tbuckley/cabot-search huggingface dataset:
CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML).
Authors: Victoria Wang, Gabriel N. Mannis, Rebecca Leah Olin, Aaron Logan, Thomas G. Martin, Lloyd Earl Damon, Danielle Kilayko, Pamela N. Munster, Charalambos Andreadis
Journal: Journal of Clinical Oncology (2017)

7040 Background: Pts with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum HGF level is an adverse prognostic factor in AML (Verstovsek, et al. 2001; Kim, et al. 2005). Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death (Kentsis, et al. 2012). Methods: We initiated a phase I study to assess the safety and tolerability of Fi combined with Cy in patients with AML who are refractory to 7+3 or have relapsed within 1 year of induction. Fi is given in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks, starting on day 0, and Cy at a fixed dose of 2g/m2 on days 2-7, using a 3x3 design. PBMCs, BM and serum are collected at defined time points to assess HGF levels and activation of the c-Met pathway. Results: Dose escalation is complete and there were no protocol-defined DLTs identified in 9 evaluable pts. All pts treated to date were refractory to induction. Four had de novo AML; 2 had undifferentiated leukemia; 2 prior MDS; 1 prior MPN. Most frequent grade 3/4 TEAEs were febrile neutropenia (56%), LFT abnormalities (11%), and electrolyte disturbance (11%). There was 1 death (11%) from sepsis and multi-organ failure on day 23, following ANC recovery. Of the 7 evaluable pts, 3 achieved a CR (43%), all in the 2 nd dose cohort. Two of the 3 CRs are long lasting 11 and 12 months following AlloHCT. All patients had detectable circulating HGF levels at baseline compared to control subjects without AML. HGF levels increased following exposure to Fi by an average of 193%. Baseline HGF levels or change from baseline were not associated with treatment response. Conclusions: Ficlatuzumab can be safely combined with HiDAC in this high-risk AML population and produce durable clinical responses. Circulating HGF levels were detectable at baseline and uniformly increased with treatment suggestive of a feedback response or immune complex stabilization. Dose expansion is ongoing. Clinical trial information: NCT02109627.
Hospitalization for patients in the United States (US) and European Union (EU) treated with inotuzumab ozogamicin (InO) vs standard of care (SOC) for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) in a global phase 3 trial.
Authors: Yun Su, Ilse van Oostrum, Erik Vandendries, Verna Welch, Fausto Rodriguez Loberiza
Journal: Journal of Clinical Oncology (2017)

e18500 Background: InO, an anti-CD22 antibody-calicheamicin conjugate, with its once a week, 1-hour infusion schedule, has demonstrated lower hospital utilization in association with superior clinical activity, favorable patient-reported outcomes (PROs), and a generally manageable safety profile versus SOC (intensive chemotherapy) for R/R ALL in the phase 3 INO-VATE trial. Here, regional-specific hospitalizations in the trial are presented. Methods: Patients receiving study treatment and recruited from the US and the EU were included in the analyses. The total number of days hospitalized for each patient was calculated. Hospital days prior to randomization and those after the end of study treatment were excluded. Due to different treatment durations for InO and SOC (median 1 vs 3 cycles), calculations were reported for cycle 1 treatment period (randomization to end of cycle 1) and for the entire treatment period (all cycles - randomization to end of treatment). Results: A total of 281 patients were available for the analyses. 154 were from the US and 127 from 11 of the EU countries. The median and mean hospitalization days were shorter for patients in the InO arm compared to the SOC arm across both regions (Table). The difference between the two treatment arms appear to be greater in the US compared to the EU. Hospitalizations in the US appear to be shorter than in the EU, particularly for patients receiving InO. Conclusions: InO treatment in R/R ALL is associated with less hospitalization across both the US and EU compared to SOC, consistent with InO’s better efficacy, tolerability, PRO and dosing schedule. The finding that US has lower hospitalization than the EU might be explained by different patient care practices in the two regions. Given that hospitalization is the biggest cost driver in cancer care, the discrepancy may lead to greater cost-savings in healthcare systems where hospitalizations are strictly managed. Clinical trial information: NCT01564784. [Table: see text]
Carfilzomib weekly-melphalan-prednisone in untreated elderly multiple myeloma: IFM2012-03.
Authors: Xavier Leleu, Guillemette Fouquet, Lionel Karlin, Brigitte Kolb, Mourad Tiab, Carla Araujo, Murielle Roussel, Pascal Bourquard, Pascal Lenain, Catherine Humbrecht-Kraut, Karim Belhadj, Marie-Odile Petillon, Marie-Lorraine Chretien, Philippe Rodon, Olivier Decaux, Arnaud Jaccard, Cyrille Hulin, Michel Attal, Philippe Moreau, Thierry Facon
Journal: Journal of Clinical Oncology (2017)

