bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer.
Authors: Madan Ravi Amrit , Singh Nishith K. , Gramza Ann Wild , Fojo Antonio Tito , Heery Christopher Ryan , Kim Joseph W. , McMahon Sheri , Rauckhorst Myrna , King Thomas H , Apelian David , Schlom Jeffrey , Gulley James L. 
Published: March 2020

TPS3127 Background: Saccharomyces cerevisiae has been genetically modified to express CEA protein and developed under a CRADA with GlobeImmune/NCI as a heat-killed immune-stimulating, therapeutic cancer vaccine (GI-6207). A phase I study with GI-6207 demonstrated safety, biomarker stabilization and enhanced immune response in some patients. CEA is over-expressed in multiple malignancies, including medullary thyroid cancer (MTC). Two therapies recently approved by the FDA for metastatic MTC (vandetanib, cabozantinib) come with toxicity and should be reserved for symptomatic/progressive disease. However, a large population of asymptomatic MTC patients has small tumor burden and/or disease that is more indolent. The standard management of these patients is observation. Preliminary data suggest that tumor growth measured by the rate of CEA and calcitonin increase can be quantified in a 3-6 months. Retrospective data from prostate cancer studies suggest vaccines can alter growth rates within 3-4 months. We hypothesize that GI-6207 can alter tumor growth rates in MTC and impact long-term outcome. Methods: A phase II study will evaluate the effect of GI-6207 onthe rates ofincrease in calcitonin in metastatic MTC. 34 patients with minimally symptomatic, radiographically evaluable, metastatic MTC will be randomized 1:1. Arm A will receive vaccine for a year from the time of enrollment. Arm B will receive vaccine after 6 months of surveillance. GI-6207 will be administered subcutaneously at 4 sites (10 yeast units/site), every 2 weeks for 3 months, then monthly up to 1 year. The primary endpoint will compare the effect of GI-6207 on calcitonin kinetics between the vaccine and surveillance arms in the first 6 months. Secondary endpoints include immunologic responses (including antigen-specific T cell responses), objective responses, time to progression, and changes in CEA kinetics. If this trial can prospectively demonstrate that vaccines can alter tumor growth rates, and if such changes are associated with clinical outcomes, then changes in tumor growth rates may become a clinical metric to evaluate vaccine efficacy in MTC and other populations.
Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: The HERACLES trial (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification).
Authors: Marsoni Silvia , Bertotti Andrea , Sartore-Bianchi Andrea , Leone Francesco , Lonardi Sara , Ciardiello Fortunato , Pinto Carmine , Aglietta Massimo , Zagonel Vittorina , Gambacorta Marcello , Grigioni Walter Franco , Rugge Massimo , Risio Mauro , Martino Cosimo , Valtorta Emanuele , Bardelli Alberto , Trusolino Livio , Comoglio Paolo M. , Siena Salvatore 
Published: March 2020

TPS3648 Background: We identified HER2 amplification as a potential onco-driver and marker of de novo resistance to anti-EGFR therapy in mCRC PTS for which other known genetic alterations conferring resistance to anti EGFR antibodies were excluded. Exploiting direct transfer xenografts of mCRC surgical samples in mice (xenoPTS), we conducted a multi-arm study in HER2-amplified xenoPTS showing that combinations of lapatinib (L) and trastuzumab (T), or L and pertuzumab (P) induced long-lasting tumor regressions while monotherapy with L led to stabilization and either monotherapy with T or P were ineffective (Bertotti et al. Cancer Discov 2011). The combination of P+T has a strong rationale for treatment of HER2-amplified mCRC, since combining the two agents is synergic in HER2+ breast cancers failing T (Baselga et al. JCO 2010), suggesting a cooperative mechanism of inhibition. On these findings we designed the HERACLES trial. Methods: HERACLES is an independent Phase II, 2-sequential cohort trial, assessing the response rate (RR) of T combined with either L (Cohort A) or P (Cohort B), in m CRC PTS harbouring an amplified HER2 tumor (SISH). Endpoints are RR and PFS. For each cohort sample size was calculated according to the Fleming & Hern 1- stage design under identical assumptions: H0 = RR 10%, H1= RR 30%. With a =0.05, power=0.85, 27 patient are required in each cohort (54 patients overall). A or B will be considered positive if ≥ 6 responses/27 PTS are observed. Detection and quantitation of genetic alterations in circulating tumor DNA (liquid biopsy) and Her2 ECD in plasma as potential markers of secondary resistance will be done q14 days until relapse. Eligibility: CRC histology with KRAS WT, HER2 IHC 3+ ≥50% cells, prior treatment with fluoropirimidines, oxaliplatin, irinotecan, anti EGFR moABs based regimens ± Bevacizumab; measurable disease (RECIST v1.0), ECOG PS ≤1, adequate organ function. Response is assessed q8w. Treatment: L 1000 mg daily po + T 4 mg/kg iv load, then 2 mg/kg iv weekly. Enrollment: since trial start (8/12/12) 198 PTS have been HER2 screened, 10 found positive and 7 are in treatment. EudraCT number : 2012-002128-33. Clinical trial information: 2012-002128-33.
Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC).
Authors: O'Reilly Eileen Mary , Lowery Maeve Aine , Yu Kenneth H. , Capanu Marinela , Stadler Zsofia Kinga , Epstein Andrew S. , Golan Talia , Segal Amiel , Segal Michal , Salo-Mullen Erin E. , Tang Laura H. , Hollywood Ellen , Moynahan Mary Ellen , Do Kinh G , Moore Malcolm J. , Kindler Hedy Lee , Mayer Robert J. , Chen Alice P. , Kelsen David Paul 
Published: March 2020

