tbuckley/cabot-search huggingface dataset:
Phase II study on lenvatinib (LEN) in recurrent and/or metastatic (R/M) adenoid cystic carcinomas (ACC) of the salivary glands (SG) of the upper aereodigestive tract (NCT02860936).
Authors: Laura Locati, Donata Galbiati, Giuseppina Calareso, Salvatore Alfieri, Roberta Granata, Paolo Bossi, Cristiana Bergamini, Carlo Resteghini, Stefano Cavalieri, Francesca Platini, Pasquale Quattrone, Moela Mancinelli, Andrea Zucchella, Luigi Mariani, Guido Fedele, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2018)

6086 Background: Systemic chemotherapy and targeted therapies (TT) are almost ineffective in R/M ACC patients (pts). Sorafenib and axitinib showed some activity, possibly through their antiangiogenic effect. LEN is a stronger second-generation antiangiogenic inhibitor. Here we report the activity of LEN in R/M ACC pts. Methods: Pts with R/M disease, 1 previous line of chemotherapy and/or TT, received oral LEN 24 mg/day. Progression within 6 months at study entry was required. Primary endpoint was objective response rate (ORR) according to RECIST 1.1; secondary endpoints were progression free survival (PFS), overall survival (OS), toxicities (CTC 4.0) and assessment of quality of life (QoL) with EORTC QLQ C-30, EORTC QLQ-H&N35, EQ-5D. A 2-stage Simon design was applied, to test the null hypothesis of response ≤ 5% versus the alternative response ≥ 20%; 3 responses were required to reject the null hypothesis. Results: Twenty-eight pts were enrolled, F 16/M 12, median age 55 years (range: 22-73), 14 ACC of major and 14 of minor SGs, 96% metastatic. PS was 0 in 14 cases, 1 in 12 and 2 in 2 pts. Treatment related adverse events (AEs) were frequent (all grades 96%): asthenia 79%, hypertension 75%, stomatitis and weight loss 71%, TSH elevation 68%, were the most common. Grade ≥ 3 occurred in 50% of pts (asthenia 25%, hypertension 18%). No G5 toxicities occurred neither bleeding. Nine SAEs were reported, 6 of them drug-related. Dose was reduced in 21 pts within 12 weeks from therapy start, only 4 pts maintained the full dose throughout treatment. Among 26 evaluable pts, partial responses were 3 (11.5%) (3/26). Target lesions reduction between 23% and 28% was observed in 4 out 20 pts with stable disease. At a median follow up of 21.9 months (95% CI, 13.8-27.8), 6 pts are still on LEN and 12 died due to progression. Median PFS and DoR were 9 (95%CI 5.5-14.2) and 3.1 (1.8-21.7+) months, respectively. Median OS was 26.1 months (95% CI, 11.1-NR). QoL analysis is ongoing. Conclusions: Tumor size reduction was seen in 27% of pts suggesting activity of LEN in ACC. Toxicity was common but manageable. QoL has been studied for the first time. A randomized study is needed to confirm efficacy. Clinical trial information: NCT02860936.
Impact of patient symptoms and caregiver tasks on psychological distress in caregivers for head and neck cancer (HNC).
Authors: Emily Castellanos, Mary S. Dietrich, Nancy L. Wells, Stewart M. Bond, Karen L. Schumacher, Barbara A. Murphy
Journal: Journal of Clinical Oncology (2018)

