bluuebunny/crossref_metadata_2025_split huggingface dataset:
KEYNOTE-412: Pembrolizumab (pembro) in combination with chemoradiation versus chemoradiation alone in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Machiels Jean-Pascal H. , Licitra Lisa , Rischin Danny , Waldron John , Burtness Barbara , Gregoire Vincent , Shekar Tulin , Brown Holly M. , Cheng Jonathan D. , Siu Lillian L. 
Published: September 2018

TPS6090 Background: Approximately half of patients (pts) with HNSCC are diagnosed with locally advanced disease and treated with surgery or concomitant chemoradiotherapy (CRT) with cisplatin. Unfortunately, disease recurs in 40% to 60% of patients. The PD-l inhibitor pembro is approved for recurrent/metastatic HNSCC. CRT has immunomodulatory effects; preclinical data suggest that efficacy can be improved by adding pembro. The phase 3 KEYNOTE-412 trial (NCT03040999) will explore if CRT + pembro can improve outcomes of pts with LA-HNSCC. Methods: Adult pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled. Study population will include p16-negative HNSCC (any T3-T4 or any N2a-N3 [AJCC 7th edition]) and p16-positive oropharyngeal cancer (any T4 or any N3). Other eligibility criteria: measurable disease per RECIST v1.1 by blinded independent central review (BICR), provision of tumor sample for biomarker analyses, ECOG PS 0 or 1, and eligible for definitive CRT but not considered for primary surgery. Pts will be randomly assigned 1:1 to receive either pembro 200 mg every 3 weeks (Q3W) plus CRT, which includes radiotherapy (RT; accelerated [70 Gy, six 2 Gy fractions/wk] or standard [70 Gy, five 2 Gy fractions/week] fractionation) plus cisplatin 100 mg/m2 Q3W for 3 cycles only, or placebo Q3W plus CRT. Pts will be stratified by RT regimen, tumor site/p16 status, and disease stage. Treatment will continue until centrally confirmed disease progression, unacceptable AEs, decision to withdraw by pt or investigator, or completion of 17 doses of pembro/placebo. Disease status will be evaluated by CT or MRI 12 weeks after end of CRT, every 4 months during the next 2 years, and then every 6 months during years 3-5. Pts will be evaluated for neck dissection at 12 weeks after CRT. AEs will be monitored and graded using CTCAE v4.0 throughout the trial and for 30 days (90 days for serious AEs) after end of treatment. Primary efficacy end point is event-free survival per RECIST v1.1 by BICR. Key secondary end points: overall survival, quality of life, and safety and tolerability of pembro. Approximately 780 pts will be enrolled. Clinical trial information: NCT03040999.
A phase II/III, multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in the treatment of newly diagnosed FLT3 mutation-positive acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy.
Authors: Cortes Jorge E. , Altman Jessica , Ritchie Ellen K. , Larson Richard A. , Claxton David , Minden Mark D. , Goldenberg Alec , Naoe Tomoki , Yoon Sung-Soo , Rousselot Philippe H. , Mueller-Tidow Carsten , del Castillo Teresa Bernal , Havelange Violaine , Ciceri Fabio , Knopinska-Posluszny Wanda , Liu Shufang , Shrivastava Archita , James Angela Joubert , Rich Elizabeth Shima , Bahceci Erkut 
Published: September 2018

TPS7068 Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3mut+) relapsed/refractory AML. In FLT3mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3mut+AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL+, or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m2; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( < 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.
H3B-8800-G0001-101: A first in human phase I study of a splicing modulator in patients with advanced myeloid malignancies.
Authors: Steensma David P. , Maris Michael B. , Yang Jay , Donnellan William Bruce , Brunner Andrew M , McMasters Malgorzata , Greenberg Peter , Komrokji Rami S. , Klimek Virginia M. , Goldberg John M. , Rioux Nathalie , Kim Amy , Kumar Pavan , Marino Alyssa J. , Buonamici Silvia , Smith Peter , Sahmoud Tarek , Warmuth Markus , Platzbecker Uwe 
Published: September 2018