TPS4144 Background: Germline mutations in BRCA1, 2 predispose to PC (Lal, G. Cancer Res, 2000). 5-8% PC have BRCA 1,2 mutations; higher in Ashkenazi Jewish (10-15%). Pre-clinical data demonstrates that platinums and poly-ADP ribose polymerase inhibitors (PARPi) have activity in BRCA-mutated PC models. Early clinical data supporting (Lowery, M. Oncol, 2011). We are evaluating the role of platinum agents and PARPi, veliparib (ABT-888), in BRCA or PALB2-mutated PC. Methods: Arm A, B: Includes non-randomized phase to optimize V dose combined with G, C (Arm A). Subsequently randomized phase II study will evaluate G, C +/- V. Primary endpoint: RECIST 1.1 response rate (RR) G, C, V (Arm A) and G, C (Arm B). Secondary endpoints: Progression-free survival, safety, disease-control rate, overall survival and correlatives involving pre, post biopsies to evaluate mechanisms of sensitivity, resistance to platinums, PARPi. Arm C: Evaluates single-agent V in previously-treated PC. Primary and secondary endpoints similar. Eligibility: BRCA, PALB2-mutated, measurable, stage III/IV PC; Untreated (Arm A, B), ≤ 2 lines therapy (Arm C); ECOG 0-1 (Arm A, B), ECOG 0-2 (Arm C). Treatment Plan: Arm A, B: V PO BID d1-12 (Arm A), q 3 weeks, G 600mg/m2 IV, C 25mg/m2IV, both d3, 10, q 3 weeks (Arm A, B). Arm C: V 400mg PO BID d1-28 q 4 weeks. Biostatistics: Arms A, B: Simon’s 2-stage minimax design per arm. Unacceptable RR 10%, promising 30%, type I, II errors 10%. N= 16 stage I, +N= 9 (stage II). If ≥ 5/25, then promising. If both arms promising, option to add N= 10, allows distinction between RR 20% and 40%, 83% power. Arm C: Simon’s 2-stage, single-arm, uninteresting RR 10%, promising if ≥ 28%. N= 15 stage I, +N= 18 (stage II). Promising RR ≥ 6/33. Total N 47- 95. Contingency for slow accrual. Progress to Date: Accrual: Arm A (non-randomized): 13 screened, N= 5 enrolled. Arm C: 9 screened, N= 4 enrolled. Israeli, Canadian, other U.S. sites opening 2013. Funding and acknowledgements: National Cancer Institute, Lustgarten Foundation. NCT01585805. Clinical trial information: NCT01585805.
A phase II randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of simtuzumab (GS-6624) combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.
Authors: Benson Al Bowen , Thai Zung , Hawkins Michael J. , Werner Douglas , Dong Hua , Lee Claudia , Bendell Johanna C. 
Published: March 2020

