosfamide 6-9 g/m2 q3wk) as first line treatment in patients with advanced TRS. Primary aim: to determine the efficacy of T vs doxorubicin-based therapy by comparing progression-free survival (PFS) in each arm. Secondary aims: comparison of PFS rates at six months, response rate (RR), PFS and RR by histological type (MRCL vs other subtypes), overall survival, safety, exploratory response evaluation by Choi criteria and pharmacogenomic analyses. Patients with confirmed TRS of the following subtypes: MRCL, alveolar soft part sarcoma,angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma,myxoid chondrosarcoma and synovial sarcoma, are stratified by performance status (PS 0 vs 1-2) and sarcoma subtype (MRCL vs other subtypes) and randomized (1:1 ratio) to T or doxorubicin ± ifosfamide. Confirmation of the translocation by fluorescence in situ hybridization is compulsory for inclusion in the primary efficacy analysis. An adaptive design was chosen to test the reduction in relative risk of progression or death with T, an interim analysis will be conducted with 45 PFS events from 80 evaluable patients. To date 117 patients have been enrolled from six countries and 29 centers. An independent data monitoring committee met on 15 November 2011 and concluded that the trial should continue as planned.
Randomized multicenter double-blind phase II trial: The immunological adjuvant OPT-821 with or without a trivalent ganglioside vaccine in metastatic sarcoma patients following metastasectomy.
Authors: Carvajal Richard D. , Chugh Rashmi , Milhem Mohammed M. , Ryan Christopher W. , George Suzanne , Chmielowski Bartosz , Agulnik Mark , Rodler Eve T. , Elias Anthony D. , Budd G. Thomas , Tawbi Hussein , Movva Sujana , Van Tine Brian Andrew , Dickson Mark Andrew , Hensley Martee Leigh , Keohan Mary Louise , Tap William D. , Bennett Cathryn M. , Maki Robert G. , Schwartz Gary K.
Published: March 2020

TPS10103

Background: The gangliosides GM2, GD2, and GD3 are strongly expressed in sarcoma and represent novel antitumor targets. We have demonstrated the safety and immunogenicity of individual monovalent ganglioside conjugate vaccines when administered with OPT821, a synthetic saponin adjuvant that augments the T-cell response. Antitumor effects are observed with anti-ganglioside antibodies in preclinical models, with greatest benefit seen in the micrometastatic setting. Patients (pts) with metastatic sarcoma rendered disease-free by surgery are at high risk for disease recurrence, with no therapy demonstrated to improve outcomes. Therefore, this population is ideally suited to test the efficacy of vaccine induced anti-ganglioside antibodies. We thus initiated this randomized double-blind phase II study of OPT821 with or without a trivalent ganglioside vaccine composed of GM2, GD2 lactone and GD3 lactone conjugated to KLH, an immunogenic carrier protein. Methods: A total of 134 pts will be randomized on a 1:1 basis stratified by disease state (relapsed disease vs metastasis at time of diagnosis), disease-free interval and number of relapses. Key inclusion criteria include stage IV sarcoma (locoregional recurrence is not sufficient) rendered disease-free following surgery or multi-modality therapy, no more than 8 weeks since surgery, and no continuous use of anti-inflammatory medications. Pts with Ewings sarcoma, GIST and rhabdomyosarcoma (except pleomorphic/anaplastic) are ineligible. Eligible pts will receive 10 subcutaneous injections in the outpatient setting over 84 weeks. The primary endpoint is progression-free survival (PFS). Secondary objectives include overall survival (OS) and 1- and 3-year PFS rate. Exploratory objectives include correlation of serologic response to outcome, comparison of tumor ganglioside expression at baseline and at recurrence, and analysis of circulating tumor cells. Enrollment began in July 2010. As of January 1, 2012, 83 patients had been recruited from 12 participating sites. Clinicaltrials.gov#: NCT01141491. Funded by Mabvax Therapeutics and NIH (R21CA13386).
A phase III, randomized trial of docetaxel plus carboplatin (TP) versus epirubicin plus cyclophosphamide followed by docetaxel (EC-T) as adjuvant treatment for triple-negative, early-stage breast cancer in Chinese patients.
Authors: Yuan Peng , Xu Binghe
Published: March 2020

