bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benefit of intensified perioperative chemotherapy within high-risk CINSARC patients with resectable soft tissue sarcomas (CIRSARC).
Authors: Italiano Antoine , Blay Jean-Yves , Le Cesne Axel , Bompas Emmanuelle , Piperno-Neumann Sophie , Duffaud Florence , Bertucci Francois , Bellera Carine A. , Honoré Charles , Stoeckle Eberhard , Bonvalot Sylvie , Chevreau Christine 
Published: March 2020

TPS11078 Background: We have recently identified a gene expression signature so called “CINSARC” which is related with chromosomal instability and highly predictive of metastasis-free and overall survival in soft-tissue sarcoma (STS) patients. The prognostic relevance of this signature has been validated recently in an independent set of sarcomas from the Cancer Genome Atlas (TCGA) consortium. Despite optimal locoregional treatment, patients with high-risk CINSARC have a very poor outcome.However, the main issues with peri-operative chemotherapy in STS patients are the identification of patients who are more likely to benefit from this approach and the characterization of the best chemotherapy regimen. Indeed, in all clinical trials investigating peri-operative chemotherapy in STS, patients were included on the basis of classical histological criteria (grade, tumor size, deep location). The CINSARC is more discriminant than grade to evaluate the prognosis of STS patients (35% of grade 3 are low-risk CINSARC and 40% of grade are high-risk CINSARC). We hypothesize than: (1) 6 cycles of anthracyclines-ifosfamide is associated with improved outcome in comparison to 3 cycles of chemotherapy (ISG-STS 10-01) in patients with high-risk CINSARC STS; (2) Chemotherapy-free strategy is not associated with detrimental outcome in low-risk CINSARC STS. Methods: This is a multicenter phase III trial (sponsor: Institut Bergonié) which aims to evaluate the efficacy (intent-to-treat analysis) of 6 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy+ surgery +/-radiotherapy (Arm B) in comparison with 3 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy + surgery +/- radiotherapy (Arm A) in terms of 3-year progression-free survival (PFS) in high-risk CINSARC patients with resectable STS. Patients with low-risk CINSARC signature will be treated at investigator discretion. 334 patients will have to be recruited over 36 months in 10 centers of the French Sarcoma Group. This is the first study assessing the impact of peri-operative chemotherapy in STS based on a prognostic molecular signature. The study is open for accrual at time of submission. Clinical trial information: NCT03805022.
CLI24-001: First-in-human study of SEL24/MEN1703, an oral dual PIM/FLT3 kinase inhibitor, in patients with acute myeloid leukemia.
Authors: Ravandi Farhad , Strickland Stephen Anthony , Solomon Scott R. , Nazha Aziz , Walter Roland B. , Valimberti Ilaria , Tagliavini Alessia , Fiesoli Caterina , Binaschi Monica , Brzozka Krzysztof , Baldini Simone , Heeger Steffen , Pellacani Andrea Ugo 
Published: March 2020

TPS7062 Background: FLT3-ITD is one of the most common genetic lesions in acute myeloid leukemia (AML). PIM kinases are oncogenic FLT3-ITD targets expressed in AML cells and increased PIM kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. In addition, inhibition of PIM kinases restores sensitivity to FLT3 inhibitors and dual FLT3/PIM inhibition eradicates FLT3-ITD+ cells including primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, demonstrates a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status, compared to monotherapy with either FLT3 or PIM inhibitors such as quizartinib or AZD1208. Methods: CLI24-001 is a First in Human, open label, non-randomized, multi-center, Phase I/II dose-escalation and cohort expansion study of SEL24/MEN1703 in AML patients (excluding APL) not suitable for chemotherapy. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the recommended phase 2 dose (RP2D). In the phase 2 part/cohort expansion, subjects will receive SEL24/MEN1703 at the RP2D, to further investigate the safety profile and signs of antileukemic activity. In both study parts, patients are eligible regardless of mutational status and/or prior exposure to FLT3 inhibitors; prior treatment with PIM inhibitors is not allowed. Main inclusion criteria comprise a white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukoapheresis permitted to lower WBC). Key secondary objectives include pharmacokinetics (PK) and single agent efficacy. The study is enrolling at 5 US sites and will be extended, both in US and EU, in the cohort expansion part. This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to be active in AML regardless of FLT3 status andwith a potential to overcome FLT3 inhibitor resistance. (Sci Adv. 2015;1:e1500221; Oncotarget. 2018 Mar 30;9(24):16917-16931) Clinical trial information: NCT03008187.
A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.
Authors: Schwartz Marc Saul , Jeyakumar Deepa , Damon Lloyd Earl , Schiller Gary J. , Wieduwilt Matthew Joseph 
Published: March 2020

