tbuckley/cabot-search huggingface dataset:
Adverse event (AE) attribution in symptom intervention and cancer prevention trials.
Authors: Jennifer Le-Rademacher, Shauna Hillman, Jeffrey P. Meyers, Charles L. Loprinzi, Paul J. Limburg, Sumithra J. Mandrekar
Journal: Journal of Clinical Oncology (2016)

e18111 Background: Assignment of AE attribution (as unrelated, unlikely, possibly, probably, and definitely related to the treatment) adds time and cost to the trial process. External factors have been shown to affect attribution reporting. Hillman et al. (2010) showed that 50% of AEs in the placebo arms of two multicenter cancer treatment trials were reported as related to the study drug. Here, we evaluate the patterns of AE attribution in symptom intervention (cancer patients) and cancer prevention (participants at high risk for cancer) setting. Methods: Seven multicenter placebo-controlled trials were analyzed separately (1253 patients, 7064 AEs). Frequency and severity of AEs were summarized by arm. Attribution and percentage of repeated AEs whose attribution changed overtime were summarized for the placebo arms. Percentage of physician over- or under-reporting of AE relatedness was calculated for the treatment arms using the placebo arm as the reference. Results: Thefrequency and severity of AEs observed in treatment and placebo arms were similar. 12 – 57% of AEs in the placebo arm were reported as at least possibly related to the treatment. Attribution changed overtime in 0 – 34% of repeated AEs. Commonly over-reported AEs include fatigue, constipation, diarrhea, and GI disorder. Conclusions: Up to50% of AEs in the placebo arms were classified as possibly related to the treatment. This combined with up to 34% change in attribution of repeated AEs in the same patient suggests that assignment of AE attribution in this setting is also unreliable and subjective. Symptom intervention Prevention Disease Various Barrett’s esophagus Bronchial dysplasia Colorectal Intervention Epoetin Alfa Iron Aspirin Metformin Sulindac Myoinositol Atorvastatin, Sulindac, ORAFTI Synergy1 # patients (placebo) 333 (165) 490 (163) 123 (30) 77 (36) 60 (30) 85 (41) 85 (22) # AEs in placebo, treatment 1378, 1379 1085, 2044 31, 46 46, 71 145, 121 211, 263 84, 160 % grade 3 – 5 in placebo, treatment 14, 16 33, 26 0, 4 1, 0 3, 3 1, 3 5, 4 % related ness in placebo (possibly, probably + definitely) 12 (10, 2) 24 (21, 3) 55 (48, 7) 57 (50, 7) 19 (19, 0) 29 (29, 0) 37 (35, 2) % repeated AEs with attribution change in placebo 25 (130/ 527) 34 (149/ 439) 0 (0/ 15) 0 (0/5) 20 (9/ 46) 11 (8/76) 8 (2/26)
In-hospital cardiac arrest among patients with malignancy.
Authors: Sheri Rosen, Kevin Eng, Jenny Yang, Sanjeev Tyagi, Mazen Odish, Rebecca Sell, Jeremy Beitler
Journal: Journal of Clinical Oncology (2017)

