tbuckley/cabot-search huggingface dataset:
Clinical pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies from a phase 1 study.
Authors: David Dai, Courtney Denton Dinardo, Eytan Stein, Stéphane de Botton, Eyal C. Attar, Hua Liu, Guowen Liu, Ian Lemieux, Samuel V. Agresta, Hua Yang, Bin Fan
Journal: Journal of Clinical Oncology (2018)

2581 Background: Mutant isocitrate dehydrogenase 1 (mIDH1) produces the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO) is a selective mIDH1 inhibitor under evaluation in patients with mIDH1 hematologic malignancies. This translational analysis explored the PK profile of IVO, the relationship between IVO exposure and 2-HG suppression, and the impact of intrinsic/extrinsic patient factors on IVO exposure from the phase 1 monotherapy study (NCT02074839). Methods: IVO was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles. As of May 12, 2017, 258 patients had received IVO at doses ranging from 100 mg BID to 1200 mg QD in dose escalation (n = 78) and at 500 mg QD (n = 180) in dose expansion. IVO levels were assessed in plasma and 2-HG levels in plasma/bone marrow using LC-MS/MS methods. Results: After single and multiple doses, IVO was readily absorbed (median Tmax 3 h). After peaking, IVO concentrations declined in a bi-exponential manner, with a mean terminal half-life of 72–138 h after a single dose. Dose-exposure nonlinearity of IVO from 300 to 1200 mg QD suggests doubling of the dose would result in a ~30% increase in AUC. Steady state (SS) was reached within 14 days. Moderate accumulation was observed after 500 mg QD, with mean AUC and Cmax accumulation ratios of 1.9- and 1.46-fold. IVO clearance was not altered by intrinsic patient factors. Concomitant administration of weak CYP3A4 inhibitors/inducers did not affect IVO clearance, though moderate/strong CYP3A4 inhibitors decreased IVO clearance and increased IVO SS exposure (AUC0-24hr by ~56%; Cmax by ~47%). Plasma 2-HG reduction reached a plateau within 14 days of dosing after multiple doses of 500 mg QD, and was reduced by ≥90% over the range of IVO SS AUC in patients with newly diagnosed and relapsed/refractory AML, regardless of IDH1-R132 mutation type. Conclusions: IVO demonstrated a long half-life suitable for QD dosing, moderate accumulation, and robust 2-HG inhibition in patients with mIDH1 myeloid malignancies. Intrinsic/extrinsic patient factors, including concomitant moderate/strong CYP3A4 inhibitors, did not significantly alter IVO exposure. Clinical trial information: NCT02074839.
Physicians’ comfort levels with prescriptions for cancer comorbidities that they and other healthcare providers write.
Authors: Chiahung Chou, Natalie S Hohmann, Tessa Hastings, Chao Li, Joel Farley, Matthew L Maciejewski, Marisa Domino, Richard Hansen
Journal: Journal of Clinical Oncology (2018)

e18523 Background: As cancer survivorship increases, cancer is becoming a chronic condition, often accompanied by many comorbidities that complicate treatment management. The roles and shared responsibilities of specialists in post-cancer care remain unclear. Therefore, the objective of this study was to determine physicians’ comfort level in prescribing medications that cancer patients frequently need during their care continuum. Methods: A cross-sectional online survey of physicians was administered using Qualtrics Panels. Survey measures included 1) physicians’ own comfort level in prescribing 23 categories of medications, 2) their level of comfort with other specialists prescribing to mutual patients, and 3) demographics. Responses were rated on a 7-point Likert scale. The survey was pre-tested with an independent sample of 12 healthcare providers and researchers to ensure content and face validity. One-way ANOVAs were used to analyze continuous variables; chi-square tests for categorical variables. Results: 150 physicians (50 oncologists, 50 PCPs, and 50 psychiatrists) completed the survey. This study focuses on the perceptions of oncologists and PCPs only. The majority of respondents were male (78%), white (66.4%), and non-Hispanic (93.9%), with PCPs reporting the highest overall personal comfort level in prescribing the most categories of medications. PCPs reported being less comfortable with oncologists prescribing antineoplastics and anticoagulants than oncologists were. However, PCPs reported being more comfortable with oncologists prescribing several categories of drugs than oncologists’ own comfort level, including immunomodulators; immunosuppressives; muscle relaxants; anticonvulsants; antidepressants; antipsychotics; anxiolytics, sedatives and hypnotics; contraceptives; vaccines; antimigraine agents; antiparkinsonian agents; and amphetamines. Conclusions: The treatment of cancer alongside chronic comorbid conditions requires a dynamic mix of providers. Our study sheds light on how physician comfort levels with prescribing for cancer and its comorbidities could influence the coordination of care for cancer patients with comorbidities.
