tbuckley/cabot-search huggingface dataset:
Phase 1 study of selinexor plus mitoxantrone, etoposide, and cytarabine in acute myeloid leukemia.
Authors: Bhavana Bhatnagar, Alison R. Walker, Alice S. Mims, Sumithira Vasu, Rebecca B. Klisovic, Gregory Behbehani, James Stewart Blachly, Karilyn T.M. Larkin, Meixiao Long, Qiuhong Zhao, Parvathi Ranganathan, John C. Byrd, William G. Blum, Ramiro Garzon
Journal: Journal of Clinical Oncology (2018)

7048 Background: Patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Selinexor (SEL), an oral inhibitor of the nuclear transport protein XPO1, has shown promising single-agent activity in clinical trials of AML and preclinical synergy with topoisomerase (topo) II inhibitors. Hence, we tested the combination of SEL plus chemotherapy with topo II inhibitor in pts with R/R AML. Methods: This phase 1, open-label 3+3, dose escalation study tested SEL plus mitoxantrone, etoposide, and cytarabine (MEC) in pts aged < 60 years with R/R AML (NCT02299518). The primary objectives were to evaluate the safety and preliminary efficacy of this combination. Pts received MEC IV on days 1-6, and up to 6 doses of SEL, across 3 dose levels ranging from 30-55 mg/m2 on days 1, 3, 8, 10, 15, and 17. Results: We enrolled 23 pts (median age 47 years); 11 were treated on the dose escalation portion. Due to dose limiting hyponatremia in 2 pts on dose level 2 (SEL 40 mg/m2), the maximum tolerated dose was 30 mg/m2. However, based on the totality of safety data from other SEL trials in R/R AML, we established the RP2D of SEL in pts with AML to be 60 mg. We treated an additional 12 pts with 60 mg of SEL in combination with MEC. Common grade ≥3 toxicities for 21 treated pts for whom all analyses are complete (2 remain on therapy) are shown in Table 1. Of 21 pts, the overall response rate was 39% with 4 pts (19%) achieving complete remission (CR), 2 (10%) with CR with incomplete count recovery, and 2 (10%) with a morphologic leukemia-free state. Five responders proceeded to allogeneic stem cell transplantation. Conclusions: SEL plus MEC is a feasible treatment for pts with R/R AML. Toxicities of the combination are similar to cytotoxic chemotherapy alone. Clinical trial information: NCT02299518.Grade ≥3 treatment-related adverse events occurring in ≥10% of pts (n = 21). Adverse Event Term no. (%) Anemia 16 (76.2) Thrombocytopenia 14 (66.7) Leukopenia 11 (52.4) Febrile neutropenia 9 (42.9) Lymphopenia 7 (33.3) Neutropenia 7 (33.3) Catheter related infection 6 (28.6) Diarrhea 5 (23.8) Hyponatremia 4 (19.0) Sepsis 4 (19.0) Fatigue 3 (14.3) Hyperglycemia 3 (14.3) Hypotension 3 (14.3) Agitation 2 (9.5) Hypophosphatemia 2 (9.5) Nausea 2 (9.5) Respiratory failure 2 (9.5)
One-step generation of monoclonal B cell receptor mice capable of isotype switching and somatic hypermutation
Authors: Johanne T. Jacobsen, Luka Mesin, Styliani Markoulaki, Ariën Schiepers, Cecília B. Cavazzoni, Djenet Bousbaine, Rudolf Jaenisch, Gabriel D. Victora
Journal: The Journal of Experimental Medicine (2018)

We developed a method for rapid generation of B cell receptor (BCR) monoclonal mice expressing prerearranged Igh and Igk chains monoallelically from the Igh locus by CRISPR-Cas9 injection into fertilized oocytes. B cells from these mice undergo somatic hypermutation (SHM), class switch recombination (CSR), and affinity-based selection in germinal centers. This method combines the practicality of BCR transgenes with the ability to study Ig SHM, CSR, and affinity maturation.
The poor outcome of patients with mCRPC whom were deemed ineligible for PSMA theranostics based on molecular imaging characteristics.
Authors: Sue Ping Thang, John A Violet, Shahneen Kaur Sandhu, Amir Iravani, Timothy J. Akhurst, Aravind Ravi Kumar, Grace Kong, Scott Williams, Rodney J Hicks, Michael Hofman
Journal: Journal of Clinical Oncology (2018)

