bluuebunny/crossref_metadata_2025_split huggingface dataset:
Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.
Authors: Koca Emre , Niravath Polly Ann , Ensor Joe , Patel Tejal Amar , Li Xiaoxian , Hemati Pej , Wong Helen , Qian Wei , Boone Toniva , Zhao Jing , Ramshesh Priya V. , Cohen Adam Louis , Murthy Asha , Nair Sindhu , Darcourt Jorge German , Belcheva Anna , Kaklamani Virginia G. , Chang Jenny Chee Ning 
Published: May 2019

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.
Correlation of the tumor mutational burden with the composition of the immune cell subpopulations in peripheral blood of triple-negative breast cancer patients undergoing neoadjuvant therapy with durvalumab: Results from the prospectively randomized GeparNuevo trial.
Authors: Seliger Barbara , Karn Thomas , Denkert Carsten , Schneeweiss Andreas , Hanusch Claus , Blohmer Jens Uwe , Jackisch Christian , van Mackelenbergh Marion , Marme Frederik , Mueller Volkmar , Huober Jens Bodo , Untch Michael , Loibl Sibylle , Mueller Anja , Biehl Katharina , Weber Karsten Ernst , Massa Chiara 
Published: May 2019

588 Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard chemotherapy with nab-Paclitaxel (nab-Pac) followed by Epirubicin plus Cyclophosphamid (EC; Loibl S et al. ASCO 2018). Since the tumor mutational burden (TMB) has been suggested to be associated with a better outcome of patients undergoing immunotherapy and an increased T cell response, we determined whether there exists a link between TMB and immune cell composition, frequency and function in patients of the GeparNuevo trial. Methods: In order to determine possible predictive and / or prognostic biomarkers, tumor biopsies taken at recruitment from 149 patients out of the 174 enrolled patients underwent deep sequencing in order to determine the TMB. In addition, for 120 patients blood samples were taken at recruitment and during different time points of treatment (after durvalumab pre-treatment, after Nab-Pac and at surgery after EC) and evaluated using multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations. Results: The TMB of the GeparNuevo cohort was in line with published data with a mean of 1.8 mutations/MB (range 0.02 – 7.65), respectively. Preliminary evaluation demonstrated a significant correlation of TMB with blood parameters, in particular with subsets of CD8+ T cells. Interestingly, the data suggest a negative correlation of TMB with the frequency of effector cells while a positive correlation exists with the effector memory cells at recruitment. In depth analyses of a correlation with treatment arm and clinical responses are currently performed. Conclusions: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Clinical trial information: NCT02685059.
Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): Results from a phase II basket trial.
Authors: Li Bob T. , Shen Ronglai , Offin Michael , Buonocore Darren J. , Myers Mackenzie L. , Venkatesh Aishwarya , Razavi Pedram , Ginsberg Michelle S. , Ulaner Gary A. , Solit David B. , Hyman David Michael , Rudin Charles M. , Gedvilaite Erika , Tsui Dana , Arcila Maria E. , Kris Mark G. , Weitsman Gregory , Ng Tony , Scaltriti Maurizio , Ho Alan Loh 
Published: May 2019

