bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparisons of RNA-seq results for cryopreserved (CRYO) and formalin fixed, paraffin-embedded (FFPE) samples.
Authors: Farooq Umar , Singh Prashant , Gooch Michael , Burian Linda , Sanders M. Melinda , Everson Richard Bernard
Published: March 2020

e22211

Background: FFPE is the worldwide clinical standard for preservation of tissue samples. Although CRYO tissues are widely used for research, most gene expression assays in clinical use analyze FFPE by RT-PCR. Use of RT-PCR limits numbers of transcripts that can be studied with material available. Next Generation Sequencing promises to overcome those limitations, but for FFPE, there are concerns related to its accuracy including bias associated with RNA truncated at the 3’ end. Little data is available illustrating the extent of truncation or considering implications for bioinformatics analysis of sequencing results. Methods: Total RNA was extracted from patient consented specimens of tumor and normal bladder tissue split with matching halves processed by CRYO and FFPE. Paired end sequencing libraries 100 bp in length were generated using Illumina TruSeq RNA sample kits with minor modifications for FFPE samples. Sequencing was performed on the Illumina HiSeq 2000, aligned with TopHat using the hg19 reference sequence, and further analyzed using open source bioinformatics tools. Results: Comparing Cryo and FFPE reads for a representative specimen, the proportion of reads that mapped to the reference genome were 69% and 63% for normal, and 66% and 63% for tumor specimens. Mapped reads yielded over 25,000 significantly expressed transcripts, isoforms, and splice variants. The extent of 3’ bias was investigated by viewing data in the Integrated Genome Viewer and using Picard tools. Preliminary estimates of 3’ bias in FFPE showed 2.22 for normal and 1.48 for tumor. After accounting for bias, transcripts in CRYO vs FFPE were significantly correlated for both normal tissue and tumor (R2 = 0.76 and 0.95, respectively). Mutations previously identified in these samples by SureSelect hybrid capture system (Agilent) were also observed in the RNA-seq data. Conclusions: FFPE samples can be successfully analyzed by RNA-Seq, allowing the analysis of standard clinical samples and vast quantities of richly annotated archival specimens. Results from CRYO and FFPE analyses are similar when performed using minor modifications to sequencing library preparation and careful attention to appropriate analysis.
Association of PARP inhibitors and docetaxel resistance through suppressing a tumor microenvironment-associated secretory program.
Authors: Zhao Song , Coleman Ilsa , Coleman Roger , Nelson Peter
Published: March 2020

e22212

Background: Acquired resistance to therapeutics accounts for the majority of treatment failures in metastatic cancer. In response to genotoxic stress induced by therapeutics such as radiation and chemotherapy, tumor microenvironment (TME) undergoes marked molecular alterations manifested by increased secretion of cytokines and growth factors, which in turn promote tumor growth, facilitate epithelial-mesenchymal transition, and ultimately result in resistance to chemotherapy. Fibroblasts are a major component of TME and a primary source of cytokines and growth factor secretion following damage. Preliminary results from our lab indicated PARP1 may be involved in regulating this secretory program. We hypothesized that PARP inhibition would suppress the TME-associated secretory program and thereby overcome chemotherapy resistance. Methods: Transcript profiles of cytokines and growth factors were analyzed with quantitative real-time PCR and cDNA microarrays in prostate fibroblasts after treatment with radiation or docetaxel, in combination with one of three PARP inhibitors (PARPi). We evaluated the effects of the docetaxel-induced fibroblast secretory program, in the absence or presence of PARPi, on the proliferation and drug sensitivity of prostate cancer cell lines. Results: Similar to radiation, docetaxel induced the secretion of cytokines and growth factors in prostate fibroblasts. PARP1 was activated by docetaxel treatment. Exposure to PARPi suppressed the docetaxel-induced secretory program. Further analysis suggested that PARPi abrogates activation of p38MAPK pathway. While conditioned medium from docetaxel-treated prostate fibroblasts stimulated growth and chemotherapy resistance, the addition of PARPi attenuated these effects. Conclusions: Docetaxel induces extracellular secretion of pro-tumorigenic cytokines and growth factors by components of the TME. PARP inhibitors attenuated docetaxel resistance through suppression of this secretory program, supporting a new mechanism of action for this class of drugs. Combinatorial use of cytotoxic agents and microenvironment-directed therapies may reduce treatment resistance.
A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13.
Authors: Fizazi Karim , Pagliaro Lance C. , Flechon Aude , Mardiak Jozef , Geoffrois Lionnel , Kerbrat Pierre , Chevreau Christine , Delva Remy , Rolland Frederic , Theodore Christine , Roubaud Guilhem , Gravis Gwenaelle , Eymard Jean-Christophe , Malhaire Jean-pierre , Linassier Claude , Habibian Muriel , Journeau Florence , Logothetis Christopher , Culine Stephane , Laplanche Agnes
Published: March 2020