e17002 Background: Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of patients with metastatic castrate-resistant prostate cancer (mCRPC) and represents a target for nuclear medicine imaging and therapy. We undertook a prospective trial of 177Lu-PSMA-617 theranostic therapy in men with mCRPC who progressed after standard therapies. The aim of this study is to determine the outcomes of men screened in this study with PSMA PET/CT who were not eligible for 177Lu-PSMA-617 therapy due to inadequate PSMA-expression. Methods: All patients underwent 68Ga-PSMA-11 and 18F-FDG PET/CT as part of trial screening which aimed to identify patients suitable for therapy. Patients were deemed ineligible to proceed with treatment if they had (1) low PSMA-expression defined by SUVmax of tumour involvement less than 1.5 times SUV of liver or (2) sites of FDG-positive PSMA-negative (discordant FDG-avid) disease. Baseline characteristics and subsequent treatments received by these patients following exclusion were recorded. Kaplan-Meier curve was used to determine overall survival (OS) defined from date of screening. Results: 18 patients (age 53-88 y.o) were excluded for theranostic therapy based on low PSMA expression (4), discordant FDG-avid disease (7) or both (7). The median PSA doubling-time was 1.7 months. 17 (72%) had Gleason score ≥8. All patients progressed after docetaxel chemotherapy, 7 (39%) after cabazitaxel and 17 patients (94%) after abiraterone or enzalutamide. Nine patients had subsequent systemic anti-tumour treatment following exclusion from trial. Seventeen of 18 patients died with a median OS of 2.6 months (95% CI 1.7 – 4.4 months), compared to median OS of 13.5 months (95% CI 10.4 – 22.7 months) in 30 eligible patients treated with 177Lu-PSMA-617. Conclusions: Low PSMA-expression or discordant FDG-avid disease in patients with mCRPC who progress after conventional therapies identifies a group with poor prognosis and short survival. The use of FDG PET/CT scan to identify discordant disease may help guide better selection of patients for PSMA-targeting radionuclide therapy.
EGFR and HER2 expression in ovarian cancer compared to clinical and pathological features of the patients.
Authors: Jamal Zidan
Journal: Journal of Clinical Oncology (2016)

e23254 Background: Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2)in ovarian carcinoma act as both a potent stimulator of proliferation and angiogenesis. Both are predictive factors in other cancers for biological targeting therapy. There is no consensus in the literature if EGFR and HER2 can be used as prognostic or predictive factors in ovarian cancer. The aim of this study was to evaluate the expression of EGFR and HER2 in ovarian cancer and to compare it with both clinical and pathological features of the patients. Methods: Forty three formalin-fixed, paraffin embedded tissue specimens presenting ovarian cancer were examined using immunohistochemistry (IHC) test for evaluation of EGFR and HER2. Recorded clinical and pathological data of each patient were summarized from the patients' files in Ziv Medical Center. Results: All 43 patients with ovarian cancer were evaluated. Ttherty three women (76.8%) were Jews, 5 Arabs (11.6%) and 15 (34.9) were other nationalities. At diagnosis stage I was diagnosed in (16.3) pts, stage II (11.6%), stage III (44.2%) and stage IV in (27.9) pts. Median age was 58 years (range: 17-82). Adenocarcinoma was diagnosed in (81.4%), endometrioid in 4 and 4 with other malignancies. Histologically, 16.3% were grade I, 16.3 grade II, 44.2% grade III and in 23.3% grade was unknown. EGFR was negative in 93%, weakly positive (+1) in 7% of pts. HER2 positive (+2) was found in 30% of the pts. In 70% of pts it was negative. HER2 was positive in 8% of pts with grade I compared to 26% of pts with grade III tumors (p < 0.05) Conclusions: In this study no EGFR expression was found in ovarian cancer. We plane not to use EGFR as prognostic nor predictive factor in this tumor. HER2 was higher in grade III compared to low grade ovarian cancer. As a result HER2 may be used as a prognostic and as a predictive factor for treatment with tyrosine kinase inhibitor drugs. Further studies with more patients are warranted to confirm these results. Conclusions:
VXM01 phase I study in patients with progressive glioblastoma: Final results.
Authors: Wolfgang Wick, Antje Wick, Felix Sahm, Dennis Riehl, Andreas von Deimling, Martin Bendszus, Philipp Kickingereder, Philipp Beckhove, Friedrich Hubertus Schmitz-Winnenthal, Christine Jungk, Sébastien Wieckowski, Lilli Podola, Christel Herold-Mende, Andreas Unterberg, Michael Platten
Journal: Journal of Clinical Oncology (2018)

