tbuckley/cabot-search huggingface dataset:
Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM).
Authors: Sagar Lonial, Rachid C. Baz, Michael Wang, Moshe Talpaz, Guohui Liu, Deborah Berg, Neeraj Gupta, Alessandra Di Bacco, Ai-Min Hui, Paul Gerard Guy Richardson
Journal: Journal of Clinical Oncology (2012)

8017 Background: MLN9708 is the first oral proteasome inhibitor to enter clinical investigation in MM. This study (NCT00932698) assessed safety, MTD, and response rate with twice-weekly oral MLN9708 in pts with relapsed and/or refractory MM, and characterized plasma pharmacokinetics (PK) and blood pharmacodynamics. Methods: Pts aged ≥18 yrs with measurable MM received MLN9708 on d 1, 4, 8, and 11 of 21-d cycles. In the dose-escalation phase, pts required ≥2 prior therapies (including bortezomib, thalidomide/lenalidomide, and corticosteroids). At the MTD (2.0 mg/m 2 ), pts were enrolled to relapsed and refractory [RR], bortezomib-relapsed [VR], proteasome-inhibitor [PI] naïve, and carfilzomib [CZ] expansion cohorts. Results: 57 pts (53% M) were enrolled, 37 to the expansion cohorts (16 RR, 14 VR, 6 PI naïve, 1 CZ). Median age was 65 yrs (range 50-86). Median number of prior lines of therapy was 4 (range 1-28); 88%, 84%, 61%, and 5% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively. Pts have received a median of 3 cycles (range 1-24) to date (data cut-off Dec 1, 2011); 7 (12%) have received ≥13 cycles. Drug-related AEs were seen in 89% of pts, including fatigue (46%), thrombocytopenia (40%), and nausea (30%); 63% had drug-related grade ≥3 AEs, including thrombocytopenia (33%), neutropenia (14%), fatigue (9%), and rash (7%). Only 6 (11%) pts had drug-related peripheral neuropathy (PN; no grade ≥3). 7 pts discontinued due to AEs. 2 pts died on study, due to PD and an unrelated cardiac disorder. Of 46 response-evaluable pts, 6 have achieved ≥PR, with 1 sCR (PI naïve cohort) and 5 PRs (2 in dose-escalation, 1 in RR, 2 in VR cohorts), and 1 VR pt has achieved MR, with duration of disease control of up to 18.6 mo. PK analyses showed MLN2238 (biologically active hydrolysis product) has linear plasma PK (0.8-2.23 mg/m 2 ), T max of 0.5-1.25 hr, and terminal half-life of 4-6 d. A dose-dependent increase in whole blood 20S proteasome inhibition was observed. Conclusions: Current data suggest MLN9708 has clinical activity in heavily pretreated MM pts, with durable responses/disease control, and is generally well tolerated with infrequent low-grade PN.
Measures of immune recovery following autologous stem cell transplantation for multiple myeloma and outcome.
Authors: Livia Hegerova, Morie Gertz, Martha Lacy, Angela Dispenzieri, Francis Buadi, Suzanne R. Hayman, David Dingli, Luis F. Porrata, Shaji Kumar
Journal: Journal of Clinical Oncology (2013)