8004 Background: Melphalan-prednisone-bortezomib (MPV) is a standard of care upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements on MPV’s safety profile, toxicity issues remain. Carfilzomib (K) is a novel generation proteasome inhibitor with a different safety profile from Bortezomib. Carmysap phase I/II study (twice a week Carfilzomib+MP) demonstrated K at 36mg/m² safe and active in eNDMM. We thought to study the K weekly-MP combination in eNDMM. Methods: IFM2012-03 is a multicenter phase I/II study in eNDMM (65 and older) aimed to determine the maximum tolerated dose (MTD) of K weekly. 4 cohorts of 6 patients each were recruited at K 36, 45, 56 and 70 mg/m 2 on days 1, 8, 15, 22 IV of 35-days cycles, with oral Melphalan and Prednisone from days 1 to 4 at usual doses. Patients received a 9-cycles induction followed by a K monotherapy maintenance at 36 mg/m 2 IV every 2 weeks for 1 year. 3 dose-limiting toxicities (DLTs) defined MTD at the lower N-1 dose. Results: 24 patients were included at K 36, 45, 56 and 70 mg/m². One DLT occurred at 36 mg/m² (grade 4 lymphopenia), one at 45 mg/m² (tumor lysis syndrome with grade 4 renal insufficiency), two at 56 mg/m² (grade 3 cardiac insufficiency and grade 3 febrile neutropenia) and two at 70 mg/m² (grade 3 nausea/vomiting and grade 3 hepatic cytolysis). One patient died from cardiac dysfunction considered related to K at 56 mg/m². 3 patients stopped therapy and 3 others required dose reduction of K. Following DSMB’s request a second 6-patients cohort was recruited at 70 mg/m², with increased attention around hyperhydration and monitoring HTA. We observed no DLT and no grade 3/4 adverse event in this cohort. Median age was 75 years, 56% patients were R-ISS 2 or 3. For the whole cohort (N=30), the overall response rate was 87% including 67% very good partial responses and 44% complete responses. Conclusions: The MTD of weekly K in the KMP combination is 70 mg/m² upfront for eNDMM, but it seems reasonable to recommend 56mg/m² after 75 years-old for safety reasons. KMP offers high response rates and possibly greater CR rate. However, since the CLARION study (VMP vs KMP) will not allow KMP’s approval in eNDMM in Europe, IFM decided to stop IFM2012-03 after phase I without performing phase II. Clinical trial information: NCT02302495.
To compare the efficacy of sunitinib and imatinib following cytoreductive resection in GIST patients with progression on imatinib: A multi-center controlled study.
Authors: Xinhua Zhang, Ye Zhou, Xin Wu, Mingming Nie, Bo Zhang, Yongjian Zhou, Lifeng Sun, Xiufeng Liu, Zimin Liu, Youwei Kou, Yongpeng Wang, Yefan Zhang, Jian Li, Lin Shen
Journal: Journal of Clinical Oncology (2018)

11530 Background: Imatinib is recommended to treat gastrointestinal stromal tumor (GIST) receiving surgery after localized tumor progression, but the progression free survival (PFS) is not satisfied. The objective of this study is to investigate the optimal therapy after cytoreductive surgery in GIST patients with unifocal or multifocal progression on imatinib. Methods: The data of GIST patients who received R0 resection or satisfied cytoreductive surgery after unifocal or multifocal progression followed by different TKIs were collected. The satisfied cytoreductive surgery was defined as the diameter of every residual tumor was less than 1cm, or the proportion of residual tumor was less than 25% after cytoreductive surgery. The primary endpoint is to evaluate the PFS of the patients receiving surgery followed by sunitinib comparing with that of followed by imatinib after tumor progression. PFS curves were constructed according to the Kaplan–Meier method and compared using a log-rank test. Results: From January 2006 to June 2017, 97 patients from 13 medical centers were enrolled in this study. Fifty-six patients continued imatinib therapy and 41 patients switched to sunitinib directly after R0 resection or satisfied cytoreductive surgery. The PFS of sunitinib group was longer than that of imatinib group (30.0 months vs 12.0 months, p = 0.009). In subgroup analysis, the PFS of sunitinib group and imatinib group were 25.5 months and 12.0 months in patients with multifocal progression (p = 0.008), 39.0 months and 13.0 months with unifocal progression (p = 0.156), respectively. Patients carrying a primary KIT exon 11 mutation had a PFS of 31 months in sunitinib compared with 11 months in imatinib (p = 0.036), respectively. And those of KIT exon 9 mutation or KIT/PDGFRA wild-type had a PFS of 25.5 months to 13 months (p = 0.06), respectively. The overall survival in sunitinib group and imatinib group were 37.0 months and 33.0 months, respectively (p = 0.794). Conclusions: R0 or satisfied cytoreductive surgery followed by sunitinib treatment in GIST patients with progression on imatinib could improve PFS compared with surgery followed by imatinib therapy.
Racial disparities in NCI Cancer Center (NCI-CC) care for multiple myeloma (MM).
Authors: Mark A Fiala, Sikander Ailawadhi, Mark A. Schroeder, Keith Stockerl-Goldstein, Ravi Vij, Tanya Marya Wildes
Journal: Journal of Clinical Oncology (2017)

