bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two phase I/II open label clinical trials evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 or MAGE-A10 in subjects with stage IIIb or stage IV non-small cell lung cancer (NCT02588612/NCT02592577).
Authors: Creelan Ben C. , Gainor Justin F. , Govindan Ramaswamy , Hardy Nancy M. , Heymach John , Mudad Raja , Reckamp Karen L. , Bardwell William , Holdich Tom , Bartlett-Pandite Arundathy N. , Amado Rafael G. 
Published: September 2018

TPS3096 Background: Non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer. Survival has recently been impacted by molecularly targeted therapies and checkpoint inhibitors (CPI), and the promising CPI results implicate a role for the immune system in NSCLC. 10-40% of NSCLC express NY-ESO-1 or MAGE-A10 cancer/testis antigens. These studies will evaluate the safety and antitumor activity of genetically engineered affinity enhanced TCRs (NY-ESO-1c259T or MAGE-A10c796T) directed towards a NYESO-1 or MAGE-A10 derived peptides complexed with HLA-A*02. In addition, correlative studies to evaluate persistence, phenotype, functionality of engineered T cells, mechanisms of resistance and antigen spreading will be performed. Methods: Patients (pt) are screened (NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression. For entry into either treatment protocol, pt must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. Following apheresis, T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259T or MAGE-A10c795 TCR, and infused into the pt following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The NY-ESO-1c259T study is a 10 pt study utilizing a dose of 1-6 x 109 transduced T cells. The MAGE-A10c796T first-in-human study is a modified 3+3 design in up to 28 pt with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T cells, with staggered treatments to allow for safety review; dose escalation will be guided by the DLT observed and by safety review committee guidance. Response to treatment will be assessed by RECIST v1.1 at weeks 4, 8, 16, 24, every 3 months (for 2 yr) and every 6 months until disease progression. Clinical trial information: NCT02588612/NCT02592577.
A phase 1b study to evaluate TAK-659 in combination with nivolumab in patients (pts) with advanced solid tumors.
Authors: Juric Dejan , Faucette Stephanie , Wang Ling , Niu Huifeng , Kannan Karuppiah , Stumpo Kate , Rong Yuanxin , Shou Yaping , Nemunaitis John J. 
Published: September 2018

TPS3104 Background: TAK-659 is an investigational, reversible, potent dual inhibitor of SYK and FLT-3. In ongoing early-phase studies (NCT02000934; NCT02323113), TAK-659 demonstrated an acceptable pharmacokinetic and safety profile, with evidence of preliminary activity in pts with DLBCL, follicular lymphoma, CLL, and AML (Kaplan et al. Blood 2016;128:624/2834). In preclinical studies, TAK-659 in combination with nivolumab, an anti-PD-1 checkpoint inhibitor, resulted in loss of myeloid suppressor cells (MDSCs), increased T-cell activation, and complete tumor growth suppression (Kannan et al. Eur J Cancer 2016;69:S92). This first-in-human combination study will investigate the efficacy and safety of TAK-659 and nivolumab in pts with advanced solid tumors. Methods: This open-label, multicenter, phase 1b study (NCT02834247) will include dose-escalation and expansion phases. Pts with advanced solid tumors who have failed ≥1 prior lines of therapy and have no effective therapeutic options available by investigator assessment will be eligible for the dose-escalation phase. Pts will receive oral TAK-659 at doses of 60–100 mg QD in a standard 3+3 schema, plus nivolumab 3 mg IV on days 1 and 15 of 28-day cycles. The expansion phase at the recommended phase 2 dose (RP2D) will include 3 cohorts of pts with relapsed/refractory metastatic triple-negative breast cancer, locally advanced/metastatic NSCLC, or locally advanced/metastatic head and neck squamous cell carcinoma (n = 30 response-evaluable pts in each cohort; 24 naïve, 6 relapsed/refractory to prior anti-PD-1/PD-L1 therapy). Ten pts in each cohort will receive 2 weeks of single-agent TAK-659 before starting combination therapy; the other 20 pts will receive combination therapy throughout. The primary endpoints are maximum tolerated dose/RP2D (dose-escalation phase) and overall response rate by investigator per RECIST v1.1 (expansion phase). Secondary endpoints include adverse events, disease control rate, duration of response, progression-free survival, overall survival, and TAK-659 pharmacokinetics. There are currently 7 pts enrolled; recruitment to the 100 mg dose-escalation cohort is ongoing. Clinical trial information: NCT02834247.
Integrate II: A randomised phase 3 double-blind placebo-controlled study of regorafenib in refractory advanced gastro-oesophageal cancer (AGOC)—An international study organized by the Australasian Gastrointestinal Trials Group (AGITG).
Authors: Sjoquist Katrin Marie , Pavlakis Nick , Martin Andrew James , Tsobanis Eric , Yip Sonia , Bang Yung-Jue , Alcindor Thierry , O'Callaghan Christopher J. , Shitara Kohei , Bekaii-Saab Tanios S. , Grothey Axel , Chen Li-Tzong , Simes John , Zalcberg John Raymond , Goldstein David 
Published: September 2018

