bluuebunny/crossref_metadata_2025_split huggingface dataset:
Representation of minorities in oncology clinical trials: Review of the past 14 years.
Authors: Duma Narjust , Vera Aguilera Jesus , Paludo Jonas , Wang Yucai , Leventakos Konstantinos , Mansfield Aaron Scott , Adjei Alex A. 
Published: September 2018

2533 Background: Many cancer clinical trials (CT) lack appropriate representation of specific patients populations, limiting the generalizability of the evidence obtained. Therefore, we determined the representation of ethnic minorities in oncology CT. Methods: Enrollment data from all therapeutic trials reported as completed in clinicaltrial.gov from 2003 to 2016 were analyzed. CT in rare cancers (< 1% incidence) or with recruitment outside of the US were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER database cancer prevalence. Chi-square test was used to estimate differences in categorical data. Results: Out of 1,012 CT, 310 (31%) reported ethnicity with a total of 55689 enrollees. Distribution by race and comparison with data from 1996-2002, US cancer prevalence and US census are described in the Table. Participation in CT varied significantly across ethnic groups, non-Hispanic Whites (NHW) were more likely to be enrolled in CT (EF of 1.2%) than African Americans (EF of 0.7%, p < 0.001) and Hispanics (EF of 0.4%, p<0.001). A decrease in African Americans (AA) and Hispanics (H) enrollment was observed when compared with historical data from 1996 to 2002. Hispanics were less represented in breast and prostate cancer CT contributing only to 3% and 1.5% of the study population; African Americans were less represented in lung (5.4%) and renal cell carcinoma (3%) trials. Asians were well represented and their recruitment doubled over the past 14 years (2% vs 5.3%). Conclusions: African Americans and Hispanics were less likely to be enrolled in CT. Comparing with historical data; we observed a decrease in minorities’ recruitment in the past 14 years. This change could be attributed to the increased complexity of CT and mandatory molecular testing as many minorities lack access to institutions with genetic testing capacity. Future trials should take extra measures to recruit participants that adequately represent the U.S. cancer population. [Table: see text]
Food effect studies and drug label recommendations: A review of recently approved oncology products.
Authors: Farha Mark , Masson Eric , Tomkinson Helen , Mugundu Ganesh 
Published: September 2018

2535 Background: Evaluation of the effect of food on the pharmacokinetics of orally administered oncology drugs is a critical aspect of drug development, as food can mitigate or exacerbate toxicities and can change and influence variability in systemic exposure. Our aim in this review of approved oncology products is to describe the approaches used by sponsors to assess food effect and decide on the final dosing recommendations. Methods: Data for small molecule oncology drugs approved between 2003-2016 was extracted from the clinical pharmacology review in the sponsor’s FDA submission package. Information on food-effect study design, outcomes, intersubject variability, exposure-response relationships for safety, and the label dosing recommendation regarding food was analyzed. Results: Of the 29 drugs analyzed, 19 food effect studies were conducted in healthy volunteers, and 10 were conducted in cancer patients. The ratio of population geometric means between fed and fasted treatments fell outside the 80-125 percent equivalence limit in 55% of compounds for AUC and in 69% of compounds for Cmax. 6 drugs (21%) are recommended to be given with food, 11 drugs (38%) in the fasted state, and 12 drugs (41%) can be dosed regardless of food. Label recommendations appeared to be driven by the exposure-response analysis. 80% of drugs with a fasted label recommendation despite an increase in bioavailability with food had an exposure-response relationship for safety. Conclusions: Optimizing study design by conducting early food effect studies designed to estimate food effect rather than confirming no food effect, and learning the impact of food early may eliminate unnecessary study arms and save sponsors money and time. Furthermore, understanding the potential of food to mitigate or exacerbate toxicities may improve patients’ experience with treatments and has been shown here to be a major driver of the final dosing recommendation regarding food.
Hormone receptor (AR/ER/PR) expression as a prognostic marker and novel candidate for drug development across multiple tumor types.
Authors: Sen Shiraj , Roszik Jason , Meric-Bernstam Funda , Subbiah Vivek 
Published: September 2018