6001 Background: SGCs are rare tumors with no approved therapy for metastatic disease. HER2 amplification occurs in 8% among all SGC histologies, and 25-33% of the aggressive salivary duct carcinoma (SDC) histologic subtype. We hypothesized that ado-trastuzumab emtansine, a HER2 targeted antibody drug conjugate, may be clinically active in these patients. Methods: A cohort of patients with HER2 amplified SGCs were enrolled into a multi-histology basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) by RECIST v1.1 or PERCIST. A Simon two-stage optimal design was applied with type I error rate under 2.7%, power of 89%, H0 10%, H1 40%; H0 will be rejected if 6 or more responses are observed in 24 patients. Other endpoints include duration of response (DOR), progression-free survival (PFS), and toxicity. HER2 amplification was identified by next generation sequencing (NGS), and tumors were subsequently tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Fluorescence lifetime imaging microscopy - Förster resonance energy transfer (FLIM-FRET) assessed the propensity for HER2-HER3 heterodimerization, which leads to receptor internalization. Results: 10 patients with HER2 amplified SGCs were treated. The median age was 65 (range 36-90 years), 90% were male. The median lines of prior systemic therapy was 2 (range 0-3). ORR was 90% (9/10, 95% CI 56-100%) including 5 complete responses after prior trastuzumab, pertuzumab and anti-androgen therapy. After a median follow up period of 12 months (range 4-20 months), median DOR (range 2-19+) and median PFS (95% CI 4–22+ months) were not reached. Toxicities included grade 1 or 2 infusion reaction, thrombocytopenia and transaminitis; there were no treatment related deaths. HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with HER2/CEP17≥2 by FISH (8/8 tested) or IHC3+ (10/10 tested). FLIM-FRET tested positive in 3/3. Conclusions: Ado-trastuzumab emtansine is highly efficacious in patients with HER2 amplified SGCs as identified by NGS. This study has met its primary endpoint, and cohort expansion is warranted to confirm these results. Clinical trial information: NCT02675829.
Gemcitabine and cisplatin (GP) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC): A phase 3, multicenter, randomized controlled trial.
Authors: Ma Jun , Zhang Yuan , Sun Ying , Xie Fangyun , Hu Weihan , Hu Guoqing , Zhang Ning , Yang Kun-Yu , Zhu Xiaodong , Jin Feng , Cheng Zhi-Bin , Shi Mei , Han Fei , Tian Ye , Sun Yan , Mo Hao-Yuan , Li Jin-Gao 
Published: May 2019

6003 Background: GP regimen has been established as the standard first-line treatment option for patients with recurrent/metastatic NPC. However, its efficacy in locoregionally advanced disease remains unclear. Methods: Patients with previously untreated, non-metastatic stage III-IVB (except T3-4N0M0, AJCC 7th) NPC, aged 18–64 years without severe comorbidities were eligible. They were randomly assigned (1:1) to receive GP IC (gemcitabine 1 g/m2on days 1 & 8, cisplatin 80 mg/m2 on day 1, q3w for 3 cycles) plus CCRT (cisplatin 100 mg/m2, q3w for 3 cycles, concurrently with intensity-modulated radiotherapy) or CCRT alone. The primary endpoint was failure-free survival (FFS). The calculated sample size was 238 per group, with an 80% power (two-sided α 0.05) to detect a treatment failure hazard ratio (HR) of 0.52. Results: From Dec 2013 to Sep 2016, 480 patients from 12 centers were randomly assigned to IC+CCRT (n = 242) or CCRT alone (n = 238) group. Baseline characteristics were well balanced. After a median follow-up of 39 months, 3-year FFS was 85.8% in the IC+CCRT group and 77.2% in the CCRT alone group (intention-to-treat population; HR 0.53, 95% confidence interval 0.34–0.81; P = 0.003). In GP+CCRT group, 239 patients started GP IC and 231 (96.7%) completed all three cycles. The most common ≥grade 3 adverse events (AE) in IC+CCRT and CCRT group were mucositis (28.9% vs. 32.1%), neutropenia (28.0% vs. 10.5%) and leukopenia (26.4% vs. 20.3%). Conclusions: Adding GP IC to CCRT significantly improved FFS in locoregionally advanced NPC and is well tolerated with favorable toxicity profile. Clinical trial information: NCT01872962. [Table: see text]
Neck dissections based on sentinel lymph node navigation versus elective neck dissections in early oral cancers: A randomized, multicenter, non-inferiority trial.
Authors: Hasegawa Yasuhisa , Tsukahara Kiyoaki , Yoshimoto Seiichi , Miura Kouki , Yokoyama Junkichi , Hirano Shigeru , Uemura Hirokazu , Sugasawa Masashi , Yoshizaki Tomokazu , Homma Akihiro , Chikamatsu Kazuaki , Suzuki Mikio , Shiotani Akihiro , Matsuzuka Takashi , Kohno Naoyuki , Miyazaki Masakazu , Oze Isao , Matsuo Keitaro , Kosuda Shigeru , Yatabe Yasushi 
Published: May 2019