TPS1135

Background: Triple-negative [estrogen receptor (ER)-/progesterone receptor (PR)-/HER2-] breast cancer (TNBC) accounts for about 15% of all breast cancers and is associated with very poor prognosis. A combination of anthracycline and taxanes represents the most commonly used adjuvant chemotherapy for TNBC patients. BRCA1, a protein responsible for repair upon DNA damage, is often dysfunctional in TNBC. As a result, TNBC is often sensitive to DNA-damaging agents (e.g., cisplatin and carboplatin). A phase II study of docetaxel plus carboplatin as neoadjuvant treatment for TNBC achieved promising response rate (Chang, CANCER, 2010). Encouraged by this important finding, we are currently conducting a phase III trial to examine docetaxel plus carboplatin as adjuvant chemotherapy in patients with early-stage TNBC (registration number at www.ClinicalTrials.gov: NCT 01150513). Methods: All participants received radical mastectomy or breast-conserving surgery for pT1-3N0-2 breast cancer. All cancers were negative for ER, PR, HER2/Neu. All participants had adequate organ function and performance status. The age ranged from 18 to 70 years. Patients randomly received a TP regimen (docetaxel 100 mg/m2 plus carboplatin AUC=6 on day 1, 21 days a cycle for 6 cycles) or a EC-T regimen (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 on d1, 21 days a cycle for 4 cycles; followed by docetaxel 100 mg/m2 on d1, 21 days a cycle for 4 cycles). Adjuvant radiotherapy was permitted in both arms. The primary endpoint is disease-free survival (DFS). Secondary endpoints included adverse event and quality of life (QoL). The study planned to recruit 500 subjects over a period of 5 years, with 5-year follow-up (once every 6 months). Target hazard ratio is 0.86 (5 year DFS of 74.0% vs. 71.0%). The estimated power is 0.80; 1-sided type 1 error was set at 0.05). The study was activated in June 2010 with enrollment of 110 subjects.
ANZ1001 SORBET: Study of estrogen receptor beta and efficacy of tamoxifen, a single arm, phase II study of the efficacy of tamoxifen in triple-negative but estrogen receptor beta-positive metastatic breast cancer.
Authors: Phillips Kelly-Anne , Kiely Belinda E. , Francis Prudence A. , Boyle Frances M. , Fox Stephen B. , Murphy Leigh , Gebski Val , Lindsay Dianne Frances , Sutherland Robert L. , Badger Heath D. , Forbes John F. ,   Australia and New Zealand Breast Cancer Trials Group
Published: March 2020

TPS1136

Background: Targeted therapies are needed for triple negative breast cancer (BC). ERβ is expressed in at least 20% of triple negative BCs.  ERβ binds estrogen and tamoxifen with a similar affinity to ERα.  ERβ has 5 isoforms but only ERβ1 is fully functional. ERβ expression has been shown to be significantly associated with improved distant disease free survival and better overall survival in tamoxifen treated ERα negative patients in retrospective studies.  This “proof of principle” study will determine the efficacy of tamoxifen in patients with triple negative but ERβ positive metastatic BC. Methods: This single arm phase II study, being conducted by the Australia and New Zealand Breast Cancer Trials Group, has a Simon's 2 stage optimal design. The primary end-point is objective response rate (complete and partial responses).  Progression free survival and clinical benefit rate will also be assessed. Eligibility criteria include histologically or cytologically confirmed metastatic triple negative BC (ER and PR absent, HER2 ISH negative or IHC 0 or 1) and measureable disease as per RECIST 1.1.  Consenting patients undergo central ERβ testing and confirmation of triple negative status on a metastatic biopsy sample. ERβ positive patients (ERβ1 nuclear staining with Allred score >4) are offered trial participation. To date 12 potentially eligible patients have been screened for ERβ; 4 had Allred score >4 (although 2 of these subsequently proved to be ineligible for the trial), 7 had Allred scores <4 and 1 result is pending. Consenting patients receive tamoxifen 20mg per oral daily until disease progression, unacceptable toxicity or withdrawal of consent. If there are ≥2 responses in the first stage of 28 patients, an additional 38 patients will be accrued. Tamoxifen will be considered worthy of further research if there are ≥6 responses in the total 66 patients recruited. Current accrual is 1. Registered on ANZCTR (12610000506099).
Q-CROC-03: A prospective biopsy driven clinical trial to study the mechanisms of resistance to chemotherapy in triple-negative breast cancer patients.
Authors: Aguilar-Mahecha Adriana , Lafleur Josiane , Seguin Carole , Mihalcioiu Catalin Liviu Dragos , Roy Josee-Anne , Desbiens Christine , Robidoux Andre , Diaz Zuanel , Pelmus Manuela , Batist Gerald , Basik Mark ,   Quebec Clinical Research Organisation in Cancer
Published: March 2020