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.
A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).
Authors: Jamy Omer Hassan , Salzman Donna E. , Di Stasi Antonio , Innis-Shelton Racquel , Luciano Costa , Lamb Lawrence S. , Mineishi Shin , Saad Ayman A. 
Published: March 2020

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.
FREEDOM: A phase 3b efficacy and safety study of fedratinib in intermediate- or high-risk myelofibrosis patients previously treated with ruxolitinib.
Authors: Verstovsek Srdan , Harrison Claire N. , Barosi Giovanni , Kiladjian Jean-Jacques , Buglio Daniela , Chia Vincent , Gerike Torsten , Jessent-Ciaravino Valerie , Mostillo Joseph , Zhang Jun , Mesa Ruben A. 
Published: March 2020

TPS7072 Background: Myelofibrosis (MF) is a serious life-threatening condition characterized by splenomegaly, constitutional symptoms, and shortened survival. Ruxolitinib (RUX) is currently the only approved drug for treatment (Tx) of Intermediate- (Int) or High-risk MF. RUX discontinuation rates are high, mainly due to lack of response, loss of efficacy, intolerance, and drug-induced cytopenias, resulting in an important unmet medical need for a JAK2 inhibitor that is effective after RUX failure. Fedratinib (FEDR) is an oral, JAK2-selective inhibitor that produces substantial spleen volume reduction (SVR) and improves constitutional symptoms as initial therapy of MF (Pardanani, 2015) and in pts resistant to or intolerant of RUX (Harrison, 2017). Methods: This multicenter, open-label, single-arm study (NCT03755518) is enrolling adult pts with primary, post-polycythemia vera, or post-essential thrombocythemia MF; Dynamic International Prognostic Scoring System (DIPSS) Int- or High-risk disease; splenomegaly; ECOG PS ≤2; and platelet counts ≥50 × 109/L. Pts must have received prior RUX Tx for ≥3 mo or during ≥28 days of RUX therapy were RUX-intolerant (developed RBC transfusion dependence [≥2 units/mo for 2 mo] or grade ≥3 thrombocytopenia, anemia, hematoma/hemorrhage). Pts receive continuous FEDR 400 mg QD in 28-day cycles. Spleen volume is assessed by MRI/CT scan at screening, after cycles 3, 6, and 12, and at end of treatment. Primary endpoint is spleen response rate (RR; ≥35% SVR from BL by cycle 6 end). Secondary endpoints include duration of spleen RR, spleen size reduction, rate and duration of symptom response (≥50% reduction in total symptom score on the Myelofibrosis Symptom Assessment Form), and safety. Risk mitigation strategies for gastrointestinal adverse events and Wernicke encephalopathy are evaluated. Exploratory endpoints include survival, patient-reported outcomes, and biomarkers of FEDR efficacy and biochemical activity. The study will enroll ~110 pts. Assuming a spleen RR of 35%, the study will have ~90% power to detect the lower bound of the 95% CI that excludes 20%. Enrollment is ongoing. Clinical trial information: NCT03755518.
ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Solomon Benjamin J. , Ahn Jin Seok , Barlesi Fabrice , Dziadziuszko Rafal , Nishio Makoto , Shaw Alice Tsang , Bordogna Walter , Meyenberg Christoph , Wu Yi-Long 
Published: March 2020

