bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression, chronic pain, and high-impact chronic pain among cancer survivors.
Authors: Osazuwa-Peters Nosayaba , Polednik Katherine M. , Tutlam Nhial T. , Tait Raymond , Scherrer Jeffrey , Barnes Justin Michael , Schootman Mario , Adjei Boakye Eric
Published: June 2021

12085

Background: The majority of the 17 million individuals living with a cancer diagnosis in the United States have experienced pain, either from the disease itself or from its treatment. Pain negatively impacts psychosocial quality of life and is associated with poorer overall outcome. However, the impact of pain on daily living differ among cancer survivors, and there is a paucity of research on chronic pain, especially high-impact chronic pain (HICP) in this growing population. We estimated the prevalence of chronic pain, and HICP among cancer survivors, and described the association between depression and these outcomes. Methods: This study used data from the 2015-2017 National Health Interview Survey. Outcomes of interest were chronic pain, defined as pain on most days or every day in the past six months, and HICP, defined as chronic pain that limited life or work activities on most days or every day during the past six months. Weighted, adjusted multivariable logistic regressions estimated association between depression and chronic pain and HICP among cancer survivors, while controlling for age, gender, marital status, education, employment, health insurance, smoking status, number of doctor’s visit, general health, and comorbidities. Results: Among 49,326 survey respondents, 11.7% (n = 5,335) had a cancer diagnosis. An estimated 43.6% of cancer survivors reported chronic pain; and 19.2% reported HICP. We found an association between depression and both chronic pain and HICP in unadjusted analyses. In the adjusted models, cancer survivors depressed within the last month had more than double the odds of reporting both chronic pain (aOR = 2.32; 95% CI 1.75, 3.07) and HICP (aOR = 2.12; 95% CI 1.50, 3.01). Other factors associated with both chronic pain and HICP among cancer survivors included being a current smoker (aORchronic pain = 1.63; 95% CI 1.14, 2.34; aORHICP = 1.83; 95% CI 1.18, 2.84) and being unemployed (aORchronic pain = 1.44; 95% CI 1.10,1.90; aORHICP = 3.10; 95% CI: 2.00−4.81). Cancer survivors with ≥2 comorbidities also had 55% increased odds of reporting chronic pain (aOR = 1.55; 95% CI 1.17,2.04) compared with those without comorbidities. Conclusions: Over 40% of cancer survivors may have a history of chronic pain, and survivors reporting being depressed are significantly more likely to report both chronic pain and HICP. The association between depression and pain in cancer survivors calls for personalized management of chronic pain, especially in cancer survivors with a history of depression.
Neuropathy severity at the time of oxaliplatin treatment alteration in patients with colon cancer (Alliance A151912).
Authors: Hertz Daniel Louis , Dockter Travis , Satele Daniel V. , Loprinzi Charles L. , Le-Rademacher Jennifer
Published: June 2021

12090

Background: Clinical guidelines recommend altering chemotherapy treatment by decreasing, delaying, or discontinuing dosing in patients (pts) experiencing chemotherapy-induced peripheral neuropathy (CIPN). There are few data available on clinical use of treatment alteration including the severity of CIPN at the time of alteration. Our objective was to investigate the incidence of oxaliplatin treatment alterations and CIPN severity at that time. Methods: This was a retrospective analysis of pts with colon cancer scheduled to receive oxaliplatin-containing combination chemotherapy on the N08CB trial of intravenous calcium and magnesium for prevention of CIPN. Dose alterations were not mandated by the N08CB protocol. Clinicians assessed CIPN using NCI-CTCAE V.4.0; pts used the sensory subscale of the EORTC-QLQ Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN8). Pts were classified as 1) completed oxaliplatin treatment without alteration, 2) dose reduction or delay due to CIPN, 3) discontinuation due to CIPN, 4) discontinuation due to other AE, or 5) discontinuation for another reason. Comparisons focused primarily on pts with alteration due to CIPN (groups 2 and/or 3) compared with pts completing treatment without alteration (group 1) using chi-squared and Kruskal-Wallis tests. Results: In this analysis of 350 N08CB pts, 135 (39%) completed oxaliplatin without treatment alteration, 70 (20%) had a dose reduction (n=66) or delay (n=4) due to CIPN and 35 (10%) discontinued early due to CIPN. Pts who experienced alterations due to CIPN were younger (p=0.0249) and more likely to be female (p=0.008). Clinician-assessed CIPN severity was greater in pts at the time of dose reduction or delay compared with CIPN severity at the end of treatment in pts with no alteration (p<0.0001). Pt-assessed CIPN severity was not different in pts who completed treatment without alteration compared to pts who had a dose reduction or delay (p=0.88) or a discontinuation (p=0.37). CIPN8 scores at cycle 4 were higher (worse) in pts who eventually had any alteration (i.e., reduction, delay, or discontinuation) compared to pts who completed treatment without any alteration (median CIPN8 11.5 vs. 7.7, p=0.023). Conclusions: Treatment alterations due to CIPN are relatively common in pts receiving adjuvant oxaliplatin for colon cancer and are associated with clinician-assessed but not pt-reported CIPN severity. Rapid CIPN8 increases early in treatment are indicative of increased likelihood of a future oxaliplatin treatment alteration, indicating a potential use of early monitoring and intervention. Support: UG1CA189823; https://acknowledgments.alliancefound.org. Clinical trial information: NCT01099449 (NCCTG N08CB).
Patient-reported benefits and burdens of direct oral-anticoagulants (DOACs) and low molecular weight heparins (LMWHs): The CANVAS pragmatic randomized trial (AFT-28).
Authors: Schrag Deborah , Uno Hajime , Zattra Ottavia , Tramontano Angela , Rosovsky Rachel Pam Greenerger , Rutherford Cynthia , Sanfilippo Kristen Marie , Villano John L. , Drescher Monic R , Jayaram Nagesh H. , Holmes Chris E. , Feldman Lawrence Eric , Cronin Christine , Basch Ethan M. , Weiss Anna , Connors Jean ,   CANVAS Investigators
Published: June 2021

