bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT078: Impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia
Authors: Park Jae H. , Rivere Isabelle , Wang Xiuyan , Senechal Brigitte , Curran Kevin , Sauter Craig , Wang Yongzeng , Santomasso Bianca , Li Daniel , Brentjens Renier , Sadelain Michel 
Published: July 2017

Abstract
Objectives: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL). However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL with a focus on impact of pre-treatment disease burden and post-CAR T cell allogeneic transplant on long-term clinical outcome.
Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion. We grouped patients into 2 cohorts based on disease burden upon T cell infusion: minimal residual disease (MRD) with &lt;5% blasts in bone marrow and morphologic disease (≥5% blasts). Median follow-up duration was 18 months (range, 0.2-57.3).
Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p=0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 - 36.2) (p=0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p=0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p=0.0326 and p=0.0001, respectively).
Conclusion: Despite comparable initial CR rates between the two cohorts, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL.
Citation Format: Jae H. Park, Isabelle Rivere, Xiuyan Wang, Brigitte Senechal, Kevin Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Daniel Li, Renier Brentjens, Michel Sadelain. Impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT078. doi:10.1158/1538-7445.AM2017-CT078
Abstract CT080: Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study
Authors: Cao Liang , Kang Zhigang , Li Linghui , Strauss Julius , Dussault Isabelle , Gulley James 
Published: July 2017

Abstract
Introduction: M7824 is a bifunctional molecule that blocks both PD-L1 and TGFβ1-3. In this first-in-human phase I dose escalation study, in addition to monitoring the pharmacokinetics of M7824, we aimed to confirm its mechanism of action, particularly against the TGFβ cytokines.
Methods: Patients were treated with M7824 intravenously at 5 dose levels of 0.3, 1, 3, 10, and 20 mg/kg every two weeks. PK analyses were performed from samples up to day 85 (7th dose). PD-L1 target occupancy was measured in CD3+ PBMCs by flow cytometry from patient blood collected at pre-dose, Day 2 (D2), D15, and D43. Further, the blood levels of TGFβ1-3 and pro-inflammatory cytokines were measured at these time points with an additional time point at D8 using analytically validated Luminex bead- and ECLIA-based multiplex immunoassays.
Results: Results indicated a half-life of 4-8 days for M7824, which increased with dose up to 3 mg/kg, and was subsequently dose independent at dose levels of &gt; 3 mg/kg. M7824 PK exposure during the first cycle increased in an approximately dose-proportional manner between 3 to 20 mg/kg, without significant accumulation within the first 85 days of treatment. There was PD-L1 target occupancy plateaued at about 80% for dose levels 3-20 mg/kg which was maintained throughout the dosing interval. Furthermore, there was a small (1.7 fold on D2) but significant induction of IFNγ at 0.3-20 mg/kg (p=0.001, n=19). TGFβ1-3 blood levels were reduced by a minimum of 99%, 92%, and 91%, respectively, at all time points for dose levels 1-20 mg/kg. At the dose of 0.3 mg/kg, TGFβ1-3 levels were depleted at D2 and D8, but not at D15 with an average reduction of 63%, 42% and 67%, respectively. Moreover, there was a correlation between the drug PK levels and the TGFβ trapping. Thus, TGFβ1-3 trapping was achieved in the circulation at drug dose level of 1 mg/kg and above.
Conclusion: This study demonstrates in vivo evidence for highly significant trapping (&gt;90%) of circulating TGFβ molecules (β1, β2, β3) by the bifunctional agent M7824 at dose levels of 1 mg/kg and higher, in addition to its high degree of peripheral PD-L1 target occupancy (80%). Further studies to evaluate the PK/PD, safety, and efficacy profile of M7824 are ongoing.
Citation Format: Liang Cao, Zhigang Kang, Linghui Li, Julius Strauss, Isabelle Dussault, James Gulley. Pharmacokinetic and pharmacodynamic analysis of M7824, a dual anti-PD-L1 and TGFβ TRAP molecule, in the first-in-human phase I dose escalation study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT080. doi:10.1158/1538-7445.AM2017-CT080
Abstract CT082: Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026
Authors: Peters Solange , Creelan Benjamin , Hellmann Matthew D. , Socinski Mark A. , Reck Martin , Bhagavatheeswaran Prabhu , Chang Han , Geese William J. , Paz-Ares Luis , Carbone David P. 
Published: July 2017