Predictors of treatment attrition in patients with metastatic colorectal cancer (mCRC).
Authors: Arvin Bahrabadi, Jenny Ruan, Gillian Gresham, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

e18041 Background: Although the treatment landscape of cancer has evolved significantly with the introduction of novel and more efficacious drugs, the positive impact of these new therapies may be limited by attrition and ultimately non-exposure to later lines of therapy. Using a population-based cohort of mCRC, our aims were to characterize rates of attrition and determine factors associated with failure to receive each line of treatment. Methods: Medical records of patients who were diagnosed with mCRC from 2008-10 and referred to any 1 of 5 cancer centers in British Columbia were merged with systemic therapy data from the provincial pharmacy database. We classified patients into mutually exclusive treatment categories: a) receipt of all available lines of mCRC therapies; b) attrition directly attributable to disease, such as cancer progression or death; c) attrition attributable to other clinical factors, including toxicity, and d) attrition secondary to non-clinical factors, including personal/social circumstances. Multivariate logistic regression models were constructed to identify predictors. Results: We identified 525 eligible mCRC patients: median age 64 years, 57% men, 55% Caucasian, 68% ECOG 0/1, 41% and 35% never and ever smokers, respectively. The attrition rate was 40% (95% confidence interval [95% CI], 36%-44%) for first line treatment, 25% (95% CI, 19%-31%) for second line treatment and 14% (95% CI, 5.5%-22.5%) for third line. While cancer progression (31%) and chemo toxicity (30%) were the most common causes of attrition, other frequent reasons included death (20%) and patient preference (14%). On multivariable analysis, first-line treatment attrition was associated with worse baseline ECOG (odds ratio [OR], 1.92; p &lt; 0.001) and older age at diagnosis of mCRC (OR, 1.04; p &lt; 0.001). When we examined attrition over all lines, it was significantly correlated with worse ECOG (OR, 2.44; p &lt; 0.001). Conclusions: Treatment attrition is a prevalent problem in mCRC and can hinder the benefits that would otherwise be possible with a sequential treatment algorithm. Some causes of attrition are potentially modifiable and may reflect opportunities for patients to maximize exposure to all lines of therapies.
Medical resource use and costs from subsequent metastases in patients with prostate cancer initially diagnosed with locoregional disease.