12112

Background: Previous randomized trials in cancer patients suggest that DOACs are non-inferior to LMWHs for preventing recurrent venous thromboembolism (VTE). However, patients’ perspectives have not been reported. Objective: CANVAS compared LMWHs to DOACs for preventing recurrent VTE in cancer patients. Key 2° endpoints were: 1) health-related quality of life (QOL); and, 2) treatment satisfaction. Methods: CANVAS was an unblinded hybrid comparative effectiveness non-inferiority trial. Between 12/2016 and 4/2020, 671 participants were randomized and followed for 6-months. Patients were assigned 1:1 to receive either a DOAC or a LMWH. Physicians could select any DOAC or LMWH at standard dosing, and patients assigned to LMWH were allowed to transition to Warfarin. Patients from 67 US practices with any invasive solid tumor, lymphoma, multiple myeloma or CLL and a diagnosis of VTE within 30 days of enrollment were eligible. The 1° analysis was conducted in the randomized modified intent-to-treat population, (all subjects who received assigned treatment). Key 2° endpoints were to establish: 1) non-inferior change in HR-QOL; 2) greater perception of benefit; and 3) lower perception of burden for participants receiving DOACs versus LMWHs. Participants reported QOL at 0, 3 and 6 months on the SF-12 survey. At 3 and 6 months, they also reported satisfaction via the Anti-Clot Treatment Scale (ACTS), which includes a burden and a benefit scale. A 2-point change was pre-specified as significant. Results: Neither QOL nor patients’ perceptions of treatment benefits differed between groups. However, patients on DOACs reported lower treatment burden compared to those assigned LMWHs. Conclusions: Among adult cancer patients with VTE, the use of a DOAC compared with a LMWH resulted in no difference in QOL but higher patient-reported satisfaction stemming from decreased perception of the burden of treatment. Clinical trial information: NCT02744092. [Table: see text]
Impact of COVID-19 pandemic on time to treatment initiation for patients with advanced cancer.
Authors: Takvorian Samuel U , Parikh Ravi Bharat , Vader Daniel , Wileyto E. Paul , Clark Amy Sanders , Lee Daniel J. , Goyal Gaurav , Rocque Gabrielle Betty , Dotan Efrat , Geynisman Daniel M. , Phull Pooja , Spiess Philippe E. , Kim Roger , Davidoff Amy J. , Gross Cary Philip , Miksad Rebecca A. , Calip Gregory Sampang , Shulman Lawrence N. , Mamtani Ronac , Hubbard Rebecca A.
Published: June 2021

