bluuebunny/crossref_metadata_2025 huggingface dataset:
MSK eConsent: Digitalizing the informed consent process to improve participant engagement and understanding.
Authors: Buckley Michael T. , Lengfellner Joseph M. , Koch Matthew J. , Search Benjamin , Hoidra Carol , Lin Mary , Kundu Sangeeta , Cambria Roy , O'Shea Molly , Galle Jesse , Wang Jennifer , Rodavitch Ann , Yataghene Karima , Pember Jaclyn , Terzulli Stephanie Lucia , Houston Collette , Cottington Eric , Sabbatini Paul
Published: May 2020

2066

Background: eConsent was developed to digitize the research participant consenting experience with an educational engagement model. The eConsent platform tiers consent document content in an easy-to-navigate format, using videos, images, and access to supplementary information. We hypothesize that enhancing the consenting experience improves participant engagement and comprehension. Methods: Here we present two projects: 1) qualitative assessment of patient engagement in the eConsent process using a standardized 5-question survey sent to all patients who used it during 9 months in 2019, and 2) a report of our preliminary findings from exempt protocol, Assessing Participant Engagement and Protocol Education in the Consent Process (X19-055) that quantitatively compares paper and electronic consenting and a) assesses patient agency and b) tests comprehension of key consent elements in 2 protocols: Storage and Research Use of Human Biospecimens (06-107) and Genomic Profiling in Cancer Patients (12-245). Results: 1) 940 patients completed the qualitative experience survey (27% response). Most respondents (777; 83%) indicated that electronic consenting was very easy (371) or easy (406) to use. Only 25 (3%) said electronic consenting was somewhat difficult to use, 3 indicated it was difficult (0.3%), and 64 were neutral. Most (896; 95%) recommended electronic consenting to other MSK patients. Those who reported a 1 unit increase in technology discomfort, only reported a .48 unit increase in eConsent discomfort ( P< .001). 2)Quantitative 10-question electronic tests were sent to each patient’s portal account within 72h after consenting via paper or eConsent to protocols 06-107 and 12-245. To date, for 06-107: 18 paper consenters completed the test with a score of 76% vs 23 eConsent users who scored 80%. For 12-245: 43 paper consenters scored 69% vs 13 eConsent users scoring 80%. Scores are a surrogate marker for patient comprehension and show that 12-245 protocol participants’ average testing scores are higher when participants are consented with eConsent vs paper (P < .01). 06-107 protocol participants’ average test scores are trending toward eConsent improving patient understanding ( P= .11). We will follow this trend as our sample size increases to a total of 500 participants. Patient agency questions received favorable responses from most patients (100%-84%). Conclusions: eConsent enhances participant engagement and understanding and does not impose a digital burden on participants.
A prospective trial of standard versus multimedia counseling in patients undergoing endometrial cancer surgery.
Authors: Tucker Katherine , Sullivan Stephanie , Allman Katie , Cuaboy Luz , Gehrig Paola A.
Published: May 2020

2067

Background: A patient’s understanding of surgery is often limited, especially in the setting of complex oncologic procedures. A recent review found that interventions such as the use of written materials, videos, and websites, improve patients’ knowledge of the procedure and their satisfaction with decision making. We sought to determine if a video-based approach in patients undergoing robotic endometrial cancer staging improves satisfaction with perioperative counseling. Secondary objectives were physician satisfaction, patient comprehension, and visit length. Methods: From 2018-2019, patients were randomized to standard physician education or multimedia-based education, which included watching two novel animated videos followed by focused physician counseling. Basic demographic information was collected. Patient satisfaction was assessed using the Client Satisfaction Questionnaire-8 (CSQ-8, a validated satisfaction survey, scored 8-32) and a global satisfaction score (10-point scale). Physician satisfaction was assessed using a global satisfaction score. Comprehension was assessed with a 9 question survey at 3 time points. Descriptive statistics were used to compare groups. Results: Of 76 patients randomized, the majority were Caucasian (68%), 50-70 years old (70%), and had at least some college education (75%). Most patients had undergone prior surgery (83%) and one fourth had a prior cancer diagnosis. Demographic variables and surgical history were similar between groups. The video patients reported higher satisfaction on the CSQ-8 (31.57 ± 1.02 vs 30.62 ± 2.09, p < 0.05) and global satisfaction score (9.95 ± 0.23 vs 9.74 ± 0.55, p < 0.05). There was no difference in comprehension scores between groups at either the initial or postoperative visit. At the time of surgery, comprehension scores were higher in the standard education group compared to the video group (p < 0.01). There was no difference in physician satisfaction between groups. Among the video group, there was improvement in physician satisfaction between the first and second half of patients enrolled (p < 0.05). There was no difference in visit length. Conclusions: While multimedia education improved patient satisfaction in the preoperative setting, this was not clinically significant. Provider satisfaction improved over time with the use of a video aid. Multimedia education may be implemented in perioperative counseling based on provider preference and consideration should be made for further study of satisfaction after the initial implementation period. Clinical trial information: NCT03899441.
The association between drug industry payments and NCCN guideline panel membership.
Authors: Mitchell Aaron Philip , Mishra Akriti A. , Dey Pranammya , Curry Michael A. , Trivedi Niti A. , Haddadin Michael , Rahman Mohammed , Winn Aaron N , Dusetzina Stacie , Bach Peter
Published: May 2020