Authors: Tracy Li, Neal D. Shore, Maneesha Mehra, Mary Beth Todd, Ryan Saadi, Gaetan Leblay, Robert I. Griffiths, Jyoti Aggarwal
Journal: Journal of Clinical Oncology (2016)

e16564 Background: In prostate cancer (PC), progression from locoregional to metastatic disease significantly impacts morbidity and mortality. We examined the impact of progression on medical resource use and healthcare costs. Methods: Using the linked United States Surveillance, Epidemiology, and End Results and Medicare databases (2000-2012), we identified patients (pts) initially diagnosed with locoregional PC who progressed to metastatic disease ≥ 4 months after PC diagnosis (cases). Cases were matched up to a 1:4 ratio to controls (pts without metastases). Pts were evaluated 12 months before and for 12 months after metastases. Healthcare costs and medical resource use related to inpatient admissions, outpatient/emergency room (ER) visits, skeletal-related events (SRE), and chemotherapy were compared between cases and controls. Medicare claims were used to calculate average costs per month and resource use. Results: There were 10,370 cases and 39,200 controls. 85% of cases had bone metastases. For cases, total healthcare costs were similar to controls from 12 to 4 months before metastases. These costs rose sharply to $11,982 in the month of metastases diagnosis vs $1305 for controls, and stayed 3 times higher than costs for controls for the remainder of the observation period. Medical resource use followed the same pattern, as shown by incremental rates and costs among cases relative to controls (Table). Conclusions: Progression to metastatic disease among PC pts initially diagnosed with locoregional disease significantly increased medical resource use and costs. Interventions to prevent or delay metastasis could result in decreased utilization of resources with associated cost reductions. Impact of progression to metastatic disease on medical resource use and average costs for cases vs controls. Months relative to subsequent metastases -12 to -4 months -3 to 3 months 4 to 12 months Incremental rate Incremental cost Incremental rate Incremental cost Incremental rate Incremental cost Inpatient care 1.1% $116 8.9% $1404 4.4% $620 Outpatient/ER visit 6.7% $72 25.4% $571 19.8% $467 SRE -0.1% -$24 7.3% $440 4.3% $183 Chemotherapy use 8.4% $128 17.3% $495 19.9% $626
Insurability and immigration trends during a time of uncertainty at the nation's oldest public hospital.
Authors: Arjun Iyengar, Domna Antoniadis, Mohammad Maher Abdul Hay
Journal: Journal of Clinical Oncology (2018)

e18687 Background: The US immigrant population currently accounts for 42.3 million or 13.0% of the total population. In a time of rapidly changing healthcare and immigration policies, it is important to better understand the unique barriers to cancer care affecting these communities. Methods: A systematic review was conducted of all the referrals from 12/1/2016-12/31/17 to a legal clinic embedded in the Bellevue Hospital Cancer Center in NYC. Several variables were ascertained for each referral including immigration status, country of origin, primary language, age, disease type, reason for referral, estimated time living in the US, and the presence of family members with documented residence. Each patient was assessed for their ability to purchase health insurance, qualify for Medicaid, and access standard of care treatment Results: Preliminarily from 12/2016-1/2017, 46 referrals were evaluated of which 32 were unique patients. Visits were classified as being new (50%), follow-up (36.9%) or no-show (13%). Patients primarily hailed from Latin America (46.88%) and Asia (18.75%). While undocumented patients accounted for a majority of referrals (62.50%), they were found to have resided on average of 12 years in the United States and at least 55% of them had first degree family members that were either citizens or had legal residence in the country. Gastrointestinal (18.75%) and breast (18.75%) malignancies and ALL (12.5%) were the most common listed diagnoses. 15.6% of patients were US citizens and only those patients qualified for Federal Medicaid. 62.5% of patients which include undocumented patients and those with legal visas qualified for NY State Emergency Medicaid which covers cancer specific treatments. At initial appointment, undocumented patients who require SCT or clinical trial (37.5%) were not insurable under any insurance systems. Conclusions: Understanding demographics and unique challenges of the immigrant population is essential to better deliver cancer care. Further studies on the impact of domestic policies on both perceptions and outcomes of immigrant health are warranted.
Suboptimal regimens in sequential treatment (ST) with ICT (induction chemotherapy) followed by CCRT (concomitant chemotherapy) in "real life" patients with locally advanced pharyngo-laryngeal squamous-cell carcinoma (LAPLSCC) and prognosis.
