tbuckley/cabot-search huggingface dataset:
Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma.
Authors: Jordan Gauthier, Alexandre V. Hirayama, Kevin Anthony Hay, Daniel Li, Alyssa Sheih, Vicky Wu, Jenna M. Voutsinas, Sindhu Cherian, Xueyan Chen, Barbara S. Pender, Reed M. Hawkins, Aesha Vakil, Tinh-Doan Phi, Rachel N. Steinmetz, Stanley R. Riddell, David G. Maloney, Cameron Turtle
Journal: Journal of Clinical Oncology (2018)

7567 Background: CD19-specific chimeric antigen receptor-modified T (CD19 CAR-T) cells achieve high complete remission (CR) rates in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), yet factors governing duration of response are unknown. Methods: We studied outcomes of 57 adults treated on a clinical trial (NCT01865617) with cyclophosphamide and fludarabine followed by 2 x 106 CD19 CAR-T cells/kg administered in a defined 1:1 ratio of CD4+/CD8+ CAR-T cells, and identified factors impacting progression-free survival (PFS) and overall survival (OS). Results: The median age was 56.5 years (range: 27 - 71) and the median number of prior therapies was 4 (range: 1 - 11). 25 patients (pts; 44%) had prior transplant, 47 (82%) had aggressive histology, and 46 (81%) had an IPI ≥ 2 at enrollment. The median lymph node burden (SPD) was 3343 mm2 (range: 124 - 16765); 8 pts (14%) had bulky disease (diameter ≥ 10 cm). The median follow-up was 15.7 months. The best overall response and CR rates were 60% and 47%, respectively. Higher peak blood CAR-T cell counts (Cmax) and area under the curve (AUC) from day 0 - 28 after infusion by qPCR were associated with longer PFS (Cmax, HR = 0.48, P < 0.001; AUC, HR = 0.45, P < 0.001) and OS (Cmax, HR = 0.63, P = 0.03; AUC, HR = 0.61, P = 0.02). Higher CD8+, but not CD4+, CAR-T cell counts by flow cytometry correlated with longer PFS (Cmax, HR = 0.55, P < 0.001; AUC, HR = 0.53, P < 0.001) and OS (Cmax, HR = 0.62, P = 0.01; AUC, HR = 0.61, P = 0.01). SPD < median was associated with longer PFS (P = 0.004) and OS (P = 0.01). In multivariate analysis, low IPI (0-1 vs 3-4, HR = 0.11, P = 0.005) and indolent histology (HR = 0.05, P = 0.009) were associated with longer PFS; low IPI was associated with longer OS (0-1 vs 3-4, HR = 0.06, P = 0.007). In pts achieving CR after CAR-T cells, the probabilities of 1-year OS and PFS were 92% and 69%, respectively. In this subgroup, the median OS and PFS were not reached (median follow-up, 15 months). Multivariate analysis after adjusting for histology showed that the IPI and SPD adversely impacted PFS (IPI, P = 0.002; SPD, P = 0.007) and OS (IPI, P = 0.01; SPD, P = 0.02). Conclusions: Histology, IPI and CAR-T cell kinetics govern duration of response in NHL pts receiving CD19 CAR-T cells. Clinical trial information: NCT01865617.
Molecular diversification of regulatory T cells in nonlymphoid tissues
Authors: Joanna R. DiSpirito, David Zemmour, Deepshika Ramanan, Jun Cho, Rapolas Zilionis, Allon M. Klein, Christophe Benoist, Diane Mathis
Journal: Science Immunology (2018)

Different tissue microenvironments differentially refine T reg cell transcriptional regulatory modules already primed in lymphoid organs.
Real-world Effectiveness of bevacizumab based on AURELIA in platinum-resistant recurrent ovarian cancer (REBECA) : A Korean Gynecologic Oncology Group study (KGOG 3041).
Authors: Jung-Yun Lee, Sang-Yoon Park, Kidong Kim, Jae-Weon Kim
Journal: Journal of Clinical Oncology (2018)