2068

Background: The high frequency of financial relationships between the pharmaceutical industry and influential oncologists who author clinical practice guidelines may influence guideline recommendations. Therefore, we assessed the financial relationships held by NCCN Guidelines panelists before and after joining the panel, compared to those held by a matched set of oncologists. Methods: Membership of NCCN Guidelines panels for the 20 most common cancers was obtained from archival guidelines and linked manually to Open Payments records of industry payments. We identified physicians who newly joined an NCCN panel during the August 2013-December 2018 study period, and we included medical oncologists who had at least 1 year of Open Payments data before and after joining. These medical oncologists who joined an NCCN panel (panelists) were matched 1:2 to medical oncologists with the same gender, institutional affiliation, and medical school graduation year, who did not join an NCCN panel (non-panelists). The dollar value of industry payments was then calculated over the 1 year before (pre-join) and after (post-join) the date that each panelist joined. We used generalized linear models to assess differences in industry payments between the panelists and matched non-panelists in the pre-join period. We used difference-in-difference estimation (DiD) to assess whether joining an NCCN panel was associated with increased payments in the post-join period. Results: There were 54 panelists and 108 non-panelists (matched from 1447 eligible oncologists at NCCN institutions). Mean per-oncologist payments among panelists were greater than non-panelists in the pre-join period ($11,259 vs $3,427, p = 0.02). From the pre-join to post-join period there was a similar increase in mean per-oncologist payments among panelists and non-panelists ($2,236 vs. $1,569, DiD estimate +$667, p = 0.77). Conclusions: Medical oncologists who were selected to an NCCN Guidelines panel had greater financial ties to industry compared to peer oncologists who were not selected. This difference was present prior to joining; oncologists did not experience a greater increase in financial payments from industry in the 1-year period after joining an NCCN panel. These results suggest an opportunity to reduce the potential influence of industry in oncology clinical practice guidelines through the selection of guideline panelists with fewer ties to industry.
Reliability and correlations among quality measures for lung, breast, and colorectal cancer.
Authors: Cleveland Jessica , Landrum Mary Beth , Wright Alexi A. , Brooks Gabriel A. , Zubizarreta Jose , Keating Nancy Lynn
Published: May 2020

2073

Background: Alternative payment models for oncology seek to improve quality and reduce spending. Yet the ability to measure high-quality care across oncology practices remains uncertain. We characterized quality of care for oncology practices using registry and claims-based measures of processes, utilization, end-of-life care, and survival and assessed correlations of practice-level performance across measure type and cancers. Methods: Using SEER-Medicare data, we studied individuals with newly diagnosed lung (N = 95,635), breast (N = 78,736), or colorectal (CRC, N = 51,385) cancers in 2010-2015 treated in oncology practices with ≥20 patients (502, 492, and 347 practices, respectively). We measured receipt of guideline-recommended treatment and surveillance (processes), hospitalizations or emergency department visits during 6-month chemotherapy episodes (utilization), care intensity in the last month of life (EOL), and 12-month survival (lung and CRC only). We calculated summary process, utilization, and EOL measures for each patient (number of measures met divided by the number for which the patient was eligible). We used hierarchical linear models with practice-level random effects to estimate summary measures and survival for each practice. We calculated practice-level reliability (a measurement’s reproducibility) for each measure based on the between-measure variance, within-measure variance, and sample size. Results: Few practices had ≥20 patients eligible for most measures (38%, 37%, and 31% of practices had ≥20 patients for any lung, breast, and CRC measures, respectively). Measure reliability was low. Only 13%, 7%, and 20% of measures for lung, breast, and CRC, respectively, had a median reliability across practices ≥0.7. Among practices with ≥20 patients with summary measures of each type within cancer, correlations across measure types were low (all correlation coefficients (r)≤0.21 except a weak correlation of the CRC process summary measure with 1-year CRC survival, r = 0.38, p < 0.001). Summary process measures were minimally or not correlated across cancer type (lung, breast, CRC; all correlation coefficients ≤0.16). Conclusions: Claims-based measures of care processes, utilization, EOL care, and survival are limited by small numbers of fee-for-service Medicare patients across practices, even after pooling 6 years of data. Measures have poor reliability and are poorly correlated across measure or cancer type. Additional research is needed to identify reliable quality measures for practice-level alternate payment models.
TeleTriage at a high-volume specialty cancer center: Aligning patient volume and need with available resource.
Authors: Robin Stutman E , Napoli Jason , Duggan Erika , Joseph Danny , Dawson Eoin , Mohabir Rennie , Erickson Lee , Otto Christian , Groeger Jeffrey S.
Published: May 2020