6070 Background: Caregiver support for HNC patients affects clinical outcomes including survival. Psychological distress in caregivers may impair the quality of support they provide. The impact of patient symptom burden and caregiver tasks on caregiver psychological distress is unknown. Methods: Patient symptom burden was assessed with the Vanderbilt Head and Neck Symptom Survey 2.0 (VHNSS 2.0; 10 domains, 3 single items). Caregiver task burden was assessed with the Caregiver Task Inventory (CTI; 11 domains), and quantified as task number and task difficulty/distress. Psychological distress was measured with the Profile of Mood States short form (POMS-SF). Two-step clustering analysis was used to independently generate clusters of caregiver distress, caregiver task burden, and patient symptom burden. Chi-Square and logistic regressions were used to test for associations of the resultant clusters of task burden and patient symptoms with caregiver distress. Results: 89 HNC patient-caregiver dyads were included. Patients were mostly male (77%) and Caucasian (88%). Median time since diagnosis was 3.7 months (IQR 2–7); 90% received combined modality therapy. Caregivers were mostly Caucasian (92%), female (85%) and spouses (80%). We found two caregiver clusters of psychological distress (40% mod-high, 60% low), and two clusters of caregiver task scores (40% mod-high, 60% low). Similarly, two clusters of patient symptom burden were found: 51% mod-high, 49% low. Caregivers with mod-high task scores were more likely than low to report mod-high levels of psychological distress (71% vs. 24%, p < 0.001). Patients with mod-high symptom burden were more likely than low to have caregivers with mod-high psychological distress (55% vs. 23%, p = 0.005). No effect modification of patient symptom burden on the association between caregiver task and caregiver psychological distress was seen (p > 0.05). Conclusions: Psychological distress in HNC caregivers is associated more strongly with caregiver task scores than patient symptoms. Further work to define the caregiver and task characteristics that lead to psychological distress should inform future interventions to support caregivers and patients.
A multicenter, randomized, double-blind, placebo-controlled phase III study of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, in combination with rituximab versus placebo in combination with rituximab in patients with treatment-naive follicular lymphoma (PERSPECTIVE).
Authors: Nathan Hale Fowler, Ian Flinn, Simon Rule, Robert W. Chen, Long Kwei, Darrin M. Beaupre, Alvina D. Chu, Leo I. Gordon
Journal: Journal of Clinical Oncology (2017)

TPS7576 Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347.
Non-invasive, blood-based DNA and RNA profiling for cancer immunotherapy and PARP inhibitor clinical trials.
Authors: Jianjun Yu, Zhixin Zhao, Amy Wang, Tak Cheung, Pan Du, Shidong Jia
Journal: Journal of Clinical Oncology (2017)

e14527 Background: The response to cancer immunotherapy (CI) and other target therapies varies widely across patients, making it difficult for physicians to select right treatment for a given patient. Studies report that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative respond to the drugs. Recent publications show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. However, as tissue biopsy remains a practical challenge in clinic due to its insufficient quantity or lack of access, non-invasive molecular test has provided a new alternative option to detect or monitor genomic alternations of tumors in clinical drug development. Methods: Based on Predicine’s Gene RADAR (RNA and DNA Single Molecule Digital Reading) technology platform, here we introduce PrediSeq-CI and PrediSeq-HRD (homologous recombination deficiency) blood tests, a non-invasive, next-generation sequencing (NGS)-based multiplex assay that enables real-time monitoring of temporal change of tumor heterogeneity and sensitive detection of genomic alterations related to cancer immunotherapy and DNA-repair homologous recombination pathways at both RNA and DNA levels. Results: Technical validation was performed to evaluate assay sensitivity, specificity and accuracy using reference samples with known genetic profiling. The panels have been further tested using tissue biopsy and plasma samples from cancer patients. Conclusions: The successful development of PrediSeq-CI and PrediSeq-HRD liquid biopsy tests offer an efficient solution to stratify and monitor cancer patients who may benefit from cancer immunotherapy as well as HRD-targeted therapeutics.
Correlation between EGFR mutation T790M predominancy in initial biopsy detected by droplet digital PCR and acquired resistant mechanism to EGFR TKI.
Authors: Hayato Koba, Taro Yoneda, Shingo Nishikawa, Takashi Sone, Hideharu Kimura, Kazuo Kasahara
Journal: Journal of Clinical Oncology (2016)