Abstract
Background: CheckMate 026 is a randomized trial of nivolumab monotherapy versus platinum doublet chemotherapy in patients with untreated stage IV or recurrent non-small cell lung cancer (NSCLC) and ≥1% programmed death-1 ligand 1 (PD-L1) tumor expression. Nivolumab was not associated with improved progression-free survival (PFS) versus chemotherapy in patients with ≥5% PD-L1 expression, however, nivolumab had a favorable safety profile compared with chemotherapy and overall survival (OS) was similar between treatment arms. In an exploratory analysis, we assessed whether patients with high tumor mutation burden (TMB) may derive enhanced benefit from nivolumab compared with platinum doublet chemotherapy.
Methods: TMB scores for missense, somatic mutations were determined in patients with sufficient samples for whole exome sequencing of tumor and matched whole blood DNA. For the initial analyses, patients were equally divided into groups based on TMB tertile distribution. Patients in the low, medium, and high TMB tertiles had 0-99, 100-242, and ≥243 mutations, respectively.
Results: Of 541 randomized patients, 312 (57.7%) had evaluable data to determine TMB. The percentage of patients with high TMB was lower in the nivolumab arm than in the chemotherapy arm (29.7% vs 39.0%). Baseline characteristics, PFS, and OS in patients evaluable for TMB were similar to all randomized patients. In patients with high TMB, PFS was improved (median PFS of 9.7 vs. 5.8 months; HR, 0.62; 95% CI, 0.38 to 1.00) and objective response rate was higher with nivolumab versus chemotherapy (46.8% vs 28.3%). OS in patients with high TMB was similar between the 2 treatment arms, which may be attributable in part to a 65% crossover rate to nivolumab in the chemotherapy arm for this subgroup.
Conclusions: This is the first pivotal randomized phase 3 trial to incorporate an analysis evaluating TMB and clinical benefit with programmed death-1 inhibitor therapy. The findings of this exploratory retrospective analysis suggest that nivolumab improves ORR and PFS compared with platinum doublet chemotherapy in patients with high TMB.
Citation Format: Solange Peters, Benjamin Creelan, Matthew D. Hellmann, Mark A. Socinski, Martin Reck, Prabhu Bhagavatheeswaran, Han Chang, William J. Geese, Luis Paz-Ares, David P. Carbone. Impact of tumor mutation burden on the efficacy of first-line nivolumab in stage iv or recurrent non-small cell lung cancer: An exploratory analysis of CheckMate 026 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT082. doi:10.1158/1538-7445.AM2017-CT082
Abstract CT102: Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort
Authors: Odia Yazmin , Schulte Jessica , Iwamoto Fabio 
Published: July 2017

Abstract
Tumor-treating fields (TTF) are approved for use in patients with glioblastomas at recurrence (2011) or adjuvant setting (2016) due to survival benefit in various trials. Since 12/2012, 46 patients were treated with TTF for de novo or recurrent gliomas at Columbia University. Rates and outcomes of combination with immunotherapy were analyzed, given the recent preclinical data of synergism between TTF and PD1 targeted therapy. The impact of compliance was also analyzed in multivariable analyses in this retrospective cohort.
Of 44 treated patients, 18 (41%) were women and 2 (5%), 4 (9%) and 36 (86%) had WHO grade II, III and IV gliomas. Median age at diagnosis was 56 (23-84) years. TTF was used at recurrence in 38 (86%), with a median of 2 (0-4) prior recurrences. Prior therapies included bevacizumab (22, 50%), surgery [25/44 (57%) gross total], radiation and temozolomide. Median TTF therapy duration was 1.8 (0.1-20.3) months. Only 2 (5%) experienced skin toxicity requiring interruptions. Compliance goal of 75% was met by 11/44 (25%) glioma patients. Concurrent systemic therapy was used in 35 (80%), including temozolomide (12, 27%), nitrosourea (2, 5%), bevacizumab (17, 39%), immunotherapy (26, 59%) or other (5, 11%).
Objective response rate (ORR) based on RANO was noted in 25/42 (60%) of all gliomas and 21/38 (55%) of glioblastomas, At interim follow-up, progression free (PFS) and overall (OS) survival were 2.7 and 6.9 months, respectively. PFS was significantly increased among glioblastoma patients treated with concurrent immunotherapy (PFS: 3.3 vs. 1.95, p=0.0364). Long-term follow-up PFS and OS will be re-analyzed, along with the potential confounding impact of compliance rates.
TTF improves survival for patients with glioblastomas. Immunotherapy shows promise for various tumor histologies. The possible synergism between these modalities in preclinical studies and this retrospective glioma series warrants further study in randomized controlled gliomas trials. We propose a single-arm phase II trial of concurrent PD1 inhibitor and TTF for patients with bevacizumab-naïve glioblastoma at second or third recurrence. OS is the primary endpoint; secondary endpoints include PFS, ORR, predictive value of PDL1 expression, and impact of compliance. Results from the EF-14 trial will serve as a historical control.
Citation Format: Yazmin Odia, Jessica Schulte, Fabio Iwamoto. Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT102. doi:10.1158/1538-7445.AM2017-CT102
Abstract CT134: Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
Authors: Weiss Glen J. , Waypa Jordan , Coats Jessica , Blaydorn Lisa , McGahey Kayla , Sangal Ashish , Whitehead Robert P. , Khemka Vivek 
Published: July 2017