2537 Background: Hormone receptor (HR) [androgen receptor (AR), estrogen receptor (ER), progesterone receptor (PR)] expression is ubiquitous across tumor types and central to breast and prostate cancer treatment. While implicated in tumorigenesis, its role as a prognostic biomarker and therapeutic target in other tumor types has yet to be elucidated. Methods: We performed bioinformatic analyses of HR expression [reported as median transcripts per million (TPM)] using RNAseq from the Cancer Genome Atlas and completed Kaplan-Meier analyses to identify associations between HR expression and median overall survival (OS). Results: 9,743 samples from 9,674 patients across 33 tumor types were analyzed. AR was highly expressed in GBM (2 TPM), low grade glioma (2 TPM), breast (15 TPM), prostate (14 TPM), ovarian (6 TPM), renal clear cell carcinoma (4 TPM) and HCC (2 TPM) . Tumors with the highest quartile of expression had improved OS in renal clear cell [53 months (mo) vs not reached (NR), p = 4x10-11] and adrenocortical carcinoma (45 mo vs NR, p = .03) and worse OS in low grade glioma (119 vs 64 mo, p = 6x10-4). PR was highly expressed in uterine (12 TPM), breast (5 TPM), and renal chromophobe (2 TPM) carcinoma. PR expression was associated with improved OS in sarcoma (49 mo vs NR, p = .03), endometrial (NR, p = .02) and renal clear cell carcinoma (58 mo vs NR, p = .003) and worse OS in low grade glioma (53 vs 97 mo, p = .01), gastric adenocarcinoma (7 vs 17 mo, p = .04), and possibly pancreatic adenocarcinoma (21 vs 44 mo, p = .07). ER was highly expressed in breast (116 TPM), endometrial (87 TPM), ovarian (32 TPM), cervical (4 TPM), thyroid (4 TPM), prostate (3 TPM), and lung adenocarcinoma (2 TPM). ER expression was associated with improved OS in mesothelioma (15 vs 28 mo, p = .03) and endometrial cancer (NR, p = .001) and worse OS in squamous lung cancer (80 vs 48 mo, p = .02). Conclusions: HR expression may represent a novel prognostic marker in multiple tumor types and a candidate for drug development in low grade glioma, gastric adenocarcinomas, squamous cell lung cancer, and pancreatic adenocarcinomas. Protein-based IHC testing and early phase clinical trials targeting HR signaling in these tumor types is warranted.
FDA analysis of MRD data in hematologic malignancy applications.
Authors: Gormley Nicole , Bhatnagar Vishal , Ehrlich Lori A. , Kanapuru Bindu , Lee Hyon-Zu , McKee Amy E. , Farrell Ann , Pazdur Richard 
Published: September 2018

2541 Background: There is considerable interest in the use of minimal residual disease (MRD) in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval. Although surrogacy has not yet been established in most hematologic malignancies (except CML), MRD data has been submitted in applications to the agency to allow for further characterization of the product’s activity. Here we describe the new drug applications (NDA) or biologics licensing applications (BLA) that included MRD data and provide an analysis of the MRD data and the Agency’s decisions. Methods: The authors reviewed internal databases for all original and supplemental NDA and BLA applications submitted to the Division of Hematology Products (DHP) between 2014 and 2016 that pertained to malignant hematologic conditions. The applications were reviewed for inclusion of MRD data. The clinical reviews and prescribing information (PI) of the identified applications were reviewed for assessment of MRD data and FDA’s findings. Results: There were 34 NDAs or BLAs submitted between 2014-2016. Of these, 13 (38%) included MRD data, in the following diseases: CML, CLL, ALL, and MM. MRD data was added to the PI in 6 cases (46%), not included in 4 (31%), and was not proposed for inclusion in 3 (23%). Among the 6 cases in which MRD data was included in the PI, 5 used PCR testing and 1 used flow cytometry. Among the 4 in which MRD data was not included in the PI, the identified issues included: missing data among those in CR, incomplete test performance characteristics data (e.g.-limit of detection), disparate sample sources (blood, bone marrow), high amount of test failure rates (i.e.-inability to identify a clonal rearrangement), lack of test validation in the proposed disease setting, and inappropriate planned statistical analyses. Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.
Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.
Authors: Vidal Boixader Laura , Curtis Kelly Kevelin , Wahl Jim , Kenny Nicholas , Moss Keren Rachel 
Published: September 2018