TPS1139

Background: Resistance to chemotherapy or targeted agents is the cause of death in most patients dying of breast cancer and one of the major challenges presently faced by oncologists. In triple negative breast cancers (TNBCs), drug resistance emerges quicker than in other breast cancer subtypes and contributes to the poor prognosis seen in these patients. The lack of targeted therapies to treat TNBC highlights the important need to better understand the molecular mechanisms contributing to chemotherapy resistance in order to develop new therapeutic strategies. However, the difficulty in obtaining tissue samples from drug resistant tumors has been one of the limiting factors in this field of study. Methods: We have designed a prospective phase II clinical trial where paired biopsies are collected from chemotherapy resistant TNBCs (NCT01276899). Four needle core biopsies are collected before the initiation of treatment and 2 weeks before surgery or at the time of progression in the neoadjuvant and metastatic settings respectively. Metastatic sites eligible for biopsy include liver, lung, skin and lymph nodes. This study is presently recruiting at 5 major health centers in Quebec and will soon open in the USA. We have currently enrolled 13 patients in the neoadjuvant setting and 2 metastatic patients. Major challenges in patient enrolment will be discussed. We have standardized the methods of collection and processing of tissue and blood specimens to ensure their molecular integrity and compatibility with different genomic and proteomic molecular platforms. Analysis of tumor cellularity has been incorporated into our quality control and we have optimized the extraction of nucleic acids to obtain high yields and optimal quality. Paired biopsies will undergo Next Gen Sequencing, flow sorted aCGH analysis, gene expression and miRNA profiling as well as phosphoproteomic profiling using reverse phase protein arrays. Collection of clinical data will allow molecular profiling data to be linked to clinical response data so as to determine DNA, RNA and protein factors correlated with tumor resistance to chemotherapy.
DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).
Authors: Hagenbeck Carsten , Melcher Carola Anna , Janni Johann Wolfgang , Schneeweiss Andreas , Fasching Peter A. , Aktas Bahriye , Pantel Klaus , Solomayer Erich-Franz , Ortmann Uta , Jaeger Bernadette Anna Sophia , Mueller Volkmar , Fehm Tanja N.
Published: March 2020

TPS1146

Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.
Phase II study of the multikinase inhibitor dovitinib (TKI258) or placebo in combination with fulvestrant in postmenopausal, endocrine resistant HER2-/HR+ breast cancer.
Authors: Andre Fabrice , Greil Richard , Denduluri Neelima , Yovine Alejandro Javier , Reddick Cathy , Squires Matthew , Zhang Yong , Blackwell Kimberly
Published: March 2020