e20602 Background: The EGFR T790M mutation is the most common mechanism about drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR-mutated lung cancer. The third generation EGFR TKI has been reported a good efficacy to the patient who has a non small cell lung cancer harvouring the EGFR T790M mutation. On the other hand, several highly sensitive assays can already detect this mutation in pretreatment tissue biopsy. This study aim to evaluate a correlation the EGFR T790M mutation dominancy about the EGFR-mutated lung cancer which was not until exposed EGFR TKI therapy and actual resistance mechanism. Methods: We assessed the 26 EGFR TKI-free samples from EGFR-mutated non-small cell lung cancer by droplet digital PCR (ddPCR). T790M mutation dominancy ratio was calculated from isolated two PCR data about common mutation and T790M mutation and was estimated according to the following various clinical characteristics, that is actual T790M mutation using standard clinical method, age, sex, smoking status, PFS and treatment response of EGFR-TKIs. Results: We can detect the T790M mutation in 19 cases (73%) in initial biopsy tissue by ddPCR. The mean value of T790M mutation dominancy ratio was 0.48% (0.00-69.09%) and it is not difference in this ratio between T790M-positive and –negative cases, using standard clinical method (p = 0.92). The other clinical characteristics were not related with T790M mutation dominancy at all. Conclusions: T790M mutation was detected in most of the EGFR TKI-free sample, however the T790M mutation dominancy in pretreatment may not be related to actual post-treatment resistant mechanism whether EGFR T790M mutation was found.
Phase 1b study of oncolytic vaccinia virus GL-ONC1 in recurrent ovarian cancer (ROC).
Authors: Robert W. Holloway, James Erasmus Kendrick, Amanda Stephens, Jessica Kennard, Jeremy Burt, Jane LeBlanc, Karen Sellers, Jamie Smith, Susan Coakley
Journal: Journal of Clinical Oncology (2018)

5577 Background: Immunotherapy can trigger immune activation including tumor-infiltrating CD8+ T cells, leading to antitumor response and survival benefits. Immunotherapeutic GL-ONC1 (modified vaccinia virus) causes oncolysis, immune activation and durable anti-cancer memory. Methods: Intraperitoneal infusion of GL-ONC1 monotherapy was given at higher repeated doses compared to a previous Ph1 trial in patients (pts) with platinum refractory/resistant disease. Primary endpoint: adverse events; Secondary endpoints: anti-tumor response by RECIST1.1 & survival. Eleven heavily pretreated pts with end-stage ROC were enrolled: 3-4 prior lines (n = 3), ≥ 5 lines (n = 8), ECOG 0 (n = 7) or 1 (n = 4), ascites/pleural effusion (n = 9) & progressive disease (PD) at baseline (n = 10). There were two dose cohorts: 3 × 109 (n = 6) or 1 × 1010 (n = 5) plaque forming units/day on 2 consecutive days. Results: (1) Adverse reactions included Grade 1-2 chills (n = 7), nausea (7), fever (6), abdominal pain/distention (4), & vomiting (3). There were no differences in toxicity for the two dose levels. (2) GL-ONC1 colonized and replicated in the tumor, as indicated by a virus-encoded glucuronidase assay. (3) Clearance of tumor cells in ascites with induction of lymphocyte infiltration was shown in 5 pts with ascites. (4) Reduction of circulating tumor cells (CTC) was identified in 6/8 (75%) pts who had baseline CTC, ranging 1-42 per 7.5 mL blood. (5) Enhanced infiltration of CD8+ T cells into tumor tissue was demonstrated by repeat biopsy. (6) Disease Control Rate (DCR = partial response (PR) + stable disease (SD) ≥ 15 weeks) was 6/11 (55%). (7) Extended progression-free survival (PFS) of 23, 35, 59 (with confirmed PR) & 71 weeks were observed in 4 pts, respectively. (8) A tumor-specific T cell response was absent at baseline but confirmed at Week-30 in the PR patient by IFN-γ ELISPOT assay. (9) More than doubling of PFS compared to the last chemotherapy regimen was recognized in 4/11 (36%) pts. Conclusions: Promising safety data, anti-tumor activity, and immune activation mechanisms were documented in this Ph1b trial, and a Ph2 trial (VIRO-15) is currently enrolling. Future studies combining GL-ONC1 and other immune therapies and/or chemotherapy are under consideration. Clinical trial information: NCT02759588.
A RARE FORM OF CANCER, THYROID CANCERS INCREASING IN YOUNG ADOLESCENTS.
Authors: Emel Cabi Unal, Nurdan Tacyildiz, Gulsan Yavuz, Handan Dincaslan, Gulsah Tanyildiz, Merih Berberoglu, Zeynep Siklar, Aydin Yagmurlu, ESRA Erden, Metin KIR
Journal: Journal of Clinical Oncology (2016)