2085

Background: The Memorial Sloan Kettering (MSK) Urgent Care Center (UCC) functions as the emergency room for MSK. With 23,000+ visits annually, increasing volume and acuity means more days over capacity. Patients experience increased wait times to see clinicians, complete evaluation, and transfer to an inpatient bed. The UCC TeleTriage Program is a remote triage program which aims to align patient volume and need with available resources, improve patient experience, and streamline flow through the UCC. By managing resources more efficiently and expediting initial evaluation, the program promotes timely patient access to care, while maintaining MSK's standard of care. Methods: UCC TeleTriage began July 2018 with the Gastrointestinal Medical Oncology service. The Service Nurse refers patients to TeleTriage on weekdays, from 9a.m.- 4:30p.m. The TeleTriage clinician contacts each patient within 30 minutes of referral, takes the history, and determines the initial plan. Patients are directed to a local ER, clinic, or UCC based on level of acuity, real-time GPS, and specific need. For stable patients coming to UCC, TeleTriage focuses on initiating testing prior to registration in UCC. Results: TeleTriage patients have (virtual) contact with a UCC clinician within 30 minutes of referral, whereas non-TeleTriage patients wait 110 minutes or more. TeleTriage patients are discharged from UCC up to 42 minutes more rapidly. TeleTriage patients who receive imaging prior to registration in UCC receive a final disposition up to 93 minutes sooner. About 4% of TeleTriage patients are managed at home. In a small number of TeleTriage patients with severe complications of cancer-treatment, significant morbidity was avoided due to early intervention and coordination of care. Conclusions: TeleTriage patients have contact with a UCC clinician measurably faster than non-TeleTriage patients. Their evaluation is also started earlier. By managing less acute patients at remote sites or at home, TeleTriage can help patients avoid unnecessary travel, (time) expenditure, and hospital contact. TeleTriage patients who come to UCC, spend less time in UCC than non-TeleTriage patients and they discharge faster. By utilizing cancer care expertise, TeleTriage can significantly impact patient outcomes and utilize resources more effectively.
Randomized phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with newly diagnosed primary central nervous system lymphoma: JCOG1114C.
Authors: Mishima Kazuhiko , Nishikawa Ryo , Narita Yoshitaka , Mizusawa Junki , Sumi Minako , Kinoshita Manabu , Nagane Motoo , Arakawa Yoshiki , Yoshimoto Koji , Shibahara Ichiyo , Shinojima Naoki , Asano Kenichiro , Tsurubuchi Takao , Sasaki Hikaru , Asai Akio , Sasayama Takashi , Momii Yasutomo , Sasaki Atsushi , Katayama Hiroshi , Fukuda Haruhiko
Published: May 2020

2500

Background: Temozolomide (TMZ) is an oral alkylating agent that penetrates the blood-brain barrier with moderate toxicity, and has shown anti-tumor activity in primary central nervous system lymphoma (PCNSL) in single arm studies. Our goal was to determine whether the addition of concomitant and adjuvant TMZ chemotherapy to standard treatment of high-dose methotrexate (HD-MTX) and whole brain radiotherapy (WBRT) for PCNSL improves survival in a randomized controlled trial. Methods: We did an open-label, randomized phase III trial at 30 hospitals in Japan enrolling immunocompetent patients (pts) aged 20-70 years with histologically confirmed newly diagnosed PCNSL. Pts enrolled at step 1 registration received HD-MTX (MTX; 3.5 g/m2 at day 1, 15, 29). Pts who received at least 1 cycle of HD-MTX were randomly assigned (1:1) at step 2 registration to receive WBRT (30 Gy) ± 10 Gy boost (control arm: A) or WBRT ± boost with concomitant TMZ (75 mg/m2 daily) and adjuvant TMZ (150-200 mg/m2 daily for 5 days every 28 days) for two years after initiation of HD-MTX or until tumor progression (experimental arm: B). Randomization was adjusted by institution, PS (0-1 / 2-3), age (≤60/≥61 years), presence or absence of intraparenchymal tumor after HD-MTX. The primary endpoint was overall survival (OS). The planned sample size was 130 pts in total, to provide an 80% power to detect a 0.52 hazard ratio (65% vs 80% in 2y-OS) for arm B to A and a one-sided alpha of 5%. Results: Between September 29, 2014 and October 15, 2018, 134 pts were enrolled, of whom 122 were randomly assigned and analyzed; 62 to arm A and 60 to arm B. At the planned interim analysis, the 2-y OS was 86.8% (95% CI: 72.5-94.0) in arm A and 71.4% (56.0-82.2) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98) with predictive probability for showing the superiority of arm B at the final analysis was calculated to be 1.3%. The study was terminated due to futility. The 2-y progression-free survival was 60.6% (43.6-73.8) in arm A and 49.9% (34.4-63.5) in arm B with a hazard ratio of 1.54 (0.88 to 2.70). The most common grade 3 and 4 toxicities were lymphopenia, observed in 7 (11.5%) pts during WBRT in arm A, 18 (30%) pts during WBRT + concomitant TMZ and 18 (37.5%) pts during adjuvant TMZ in arm B. Conclusions: This study failed to demonstrate the benefit of the addition of TMZ to WBRT and adjuvant TMZ in newly diagnosed PCNSL. Possible biomarkers including methylation status of the MGMT promoter in the tumors will be analyzed. Clinical trial information: jRCTs031180207 .
Randomized phase II study of rituximab, methotrexate (MTX), procarbazine, vincristine, and cytarabine (R-MPV-A) with and without low-dose whole-brain radiotherapy (LD-WBRT) for newly diagnosed primary CNS lymphoma (PCNSL).
Authors: Omuro Antonio Marcilio Padula , DeAngelis Lisa Marie , Karrison Theodore , Bovi Joe A , Rosenblum Marc , Corn Benjamin W. , Correa Denise , Wefel Jeffrey Scott , Aneja Sanjay , Grommes Christian , Schaff Lauren , Waggoner Steven E. , Lallana Enrico C. , Werner-Wasik Maria , Iwamoto Fabio , Robinson Timothy J. , Donnelly Eric , Struve Timothy , Won Minhee , Mehta Minesh P. ,   NRG
Published: May 2020