e17547 Background: Adding to bevacizumab to chemotherapy improves progression-free survival for platinum-resistant ovarian cancer. This study evaluates effectiveness of 2nd-line or 3rd-line bevacizumab with single agent chemotherapy in real-world clinical settings. Methods: Adding to bevacizumab to chemotherapy improves progression-free survival for platinum-resistant ovarian cancer. This study evaluates effectiveness of 2nd-line or 3rd-line bevacizumab with single agent chemotherapy in real-world clinical settings. Results: Of total 392 patients, 259 (66.2%) received bevacizumab with PLD and 94 (24.0%) with topotecan and 38 (9.7%) with weekly paclitaxel. Median PFS was 6.1 months with bevacizumab containing therapy. Although PLD-bevacizumab arm had inferior PFS than weekly paclitaxel-bevacizumab arm (P = 0.03), this founding was not found in patients with previous platinum-free interval less than 3 months. For 2nd line therapy (n = 215, 55.0%), topotecan-bevacizumab regimen had superior PFS2 and OS than other regimens (P < 0.001). For 3rd line therapy (n = 176, 45%), we found no significant difference of PFS and OS in three arms. The median duration of therapy was 5 cycles (range, one to 20 cycles) and 29 patients (7.4%) discontinue treatment due to severe adverse events from bevacizumab containing regimens. Conclusions: The safety and efficacy of bevacizumab containing chemotherapy were consistent with results from randomized controlled study.
Breast cancer patients' willingness to travel to participate in a clinical trial.
Authors: Nicholas Zdenkowski, James F. Lynam, Laura Wall, Scott Brown, Kathryn Wells, Victoria Sproule
Journal: Journal of Clinical Oncology (2017)

e14031 Background: The option of clinical trial participation is an important component of high quality care for oncology patients. Despite a recognised need for generalizable research results to guide future practice, and the desire of current oncology patients to participate in trials, only 2-5% of oncology patients in developed nations enroll in a clinical trial. We aimed to determine the willingness of patients to travel, change location and/or clinician to participate in a clinical trial. Methods: Members of a national breast cancer consumer organization were invited by email to respond to an online cross-sectional survey. Questions included demographics, remoteness of residence, prior involvement in clinical trials and location of usual care. This was followed by a Discrete Choice Experiment (DCE) comprising an introduction and 10 hypothetical scenarios to test the effect of variation in travel time, clinician, treating centre, travel cost and type of trial. Results: Between July and August 2016, 288 responses were received, mean age 58. 86% had early stage disease, 51% were currently receiving treatment, 21% had prior clinical trial involvement. Ninety percent were willing to participate in a clinical trial in at least one scenario. Factors that decreased the likelihood of interest in clinical trial participation were increasing travel time, change in oncologist and out of pocket expenses. Type of trial (randomised placebo controlled; randomised open label; single arm) did not influence the decision. If the oncologist remained the same and there were no costs, respondents were willing to travel a mean extra 127 minutes, however if the oncologist changed and there were additional costs, they were willing to travel a mean of 30 minutes. If the oncologist changed and there was no cost, they were willing to travel a mean of 82 minutes. Conclusions: This group of respondents with a past history of breast cancer expressed interest in clinical trial participation, however willingness to travel in the most likely scenario (change oncologist and pay no additional cost) was 82 minutes. To facilitate optimal access to clinical trials, clinicians should consider referral within and between institutions.
P01.140 An H3.3K27M long peptide vaccine induces expansion of specific CD4 and CD8 T cell clones in a patient with progressive H3.3K27M-mutant midline glioma
Authors: K Sahm, I Mildenberger, L Bunse, E Green, W Wick, M Platten
Journal: Neuro-Oncology (2018)

Diffuse gliomas of the thalamus, brain stem, spinal cord or other midline structures represent a well-defined subgroup of high grade gliomas typically occurring in children and adolescents but also in adult patients. On a molecular level, diffuse midline gliomas harbor an amino acid exchange at position 27 of the histone-3 gene (H3.3K27M) as a characteristic driver mutation in > 70% of cases. We have previously demonstrated that a peptide vaccine encoding the H3.3K27M epitope induces a major histocompatibility complex (MHC) class I-restricted CD8+ T cell as well as an MHC class II-restricted CD4+ immune response. These immune responses effectively inhibited growth of H3.3K27M-overexpressing flank tumors in an MHC-humanized A2DR1 mouse model. Here, we show immune monitoring results of an HLA-A2+ patient with progressive H3.3K27M-mutant glioma vaccinated with an H3.3K27M long peptide emulsified in Montanide in combination with Nivolumab on a compassionate-use basis. Treatment was well tolerated and immunogenicity analyses of peripheral blood monocytes showed induction of a mutation-specific peripheral IFNγ immune response after four vaccines. Moreover, single CD8+ and CD4+ T cells specifically responding to H3.3K27M were expanded in vitro and subjected to single-cell-sorting and subsequent T cell receptor (TCR) sequencing. Here, 6 TCR clonotypes showing clear expansion after vaccination have been identified. TCR clonotypes were also assessed in CSF to evaluate mutation-specific immunity within the CNS. These data demonstrate immunogenicity of an H3.3K27M peptide vaccine inducing mutation-specific CD4+ and CD8+ T cells and pave the way for the development of adoptive T cell therapy for patients with H3.3K27M-mutant midline gliomas using TCR-transgenic T cells derived from vaccinated patients targeting the clonal H3.3K27M neoepitope.
Profiling circulating tumor (ct)DNA mutations after panitumumab treatment in patients with refractory metastatic colorectal cancer (mCRC) from the phase III ASPECCT study.
Authors: Michael Boedigheimer, Agnes Ang, Timothy Jay Price, Marc Peeters, Tae Won Kim, Peter Gibbs, Anne L. Thomas, Kristina Hool, Bruce A. Bach
Journal: Journal of Clinical Oncology (2017)

