tbuckley/cabot-search huggingface dataset:
Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Georg Lenz, Eliza Hawkes, Gregor Verhoef, Corinne Haioun, Lim Soon Thye, Dae Seog Heo, Kirit Ardeshna, Geoffrey Chong, Jacob Haaber Christensen, Vivian Shi, Susanne Lippert, Florian Hiemeyer, Paolo Piraino, Carol Elaine Pena, Viktoriya Buvaylo, Barrett H. Childs, Igor Gorbatchevsky, Gilles A. Salles
Journal: Journal of Clinical Oncology (2017)

7536 Background: Relapsed/refractory (r/r) DLBCL patients (pts) are characterized by poor prognosis. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor, with modest single-agent activity in unselected DLBCL pts. Here we report the treatment effect of copanlisib in r/r DLBCL pts with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with r/r DLBCL and ≥1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered on days 1, 8 and 15 of a 28-day cycle. Tumor samples were evaluated for COO, CD79B mutations and &gt; 400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) by COO and CD79B status. Results: The full-analysis (FAS) and per-protocol sets (PPS; ≥3 doses, post-baseline scans and NGS/COO data) included 67 and 40 pts, respectively. Pts were 58% male, median age 69 (range 25-93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1-13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the PPS was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC pts. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL-wtCD79B pts and one GCB DLBCL-mCD79B responded (ongoing &gt; 17 cycles). NGS analysis in 54 pts detected 348 mutations; BCL2 (54% of pts), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on BCL2, BCL6, MYC, and MYD88 mutations. With a median of 6 cycles (range 1-29), the most common AEs (% all grade/gr3+4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 gr5 AEs (none drug-related). Conclusions: Copanlisib treatment of r/r DLBCL pts resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Clinical trial information: NCT02391116.
Risk of bleeding and arterial cardiovascular events in patients with splanchnic vein thrombosis in Denmark: a population-based cohort study
Authors: Kirstine Kobberøe Søgaard, Kasper Adelborg, Bianka Darvalics, Erzsébet Horváth-Puhó, Jan Beyer-Westendorf, Walter Ageno, Henrik Toft Sørensen
Journal: The Lancet Haematology (2018)
Tenascin C to regulate the function of sHER3, an endogenous inhibitor of neuregulin signaling.
Authors: Chunlin Cai, Mojun Zhu, Nita J. Maihle
Journal: Journal of Clinical Oncology (2017)

e23002 Background: HER3 expression is associated with poor prognosis in melanoma patients but the mechanistic basis has not been determined. An endogenous secreted isoform of HER3, p85-sHER3, has been shown by us to inhibit neuregulin-1 mediated, Akt-dependent breast and ovarian cancer cell growth in vitro. Here we demonstrate that p85-sHER3 also regulates neuregulin-dependent melanoma cell migration via an Akt- independent, tenascin C-dependent mechanism. Methods: Immunoblot analysis and RT-PCR were used to study HER3 and p85-sHER expression. Cell proliferation and chamber assays were conducted to determine the effect of p85-sHER3 on melanoma cell growth and migration. Mass spectrometry (MS) was performed to identify sHER3-interacting proteins. CRSPR in vitro editing methods were used to knock out tenascin C (TNC) expression. Results: HER3 and p85-sHER3 were expressed in 5 of 6 human melanoma-derived cell lines tested, with exception of SK-MEL-103 which did not express either gene product. Exogenous addition of 10 nM p85-sHER3 inhibited growth in 3 cells lines, although Akt phosphorylation was not reduced. Protein extracts from M14-MEL cell conditioned media were characterized by MS, and identified p85-sHER3 and TNC. Their association was confirmed by co-immunoprecipitation. sHER3 was further shown to inhibit neuregulin stimulated cell migration in 2 cell lines which exhibited high levels of TNC. CRSPR knockout of TNC in these cell lines (but not in control lines) eliminated sHER3 inhibition of neuregulin stimulated melanoma cell migration. Conclusions: Our results suggest that p85-sHER3, predominantly secreted by HER3-expressing melanoma cells, inhibits melanoma cell proliferation and migration via an Akt-independent mechanism, which is likely achieved through interaction(s) with TNC. TNC promotes an intermediate adhesive state favoring cell migration and this state appears to be mediated by Rho-associated kinase signaling. The Rho inhibitor, CCG-203971 has been shown to inhibit melanoma cell migration. Together, these results suggest the existence of a TNC and HER3-dependent signaling pathway in melanoma that regulates cell migration, and therefore may be correlated with poor patient survival.
Quality of life of acute myeloid leukemia patients in a real-world setting.
Authors: Bhavik J. Pandya, Anna Hadfield, Bruno C. Medeiros, Samuel Wilson, Cat N. Bui, Tom Bailey, Scott Flanders, Alex Rider, Laura E. Horvath
Journal: Journal of Clinical Oncology (2017)