TPS4136 Background: AGOC has a poor prognosis with no established standard treatment following failure of chemotherapy (CT). Regorafenib (BAY 73-4506)(REG) is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET and KIT). INTEGRATE (phase 2) demonstrated REG was highly effective in prolonging PFS across a range of AGOC pts, with a positive OS trend. Regional differences were found in magnitude of effect, but REG was effective in all regions/subgroups. The phase 3 INTEGRATE II will explore whether REG is effective in prolonging survival in patients overall, and in the Asian sub-population. Methods: International (Australia/New Zealand (NHMRC CTC); Canada (CCTG), Korea, Japan, Taiwan, USA (ACCRU)) randomised phase III, double-blind, placebo-controlled trial with 2:1 (REG:placebo)(PBO) randomisation and stratification by: Location of tumour, Geographic region, prior VEGF inhibitors. Eligible patients (histologically confirmed AGOC), with evaluable metastatic or locally advanced disease refractory to, or relapsed following second line CT, will receive best supportive care plus 160mg REG or matched placebo orally on days 1-21 of each 28 day cycle until disease progression or prohibitive adverse events. Primary endpoint is OS. Secondary endpoints: PFS, response rate, quality of life, safety, identification of prognostic/predictive biomarkers for study endpoints, and REG PK across geographical regions. 350 patients (50% from Asia) randomized in a 2:1 ratio will provide 90% power to detect a hazard ratio (HR) for OS of 0.67 with a 2-sided α of 0.05 assuming PBO median survival is 4.5 mos. The sample size accommodates 2 interim analyses undertaken at 1/3 and 2/3 of required events. As of January 2017, 12 of 28 planned ANZ sites are open, with 4 patients enrolled. Regulatory approval has been received for 12 Canadian sites, and 12 Korean sites. Korean recruitment is expected to commence in February 2017. Regulatory submissions are pending in Taiwan, Japan, and the USA. Clinical trial information: NCT02773524.
A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Powles Thomas , Fizazi Karim , Gillessen Silke , Drake Charles G. , Rathkopf Dana E. , Narayanan Sujata , Green Marjorie C. , Mecke Almut , Schiff Christina , Sweeney Christopher 
Published: September 2018

TPS5090 Background: In the past decade, several therapies have been approved for patients (pts) with mCRPC, including the androgen receptor (AR) antagonist enzalutamide (enza) and the androgen synthesis inhibitor abiraterone acetate (abi). Despite these advances, most pts experience disease progression and there are inadequate data to guide the sequencing of agents to optimize outcomes. Pts with mCRPC who progress on enza have increased circulating PD-L1/PD-L2–positive dendritic cells compared with enza-naive pts or pts who are still responding to treatment (Bishop et al. Oncotarget. 2014). In two recent studies, PSA and radiographic responses were observed in mCRPC pts treated with a PD-L1/PD-1 pathway inhibitor with or without enza (Graff et al. Oncotarget. 2016; Hansen et al. Ann Oncol. 2016). Atezolizumab (atezo) is an anti–PD-L1 monoclonal antibody that inhibits the interaction between PD-L1 and its receptors, PD-1 and B7.1, enhancing T-cell responses and improving anti-tumor activity. Taken together, this suggests that the combination of atezo and enza may provide an effective treatment option for mCRPC pts. Methods: A Phase III randomized, multicenter, clinical trial (NCT03016312) is being conducted to evaluate the efficacy and safety of atezo with enza compared with enza alone in mCRPC pts who have received prior abi treatment and have progressed on, are ineligible for, or have refused a taxane regimen. Eligibility criteria include mCRPC or locally advanced, incurable CRPC and ECOG PS 0-1. Exclusion criteria include CNS metastasis, autoimmune disease, history of seizures, prior immunotherapy and prior treatment with enza or any other newer AR antagonists. Pts will be randomized 1:1 to receive atezo 1200 mg q3w and enza 160 mg qd or enza alone. The primary endpoint is OS, and secondary endpoints include PSA response rate, rPFS, ORR and safety. Exploratory biomarkers associated with responses to atezo and enza will be evaluated in tumor tissue collected at baseline and progression. Approximately 550 pts will be enrolled at 150 sites globally. Clinical trial information: NCT03016312.
ARASENS phase 3 trial of ODM-201 in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Smith Matthew Raymond , Saad Fred , Hussain Maha , Sternberg Cora N. , Fizazi Karim , Crawford E. David , Yamada Karin Sayuri , Kappeler Christian , Kuss Iris , Tombal Bertrand F. 
Published: September 2018