2017 Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for vascular endothelial growth factor receptor (VEGFR)-2. The bacterium is a vector via the oral route of administration carrying the plasmid into the Peyer's plaques. The vaccine elicits a systemic T-cell response targeting VEGFR-2. This trial examined safety and tolerability, clinical and immunogenic response to VXM01 after at least four vaccinations [106 or 107 colony-forming units (CFU)] in patients with progressive glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive operable glioblastoma were subjected to VXM01 in one oral administration each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after surgery. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 12-weekly thereafter T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Fourteen patients have been treated with VXM01. Three out of them with additional nivolumab. Surgery has been performed in eight patients. Under VXM01 treatment 119 adverse events, mostly unrelated to VXM01, were observed after a median of 8 doses per patient. ELISpot analysis showed a detectable VEGFR-2 specific T cell response in 7 out 12 (58%) patients measured. In the observation period of up to 20 months 7 patients are alive, 5 out of them survived for more than one year, 2 patients are ongoing at month 10. In one patient there was an objective and durable T1 response. Survival seemed to be correlated with a higher CD8/Treg ratio in progressive and primary tumor, which further increased after VXM01 treatment. In patients with prolonged survival a decrease in intratumoral PD-L1 was observed arguing for combination of VXM01 with an anti-PD-L1 checkpoint inhibitor. Conclusions: VXM01 was safe and produces detectable specific peripheral immune responses as well as CD8/Treg ratio increase in post-vaccine tumor tissue. There was one patient with an objective response. As a next step, a combination study of VXM01 and anti-PD-L1 checkpoint inhibitor has been launched. Clinical trial information: NCT02718443.
A systemic review and meta-analysis to evaluate the efficacy and postprogression survival of second-line chemotherapy for gemcitabine-refractory pancreatic cancer.
Authors: Akiyoshi Kasuga, Yasuo Hamamoto, Yu Aoki, Kenta Kawasaki, Takeshi Suzuki, Kenro Hirata, Yasutaka Sukawa, Hiromasa Takaishi, Takanori Kanai
Journal: Journal of Clinical Oncology (2017)

e15768 Background: We previously reported positive relationship between overall survival (OS) and both of postprogression survival (PPS) and post-trial anti-cancer therapies in first-line pancreatic cancer patients. We conducted a meta-analysis to gain a better understanding of the impact of PPS and post-trial anti-cancer therapies on OS and to determine the efficacy of second-line systemic therapy. Methods: We searched randomized trials of second-line systemic therapy for pancreatic cancer patients. We evaluated the relation between OS and either progression-free survival (PFS) or PPS and calculated the pooled effect size by using random effects models. Results: Eleven randomized trials with 23 treatment arms that involved examining 2267 patients were analyzed. Median OS was strongly associated with median PPS and PFS (r = 0.908 and 0.754, respectively), but no correlation between rate of post-trial anti-cancer therapies and OS was detected (r = 0.050). Average OS, PFS and PPS were significantly longer in recent trials than in older trials, (6.08 versus 4.17 months, p &lt; 0.001), (2.65 versus 1.95 months, p &lt; 0.001) and (3.43 versus 2.25 months, p &lt; 0.001), respectively. Overall, experimental therapies compared to control did not significantly improve PFS (HR, 0.83; 95% CI, 0.67-1.03; I 2 = 73%) or OS (HR, 0.89; 95% CI, 0.72-1.11; I 2 = 69%). When the analysis was restricted to fluoropyrimidine compared to irinotecan or oxaliplatin in combination with fluoropyrimidine, each therapy produced advantage in a term of PFS (HR, 0.65; 95% CI, 0.47-0.88; I 2 = 39% for irinotecan, HR, 0.81; 95% CI, 0.67-0.98; I 2 = 13% for oxaliplatin) but only irinotecan produced advantage in a term of OS (HR, 0.70; 95% CI, 0.55-0.89; I 2 = 0% for irinotecan, HR, 1.04; 95% CI, 0.65-1.65; I 2 = 82% for oxaliplatin). Conclusions: Although second-line treatment benefit for OS can be skewed by PPS in patients with gemcitabine-refractory pancreatic cancer, the effects of subsequent therapies are weak in the salvage setting.
Validation of the Princess Margaret immune oncology prognostic index (PM-IPI) for patients (pts) treated in immune oncology (IO) early phase trials.
Authors: Daphne Day, Anna Spreafico, Stephanie Lheureux, Albiruni Ryan Abdul Razak, Aaron Richard Hansen, Lisa Wang, Marcus O. Butler, Lillian L. Siu, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2017)