e18525 Background: There is currently limited data on the quality-of-life (QoL) of patients with acute myeloid leukemia (AML) in the real-world setting. The objective of this analysis was to understand the impact of AML on patients receiving first-line treatment vs those who were relapsed/refractory to first-line treatment and therefore on later lines of therapy. Methods: The Adelphi AML Disease-Specific Programme, a real-world, cross-sectional survey involving 61 US hematologists/hemato-oncologists and their consulting AML patients, was conducted between February–May 2015. Physicians provided details on patient demographics and clinical information. Each patient was asked to complete both the EQ-5D-3L and Functional Assessment of Cancer Therapy Leukemia (FACT-Leu). Scores range from −1.09–1 (EQ-5D-3L) and 0–176 (FACT-Leu), where a higher score indicates a better QoL. Data from physician-completed record forms and corresponding patient self-completion forms on a matched sample of 75 patients were analyzed. Results: Of the patients who took part in the survey, 75% (n = 56) were receiving first-line treatment for AML and 25% (n = 19) were relapsed/refractory to first-line treatment and had progressed to later lines of therapy. The first-line patients had a mean age of 56.6 years and an average of 2.1 symptoms whereas the relapsed/refractory patients had a mean age of 56.9 years and an average of 2.4 symptoms, according to the physician. First-line patients may have a directionally better QoL scores than those on later lines of therapy, according to both the EQ-5D (0.75 and 0.71 respectively, P= .51) and the FACT-Leu (103.7 and 92.5 respectively, P= .098) measures. Results from the FACT-Leu-Physical Well-Being sub-domain show that relapsed/refractory patients were significantly more likely than first-line patients to be affected physically by their AML condition (13.0 and 17.6 respectively, P= .005). Conclusions: AML patients who have relapsed or become refractory to first-line treatment report worse QoL than those still on first-line treatments. These observational data shows a need for effective and tolerable treatments that can maintain or improve patients’ QoL, especially for patients with relapsed or refractory disease.
Immune-related saliva micro-RNA’s to predict clinical response to a combination of cetuximab and low-dose chemotherapy in head and neck cancer (HNSCC) patients (pts) with poor performance status (PS).
Authors: Marcelo Raul Bonomi, Safoa Ado, Mitra Kooshki, Tamjeed Ahmed, Christopher Sullivan, Joshua Waltonen, Pierre Triozzi
Journal: Journal of Clinical Oncology (2017)