TPS5092 Background: Androgen deprivation therapy (ADT) ± docetaxel is recommended first-line therapy for mHSPC, but most patients progress to castration-resistant PC (CRPC). BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, ODM-201 and its main circulating metabolite are active also in known AR mutants (eg, W742L, F877L), and have been found to have negligible blood-brain barrier penetration. In the phase 1 ARAFOR and phase 1/2 ARADES trials, ODM-201 had antitumor activity and was well tolerated in men with mCRPC (Massard et al. Eur Urol. 2016;69:834‒840; Fizazi et al. Lancet Oncol. 2014;15:975‒985). Given this promising activity in mCRPC, the ARASENS trial is evaluating ODM-201 plus standard ADT + docetaxel in men with metastatic disease (mHSPC). Methods: This international, randomized, double-blind, placebo-controlled, phase 3 trial (NCT02799602) is being conducted in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to either ODM-201 600 mg twice daily (2×300 mg tablets) orally with food or placebo, both with ADT + docetaxel (6 cycles after randomization), and stratified by extent of disease and alkaline phosphatase levels. Key inclusion criteria are histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation anti-androgen therapy ≤12 weeks before randomization, and Eastern Cooperative Oncology Group performance status 0 or 1. The primary objective is to show superior overall survival with ODM-201 vs placebo, both with ADT + docetaxel. Secondary end points include time to CRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event-free survival (SSE-FS), time to first SSE, initiation of opioid use, pain progression, and worsening of physical symptoms, all measured at 12-week intervals. Safety will be assessed by adverse events. The trial is open for enrollment; first patient first visit was in November 2016 and > 10 sites are open for recruitment and enrolling patients. Clinical trial information: NCT02799602.
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer: The ENGOT-EN2/DGCG trial.
Authors: Mirza Mansoor Raza , Lundgren Caroline , Kridelka Frederic , Ferrero Annamaria , Greggi Stefano , Christensen Rene dePont , Santaballa Ana , Soliman Pamela T. , Levy Tally , Sehouli Jalid , Cibula David , Auranen Annika , Lund Bente , Roennengart Eva , Amant Frederic 
Published: September 2018

TPS5613 Background: Patients with medium and high-risk stage I and II endometrial cancers (EC) have, despite radical surgery, a high risk for progression. Adjuvant brachytherapy or EBRT is the traditional therapy for many decades although without impacting on survival. Several studies have failed to demonstrate superiority of adjuvant chemotherapy in unselected population with a high number of low-risk patients. It is of utmost importance to demonstrate efficacy of adjuvant combination chemotherapy in a randomized trial comparing to no further treatment in the medium and high-risk node negative stage I and stage II patients. Methods: The primary objective of this trial is to evaluate the effect on overall survival of carboplatin-paclitaxel combination chemotherapy against no further systemic treatment. Key eligibility criteria include: histologically confirmed EC, stage I grade 3 endometrioid adenocarcinoma or stage II endometrioid adenocarcinoma or stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, carcinosarcoma or undifferentiated carcinoma); prior surgery with pelvic lymphadenectomy or sentinel lymph node biopsy. Patients may receive vaginal brachytherapy in both arms. 240 patients are randomized to receive six courses of adjuvant carboplatin (AUC5) and paclitaxel (175mg/m2) combination on day one every 21 days or no further treatment (1:1 randomization). Primary endpoint is overall survival of endometrioid subgroup. Secondary endpoints include overall survival of whole study population, disease specific survival, progression-free survival, toxicity, compliance, Quality of Life (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24), rate of isolated pelvic or distant relapses, as well as mixed relapses. Trial is enrolling patients. The following cooperative groups are participating: DGCG (DK), NSGO (DK, FIN, SWE), BGOG (BEL), MaNGO (ITA), MITO (ITA), GEICO (SPA), NOGGO (GER), CEEGOG (Czech), ISGO (ISR) & MDACC (USA). Clinical trial information: NCT01244789.
A randomized, double-blind phase II study of pembrolizumab versus placebo in patients with head and neck cancers at high risk for recurrence or low-volume residual disease: The PATHWay Study.
Authors: Bauml Joshua , Karrison Theodore , Vokes Everett E. , Cohen Roger B. , De Souza Jonas A. , Aggarwal Charu , Saloura Vassiliki , Agrawal Nishant , Saba Nabil F. , Langer Corey J. , Seiwert Tanguy Y. 
Published: September 2018