8581 Background: Autologous stem cell transplant (ASCT) improves survival in patients with multiple myeloma (MM). Recent studies have elucidated the relationship in ASCT between absolute lymphocyte count (ALC) recovery and improved survival, highlighting the importance of immune recovery. We conducted a retrospective analysis of patients with multiple myeloma to observe the impact of different measures of immune recovery at day 100 post-ASCT on outcome. Methods: Retrospective analysis of data from the existing clinical databases identified 1184 patients with multiple myeloma that underwent ASCT at Mayo Clinic between 1987-2011. Markers of immune recovery analyzed on day 100 status-post ASCT included ALC, monocyte count, and immunoglobulin levels. Kaplan Meier analysis was performed to determine progression free survival (PFS) and overall survival (OS). Results: Among the 1184 patients, median age at diagnosis of multiple myeloma was 57 (range, 23-75 yr), and median age at time of transplantation was 59 (range, 24-75 yr); 59% were male. The median OS and PFS post-transplant were 80 months and 34 months respectively. 62% of patients were alive 5-years post-transplant. The median OS was not improved with normal vs. abnormal IgG levels at day 100 (p=.298). In contrast, monocyte recovery was a significant predictor of OS. Patients with normal monocyte counts of greater than 0.3 x 10⁹ cells/L at day 100 showed superior survival (65 vs. 37 months, p= .001). Similarly, patients with normal monocyte recovery at day 15 post-transplant showed a significant survival benefit (68 vs. 50 months, p=.007). Early ALC recovery, which has been shown to be a positive prognostic indicator at day 15 post-transplant, was not prognostic at day 100 (p= .960). Conclusions: The present study further elucidates prognostic indicators after ASCT for MM highlighting the importance of various markers of immune recovery. Immunoglobulin recovery was not associated with superior survival, while monocyte recovery at day 15 and day 100 post-transplant translated to an improved survival and requires further study. It may be hypothesized that early immune system reconstitution may have a positive effect against disease post-transplant.
Phase II clinical and pharmacokinetic (PK) trial of zalypsis (Z) in patients with urothelial carcinoma (UC) progressing after a first-line platinum-based regimen.
Authors: Ismael Ghanem, Joan Carles, Joaquim Bellmunt Molins, Cinthya Coronado, José Pablo Maroto, Albert Font Pous, Rafael Morales, Cristina Suarez, Olatz Etxaniz, Laia Capdevila, Cristina Martin Lorente, Cleofe Rodriguez, Carmen Maria Kahatt, Manuel Luque, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2012)

e15001 Background: Platinum-based chemotherapy (CT) is beneficial as first-line treatment of advanced UC. However, the majority of patients develop recurrent disease with poor long-term survival rates. Attempts to improve second-line treatments have evaluated single agents and multi-drug combinations, neither of which has managed to improve survival or achieve durable responses. Z is a cytotoxic agent that induces apoptosis by acting at cell cycle level, has DNA-binding properties and inhibits transcriptional responses. Z has shown anti-tumor activity in vitro and in vivo in xenograft models. Based on the activity observed in a phase I study (1PR and 2 SD) in advanced bladder cancer, we have designed a phase II study to explore the efficacy of Z in this setting. Methods: Patients with histologically-confirmed advanced or metastatic UC, who had failed one prior line of platinum-based CT, with proven progression or relapse before study entry, were included. Patients were treated with a Z intravenous infusion of 3 mg/m 2 over 1-hour and every 3 weeks. A two-stage design was chosen; at least four (of 17) evaluable patients had to reach the primary endpoint during the first stage in order to progress into a second stage of up to 37 patients. The primary endpoint was tumor control rate (TCR): percentage of patients with objective response (OR) of any duration or patients alive and progression-free (PFS) at three months. Results: Twenty patients of a median age of 71 years (r: 54-83) were enrolled after a median of one prior treatment line (r:1-2). One patient was considered non-evaluable. No ORs were observed and only one patient had PFS ≥ 3 months. The median time on treatment was 1.68 months (r: 0.76-4.21). Toxicity consisted mostly of grade 1-2 fatigue, anorexia and nausea. Five patients had isolated troponin I increases (with no ECG or LVEF findings). Hematological toxicity was mild, one patient had grade 3 neutropenia and one patient had grade 3 thrombocytopenia. Conclusions: Only one patient reached the primary endpoint (TCR) during the first stage; consequently, the study was closed and no further development was considered.
Relationship of the topography of <i>KIT</i> exon 11 alterations and predictive value for PFS in patients with advanced GIST: Results of the BFR14 prospective French Sarcoma Group randomized phase III trial.
Authors: Jean-François Emile, Isabelle Ray-Coquard, Binh Bui, Antoine Adenis, François Bertucci, Florence Duffaud, Didier Cupissol, Christine Chevreau, Emmanuelle Bompas, Jean-Michel Coindre, Olivier Mir, David Pérol, Sylvie Chabaud, Jean-Yves Blay, Axel Le Cesne
Journal: Journal of Clinical Oncology (2013)