e17548 Background: Recurrent/Metastatic HNSCC is an immunosuppressive disease, especially in the group of patients with poor performance status. Recent studies have shown that low dose chemotherapy, which is much better tolerated than full dose cytotoxic chemotherapy, can increase the anti-tumor immune response and cause tumor regression. In this study we assessed the immune-effects of weekly cetuximab in combination with low dose weekly chemotherapy in HNSCC pts with poor PS by measuring saliva and plasma immune modulatory micro RNAs (miRs). Methods: Patients with recurrent/metastatic HNC with an ECOG PS of 2 or 3 were treated with low-dose weekly carboplatin (AUC 1) and paclitaxel (25 mg/m2) along with weekly cetuximab (400mg/m2 followed by 250 mg/m2). Seven immune modulatory miRs (146a, 155, 181, 20a, 223, 335, 125b) were measured in the saliva and plasma by quantitative PCR prior to treatment and at week 5. Results: Between 4/2016 and 1/2017, 30 patients were enrolled in this study. 24 patients were evaluable for response. Mean age was 69 years (range 51-89), Male/Female: 14/8. ECOG PS 2/3: 13/9. Site of disease: oral cavity 7, pharynx 9, larynx 4, para-nasal 2, unknown 2. Treatment was well tolerated. The most common dose limiting toxicity was skin rash in 10/24 pts (41.5%). Response: partial response 12 (50%); stable disease 4 (16.5%); progressive disease 8 (33.5%). Reduction in miR levels by week 5 were associated with clinical response. Reduction in saliva levels of miRs 146a and 181 correlated with clinical benefit (PR+SD). Pre-treatment saliva levels of miR 146a also showed to be a predictor of tumor response to therapy. Plasma levels of the immune modulatory miRs tested were not associated with response to therapy. Conclusions: The combination of cetuximab and low-dose chemotherapy is active and well tolerated in HNSCC patients with poor PS. Reduction in saliva levels of immune modulatory miRs 146a and 181 were associated with clinical benefit to therapy.
Triple combination treatment of cetuximab, chemotherapy, and anti-PD1 check-point inhibitor for recurrent and/or metastatic head and neck squamous cell carcinoma: A single institute experience.
Authors: Ying-Chu Lin, Wu-Ching Uen, Sheng-Po Hao, Chen-Yu Hsiao, Hung-Chih Lai
Journal: Journal of Clinical Oncology (2018)

e18001 Background: The 1st line standard treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M SCCHN) was platinum-based chemotherapy plus cetuximab, established by Vermorken at al (EXTREME regimen) since 2008. However, the toxicities and poor overall survival rate were reported in long follow-up. Recently, anti-PD1 check-point inhibitors were approved in R/M SCCHN as single agent. The low response rate and long time to response anti-PD1 therapy also limited the usage in R/M SCCHN. The ADCC effect of cetuximab was noted in previous literatures, which might improve activities of immunotherapy. Therefore, we hypothesis that the combination of cetuximab, chemotherapy and anti-PD1 therapy might have therapeutic effects in R/M SCCHN. Methods: We performed a retrospectively review of charts in patients with R/M SCCHN who received combination therapy of cetuximab, chemotherapy and anti-PD1 therapy from Feb. 2017 to Jan.31 2018. Results: A total of 15 patients with R/M SCCHN who received combination therapy were reviewed. Previous treatments of R/M SCCHN included: chemotherapy (40%), anti-EGFR (20%), anti-PD1 check-point inhibitor (20%). One patient died. Twelve patients were evaluable for response. The best responses were: 7 PR (58.3%), 4 SD (33.3%), and 1 PD(8.3%). Overall response rate 58.3 % and clinical benefit rate 91.6 % were observed. All grade adverse effects included: Anemia (86%), renal impairment (46.6%), skin rash (33.3%), fatigue (26.6%), mucositis (26.6%), acne (20%). The grade 3/4 adverse effect was limited, except for peripheral neuropathy was observed in 1 patient. Conclusions: This retrospective study of 15 R/M SCCHN patients provided a real world data for triple combination therapy of cetuximab, chemotherapy and anti-PD1 check-point inhibitor with an ORR of 58.3% and CBR of 91.6%. The treatments were well-tolerated. Further prospective study of triple combination therapy is recommended.
A pilot study of individualised monitoring of patients with metastatic melanoma using plasma and urine DNA.
Authors: Jonathan Wan, Suzanne Murphy, Davina Gillian Gale, James Anthony Morris, Florent Mouliere, Andrew Gill, Francesco Marass, Katrin Heider, Christine Parkinson, Ferdia Aidan Gallagher, Amer J Durrani, Ultan McDermott, Charles Massie, Philippa Corrie, Nitzan Rosenfeld
Journal: Journal of Clinical Oncology (2017)