e18061 Background: Despite a favorable genetic profile, African-Americans (AAs) with mm have poorer outcomes secondary to inferior treatment. NCI-CCs provide the highest-quality of care and attendance has been associated with better outcomes in many cancers. AAs have greater access to NCI-CCs proximally; however, they attend these facilities at lower rates than their white peers. The impact of attendance at NCI-CCs on mediating racial disparities in mm outcomes has not been reported on to date. Methods: We reviewed cases of mm the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database from 2000-2011 who were enrolled in Medicare Part A and B &gt; 1 year prior to diagnosis, excluding cases enrolled prior to age 65 and those where mm diagnosis occurred post-mortem. Any center designated a NCI-clinical or -comprehensive center in 2002, 2005, or 2010 was considered a NCI-CC; attendance was defined as 2 or more claims on separate dates (MEDPAR and Outpatient files) from a NCI-CC in the 12 months following mm diagnosis. Logistic regression was performed to determine if race was associated with attendance, Cox regression to determine the association of attendance with survival. Results: 21,843 cases were analyzed; the median age was 77 years; 80% were white, 15% AA/Black. Overall NCI-CC attendance was low, only 11% of the population. Compared to white patients, black patients had a 13% decreased odds (aOR 0.87, 95% CI 0.75-0.99) of NCI-CC attendance after controlling for age, gender, socioeconomic status, geographic, and overall health variables. Attendance was associated with a 28% decrease risk for death (aHR 0.72, 95% CI 0.68-0.76), but had little impact on black-white outcome disparities. Black patients had a 9% increase in risk (aHR 1.09, 95% CI 1.04-1.13) after controlling for NCI-CC attendance. Conclusions: Black patients with mm have lower NCI-CC attendance. This may be related to referral bias and/or patient declining referral. NCI-CC attendance was associated with superior outcomes; however, controlling for attendance did not mediate black-white outcome disparities suggesting that racial treatment disparities pervade beyond access to NCI-CCs.
Association of activin type II receptor mutation with microsatellite instability in gastric cancer.
Authors: Kizuki Yuza, Masayuki Nagahashi, Hiroshi Ichikawa, Masato Nakajima, Takaaki Hanyu, Takashi Ishikawa, Yoshifumi Shimada, Jun Sakata, Hitoshi Kameyama, Takashi Kobayashi, Satoru Nakagawa, Nobuaki Sato, Keiichi Honma, Takashi Kawasaki, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2017)

e23191 Background: Microsatellite instability-high status (MSI-H) and alterations in the DNA mismatch repair pathway associate with the efficacy of 5-FU and immune checkpoint inhibitors in patients with gastrointestinal cancers. The activin type II receptor (ACVR2) that binds to the transforming growth factor beta superfamily of ligands is frequently mutated in MSI-H colorectal cancer. However, the incidence of ACVR2 mutations in gastric cancer patients remains unclear. The aim of this study is to reveal the incidence and to examine the association between the MSI-H and ACVR2A mutations in gastric cancer patients. Methods: 124 archived FFPE gastric cancer tissues (stage I-IV), who were operated at Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital, were analyzed for ACVR2A mutation and MSI status with the NGS-based comprehensive genomic test platform. Clinicopathological characteristics of the patients were also examined. Results: All 124 gastric cancer patients were successfully analyzed. 13 out of 124 patients (10.4%) showed MSI-H status. Interestingly, 10 of 13 MSI-H patients (76.9%) showed ACVR2A mutation, where none (0%) was found among patients with microsatellite stable status (P &lt; 0.001), indicating the strong association between ACVR2A mutation and MSI status in gastric cancer patients. In the ACVR2A mutated group, there was a female predominance (P &lt; 0.05), and cancers of the lower part of the stomach were more common (P &lt; 0.05), compared with the wild type group. Only one of 10 patients with ACVR2A mutation died, and the patients with ACVR2A mutation show a 5-year overall survival rate of 90%. No statistically significant difference in survival was achieved between patients with ACVR2A mutation and wild type; this is probably due to the small number of patients. Conclusions: 10 of 13 MSI-H patients showed ACVR2A mutation. Our results indicate a strong association between ACVR2A mutation and MSI-H in gastric cancer patients.
Second malignancies in childhood cancer survivors.
Authors: Rejin Kebudi, Omer Gorgun, Inci Ayan, Fulya Yaman Agaoglu, Abut Kebudi, Bulent Zulfikar, Emin Darendeliler
Journal: Journal of Clinical Oncology (2016)