6007 Background: The objective of the study is to evaluate the non-Inferiority of survival, the superiority of postoperative disability, and the complication of the neck in neck dissections based on sentinel lymph node navigation in early oral cancer patients, compared with standard selective neck dissections. Methods: This study was a randomized, multicenter, non-inferiority trial at 16 institutions in Japan. Eligibility criteria included histologically confirmed squamous cell carcinoma in the oral cavity; clinical categories T1 and T2, N0M0 by UICC TNM classification 7th edition, clinical depth of invasion (DOI) of T1 was over 4mm (defined as late T1); previously untreated; age at least 18 years; and written informed consent. We randomly assigned patients (1:1) to receive either sentinel lymph node biopsy (SNB) or standard selective neck dissections (ND) with stratification of T category (lateT1 vs T2) and subsite (tongue vs others). The primary endpoint was 3-year overall survival with a non-inferiority margin of 12%. Sentinel nodes (SNs) were detected using radioisotope method and examined with multislice frozen section analysis intraoperatively, following HE and cytokeratin stain for a final postoperative diagnosis. Patients with positive SNs had neck dissections in a one-stage or back up procedure. Results: Between November 2011 and January 2016, 271 patients were enrolled and randomized to SNB group (134 patients) and ND group (137 patients) with a median follow-up of 37 months (IQR 36-39). Pathological positive nodal status was 34% (46/132) in SNB group and 26% (34/133) in ND group (Chi-Square p = 0.10). 3-year overall survival in SNB group was 89% (95%CI 82-93%), which was non-inferior to that in ND group (86%, 95%CI 79-91%). 3-year relapse-free survival was 80% (95%CI 72-86%) in SNB group and 81% (95%CI 73-87%) in ND group. Arm abduction of postoperative 1 and 3 months in ND group was disturbed significantly compared with SNB group. Conclusions: SNB navigated ND could replace elective ND without survival disadvantage and reduce postoperative disability of the neck in patients with early oral cancer. Clinical trial information: 000006510.
Discordant treatment response in primary tumors and lymph node metastases after four weeks of preoperative PD-1 blockade in head and neck squamous cell carcinoma (HNSCC).
Authors: Luginbuhl Adam , Johnson Jennifer Maria , Tuluc Madalina , Mardekian Stacey , Harshyne Larry , Leiby Benjamin , Zinner Ralph , Curry Joseph M. , Cognetti David M. , Rodeck Ulrich , Argiris Athanassios 
Published: May 2019