3070 Background: We previously developed the PM-IPI (ECOG performance status [PS] &gt; / = 1, albumin &lt; lower limit of normal [LLN] and &gt; 2 metastatic sites) from a retrospective cohort of 192 pts treated in phase I IO trials (development cohort). The PM-IPI prognosticated for overall survival (OS), 90-day mortality (90DM) and was associated with improved overall response rate (ORR) and progression free survival (PFS). Our aim was to prospectively validate the PM-IPI in an independent cohort of pts treated on IO trials. Methods: We included 152 consecutively treated advanced solid tumor pts at PM from Aug 2015 to Aug 2016 in 24 IO early phase trials, targeting immune checkpoints and/or co-stimulatory molecules. Pts from the development cohort were excluded. The ability of the PM-IPI to prognosticate OS and 90DM, and predict PFS and ORR was compared with the previously published Royal Marsden Hospital prognostic score (RMI: albumin &lt; 35g/L, LDH &gt; upper limit of normal and &gt; 2 metastatic sites) using the C-index (0.5 = no discrimination, 1 = perfect discrimination) and Area Under the Curve (AUC). Results: Median age was 59y (range 20-86), 28%/72% of pts were ECOG PS 0/1, and 88% had at least 1 prior systemic therapy (range 0-7). The most common tumor sites were gastrointestinal (23%), gynecological (16%), head and neck (15%) and urological (10%). Median PFS and OS were 9.0 and 39.7 wk respectively and 90DM was 14%. ORR was 7% by RECIST 1.1, immune related RECIST or immune related response criteria. In multivariable analysis, ECOG PS &gt; / = 1 (HR 2.7, p = 0.01), albumin &lt; LLN (HR 2.1, p = 0.01) and &gt; 2 metastatic sites (HR 1.8, p = 0.04) were independently prognostic for OS. Pts with a PM-IPI score of 2-3 compared to 0-1 had significantly shorter OS (HR 3.3, p &lt; 0.0001), PFS (HR 1.7, p = 0.005) and higher 90DM (OR 12.2, p = 0.019), and a trend towards lower ORR (OR 0.4, p = 0.15). The prognostic performance of PM-IPI was superior to the RMI for OS and 90DM, but not PFS and ORR (Table). Conclusions: In this independent validation cohort, the PM-IPI prognosticated for OS and 90DM and was associated with PFS. Validation in a large external cohort is ongoing. [Table: see text]
Implementation of precision oncology in the Veterans Health Administration (VHA).
Authors: Michael J. Kelley, Jill Duffy, Bradley J Hintze, Christina D. Williams, Neil L Spector
Journal: Journal of Clinical Oncology (2017)

6507 Background: VHA is the US’s largest integrated healthcare system providing care to over 6 million Veterans (~40% in rural areas). Precision Oncology offers the promise of effective, low-toxicity targeted therapies tailored to individual tumor genomics but is unequally available to patients in the US. As part of the Cancer Moonshot, VHA is implementing a system-wide Precision Oncology Program (POP) including patients in rural areas, where specialty oncology care has historically had limited availability. Methods: Patients tested with multigene NGS tumor sequencing through 1 of 2 contracted vendors were identified from POP records and cancer characteristics were extracted from POP and medical records. Drug use data was obtained from the VA Corporate Data Warehouse. NGS testing results and annotations were extracted from POP records. Results: A total of 978 tumor samples were sent for NGS testing since program inception in 2015. The most common diagnoses are lung (464: adeno 314, squamous 107), GI (87), LN (75), liver (56), H&amp;N (52), and prostate (43). The rate of sample test requests increased rapidly after national implementation in July 2016 (mean 23 samples/month prior to implementation to mean 126 samples/month 3 months later) as did the number of participating facilities (mean 8/month to 27/month). Sequencing success rate increased from 68% to 71% over the same interval while mean turn around time remained similar at 19.7 and 19.1 d, respectively. NGS results are available for a cohort of 344 patients including: lung 200 (adeno 138, squamous 51), skin 28, LN 20, liver 19, GI 16. 979 variants were found including TP53 278, KRAS 106, STK11, APC 38, PIK3CA 38, and CDKN2A 37. 228 patients had actionable results (on-label drug 24, off-label drug 165, clinical trial 213). To date, 8 patients received a recommended drug outside a clinical trial between 11 and 288 d after testing (median 82 d); 4 additional patients had received an NGS-recommended drug prior to testing. Conclusions: Implementation of tumor NGS testing as part of Precision Oncology Program in a US distributed healthcare system is feasible. Further program implementation and provision of appropriate targeted drugs both on and off study will be necessary to impact patient outcomes.
Accuracy of self-reported chemotherapy regimens in young breast cancer survivors.
Authors: Kelly C. Gast, Elizabeth Jane Cathcart-Rake, Aaron Norman, Leah Eshraghi, Nwamaka Obidegwu, Kathleen J. Yost, Fergus Couch, Celine Vachon, Kathryn Jean Ruddy
Journal: Journal of Clinical Oncology (2018)

