bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II trial of abiraterone, olaparib or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair defects.
Authors: Reichert Zachery , Carneiro Benedito A. , Daignault-Newton Stephanie , Sullivan Amanda , Feng Felix Yi-Chung , Morgan Todd Matthew , Tomlins Scott A. , Chinnaiyan Arul M. , Hussain Maha 
Published: September 2018

TPS5086 Background: Approximately 20% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in genes encoding DNA repair proteins (e.g. ATM, BRCA1, BRCA2, PALB2, RAD51, CHEK2, FANCA). These mutations impact base excision repair and alternative end-joining, which rely on the activity of poly(ADP-ribose) polymerase (PARP). Olaparib (olap) inhibits PARP and showed activity in a post hoc analysis in mCRPC patients with DNA repair defects (DRD). In a subgroup analysis of the NCI 9012 trial evaluating abiraterone (abi) +/- veliparib (a PARP inhibitor), patients with DRD in both treatment groups had a > 80% prostate-specific antigen (PSA) response rate and prolonged progression free survival (PFS) (13.8 mos vs. 7.8 mos; P = 0.01). Preclinical data suggests interactions between androgen signaling and PARP activity. These observations provide the rationale to evaluate the efficacy of olap, abi or the combination in patients with DRD. Methods: This is a prospective, randomized, open-label phase 2 clinical trial with a primary endpoint of objective PFS (radiographic + clinical). Secondary endpoints: objective disease and PSA response rates. Analysis of tumor specimens, circulating tumor cells/DNA will be performed. Eligible patients with progressive mCRPC, no prior mCRPC therapy with tumor loss of ATM, BRCA1 or BRCA2 (based on known germline loss, prior CLIA certified tumor analysis or new metastatic biopsy) will be stratified by germline vs. somatic mutational status and randomized 1:1:1 to abi (1000 mg daily) + prednisone (5 mg bid), olap (300 mg daily) or olap + abi + prednisone (same doses). Patients in single agent arms may cross over to opposite single agent therapy at progression. An exploratory cohort of patients with DNA repair defects besides ATM, BRCA1, BRCA2 may receive olap. Statistical analysis will provide median, 12-month, and 24-month product-limit estimates of PFS by treatment arm. The study is recruiting 60 randomized patients at sites in the US. The trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC and funded by AstraZeneca. Clinical trial information: NCT03012321.
A randomized, triple negative breast cancer enrolling trial to confirm molecular profiling improves survival (ARTEMIS).
Authors: Yam Clinton , Hess Kenneth R. , Litton Jennifer Keating , Yang Wei Tse , Piwnica-Worms Helen , Mittendorf Elizabeth Ann , Ueno Naoto T. , Lim Bora , Murthy Rashmi Krishna , Damodaran Senthil Kumar , Helgason Thorunn , Huo Lei , Thompson Alastair Mark , Gilcrease Michael , Santiago Lumarie , Candelaria Rosalind P , Rauch Gaiane , Adrada Beatriz , Symmans William Fraser , Moulder Stacy L. 
Published: September 2018

TPS590 Background: Following neoadjuvant chemotherapy (NACT), patients (pts) with triple negative breast cancer (TNBC) achieving pathologic complete response/residual cancer burden-0 (pCR/RCB-0) or minimal residual disease (RCB-I) have an improved relapse free survival when compared to pts with more extensive residual disease (RCB-II/III) (Symmans et al, JCO 2017). Pts with chemo-resistant TNBC have a poor prognosis as there are currently no FDA-approved targeted agents available for TNBC. We previously reported the ability of a novel gene expression signature (GES) to predict sensitivity to NACT (Hatzis et al, JAMA 2011). Here we seek to prospectively validate the use of this GES in combination with imaging to predict response to NACT and establish the clinical impact of selecting pts predicted to have non-responsive disease (NRD) for enrollment in clinical trials of targeted therapy. Methods: All pts will undergo a biopsy of the primary tumor for molecular characterization (MC) and will be randomized 2:1 to know their MC results (intervention arm) or not (control arm). A maximum of 360 pts will be enrolled and randomized using a group sequential design with one-sided O’Brien-Fleming boundaries, with two equally spaced binding interim tests for futility and superiority and one final test, having an overall Type I error of 0.05 and power of 0.80 to detect an improvement in pCR/RCB-I from 50% to 64%. Secondary endpoints include rates of clinical trial enrollment, disease free survival and integrated biomarker analyses. All pts will receive 4 cycles of anthracycline-based NACT with imaging done every 2 cycles to assess response. After completion or progression on anthracycline-based NACT, pts predicted to have NRD based on MC/imaging (intervention arm) or imaging alone (control arm) will be offered enrollment on a clinical trial. Pts are eligible if they have stage I-III TNBC with a primary tumor that is ≥1.5cm. Pts with contraindications to anthracyclines and/or taxanes are excluded. Enrollment began in November 2015. 105 pts have been enrolled to date with 71 and 34 pts randomized to the intervention and control arms, respectively. Clinical trial information: NCT02276443.
CASCADE: A phase 3, randomized, double-blind study of vadastuximab talirine (33A) versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML).
Authors: Wang Eunice S. , Adés Lionel , Fathi Amir Tahmasb , Kreuzer Karl A , O'Meara Megan Marie , Liang Shang-Ying , Ravandi Farhad 
Published: September 2018