1528

Background: The COVID-19 pandemic has disrupted US healthcare delivery and led to delays in life-prolonging therapy for some conditions. Its impact on diagnosis and timely care delivery for patients (pts) with cancer is unknown. We assessed the pandemic’s impact on time from advanced diagnosis to systemic treatment initiation (TTI) for pts with newly diagnosed advanced solid cancers. Methods: We performed a controlled interrupted time series analysis using the nationwide Flatiron Health electronic health record-derived de-identified database, which originated from ̃280 US cancer clinics. The study sample included pts ≥ 18 years diagnosed with advanced solid cancers from Jan 1-Jul 31 in 2019 or in 2020, excluding a 30-day period (Mar 8-Apr 7) encompassing the start of most state stay-at-home orders. We used Cox proportional hazards models to estimate standardized predicted probabilities of TTI within 30 days of advanced diagnosis before (Jan-Mar) and during (Apr-Jul) the pandemic in 2020, compared to historical controls in 2019, adjusted for age, sex, race, insurance, performance status, and cancer type. Interactions by cancer type and race examined heterogeneity of effects. Results: The study included 12,977 pts (median age 69 yrs [IQR 61-77]; 47.4% female; 59.4% non-Hispanic white). At the time of analysis, fewer advanced cancer diagnoses were recorded in 2020 (Jan-Mar 2,409; Apr-Jul 3,027) than in 2019 (Jan-Mar 2,910; Apr-Jul 4,631). Compared to Apr-Jul 2019, pts diagnosed with advanced cancer during the COVID-19 period were more likely to have de novo (vs recurrent) disease (67.3% vs 56.8%). In adjusted models, the COVID-19 period was associated with an increased probability of treatment within 30 days (adjusted difference-in-differences +5.2 percentage points [ppts]). TTI improvements were not observed for pts with advanced breast cancer or Black pts, but effect differences across subgroups were not statistically significant (Table). Conclusions: Among pts diagnosed with advanced cancer, the COVID-19 pandemic was associated with shorter time to systemic therapy initiation. These treatment patterns may reflect the fewer advanced cancer diagnoses and higher proportion of de novo cancers observed during this period. Longer follow-up and data maturity are needed to understand the impact of the pandemic on clinical outcomes.[Table: see text]
Utilization of preoperative breast MRI among women with newly diagnosed breast cancer.
Authors: Pan I-Wen , Yen Tina W.F. , Bedrosian Isabelle , Shih Ya-Chen T.
Published: June 2021

1546

Background: The use of preoperative (pre-op) breast MRI remains controversial. Current practice may rely on patient characteristics and providers’ clinical judgment. This national study examined factors associated with pre-op breast MRI among women with newly diagnosed breast cancer (BC) and explored sources of variations. Methods: We applied the Nattinger algorithm to identify women with incident BC diagnosed between Mar 2008 and Dec 2018 from OPTUM Clinformatics database. Patients who had 26 months of full enrollment, 14 months before and 12 months after the first (index) BC surgery, and no pre-op radiotherapy were included. We defined pre-op MRI as patients who had an MRI between the date of BC diagnosis and date of index surgery. We conducted multivariable logistic regression models to examine factors associated with pre-op MRI and performed separate analyses for elderly (age > = 65) and non-elderly (age < 65) women. Results: 61,865 women (non-elderly: 27,309, elderly: 34,556) were included in the analysis. The crude rate of pre-op MRI increased from 7.4% in 2008 to 14.6% in 2018 (p-value <.001). For the non-elderly, women who were older (adjusted rates: 60-64, 10% vs 20-49, 12.1%), had no distant metastasis (10.6% vs. 12.3% with metastasis), no neoadjuvant chemotherapy (9.9% vs 15.0% with neoadjuvant), and 2 or more comorbidities (9.0% vs. 11.1% with zero comorbidity) were less likely to undergo pre-op MRI (all p-value <.001). Compared to white women (adjusted rate 10.6%), African Americans were more likely to have pre-op MRI (12.7%, p <.001) and Hispanics were less likely (8.14%, P <.001). There was no association between Health Management Organization (HMO) status and receipt of pre-op MRI among non-elderly. For elderly women, older age, more comorbidities, no distant metastasis, and no neoadjuvant chemotherapy were similarly associated with less pre-op MRI use. There was no significant association between race and receipt of pre-op MRI. Moreover, elderly women with HMO insurance were less likely to receive pre-op MRI. In both age groups, we observed wide geographic variations, with significant interaction between census division and HMO enrollment among elderly group only (Table). Conclusions: The use of pre-op MRI nearly doubled from 2008 and 2018. In addition to demographic and clinical characteristics, regional practice pattern variations and insurance type played a key role in the receipt of pre-op MRI among newly diagnosed breast cancer patients. Future study to understand this phenomenon is warranted.[Table: see text]
Combining hematoxylin and eosin (H&E) stained images and RNA sequencing (RNA-Seq) data to predict overall survival (OS) in patients with non-small cell lung cancer (NSCLC).
Authors: Karrer Teresa M , Garmhausen Marius , Li Xiao , Jansen Gunther
Published: June 2021