e22143 Background: Patient-reports of chemotherapy treatments are often used in oncology research, including to assess predictors of recurrence and long-term side effects. The purpose of this study was to evaluate the accuracy of patient-reported chemotherapy regimens compared to medical records in young breast cancer survivors. Methods: Participants were recruited through a Dr. Susan Love Research Foundation Army of Women email blast, which included a request for women diagnosed with breast cancer under age 50 and within the past ten years. Those who provided their contact information were mailed a study consent form and authorization to access their medical records. After each returned the informed consent, she received a web-based survey that inquired about use of and type of chemotherapy, if applicable (with generic and brand names provided as options). Medical records were reviewed for concordance with survey responses. Major discrepancies were defined as those in which the patient reported a different class of drug than documented in the medical record, or responded “don’t know.” Minor discrepancies were defined as those related to report of a different medication in the same drug class. Results: Completed questionnaires and medical records were available for 99 women with a median age at diagnosis of 41 years (range 25-49) and median time from diagnosis 67 months (range 7-131). There was a 100% concordance between self-report and medical records regarding receipt of chemotherapy (yes vs. no), but with regard to specific chemotherapy type, major discrepancies were identified in 30%, and minor discrepancies in 2%. Please see Table for additional details. Conclusions: Young women diagnosed with breast cancer more than five years prior accurately report whether or not they received systemic chemotherapy. However, even in a highly educated group of survivors, our data indicate that self-reports regarding specific drugs should be confirmed by medical record review. Characteristic N % with a major discrepancy in chemotherapy type identified Time between diagnosis and survey < 5 years 43 30.2% 5+ years 56 30.4% Age at survey < 45 years 73 24.7% 45+ years 26 46.2% Education < College grad 8 25.0% College grad 91 30.8%
Validation of a thrombosis risk assessment model in patients with newly diagnosed multiple myeloma.
Authors: Brea Lipe, Hailey Baker, Brandon Weckbaugh, Carol Webb, Alexandra Brown, Jonathan Mahnken, Theresa Shireman
Journal: Journal of Clinical Oncology (2016)

8055 Background: Within their first year of diagnosis, as many as 1 in 3 multiple myeloma (MM) patients will experience a venous thromboembolism (VTE). The International Myeloma Working Group (IMWG) has issued thromboprophylaxis guidelines that stratify patients into low or high risk for thrombosis and subsequently recommend aspirin (ASA, low risk) versus low molecular weight heparin (LMWH) or therapeutic warfarin ( high risk). We conducted a matched case-control study to determine if these guidelines are used in practice, and when they are, if they result in fewer VTEs for MM patients. Methods: The Healthcare Enterprise Repository for Ontological Narration (HERON) database was used to identify case patients with MM and a VTE. Controls, patients with MM who had not experienced a VTE, were matched (~ 1:3) to the cases based on gender, age (+/- 5 years), and time of diagnosis (+/- 5 years). Patient charts were manually extracted to identify treatment history, disease history, and risk factors for VTE. We then evaluated the distribution of risk of VTE per the IMWG guidelines with use of prophylactic anticoagulation. Using conditional logistic regression, we examined an association between risk of VTE, medications use, and the interaction between risk category for the matched patients at the time of diagnosis and at the time of the VTE. Results: There were a total of 297 patients in the final cohort, 86 cases and 211 controls. The median time from diagnosis to VTE was 952 days. Patients with a higher risk of VTE were more likely to be on LMWH or warfarin versus ASA or no prophylaxis (p < .001). We did not find an association between risk category or prophylactic medication with the rate of VTE when considering baseline risk factors. The risk category of case patients changed to a higher risk group over time and this was associated with a higher risk of clot (p = .06). Conclusions: Our data suggest that VTE in MM may occur later in the disease process than has historically been reported. While we were unable to validate the IMWG recommendations for thromboprophylaxis at diagnosis, our results suggest that the risk for VTE may change over time and that patient’s require ongoing assessment of VTE risk and thromboprophylaxis throughout the disease course.