TPS7066 Background: AML is associated with poor survival rates in patients (pts) who are not eligible for intensive chemotherapy or allogeneic stem cell transplant (allo-SCT) due to advanced age, comorbidities, and/or disease risk factors. Non-intensive therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, are frequently employed in this setting; however, response rates and survival remain suboptimal in this pt population. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Upon binding, 33A is internalized and transported to the lysosomes where PBD is released via proteolytic cleavage of the linker, leading to DNA crosslinking and cell death. In preclinical studies, HMA priming followed by 33A exposure upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. In a phase 1 study, 33A plus HMA was generally well tolerated without a significant pattern of off-target toxicity. Activity of the combination was markedly improved compared to historical data of HMA monotherapy, with a high MRD-negative remission rate and activity maintained in the highest risk subgroups (Fathi et al, ASH 2016). Methods: This phase 3, randomized, double-blind, placebo-controlled global study was designed to compare overall survival between pts treated with 33A plus HMA vs. pts treated with placebo plus HMA (NCT02785900). Secondary endpoints include composite complete remission rate (CR/CRi), event-free survival, and safety. Approximately 500 pts will be randomized in a 1:1 manner to one of the study arms. Investigators may select either HMA (azacitidine or decitabine). Eligible pts are adults with newly diagnosed, previously untreated, de novo or secondary AML, and have intermediate or adverse cytogenetic risk. Pts must not have AML associated with favorable risk karyotype or be a candidate for allo-SCT. Combination treatment may be repeated every 4 weeks until disease progression, leukemic recurrence, or unacceptable toxicity. Study enrollment began in June 2016.
A phase I, first-in-human study of MGD006/S80880 (CD123 x CD3 DART) in AML/MDS.
Authors: Vey Norbert , Davidson-Moncada Jan Kenneth , Uy Geoffrey L. , Rizzieri David , Khoury Hanna Jean , Foster Matthew Charles , Godwin John E. , Topp Max S. , Martinelli Giovanni , Ciceri Fabio , Carrabba Matteo Giovanni , Huls Gerwin A , Wegener Antje , Tran Kathy C. , Shannon Michele , Sun Jichao , Wigginton Jon M. , DiPersio John F. 
Published: September 2018