TPS1148

Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive “cross-talk” between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/HER2- breast cancer patients (pts) have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy but can be overcome via FGFR1 inhibition in preclinical models. Dovitinib is a potent FGF, VEGF, and PDGF receptor tyrosine kinase inhibitor that demonstrated antitumor activity in heavily pretreated breast cancer pts with FGF pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and is studied here to determine if it can improve outcomes when combined with fulvestrant. Methods: Postmenopausal HER2-/HR+ locally advanced or metastatic breast cancer pts (N»150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting will be enrolled in this multicenter, randomized, double blind, placebo controlled, phase II trial. Pts will prospectively undergo molecular screening to enrich for FGF-amplification (FGFR1, FGFR2, or FGF3 amplification by qPCR; 45 amplified and 30 non-amplified pts per arm). Pts will be randomized 1:1 to receive fulvestrant (500 mg q4w [with an additional dose 2 wks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, ECOG performance status and patient reported outcome scores over time, and safety. The pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored.
REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab (BV) in relapsed glioblastoma (GB).
Authors: Reardon David A. , Vredenburgh James J. , Desjardins Annick , Steis Ronald G. , Dunbar Erin M. , Chandramouli Nitin B. , Rixe Olivier , Green Jennifer A , Davis Thomas A. , Sampson John Howard ,   ReACT Study Group
Published: March 2020

TPS2103

Background: EGFRvIII is a constitutively active tumorigenic deletion mutation of EGFR. It is expressed in ~30% of primary GB where it is linked to poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 150ug GM-CSF as an adjuvant). Remarkably consistent and promising results across 3 phase II studies in newly diagnosed, resected EGFRvIII+ GB (Lai 2011) represent a statistically significant improvement over a historical control cohort matched for major eligibility criteria (median overall survival [OS] = 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and median progression-free survival [PFS] = 12.3 - 15.3 vs. 6.4 m). ACT IV, a phase III trial in this population, is ongoing. The immunosuppressive influence of residual/advanced GB presents a challenge to activation of efficacious antitumor immune responses. Anecdotal evidence (compassionate use cases, Sampson 2008) suggests that rindopepimut may induce specific immune responses and regression in multifocal and bulky residual tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive properties (including impaired maturation of dendritic cells and disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) may further optimize EGFRvIII-specific immune response and antitumor activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in patients (pts) with 1st or 2nd relapse of EGFRvIII+ GB. BV-naïve pts will be enrolled to Group 1 (n=70: randomized 1:1 to BV plus either rindopepimut/GM-CSF or control injection [low-dose KLH]) while BV-refractory patients will enter Group 2 (n=25: to receive BV plus open-label rindopepimut/GM-CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or open-label vaccine is given in priming phase (days 1, 15 and 29), then monthly until PD. Tumor response is assessed every 8 weeks, and patients are followed for survival after PD. Objectives are PFS at 6 months (primary), objective response rate, PFS, OS, safety, immunogenicity and elimination of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328).
A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (NCIC CTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677).
Authors: Perry James R. , O'Callaghan Christopher J , Ding Keyue , Roa Wilson , Mason Warren P. , Cairncross J. Gregory , Brandes Alba Ariela , Menten Johan , Phillips Claire , Fay Michael F. , Nishikawa Ryo , Winch Chad , Laperriere Normand
Published: March 2020