e21583 Background: Malignancy is generally considered a poor prognosticator for in-hospital cardiopulmonary arrest. Recent studies have shown that overall survival in those with localized disease and fewer than two comorbidities approximates the general population, likely reflective of advances in cancer treatment and more selective use of cardiopulmonary resuscitation. The present study was conducted to evaluate whether malignancy is an independent risk factor for death before discharge following in-hospital cardiopulmonary arrest. Methods: This single-center retrospective study included consecutive in-hospital cardiac arrests for whom cardiopulmonary resuscitation was attempted between 2011-2015. Patients were identified from an inpatient cardiac arrest registry and excluded if the arrest occurred in the operating room or emergency department prior to admission. Data related to each patient’s oncologic history was obtained via manual chart review by physician investigators. The primary outcome was survival to discharge among patients according to malignancy status. Results: Over the five-year study, 532 patients experienced in-hospital arrest and met inclusion criteria. Fifteen percent (n = 81) had a known cancer diagnosis at the time of arrest; 9% of arrests (n = 46) had a cancer that was considered active (not in remission). One-fourth of all cancer diagnoses at time of arrest were hematologic malignancies. Overall post-arrest survival to discharge was 34%. Survival did not differ significantly for patients with versus without current or prior malignancy (OR 0.69, 95% CI 0.41-1.18; p = 0.17), nor with active malignancy at time of arrest (OR 0.52; 95% CI 0.25-1.07; p = 0.08). The subgroup of patients with hematologic malignancy had significantly lower survival (OR 0.21, 95% CI 0.05-0.91; p = 0.04). Conclusions: Malignancy was not associated with decreased survival to hospital discharge among patients experiencing in-hospital arrest for whom resuscitation was attempted.
Association of T cell responses after vaccination with HPV16 long peptides for late stage cervical cancer with prolonged survival.
Authors: Winald R. Gerritsen, Cornelis Joseph Melief, Marij Welters, Ignace Vergote, Judith R. Kroep, Gemma Kenter, Nelleke Ottevanger, Wiebren Age Tjalma, Hannelore Denys, Mariette IE van Poelgeest, Hans Nijman, An K.L Reyners, Thierry J. Velu, Frederic Goffin, Roy Iqbal Lalisang, Richard B. Stead, Brent A. Blumenstein, Sjoerd van der Burg
Journal: Journal of Clinical Oncology (2017)

5525 Background: Therapeutic vaccination with HPV type 16 synthetic long peptides (HPV16-SLP) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install effective immunity in patients with advanced HPV16-positive cervical cancer. We showed that HPV16-SLP vaccination in mice and in patients with advanced cervical cancer patients fosters robust HPV16-specific T cell responses, when combined with chemotherapy (Welters et al. Sci. Transl. Med., 2016). Methods: We have now completed a chemo-immunotherapy study in 70 patients with late stage HPV16+ cervical cancer (clinical trials.gov NCT02128126). Three HPV16-SLP vaccine doses were given 2 weeks after the second, third and fourth cycle of standard chemotherapy (carboplatin, AUC 6; paclitaxel 175 mg/ m 2 ). Cohorts of 12 patients each were vaccinated with each of 4 dose levels (20, 40, 100 and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the length of the 2 E6 and E7 proteins. Two additional cohorts of 6 patients each were vaccinated with the most promising doses of 40 and 100 µg/ peptide. Results: Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-γ Elispot were observed and were sustained until at least 30 days after the 6 th cycle of chemotherapy. In addition the chemotherapy augmented recall responses to microbial antigens. Such robust T cell responses were not noted in previous trials when similar patients were vaccinated without timing of vaccination during chemotherapy. A marked and significant positive correlation was observed between the strength of the vaccine-induced immune response and overall survival. No such correlation was observed between the strength of the T cell response against common recall antigens and survival. In addition a remarkably high proportion of patients survived beyond 2 years after the start of therapy. Conclusions: The results suggest that survival duration is directly related to the strength of the vaccine-induced HPV16-specific T cell response and is not due to generally better immuno-competence. Clinical trial information: NCT 02128126.
Computer-assisted Curie scoring for metaiodobenzylguanidine (mIBG) scans in patients with neuroblastoma.
Authors: Elizabeth Sokol, Roger Engelmann, Navin R. Pinto, Adam Starkey, Melanie Nall, Hollie Lai, Helen R Nadel, Barry L. Shulkin, Yonglin Pu, Daniel Applebaum, Gregory A. Yanik, Susan Lerner Cohn, Samuel Armato, III, Samuel Louis Volchenboum
Journal: Journal of Clinical Oncology (2016)