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.
A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results.
Authors: Schmid Peter , Forster Martin David , Summers Yvonne J. , Good Jane , Sarker Shah-Jalal , Lim Louise , Mousa Kelly , Middleton Gary William 
Published: September 2018

2548 Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours and interact to promote tumour growth and therapeutic resistance. Activity of single pathway inhibition is limited due to compensatory activation of alternative signalling pathways. Dual pathway inhibition has demonstrated synergistic activity in preclinical models, with broad activity across a range of molecular backgrounds. This study was designed to evaluate the optimal doses and schedule of vistusertib (dual mTOR1/2 inhibitor) and selumetinib (MEK1/2 inhibitor) when given in combination. Methods: Thisphase Ib/IIa trial with a dose escalation part (Ib) in treatment refractory advanced solid tumours and expansion cohorts in TNBC, squamous and non-squamous NSCLC (KRASmt & WT) (IIa). Both, continuous daily (CC) (25, 35, 50mg BD) and intermittent (IC) schedules (50, 100, 125mg BD 2ds on, 5 ds off) of vistusertib were investigated. Selumetinib dose was given at a dose of 75mg BD daily. Treatment was given until PD (RECIST 1.1) or intolerable toxicity. The primary endpoint was DLTs. Secondary endpoints included response, clinical benefit, PFS and PK. Results: 23 evaluable patients were enrolled in the PhaseIb part. For the intermittent schedule, no DLTs were reported at any of the dose levels IC1-3. For the continuous schedule, 2 out of 9 patients treated at dose level C2C developed DLTs (G3 mucositis, dizziness and rash). Dose level C3C was not tolerated with DLTs observed in 2 out of 3 patients (G3 mucositis and G3 LFTs). Separate MDTs were determined for intermittent (I3C) and continuous schedules (C2C). Adverse events were in keeping with established single agent safety profiles. Anti-tumour efficacy was demonstrated at various dose levels and across tumour types including uveal melanoma, breast, cervical, uterine, skin or colorectal cancers. There were no objective responses but confirmed stable disease for > 16 weeks were observed in 7 patients with a duration of response ranging up to 55+ weeks. Conclusions: Based on DLTs, dose intensity and cumulative toxicity, the intermittent schedule I3C was selected as RP2D for expansion cohorts. Preliminary anti-tumour activity was observed. Clinical trial information: NCT02583542.
Population pharmacokinetics of durvalumab and fixed dosing regimens in patients with advanced solid tumors.
Authors: Baverel Paul , Dubois Vincent , Jin Chaoyu , Song Xuyang , Jin Xiaoping , Mukhopadhyay Pralay , Gupta Ashok Kumar , Dennis Phillip A. , Ben Yong , Roskos Lorin , Narwal Rajesh 
Published: September 2018

2566 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V1) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters < 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562.
A phase Ia study of CC-90003, a selective extracellular signal-regulated kinase (ERK) inhibitor, in patients with relapsed or refractory BRAF or RAS-mutant tumors.
Authors: Mita Monica M. , LoRusso Patricia , McArthur Grant A. , Kim Edward S. , Bray Gordon L. , Hock Nanette H , Laille Eric J. , Aronchik Ida , Filvaroff Ellen , Wu Xiaoling , Bendell Johanna C. 
Published: September 2018