TPS4149 Background: Lysyl oxidase-like molecule 2 (LOXL2) is an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors. Simtuzumab (GS-6624) is a humanized antibody that specifically inhibits LOXL2 enzymatic activity. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. Methods: The primary objective and of the study is to compare the additive efficacy of simtuzumab vs. placebo in combination with gemcitabine as measured by improvement in progression free survival (PFS). The secondary objective is to compare the additive efficacy of simtuzumab vs. placebo as measured by overall survival (OS) and objective response rate. Study Design: The study is a randomized, double-blind, placebo controlled Phase 2 trial in subjects with metastatic pancreatic adenocarcinoma. A total of 234 subjects will be randomized to 200 mg simtuzumab, 700 mg simtuzumab, or placebo at a 1:1:1 ratio (78 subjects per treatment group) in combination with gemcitabine in cycles of 28 days. In each cycle, subjects will receive IV GS-6624 or placebo infused on Days 1 and 15, and IV gemcitabine (1000 mg/m2) on Days 1, 8, and 15. CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. Subjects will continue courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity. As of January 30, 2013, 162 subjects have been randomized. Clinical trial information: NCT01472198.
MetGastric: A randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Cunningham David , Bang Yung-Jue , Tabernero Josep , Shah Manish A. , Lordick Florian , Hack Stephen Paul 
Published: March 2020

TPS4155 Background: Dysregulation of the HGF/MET pathway in patients with gastroesophageal cancer (GEC) is associated with diminished survival and poor prognostic features, such as nodal and organ metastasis, disease stage and tumor invasiveness. Preclinical data suggest that inhibition of the HGF/MET axis may increase the anti-tumor properties of platinum agents by overcoming HGF-mediated resistance mechanisms. Overexpression and inappropriate activation of the MET pathway has been shown to promote peritoneal metastasis in murine models of GEC. Overexpression of HGF or MET has also been linked to metastatic spread to the liver and peritoneum in patients with GEC. Clinical studies suggest that antibody-based inhibitors of the HGF/MET pathway are active in GEC. Onartuzumab, a monovalent monoclonal antibody, specifically binds to the MET receptor preventing HGF binding thereby inhibiting signal transduction. The most commonly reported adverse events associated with onartuzumab are grade 1–3 peripheral edema, hypoalbuminemia and fatigue. Methods: MetGastric is a randomized placebo-controlled, international phase III study in patients with previously untreated metastatic GEC. Only patients with tumors classified as both HER2-negative and MET-positive (by IHC) are eligible. Patients will be randomized (1:1) to receive mFOLFOX6 plus onartuzumab or mFOLFOX6 plus placebo. A maximum of 12 cycles of mFOLFOX6 are permitted. Onartuzumab or placebo will be continued until disease progression. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, overall response rate, safety and correlative biomarker studies. Primary and secondary analyses will include all randomized patients, analyzed according to treatment arm assignment and MET IHC score. Safety will be assessed in all patients who receive at least one dose of study treatment. This study is open for accrual. Clinical trial information: NCT01662869.
ST03: A randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with operable gastric, esophagogastric junction (OGJ), or lower esophageal adenocarcinoma.
Authors: Smyth Elizabeth Catherine , Langley Ruth E. , Stenning Sally P. , Stevenson Laura , Robb Claire , Allum William H. , Grabsch Heike , Alderson Derek , Riddell Angela M. , Crosby Thomas , Mason Robert , Griffin Michael , Mansoor Wasat , Coxon Fareeda Y. , Falk Stephen , Furniss Debra , Middleton Gary William , Sumpter Katherine Anne , Blazeby Jane M. , Cunningham David 
Published: March 2020