10559 Background: Curie scores have shown prognostic significance in high risk neuroblastoma. However, the potential for significant inter and intra-observer variability exists when determining (and recording) individual patient scores. We have created a deployable and scalable system for recording and tracking MIBG Curie scores that is comparable to current practice, while allowing lesion tracking. Methods: We designed three computer-assisted methods for recording Curie scores. Method A recapitulates current practice, allowing the radiologist to record a score of 0-3 for each anatomic region. Method B facilitates the marking of lesions and the assignment of a region from a schematic. Method C permits a user-driven segmentation of the image, computer-assisted marking of lesions, and automatic determination of score. For testing, 38 MIBG scans representing a range of ages and extent of disease were selected. Five experienced radiologists from four academic medical centers scored the 38 scans using each method and were surveyed for feedback. Results: There was no significant difference in total scores among the three methods (p = 0.91) or among the observers (p = 0.14). Methods B and C took an average of 58 and 111 seconds longer than Method A, respectively, due to marking each lesion. Overall, radiologists felt that tracking lesions would be very useful for oncologists. Of the three methods, marking the lesions and selecting the region (Method B) was preferred. Conclusions: A computer-assisted approach to determining Curie scores for MIBG scans successfully provides clinicians with a mechanism to track neuroblastoma lesions over time without loss of score reliability or consistency. The software is built on an easily-deployable platform for use at any medical center as both a research tool and clinical instrument. Given the growing necessity to Curie score MIBG scans, longitudinal lesion tracking and score recording could have an important impact on the care and treatment of children with neuroblastoma.
Population pharmacokinetic and pharmacodynamic analysis of osimertinib.
Authors: Martin Johnson, Henning Schmidt, Mikael Sunnaker, Anthony F Nash, Suman Nayak, Helen Tomkinson, Karthick Vishwanathan
Journal: Journal of Clinical Oncology (2017)

e20536 Background: Osimertinib is an oral, potent, irreversible, CNS active EGFR-TKI, selective for sensitizing (EGFRm) and T790M resistance mutations, indicated for the treatment of patients with T790M positive advanced non-small cell lung cancer who have progressed on or after EGFR-TKI therapy. Osimertinib pharmacokinetics (PK) were evaluated using a population approach and pharmacodynamic (PD) relationships using appropriate modeling approaches. Methods: To understand the impact of covariates on osimertinib PK, a population PK analysis was performed using data from patients who received osimertinib (20–240 mg) during the AURA studies. Exposure metrics were derived from a PK model and used to assess the exposure-response (safety/efficacy) relationship. Efficacy analysis included patients who were T790M positive (n = 710) and safety analysis included all dosed patients (n = 1088). The impact of covariates on exposure-response was assessed. Models accounting for rare safety events were applied to quantify the association between events and exposure. Results: Population PK analyses supported dose- and time-independent PK of osimertinib with no clinically meaningful covariates identified. Patients in the highest exposure quartile (Q4) had a numerically shorter median progression-free survival (8.3 months [95% CI 6.9, 10.5]) compared with patients in Q1, Q2 and Q3 (all 11.2 months [95% CIs 9.7, 12.7; 8.5, 15.6 and 8.7, 13.7, respectively]). A model-based analysis indicated that this effect is likely due to a larger number of patients in Q4 with poor prognostic features, i.e. worse performance status (WHO 1 or 2) and lower baseline serum albumin compared with Q1, Q2 and Q3, rather than to osimertinib exposure. Model-predicted probability of a relationship between osimertinib exposure and LVEF changes was not evident. Model-based analysis predicted that, compared with the median probability (0.03), the probability of a patient experiencing interstitial lung disease may increase with increasing osimertinib exposure (Q1 probability 0.01 [steady-state AUC 6361 nM*h] vs Q4 0.06 [24460 nM*h]) at the 80 mg dose. Conclusions: Population PK and PK-PD analysis is supportive of 80 mg as an appropriate dose for osimertinib. Clinical trial information: NCT01802632; NCT01802632; NCT02094261; NCT02151981.
Phase II clinical trial of first-line combination of radiation followed by gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy for early-stage extranodal natural killer/T-cell lymphoma with unfavorable prognostic factors: The GREEN study (NCT02276248).
Authors: Fei Qi, Wei-Hu Wang, Ye-Xiong Li, Mei Dong, Xiao-hui He, Jianliang Yang, Sheng Yang, Hui Fang, Bo Chen, Shunan Qi, Yan Qin, Yuting Zhao
Journal: Journal of Clinical Oncology (2017)