Authors: Carmen Orte, Isabel Pajares Bernad, Eugenia Ortega Izquierdo, Eugenio Vicente Gonzalez, Beatriz Bonaga Serrano, Ramon Terre Falcon, Lucrecia Roque Taveras, Javier Martinez-Trufero
Journal: Journal of Clinical Oncology (2018)

6075 Background: ST is a treatment modality widely used in LAFLSCC. Although ICT with TPF (docetaxel-Cisplatin-5FU) and CCRT with 3- weekly Cisplatin have been proved as the most active regimens, unfit patients (p) often cannot receive them. There are few data about efficacy of modified ST regimens in unselected population. Methods: From 1998 to 2013, data from LAFLSCC patients treated in our institution with ST were retrospectively reviewed. Patient and treatment-related prognostic factors (PFs) were collected. Both uni and multivariate proportional hazards were used to determine associations with overall survival (OS) and DFS (disease-free survival). Local Ethical Committee approval was obtained. Results: 337 consecutive patients were treated with ST with ICT and CCRT. Median age: 57 years. Male:92%. Stage: 135 p III (40.1%), 202p IV (59.9%). Median follow-up: 38.9 m (0- 222 m). Median OS: 48,3m (95%CI 36-60). Median DFS: 105,3 m (95%CI 90-120). Analyzed tumor-related PFs: location, stage, differentiation. Patient-related PFs: age, blood cells ratios (NLR, dNLR, LMR), ACE-27 comorbidity index, Hemoglobin, albumin. Treatment-related PFs: ICT type , CCTR type, ICT response. In Multivariate analysis (MA) several PFs independently correlated with OS and DFS (Table 1). Use of TPF as ICT was independently linked to better OS and DFS. Use of 3-weekly Cisplatin as CCRT was associated with better OS. Conclusions: In unselected LALFSCC patients treated with ST, selection of proved efficacious therapies affects outcome, independently of other tumor and patient-related PFs. Suboptimal regimens work worse. In unfit patients other alternatives should be considered. Outcome measure Independent Prognostic factors (MA) p-value HR(95%CI) OS Stage ( IV vs III) 0.007 1,70(1,15-2,49) Post-ICT Hemoglobin ( < 10vs > 10 gr/dL) 0.001 2,83(1,55-5,14) ICT response (Non CR vs CR) 0.009 1,71(1,14-2,56) ICT( Non TPF vs other) 0.027 1,58 (1,05-2,38) CCRT (Non CDDP vs CDDP) 0.006 1,63 (1,15-2,32) LMR ( < 3.1 vs > 3.1) 0.013 1,71(1,11-2,61) DFS ICT (non TPF vs TPF) 0.035 1,80(1,04-3,13)
PD.2.02 Central Nervous System (CNS) Metastasis in Patients with T790M EGFRm Lung Cancer – Real World Data from a Brazilian Cohort
Authors: C. Baldotto, L. Araujo, P. De Marchi, G. Werutsky, G. Borges, C. Mathias, H. Freitas, A. Calabrich, C. Costa, F. Franke, E. Lima, Y. Neron, G. Schwartsmann, M. Custodio, C. Sansevero, G. Castro
Journal: Journal of Thoracic Oncology (2018)
Talapro-2: A 2-part, placebo-controlled phase 3 study of talazoparib (TALA) with background enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage repair deficiencies.