TPS2104

Background: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly diagnosed GBM found improved survival with concomitant and adjuvant temozolomide (TMZ) added to radiotherapy (RT). Study pts were 18-71 (median 56) years; however a sub-group analysis noted a trend of decreasing benefit from the addition of TMZ with increasing age, such that for age 65-71, the hazard ratio of 0.8 did not reach statistical significance (p=0.340). Recent RCTs in elderly GBM found improved survival with RT compared to supportive care alone and detected non-inferiority of 40 Gy/15 vs. a 60 Gy/30 RT regimen. Based upon these results short-course hypofractionated RT is often recommended for elderly pts. However, whether the addition of TMZ to RT confers a survival advantage in elderly pts remains unanswered. Methods: Patients ≥65 yrs of age with histologically confirmed newly diagnosed glioblastoma, ECOG 0-2, are randomized 1:1 to receive 40Gy/15 RT vs. 40Gy/15 RT with 3 weeks of concomitant temozolomide plus monthly adjuvant TMZ until progression or 12 cycles. Stratification is by centre, age (65-70, 71-75, or 76+), ECOG 0,1 vs 2, and biopsy vs resection. For 90% power to detect a 25% reduction in the primary outcome of overall survival (increased MST from 6 to 8 months) between arms, using a two-sided 5% alpha, a minimum of 520 deaths must be observed prior to analysis; total sample size is 560 patients. The trial is open in Canada (NCIC CTG), Europe (EORTC), Australia and New Zealand (TROG), and Japan. As of Jan 25, 2012, 361 (65%) of the target 560 pts were randomized (147 Canada, 144 Europe, 64 Australasia, 6 Japan). Median age of randomized patients is 73 (65-88) years. A planned futility analysis after 120 events by the independent DSMB resulted in a recommendation that the trial continue.Accrual is expected to be complete in 2013. A comprehensive molecular companion analysis, including MGMT promoter methylation, is planned.
Bevacizumab plus radiotherapy for elderly patients with glioblastoma (ARTE).
Authors: Tabatabai Ghazaleh , Weller Michael
Published: March 2020

TPS2105

Background: The standard of care for patients with newly diagnosed glioblastomas after surgical resection is radiotherapy with concomitant and adjuvant temozolomide chemotherapy. Yet, inclusion into the pivotal trial was limited to patients up to the age of 70, and subgroup analyses suggested that older patients did not gain benefit from combined modality treatment. Further, the efficacy of radiotherapy has been confirmed in a randomized trial comparing best supportive care versus radiotherapy alone. Of note, hypofractionated radiotherapy is equieffective in patients aged 65-70 years and more. Two randomized trials in elderly patients (NOA-08, Nordic Trial) indicated smilar efficacy of primary temozolomide chemotherapy alone compared with radiotherapy alone. Combined radiochemotherapy is compared with radiotherapy alone in an ongoing NCIC-CTG EORTC TROG Japanese group trial 26062-22061. Thus, radiotherapy alone is the standard of care for newly diagnosed glioblastoma of elderly patients. These clinical data justify the exploration of new, temozolomide-free first-line treatment strategies in elderly patients. Methods: The ARTE trial will therefore investigate bevacizumab when added to a short course of radiotherapy and bevacizumab maintenance therapy until progression. The translational research program shall include blood and urine biomarker analysis and FET-PET in addition to MRI for monitoring the course of the disease. This trial is an explorative randomized, non-comparative phase II trial aiming at recruiting 60 patients in Switzerland. Elderly patients (> 65) will be randomized 2:1 either to the experimental arm (bevacizumab plus radiotherapy) or the standard arm (radiotherapy). The primary endpoint is median overall survival. Secondary endpoints include overall survival at 6 months, overall survival at 12 months, median progression-free survival, progression-free survival at 6 months, median time to treatment failure.
Phase III trial of tumor-treating fields (TTFields) together with temozolomide compared with temozolomide (TMZ) alone in patients with newly diagnosed glioblastoma multiforme (NCT00916409).
Authors: Kesari Santosh , Taillibert Sophie , Kanner Andrew , Weinberg Uri ,   on behalf of the EF-14 Study Investigators
Published: March 2020