3523 Background: ASPECCT was a clinical trial performed in the chemotherapy-refractory third-line mCRC setting (N = 1010). This biomarker analysis explores the mutational landscape in panitumumab monotherapy subjects. Analysis of plasma ctDNA at baseline and post-treatment (PT) by next-generation sequencing provides a snapshot of the main changes in key genes before and after therapy. Methods: CtDNA collected at baseline and PT was analyzed for mutations using the Plasma Select-R™ 63-gene panel (0.1% limit of detection). Gain or loss of mutation was defined at the amino acid level. Net change is the sum of mutations gained minus the sum of mutations lost. A single individual could have both net gain and/or net loss of mutations within a single gene. Results: Significant tumor clonal diversification was observed during therapy. In 238 subjects with paired plasma samples,29% of subjects had multiple mutations in the same gene at baseline and 41% of subjects had multiple mutations in the same gene PT. At least 10% of subjects demonstrated an on-therapy acquired mutation in at least one of the following genes: APC, EGFR, ALK, HER4, TP53, AR, KRAS, BRAF, PDGFRA, STK11, ESR1, FBXWT, and KIT (ordered by frequency). New mutations were noted both inside and outside the EGFR pathway. Unexpectedly, patients with a large decrease in mutant DNA burden after anti-EGFR treatment were also seen. EGFR pathway genes with significant net gain were: KRAS, EGFR, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1. Non-EGFR pathway mutations gained included: APC, CDK6, SMARCB1, FBXW7, TERT, RB1, CTNNB1, and IDH1. Conclusions: This 63-gene plasma analysis suggests that there are significant dynamic changes in clonal mutational fraction under anti-EGFR selection. Our analysis reveals that increasing global tumor heterogeneity is associated with poorer overall survival. A subset of patients demonstrated an overall decrease in tumor heterogeneity on panitumumab therapy (28%), indicating that under anti-EGFR selective pressure mutational heterogeneity can also decrease. Clinical trial information: NCT01001377.
Efficacy of combined endoscopic resection and chemoradiotherapy for clinical stage I esophageal squamous cell carcinoma (ESCC): A single-arm confirmatory study (JCOG0508).
Authors: Manabu Muto, Keiko Minashi, Keiji Nihei, Junki Mizusawa, Tomonori Yano, Yasumasa Ezoe, Tomohiro Tsuchida, Hiroyuki Ono, Toshiro Iizuka, Noboru Hanaoka, Ichiro Oda, Yoshinori Morita, Masahiro Tajika, Junko Fujiwara, Chikatoshi Katada, Shinichiro Hori, Haruhiko Fukuda, Kohei Takizawa
Journal: Journal of Clinical Oncology (2016)