e22004 Background: We believe that the incidence of a rare tumor, differentiated thyroid cancers in children, are increasing following The Chernobyl Nuclear catastrophe. The most common presenting findings of thyroid cancers are thyroid nodules and cervical lymphadenopathy. Positive family history and neck irradiation are risk factors for development of thyroid carcinoma. Methods: Between 1990- February 2016, 28 cases of thyroid carcinoma have been diagnosed. Twenty-two were females, 6 were males with an age range of 15.8+3.2 years. One had cranial RT for ALL, one had neck irradiation because of HD, one patient who had lived in Kiev, had family history in both parents. Histopathologically 13 cases had differentiated papillary thyroid carcinoma, 7 had papillary thyroid variant, 1 follicular and 1 medullary thyroid carcinoma.In 3 of the cases thyroid nodules were < 10mm in size. In 3 there were microcalsifications; in 5 there were increased vascularization. Results: Following surgery, there was lymph node infiltration in one case, whereas in one, there was distant - lung metastasis. Three patients experienced hypoparathyroidism, in one case there was vocal chord problems. All patients received adjuvant radioactive iodine therapy and were put on thyroid hormone replacement therapy. B-RAF 600 mutation studies were carried out in case of adding targeted therapy i.e sorafenib to metastatic recurrent cases. The patients are monitored by measuring serum human TG levels and by ultrasound for recurrences. Conclusions: Although the treatment modality in children with thyroid cancers is still controversial, total thyroidectomy together with lymph node sampling / dissection represent the dominant method of surgical treatment, enabling the success rate of RAI therapy and provide a longer disease free survival.
Ultrasound guided biopsies in phase I trials: Single center experience of 350 consecutive cases.
Authors: Vasiliki Michalarea, Anastasia Constantinidou, Michela Guardascione, Nikolaos Diamantis, Raquel Perez, Karim Rihawi, Elena Geuna, Juanita Lopez, Stanley B. Kaye, Timothy Anthony Yap, Johann S. De Bono, Udai Banerji, L. Rhoda Molife, Nina Tunariu
Journal: Journal of Clinical Oncology (2016)

11579 Background: Emerging targeted and combination treatments of novel anticancer drugs in the molecular era mandate an increasing number of paired fresh tumour biopsies. We aimed to assess risks and complications of Ultrasound (US) guided biopsies performed in patients (pts) enrolled in phase I trials. Methods: Retrospective analysis of 350 cases of biopsies performed within the Drug Development Unit (DDU) at the Royal Marsden Hospital. Data were collected from electronic pt notes between August 2008 and December 2015. Results: Three hundred and forty (340) biopsies were performed on 195 pts participating in 46 different phase I trials. Nine biopsies were not performed due to medical reasons and one patient declined. 139 pts (72%) had paired biopsies, 13 pts had more than 2, and 3 pts had paired biopsies in the same day. Of all biopsies 287 (82%) were mandatory and 177 (51%) were superficial. The most commonly biopsied organ was the liver (137). All biopsies were performed under US guidance by one of the two DDU-dedicated radiologists. The median age was 59 (27-79) with 60 pts being older than 65y. Median ECOG performance status was 1 (0-3) and predominant gender was male (100/195). 24 (12%) pts were on anti-coagulation treatments and 9 had thrombocytopenia National Cancer Institute Common Toxicity Criteria (NCI-CTC) Grade 1 or 2. All biopsies were core biopsies; the number of cores ranged between 2-6. The most commonly needle size used was 18G. Reported complications included post procedure pain 16 (4.7%), infection 2 (0.6%) and conservatively treated bleeding 2 (0.6%), all at grade 1.). None of the complications required admission to hospital or prolongation of admission. Conclusions: In the era of new molecular targeted therapies and combination strategies, biopsies are necessary for the comprehension and further development of such treatments. We have demonstrated that paired, fresh biopsies in the context of phase 1 trials, can be performed safely using US guidance with minimal complication rates in all age groups.
Apatinib, a novel VEGFR inhibitor, combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer: A single-arm, open-label, phase 2 study.
Authors: Chunyan Lan, Yin Wang, Ying Xiong, Judong Li, Yanfang Li, Yanna Zhang, Min Zheng, Yanling Feng, Huiqiang Huang, Xin Huang
Journal: Journal of Clinical Oncology (2018)