TPS2106

Background: TTFields therapy is a novel, non-invasive, anti-mitotic treatment, inhibiting tumor growth by interfering with the metaphase to anaphase transition during mitosis (Lee et al., 2011). TTF therapy was recently approved by the FDA for recurrent GBM following a prospective, randomized trial. Preclinical studies have shown TTFields and TMZ to have an additive inhibitory effect on glioma cell proliferation. The design for the current study was supported by results from a pilot study with TTFields therapy and TMZ in patients with newly diagnosed GBM demonstrating favorable safety, tolerability and promising efficacy (Kirson et al., 2009). Methods: The hypothesis of the current study is that the addition of TTFields therapy to maintenance TMZ will increase progression free survival (PFS) of newly diagnosed GBM patients. Secondary endpoints include overall survival (OS), radiological response, quality of life and safety. Eligible patients will be randomized (2:1) to continuous TTFields therapy (200 kHz) in combination with maintenance TMZ versus maintenance TMZ alone. Maintenance TMZ will be administered as per the Stupp Protocol for 6 courses (Stupp et al., 2005). TTFields therapy may be administered for up to 24 months. Patients will be stratified based on: extent of resection and MGMT methylation status. Eligibility criteria include: pathological diagnosis of GBM; Karnofsky ≥ 70; previous chemoradiotherapy per Stupp Protocol; no progressive disease at baseline. Patients with infratentorial tumor or implanted electronic devices are excluded. The sample size of 700 patients will have 80% power to detect a 2 month (9 vs 7 months) improvement in PFS using log-rank test with an overall 5% 2-sided type I error. The trial is also powered to detect a 4.5 month increase in median OS in NovoTTF-100A/TMZ patients. Patients will be followed clinically monthly and with bimonthly MRI to assess tumor progression and additional endpoints. 221 patients have been enrolled at the time of abstract submission. The DMC last reviewed the trial in October 2010 and recommended that the trial continue as designed.
A randomized, double‑blind, controlled phase IIb study of the safety and efficacy of ICT‑107 in newly diagnosed patients with glioblastoma multiforme following resection and chemoradiation.
Authors: Hawkins Elma S. , Aiken Robert , Chandler James , Fink Karen L. , Glantz Michael J. , Grewal Jai , Gruber Michael L. , Kesari Santosh , Landolfi Joseph C. , LaRocca Renato V. , Lesser Glenn Jay , Markert James , Mayer Tina M. , O'Rourke Donald , Peereboom David M. , Phuphanich Surasak , Schiff David , Sloan Andrew E. , Stea Baldassarre , Zhu Jay-Jiguang
Published: March 2020

TPS2107

Background: Tumor stem cells have been correlated with recurrence and clinical outcome in glioblastoma multiforme (GBM). ICT‑107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic peptide CTL epitopes targeting the GBM tumor and tumor‑stem cell associated antigens MAGE‑1, HER‑2, AIM‑2, TRP‑2, gp100 and IL‑13Rα2. Phase I results showed a good safety profile and interesting clinical potential (ASCO, 2010, abs#2097 and ASCO, 2011, abs#2042) in 16 newly diagnosed GBM patients with a median progression-free survival (PFS) of 16.9 months (measured from surgery) and a median overall survival (OS) of 38.4 months. Methods: In this Phase II study eligible patients have newly diagnosed GBM and complete surgical resection or minimum residual tumor < 1 cm3, are HLA-A1 and/or HLA-A2 positive, older than 18, have Karnofsky Performance Score (KPS) of ≥ 70% and have adequate hematologic and chemistry parameters. Patients with a serious immune or autoimmune disorder or other systemic disease are excluded. Patients undergo apheresis to isolate peripheral blood mononuclear cells (PBMCs) to be used for preparation of study treatment (ICT‑107 and Control). Pre-study treatment consists of 6 weeks of concurrent temozolomide (TMZ) and radiation. After stratification by site and age, patients are randomized 2:1 to receive either ICT-107 or its matching control (autologous, unpulsed dendritic cells). Patients then receive induction ICT-107 or control once a week for four weeks. All patients subsequently receive maintenance TMZ for 5 days per month for 12 months. Booster vaccinations occur at Cycles 1, 3, 6 and 10, and every six months thereafter. The primary endpoint is OS and secondary endpoints include PFS, rates of OS and PFS at 6 months after surgery and every 3 months thereafter, safety and tolerability of ICT‑107, immune response to ICT-107 and predictors of response. 120 patients have been enrolled in this ongoing trial. It is expected that approximately 200 patients will be enrolled for screening with the intention to randomize at least 102 patients. The trial significance is alpha=0.025 one-sided.
Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus in patients with solid, endometrial, and ovarian cancers.
Authors: Chon Hye Sook , Lee Ji-Hyun , Herschberger Amber B , Wenham Robert M
Published: March 2020