TPS7075 Background: Dysregulated mRNA splicing is important in tumorigenesis and in resistance to cancer therapy. Somatic heterozygous mutations in core spliceosome genes (e.g. SF3B1, SRSF2, U2AF1) have been reported at high frequencies in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). These mutations confer a change of function resulting in aberrant mRNA splicing that, in preclinical models, results in defects in hematopoietic cell development and myelodysplasia. Recurrent mutations in the spliceosome of patients with malignancies suggests importance in disease pathogenesis. Cells bearing splicing mutations depend on wild-type spliceosome function, suggesting the spliceosome as a therapeutic target. In vitro data indicate preferential induction of apoptosis (measured by caspase 3/7 activation) in SF3B1-mutant cells following treatment with the SF3B1 modulator H3B-8800. H3B-8800 inhibits growth in human AML cell lines, including those with mutations in U2AF1, SRSF2 or SF3B1. Oral administration of H3B-8800 modulates splicing and induces antitumor activity in xenograft leukemia models expressing mutant core spliceosome components. Methods: This study explores the safety of H3B-8800 in patients with myeloid cancers. Dose escalation (Cohort A) follows a 3+3 design with a starting dose of 1 mg daily for 5 consecutive days every 14 days in a 28 day cycle. Cohort A is open to patients with MDS, AML or CMML, irrespective of spliceosome mutations. In parallel to dose escalation, up to 6 patients with mutations of interest may be enrolled at doses determined to be safe in Cohort A (Cohort B). After determining the recommended phase 2 dose, 4 expansion cohorts will enroll patients with: (1) International Prognostic Scoring System (IPSS) low/int-1 risk MDS with SF3B1 mutations, (2) IPSS low/intermediate risk-1 MDS with mutations in SRSF2, U2AF1, or ZRSR2, (3) high/intermediate risk-2 MDS or AML, and (4) CMML; 3 and 4 having mutations in SF3B1, SRSF2, U2AF1, or ZRSR2. The first cohort enrolled 3 patients and the trial is currently enrolling patients at the second dose level. Clinical trial information: NCT02841540.
Zuma-6: Phase 1-2 multicenter study evaluating safety and efficacy of axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab in patients with refractory diffuse large b-cell lymphoma (DLBCL).
Authors: Locke Frederick Lundry , Westin Jason R. , Miklos David Bernard , Herrera Alex Francisco , Jacobson Caron Alyce , Lee Lillian , Rossi John , Bot Adrian , Xue Allen , Navale Lynn , Aycock Jeff , Wiezorek Jeffrey S. , Roberts Zachary 
Published: September 2018