1547

Background: IMpower150 was a phase 3 clinical trial that evaluated the efficacy of atezolizumab in patients with metastatic nonsquamous NSCLC; it demonstrated no significant OS benefit in the ACP (atezolizumab+carboplatin+paclitaxel) arm vs the BCP (bevacizumab+carboplatin+paclitaxel) control arm (hazard ratio [HR]=0.85; 95%CI, 0.71-1.03). The objective of this analysis was to identify a subpopulation of patients that benefits from ACP using H&E stained images and RNA-Seq data. Methods: Spatial statistics algorithms were applied to the coordinates of tumor cells and lymphocytes of the H&E stained images to capture spatial heterogeneity of the tumor microenvironment. The normalized and log-transformed RNA-Seq data underwent a nested feature selection procedure using a Cox proportional hazard model with L1 regularization and stability selection. Cutoffs for gene selection were determined using a permutation strategy with a false discovery rate <0.001. To investigate the association between the 41 derived spatial features, significant genes and OS, a Cox proportional hazard model with L2 regularization was fitted only for the ACP group. Survival groups were further identified using nested Monte Carlo Cross Validation to prevent over-fitting. Results: A total of 236 ACP and 235 BCP patients who had both H&E stained images and RNA-Seq data were analyzed. In the predicted long survival group, ACP patients had significantly longer median OS vs BCP patients based on H&E stained images (HR=0.61; 95%CI, 0.41-0.90; P=0.013) and RNA-Seq data (HR=0.64; 95%CI, 0.41-0.99; P=0.042). The combination of both modalities further improved the OS benefit between the arms (HR=0.44; 95%CI, 0.27-0.73; P=0.001). Data-driven selection of genes relevant for the prediction of OS included MAML3, AC024475.4, RGPD1, LCE3D and AC004156.1. Conclusions: Our approach was able to stratify a subpopulation of patients that significantly benefited from ACP compared with BCP treatment, particularly when integrating both H&E stained images and RNA-Seq data, which demonstrated the complementary value of both modalities. Our results could inform the development of a companion diagnostic that predicts individualized treatment response. Clinical trial information: NCT02366143.
Pre-screening as a tool for increasing oncology trial enrollment.
Authors: Wu Jennifer J. , Yakubov Amin , Abdul Hay Mohammad Maher , Love Erica , Kroening Gianna , Cohen Deirdre Jill , Spalink Christy , Joshi Ankeeta , Balar Arjun Vasant , Joseph Kathie-Ann P. , Ravenell Joseph , Mehnert Janice M.
Published: June 2021

1577

Background: Recruiting underserved patients onto therapeutic oncology trials is imperative in light of cancer disparities. Many institutions have increased enrollment with data mining tools that match patients to clinical trials, but such expensive tools are unavailable in a public safety net healthcare system. Methods: The NYU Perlmutter Cancer Center Clinical Trials Office implemented a quality improvement program aimed to increase therapeutic trial enrollment at Bellevue Cancer Center (BCC), an affiliated public hospital. The initiative utilized one employee to manually pre-screen patients via the EMR, cancer registries, and conferences. The program aimed to identify eligible patients for therapeutic trials and those subsequently enrolled. Results: During the two years preceding the pre-screening program, 31 patients were enrolled onto therapeutic clinical trials at BCC. For a period of two years (7/2017-7/2019) following the initiation of this program, 255 patients were identified, of which 143 (56.1%) enrolled onto trials. Of those enrolled, 55 were referred to NYU for trials not open at BCC. Among the 143 enrolled patients, 64% were female, 56% were non-white, and 57% did not speak English (spanning 16 languages). The median age was 55, and the top three disease groups were breast, GI, and thoracic. 83% of our patients reside in low-income areas, with 62% in both low income and Health Professional Shortage Areas (HPSA). Conclusions: Dedicating one employee to screening led to a 4.6 fold increase in accruals, successfully augmenting therapeutic trial enrollment in a healthcare setting with scarce resources, providing broader access to clinical trials for underserved populations.[Table: see text]
Cancer patient satisfaction with telehealth: Survey results from a large NCI-designated cancer institute.
Authors: Natesan Divya , Niedzwiecki Donna , Oyekunle Taofik , Emmons Aviva , Zafar Yousuf , Blitzblau Rachel
Published: June 2021

1579

Background: Telehealth (TH) utilization for patients at our cancer institute increased in 2020 in response to the COVID-19 pandemic, however oncology-specific TH patient satisfaction is unknown. Methods: Monthly TH utilization at a single large NCI-designated institute from 3/1/2020-11/30/2020 was reviewed. Utilization was calculated as chargeable TH visits (new video, established video, phone) as a proportion of all consult/follow up visits. Patient satisfaction surveys for oncology TH visits for MD/PA/NP providers were reviewed from 4/1/2020-11/30/2020. Surveys were sent after every TH visit, unless the patient had a prior visit in the past 3 months. Percent (%) top box score (TBS) was defined as proportion of responses in the highest possible response category (i.e. very good). % TBS was reported for 14 survey items in 4 domains: technology, access, care provider (CP), and overall assessment. Satisfaction was assessed over time and according to patient factors: generation, gender, insurance type, employment status, and clinic site. The Cochrane-Armitage trend test was used to compare proportions of TBS responses across monthly time points. Results: TH comprised 21% (22,055/103,461) of all encounters in the study period. TH use increased from 9% in 3/2020 to a peak of 47% in 4/2020. In 11/2020, TH use was 18%. 28.0% (2,286/8,173) of TH patient surveys were returned. Multiple patient satisfaction metrics were improved over time (Table). Patients had higher satisfaction with phone compared to video visits with regards to technology (86% vs 76%) and access (80% vs 72%). Millennials (born 1981-1995) had higher satisfaction with access to TH (87%) compared to Gen X (1965-1980) (77%), Baby Boomer (1946-1964) (74%), and Silent Generation (1928-1945) (72%), however all generations had similar levels of satisfaction with technology (range 77-80%). Disabled patients had higher overall satisfaction of TH (82%) versus those working full time or retired (71%). Patients with commercial insurance had worse overall satisfaction of TH compared to other insurance types (65% vs 72%). Patients with encounters in genitourinary, thoracic, and endocrine oncology clinics had the highest levels of overall satisfaction (75%) compared to other clinics (69%). There were no observed differences in TH satisfaction according to gender. Conclusions: TH cancer patient satisfaction is high and has improved over time, however satisfaction differs by patient demographics. Further data are needed to best select patients appropriate for TH.[Table: see text]
Telehealth: Reducing or increasing cancer care disparities?
Authors: Jewett Patricia , Vogel Rachel I. , Ghebre Rahel G. , Rao Arpit , Hui Jane Yuet Ching , Parsons Helen , Blaes Anne Hudson
Published: June 2021