2501

Background: MTX-based chemoradiotherapy is effective in PCNSL, but carries a risk of severe neurotoxicity (NT), especially in the elderly. In a phase II single arm study, R-MPV-A chemotherapy was combined with substantially reduced doses of radiotherapy (23.4 Gy), achieving prolonged progression free survival (PFS) and overall survival (OS) with acceptable NT. Because R-MPV-A had never been tested without radiotherapy, we conducted a randomized study to determine if the low doses of radiation played a role in the observed disease control, and to characterize NT as compared to chemotherapy alone. Methods: Patients were stratified by MSK RPA class and randomized to receive R-MPV-A with LD-WBRT (chemoRT arm) versus R-MPV-A alone (chemo arm). MTX dose was 3.5g/m2 infused over 2 hours. Filgrastim and pegfilgrastim support was given to all patients. LD-WBRT dose was 23.4 Gy (1.8 Gy X 13). The primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63, with one-sided alpha level of 0.15. Results: A total of 91 patients were randomized, of whom 4 were ineligible. Among eligible patients, 43 were enrolled in the chemoRT arm and 44 in the chemo arm. Median age was 66 (chemoRT) and 59 (chemo). Median KPS was 80 for both arms. Response rates following R-MPV were 81% (chemoRT) and 83% (chemo). In the chemoRT arm, 37 patients (86%) received LD-WBRT. After median follow-up of 55 months (m), the median ITT PFS was 25 m in the chemo arm and not reached in the chemoRT arm (HR 0.51; 95% CI [0.27, 0.95]; p = 0.015). The 2-year PFS was 54% (chemo) and 78% (chemoRT). Salvage radiotherapy has been given to 11 patients in the chemo arm. Median OS was not reached in either arm, with data still maturing. In both arms, most common grades 3 or 4 toxicities were anemia (27%), lymphopenia (41%), neutropenia (35%), thrombocytopenia (26%), ALT (23%) and AST (13%). One patient died from sepsis (chemo arm). As per investigators’ assessment, the rate of clinically defined moderate to severe NT was 11.4% (chemo) and 14% (chemoRT), p = 0.75. Conclusions: The study met the primary endpoint, demonstrating the addition of LD-WBRT to R-MPV-A improves PFS in newly diagnosed PCNSL. As per investigator’s assessment, NT rates were not statistically significantly increased, but further neuropsychological testing and neuroimaging analyses are ongoing to characterize cognitive decline and how it compares to other consolidation treatments. Clinical trial information: NCT01399372 .
Vorasidenib (VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (pts) with recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma population.
Authors: Mellinghoff Ingo K. , Peters Katherine B. , Cloughesy Timothy Francis , Burris III Howard A. , Maher Elizabeth Anne , Janku Filip , Cote Gregory Michael , De La Fuente Macarena Ines , Clarke Jennifer Leigh , Le Kha , Liu Li , Yuen Man , Arnofsky Marissa , Hassan Islam , Steelman Lori , Pandya Shuchi Sumant , Wen Patrick Y.
Published: May 2020