TPS7572 Background: Approximately 1/3 of patients with DLBCL, the most common type of B-cell lymphoma, will become refractory to standard combination chemotherapy and have uniformly poor clinical outcomes (Crump, ASCO 2016). Axi-cel (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) has shown promising response rates in patients with refractory DLBCL compared with standard approaches, although some patients do not respond or progress after an initial response (Locke, Mol Ther 2016). Expression of PD-L1 on DLBCL cells and activation-dependent expression of PD-1 on CAR T cells after infusion led to the hypothesis that PD-1 pathway blockade may augment the activity of axi-cel and result in improved clinical outcomes. This study will evaluate safety and efficacy of axi-cel when given with atezolizumab (anti–PD-L1 antibody), delivered sequentially, in patients with refractory DLBCL. Methods: Phase 1 will enroll ~3-9 patients to estimate the incidence of dose-limiting toxicities. Phase 2 will enroll ~22 patients to evaluate safety and efficacy, with a primary endpoint of complete response (CR) rate (Cheson 2007). Secondary endpoints include key efficacy outcomes such as objective response rate (CR+partial response [PR]), duration of response, progression-free and overall survival, and safety and biomarker outcomes. Eligible adult patients will have received prior adequate therapy (including anti-CD20 monoclonal antibody and an anthracycline-based regimen) and have an ECOG PS of 0-1 and adequate bone marrow and organ function. Patients with a history of Richter transformation, transformed follicular lymphoma, CNS disease, or active infection are not eligible. Patients will receive fludarabine 30 mg/m2/d and cyclophosphamide 500 mg/m2/d × 3 d, followed by a single infusion of axi-cel (target dose, 2 × 106anti-CD19 CAR T cells/kg) followed by atezolizumab 1200 mg given every 21 d for 4 doses (phase 1, first dose to occur 21, 14, and 1 d after axi-cel infusion in cohorts 1, 2, and 3, respectively). The study opened to accrual in September 2016. Clinical trial information: NCT02926833.
Phase I/II study of durvalumab (anti–PD-L1 antibody) as monotherapy and in combination in patients with lymphoma or chronic lymphocytic leukemia.
Authors: Witzig Thomas E. , Casulo Carla , Cartron Guillaume , Ruan Jia , Rule Simon , Ando Kiyoshi , Burton Cathy , Pinto Antonio , Le Gouill Steven , Fowler Nathan Hale , Zinzani Pier Luigi , De Bedout Sabine , Kilavuz Nurgul , Rettby Nils , Czuczman Myron Stefan , Santoro Armando ,   And the MEDI4736-NHL-001 Trial Investigators
Published: September 2018

TPS7574 Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells to evade immune cell detection and inhibit antitumor responses. PD-1/PD-L1 expression in multiple hematologic malignancies may provide an effective target for enhancing anticancer immune response. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and has shown preliminary evidence of antitumor activity across multiple tumor types. Study objectives are to evaluate durvalumab monotherapy and combinations to determine dose and safety, as well as identify histologies and combinations that show the best complementary antitumor signals for future study. Methods: This is a phase I/II open-label, global, multicenter study of durvalumab as a monotherapy and in combination in relapsed/refractory B-cell lymphoma or CLL (MEDI4736-NHL-001; EUDRA CT 2015-003516-21; NCT02733042). Patients must have histologically-confirmed FL, MCL, splenic or nodal MZL, T-cell/histiocyte rich BCL, PMBCL, ALK+ large BCL, transformed large BCL, Richter’s transformation, DLBCL (NOS), CLL/SLL, or classical HL during the dose-finding part. Inclusion criteria are ECOG PS 0-2, and ≥1 prior antilymphoma therapy. Up to 253 patients may enroll in 4 treatment arms, which include fixed-dose durvalumab 1500 mg Q4W monotherapy or combinations with lenalidomide/rituximab, ibrutinib, or bendamustine/rituximab. The study has 3 parts: dose finding, dose confirmation, and dose expansion. The monotherapy arm does not have a dose finding or expansion part; upon progression, patients may receive combination therapy or involved-field radiation to a single nodal site (evaluating for systemic abscopal antitumor effect). Primary endpoints are safety, identification of recommended phase II dose (phase I, 3+3 design), and overall response rate (ORR; phase II); secondary endpoints include DOR, PFS, and PK/PD. ORR is measured by 2014 IWG criteria for lymphoma or modified 2008 iwCLL criteria for CLL; safety is assessed per NCI CTCAE v4.03 criteria. Recruitment is ongoing, with a target enrollment of 253 patients across 60-80 centers globally. Clinical trial information: NCT02733042.
Phase 1 study to evaluate the safety and efficacy of immunotherapy with tremelimumab and durvalumab in multiple myeloma patients receiving high dose chemotherapy and autologous stem cell transplant (HDT/ASCT) + peripheral blood lymphocyte (PBL) reinfusion.
Authors: Lesokhin Alexander M. , Chung David J. , Cho Hearn J. , Shohara Lisa , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Venhaus Ralph Rudolph 
Published: September 2018