1582

Background: During the COVID-19 pandemic, most cancer care in the United States transitioned to telehealth (phone or video visits) to reduce infection risks for patients and providers. Telehealth may simplify care logistics (e.g. reduce travel and waiting times), but it may also unintentionally exacerbate existing disparities in healthcare utilization by race/ethnicity, age, or rural/urban status. As telehealth will likely continue long-term, we examined telehealth use at a comprehensive cancer center during the COVID-19 pandemic across patient populations with established disparities in cancer treatment and outcomes. Methods: We retrospectively reviewed telehealth visits from March until December 2020 among individuals diagnosed with cancer at the University of Minnesota Masonic Cancer Center (MCC). We used Chi-squared tests and GEE logistic regression to compare video vs. phone visits by age, urban/rural status, and race/ethnicity (American Indian / American Native [AIAN], Asian, Non-Hispanic Black/African American [NH Black/AA], Hispanic, Multiple, Native Hawaiian / Pacific Islander [NHPI], NH White). Results: Over the study period, 42,171 telehealth visits were performed with 11,097 patients at the MCC. Patients had a mean age of 62.7±13.9 years; 59.2% were female; 88.7% lived in urban areas; 90.0% of patients were NH White, 4.4% NH Black/AA, 3.0% Asian, 1.5% Hispanic, 0.8% AIAN, 0.3% of multiple races, and 0.1% NHPI. The most common cancer sites were breast (24.1%), hematological (21.0%), gynecologic (10.0%), and lung (8.4%). NH White individuals were more likely (53.9%) to use video than AIAN (39.7%), Black/AA (37.8%), or NHPI individuals (34.9%). Video use was less common among rural (45.3%) than urban (53.7%; p<.0001) residents, and among individuals aged 65 or older (45.2%) vs. younger than 65 (59.5%; p<.0001). In a logistic regression, adjusted for continuous age and urban/rural status, all race/ethnic groups except Multiple were less likely to use video than NH White individuals (vs. phone; Table). Conclusions: Our findings underscore disparities in telehealth use for cancer care across historically underserved populations. Future research should evaluate potential underlying contributors to these disparities such as technology access, internet capability, and fear of discrimination. Additional research is also needed to determine whether video vs. phone visits affect cancer outcomes, therefore indicating true disparity.[Table: see text]
Evaluating the benefit of adaptive randomization in the CC-115 arm of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A phase II randomized Bayesian adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma.
Authors: Rahman Rifaquat , Trippa Lorenzo , Fell Geoffrey , Lee Eudocia Quant , Arrillaga-Romany Isabel , Touat Mehdi , Drappatz Jan , Galanis Evanthia , Ahluwalia Manmeet Singh , Colman Howard , Nabors Louis B. , Hepel Jaroslaw T. , Schiff David , Welch Mary Roberta , Meredith David M. , Chiocca E. Antonio , Reardon David A. , Ligon Keith L. , Alexander Brian Michael , Wen Patrick Y.
Published: June 2021