TPS3114

Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signalling is associated with resistance to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin (PC) have broad activity including endometrial, ovarian, and many cancers. mTOR inhibition with PC has synergistic and additive effects in solid tumors. A common defect in endometrioid ca is mutation of PTEN, causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS over hormonal therapy of metastatic endometrial cancer in a randomized phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). In 35 patients in a phase II study of RIDA, there were 7.7% partial response (PR) and 58% with stable disease with median duration 6.6 months (Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca ultimately develops a phenotype resistant to taxanes that may be overcome with mTOR inhibition. RIDA may therefore potentiate the response of endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) with advanced solid ca and measureable disease and up to 3 prior therapies received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics (PD) are collected. More than 1 anticipated DLT of thrombocytopenia or neutropenia in the latter part of the cycle shifts the escalation of RIDA to an alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 endometrial, 1 urethral ca. The second cohort of an alternate schedule has been filled and evaluation continues. Further characterization of tolerability, efficacy, and PD are planned at the MTD in the phase IB expansion cohorts of 15 ovarian/15 endometrial cancers.
BARIS: A phase I trial to evaluate the safety and tolerability of combined BIBF 1120 and RAD001 in solid tumors and to determine the maximum tolerated dose (MTD) of the combination.
Authors: Scheffler Matthias , Nogova Lucia , Gardizi Masyar , Bos Marc Christiaan Allardt , Papachristou Irini , Sos Martin , Zander Thomas , Mattonet Christian , Wolf Juergen
Published: March 2020

TPS3115

Background: Simultaneious inhibition of several signallingpathways involved in angiogenesis as well as in tumor cell growth regulation by kinase inhibitor combination therapy may increase therapeutic efficacy. Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120in a phase I trial in advanced solid tumors.In addition we use DCE-MRI for early identification of patients with benefit from BIBF 1120. Methods: This is an open-label, monocentric phase I trial with three dosage arms in a classical "3+3" design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 1120 will be given. There is no interindividual dose escalation, and the enrollment of the patients will be performed sequentially. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors (UICC stage IV) and an ECOG performance state of 0-1 for whom no further standard therapies are available and who have predefined adequate organ functions. All patients will start with a 2-week run-in phase of 2 x 200 mg BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans will be performed at baseline staging, on day 3 and day 14. On day 14, there will also be 12 hours-pharmacokinetic (PK) assessment. Combination therapy within the forementioned dosage arms starts on day 15. After two weeks of combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will be performed. Restaging for the evaluation of the efficacy will be performed on day 57. The safety of this combination will be assessed throughout the complete therapy phase using CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed until day 42. Patients who experience clinical benefit (i.e., response or stable disease) on day 57 with adequate tolerability of the combination will further receive the medication, as long as the benefit lasts. The trial is registered under NCT01349296 (clinicaltrials.gov). Recruitment in arm A has started in February 2012.
A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer.
Authors: Janjigian Yelena Yuriy , Ilson David , Kelsen David Paul , Schattner Mark , Heguy Adriana , Vakiani Efsevia
Published: March 2020

TPS4144

Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.
A multicenter, randomized, double-blind, phase III study of ramucirumab (IMC-1121B; RAM) and best supportive care (BSC) versus placebo (PBO) and BSC as second-line treatment in patients (pts) with hepatocellular carcinoma (HCC) following first-line therapy with sorafenib (SOR).
Authors: Zhu Andrew X. , Chau Ian , Blanc Jean-Frédéric , Okusaka Takuji , Rojas Maria , Yang Ling , Von Broen Ingo
Published: March 2020