TPS8569 Background: Patients with early-stage NSCLC (stage IA–IIIA) account for ~40% of cases at diagnosis; despite surgery, 5-year survival rates are low. Platinum-based adjuvant chemotherapy is the standard of care (SoC) for stage II–IIIA disease. Although patients with stage IA NSCLC do not benefit from adjuvant chemotherapy, patients with stage IB disease and large tumors (≥4cm) do. Adjuvant chemotherapy produces a 4–5% increase in 5-year survival rates, leaving significant unmet need for improved treatments. Approximately 5% of patients with NSCLC harbor an oncogenic fusion of the ALK gene. Treatment of advanced ALK+ NSCLC with ALK inhibitors improves efficacy and safety compared with chemotherapy. Alectinib, a potent ALK inhibitor, is the SoC first-line treatment for advanced ALK+ NSCLC. The ongoing ALINA trial will compare alectinib versus chemotherapy as adjuvant treatment for patients with stage IB–IIIA ALK+ NSCLC. Methods: ALINA is a randomized, multicenter, open-label phase III study investigating the efficacy and safety of adjuvant alectinib versus chemotherapy in ALK+ NSCLC (confirmed by an FDA-approved and CE-marked test). Adult patients (≥18 years) with completely resected stage IB (tumors ≥4cm) to IIIA disease and ECOG PS 0–1 are eligible for inclusion. Patients (N=255) from ~170 centers across ~30 countries will be randomized 1:1 to receive twice-daily alectinib 600mg for 24 months or four 21-day cycles of platinum-based chemotherapy (cisplatin 75mg/m2 [day 1] plus vinorelbine 25mg/m2 [days 1 and 8] or gemcitabine 1250mg/m2 [days 1 and 8] or pemetrexed 500mg/m2 [day 1]) according to local prescribing information. Stratification factors are disease stage (stage IB [≥4cm] vs stage II vs stage IIIA) and race (Asian vs non-Asian). Treatment will continue until planned completion, disease recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. The primary endpoint is disease-free survival per investigator; secondary endpoints are overall survival, safety, and pharmacokinetics. Clinical trial information: NCT03456076.
Tislelizumab (BGB-A317) + concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy for newly diagnosed locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) in a phase III study (RATIONALE 001).
Authors: Paz-Ares Luis G. , Senan Suresh , Planchard David , Wang Luhua , Cheong Alicia , Nguyen Marie Huong , Slepetis Ruta , Vokes Everett E. 
Published: March 2020

TPS8574 Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]
NRG Oncology CC003: A randomized phase II/III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small cell lung cancer.
Authors: Gondi Vinai , Pugh Stephanie L , Mehta Minesh P. , Tome Wolfgang , Benzinger Tammie , Bovi Joseph A , Corn Benjamin W. , Fogh Shannon E. , Robinson Cliff Grant , Wefel Jeffrey Scott , Kachnic Lisa A. 
Published: March 2020

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.
CCN3/NOV as a functional driver and prognostic biomarker of prostate cancer bone metastasis.
Authors: Ouellet VéRonique , Dankner Matthew , Desreumaux-Communal Laudine , Schmitt Estelle , Perkins Dru , Annis Matthew G , Barres Veronique , Caron Christine , Mes-Masson Anne-Marie , Saad Fred , Siegel Peter 
Published: March 2020

182 Background: Prostate cancer commonly metastasizes to the bone, resulting in pathological fractures and poor prognosis. CCN3/NOV (Nephroblastoma overexpressed) has been implicated in promoting the formation of osteolytic prostate cancer (PC) bone metastases. The C-terminal domain of CCN3 binds growth factors, heparin sulfate proteoglycans, activates Notch signaling and promotes dimerization of CCN family members. We hypothesize that the CCN3 CT domain is required to promote osteolytic PC bone metastasis and that CCN3 represents a prognostic biomarker in primary PC tumors to predict recurrence to bone. Methods: CCN3WT and CCN3∆CT were overexpressed in LNCaP C4-2 cells. The role of CCN3 was assessed with in vitro proliferation, migration and invasion assays, and in vivo through intracardiac injection in male Nude mice (Nu/Nu). Ex vivo µCT scans were performed on bone specimens. CCN3 expression was assessed in two unique tissue microarrays (TMA) comprising over 1,500 primary prostate tumor using different anti-CCN3 antibodies with immunohistochemistry and immunohistofluorescnece, respectively. Results: While CCN3WT and CCN3∆CT had little effect in vitro on cell proliferation, migration or invasion, intracardiac injection of CCN3WT resulted in increased incidence of bone metastasis compared to empty vector control and CCN3∆CT. Ex vivo µCT revealed decreased bone mineral density in bones from mice injected with CCN3WT cells compared to control and CCN3∆CT expressing cells. In both TMAs studied, high CCN3 expression in tumor epithelium correlated with increased risk of biochemical relapse and bone metastasis at 5 years and 15 years post-resection, respectively. Conclusions: CCN3 requires its C-terminal domain for its bone metastatic function, and CCN3 is correlated with aggressive disease biology in prostate cancer. These findings point to CCN3 as a biomarker that can be useful to predict prostate cancer aggressiveness, while providing clarity on its role as a functional mediator of prostate cancer bone metastasis.