Authors: Neeraj Agarwal, Arun Azad, Andre Fay, Joan Carles, Neal D. Shore, Luke T. Nordquist, Lawrence Ivan Karsh, Curtis Dunshee, Srinand Ponnathapura Nandakumar, Beth Sullivan, Akos Czibere, Fong Wang, Karim Fizazi
Journal: Journal of Clinical Oncology (2018)

TPS5091 Background: ENZA is approved to treat men with mCRPC. TALA is a dual-mechanism PARP inhibitor that inhibits PARP1 and PARP2 catalytic activity and traps PARP on DNA, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells. A combination of TALA with ENZA in DNA damage repair (DDR)+ mCRPC may improve clinical outcomes. Methods: Part 1 (P1) is open label to confirm the starting dose of TALA to be given in combination with ENZA. Part 2 (P2) is a double-blind assessment of efficacy and safety. Approximately 352 patients (pts) will be enrolled (P1, n=12; P2, n=340). Eligible pts for both parts are ≥18 yrs of age (≥20 in Japan) with asymptomatic or mildly symptomatic mCRPC; ECOG PS ≤1; no brain metastases; and who have not been treated with taxanes or novel hormonal therapy (NHT) initiated after the onset of mCRPC. Pts who received cytotoxic chemotherapy (CT), other HT, biologic, or radionuclide therapy within 28 days of screening or who received a prior PARP inhibitor, platinum-based CT, cyclophosphamide, or mitoxantrone are excluded. For P2, pts must have DDR+ mCRPC. In P1, pts will receive open-label TALA 1 mg/d orally with ENZA 160 mg/d. In P2, pts will receive open-label ENZA and will be randomized 1:1 to also receive TALA 0.5-1 mg/d or placebo. The starting dose of TALA for P2 will be determined in P1. Randomization will be stratified by prior treatment with NHT for castration-sensitive prostate cancer or non-mCRPC and prior treatment with taxane-based CT for castration-sensitive prostate cancer (yes/no). For P1, the primary endpoint is safety; the secondary endpoint is pharmacokinetics of TALA and ENZA. For P2, the primary endpoint is radiographic progression-free survival (rPFS); key secondary endpoints include overall survival, objective response in measurable soft tissue disease, PSA progression, and time to initiation of cytotoxic CT. Efficacy will be assessed by radiographic assessments every 8 wks through week 25 and every 8-12 wks thereafter. P2 analysis for rPFS is powered at 90% using a 2-sided log-rank test with alpha of 0.05. Clinical trial information: NCT03395197.
The impact of preoperative malnutrition on surgery outcome and overall survival in ovarian or peritoneal cancer patients: A prospective study.
Authors: Jalid Sehouli, Paulina Ali, Elena Ioana Braicu, Radoslav Chekerov, Jacek P. Grabowski
Journal: Journal of Clinical Oncology (2016)

5574 Background: The aim of our study was to evaluate the impact of preoperative malnutrition on surgical outcome and overall survival in ovarian or peritoneal cancer patients. Methods: Nutritional status of ovarian and peritoneal cancer patients was assessed prospectively prior to cytoreduction surgery in our department between 01/2007 and 12/2008. The Nutritional Risk Score (NRS-2002) was used to determine patients at high nutritional risk (NRS ≥ 3). The Bioelectrical Impedance Analysis (BIA) identified malnourished individuals (phase angle alpha Phα ≤ 4,5°) basing on body composition evaluation. Surgical data together with follow-up information were correlated with nutritional parameters. Results: Overall, 152 patients were included in this study. 79 women suffered from primary and 73 from recurrent disease. The median age was 56 years (range 19-84). 28 (18.4%) patients were classified as high nutritional risk group (NRS ≥ 3) and 44 (29.1%) were malnourished according to Phα. The complete cytoreduction rate was significantly lower in women with NRS ≥ 3 in comparison to patients with NRS < 3 (32.1% vs. 69.1%, p = 0.014). The median overall survival showed highly significant difference between malnourished (NRS ≥ 3) and well-nourished patients (NRS < 3) (7 months vs. 46 months, 95%CI = 0.24, p = 0.001). In a multivariate analysis malnutrition was identified as an independent predictor for incomplete cytoreduction in ovarian cancer patients (OR: 4.55, 95%CI = 1.45-14.29, p = 0.009 for NRS; OR: 5.56, 95%CI = 1,75–16,67, p = 0.003 for Phα). Additionally, malnutrition defined by Phα ≤ 4,5° is an independent prognostic factor for overall survival (HR: 2,88, 95%CI = 1.60–5.19, p < 0.001). Conclusions: According to the results of our prospective study, malnutrition is an independent predictor of incomplete cytoreduction in ovarian and peritoneal cancer patients. Moreover, defined by Phα it is also an independent prognostic factor for poor overall survival. The preoperative nutritional assessment is an effective tool in identification of risk group within ovarian or peritoneal cancer patients characterizing with poor clinical outcome.