6016 Background: Discordant radiographic responses are described in other tumor types in response to immunotherapy with response at some anatomic sites and progression in others. Here we determined the frequency of discordant treatment effects (TE) in HNSCC patients treated with immunotherapy in the context of a neoadjuvant trial. Methods: 23 Patients with resectable primary HNSCC were 1:1 randomized to receive nivolumab (240 mg IV Q 2 weeks x 2) or nivolumab and tadalafil 10 mg daily. Surgery was performed 4 weeks after the first nivolumab infusion. Resection specimens were graded histopathologically by two pathologists. Areas exhibiting TE (defined by fibrosis with chronic inflammation, foamy macrophage reaction and multinucleated giant cells) were expressed relative to the total tumor area. This was assessed in the primary tumor and all lymph nodes (LN). Each primary lesion and individual LN was defined as a) no response 0%TE, b) minimal response 1-19%TE, c) response 20-99% or d) complete response 100%. Concordance was defined if primary lesion and LNs were in the same ordinal data set. Results: 11/23 (48%) of subjects experienced concordant ΤΕ in the primary tumor and LNs. Within this cohort, 3 patients had a complete pathologic response both at the primary site and LNs. In contrast, 12/23 patients (52%) revealed discordant ΤΕ between the primary tumor sites (average of 17% TE) and involved LNs (average of 62% TE), (p= 0.018; signed rank test). Interestingly, in the discordant group, TE effects in LNs were invariably greater than in primary lesions. In 5 of 11 patients with multiple involved LN, the TE varied between nodes. This included patients with adjacent LNs demonstrating 0% and 100% TE in the same level. Systemic and local immune parameters as they relate to concordant and discordant TEs in individual patients will be presented including a type 1 immune bias. Conclusions: Early histologic evaluation of TE in patients with HNSCC receiving immunotherapy demonstrate a wide variety of response between the primary tumor and LNs. Further investigations will lend insight into complex interactions of cancer cells with the microenvironment. Clinical trial information: NCT03238365.
Mature results of the LCCC1413 phase II trial of de-intensified chemoradiotherapy for HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Chera Bhishamjit S. , Amdur Robert , Shen Colette J. , Gupta Gaorav P. , Tan Xianming , Knowles Mary , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Patel Shetal Arvind , Zanation Adam M. , Hackman Trevor , Zevallos Jose , Blumberg Jeffrey , Patel Samip , Kasibhatla Mohit , Sheets Nathan Christopher , Weissler Mark Christian , Yarbrough Wendell Gray , Mendenhall William M. 
Published: May 2019

6022 Background: To report the mature results from a prospective phase II clinical trial of highly de-intensified chemoradiotherapy (CRT) for patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: 1) T0-T3, N0-N2, M0, 2) p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin 30 mg/m2(second choice was cetuximab). Patients with T0-T2 N0-1 disease did not receive chemotherapy. All patients had a 10 to 12-week post-treatment PET/CT to determine need for planned neck dissection. The primary study endpoint was 2 year progression free survival (PFS). Secondary endpoint measures include 2 year local control (LC), regional control (RC), distant metastasis free survival (DMFS), cause specific survival (CSS) and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: 114 patients were enrolled (median f/u of 28.8 months, range 2.6 to 51.4) with 84 having a minimum follow-up of 2 years. Smoking status was as follows: 47% never, 33% ≤ 10 pack years, and 19% > 10 pack years. Post-treatment PET/CT complete response rate was 93% at the primary site and 80% in the neck. Eleven patients had planned neck dissection with 4 having pathological residual disease. Two year LC, RC, DMFS, PFS, CSS, and OS were the following: 96%, 99%, 91%, 88%, 97%, and 95%. Neither smoking status nor receipt of cetuximab correlated with recurrence. Four patients with recurrent disease had PIK3CA mutations. Thirty four percent of patients required a feeding tube (none permanent) for a median of 10.5 weeks. Mean pre- and 2-year post-treatment EORTC QOL scores were: Global 79/83 (lower worse), Swallowing 8/9 (higher worse), Dry Mouth 14/45 (higher worse), and Sticky Saliva 9/28 (higher worse). Mean pre- and 2 year post-treatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.7 and Dry mouth 0.4/1.4. There were no ≥ Grade 3 late adverse events. Conclusions: Clinical outcomes with a highly de-intensified CRT regimen of 60 Gy IMRT with concurrent low-dose cisplatin are excellent in patients with HPV-associated OPSCC. Clinical trial information: NCT02281955.
NRG-HN003: Phase I and expansion cohort study of adjuvant cisplatin, intensity-modulated radiation therapy (IMRT), and MK-3475 (Pembrolizumab) in high-risk head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Harris Jonathan , Uppaluri Ravindra , Yao Min , Ferris Robert L. , Chen Josephine , Jordan Richard C. , Joshi Nikhil Purushottam , Jujjuvaparu Srinivas , Blakaj Dukagjin , Razaq Mohammad , Sheqwara Jawad , Mell Loren K. , Sen Neilayan , Clump David Anthony , Garg Madhur , Yilmaz Emrullah , Le Quynh-Thu 
Published: May 2019