TPS8051 Background: Multiple myeloma (MM) remains an incurable hematologic malignancy despite the advent of new classes of drugs, including immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies. The success and synergistic activity of immunotherapy (IMT) in solid tumors and hematologic malignancies has fueled their investigation in MM. HDT/ASCT as consolidation or as treatment for relapse remains a cornerstone for improving overall survival. HDT/ASCT transiently eliminates immune-suppressive cell populations and provides a viable IMT platform. Reinfusion of PBLs harvested pre-HDT induces immune responses, supporting its inclusion in IMT combinations. This study evaluates the effect of IMT, using tremelimumab (T), an anti-CTLA-4 monoclonal antibody, and durvalumab (D), an anti-PD-L1 monoclonal antibody, together with autologous PBL reinfusion and starting T ± D at Day 100 and earlier (Day 30) post-ASCT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02716805) evaluates the safety and preliminary efficacy of T and D administered on 2 schedules in MM patients at high risk for relapse as outlined below. Cohort initiation requires dose-limiting toxicity in < 2/6 patients in the previous cohort. The primary endpoint is safety. Secondary endpoints are objective response rate per IMWG, minimal residual disease, progression free and overall survival, and 100-day ASCT-related mortality. Exploratory endpoints include immunological effects and immune response. Enrollment opened 18 Nov 2016. As of 31 Dec 2016, 1 patient is enrolled in Cohort 1; enrollment is ongoing. Clinical trial information: NCT02716805. [Table: see text]
A phase 1/2 study of durvalumab (DURVA) in combination with lenalidomide (LEN) with or without dexamethasone (DEX) in patients (pts) with newly diagnosed multiple myeloma (NDMM).
Authors: Lonial Sagar , Oriol Albert , Mateos Maria-Victoria , Rodriguez-Otero Paula , Bahlis Nizar J. , Bensinger William , Porkka Kimmo , Van De Donk Niels , Yiu Wai , Di Casoli Carl , Ervin-Haynes Annette L. , Zaki Mohamed H. , Vangsted Annette 
Published: September 2018

TPS8055 Background: LEN + DEX (Rd) is approved for pts with newly diagnosed MM, including those who are transplant non-eligible (TNE). DURVA is a monoclonal antibody to programmed death ligand 1 (PD-L1) that blocks PD-L1 binding to programmed death-1 (PD-1). Preclinical studies showed anti-MM immune responses with PD-1/PD-L1 blockade that were enhanced with LEN (Görgün et al, 2015). Here, we present a phase 1/2, multicenter, open-label trial in progress (MEDI4736-MM-002) designed to evaluate DURVA in combination with LEN ± DEX in a target population of pts who are TNE and/or with high-risk NDMM. Methods: Enrollment of up to 138 pts from the US, Canada, and Europe is planned to determine the recommended dose of DURVA (primary endpoint) with LEN ± DEX for the treatment (Tx) of NDMM. Key secondary endpoints include safety, response outcomes, pharmacokinetics, progression-free survival, and overall survival. Pts with previously untreated MM with ≥ 1 of the following will be included: 1 of the CRAB criteria or clonal bone marrow plasma cells ≥ 60% and an Eastern Cooperative Oncology Group performance status of ≤ 2. Pts with a history of primary immunodeficiency will be excluded. Each independent cohort (A, B, C) will enroll 6 pts in parallel in the dose-finding phase (Table). Dose-limiting toxicities will be evaluated during the first cycle of Tx. The optimal regimen will be determined from the dose-finding phase and a parallel dose-expansion phase of up to 40 pts per cohort. Tx will continue until progressive disease or unacceptable toxicity. To date, 15 pts have enrolled. Clinical trial information: NCT02685826. [Table: see text]
Phase 2, open-label study of venetoclax in combination with carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Bueno Orlando , Xu Tu , Cordero Jaclyn , Morris Lura , Ross Jeremy , Freise Kevin , Munasinghe Wijith , Leverson Joel , Mudd Sarah , Verdugo Maria 
Published: September 2018