TPS7070 Background: MGD006/S80880 is a novel CD123 x CD3 DART molecule designed to target CD123-positive cells for recognition and elimination by CD3-expressing T lymphocytes as effector cells. CD123, the alpha chain of the interleukin 3 receptor (IL-3Ra) is known to be highly expressed in > 90% of AML patients and at least 50% of MDS patients. Based on these observations, targeting CD123 could be a promising strategy in the preferential ablation of AML and MDS cells. Methods: MGD006 is currently being evaluated in a Phase 1 dose-escalation and cohort expansion study in relapsed/refractory (R/R) AML or intermediate-2/high risk MDS. The objectives of the study are to determine the MTDS and safety profile, and describe the pharmacokinetics and preliminary activity of MGD006. Patients are dosed in 28-day cycles. All patients start with a lead-in continuous IV infusion of 30ng/kg/day for 3 days followed by 100ng/kg/day for 4 days. Subsequent weeks (2-4) are dosed in two different schedules. One arm receives MGD006 for 4 days on/3 days off and the second arm receives MGD006 for 7 days continuously at the maximal dose assigned to each cohort (up to 1000ng/kg/day). Beginning with the second cycle, all patients are administered MGD006 for 4 days on/3 days off at the maximal dose/cohort. Patients can continue on treatment until 2 cycles (8 weeks) after the attainment of a CR, maximum of 12 cycles of MGD006, DLT or treatment failure. Once the MTDS is identified, two cohorts of 24 patients each, one in AML and one in MDS, will be enrolled. Response is assessed by IWG or IPSS criteria for AML and MDS, respectively. Signs and symptoms of cytokine release syndrome (CRS), a common AE, are graded according to Lee criteria. The study continues to enroll patients with open sites in the US, France, Germany, Italy, and The Netherlands. ClinicalTrials.gov #NCT02152956. EudraCT #2015-003813-11.
The OMNI patient registry: A prospective observational registry to assess vascular safety in patients with CML and Ph+ ALL treated with ponatinib.
Authors: Stemhagen Annette , Adib Deyaa , Lustgarten Stephanie , McGarry Lisa , Du Moulin Ruth , Santillana Sergio 
Published: September 2018

TPS7073 Background: Ponatinib is an oral TKI with potent activity against BCR-ABL1. The pivotal PACE study (NCT01207440) formed the basis for approval of ponatinib in the US for the treatment of patients with resistant/intolerant CML or Ph+ ALL, or those with the T315I mutation. Long-term follow-up of PACE showed a higher cumulative incidence of vascular occlusive events (VOEs) than reported at the time of approval — dose reductions were later implemented to mitigate VOEs. VOEs comprise arterial occlusive events (AOE) and venous thromboembolic events. The exposure-adjusted incidence of AOEs has not increased over time in PACE; in patients with a history of ischemic disease, the relative risk of serious AOEs was 2.6 in those with ≥2 vs 0 risk factors. The primary objective of this patient registry is to assess VOEs occurring during ponatinib use in routine clinical practice in the US. Methods: OMNI (NCT02455024) is a prospective observational registry of eligible patients (Table) with CML or Ph+ ALL for whom the decision to initiate treatment with ponatinib has already been made for the approved US indications. Patients voluntarily enroll into the registry, which is non-interventional with no protocol-mandated tests/procedures — all treatment decisions are made at the discretion of the health care practitioner in consultation with their patient. Study duration is anticipated as ~30 mo (~18-mo enrollment followed by 12 mo of data collection, which will occur every 3 mo). The primary analysis will be performed 12 mo after last patient enrolled and will estimate the incidence of VOEs by duration of ponatinib exposure. To understand differences between those with and without VOEs, exploratory analyses will be performed, considering factors such as patient demographics, risk factors for developing VOEs, dose and duration of ponatinib treatment, and concomitant medications. VOE outcomes also will be assessed. Enrollment will begin in 2017, with a target of ≥300 patients. Clinical trial information: NCT02455024. [Table: see text]
Ironclad: A randomized phase III study of ibrutinib (Ibr) or no consolidation following autologous hematopoietic stem cell transplantation (AutoHCT) for relapsed/refractory activated-B-cell (ABC) subtype diffuse large B-cell lymphoma (DLBCL).
Authors: Andreadis Charalambos , Fenske Timothy S , Hill Brian Thomas , Stiff Patrick J. , Grinblatt David L. , Hsi Eric D. , Kelley Todd , Richards Kristy L. , Kostakoglu Lale , Schöder Heiko , Jung Sin-Ho , Pitcher Brandy , Pike Kristen , Plona Teri , Baugher Ryan , Mellott Stephanie , Bartlett Nancy L. , Leonard John , Shea Thomas C. , Devine Steven Michael 
Published: September 2018