2006

Background: Adaptive randomization adjusts enrollment rates based upon early trial results, which can allow for decreased enrollment for therapies less likely to meet the primary endpoint of a trial. CC-115, a CNS-penetrant, oral inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK), was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. As CC-115 was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio, we sought to investigate the impact of adaptive randomization in its testing. Methods: In INSIGhT, adults with newly diagnosed MGMT-unmethylated glioblastoma and available genomic data are adaptively randomized to an experimental arm or the control arm of standard radiotherapy with concurrent and adjuvant temozolomide. Patients randomized to CC-115 received it (10mg po BID) with radiotherapy and as adjuvant monotherapy, and a safety lead-in 3+3 design was used for this arm. By simulating the INSIGhT trial with standard uniform randomization, we estimated the reduction of enrollment rate and sample size of the CC-115 arm that was attributable to adaptive randomization. Results: Twelve patients were randomized to CC-115; 58% (n = 7) patients had possible treatment-related CTCAE grade > 3 toxicity. Compared to the control arm, there was no significant difference in progression-free survival (PFS, HR 0.66, 95% CI 0.32-1.36, p = 0.3) or overall survival (OS, HR 0.93, 95% CI 0.43-2.03, p = 0.8). Based on early PFS results, randomization probability to CC-115 decreased from 25% to 16%. At the time of the CC-115 arm closure, 14% of enrolled INSIGhT patients had been randomized to this arm. Compared to average expected enrollment by standard randomization, the use of adaptive randomization decreased the number of patients randomized to CC-115 by 50% (12 patients vs. 18 patients [95% CI 11-25 patients]). Conclusions: The INSIGhT trial, designed with adaptive randomization, facilitated more efficient testing of CC-115 and decreased the number of patients allocated to the CC-115 arm relative to a standard randomization design. Clinical trial information: NCT02977780.
Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI).
Authors: Ducray Francois , Sanson Marc , Chinot Olivier L. , Fontanilles Maxime , Rivoirard Romain , Thomas-Maisonneuve Laure , Cartalat Stephanie , Tabouret Emeline , Bonneville-Levard Alice , Darlix Amelie , Ameli Roxana , Meyronet David , Gueyffier Francois , Remontet Laurent , Maucort-Boulch Delphine , Dehais Caroline , Honnorat Jerôme ,   POLA Network
Published: June 2021

2007

Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies. Clinical trial information: NCT03561870.
The efficacy and clinical survival outcome of different first-line treatments in EGFR-mutant non-small cell lung cancer with brain metastases.
Authors: Wang Huijuan , Xing Ruyue , Zhang Mina , Zhang Xiaojuan , Yang Jinpo , Li Mengmeng , Ma Zhiyong
Published: June 2021

2028

Background: Brain metastasis is one of the most important factors for poor prognosis of lung cancer, and the incidence of brain metastasis in EGFR-mutant(m+) advanced NSCLC is more common. The first-generation EGFR TKI is a standard first-line treatment. The purpose of this study is to explore the best method for EGFRm+ NSCLC with brain lesions, and to find out correlative factors influencing survival outcome. Methods: The clinical data of NSCLC with brain metastases was retrospectively analyzed. All patients had received 1st generation EGFR TKI, and patients were divided into 4 group, group A : EGFR TKI monotherapy, group B: EGFR TKI plus chemotheapy(CT),Group C:EGFR TKI plus bevacizumab, group D :EGFR TKI plus CT plus bevacizumab.The efficacy of intracranial and extracranial lesions and survival outcome were analyzed. Results: A total of 584 EGFRm+ advanced NSCLC patients from December 2017 to May 2020 were screened,and 228(39%) had brain metastasis at baseline in the treatment-naive. Among them, 194pts had complete medical record and follow-up data. At the follow-up date (January 1, 2021), 147pts had disease progressed and 78pts had died. Intracranial PFS of group A,B,C,D were 11.1m(n = 97), 11.3m(n = 59)，21.2m(n = 19), and 18.9m(n = 19), respectively. No difference was found between A and B group (P = 0.745), so as C and D group (P = 0.684).But, the intracranial PFS of group C+D(with bevacizumab) was significantly longer than group A+B(11.3m (95%CI 12.2-14.8) vs 21.0m (95%CI 15.2-22.7), P = 0.007).The extracranial PFS of groups A, B, C, and D were 11.0m, 14.3m, 21.7m, and 18.9m, respectively,and the P value were 0.006, 0.002, and 0.011, respectively when compared with group A. The mOS of groups A,B were 27.8m and 24.2m,respectively, but group C and D had not yet reached. The intracranial ORR of group A, B, C, and D were 17.9% (14/78), 37.3% (19/51), 60.0% (9/15), and 66.7% (10/15), respectively. The extracranial ORR were 48.5% (47/97), 81.1% (43/53), 73.7% (14/19), and 73.7% (14/19),respectively. Conclusions: For EGFR-mutant NSCLC with brain metastases, the first-generation EGFR-TKI plus bevacizumab can significantly improve the efficacy of intracranial lesions, delay the progression of intracranial lesions, and prolong suvival time, Although the first-generation EGFR-TKI plus CT could improve extracranial ORR when compared with ERGF-TKI monotherapy, it has limited efficacy on intracranial lesions and could not increase survival time.
ATRXLoss to impair glioma stem cell viability and self-renewal via proton radiotherapy induced necrosis.
Authors: Garces Angel Adrian , Bronk Lawrence , Bhat Krishna , Grosshans David R
Published: June 2021