2504

Background: Isocitrate dehydrogenase 1 and 2 mutations (m IDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D-2-hydroxyglutarate. In this ongoing phase 1 trial, VOR, a potent, oral, reversible, brain-penetrant, first-in-class dual inhibitor of mIDH1/2, is being evaluated in advanced m IDH1/2 solid tumors, including gliomas. Safety and preliminary results were presented previously (Mellinghoff et al., J Clin Oncol 2018). Here, we report updated data for the non-enhancing glioma pt population. Methods: Pts with recurrent/progressive m IDH1/2 glioma received VOR daily (continuous 28-day cycles). Key eligibility criteria included: ≥18 years; histologically or cytologically confirmed glioma with documented m IDH1/2; ECOG 0-2; and evaluable disease by RANO-LGG criteria. Dose escalation cohorts enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Tumor response was evaluated by MRI every 8 weeks using RANO-LGG criteria by local assessment. Results: As of 28 Nov 2019, 22 pts with non-enhancing glioma had received VOR and 8 (36%) remain on treatment. M/F, 8/14; grade 2/3, 17/5; median age, 47 years; m IDH1/2, 20/1; 1p19q intact, 9/22; median (range) number of prior systemic therapies, 2 (1–4). Common (≥5 pts) treatment-emergent adverse events (AEs) of any grade and regardless of causality included increased ALT/AST (63.6%/59.1%), headache (45.5%), nausea (40.9%), neutropenia (31.8%), fatigue and hyperglycemia (27.3% each), and seizures and decreased white blood cell count (22.7% each). Transaminase elevations were grade 1 in severity at dose levels < 100mg and were less frequent (5 [38.5%] of 13 pts). Three subjects had related grade ≥3 AEs; 2 discontinued due to AEs. Objective response rate was 13.6% (1 partial response, 2 minor responses), and 17 (77.3%) pts achieved stable disease. 60.5% of pts were progression free and alive at 24 months. Conclusions: In this previously treated population with non-enhancing glioma, VOR was associated with a favorable safety profile. The study results also show encouraging preliminary activity within that population, with PFS duration extending to 24 months or longer in 60% of participants. A global randomized phase 3 study of VOR in grade 2 non-enhancing glioma pts who have had surgery only is currently enrolling (NCT04164901). Clinical trial information: NCT02481154 .
A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant gliomas: Safety and efficacy as single agent and in combination with azacitidine.
Authors: De La Fuente Macarena Ines , Colman Howard , Rosenthal Mark , Van Tine Brian Andrew , Levaci Danijela , Walbert Tobias , Gan Hui Kong , Vieito Maria , Milhem Mohammed M. , Lipford Kate , Forsyth Sanjeev , Guichard Sylvie Mireille , Mikhailov Yelena , Sedkov Alexander , Thomson Blythe , Kelly Patrick Francis , Monga Varun
Published: May 2020

2505

Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent, brain penetrant (Kpuu=0.4 in intact rodent), and selective inhibitor of mutated IDH1 protein. Methods: Patients (pts) with relapsed/refractory (R/R) mIDH1 gliomas received olutasidenib 150 mg BID, orally either as single agent (SA) or in combination (CO) with azacitidine in a dose confirmation phase Ib followed by efficacy evaluation phase II study (NCT: 03684811). Results: As of 31-Oct-2019, 29 pts with R/R mIDH1 glioma were treated with olutasidenib as SA (n=24) or CO (n=5). The median age was 45 yrs (range: 23-64) & 62% were male. WHO Glioma Grade (Gr) at study entry was: II (17%), III (52%) & IV (31%). Median number of prior treatments was 2 (1-5); 86% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H (86%), R132L (7%), R132C (3.5%) & unspecified (3.5%). The median duration of olutasidenib treatment for SA & CO was 4.8 (1-11.4) & 1 (0.2-2.3) months, respectively. Fifteen pts discontinued (disease progression [n=12], AE [n=1], withdrew consent [n=1], other [n=1]). For SA, the most common (>25%) TEAEs (all grades, regardless of attribution) were: fatigue (50%), nausea (50%), diarrhea (33%), ALT increase (29%) & headache (29%). For CO, TEAEs that occurred in ≥ 2 pts were: nausea (n=4), fatigue (n=2), neutropenia (n=2), ALT increase (n=2) & AST increase (n=2). There were 2 protocol defined DLTs in the CO cohort, 1 pt with Gr 4 ALT, Gr 3 AST & Gr 3 GGT elevations & 1 pt with Gr 3 ALT elevation. No pts experienced a TEAE of QTcF prolongation. SA best responses are shown in Table; CO pts are too early for response assessment. The median PFS for SA was 8.3 months. Twenty (87%) and 11 (48%) pts were alive and progression-free at 6 & 12 months, respectively. Conclusions: SA olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in glioma pts. Evaluation of CO is ongoing. Updated safety and clinical activity, as well as evaluations of serum/CSF PK/PD will be provided. Clinical trial information: NCT03684811 . [Table: see text]
Single cell mapping of human brain tumors reveals tumor-specific education of tissue-invading leukocytes.
Authors: Friebel Ekaterina , Kapolou Konstantina , Unger Susanne , Nunez Nicolas , Utz Sebastian , Rushing Elisabeth Jane , Regli Luca , Weller Michael , Greter Melanie , Tugues Sonia , Neidert Marian Christoph , Becher Burkhard
Published: May 2020