TPS8056 Background: A significant unmet need for multiple myeloma (MM) therapy remains as many patients eventually relapse after or become refractory to current treatment options. Investigation of novel agents and combinations in relapsed/refractory (R/R) patients are therefore critical to advance therapy and improve patient outcomes. Venetoclax is a potent, selective, orally bioavailable inhibitor of BCL-2. Combination of venetoclax with dexamethasone and bortezomib, a proteasome inhibitor that can inhibit MCL-1 indirectly via stabilizing the MCL-1-neutralizing protein NOXA, showed high rates of clinical response in a Phase 1 study. The mechanism of MCL-1 inhibition is thought to be a class effect of proteasome inhibitors. Given the clinical data supporting the combination of venetoclax with a proteasome inhibitor, this study will evaluate whether venetoclax combined with carfilzomib and dexamethasone can provide a well-tolerated and efficacious treatment option for R/R MM patients. Methods: This Phase 2, open-label study will assess the combination of venetoclax, carfilzomib, and dexamethasone in patients with R/R MM (NCT02899052). Primary objectives are to assess the safety and tolerability of this combination. Secondary objectives include evaluation of the pharmacokinetics of venetoclax and carfilzomib, preliminary efficacy of the combination (including overall response rate, very good partial response or better rate, progression-free survival, time to progression, and duration of response), and minimal residual disease (MRD) in bone marrow by next generation sequencing. Exploratory objectives will assess pharmacodynamic and predictive biomarkers, MRD by PET, pharmacogenetics, and patient-reported outcomes. Safety and pharmacokinetic profiles of the combination will be evaluated in initial dose escalation cohorts to determine appropriate doses of venetoclax and carfilzomib to be used with dexamethasone; a dose expansion phase will evaluate the safety and efficacy profiles of the combination based on selected doses. Study recruitment began in January 2017, with target enrollment of ~40 patients from 10–15 sites in the United States. Clinical trial information: NCT02899052.
A phase II study of atezolizumab as neoadjuvant and adjuvant therapy in patients (pts) with resectable non-small cell lung cancer (NSCLC).
Authors: Owen Dwight Hall , Bunn Paul A. , Johnson Bruce E. , Kwiatkowski David J. , Kris Mark G. , Wistuba Ignacio Ivan , Gandhi Mayank , Phan See , Shames David S. , Schulze Katja , Yu Wei , Aisner Dara , Chaft Jamie E. , Garon Edward B. , Lee Jay M , Minna John D. , Rusch Valerie W. , Reckamp Karen L. , Wozniak Antoinette J. , Carbone David P. ,   LCMC3 Investigators
Published: September 2018

TPS8580 Background: Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with early stage disease. Atezolizumab is a humanized IgG1 monoclonal antibody that inhibits PD-L1 from binding to its receptors PD-1 and B7.1, thereby restoring anti-tumor immune response. In the OAK trial, a randomized phase III trial of patients with metastatic NSCLC who progressed on platinum based chemotherapy, atezolizumab improved overall survival in patients regardless of PD-L1 expression compared with docetaxel (13.8 months vs. 9.6 months, HR 0.73 [95% CI 0.62 – 0.87]) with a manageable safety profile. Methods: NCT02927301 is a phase II, open-label, single-arm study designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant and adjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. The study has two parts: the primary part will evaluate the ability of neoadjuvant atezolizumab to produce pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit in Part 1. The primary endpoint is major pathologic response rate (defined as ≤ 10% of viable tumor tissue) based on surgical resection. Secondary end points include overall response rate by status of mutation load, neoantigen score and gene expression signatures. OS and DFS are exploratory end points. This trial presents a unique opportunity to evaluate exploratory biomarkers given the availability of pre- and post-treatment biopsy specimens for assessment of evolution of immune related markers associated with response. The study opened to accrual in January 2017. Clinical trial information: NCT02927301.