TPS4156 Background: Perioperative ECX chemotherapy is a standard of care for localised operable gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham, NEJM 2006). In combination with chemotherapy B, a monoclonal antibody targeting VEGF-A, results in improved response rates (RR) and progression free survival in advanced gastric cancer (Ohtsu, JCO 2011). ST03 aims to assess the safety and feasibility (stage I, 200 pts) and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. Methods: ST03 is a multicentre, open-label, phase II/III randomised trial open at 106 UK centres. Eligibility criteria are histologically proven, untreated, resectable, lower oesophageal, OGJ or gastric adenocarcinoma; age ≥18 years; WHO PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are TIA/CVA or MI ≤1 year; uncontrolled hypertension; ≥ Grade 2 NYHA heart failure; recent gastrointestinal inflammatory conditions or major surgery/trauma/open biopsy <28d of study entry. Pts receive 3 pre- and 3 postoperative ECX (epirubicin 50 mg/m2 iv D1, cisplatin 60 mg/m2 iv D1 and capecitabine 1250mg/m2/D1-21) +/- B 7.5mg/kg D1 q3wk during chemotherapy, then 6 B q3wk (investigational arm). Surgery is pre-specified and laparoscopic procedures allowed only after quality assurance review. All specimens undergo central pathology review; blood and tissue collection for translational studies is ongoing. Stage I Safety results including cardiac EF have been reported (Okines Ann Oncol 2012). The stage II primary outcome measure is overall survival. Secondary outcome measures are RR, resection rate, disease free survival, toxicity, and QoL. MRI and PET substudies are ongoing. 877 of 1,100 pts have been recruited, accrual expected to complete in Q4 2013. A pilot study within ST03 randomising HER2 positive pts to ECX ± lapatanib (L) opened Q1 2013 and will assess safety, HER2 positivity rate and feasibility in 40 pts randomised between standard ECX and modified ECX+L. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and funded by Cancer Research UK (CRUK06/025, NCT00450203). Clinical trial information: NCT00450203.
Open-label, phase I/randomized, phase II trial of the triple angiokinase inhibitor, nintedanib, versus sorafenib in previously untreated patients with advanced hepatocellular carcinoma (HCC).
Authors: Palmer Daniel H. , Peck-Radosavljevic Markus , Ma Yuk Ting , Graham Janet , Fartoux Laetitia , Hubner Richard , Loembe Arsene Bienvenu , Studeny Matus , Hocke Julia , Meyer Tim 
Published: March 2020

TPS4160 Background: While sorafenib is established as the standard first-line treatment for patients with advanced HCC, its use can be complicated by the occurrence of drug-related adverse events (AEs). Nintedanib, a potent, oral triple angiokinase inhibitor that targets VEGF, PDGF and FGF signaling (as well as Flt3 and RET), has demonstrated clinical activity in various advanced solid tumors with a relatively low incidence of AEs typically associated with angiogenesis inhibitors (e.g. skin toxicity, hypertension, hemorrhage, and hematologic toxicity) and is currently in phase III for non-small cell lung cancer and ovarian cancer. In the Phase I, dose-finding stage of this ongoing, multicenter, open-label Phase I/II trial (NCT01004003), 200mg twice daily (bid) was established as the maximum tolerated dose of nintedanib in previously untreated patients with advanced HCC (Palmer D, et al. Ann Oncol 2012;23(Suppl 9):ix245[Abs 740P]). Nintedanib had an acceptable liver AE profile; the most common AEs were mild/moderate gastrointestinal toxicities. Methods: The randomized Phase II stage of the trial aims to assess the efficacy, safety, and pharmacokinetics of nintedanib in comparison with sorafenib. Eligible patients have pathologically confirmed, measurable HCC that is not amenable to local therapy, ECOG Performance Status of ≤2, Child-Pugh score of 5–6 (Class A), AST/ALT levels ≤2× upper limit of normal, and no prior systemic therapy. Patients are being stratified by macrovascular invasion and/or extrahepatic spread and then randomized 2:1 to receive nintedanib 200mg bid or sorafenib 400mg bid in continuous 28-day cycles until progression or unacceptable toxicity. Overall, 93 patients were randomized between Sept 2011 and Nov 2012. The primary endpoint is time to progression (TTP) by independent review, according to RECIST 1.0. TTP will be estimated in the treated set by Kaplan–Meier methodology with treatment effects compared using a Cox proportional hazards model. Secondary endpoints include overall survival, tumor response, progression-free survival, safety and pharmacokinetics. Results are due late 2013. Clinical trial information: NCT01004003.
Phase II randomized study of dalantercept in combination with axitinib compared to axitinib alone as second-line treatment in patients with metastatic renal cell carcinoma.
Authors: Atkins Michael B. , Bhatt Rupal Satish , Voss Martin Henner , Rini Brian I. , Jonasch Eric , Plimack Elizabeth R. , Alter Robert , Barger Rachel , Wilson Dawn , McClure Ty , Kumar Ravi , Attie Kenneth M. , Sherman Matthew L. , Pandya Shuchi Sumant 
Published: March 2020