2509

Background: Brain tumors can be both of intracranial origin (e.g. gliomas) or spread from another location in the body (metastases). Tumor growth in the CNS is commonly favored by a highly immunosuppressive tumor microenvironment (TME). Whether the TME is predominantly shaped by the CNS microenvironment or by the nature of the malignancy is unknown, as is the origin and function of CNS tumor-associated macrophages (TAM). Methods: We have mapped the leukocyte landscape of brain tumors using high-dimensional profiling with mass cytometry (CyTOF). We designed two CyTOF panels (one lymphoid and one myeloid focused) measuring 74 parameters at the single-cell level and analyzed samples from 47 individuals with the most common tumor entities being glioblastoma and metastases from melanoma and lung cancer as well as control tissue from epilepsy surgery. Results: The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between glioblastoma and metastases. Tissue-invading leukocytes accumulate in metastases, whereas gliomas predominantly contain tissue-resident reactive microglia. In gliomas, isocitrate dehydrogenase 1 (IDH1) mutations are associated with minimal host responses whereas IDH1-wildtype gliomas comprise monocyte-derived macrophages (MDM) similar to metastases. These MDM show a distinctive signature trajectory indicative of tumor-driven education. Conclusions: The immune cell composition of the brain tumor TME is tumor entity-specific, rather than dictated by the CNS tissue. Defining the distinct immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.
Updated safety phase I trial of anti-LAG-3 alone and in combination with anti-PD-1 in patients with recurrent GBM.
Authors: Lim Michael , Ye Xiaobu , Piotrowski Anna F. , Desai Arati Suvas , Ahluwalia Manmeet Singh , Walbert Tobias , Fisher Joy D. , Desideri Serena , Nabors Louis B. , Wen Patrick Y. , Grossman Stuart A.
Published: May 2020

2512

Background: Preclinical GBM data targeting the checkpoint molecule Lag-3 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and in combination with anti-PD-1. Methods: A phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) alone or in combination with anti-PD-1 in patients at first recurrence of GBM was carried out in The Adult Brain Tumor Consortium (ABTC) (1501). The primary objectives were safety and to define MTD (DLT rate < 33%) for both the mono and combination arms. The major secondary objective was efficacy. The key inclusion criteria were: adults with first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, on a stable corticosteroid regimen, measurable disease, and written informed consent. Three pre specified dose levels of anti-Lag-3 at 80mg, 160mg, and 800mg were tested. Anti-PD-1was given at a flat dose of 240 mg in combination with anti-LAG-3 at 80 mg and 160 mg. Results: To date, the phase I portion of study completed its accrual and 33 patients were enrolled into the anti-LAG-3 alone or in combination with anti-PD-1 arms. The median age and KPS was 56 and 90 respectively. 39% tumors were MGMT methylated and the median treatment cycle was 3. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. Two DLT were observed in combination arms of Anti-LAG-3 +anti-PD-1 (80 mg/240mg), a grade 3 muscle weakness and a grade 4 edema. Three DLTs were observed in the higher Anti-LAG-3 + anti-PD-1 group (160 mg/240mg): grade 3 hypertension, syncope, and edema. 80% of the DLTs occurred after cycle 2 of the treatment. The estimated overall mOS was 8 months. Seven (44%) patients in the combination arm are still alive and 3 out of the 7 are living beyond 20 months suggesting a subset benefit. Conclusions: The phase I part of trial has completed enrollment. The MTD is 800mg for anti-LAG-3 as a monotherapy. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 was the MTD. DLTs were late onset events. Clinical trial information: NCT02658981 .
MDNA55 survival in recurrent glioblastoma (rGBM) patients expressing the interleukin-4 receptor (IL4R) as compared to a matched synthetic control.
Authors: Sampson John H. , Achrol Achal , Aghi Manish K. , Bankiewicz Krystof , Bexon Martin , Brem Steven , Brenner Andrew Jacob , Chandhasin Chandtip , Chowdhary Sajeel A. , Coello Melissa , Das Sunit , Han Seunggu Jude , Kesari Santosh , Merchant Fahar , Merchant Nina , Randazzo Dina , Vogelbaum Michael A. , Vrionis Frank , Zabek Miroslaw , Butowski Nicholas A.
Published: May 2020

2513

Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .
A phase I/II clinical trial of autologous CMV-specific T cells in glioblastoma (GBM) patients to reveal a lack of immune effector function.
Authors: Weathers Shiao-Pei S. , Penas-Prado Marta , Banerjee Pinaki Prosad , Bdiwi Mustafa , Shaim Hila , Alsuliman Abdullah , Shanley Mayra , Long James , De Groot John Frederick , O'Brien Barbara Jane , Majd Nazanin , Harrison Rebecca A. , Kamiya-Matsuoka Carlos , Fuller Gregory N. , Chi Linda , Rao Ganesh , Lang Frederick F. , Shpall Elizabeth J. , Rezvani Katayoun , Heimberger Amy B.
Published: May 2020