TPS7566 Background: Relapsed DLBCL in the rituximab era portends a poor prognosis with only about 25% of patients achieving long-term disease control following 2ndline therapy and AutoHCT. Patients with the ABC subtype have an inferior prognosis at diagnosis than those with GC and are overrepresented at relapse. In order to improve outcomes in ABC-DLBCL, we designed a study targeting disease pathobiology at the time of AutoHCT. Ibr has a safety profile allowing combination with cytotoxic chemotherapy and has single-agent activity with a 37% response rate in patients with relapsed/refractory ABC-DLBCL. Methods: This is an intergroup, randomized, placebo-controlled phase III study combining Ibr or placebo with high-dose chemotherapy during conditioning with AutoHCT and for 12 months following AutoHCT. Pts with relapsed or refractory DLBCL have tissue submitted centrally for real-time review and subtype assignment by GEP (Frederick Laboratory). Key eligibility criteria include no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no progression on prior Ibr. Pts with chemosensitive ABC-DLBCL are randomized to Ibr 560 mg or placebo with BEAM or CBV chemotherapy until day 0. After engraftment, pts receive Ibr 560 mg daily or placebo for 12 additional cycles. Pts with progressive disease on placebo can cross over to Ibr monotherapy. An initial safety cohort of 6 pts is being enrolled to evaluate the tolerability of Ibr with concurrent BEAM and CBV therapy. The primary endpoint is superior 2-year PFS (Ha/H0: 67% vs 50%). Secondary endpoints include time to count recovery, post-transplant response rates, OS, PFS, and incidence of 2arymalignancies. In correlative studies, we will assess the prognostic and predictive role of pre-transplant FDG-PET in the setting of Ibr or placebo therapy, the role of emergent BCR pathway mutations, double hit genetics, and pharmacogenetic determinants on treatment outcome and toxicities. We expect to accrue 296 patients over 4 years. An Alliance/BMT-CTN study: NCT02443077 Clinical trial information: NCT02443077.
EA5142 adjuvant nivolumab in resected lung cancers (ANVIL): The newest study in the ALCHEMIST platform.
Authors: Chaft Jamie E. , Dahlberg Suzanne Eleanor , Gerber David E. , Oxnard Geoffrey R. , Malik Shakun M. , Simone Charles B. , Edelman Martin J. , Heymach John , Rudin Charles M. , Ramalingam Suresh S. 
Published: September 2018

TPS8575 Background: There have been no advances in the systemic treatment of resected lung cancers in the last decade. This is in contrast to advanced disease where molecularly targeted therapies for patients with oncogene-driven tumors have replaced and/or delayed chemotherapy and where immunotherapy drugs that target the programmed death receptor pathway (PD-1 or PD-L1) are now utilized in first and second line. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is a National Cancer Institute (NCI) sponsored National Clinical Trials Network (NCTN) initiative to address the role of genomic testing and personalized therapies in the adjuvant treatment of non-small cell lung cancers. EA5142 is the newest of the ALCHEMIST studies, investigating adjuvant nivolumab in patients not eligible for the EGFR or ALK directed trials. Methods: ALCHEMIST is a clinical trial platform that consists of integrated protocols: ALCHEMIST Screening (A151216; NCT02194738), ALCHEMIST-EGFR (A081105; NCT02193282), ALCHEMIST-ALK (E4512; NCT02201992), and ALCHEMIST-nivo (EA5142; NCT02595944). In ALCHEMIST-Screening, up to 8,000 patients with pathologically confirmed stage IB (≥ 4 cm)-IIIA NSCLC will be enrolled either before or after surgical resection. Tumors that are non-squamous histology will be centrally genotyped for EGFR mutations and ALK rearrangements. Patients with EGFR or ALK-positive tumors are offered enrollment in trials evaluating adjuvant erlotinib or crizotinib, respectively. In the ~80% of patients enrolled with tumors that have wildtype EGFR and ALK or those with squamous histology central testing will be performed for PD-L1 utilizing immunohistochemistry (DAKO 28-8). Adjuvant therapy is allowed but not required. Patients are randomized to nivolumab 240 mg IV over 3 minutes every 2 weeks for up to 1 year versus standard of care observation, stratified by stage, histology, prior adjuvant treatment, and PD-L1 status ( > / = 1% or < 1%). ANVIL has enrolled 52 of 714 planned patients to detect co-primary endpoints of a 30% improvement in overall survival and/or a 33% reduction in disease free survival favoring nivolumab. EA5142 is currently open at over 400 centers nationwide. Clinical trial information: NCT02595944.
A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010.
Authors: Wakelee Heather A. , Altorki Nasser K. , Vallieres Eric , Zhou Caicun , Zuo Yunxia , Howland Michael , Xia Fan , Sandler Alan , Felip Enriqueta 
Published: September 2018