10542 Background: The mutations of KIT exon 11 are those most frequently observed in GIST, but there is a substantial level of heterogeneity in their nature and topography. We investigated the impact of the type of KIT exon 11 mutations on clinical presentation and outcome under imatinib in advanced GIST patients (pts) included in the BFR14 study. Methods: Among the 434 pts included, 167 were identified as having GIST with KIT exon 11 mutation (85% of all KIT mutations and 73% of all mutations available in the entire cohort). We analyzed the topography of the mutations and identified 3 groups (G) of mutations according to the first codon involved in the genetic alteration in which the precise topography was available (from codon 549 to 579). The distribution of these G in the different clinical presentations was investigated, as well as their predictive value for progression-free (PFS) and overall survival (OS). Results: Three G with distinct sites of altered codons were distinguished: G1 whose 1 st mutated codon was &lt;556 (n=41, 24.5%), G2 whose 1 st mutated codon was 557 and 558 (n=74, 44.3%), including those with the deletion 557-558 (n=37, 22.1%), and G3 whose 1 st mutated codon was 559 and beyond (n=52, 31.1%). All investigated parameters at inclusion, gender, tumor site and size, site of metastases, age, PS, CD34 expression, biological characteristics were well balanced between the three G of patients. Pts of G2 reached a statistically difference in terms of complete response under imatinib (p=0.028). In contrast, this G have the poorer PFS compared to the other two groups: the median PFS were 30.6 months (CI95%: 21.5;39.4), 49.4 months (CI95%: 33.5; 109.9) and 63.3 months (CI95%: 27.6; 84.7) for the G 2, 1 and 3 respectively (p=0.0176). OS was not significantly different in the 3 G of pts. Conclusions: Despite a favorable sensitivity to imatinib, GIST pts harbouring a genetic alteration initially involving the 557 and 558 codons develop statistically more secondary resistance than the others. These results deserve confirmation in other prospective series in advanced GIST and may be worth exploring in adjuvant series.
Biomarker testing and time-to-treatment decision in patients with advanced non-small cell lung cancer.
Authors: Charles Henry Lim, Lisa Le, Frances A. Shepherd, Ronald Feld, Ronald L. Burkes, Geoffrey Liu, Suzanne Kamel-Reid, Ming Sound Tsao, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2014)

6595 Background: Testing for tumour biomarkers including EGFR mutation and ALK rearrangement has become standard in the management of advanced non-small cell lung cancer (NSCLC). At our institution, EGFR testing became routine in March 2010 and ALK testing in April 2012. We assessed the prevalence and timing of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. Methods: We conducted a retrospective chart review of patients with advanced NSCLC referred to the Princess Margaret Cancer Center from April 1, 2010 to March 31, 2013. A random sample of one fourth of patients referred was chosen using a random numbers generator. Results: Of 278 patients reviewed, 136 (49%) had biomarker testing performed. Of these, 29% had documented EGFR mutations and 2% ALK rearrangement. Patients tested for biomarkers were more likely to be female (50% vs. 34%, p=0.006), Asian (22% vs. 9%, p=0.008) and non-smokers (41% vs. 8%, p<0.0001). Of 137 patients with newly diagnosed non-squamous NSCLC, 96 (69%) had biomarker testing performed and 16 (12%) had results available at the time of initial oncology consultation. There was a non-significant trend towards shorter mean time from consultation to treatment decision (29 vs. 42 days, p=0.42) and mean time to treatment start (38 vs. 50 days, p=0.46) for patients with results available at initial consultation compared to those without. Reflex testing resulted in 84% of samples undergoing testing compared to 59% if clinician-initiated, and a non-significantly shorter mean time for results (53 vs. 84 days, p=0.34). 10% of patients did not have adequate tissue for biomarker analysis at the time of first consultation; 56% of these went on to have repeat biopsy for molecular testing. Of those with an EGFR mutation, 16% started chemotherapy prior to results becoming available to the clinician. Conclusions: Awaiting biomarker test results can increase wait times to treatment decisions for patients with advanced NSCLC. This may be improved by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens.
Paediatrician who ignored calls to examine child who later died is struck off
Authors: Clare Dyer
Journal: BMJ (2017)