e22011 Background: The 20 year cumulative risk of second malignancies (SM) in childhood cancer survivors is reported as 3.2 %. The aim of this study is to assess the incidence and outcome of SM in pediatric cancer survivors in a tertiary center in 25 years. Methods: 1500 childhood cancer survivors treated in theIstanbul University, Oncology Institute during 1990-2010 and followed up for at least 5 years from diagnosis were evaluated for second malignancies. Results: 36 SM were identified in 33 survivors at a median of 7 years (1-17) from diagnosis (AML/MDS 3[1-8], solid tumors 9 [2-17] years). The primary diagnosis was sarcomas in 11 ( 5 rhabdomyosarcomas [RMS]), CNS tumor 5, retinoblastoma 4, ALL/MDS/lymphoma 8, neuroblastoma 3, nasopharngeal sarcoma 1, disgerminoma 1. The SM were 12 sarcomas (8 osteosarcomas,1 fibrosarcoma, 1 Ewing Sarcoma, 1 Kaposi sarcoma, 1 leiomyosarcoma), 8 AML/MDS, 3 thyroid cancer, 3 malignant nerve sheath tumors (MNST) , 2 renal cell carcinomas (RCC), 2 breast cancers, 2 glioblastoma multiforme (GBM), 1 non Hodgkin's lymphoma, 1 meningioma, 1 histiocytosis (LCH). Three patients developed two separate SM each. 18 patients had previously recieved radiotherapy: 11 developed solid tumors (5 sarcomas, 3MNST, 1 GBM, 1 meningioma, 1 thyroid cancer) within the radiation field, 3 (2 RMS, 1 LCH) in proximity; 4 developed AML/MDS. 3 had prior HSCT (1 MDS developed osteosarcoma, 2 relapsed lymphomas: AML, LCH). 15 survivors are alive at a median of 4 (1-18) years after SM, 13 with no evidence of disease (NED). 18 have died at a median of 1(0.1-3)year. 1/8 with MDS/AML is alive.All survivors with thyroid cancer, renal cell carcinoma , breast cancer; also 1 MNST, 1 LCH, 6 sarcomas (1 fibrosarcoma , 4 osteosarcomas ,1 Kaposi sarcoma) are with NED, all were detected early during regular surveillance. Conclusions: The risk of SM in our series has increased with longer follow-up,(incidence 2.4 vs 1 %, the number of SM has increased from 16 to 36 in the same cohort from 2011 to 2015), empasizing the need for longer follow-up and regular surveillance which leads to early detection of SM, thus improved survival. Since, the risk of SM is associated with the cumulative dose of some chemotherapeutics, the radiation dose/field; using the most efficient and least toxic protocols is important.
Abstract 20290: Protein Half-Life of Degradation Machineries in Healthy and Stressed Myocardium
Authors: Quan Cao, Jennifer S Polson, Jie Wang, Jesscica Lee, Sarah B Scruggs, Maggie P Lam, Dominic C Ng, Peipei Ping, Ding Wang
Journal: Circulation (2016)

Introduction: Proteasomes are essential to maintaining myocardial proteome homeostasis; mounting evidence documents their dysfunction as a cardiac disease driver. Regulation of proteasomal function...
A phase I/II Trial of CRISPR-Cas9-mediated PD-1 knockout Epstein-Barr virus cytotoxic lymphocytes (EBV-CTLs) for advanced stage EBV associated malignancies.
Authors: Jia Wei, Jing Yan, Shu Su, Jie Shao, Yang Zhao, Qiuping Xu, Yang Yang, Zhengyun Zou, Xingxu Huang, Baorui Liu
Journal: Journal of Clinical Oncology (2018)