TPS8576 Background: The anti–PD-L1 mAb atezo blocks the interaction between PD-L1 and its receptors PD-1 and B7.1 and restores anti-tumor immunity. In the OAK trial, pts with 2L/3L advanced NSCLC had improved mOS in the atezo arm (13.8 mo) vs the docetaxel (doc) arm (9.6 mo), with a survival benefit observed regardless of PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). However, more effective treatment options are needed for pts with early-stage NSCLC. A global Phase III, randomized, open-label trial, IMpower010 (NCT02486718), is being conducted to evaluate the efficacy and safety of atezo vs BSC following adjuvant cisplatin (cis)–based chemotherapy (chemo) in pts with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC. Methods: Pts eligible for study must have complete tumor resection 4 to 12 weeks prior to enrollment for pathologic stage IB (tumors ≥ 4 cm)-IIIA NSCLC, be adequately recovered from surgery, be able to receive cis-based adjuvant chemo and have an ECOG PS 0-1. Pts with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemo or immunotherapy are excluded from study. Approximately 1127 pts will be enrolled regardless of PD-L1 status. Pts will receive up to four 21-d cycles of cis-based chemo (cis [75 mg/m2 IV, d 1] + vinorelbine [30 mg/m2 IV, d 1, 8], doc [75 mg/m2 IV, d 1] or gemcitabine [1250 mg/m2 IV, d 1, 8], or pemetrexed [500 mg/m2 IV, d 1; only non-squamous NSCLC]). No adjuvant radiation therapy is permitted. After adjuvant chemo, eligible pts will be randomized 1:1 to receive 16 cycles of atezo 1200 mg q3w or BSC. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [ < 5%] and IC2/3 vs TC0/1 and IC0/1 [ < 5%]). The primary endpoint is disease-free survival; secondary endpoints include OS and safety. Exploratory biomarkers, including PD-L1 expression, immune- and tumor-related biomarkers before, during and after treatment with atezo and at radiographic disease recurrence, or confirmation of new primary NSCLC, will be evaluated. Clinical trial information: NCT02486718.
Randomized phase III trial of concurrent chemoradiation followed by nivolumab or placebo for locally advanced non-small cell lung cancer (NSCLC) (RTOG 3505).
Authors: Gerber David E. , Urbanic James John , Langer Corey J. , Hu Chen , Chang I-Fen , Lu Bo , Movsas Benjamin , Jeraj Robert , Curran Walter John , Bradley Jeffrey D. 
Published: September 2018

TPS8579 Background: Despite aggressive therapy with concurrent chemoradiation, fewer than 25% of patients with stage 3 NSCLC achieve 5-year survival and are presumably cured. To date, treatment modifications—including consolidation chemotherapy, maintenance therapy with molecularly targeted agents, concomitant administration of monoclonal antibodies, and escalation of radiation therapy (RT) dose—have not improved these outcomes. Immune checkpoint inhibitors represent an effective treatment for advanced NSCLC and may enhance RT-associated anti-tumor immunity. RTOG 3505 will test whether the addition of the anti-programmed death 1 (PD1) antibody nivolumab after chemoradiation improves overall survival (OS) and progression-free survival (PFS) in this population. Methods: Key eligibility criteria include surgically unresectable stage 3 NSCLC, ECOG 0-1, adequate organ function, available archival tissue, and absence of active autoimmune disease. Patients will receive thoracic RT to 60 Gy with concurrent cisplatin 50 mg/m2 IV on Days 1, 8, 29, and 36, and etoposide 50 mg/m2 IV on Days 1-5 and 29-33. This regimen was selected to (1) minimize risk of pulmonary toxicity and steroid requirements, and (2) optimize timing of immunotherapy. Between 4 and 12 weeks after completion of chemoradiation, eligible patients will be randomized to nivolumab 240 mg IV or placebo every 2 weeks for 1 year. Stratification factors include performance status, histology, and tumor PD-L1 status. Co-primary endpoints are OS and PFS, as determined by central radiology review. Secondary objectives include toxicity assessment, patient-reported outcomes and quality of life, and OS and PFS according to PD-L1 expression. Exploratory objectives include biomarkers to predict treatment efficacy and toxicity. A total of 660 patients will be enrolled to provide ≥90% power to detect (1) a hazard ratio (HR) of 0.7 for OS with two-sided type I error of 0.04, and (2) HR of 0.667 for PFS two-sided type I error of 0.01, allowing a 16.7% drop-out rate before randomization. Clinical trial information: NCT02768558.