7540 Background: Currently concomitant or sequential chemotherapy with radiotherapy has been recognized as the standard treatment for extranodal natural killer/T-cell lymphoma, nasal type (ENKTL). However, the optimal schedule has not been fully defined. Methods: We designed a phase II prospective study to investigate the efficacy and toxicity profile of sequential radiation followed by systemic GDP (gemcitabine, dexamethasone and cisplatin) chemotherapy on previously untreated early-staged (stage IE/IIE) ENKTL patients with at least one unfavorable prognostic factor. The primary endpoint was 2-year progression-free survival (PFS). Secondary endpoints were 2-year overall survival (OS), overall response rate (ORR), and toxicity. Results: A total of40 patients were enrolled and completed the entire course of treatment between June 2010 and June 2014. The median age was 38 (range 25-63) years old. All the enrolled patients presented with at least one unfavorable prognostic feature: age &gt; 60 years (5.0%), B symptom (40%), elevated serum LDH (40.0%), regional lymph node involvement (32.5%) and primary tumor invasion (87.5%). At the completion of the whole treatment, ORR was 97.5% and the complete remission rate was 95.0%. Median follow-up time was 43.7 months (range 9.4-72.3 months). 2-, 3-, 5-year PFS rates were 84.7%, 82.1%, 77.5%, and OS rates were 89.9%, 87.1%, 79.7%, respectively. Recurrence within the RT field was observed in four patients and systemic failure in three individuals. Grade 1-2 skin reaction and mucositis were the main toxicity related to radiation. Grade 3-4 neutropenia (12/40), thrombocytopenia (7/40) and anemia (2/40) were observed during GDP chemotherapy. No clinically significant late toxicities were observed during follow-up visits. Conclusions: The current results indicates that first-line radiation followed by GDP chemotherapy can be one of the most effective and feasible treatment schedule for early-stage ENKTL patients, especially those with poor prognostic factors. Clinical trial information: NCT02276248.
Association of high cost sharing and target therapy initiation among Medicare patients with metastatic renal cell carcinoma.
Authors: Pengxiang Li, Yu-Ning Wong, Jordan Jahnke, Jalpa A. Doshi
Journal: Journal of Clinical Oncology (2016)

4562 Background: Targeted therapies (TTs) extend survival in mRCC, but high out-of-pocket (OOP) costs may limit access. This is particularly true for oral TTs covered under Medicare Part D wherein patients without low-income subsidies (non-LIS) typically face 25%-33% coinsurance (initial coverage phase), followed by ~50% coinsurance (coverage gap phase), and then 5% coinsurance (catastrophic phase). On the other hand, LIS patients face nominal cost sharing of ≤ $5 under Part D. In contrast, infusible TTs are covered by Medicare Part B and available at low OOP costs to both groups given supplemental insurance. Methods: We used 2011-2013 100% Medicare claims to examine oral TT (sorafenib, sunitinib, everolimus, pazopanib, or axitinib) initiation rates among fee-for-service non-LIS RCC patients newly diagnosed with metastases in the liver, lung, or bone, as compared to their LIS counterparts. We also compared initiation rates for infusible TTs (temsirolimus or bevacizumab) across the two groups. Logistic regressions controlling for patient (e.g. age, gender, race, metastatic site, Charlson score, nephrectomy) and plan characteristics (e.g. Part D plan type and formulary coverage, prior authorization (PA) for oral TTs) were used to model initiation rates. Results: The final sample included 1554 mRCC patients (mean age 72 years, 60% male, 85% White, mean Charlson score 1.1). On average, 86% of oral TTs covered by the patient’s plan formulary were subject to PA. Non-LIS patients (n = 1080) were less likely than LIS patients (n = 474) to have an oral TT claim within 6 months of first metastases claim (25% vs. 37%; adjusted odds ratio [adj-OR] = 0.52, p < 0.001). Initiation rates of infusible TTs were similar across both groups (11% vs. 12%; adj-OR = 1.11, p = 0.687). Non-LIS patients were less likely to initiate any (oral or infusible) TT within 6 months of metastases diagnosis (33% vs. 45%; adj-OR = 0.45, p < 0.001). Extensive subgroup and sensitivity analyses showed consistent findings. Conclusions: High cost sharing was associated with reduced and/or delayed access to oral TTs under Medicare Part D. Lower initiation of oral TTs was not offset by an increase in use of infusible TTs.
Outcomes in non-Hodgkin lymphoma by Latino country-of-origin (COO).
Authors: Oscar Calzada, Yizhao Xi, Madhusmita Behera, Jean Louise Koff, Christopher Flowers, Yuan Liu, Jonathon Brett Cohen
Journal: Journal of Clinical Oncology (2018)