2515

Background: Cytomegalovirus (CMV) antigens are present in > 90% of GBMs but not in normal brain making it an attractive immunological target. Methods: Highly functional autologous polyclonal CMV pp65 specific T cells were expanded under GMP-compliant conditions from GBM patients and administered after 3 weeks of lymphodepleting dose-dense temozolomide (ddTMZ, 100 mg/m2). The phase I component used a 3+3 design ascending through four dose levels (5 x 106 cells to 1 x 108 cells). Treatment was repeated every 6 weeks for a total of 4 cycles. Dose expansion was conducted in recurrent GBM patients undergoing resection and in newly diagnosed GBM patients following concurrent chemoradiation. In vivo persistence and effector function of the adoptively transferred CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially-sampled peripheral blood and in the tumor microenvironment. Results: 65 patients were screened, 25 underwent leukapheresis, and 20 completed at least 1 cycle. Median age 48 (27-69), 35% were MGMT methylated, and 10% were IDH mutated. No dose limiting toxicities (DLTs) observed. Complete radiographic response was observed in 1 patient, partial responses in 2, stable disease in 9, and progressive disease in 8. The median PFS time was 1.3 months (95% CI: 0-8.3 months) and the median OS time was 12 months (95% CI: 6 months to not reached). Repeated infusions of CMV-TC were associated with significant increase in circulating CMV+ CD8+ T cells, but cytokine production reflective of effector activity (CD107a, TNFα, IFNγ, IL2) was suppressed in these cells including directly from the GBM microenvironment. Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepleting ddTMZ was well-tolerated. However, effector function of the adoptively transferred T cells was attenuated indicating further modulation of the T cell is required to prevent its dysfunction prior to proceeding to large scale clinical studies. Clinical trial information: NCT02661282 .
Long-term analysis of the WHO-defined molecular subgroups of high-risk grade II gliomas treated with radiation and temozolomide on NRG Oncology/RTOG 0424.
Authors: Bell Erica Hlavin , Pugh Stephanie L. , Fisher Barbara Jean , Lesser Glenn Jay , Macdonald David R. , Fleming Jessica L. , McElroy Joseph P. , Becker Aline P. , Rogers C Leland , Doyle Thomas J. , Werner-Wasik Maria , Bahary Jean-Paul , Yu Michael , D'Souza David , Laack Nadia N. , Sneed Patricia Penny , Kwok Young , Howard Steven P. , Mehta Minesh P. , Chakravarti Arnab
Published: May 2020

2518

Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p<0.001) and OS ( IDHmt/co-del = 9.4yrs (8.2-NR); IDHmt/non-codel = 8.8yrs (5.9-NR); IDHwt = 2.3yrs (1.4-3.4), p<0.001) relative to the IDHwt subgroup. Upon univariate and multivariate analyses, both molecular IDHmt subgroup comparisons relative to IDHwt remained significant (p<0.001) even after incorporation of known clinical variables. Conclusions: These analyses suggest that G2 glioma patients harboring IDH1/2 mutations, regardless of co-deletion status, demonstrated longer survival with RT + TMZ relative to IDHwt tumors, although sample size is limited and analyses were post-hoc. These results also support the notion that outcomes for IDHwt high-risk G2 gliomas remain dismal (median = 2.3yrs, similar to G3 anaplastic astrocytoma); these patients should be separated from IDHmt patients in future G2 glioma trials, and warrant novel treatment strategies. Funding: U10CA180868, U10CA180822, U24CA196067, CURE, PA Dept. of Health, and Merck. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850, BTFC, OSUCCC (all to AC). Clinical trial information: NCT00114140 .
A phase II double-blind, randomized clinical trial assessing the tolerability of two different ratios of cannabis in patients with glioblastoma multiforme (GBM).
Authors: Lacey Judith , Schloss Janet Margaret , Sinclair Justin , Steel Amie , Sughrue Mike , Teo Charles , Sibbritt David
Published: May 2020

2530

Background: Cannabis has been used for cancer-related symptoms but few trials have assessed quality of life or tolerability, and trials assessing tumour response or survival remain scarce. Treatment for recurrent glioblastoma (rGBM) remains palliative with poor prognosis. The tolerability of THC-containing cannabis products, and their effect on symptoms and quality of life in people with rGBM patients is poorly defined but is essential before efficacy trials can be conducted. Methods: We conducted a randomised double-blinded trial assessing the tolerability of two preparations of cannabis in 88 people with rGBM. The two preparations used different cannabidiol (CBD) to tetrahydrocannibidiol (THC) ratios; 1:1 (5.8mg/ml:5.6mg/ml) and 1:4 (3.8mg/ml:15mg/ml). Daily evening doses were individually monitored and titrated. Outcomes included disease response by FACT-Br, MRI imaging 12 weekly, blood pathology, NCI-CTC and clinical monitoring. Symptom assessments were performed 4 weekly for 12 weeks. Results: 921 people volunteered for screening across Australia, with 642 excluded, 92 recruited with 88 enrolled. 61 participants completed 12-week follow-up (attrition 30%). Both cannabis oils were well tolerated. Total FACT-Br was similar for both preparations, however, statistical significance was found for the physical section (p = 0.025) and functional (p = 0.014) identifying the 1:1 ratio as the more appropriate combination. Comparing groups to baseline, participants reported improvement of sleep (p = 0.009), improved energy (p = 0.015), and contentment with QoL (p = 0.006). Total cohort compared to baseline, participants reported improvement of sleep (p = 0.0001), pain (p = 0.046), nausea (p = 0.017), anxiety (p = 0.005) and seizure activity (p = 0.022). There were no major adverse events attributable to the cannabis with main side effects noted as dizziness, drowsiness, tiredness, and dry mouth. No abnormal blood pathology nor variance in NCI-CTCAE scores were observed. Conclusions: A single nightly dose of THC-containing cannabis was well tolerated in patients in both groups with rGBM and significantly improved sleep and functional wellbeing and QOL in a sample of patients compared to baseline. From this trial, the 1:1 ratio has been identified as the better tolerated product with suprerior symptom and QoL outcomes compared to the 1:4 product. Clinical trial information: ACTRN12617001287325 .
Concurrent nivolumab and ipilimumab with brain stereotactic radiosurgery for brain metastases from non-small cell lung cancer: A phase I trial.
Authors: Li Jing , Wang Yan , Tang Chad , Welsh James William , Guha- Thakurta Nandita , Carter Brett W. , Wefel Jeffrey Scott , Ghia Amol J. , Yeboa Debra , McAleer Mary Frances , Chung Caroline , Woodhouse Kristina D , Elamin Yasir , Le Xiuning , Cascone Tina , Negrao Marcelo Vailati , Skoulidis Ferdinandos , Ferrarotto Renata , Heymach John , Altan Mehmet
Published: May 2020