A paediatric registrar who ignored nurses’ requests to examine an ill child and then falsified records to claim that she had seen the boy has been struck off for misconduct.

Vasudha Mashankar, who was an on-call registrar at North Tees Hospital on the night of 27 March 2015, continued to rely on a diagnosis of viral gastritis made by a consultant, even as the boy’s symptoms worsened and he began to complain of neck pain as well as headache.

He finally underwent computed tomography the next day after a further sharp deterioration; it revealed an intracranial bleed, from which he died hours later. The boy, whose age was not disclosed …
Association between arterial thrombosis and the promoter polymorphism (-260c/t) of the monocyte lipopolysaccharide receptor, CD14
Authors: Yoko Yatabe, Daisuke Ito, Norio Tanahashi, Yasuo Fukuuchi, Mie Tanaka, Shiro Iwanaga, Satoshi Ogawa, Ikuo Saito, Akira Sonoda, Atsumi Ohta, Eiko Takeshita, Mitsuru Murata, Yasuo Ikeda, Kiyoaki Watanabe
Journal: Blood (2000)
The utilization of palliative radiation therapy to the liver for hepatocellular carcinoma.
Authors: Sara-Jane N. Onyeama, Abdulrahman Y Hammad, Fabian McCartney Johnston, T. Clark Gamblin, Jared Rex Robbins
Journal: Journal of Clinical Oncology (2017)

474 Background: Despite retrospective and prospective clinical trials conveying the efficacy of palliative radiation therapy (RT) to the liver, this modality is not commonly used. The purpose of this project is to evaluate trends, dose schemas, and techniques of palliative RT to the liver in current practice. We aim to identify factors associated with overall survival using patient data from the National Cancer Database (NCDB). Methods: Using the NCDB, we analyzed patients with hepatocellular carcinoma (HCC) diagnosed from 2004-2012 treated with palliative RT. Various patient factors were reviewed and survival analyses were performed. Doses were converted to biological effective dose (BED) to compare the different fractionation schemas. Univariate and multivariate analyses were performed with Kaplan Meier and Cox regression tests. Results: A total of 3,267 HCC patients were identified who were treated with palliative intent. Of these 877 (27%) received radiation therapy and only 138 (4% of total, 16% of RT) received radiation therapy to the liver. For those treated with palliative radiation to the liver, the median age was 61 years. Patients with stages I, II, III and IV disease comprised 15%, 15%, 45%, and 25% respectively. Various dose schema and techniques were used. 38% were treated with advanced radiation techniques (24% stereotactic body radiation therapy (SBRT), 14% Intensity-modulated radiation therapy (IMRT). A total of 79 (57%) patients received 10 or fewer fractions, but 32 (40%) of those were SBRT. The median survival was 4.7 months with 16% mortality at 1 month. On multivariate analysis, stage 3 (HR 2.625, p = 0,013) and stage 4 tumors (HR 2.701, p = 0.018), no chemotherapy (HR 1.743, p = 0.025), and lower radiation dose (HR 0.982, p = 0.003) was associated with worse overall survival. Conclusions: Palliative radiation to the liver is not frequently used in patients with HCC. As a result, there is minimal standardization of dose, modality, or treatment schedule. Better understanding of prognostic factors may help better determine the most appropriate plan for each patient to coordinate treatment length with projected survival.
Use of the 21-gene recurrence score assay (RS) and chemotherapy (CT) across health care (HC) systems.
Authors: Anosheh Afghahi, Aya Mitani, Manisha Desai, Peter Paul Yu, Monique A. De Bruin, Tina Seto, Cliff Olson, Pragati Kenkare, Scarlett Lin Gomez, Amar K. Das, Harold S. Luft, Amy P. Sing, Allison W. Kurian
Journal: Journal of Clinical Oncology (2014)