TPS3118 Background: EBV associated malignancies exhibits high amplification of PD-L1 as distinguished from EBV non-associated malignancies (Kim et al. Gastroenterology 2015; Chen et al. Clinical Cancer Research 2013). The up-regulation of PD-L1 restricts antitumor effect of EBV-CTLs by immune tolerance and results in poor prognosis of patients. Our previous work has generated PD-1-disrupted CTLs by CRISPR-Cas9 system which could up-regulate IFN-γ production and enhance cytotoxicity in tumor cell lines and mouse model (Su et al. Oncoimmunology 2016). Methods: This phase I/II prospective single center clinical study (clinicaltrials.gov NCT03044743) was designed to evaluate the safety of PD-1 knockout EBV-CTLs in treating EBV positive advanced stage malignancies. Patients included should be pathologically verified EBV positive stage IV gastric carcinoma, nasopharyngeal carcinoma or lymphoma progressed after standard treatment with measurable lesions. Patients will be divided into three groups and receive 2 to 4 cycles of cell therapy according to their tolerance. PD-1 knockout EBV-CTLs from autologous origin will be generated and 2 x 10^7/kg of specific T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20%, 30% and 50% respectively. To modify immune microenvironment, Fludarabine at 30mg/m2 and cyclophosphamide at 300mg/m2 will be administered 3 days (intravenous injection, i.v.) before cell infusion. Interleukin-2 will be given daily (i.v.) from the first day of the cell infusion for 5 consecutive days at the dose of 4000,000 international unit (IU)/day to sustain the survival of infused T cells. The adverse events will be evaluated after each cycle by Common Terminology Criteria for Adverse Events (CTCAE v4.0) as primary endpoint. Progression-free survival (PFS), the duration of the normalization of tumor marker and immunological markers will be evaluated as the secondary endpoints. Immunological markers will continuously be examined every two cycles. Clinical trial information: NCT03044743.
Mortality among elderly patients newly diagnosed with acute lymphoblastic leukemia (ALL) using 100% Medicare ALL data.
Authors: Shuling Li, Julia T. Molony, Victoria M. Chia, Aaron J. Katz
Journal: Journal of Clinical Oncology (2016)

7022 Background: ALL is a rare disease with markedly poor prognosis in older adults. As large population-based mortality data are limited, we described the risk of death among older adults diagnosed with ALL. Methods: Using 100% Medicare ALL data, 2007-2012, we identified patients ages ≥ 66 years newly diagnosed with ALL in 2008-2011 and continuously enrolled in Medicare fee-for-service (FFS) for 12 months prior to ALL index date (baseline period). Presence of ALL was defined as 1 inpatient (IP) or 2 outpatient (OP) claims on different dates in any 2-month interval carrying an ALL code. The index date was defined as the earlier date of the 1st IP or the 2nd OP code. Baseline comorbidity level was defined using a modified Charlson Comorbidity Index. Follow-up (F/U) began on the index date and ended at the earliest of death, disenrollment from FFS, 3 years, or December 31, 2012. Unadjusted cumulative probability (CP; 95% CI) of death was estimated using the Kaplan-Meier method; the log-rank test was used to compare the CP of death by patient characteristics. Results: The cohort included 1843 patients (mean [SD] age: 78.7 [7.8] years; 53% female; 88% white). Comorbidity level was low, medium, and high for 52%, 30%, and 18% of patients, respectively. During the mean (SD) 12.8 (13.1) months of F/U, 1280 patients (70%) died. The CP (95% CI; %) of death was 21.5 (19.7-23.5) at 30-days, 46.5 (44.2-48.8) at 6 months, 57.4 (55.2-59.7) at 1 year, and 72.9 (70.7-75.1) at 3 years overall, and significantly higher for those diagnosed at older ages and with greater comorbidity (Table; P < 0.001). Conclusions: Risk of death significantly increased with advancing age and comorbidity level in elderly patients newly diagnosed with ALL. Given the high risk observed for early death, further analyses are warranted to understand the real-world management of ALL in older adults. CP (%): 30-day 90-day 6-month 1-year 2-year 3-year All 21.5 36.4 46.5 57.4 67.9 72.9 Age 66-69 11.6 22.9 30.6 42.3 53.8 57.7 70-74 15.5 26.1 36.2 49.0 61.8 66.1 75-79 17.7 33.5 42.7 53.4 64.4 67.8 80-84 26.1 42.5 54.7 64.2 72.6 79.0 ≥85 31.6 50.6 60.9 71.1 80.1 86.5 Comorbidity Low 19.6 33.9 43.3 55.1 65.8 71.7 Medium 22.0 36.4 46.8 55.9 66.2 70.6 High 26.2 43.7 55.1 66.6 76.6 80.5