4013 Background: For clinical(c) stage I submucosal (T1b) thoracic ESCC, surgery with lymph node dissection is the standard treatment. However, pathologic diagnosis after resection sometimes reveals mucosal cancer (T1a), which is treatable by endoscopic resection (ER) alone. T1b ESCC is also treatable with chemoradiotherapy (CRT) but has risk of loco-regional failure and cardiopulmonary adverse events (AEs). We investigated the efficacy and safety of combined ER+CRT for cT1b ESCC. Methods: The eligibility criteria included: histologically proven thoracic ESCC, T1b diagnosed by endoscopic ultrasound, cN0M0, primary tumor size ≤ 5 cm and esophageal lumen circularity ≤ 3/4, and age 20-75 years. After ER, additional treatment was indicated by histologic diagnosis: Group A, pT1a with negative resection margin and no vascular invasion -no additional treatment; Group B, pT1b with negative resection margin and pT1a with vascular invasion -prophylactic CRT; Group C, pT1b with positive resection margin -definitive CRT. Chemotherapy comprised of 5-fluorouracil (700 mg/ m2/day, days 1-4 and 29-32, civ), and cisplatin (70 mg/ m2/day, days 1 and 29). Radiotherapy dose was 41.4 Gy/23 fr, delivered to the loco-regional lymph-node area (Group B) or 50.4 Gy/28 frs with a boost to the primary site (Group C). Primary endpoint was 3-year overall survival (OS) of Group B. Key secondary endpoint was 3-year OS of all enrolled patients (pts). The required sample size was 82 for primary analysis, with one-sided alpha of 0.05 and power of 90%, based on the expected and threshold 3-year OS as 90% and 80%. Results: Of 177 pts registered in 2006-2012 [M/F, 147/30; Age, 63 years (42-75); lesion diameter, 2.5cm (0.5-5.0)], ER was performed in 176 pts (Group A/B/C, 74/87/15). There were no grade 3/4 AEs due to ER; 8 of 96 pts who received CRT suffered from late cardio-pulmonary AEs. The 3-year OS was 90.7% (90% CI; 84.0-94.7) of 87 pts in Group B and 92.6% (90% CI; 88.5-95.2) overall. Conclusions: Combined ER+CRT for T1b ESCC is considered to be comparable to surgery in efficacy and can be new minimally invasive treatment option. Clinical trial information: 000000553.
Entinostat in combination with nivolumab for patients with advanced cholangiocarcinoma and pancreatic adenocarcinoma.
Authors: Marina Baretti, Jennifer N. Durham, Rosalind Walker, Amber-Lynn Mitcheltree, Brian Christmas, Leslie Cope, Elizabeth M. Jaffee, Nilofer Saba Azad
Journal: Journal of Clinical Oncology (2018)

TPS4151 Background: The use of antibody therapy targeting immune checkpoints has become a major focus of cancer immunotherapy, with the most compelling activity seen in the minority of patients with immunogenic tumors, where T cell infiltration naturally occurs while most pancreatic cancer (PDAC) and cholangiocarcinoma (CC) are not highly immunogenic, due to an immunosuppressive microenvironment and lack of tumor antigen expression and recognition. Our laboratory has explored entinostat, a histone deacetylase inhibitor (HDACi) to alter the function of suppressive myeloid derived suppressor cells (MDSC) in favor of recruiting T cells in murine PDAC models, showing that entinostat improves survival when given with anti-PD1 therapy. Our efforts are focused on producing new treatment options for CC and PDAC patients using epigenetic and immunotherapy combinations. Methods: An open-label, two-arm study enrolling patients with histologically confirmed unresectable or metastatic CC or PDAC, who have progressed after at least one line of prior therapy. Eligibility criteria include having measurable disease, performance status ≤1, and good end organ function. Exclusion criteria include history of autoimmune disease. Patients have a pre-treatment biopsy followed by 14 days of entinostat at a dose of 5 mg oral once a week followed by a second biopsy. Patients then begin nivolumab 240 mg every two weeks combined with entinostat until disease progression. The study is planned with 27 evaluable subjects per histology based on a Simon’s two-stage design that allows early termination for lack of efficacy. The primary objective of the trial is to determine whether the combination of entinostat plus nivolumab yields a clinically compelling antitumor activity measured as objective response rate (ORR, assessed by RECIST 1.1). Secondary objectives will include progression free survival (PFS), overall survival (OS), safety and immunological correlates to evaluate the effect of HDAC inhibition on the TME by interrogating clinical specimens. The clinical study has been activated in November 2017 (NCT03250273) and 10 of planned 54 patients have been enrolled. Clinical trial information: NCT03250273.
Exploring the time delay between regulatory approval and health techonology assessments (HTAs) of oncology therapies in France, Germany, England, Scotland, Canada, and Australia.
Authors: Ashley Jaksa, Anson Pontynen, Alexander Bastian
Journal: Journal of Clinical Oncology (2017)