2531

Background: Nivolumab (nivo) and ipilimumab (ipi) were found in the recent phase III CheckMate 227 trial to have an overall survival benefit over chemotherapy for advanced non-small cell lung cancer (NSCLC). However, patients (pts) with untreated brain metastasis (mets) were excluded from that trial. Because 30% of NSCLC pts develop brain mets, we tested nivo/ipi with concurrent stereotactic radiosurgery (SRS) for NSCLC pts with active brain mets. Methods: We report the safety data from the phase I portion of an ongoing phase I/II single-institution trial in which one treatment group was given SRS with nivo (3 mg/kg) every 2 weeks (wks) plus ipi (1 mg/kg) every 6 wks x 4 cycles, followed by maintenance nivo (480 mg) every 4 wks until disease progression, unacceptable toxicity, or withdrawal of consent. Brain SRS was delivered within 7 days of initiation of nivo/ipi. The primary endpoints were safety and 4-month (mo) intracranial progression-free survival (PFS). Dose-limiting toxicity (DLT) was defined as > 15% intracranial toxicity (>G3 hypophysitis / neurologic toxicity) or > 30% extracranial toxicity (>G3 non-dermatologic non-lab toxicity or >G4 dermatologic / lab toxicity), refractory to medical management, assessed at 8 wks after treatment initiation. Target accrual for phase I was 10 evaluable pts, with enrollment suspended after every 5 pts for DLT assessment. Results: Since June 15, 2018, 13 pts were enrolled and 10 were evaluable for DLT. The median follow-up time was 6.8 mo (range 1.2‒18). As of January 6, 2020, only 1 pt had DLT-defined toxicity and thus the predefined stopping criteria were not met. This pt had G3 seizure right after SRS that resolved within a week, and then had increased but asymptomatic CNS edema 4 wks later. Aside from DLTs, 3 pts (25%) developed treatment-related G3 (elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis) or G4 events (pneumonitis/acute respiratory distress syndrome in 1 pt with confirmed influenza at 7 mos after treatment initiation). This pt subsequently died of hemophagocytic lymphohistiocytosis (considered possibly related to the study drugs). Median intracranial PFS time was 9.7 mo, and the 4-mo intracranial PFS rate was 75%. Extracranial objective response rate was 33% in the 12 evaluable pts with a median response duration of 9.1 mo. Conclusions: Concurrent SRS withnivo/ipi was safe for pts with active NSCLC brain mets. Preliminary analyses of efficacy were encouraging for durable intracranial and extracranial response. Clinical trial information: NCT02696993 .
Accelerator-based BNCT in rescue treatment of patients with recurrent GBM: A multicenter phase II study.
Authors: Miyatake Shin-Ichi , Kawabata Shinji , Goto Hiromi , Narita Yoshitaka , Suzuki Minoru , Hirose Katsumi , Takai Yoshihiro , Ono Koji , Ohnishi Takanori , Tanaka Hiroki , Kato Takahiro
Published: May 2020

2536

Background: Boron neutron capture therapy (BNCT) is tumor-selective particle radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM. Methods: The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above mentioned AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose which was decided by preceding phase I trial. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS) and so on. The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002. Results: 1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0-90.8) and 18.7 months (95% CI:12.9-23.4) (data cutoff = 20 Jun 2019) respectively, while those of JO22506 was 34.5% (90% CI:20.0-49.0) and 10.5 months (95% CI:8.2-12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. 21 out of 27 cases were treated with bevacizumab after progress disease. Conclusions: AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled with bevacizumab. Clinical trial information: JapicCTI-194742 . [Table: see text]