6580 Background: The Oncotype DX (Genomic Health, Redwood City, CA; GHI) RS estimates 10-yr risk of distant recurrence and CT benefit in patients (pts) with ER+, early-stage breast cancer (EBC). After 10 yrs of RS use, variability across HC settings is poorly understood. Methods: Patient-level clinical data from electronic medical records (EMR) of Stanford University (HC-U) and Palo Alto Medical Foundation, a community practice (HC-C) in the same catchment area, were linked with demographic data from the California Cancer Registry. RS results were obtained from GHI. Multivariable analysis, adjusted for patient age, year of diagnosis, race/ethnicity, institution, stage, nodal status, grade and histology, was used to identify factors associated with use of RS and CT. Results: 3,584 EBC pts met RS indications (Stage I-II, ER+, HER2-negative). RS use was only 10.4% (373 pts, 95% confidence interval [CI] 9.5-11.5%), increasing over time (2010-2011 vs. 2005-2007: odds ratio [OR] 3.03, CI 2.23-4.10). On multivariable analysis, based on subjects with complete data, factors inversely associated with RS use were high grade (vs. low: OR 0.66, CI 0.44-0.99), involved nodes (vs. none: 0.17, 0.11-0.27) and age <40 (vs. 50-64: 0.37, 0.20-0.70) or ≥65 (0.24, 0.18-0.34). Low RS results were usually associated with less (vs. no RS: 0.39, 0.25-0.59), and high results with more (7.96, 2.49-25.5) CT use. However, the 638 (17.8%) pts seen in both HC systems more often had RS (vs. HC-U only: 3.72, 2.77-5.01), and received more CT (1.51, 1.17-1.95). Conclusions: In 2 HC systems, CT use usually followed RS guidance. Although lower than expected, RS use rose over time, perhaps a sign of clinicians’ growing familiarity with RS. By contrast, the 17.8% of pts treated in both HC systems used more CT across all RS risk groups, suggesting less guidance by RS and over-utilization of care. These results may inform efforts to reduce unwarranted variability and optimize value.
Safety and effectiveness of regorafenib (REG) in patients with metastatic colorectal cancer (mCRC) in routine clinical practice: An interim analysis (IA) from the prospective, observational CORRELATE study.
Authors: Michel Ducreux, Leopold Öhler, Werner Scheithauer, Jean-Philippe Metges, Louis-Marie Dourthe, Jan Willem De Groot, Joseph Thaler, Kun-Huei Yeh, Jen-Kou Lin, Alfredo Falcone, Cornelis J. A. Punt, Ann M. Contijoch, Sabine Fiala-Buskies, Andres Cervantes-Ruiperez, Juan Manuel O Connor
Journal: Journal of Clinical Oncology (2017)