TPS4595 Background: The treatment of metastatic renal cell cancer (mRCC) with therapies targeting the vascular endothelial growth factor (VEGF) pathway delays disease progression; however, overcoming tumor resistance to these agents remains a therapeutic challenge. Activin receptor-like kinase 1(ALK1) is a type 1 receptor in the TGF-ß superfamily and is selectively expressed on activated endothelial cells. While VEGF drives the proliferative stage of angiogenesis, ALK1 is primarily involved in the maturation phase. Dalantercept is a human ALK1-Fc receptor fusion protein that binds to bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and acts as a ligand trap. Preclinically, dalantercept showed delayed tumor growth in solid tumor models, including RCC models alone and in combination with sunitinib. In RCC models, the addition of dalantercept to sunitinib enhanced the reduction in tumor blood flow compared to sunitinib alone. Dalantercept showed anti-tumor activity in a completed phase 1 study in 37 pts. with advanced solid tumors. Based on this promising data, we hypothesize that ALK1 inhibition may be synergistic with axitinib, a VEGFR tyrosine kinase inhibitor (TKI), in pts. with mRCC. Methods: A two-part, multi-center, open label phase 2 study to evaluate safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of dalantercept plus axitinib as second line therapy is ongoing. In Part 1, dose escalation using a 3+3 design will assess the safety and PK of dalantercept SC every 3 weeks plus axitinib 5 mg PO BID until disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) has been determined, up to 20 pts. may be enrolled in an expansion cohort to establish safety for the recommended dose for Part 2. Part 2 will include 112 pts. randomized 1:1 to dalantercept plus axitinib vs. axitinib alone. Key eligibility criteria are one prior TKI in the first-line setting, ECOG </= 1, and measurable disease. The primary efficacy endpoint is PFS. Secondary endpoints are OS, TTP, ORR, DOR, DCR, and PD biomarkers on archived tumor and serum specimens including BMP9/10 and ALK1 expression. Clinical trial information: NCT01727336.
A phase I study of cabozantinib (Cabo) plus docetaxel (D) and prednisone (P) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H. , Madan Ravi Amrit , Apolo Andrea Borghese , Parnes Howard L. , Wright John Joseph , Trepel Jane B. , Beatson Melony A. , Harold Nancy , Couvillon Anna , Steinberg Seth M , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L. 
Published: March 2020

TPS5095 Background: In mCRPC, two randomized trials demonstrated an overall survival (OS) benefit with the chemotherapeutic agent D. However, the survival improvement is modest and new strategies are needed to enhance clinical response. D-based combinations have been evaluated as one alternative strategy. Cabo targets multiple tyrosine kinases including c-Met, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. Cabo has shown activity in mCRPC, with resolution of bone lesions on bone scan, regression of soft tissue/visceral disease, and reductions in circulating tumor cells and bone biomarkers (Smith, et al, J Clin Oncol 30, 2012 [suppl; abstr 4513]). We hypothesize the addition of Cabo to D and P, in patients (pts) with mCRPC, will have an acceptable toxicity profile and could lead to improved survival by targeting different cellular pathways simultaneously. This combination therapy may represent a safe and effective strategy to improve the outcome of mCRPC pts treated with D-based chemotherapy. Methods: This is a phase I trial to determine the safety profile and the recommended phase II dose of Cabo in combination with D and P. Pts receive a fixed dose of D (75 mg/m2 IV day 1 of each 21 day cycle) and P (5 mg po q12 hours) in combination with Cabo at three escalating doses: dose level 1 is 20 mg, level 2 is 40 mg, and level 3 is 60 mg (all po qdaily). Using a standard 3 + 3 design, three patients will initially be treated at each dose level until the maximum tolerated dose (MTD) has been defined. An expansion cohort will then be enrolled at the MTD. The accrual ceiling for the study, including both the dose escalation and the expansion phases, is set at 24 pts. Secondary objectives include assessments of pharmacokinetics of each agent, evaluation of antitumor activity of the combination therapy, and assessment of changes in molecular biomarkers for receptor tyrosine kinase and angiogenesis pathways, as well as biomarkers for bone metabolism. Restaging with bone and CT scan will be undertaken every 3 cycles. Enrollment at dose level 1 has been completed without dose-limiting toxicity. Accrual is ongoing at the second dose level. Clinical trial information: NCT01683994.