e21032 Background: Circulating tumour DNA (ctDNA) is released by cancer cells into the bloodstream and can be analysed via liquid biopsy, providing a real-time snapshot of tumour burden. After treatment, ctDNA concentrations may be low, making detection challenging, and collecting larger sample volumes may be impractical. Our study aims to achieve high-sensitivity monitoring of melanoma patients melanoma on therapy, maximising the number of mutations targeted per patient by individualised sequencing. Methods: 72 patients with stage 3 or 4 melanoma have so far been recruited to MelResist, a translational research study. 235 plasma, urine, tumour and buffy coat samples have been analysed for 10 BRAF mutant metastatic melanoma patients receiving systemic therapies, and 30 matched CT scans were analysed for RECIST response. Exome or targeted sequencing were carried out on tumour samples and plasma at baseline and progression and mutations identified were used to design individualised amplicon and hybrid-capture sequencing panels targeting hundreds to thousands of mutations per patient. Results: Baseline ctDNA allele fraction predicted for overall survival ( r = -0.56, p &lt; 0.05). Longitudinal analysis of ctDNA showed that mutant allele fractions significantly correlated with tumour burden from CT imaging ( r = 0.79, p &lt; 0.0001) and ctDNA changes were concordant with 20/22 (90%) of RECIST response events. ctDNA allele fractions increased with a lead time of 70 days relative to serum lactate dehydrogenase, a standard measure of disease burden (IQR = 42-142 days). Targeting multiple mutations per patient enabled detection of less than one mutant genome copy per sample and allowed comprehensive monitoring of clonal evolution on therapy, even using limited sample volumes. Conclusions: Analysis of an initial cohort of BRAF mutant metastatic melanoma patients has confirmed feasibility to apply an individualised targeted sequencing panel on both plasma and urine DNA. For a given sample volume, monitoring multiple mutations improves detection sensitivity compared to targeting individual loci, has predictive value and can be applied to all melanoma patients, irrespective of BRAF mutation status.
Ruxolitinib (RUX) in combination with azacytidine (AZA) in patients (pts) with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs).
Authors: Rita Assi, Jorge E. Cortes, Naveen Pemmaraju, Elias Jabbour, Prithviraj Bose, Tapan M. Kadia, Courtney Denton Dinardo, Lingsha Zhou, Sherry Pierce, Stephanie Van Derbur, Carla Tuttle, Gautam Borthakur, Zeev Estrov, Guillermo Garcia-Manero, Hagop M. Kantarjian, Srdan Verstovsek, Naval Guastad Daver
Journal: Journal of Clinical Oncology (2017)

7064 Background: Clinical trials exclusively focusing on pts with MDS/MPNs are lacking. Combining RUX and AZA may target distinct manifestations of MDS/MPNs. Methods: Pts were treated with single-agent RUX 15 mg or 25 mg (based on platelets count) orally twice daily continuously in 28-day cycles for the first 3 cycles. AZA 25 mg/m 2 (day 1-5) was added on each cycle starting cycle 4 and could be increased to 75 mg/m 2 (maximum) or started earlier than cycle 4 and/or at higher dose in pts with proliferative features or high blasts. Results: 35 pts with med age 70 years (range, 43-79) were enrolled (MDS/MPN-U, n = 14; CMML, n = 17; atypical CM (aCML), n = 4), 28 (80%) were Int-2/High per MF DIPSS, 14 (41%) had splenomegaly &gt; 5 cm, and 12 (34%) had EUMNET MF-2/MF-3 fibrosis. Common mutations on a 28-gene sequencing panel included JAK2 (29%), RAS (27%), ASXL1 (21%), TET2 (18%), and DNMT3A (12%). All 35 pts were evaluable for response per MDS/MPN IWG criteria and 17 (49%) responded. 6/17 (35%) IWG responses occurred after the addition of AZA (med time after AZA = 1.8 months). JAK2 mutated pts had a trend to higher responses vs those with non-mutated pts (8/10 vs 9/25, P = 0.19). Ten pts had &gt; 5% pretreatment BM blasts and 7 achieved a reduction in blasts to &lt; 5% (70%). A &gt; 50% reduction in palpable spleen length reduction at 24 weeks was seen in 9/12 (75%) pts. New grade 3/4 anemia and thrombocytopenia occurred in 18 pts (51%) and 19 (54%) pts but were manageable with dose modifications. Only one pt discontinued therapy due to cytopenias. At a med follow-up of 17.4 mo (range, 1.2-36.8+), 14 (40%) pts died: pneumonia (n = 4), sepsis (n = 4), progression to AML (n = 4), and cardiac arrest (n = 1). The med survival for all pts was 16.6 mo (1.0 - 36.8). Compared to CMML and aCML, MDS/MPN-U pts had significantly better med survival (26.4+ vs 15.0+ vs 1.5+ mo, respectively; p = 0.01). Conclusions: The combination of RUX and AZA showed an IWG-response rate of 49% in pts with MDS/MPNs, and was well-tolerated. The benefit appears more profound in pts with MDS/MPN-U. This study is ongoing. (ClinicalTrials.gov Identifier: NCT01787487).
Evaluating disparities in clinical trial accrual in an urban academic radiation oncology department.
Authors: Alyssa M Asaro, Nitin Ohri, Madhur Garg, Shalom Kalnicki
Journal: Journal of Clinical Oncology (2018)