700 Background: REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in the randomized, double-blind, phase 3 trials CORRECT and CONCUR. CORRELATE aims to characterize the safety and effectiveness of REG for the treatment of mCRC in an unselected real-world patient population treated in routine clinical practice. Here we report the results of a planned IA. Methods: This global study aims to recruit 1000 patients with mCRC previously treated with approved therapies and for whom the decision to treat with REG has been made by the treating physician according to the local health authority approved label. Dose interruptions and reductions are permitted for the management of adverse events (AEs). The primary endpoint is the incidence of treatment-emergent AEs (TEAE; NCI-CTCAE v4.03). Secondary endpoints include OS, progression-free survival, and the disease control rate. The first planned interim analysis includes the first 500 patients observed for at least 3 months. Here, we report an IA of safety. Results: Median age was 65 years (range: 29–89) and 61% of patients were male. Most patients had a baseline ECOG PS 0/1 vs 2–4 (41%/43% vs 8%) and 50% had KRAS mutations. Most common metastatic sites at study entry were liver (52%) and lung (43%). The median treatment duration was 2.4 months (range: 0.1–10.6). The daily starting REG dose was 160 mg, 120 mg, and 80 mg in 53%, 34%, and 12% of patients, respectively; 26% of patients had dose reductions, 21% due to TEAEs. TEAEs of any grade occurred in 91% of patients, and in 76% TEAEs were considered REG related. Grade ≥ 3 TEAEs occurred in 55% of patients. In 31%, grade ≥ 3 TEAEs were REG related, with fatigue (7%), hand-foot skin reaction (5%), and hypertension (5%) being most common. Grade 5 TEAEs occurred in 13% of patients and were REG related in &lt; 1%. Conclusions: In this observational study, the planned IA showed that the rate of REG-related grade ≥ 3 TEAEs appeared to be somewhat lower than rates observed in the phase 3 trials in patients with mCRC. The starting dose for approximately half the patients was less than 160 mg/day. Clinical trial information: NCT02042144.
Phase I dose-escalation study with extended daily administration of Debio1143, an oral inhibitor of apoptosis protein inhibitor, in patients with solid tumors.
Authors: Henry C. Pitot, Herbert Hurwitz, Claudio Zanna, Jeffrey Mark Brill, Gregoire Vuagniaux, Elisabeth Rouits, J. Mel Sorensen, David C. Smith
Journal: Journal of Clinical Oncology (2015)

2531 Background: Inhibitors of apoptosis proteins (IAPs) play a critical role in modulating multiple processes, including caspases activation and NF-κB signaling. Because high expression of IAPs represent a frequent oncogenic event in human cancers, therapeutic targeting of IAPs is considered as a promising approach. The small molecule Debio 1143 is a potent orally-active IAP antagonist able to promote apoptosis in tumour cells by restoring caspase activity, and modulating NF-κB signaling and TNFα effects in various preclinical models. A shorter schedule of Debio1143 (daily x 5, every 21 days) was well tolerated in cancer patients up to 900 mg QD. Methods: Oral Debio1143 was administered to patients with advanced solid tumors according to a novel extended schedule: daily x 14, every 21 days. The starting dose was 200 mg QD. The MTD was exceeded when any two patients within the same cohort experienced dose-limiting toxicity (DLT). Serial blood samples and urine were collect on cycle 1 for PK and PD assessments. Results: Six-teen patients received doses from 200 to 400 mg QD. Only one DLT (G3 reversible ALT and ALP elevation) was reported at 200 mg. Most common AEs of any grade deemed related to study drug were fatigue (31%), nausea (29%), decreased appetite (20%), vomiting (16%), diarrhea (14%) and rash (14%). Average tmax and t½ were about 2 and 7 h, respectively. Exposure increased in a relatively dose- proportional manner without accumulation over 14 days. The exposure of the main metabolite Debio1143-MET1 increased in a greater than dose proportional manner. Renal excretion of Debio 1143 was less than 15% of dose. Rapid and sustained degradation of cIAP-1 in surrogate tissue was observed at all doses. Debio1143 induced plasma MCP-1, TNFα, M30 and M65 increase. No changes were observed for IL-8. No responses were seen in 16 evaluable patients. Conclusions: The MTD was not reached and 400 mg was the highest tested dose. The extended schedule administration of oral Debio 1143 was well tolerated with significant PD activity at the doses investigated. A phase Ib trial of this extended schedule of Debio1143 in combination with concurrent chemo-radiation in LA-SCCHN is ongoing. Clinical trial information: NCT01078649.