2577 Background: CC-90003 is an irreversible inhibitor of ERK 1/2 with potent anti-proliferative activity in KRAS and BRAF mutant tumor models. We conducted a first-in-human study of CC-90003 in patients with RAS or BRAF mutant tumors. Methods: Patients received escalating doses of oral CC-90003 on a 21/28 day cycle. Standard safety (adverse events, chemistry/hematology, physical findings, ECGs and cardiac ECHO/MUGA scans) and PK parameters were assessed. Response was assessed per RECIST 1.1. A proprietary ELISA-based assay measured ERK levels unbound to CC-90003 in peripheral blood mononuclear cells. Results: Nineteen patients (median age: 60 yrs) harboring KRAS (n = 15), NRAS (n = 1), or BRAF (n = 3) mutant tumors received CC-90003 doses from 20 to 160 mg /day. The MTD was 120 mg based on the occurrence of Grade 3 transaminase elevations (n = 2) and hypertension (n = 1) observed at 160 mg (the NTD). Patients completed a median of 2 cycles (range: 1 to 5). AEs (mostly Grade 1 or 2) reported in ≥ 3 patients included constitutional (asthenia, fatigue), gastrointestinal (anorexia, nausea/vomiting, diarrhea), hepatic (transaminase elevations) and neurologic (dizziness, gait disturbance, paresthesias) toxicities. Grade 1-3 neurotoxicity was observed primarily at doses from 80 to 160 mg/day and resolved with dose reduction/interruption. PK parameters were highly variable, with AUC and Cmax increasing overall, with increasing dose. CC-90003 accumulation was observed after multiple doses. There were no objective responses. Levels of free ERK were reduced by ≥80% compared to baseline by C1D8 at doses ≥ 80 mg/day. Conclusions: ERK inhibition may be an attractive target for the management of mutant RAS or BRAF-driven tumors, however proof-of-concept demonstration for CC-90003 was limited by a lack of objective responses, an unfavorable PK profile and unanticipated neurotoxicity. Clinical trial information: NCT02313012.
SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173).
Authors: Algazi Alain Patrick , Moon James , Chmielowski Bartosz , Lo Roger , Kendra Kari Lynn , Lao Christopher D. , Lewis Karl D. , Gonzalez Rene , Kim Kevin , Godwin John E. , Curti Brendan D. , Othus Megan , Ribas Antoni 
Published: September 2018

2578 Background: Aberrant PI3K/AKT signaling in BRAF mutant cancers contributes to resistance to MAPK pathway blockade. We conducted parallel phase 1 dose escalation studies of the doublet of the BRAFi dabrafenib with the AKT inhibitor GSK2141795 and of the triplet of dabrafenib, the MEKi trametinib, and GSK2141795. Methods: Patients (pts) with BRAF-V600E/K mutant advanced solid tumors with adequate end-organ function were eligible regardless of prior BRAFi and MEKi exposure. All pts received dabrafenib at 150 mg twice daily (bid), in the doublet cohorts together with dose escalation (3 + 3 scheme) of GSK2141795 started at 50 mg daily (qd), and in the triplet cohorts with dose escalation of both trametinib starting at 1.5 mg qd and GSK2141795 starting at 25 mg qd. DLTs included significant grade 3 and 4 adverse events (CTCAE v4) within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. Results: No DLTs were observed in the doublet cohorts (N = 8) up to dabrafenib 150 mg bid and GSK2141795 75 mg qd. In the triplet cohorts (N = 11), no DLTs were observed at doses of up to trametinib 1.5 mg daily with GSK2141795 75 mg daily. At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash. 2/2 treatment-naïve in the doublet cohorts had PRs (1 melanoma and 1 thyroid) the latter lasting over 1 year. 1/6 BRAF inhibitor-refractory (melanoma) pts also had an objective response. In the triplet cohorts, 3 of 6 treatment-naïve pts had a PR (1 melanoma, 2 lung). One lung pt remains in PR at 2 months and the otherhas an uPR at 1.2 months. Conclusions: Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted. Funding: Supported in part by NIH/NCI grants CA180888, CA180819; and in part by Novartis Pharmaceuticals Corporation and GlaxoSmithKline, LLC. Clinical trial information: NCT01902173.