Abstract
Background: Pembrolizumab (P) is a checkpoint inhibitor that blocks the interaction between programmed cell death protein 1 on T-cells and PD-L1 and PD-L2 on tumor cells. We conducted a single center phase Ib/II study of gemcitabine, nab-paclitaxel, and P (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) (NCT02331251).
Methods: PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% were eligible and received gemcitabine and nab-paclitaxel on days 1 and 8 and P 2 mg/kg on day 1 every 21 days until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months.
Results: 17 pts with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Any grade drug-related treatment adverse events (AEs) occurred in 100% of patients; the most common (&gt;20% pts) were anemia, thrombocytopenia, hypoalbuminemia, ALT and ALK elevation, fatigue, rash, nausea, vomiting, diarrhea, fever, insomnia, and edema in limbs. Grade 3 events (&gt;10% pts) were hyponatremia, thrombocytopenia, and neutropenia (2 case each, 11.8%). Dose-limiting toxicities occurred only in previously treated PDAC (grade 3 thrombocytopenia; grade 3 fatigue and thrombocytopenia) and the cohort was subsequently divided into chemo naïve and previously treated pts. The recommended phase II dose (RP2D) for chemo naïve PDAC was gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. Of the 8 evaluable chemo naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 2 PR on treatment for ~11 and 15 months and there are 3 pts still too early to assess. The primary endpoint of &gt;15% complete response was not met. The best response for previously treated pts was SD. For chemo naïve and previously treated PDAC, the 6-month survival rate is 89% (with 3 pts still on study less than 3 months) and 40%, respectively. The median PFS and OS is 5 and 10.3 months and 2.1 and 4.1 months for chemo naïve and previously treated pts, respectively.
Conclusions: GNP can be safely given to chemo naïve PDAC pts. Efficacy appears to be similar to slightly improved over previously reported results for standard weekly x 3 every 28 day gemcitabine and nab-paclitaxel dosing.
Citation Format: Glen J. Weiss, Jordan Waypa, Jessica Coats, Lisa Blaydorn, Kayla McGahey, Ashish Sangal, Robert P. Whitehead, Vivek Khemka. Phase I/II trial of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT134. doi:10.1158/1538-7445.AM2017-CT134
Abstract CT141: Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy
Authors: Rulseh Aaron , Šroubek Jan , Klener Jan , Vymazal Josef 
Published: July 2017

Abstract
Introduction: Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy.
Materials and Methods: Tumor treating fields (TTFields) therapy is a novel treatment technique that has recently shown significant prolonged progression free survival and overall survival innewly diagnosed GBM. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest.
Results: Our center was the first in the world to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 12 years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment.
Conclusions: Our results indicate that TTField treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. Further investigation is needed to identify any unique characteristics of these patients. We recommend that TTField treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment.
Citation Format: Aaron Rulseh, Jan Šroubek, Jan Klener, Josef Vymazal. Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT141. doi:10.1158/1538-7445.AM2017-CT141
Abstract CT161: METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC
Authors: Mehta Minish P. , Gondi Vinai , Brown Paul D. 
Published: July 2017

Abstract
BACKGROUND
Tumor Treating Fields (TTFields) are noninvasive regional antimitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly diagnosed glioblastoma patients.
TRIAL DESIGN
270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression.
Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population.
Endpoints: Time to 1st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary).
Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain.
Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease.
Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.
Citation Format: Minish P. Mehta, Vinai Gondi, Paul D. Brown. METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT161. doi:10.1158/1538-7445.AM2017-CT161
Abstract DDT01-01: The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma
Authors: Hughes Paul E. 
Published: July 2017

Abstract
Mcl-1 is a prosurvival member of the Bcl-2 family of proteins, which regulate programmed cell death via protein-protein interactions between prosurvival and proapoptotic members of the family. A variety of studies have demonstrated that Mcl-1 is a key prosurvival factor for many human cancers, making it a highly desirable target for therapeutic intervention. However, targeting Mcl-1 to induce tumor cell death has been an exceptional challenge for the development of drug-like small molecule inhibitors due to the high-affinity interaction of Mcl-1 with proapoptotic binding partners and the lack of an obvious small molecule binding pocket. In this presentation we will describe the application of structural analysis and molecular modeling to the optimization of an HTS screening hit that culminated in the identification of a clinical candidate, AMG 176. In addition, we will present data demonstrating that AMG 176 is a potent, highly selective, and reversible Mcl-1 inhibitor. Mechanism-of-action studies revealed that AMG 176 induces a rapid and irreversible commitment to apoptosis in tumor cells via the disruption of protein-protein interactions with proapoptotic members of the Bcl-2 family. Furthermore, the extensive profiling of a large and diverse tumor cell line panel revealed that lines derived from hematologic malignancies, such as multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma, are particularly sensitive to Mcl-1 inhibition with the expression of Bcl-xL inversely correlating with response. In addition, cell line profiling data revealed an activity profile distinct from a selective Bcl-2 inhibitor, further underscoring the unique therapeutic opportunity for an Mcl-1 inhibitor. Synergistic combinations were identified with therapies selectively targeting Bcl-2, the MAPK pathway, and proteasome inhibitors. In vivo, AMG 176 demonstrated robust inhibition of tumor xenograft growth with a clear PK/PD relationship, exhibiting on-mechanism activity as measured by Bak and caspase activation on a discontinuous dosing schedule of once or twice weekly. An ongoing phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma.
Citation Format: Paul E. Hughes. The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2017-DDT01-01