TPS4146

Background: Blockade of vascular endothelial growth factor (VEGF) signaling in HCC has been shown in preclinical models with monoclonal antibodies and small molecule multikinase inhibitors, and in clinical trials with SOR, to have anti-tumor activity and improve survival. RAM, a fully human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2), potently blocks the binding of the VEGF ligand to VEGFR-2, inhibits VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced mitogenesis of human endothelial cells. In a single-arm, Phase 2 study of RAM as 1st-line monotherapy in 42 pts with advanced HCC (Zhu, ILCA 2010, abstr. O-033), preliminary results included median progression-free survival (PFS) of 4 months (m), time to progression (TTP) of 4.2 m, overall survival (OS) of 12 m and disease control rate of 70% (best overall response: 10% partial response, 60% stable disease). Methods: Pts with HCC with disease progression during or following 1st-line therapy with SOR (or who were intolerant to SOR) are randomized 1:1 to receive RAM (8 mg/kg) or PBO once every 2 weeks, with BSC, until disease progression or intolerable toxicity. Eligibility includes prior SOR as 1st-line systemic treatment for HCC, Child-Pugh A, B7 or 8 cirrhosis, ECOG PS 0-1, bilirubin < 3 mg/dL, transaminases ≤ 5 × upper limit of normal (ULN), creatinine ≤ 1.2 × ULN, and platelets ≥ 75×103/µL. The primary endpoint is OS. Secondary endpoints include PFS, best objective response rate, TTP, patient-reported outcome measures of disease-specific symptoms and health-related quality of life, safety, and RAM pharmacokinetics, pharmacodynamics, and immunogenicity. With 544 patients, this study is designed to detect an increase in OS (median 6 m with PBO to 8 m with RAM; 1-sided α= 2.5%, 85% power). As of 18 January 2012, approximately 52% of planned pts have been randomized. The IDMC reviewed this study on 21 June and 3 November 2011 and recommended the study to continue unmodified.
Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib (E7080) and everolimus.
Authors: Molina Ana M. , Motzer Robert John , Hutson Thomas E. , Larkin James M. G. , Gold Anne , Andresen Corina , Wood Karen , Michaelson M. Dror
Published: March 2020

TPS4682

Background: Lenvatinib (E7080) is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1-4, RET, KIT and platelet-derived growth factor receptor beta. Lenvatinib has demonstrated acceptable toxicity and antitumor activity in Phase I and II studies (Glen H et al. JCO 2008, 26;15S: 3526;Yamada K et. al. Clin Cancer Res 2011, 17:2528-2537; Sherman S I et al. JCO 2011, 29; 15S: 5503). Improved understanding of the molecular basis of renal cell carcinoma (RCC) has led to the development of targeted therapies (inhibitors of mTOR and of the VEGF pathway) that have shown clinical benefit in patients with metastatic RCC. However patients develop resistance and ultimately progress during treatment with available single agents. Combination therapy targeting different pathways have the potential to improve efficacy. Methods: This multicenter, randomized, open-label, phase Ib/II study is investigating everolimus (an oral mTOR inhibitor) in combination with lenvatinib in RCC patients with unresectable or metastatic disease (NCT01136733). The study is being conducted in two phases. The phase Ib dose-escalation component will determine the maximum tolerated dose (MTD) of the combination; starting doses are 12 mg/day lenvatinib and 5 mg/day everolimus. A cohort expansion will follow to confirm the MTD and establish a recommended phase II dose (RP2 dose). Approximately 150 patients will be enrolled in phase II and randomized 1:1:1 to receive: lenvatinib and everolimus at the RP2 dose (Arm A); lenvatinib 24 mg/day (Arm B); or everolimus 10 mg/day (Arm C). Patients with clear cell RCC, ECOG performance score <2 and progression during or after one prior VEGF-targeted treatment are eligible for phase II. The primary endpoint for Phase II is to compare progression-free survival of the investigational arms (A and B) with single agent everolimus (Arm C). Three phase Ib dose escalation cohorts have completed enrollment, and enrollment of the expansion cohort commenced in November 2011. Participating phase II centers will be located in the US, UK, Spain, Poland and Czech Republic and are expected to enroll patients throughout 2012.
Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).
Authors: Swanton Charles , Cromer Jamie ,   1200.89 study group
Published: March 2020

TPS650

Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene ampliﬁcation (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.