6545 Background: Drugs in the USA become available from the moment of FDA approval. Access to oncology therapies outside of the USA may be delayed by regulatory and additional payer HTA processes. This study aimed to examine the time from regulatory approval to an HTA reimbursement decision in countries with mandatory HTA. Methods: Oncology HTAs (N=569) for medicines approved by the EMA, Health Canada, and the Therapeutic Goods Administration (Australia) were matched on indication with HTAs from France, Germany, Canada, England, Scotland, and Australia. Resubmissions were excluded. The date of the first reimbursement decision was subtracted from the date of the regulatory approval to determine the time taken to complete HTA and to issue reimbursement decision. Trends by country were examined. Results: Time between regulatory approval and HTA reimbursement required a mean of 321 days (Median=214 days; Std.Dev. 330 days). Access in England took the longest, on average, (547 days) to issue a decision compared to the other countries. This time was two to three times longer than any other country. Australia had the shortest time to issue a reimbursement decision, which was approximately 6 months. Conclusions: Approximately one additional year is required after regulatory approval for oncology medicines to complete HTA and receive a reimbursement decision, potentially delaying patient access to oncology medicines outside the USA. The large variability in time to a reimbursement decision by country is likely due to varying processes. Additional research is needed to clarify the impact of these delays on access to care and patient outcomes. [Table: see text]
PISARRO: A EUTROC phase Ib study of APR-246 in combination with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in platinum sensitive relapsed high grade serous ovarian cancer (HGSOC).
Authors: Charlie Gourley, John Green, Hani Gabra, Ignace Vergote, Bristi Basu, James D. Brenton, Ulf Björklund, Austin M. Smith, Mikael Von Euler
Journal: Journal of Clinical Oncology (2016)

5571 Background: P53 is ubiquitously mutated in HGSOC. APR-246 is a novel agent which stabilises mutant P53 in the wild-type conformation, increasing cancer cell chemo-sensitivity. Our aim was to establish the recommended phase II dose (RPTD) of APR-246 in combination with C and PLD. Methods: A 3+3 dose escalation of APR-246 (35, 50 and 67.5 mg/kg given IV days 1-4) in combination with C AUC 5 and PLD 30mg/m2 given day 4 in a 28 day schedule was performed in patients with platinum sensitive relapsed HGSOC whose archival tumour specimen demonstrated mutant P53 IHC staining. After the three cohorts were fully recruited (3+6+6) further patients were included in the high and low cohorts to allow a better evaluation of the possible dose dependency of safety and efficacy. Patients were followed with CA-125 after each cycle and by CT scan every two cycles. Results: All three dose cohorts were fully recruited with expansion of middle (DLT) and high (RPTD) cohort. One DLT (ruptured diverticulum) occurred at dose level 2. No difference in dose dependent activity or toxicity was demonstrated. In the expanded cohorts (9 in lower and 11 in higher) two additional DLT events (myelosuppression and fatigue) occurred. The main toxicity attributable to APR-246 rather than chemotherapy was dizziness, which occurred in 20 out of 28 patients (71%; 18 grade 1/2, 2 grade 3). This was self-limiting, resolving within 24 hours of APR-246 infusion. Pharmacokinetic analysis revealed no interaction between APR-246 and C or PLD. In the 17 patients evaluable for GCIG response that had received at least 2 cycles (11 partially platinum sensitive; PPS) 14 responded (9 PPS). Response rate was 7/8 (88%) in the high dose cohort. Of 20 patients evaluable for best response by RECIST 1.1, 3 had a CR, 9 had a PR (4 await confirmatory scan), 8 had SD and 0 had PD. Overall response rate (GCIG or RECIST) was 17/23 (74%), 11/16 (69%) in PPS patients. Conclusions: An APR-246 dose of 67.5 mg/kg has been selected for use in combination with C and PLD for phase 2 evaluation. The combination activity in the phase 1b study is encouraging, particularly in patients with partially platinum sensitive disease. Clinical trial information: 2013-001472-38.
TCT-870 Do we need wedge pressure for calculation of the index of microcirculatory resistance (IMR) post primary percutaneous coronary intervention (PPCI) in patients with ST segment elevation myocardial infarction (STEMI)?
Authors: Grigoris Karamasis, Andreas Kalogeropoulos, Valeria Marco, Firas Al-Janabi, Rohan Jagathesan, Alamgir Kabir, Nicholas Robinson, Jeremy Sayer, Gerald Clesham, Rajesh Aggarwal, Paul Kelly, Reto Gamma, Kare Tang, Francesco Prati, Thomas Keeble, John Davies
Journal: Journal of the American College of Cardiology (2018)