LBA4500

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Randomized, open-label, phase III study of pemetrexed plus carboplatin followed by maintenance pemetrexed (Arm A) versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab (Arm B) in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).
Authors: Zinner Ralph , Ross Helen J. , Weaver Robert , Govindan Ramaswamy , Holden Viran R. , Chowhan Naveed Mahfooz , Beck J. Thaddeus , Waterhouse David Michael , Modiano Manuel , Rao Vijay Phooshkooru , Liu Jingyi , Koustenis Andrew , Melemed Symantha , Guba Susan C. , Ortuzar Waldo Feliu , Desaiah Durisala , Spigel David R. , Obasaju Coleman K.
Published: March 2020

LBA8003

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Randomized proteomic stratified phase III study of second-line erlotinib (E) versus chemotherapy (CT) in patients with inoperable non-small cell lung cancer (PROSE).
Authors: Lazzari Chiara , Novello Silvia , Barni Sandro , Aieta Michele , De Marinis Filippo , De Pas Tommaso , Grossi Francesco , Mencoboni Manlio , Bearz Alessandra , Floriani Irene , Torri Valter , Bulotta Alessandra , Grigorieva Julia , Roder Joanna , Doglioni Claudio , Roder Heinrich , Righi Luisella , Foti Silvia , Bachi Angela , Gregorc Vanesa
Published: March 2020

LBA8005

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Digoxin as an inhibitor of global hypoxia inducible factor-1α (HIF1α) expression and downstream targets in breast cancer: Dig-HIF1 pharmacodynamic trial.
Authors: Bardia Aditya , Santa-Maria Cesar Augusto , Jacobs Lisa K. , Cimino-Mathews Ashley , Huang Peng , Russell Stuart , Camp Melissa , Habibi Mehran , Lange Julie R. , Jeter Stacie , Powers Penny , Slater Shannon , Gabrielson Edward , Carducci Michael Anthony , Semenza Gregg , Stearns Vered
Published: March 2020

TPS1144

Background: Unlike normal cells, tumor cells thrive in a hypoxic microenvironment, and intratumoral hypoxia correlates with increased tumor invasiveness, metastasis, and poor prognosis in cancer. The hypoxic microenvironment is primarily mediated through HIF1α, a transcription factor for over 200 genes involved in cellular metabolism, proliferation, and angiogenesis. In pre-clinical models, cardiac glycosides, including digoxin, act as potent inhibitors of HIF1α protein synthesis and expression of HIF1α target genes (Zhang et al, PNAS 09). Methods: Trial design: The proposed study is a randomized, controlled, two arm, pre-surgical study. Eligible patients include women with stage I-III carcinoma of the breast scheduled to undergo definitive surgery, tumor size ≥ 1cm, grade 2/3 or Ki-67 ≥ 10%, normal organ function, and no known cardiac arrhythmias. Participants will receive oral digoxin daily, or no therapy, for 14 days (±4 days) prior to scheduled surgery. Trial Objectives: 1) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces HIF1α expression by IHC and mRNA or its target genes (VEGF, CA-9, and GLUT1) in breast cancer tissue. 2) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces levels of serum VEGF & PAI-1, reduces tissue Ki-67 expression, and modulates proteomic profiles of breast cancer tissue. 3) To assess safety and tolerability of digoxin therapy in the pre-surgical setting. Statistical methods: The primary hypothesis is that 2 weeks of digoxin therapy will reduce the level of HIF1α expression in breast cancer tissue assessed by pathologists blinded to the treatment assignment. Our preliminary study shows the mean HIF1α expression level is 2.43. A 33% reduction would be considered clinically relevant. Allowing for up to 20% attrition, a total sample size of 64 will provide more than 85% power to detect 33% reduction with a two-sided significance level of 0.05. Target accrual: 64 (32 each arm). Funding and Acknowledgement: Dept. of Defense, Commonwealth Foundation, ASCO YIA. Contact Person: Dr. Vered Stearns, Email: vstearn1@jhmi.edu .ClinicalTrials.gov Identifier: NCT01763931. Clinical trial information: NCT01763931.
A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.
Authors: Rizvi Naiyer A. , Infante Jeffrey R. , Gibney Geoffrey Thomas , Bertino Erin Marie , Cooley Sarah A. , Lekatis Kiki , Wigginton Jon M. , Gutierrez Andres A. , Gupta Ashok Kumar , Kim Su Young , Hodi F. Stephen
Published: March 2020