2046

Background: Glioblastoma Multiforme (GBM-Grade IV) is the most aggressive form of glioma in the USA carrying only a 15 month median survival time. Although IDH1R132H is traditionally associated with improved glioma patient survival and clinical response to chemotherapy, astrocytoma (LGG) patients also harbor ATRXLoss, an inactivation of the ATRX chromatin remodeling protein shown to impair DNA damage repair via non-homologous end joining. The recent discovery of glioma stem cells (GSCs), a subpopulation of chemoradioresistant, self-renewable, tumor initiating cells known to promote tumor recurrence, presents a new target for therapeutic intervention. However, the mechanisms by which ATRXLoss contributes to GSC proton radiotherapy (PRT) sensitivity, a more tumor specific and cytotoxic form of radiation therapy than conventional X-rays (XRT), are not well understood. We hypothesize that ATRXLoss impairs GSC post-radiation viability and self-renewal capacity by promoting necrosis to a higher extent after PRT than XRT. Methods: Isogenic TS543-ATRXWT and TS543-ATRXLoss patient derived glioma cells were cultured as neurospheres and treated with 2-8 Gy XRT or PRT. GSC viability was quantified using the CellTiterGlo 3D assay 12 days after irradiation. The Annexin V apoptosis and necrosis assay was conducted every 8 hours up to 72 hours after irradiation. GSC self-renewal, based on neurosphere formation frequency, was quantified using extreme limiting dilution analysis (ELDA). Results: ATRXLoss significantly decreased TS543 GSC viability after 2-8 Gy radiation therapy compared to ATRXWT (Unpaired t-test with Welsh’s correction and Holm-Sidak’s Multiple Comparisons Test p<0.0001). TS543-ATRXLoss also significantly inhibited GSC self-renewal over TS543-ATRXWT when subject to either 6 Gy PRT or XRT (Pairwise Pr(>χ2)<0.01). Interestingly, PRT significantly reduced GSC viability to a higher extent than XRT in both TS543-ATRXWT and TS543-ATRXLoss, which demonstrates the effectiveness of PRT to treat ATRXLoss gliomas. Follow up studies confirmed that ATRXLoss sensitizes TS543 GSCs more extensively to the cytotoxic effects of PRT compared to XRT via the upregulation of necrosis at 72 hours post-irradiation (Two-way ANOVA with Tukey’s post-hoc Multiple Comparisons Test p<0.0001). Conclusions: We conclude that ATRXLoss substantially contributes to PRT sensitivity in GSCs, thereby supporting the benefits of PRT for astrocytoma patients. Our future experiments will further elucidate the biological mechanisms by which ATRXLoss confers PRT sensitivity, especially via dsDNA damage.
Evaluation of GM-CSF and AS01B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM).
Authors: Wen Patrick Y. , Reardon David A. , Forst Deborah Anne , Lee Eudocia Quant , Iwamoto Fabio Massaiti , Diaz-Mitoma Francisco , Anderson David E , Lassman Andrew B.
Published: June 2021

2047

Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We enrolled a total of 20 patients with KPS at least 70 and first recurrence of GBM into 2 arms of the Phase IIa extension of gB/pp65 enveloped virus-like particles (eVLPs) adjuvanted with either GM-CSF given intradermally or with AS01B given intramuscularly (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Results: 10 patients (6 women, 4 men) with a median age of 58 (33-67 yrs) were enrolled into the GM-CSF arm and 10 patients (3 women, 7 men) with a median age of 65 (40-67) enrolled into the AS01B arm. Disease control rates of 40% and 50% were observed in the GM-CSF and AS01B arms, respectively, with 2 sustained PRs in the GM-CSF arm. The 6-month OS rate for the GM-CSF arm is 80% and is estimated to be comparable for the AS01B arm. CMV-specific CD4+ effector memory T cells may correlate with tumor responses in both arms of the study, with AS01B boosting higher frequencies of these cells regardless of baseline CD4/CD8 ratio. Conclusions: These encouraging results from both arms of the trial justify further clinical evaluation in a randomized, controlled trial expected to begin later in 2021. Clinical trial information: NCT03382977.
Impact of circulating tumor DNA (ctDNA) detection on survival outcomes of patients (pts) treated with immune-checkpoint inhibitors (ICIs) in early clinical trials.
Authors: Galvao Vladimir , Matos Ignacio , Moreno Ana , Alonso Guzman , Brana Irene , Villar Maria , Saavedra Santa Gadea Omar , Oberoi Honey Kumar , Ros Javier , Berche Roger , Ann Wornham Natassia , Arenillas Carlota , Saura Cristina , Oaknin Ana , Felip Enriqueta , Muñoz-Couselo Eva , Elez Elena , Tabernero Josep , Toledo Rodrigo , Garralda Elena
Published: June 2021