TPS6095 Background: Head and neck squamous cell carcinoma (HNSCC) is a major medical problem worldwide. While some patients may be cured with a combination of surgery, radiation, and systemic therapies, a significant percentage of patients will have recurrent and incurable disease. Despite our epidemiologic understanding of which patients are likely to recur, there are no consolidative therapies that have been shown to improve outcomes in this high-risk population. Pembrolizumab is a PD-1 inhibitor that has shown significant single agent activity in recurrent/metastatic HNSCC after treatment with other systemic therapies. While drug development of pembrolizumab is ongoing in Phase III studies in the 2nd and 1stline recurrent/metastatic disease settings, the ultimately the biggest potential impact based on patient volume and survival will potentially be in the curative intent setting. This randomized study is intended to explore the incorporation of pembrolizumab into the treatment of patients with locally advanced HNSCC at high risk for recurrence. Methods: Eligible patients must have HNSCC, completed therapy with definitive intent, and have an estimated risk of recurrence ≥40-50% (including tumors with extensive lymphadenopathy, extracervical lymphadenopathy, indeterminate residual local or distant mass after treatment, non-responders to induction chemotherapy, incomplete definitive therapy, receipt of salvage therapies, or oligometastatic disease treated definitively). Patients will be randomized to 1 year of either pembrolizumab 200 mg or placebo, administered intravenously day 1 of each 3-week cycle. The primary hypothesis of the study is that the addition of pembrolizumab will improve the 2-year progression-free survival (PFS) rate, compared to placebo. A sample size of 90 (45 patients per treatment arm, assuming 10% loss of follow up in N = 100 patient trial) will achieve 92.7% power at alpha = 0.10 (one-sided) to detect a difference between 50% and 72.5% PFS at 2 years. Approximately 51 events are required to detect such a difference. Patient screening and enrollment are expected to begin spring 2017.
A phase Ib study of atezolizumab (atezo) alone or in combination with lenalidomide or pomalidomide and/or daratumumab in patients (pts) with multiple myeloma (MM).
Authors: Cho Hearn J. , Cole Craig , Martin Thomas G. , Zonder Jeffrey A. , Fay Joseph W. , Vij Ravi , Byon John CH , Stewart A. Keith , Dhodapkar Madhav V. 
Published: September 2018

TPS8053 Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.
Durvalumab (DURVA) plus daratumumab (DARA) in patients (pts) with relapsed and refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Bensinger William , Weisel Katja C. , Boyd Kevin , Ramasamy Karthik , Gonzalez Esther , Favre-Kontula Linda , Peluso Teresa , Sternas Lars Axel , Di Casoli Carl , Zaki Mohamed H. , Facon Thierry 
Published: September 2018

TPS8054 Background: DARA, a monoclonal antibody (mAb) against CD38, is approved for RRMM. Combination treatment (Tx) with DARA + DURVA, a mAb against programmed death ligand-1 (PD-L1), may enhance host anti-MM immunity and response. DARA and PD-L1 mAbs have each demonstrated clinical activity in combination with pomalidomide (POM) + low-dose dexamethasone (LoDEX) in MM. Thus, the phase 2 MEDI4736-MM-003 trial is evaluating DURVA + DARA in RRMM, and, in an exploratory analysis, the addition of POM + LoDEX to DARA + DURVA either upon progressive disease (PD) with DARA + DURVA or as up-front Tx will be assessed. Methods: ≈ 144 pts with RRMM are being enrolled. Pts with measurable MM who received ≥ 3 prior anti-MM Txs, including a protease inhibitor and an immunomodulatory agent, or are double-refractory to these 2 agents will be included. Exclusion criteria include allogeneic stem cell transplant (SCT), autologous SCT ≤ 12 weeks, and prior DARA or other CD38 antibody therapies. Primary endpoints are overall response rate (ORR) and safety. Secondary endpoints are time to response, duration of response, progression-free survival, and pharmacokinetics. The study includes a 3 + 3 safety run-in phase to confirm the tolerability of the recommended phase 2 doses (RP2Ds) of DURVA and DARA. Dose-limiting toxicities will be evaluated during the first Tx cycle. Safety and efficacy will be assessed by a Simon 2-stage design (Table). POM + LoDEX may be added to DARA + DURVA in pts who received ≥ 2 cycles of DARA + DURVA and had confirmed PD. Based on preliminary safety and efficacy, the 4-drug regimen may be explored as up-front Tx. Tx with either the 2- or 4-drug regimens will continue until PD or unacceptable toxicity. Pts treated with POM will be followed for second primary malignancies every 6 mos until the end of the trial. To date, 6 pts have enrolled in the run-in phase. Clinical trial information: NCT02807454. [Table: see text]