TPS3106

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

TPS3110

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

TPS3123

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

TPS3645

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

TPS4145

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

TPS4154

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

TPS4163

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

TPS4589

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

TPS5094

Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone micro-environment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/duration, PSA response, PSA time-to-progression. A Simon's two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is <0.45; it would be of definite clinical interest if the 12-week PF proportion is >0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.
Randomized, double-blind, placebo-controlled proof of concept study of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) who experience response or stabilization during first-line docetaxel chemotherapy.
Authors: Fizazi Karim , Heidenreich Axel , Daugaard Gedske , Bellmunt Joaquim , Germann Nathalie , Chetaille Eric
Published: March 2020

TPS5098^

Background: Docetaxel is the standard first-line chemotherapy for mCRPC. Most patients experience disease response or stabilization on docetaxel, although no treatment is currently used to maintain efficacy when docetaxel is stopped. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, with immunomodulatory, anti-angiogenic and anti-metastatic activity and a manageable safety profile. Tasquinimod demonstrated significantly improved PFS (7.6 v 3.3 mo) in asymptomatic to mildly symptomatic mCRPC (Pili, R. et al. J Clin Oncol 2011; 29: 4022-8) and is in phase III development. The purpose of this study is to assess whether tasquinimod used as a switch maintenance therapy can postpone cancer progression in patients with mCRPC with response or stabilization on first-line docetaxel therapy. Methods: Design: Phase II, multinational, randomized, double-blind, placebo-controlled proof of concept study. Patients with mCRPC will be randomly assigned (ratio 1:1) to receive tasquinimod or placebo. Randomization will be stratified by presence of visceral metastases and opioid analgesic use for cancer-related pain. Patient population: 140 male patients aged ≥18 years with histologically documented mCRPC and ECOG performance status 0 or 1 will be randomized. Before study entry, patients should have received ≥6 cycles of docetaxel and not experienced cancer progression according to PSA and RECIST criteria. Recruitment is ongoing. Dosage: Patients will receive a starting dose of 0.25 mg/day tasquinimod or placebo, with escalation to 0.5 mg/day and 1 mg/day based on individual safety and tolerability. Primary endpoint: Radiological PFS including skeletal-related events, from randomization to the date of radiological progression or death due to any cause. Secondary endpoints: Overall survival, symptomatic PFS, quality of life, pharmacokinetics, safety, PFS on next-line therapy, time to PSA progression, and changes in biomarkers over time. Clinical trial information: NCT01732549.
A phase II study of trebananib (AMG 386) and abiraterone in metastatic castration resistant prostate cancer.
Authors: Shah Avani Atul , Karzai Fatima , Madan Ravi Amrit , Figg William Douglas , Chau Cindy H. , Gulley James L. , Chun Guinevere , Wright John Joseph , Apolo Andrea Borghese , Parnes Howard L. , Dahut William L.
Published: March 2020

TPS5102

Background: Preclinical studies support the use of an antiangiogenic approach in the treatment of prostate cancer. Trebananib is a novel peptide-Fc fusion protein that sequesters angiopoeitin 1 and angiopoeitin 2, thereby preventing their interaction with their common receptor Tie2, and inhibiting tumor endothelial cell proliferation and tumor growth. Trebananib is currently in Phase 3 trials for the treatment of ovarian carcinoma and has been shown to have clinical activity in multiple tumor types. Previous studies have demonstrated that in vivo alterations of testosterone levels regulate the expression of vascular endothelial growth factor, fibroblast growth factor, and angiopoietin associated factors. Dual inhibition of the androgen and angiogenic axis represents a novel strategy of combined targeted therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). We hypothesize that the addition of trebananib to CYP17 inhibitor abiraterone and prednisone will increase the median progression free survival (PFS) in chemotherapy-naïve mCRPC. Methods: This phase 2 study will evaluate the treatment effect as measured by progression free survival in patients treated with trebananib plus abiraterone/prednisone relative to abiraterone/prednisone alone. 72 patients with progressive, mCRPC will be randomized 1:1 to either study arm. Trebananib is administered intravenously every week, on days 1, 8, 15 and 22 of each 28-day cycle. Abiraterone acetate is taken once daily with prednisone 5 mg twice daily. We have completed the initial run-in phase of trebananib at 15mg/kg and 30mg/kg. The randomized phase of the study will use the 30 mg/kg dose of trebananib with the standard dose (1000 mg) of abiraterone. The primary end point is radiographic PFS. Secondary end points include overall survival, changes in genetic biomarkers related to the androgen and angiogenesis signaling axis, molecular markers of angiogenesis, circulating tumor cells and androgen receptor signaling status in circulating tumor cells before and after treatment. This combination of angiogenesis inhibition and abiraterone has the potential to improve clinical outcomes in front-line therapy for mCRPC. Clinical trial information: NCT01553188.
Early prediction of efficacy of endocrine therapy in breast cancer (BC): Pilot study and validation with 18F fluoroestradiol (18F-FES) PET/CT.
Authors: Gennari Alessandra , Amadori Dino , Brain Etienne , Cortes Javier , Harbeck Nadia , Puntoni Matteo , Wuerstlein Rachel , Nanni Oriana , Muñoz-Couselo Eva , Paganelli Giovanni , Lopera Sierra Maribel , Matteucci Federica , Piccardo Arnoldo , Bruzzi Paolo
Published: March 2020