2542

Background: Detection of ctDNA is a promising tool for managing pts in oncology. Most methods require whole-genome sequencing of tumor samples followed by the design of personalized panels for tracking purposes. In this work, we evaluated the prognostic and predictive value of total ctDNA quantification, using shallow whole-genome sequencing (shWGS) exclusively from plasma samples, in a prospective cohort of pts treated with ICIs in early clinical trials. Methods: IchorCNA pipeline was used to quantify ctDNA of shWGS from plasma ctDNA samples of pts treated with ICIs in phase 1 trials, collected at baseline and prior to cycle 2 (prec2). We investigated the association and correlation of ctDNA levels with surrogate markers for tumor burden (LDH levels, summatory of target lesions (TL), liver metastasis) using Spearman and Kruskal-Wallis tests. Kaplan-Meier estimates of overall survival (OS) of pts with baseline detectable ctDNA levels versus undetectable ctDNA were calculated. A multivariate Cox proportional hazards model, including continuous classical prognostic factors (LDH, albumin, hemoglobin, derived Neutrophil-to-Lymphocyte ratio (dNLR), platelets, number of metastases sites, ECOG PS) and ctDNA was performed. An estimate of progression free survival (PFS) of pts with ctDNA increase levels in preC2 versus a non-increase group was evaluated. Results: Since January 2018, 113 pts with no standard-treatment options were included. Median (m) follow up was 14.8 months (mo). Baseline ctDNA levels correlated significantly with baseline TL (R = 0.4, p < 0.001) and LDH levels (R = 0.61, p < 0.001). Pts with liver metastasis had higher levels of ctDNA (11,68 ng/ml) versus pts with no liver disease (2,31 ng/ml) (p < 0,001). In the survival analysis pts with detectable baseline ctDNA (74 pts) had significantly shorter OS compared with pts with undetectable ctDNA (39 pts); median 9.6 m (8.4 – 16.4) and NA m (13.6-NA), respectively (HR = 2.25 [1.18-4.29] p < 0.01). In the multivariate analysis, only ctDNA and albumin levels maintained the impact in OS (HR = 1.03, p < 0.05 and HR = 0.22, p < 0.05, respectively). Pts with early increases in ctDNA had a shorter PFS compared with those with a stabilization or decrease, median 1.9 m (1.6 – 4.0) and 3.0 m (2.6 – 3.8), respectively (HR = 2.19 [1.31-3.67], p < 0.01). Conclusions: Quantification of baseline ctDNA using shWGS is a strong independent prognostic factor. Early dynamic changes of ctDNA could be a useful tool to predict PFS outcomes.
Phase 1A clinical trial of the first-in-class fascin inhibitor NP-G2-044 evaluating safety and anti-tumor activity in patients with advanced and metastatic solid tumors.
Authors: Chung Vincent , Jhaveri Komal L. , Von Hoff Daniel D. , Huang Xin-Yun , Garmey Edward Graeme , Zhang Jillian , Tsai Frank Yung-Chin
Published: June 2021

2548

Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]
Targeting innate immunity with BXCL701 in combination with pembrolizumab in patients with advanced solid cancers: Phase 2 basket study.
Authors: Karakuzu Ozgur , Tsimberidou Apostolia Maria , Holley Veronica R. , Adat Abha , Patel Sapna Pradyuman , Sood Anil K. , Conley Anthony Paul , Urschel Gabriele E , Healey Diane I. , O'Neill Vincent , Janku Filip
Published: June 2021

2558

Background: BXCL701 is an oral competitive inhibitor of dipeptidyl peptidases (DPPs), primarily DPP8/9, which triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods: This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1-14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to an immune checkpoint inhibitors (iCPI) naïve cohort and iCPI pretreated cohort. Each cohort is planned to enroll 9 patients in the first stage, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients in the second stage. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results: As of February 11, 2021, 16 patients were treated; 5 patients (prostate cancer, endometrial cancer, liposarcoma, basal cell carcinoma, squamous cell carcinoma of unknown primary) were enrolled in the iCPI naïve cohort and 11 patients (leiomyosarcoma [2], squamous cell carcinoma of unknown primary, triple negative breast cancer, uveal melanoma, melanoma, uterine myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to iCPI pretreated cohort. Among all 16 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701, which resulted in implementation of risk-mitigation strategies such as gradual dose escalation and blood pressure monitoring. In the CPI naïve cohort, of 4 patients with available imaging, 1 had a PR (microsatellite stable endometrial cancer [-62%]) and 1 durable stable disease (SD -10%, basal cell carcinoma on therapy for 6+ months). In the CPI pretreated cohort, of 9 patients with available imaging, 1 had a PR (-31%, uveal melanoma) and 3 durable SD (-22%, pleomorphic sarcoma on therapy for 8+ months; +4%, squamous cell carcinoma of unknown primary on therapy for 6 months; +5%, uterine myxoid sarcoma on therapy for 6 months). Conclusions: BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Prespecified efficacy endpoints were met in the first stage and both cohorts will proceed to second-stage of the study Clinical trial information: NCT04171219.