5515 Background: Anti-angiogenic therapy combined with chemotherapy could improve the outcome of platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor which selectively inhibits VEGFR2. We assessed the efficacy and safety of combination of apatinib and oral etoposide, which has the advantage of home administration without an infusion pump and hospitalization, in patients with platinum-resistant or platinum-refractory ovarian cancer. Methods: In this phase 2, single-arm, open-label study, we included patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer. Patients received oral etoposide 50 mg on days 1 to 14 in a 21-day cycle for a maximum of six cycles. In addition to the chemotherapy, apatinib 500 mg was administered orally once daily. The primary endpoint was objective response rate by RECIST version 1.1. A Simon two-stage design was employed. This study was registered with ClinicalTrials.gov, number NCT02867956. Results: Between Aug 10, 2016 and Nov 9, 2017, 35 patients were enrolled. At data cutoff (Dec 31, 2017), 20 (57.1%) of 35 patients had discontinued study, and 15 (42.9%) patients remained on treatment. The reasons for treatment discontinuation included disease progression (n = 10), adverse events (n = 4), consent withdrawal (n = 2), lost of follow-up (n = 2), and others (n = 2). Objective responses were achieved in 19 (54.3%; 95% CI: 36.6–71.2) of 35 patients and disease control was obtained in 30 (85.7%; 95% CI: 69.7–95.2) patients. The median progression-free survival was 8.1 months (95% CI: 2.8–13.4). The most common grade 3 or 4 adverse events were neutropenia (41.2%), fatigue (32.4%), anaemia (29.4%), and mucositis (23.5%). No treatment-related death was recorded. All of the adverse events were manageable. Dose reductions occurred in 82.4% of the patients for apatinib and 76.5% of the patients for oral etoposide. Conclusions: The combination of apatinib with oral etoposide shows promising activities and manageable toxicities in patients with platinum resistant or refractory recurrent ovarian cancer, and warrants further study in phase 3 trials. Clinical trial information: NCT02867956.
Integrated genomics-based discovery of new druggable kinases as a therapeutic target and cancer biomarker for lung cancer.
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2017)

e23144 Background: Since the number of lung cancer patients responding well to current standard therapies is still small, further development of new anti-cancer agents with minimum risk of adverse effect and highly sensitive cancer biomarkers is eagerly awaited. Methods: We have been developing new molecular therapies targeting oncoproteins with their biomarkers; i) To identify up-regulated genes in 120 lung cancers by the gene expression microarray representing 27,648 genes, ii) To verify the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 407 non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNA and antibody assays, and v) To measure their serum protein levels by ELISA in 343 lung cancer patients. Results: We identified 50 druggable oncoproteins and selected a LSERT (lung cancer-specific receptor tyrosine kinase). Strong LSERT protein expression was associated with poor prognosis for NSCLC patients (P &lt; 0.0001; N = 407) as confirmed by multivariate analysis. We established an ELISA to measure serum LSERT (a cleaved form of its extracellular domain) and found that the proportion of serum LSERT-positive cases was 149 (56.4%) of 264 NSCLC and 35 (44.3%) of 79 SCLC patients, while only 6 (4.7%) of 127 healthy volunteers were falsely diagnosed. A combined ELISA for both LSERT and CEA classified 77.2% of the NSCLC patients as positive, and the use of both LSERT and ProGRP increased sensitivity in the detection of SCLCs up to 77.5%, while the false positive rate was 7 - 8%. Oncogenic LSERT activity was suppressed by treatment of lung cancer cells with anti-LSERT antibody or siRNA. Induction of LSERT increased the cellular growth and invasion by directly phosphorylating oncogenic driver kinase proteins for lung cancer and enhancing their downstream signaling of MAPK, AKT, and STAT3. Conclusions: Integrated cancer genomics might facilitate the development of diagnostic and prognostic biomarkers as well as therapeutic targets for small molecules, monoclonal antibodies, nucleic acid drugs, and cancer vaccines.