TPS649

Background: Almost 70% of early BC are endocrine responsive, as defined by estrogen receptor (ER) expression; however roughly 30% of ER+ BC patients will relapse despite adjuvant ET. Moreover, 10 to 20% of BC metastases lose ER expression. The upfront administration of ET in ER+ women with MBC is recommended by major guidelines. However, the early identification of endocrine resistance might improve systemic treatment options, sparing unnecessary toxicities and inactive drugs. 18F-FES, an oestradiol analogue labeled with 18F, may allow to test the performance of ERs, by testing their in vivo linkage ability. In MBC, 18F-FES uptake has been proposed to be a better predictor of response to ET than ER expression itself. The aim of the ET-FES study is to validate the predictive value of 18F-FES uptake at PET/CT scan in metastatic ER+ patients. Methods: This is aphase II, multicentric european comparative study of first line ET vs CT in ER+ MBC with low 18F- FES uptake. The primary endpoint is disease control rate (DCR). Correlative studies include: 1. Optimization of 18F-FES production; 2. Association between gene alterations in ESR1/ESR2 genes and 18F- FES uptake; 3. Development of a predictive score of endocrine responsiveness based on 18F-FES SUV value and clinical and biological information. All patients with ER+ MBC candidate to first line ET will receive a 18F-FES CT/PET at baseline, in addition to standard staging. Patients with 18F-FES uptake (SUV) > 2 will receive ET. Patients with 18F-FES SUV < 2 will be randomized to ET until disease progression (control arm) or CT (single agents) until PD. A total of 220 patients with ER+ MBC will be enrolled. Of these, approximately 50% (n=110) will show a 18F-FES SUV < 2 and will be randomized to ET or CT. The study will have 85% power to detect an absolute 20% difference in the DCR between arms after 3 months of therapy, assuming a 5% two-sided alpha level and a 10% drop-out rate. Current status: The ET-FES study was approved for funding by the ist Join TRANSCAN European call. 18F-FES production is currently on final development (GMP), and the clinical protocol is being finalized for EC approval in the different EU countries. Clinical trial information: 2013-000287-29.
A randomized, multicenter, double-blind phase III study of palbociclib (PD-0332991), an oral CDK 4/6 inhibitor, plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER(+), HER2(–) breast cancer who have not received any prior systemic anticancer treatment for advanced disease.
Authors: Finn Richard S. , Dieras Veronique , Gelmon Karen A. , Harbeck Nadia , Jones Stephen E. , Koehler Maria , Martin Miguel , Rugo Hope S. , Im Seock-Ah , Toi Masakazu , Gauthier Eric Roland , Huang Xin , Randolph Sophia , Slamon Dennis J.
Published: March 2020