e18759 Background: Clinical cancer trials suffer from underrepresentation of racial and ethnic minorities as well as subjects with low socioeconomic status (SES). Here we examine if these disparities exist within our urban academic radiation oncology department. Methods: We identified all subjects enrolled on prospective therapeutic or supportive care clinical trials in our department from March 2015 through November 2017. Study subjects were matched (1:2) to contemporary controls who were treated in our department for the same diagnosis and not enrolled on a clinical trial. Patient characteristics, including age, race, ethnicity, primary language, and SES score (based on home address using neighborhood-level data), were tabulated. Characteristics of the two groups were compared using t-tests and chi-square tests. Results: 268 subjects were enrolled on twenty clinical trials. Fourteen studies were therapeutic, and six tested supportive care interventions. Ten were investigator-initiated studies, eight were cooperative group trials, and two were industry-sponsored studies. Mean subject age was 63. Thirty-two percent of subjects were African American, 25% were Hispanic, and 82% identified English as their primary language. 190 trial subjects were matched to 379 patients who were not enrolled on trials. There were no statistically significant differences between the two groups with respect to age, race, ethnicity, primary language, or SES. Subset analyses based on trial intent or study sponsor continued to show no differences between study subjects and matched controls. Conclusions: Within our diverse and underserved patient population, we found no disparities in clinical trial enrollment with respect to demographic or social factors. The underrepresentation of minorities in multi-institutional studies could be addressed by ensuring that minorities have access to participate in clinical trials.
Oncology patient and practitioner experience with complementary/alternative medicine at the NIH Clinical Center.
Authors: Tara A. Berman, Christina M. Annunziata, Ann Berger
Journal: Journal of Clinical Oncology (2018)

e22188 Background: Complementary/alternative medicine (CAM) use in oncology patients is widespread and increasing. Oncologists may be aware of patients’ use of CAM in conjunction with conventional cancer therapy, but whether these therapies are effective or deemed acceptable in the outpatient setting remains elusive. The purpose of this study is to assess the prevalence of CAM use in the NIH Clinical Center and inquire into the experience of CAM use from both the patient and practitioner perspective. Methods: Two questionnaires were developed: one for patients’ use of CAM, and the other for practitioners’ awareness of CAM use by their patients. Both queried CAM use within categories of diet, supplements, hands-on therapy, and movement therapy. Questionnaires were reviewed by and administered in compliance with Office of Human Subjects Protection guidelines (OHSRP ID# 17-NCI-00318). Subjects were either patients at least 18 years of age, attending the outpatient cancer clinics at the NIH Clinical Center in Bethesda, MD between July 2016 and February 2018, or practitioners involved in outpatient oncology care. After acknowledging the participant consent narrative, participants completed a 48-51 item self-administered questionnaire emailed via SurveyMonkey. Results: Results report the prevalence of CAM use by over 400 patients at the NIH Clinical Center, as well as clinician evaluation of CAM use and efficacy in their patients. All analyses are performed using data collected from the surveys via SurveyMonkey. Descriptive statistics incorporate subjective interpretation of outcomes with each modality, as perceived by either patient or physician, and include frequency distribution within each category. Conclusions: CAM use is widespread at the NIH Clinical Center. Patients incorporating CAM into their treatments are eager to discuss their use with clinicians and welcome physician guidance. This justifies more rigorous clinical investigation of CAM to help practitioners advise regimens to ameliorate cancer patients’ symptoms and side effects.