<i>Notes from the Field:</i> Enterovirus A71 Neurologic Disease in Children — Colorado, 2018
Authors: Kevin Messacar, Alexis Burakoff, W. Allan Nix, Shannon Rogers, M. Steven Oberste, Susan I. Gerber, Emily Spence-Davizon, Rachel Herlihy, Samuel R. Dominguez
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In May 2018, the Colorado Department of Public Health and Environment was notified by Children's Hospital Colorado of an increase in pediatric cases of meningitis and encephalitis, in which patients tested positive for enterovirus, which can cause hand, foot, and mouth disease and neurologic disease in children aged <5 years.
A phase II trial of albumin-bound paclitaxel and gemcitabine in patients with newly diagnosed PD-L1 IHC low/unknown stage IV squamous cell lung cancers.
Authors: Paul K. Paik, Aparajita Srikakulum, Linda Su Hyun Ahn, Andrew J. Plodkowski, Kenneth K. Ng, Daniel McFarland, John Joseph Fiore, Afsheen Iqbal, Juliana Eng, Charles M. Rudin
Journal: Journal of Clinical Oncology (2018)

e21035 Background: Therapeutic options for SQCLC pts are limited. The efficacy of platinum doublets, the standard first-line treatment for PD-L1 < 50% pts and pts who have progressed on first-line pembrolizumab, is static, with ORR = 30-40%. Compelling evidence of anti-tumor synergy between gemcitabine (GEM) and albumin-bound paclitaxel (ABP) was demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase, leading to increased intratumoral concentration of GEM (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + GEM in pts with SQCLC. Methods: This is a Simon two-stage phase 2 study of ABP + GEM in chemotherapy-naïve, PD-L1 low/unknown advanced SQCLC pts (NCT02525653). Primary endpoint: best ORR. H0 = 25% (≥6/17 responses) and HA = 45% (≥16/41 responses). ABP (100mg/m2) + GEM (1000mg/m2) was initially given on D1, D8, D15 of an every 4 week cycle for up to 6 cycles (A1). After clearing the first stage, the study was amended to a 3 week cycle (D1, D8 treatment) and to allow maintenance ABP to begin after C4 (A2). All patients underwent NGS by MSK-IMPACT for genotype correlation. Results: N = 30 pts have been enrolled to date. N = 14 pts were treated on A1. N = 9 patients are evaluable on A2 . N = 4 pts have not had their first scan; N = 3 patients are not evaluable. Median age = 70 (≥70 = 60%), female = 30%, median KPS = 80%, smokers = 93% (median py = 40). 46% of pts had PD-L1 IHC < 50% (0-20%). 54% were PD-L1 unknown. Grade ≥3 related AEs were: fatigue (13%), periph neuropathy (4%); diarrhea (4%); lung infection (4%), anemia (9%); thrombocytopenia (4%), decreased WBC (4%). 4 patients (17%) experienced related SAEs including G3 febrile neutropenia, G3 WBC decrease, G3 thrombocytopenia, and G3 anemia, respectively. ORR in A1 = 50% (7/14 PR). ORR in A2 = 67% (N = 9, 5 PR, 1 CR). 8 pts in A1 had dose changes in the first 2 cycles resulting in a dose density equivalent to A2. ORR in the A2+A1 dose attenuated cohort = 71% (N = 17, 11 PR, 1 CR). PFS and OS data are not yet mature. Conclusions: ABP + GEM is well-tolerated in this older population with promising efficacy following the pre-planned interim analysis of the first-stage of the study. Accrual is ongoing in the second-stage. Clinical trial information: NCT02525653.