TPS652

Background: Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK4/6 that prevents DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. In a randomized phase II trial comparing palbociclib (PD-0332991) plus letrozole (P + L) to letrozole (L) in postmenopausal women with ER(+), HER2(–) advanced breast cancer (ABC) who had not received any prior systemic anticancer therapy for their advanced disease, P + L demonstrated significantly longer progression-free survival (PFS) vs L (26.1 vs 7.5 mo; HR = 0.37, P < .001) and was generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event (Finn et al SABCS 2012). Methods: Based on phase II data, a global, randomized, double-blind, phase III clinical trial was designed to demonstrate that P + L provides superior clinical benefit compared with L + placebo in postmenopausal women with ER(+), HER2(–) ABC who have not received any prior systemic therapy for their advanced disease. The study aims to assess whether P + L improves median PFS over L at HR of at least 0.7. Approximately 450 eligible patients with locoregionally recurrent or metastatic, pathologically confirmed ABC who are candidates to receive L as first-line treatment for their advanced disease will be randomized 2:1 to receive either P (125 mg QD 3 wk on, 1 wk off) + L (2.5 mg QD) or L (2.5 mg QD) + placebo. Patients who received anastrozole or letrozole as part of their (neo)adjuvant regimen are eligible if their disease progressed more than 12 months from completion of adjuvant therapy. Tumor tissue is required for participation. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, and patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms. Clinical trial information: NCT01740427.
BOLERO-6: Phase II study of everolimus plus exemestane versus everolimus or capecitabine monotherapy in HR+, HER2- advanced breast cancer.
Authors: Ejlertsen Bent , Jerusalem Guy Heinrich Maria , Hurvitz Sara A. , De Boer Richard H. , Taran Tanya , Sahmoud Tarek , Burris Howard A.
Published: March 2020

TPS660

Background: Everolimus (EVE), an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR), has shown clinical activity as monotherapy and in combination with endocrine therapy (ET) in hormone-receptor–positive (HR+; estrogen and/or progesterone receptors) advanced breast cancer (ABC). In a pivotal phase 3 trial in patients with HR+ ABC progressing on ET, EVE + exemestane (EXE) significantly prolonged median progression-free survival (PFS) vs EXE alone per local (7.8 vs 3.2 months; log-rank P<.0001) or central (11.0 months for EVE+EXE vs 4.1 months for EXE alone; log-rank P<.0001) assessment. Capecitabine, an orally administered fluoropyrimidine carbamate indicated as monotherapy in paclitaxel and/or anthracycline-refractory ABC, has shown clinical benefit in patients with HR+, human epidermal growth factor receptor 2-negative (HER2-) ABC. The BOLERO-6 study in patients with HR+, HER2- ABC progressing on prior anastrozole or letrozole will compare PFS following EVE+EXE combination therapy vs EVE or capecitabine monotherapy. Methods: In this multicenter, open-label, randomized, 3-arm, phase 2 study, 300 patients will be randomized to receive either EVE (10 mg/d) + EXE (25 mg/d) combination therapy, or EVE (10 mg/d) alone, or capecitabine (1,250 mg/m2twice daily for 14 d/3-wk cycle) alone, until disease progression. Patients will be stratified based on the presence of visceral disease. Key eligibility criteria include age ≥18 years, postmenopausal status; histologic or cytologic confirmation of estrogen-receptor–positive, HER2- ABC; radiologic or objective evidence of recurrence or progression on prior aromatase inhibitors; Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The primary endpoint is PFS with EVE+EXE vs EVE, based on local radiologic assessment (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). The key secondary endpoint is PFS with EVE+EXE vs capecitabine. Other secondary endpoints include overall survival, objective response rate, clinical benefit rate, safety, quality of life, and patient satisfaction with treatment. Enrollment will start in Q1 2013. Estimated study completion in Q1 2015. Clinical trial information: NCT01783444.
Human epidermal growth factor receptor 2 (HER2) suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (HALT: LPT112515).
Authors: Lin Nancy U. , Danso Michael A. , David Alice K. , Muscato Joseph J. , Rayson Daniel , Houck William A. , Ellis Catherine Elizabeth , DeSilvio Michelle , Garofalo Amanda , Levin Jeremy , Winer Eric P.
Published: March 2020

TPS664

Background: Evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2+ breast cancer (BC). In patients with prior trastuzumab (T)-treated HER2+ metastatic BC (MBC), treatment with T plus lapatinib (L) was associated with longer progression-free survival (PFS) and overall survival (OS) compared with L alone, and had an acceptable safety and tolerability profile. In patients with stage II/III BC, preoperative treatment with T plus L plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This study is designed to evaluate whether the addition of L improves PFS among women with HER2+ MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 patients will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w) alone until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Eligible patients are females, aged ≥18 years with HER2+ MBC who have completed 12-24 weeks of first-/second-line treatment with T plus chemotherapy with an objective response or stable disease at chemotherapy discontinuation. Patients with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the intent-to-treat population. A total of 193 PFS events is required to detect a 50% increase in median PFS from 18 weeks (T alone) to 27 weeks (L+T) with an associated hazard ratio of 0.667, an 80% power and a 1-sided type I error of 0.025. One interim analysis is planned for futility when ~97 PFS events (50% of required events) have been observed. Safety endpoints will be analyzed in all randomized patients who receive ≥1 dose of study medication. The trial is currently open for accrual in the United States and Canada. Clinical trial information: NCT00968968.