e18727 Background: Despite significant geographic, genetic, and environmental heterogeneity among Latinos living in the U.S., differences in epidemiology and outcomes among Latino subgroups diagnosed with non-Hodgkin Lymphoma (NHL) remain understudied. We examined the impact of Latino COO on clinical outcomes in NHL patients (pts) in a large national cohort. Methods: We utilized the National Cancer Database (NCDB) to evaluate pts of Latino descent (independently grouped as anyone originating from Mexico, Puerto Rico, Cuba, South or Central America, or the Dominican Republic) diagnosed with NHL between 2004-2013. Overall Survival (OS) was estimated using the Kaplan-Meier method. Uni- and multivariable Cox proportional hazards models were fit to evaluate associations between COO and OS. Results: Of 447,677 NHL patients identified in the NCDB, 8,534 (2.0%) claimed Latino origin. Among Latino pts, 45% self-identified as Mexican or Chicano, 25% as South or Central American, 14% as Puerto Rican, 11% as Cuban, and 5% as Dominican. Median age was 59 years, and 55% pts were male. 45% pts were treated at a high volume/academic research institution. Compared to other Latino subgroups, Mexicans and Central and South Americans were more likely to be uninsured at time of diagnosis (p < 0.001), present with a Charlson-Deyo co-morbidity score of 0 (p < 0.001) and harbor aggressive NHL subtypes (p = 0.032). Mexicans and Dominicans were more likely to reside in neighborhoods where > 21% of residents did not earn a high school degree (p < 0.001) and median incomes were < $38,000 (p < 0.001). In multivariable analysis, male sex, comorbidity score ≥ 1, B symptoms, lack of private insurance, and aggressive NHL subtype were significant predictors of worse outcomes. COO was not associated with differences in OS when NHL subtype remained unstratified. However, Dominicans with aggressive NHL experienced improved OS (HR 0.55: 95% CI 0.40-0.76) compared to other Latino subgroups. Conclusions: Our work represents an important first step towards eliminating the critical knowledge gap surrounding cancer outcomes among Latino NHL pts. In particular, the association of Dominican origin with improved OS in aggressive NHL warrants further study.
Food and Drug Administration analysis of 1332 single patient and emergency use expanded access (compassionate use) requests for patients with cancer over a duration of three years (2012-2014).
Authors: Steven J. Lemery, Sham Mailankody, Dickran Kazandjian, Marie-Anne Damiette Smit, Gideon Michael Blumenthal, Tamy Kim, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2016)

6523 Background: Single patient INDs (SPIs), including SPIs for emergency use, facilitate expanded access of investigational drugs to patients with cancer who cannot enroll in a clinical trial. Due to the life-threatening nature of many cancers, many expanded access requests are submitted to FDA’s Office of Hematology and Oncology Products (OHOP). An evaluation of these requests was undertaken to increase the transparency related to SPIs and foster awareness of the process. Methods: Data from FDA’s database were extracted for all single patient and emergency use INDs submitted from 1/2012 to 12/2014. Data collected included IND received dates, dates the IND was allowed to proceed, drug names, underlying malignancy of patients, location of requests, whether the IND was placed on hold, whether safety or annual reports were submitted, and demographics (where available). Results: Data from 1332 individual INDs were analyzed including data from 525 emergency INDs. Of the 1332 INDs, 1330 (99.8%) were allowed to proceed. Of the two INDs placed on clinical hold, one was subsequently allowed to proceed. Median review time of 1309 INDs with documented receipt and may proceed dates was 1 day (mean = 2) with 75% reviewed within 3 days. Of 1332 requests, there were ~157 unique drugs. Approximately 59% of requests were for a drug subsequently approved. The most frequent requests were for patients with CML (28%), breast cancer (12%), ALL (9%), AML (not APL) (6%), ovarian cancer (6%), and sarcoma (5%). FDA received submissions from all but one state. An estimated 67% of patients were treated at major university-related hospitals, 6% at dedicated children’s hospitals, and 0.7% at VA hospitals. Among 827 patients with data on age, median age was 54 years and 9% were patients 18 years or younger. Of 869 patients, 53% were women. FDA received few annual reports (15%). Conclusions: OHOP’s review time and approval of nearly all cancer-related single patient expanded access requests is consistent with FDA goals to facilitate expanded access. OHOP is continuing to work to improve this process and increase transparency to facilitate access for more patients.