6023 Background: Pembrolizumab, an anti-PD1 monoclonal antibody, improves survival in advanced HNSCC. Patients with pathologic high risk, HPV-negative HNSCC have a high recurrence rate despite adjuvant cisplatin-IMRT (CRT), the current standard. Immunosuppression is induced by HNSCC and CRT, and may be reversible by targeting PD1. Methods: We conducted a phase I trial with expansion cohort to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to adjuvant CRT (NCT02775812). Eligibility: oral cavity, pharynx, or larynx primary; HPV-negative; pathologic high risk (positive margin or extranodal extension [ENE]); Zubrod 0-1. During phase I, patients enrolled in descending cohorts of 12 (Table). RP2S was declared if ≤ 3 dose-limiting toxicities (DLT) occurred. DLT was defined as ≥ Grade 3 non-hematologic adverse event (AE) related to pembrolizumab, immune-related (ir)AE requiring > 2 weeks of systemic steroids, or unacceptable delay in IMRT. The expansion cohort enrolled 20. Results: From Nov 2016-Oct 2018, 34 eligible patients enrolled at 22 NRG institutions. During the first cohort, 1 DLT was observed (Grade 3 fever). RP2S was declared as Schedule 3 and the expansion cohort triggered. Among all 34 patients, median age was 60 years (26-83); 68% were male; 74% had Zubrod 1; 85% had oral cavity; 88% had ENE; 21% had positive margin. During expansion, 3 additional patients with DLT were observed: wound infection; diverticulitis; nausea. No DLT unacceptably delayed IMRT. Twenty-eight of 34 (82%) received ≥ 5 doses of pembrolizumab; 17 (50%) got all 8 doses. Thirty-one of 32 (97%) DLT-evaluable patients received all adjuvant RT; 1 withdrew consent after starting protocol. Conclusions: The RP2S is pembrolizumab 200 mg IV q 3 weeks for 8 doses, starting the week before adjuvant CRT. This regimen was safe and feasible in a cooperative group setting. irAE were rare in this population. Clinical trial information: NCT02775812. [Table: see text]
Safety and antitumor activity of accelerator-based boron neutron capture therapy in patients with inoperable recurrent and locally advanced head and neck cancer: A phase II study.
Authors: Hirose Katsumi , Konno Akiyoshi , Yoshimoto Seiichi , Ono Koji , Otsuki Naoki , Hatazawa Jun , Hiratsuka Junichi , Takai Yoshihiro 
Published: May 2019

6028 Background: To assess safety and efficacy of accelerator-based boron neutron capture therapy (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent squamous cell carcinoma (R-HNSCC) or recurrent/locally advanced non-squamous cell carcinoma (R/LA-HNNSCC) of the head and neck. Methods: The multi-institutional open-label, a world-first phase II trial of AB-BNCT in patients with inoperable R-HNSCC which present resistance to platinum-based chemotherapy, or with inoperable R/LA-HNNSCC, was conducted to assess safety and antitumor activity of AB-BNCT with BNCT30 and SPM-011. SPM-011 was administered at 200 mg/kg/h intravenously for 2 hours, followed by neutron irradiation with continuous infusion of SPM-011 at 100 mg/kg/h. The irradiated dose for tumor was determined passively as a mucosal maximum dose was given 12 Gy-Eq in calculation with a blood boron concentration measured just before the start of neutron irradiation. Primary endpoint was objective response rate (ORR) by central review. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) ver 1.1 every 4 weeks for the first 3 months and every 12 weeks thereafter. Results: Eight R-HNSCC and thirteen R/LA-HNNSCC patients were enrolled and received AB-BNCT. All R-HNSCC patients had prior radiotherapy with a median dose of 65.5 Gy (range 59.4–76.0). The median irradiation time was 43 min (range 26–65). The median tumor minimum dose was 31.0 Gy-Eq (range 16.1–42.6). For adverse event, nausea (81%), dysgeusia (71%), parotitis (67%) were observed more frequently. The ORR for all patients were 71.4%, and CR/PR were 50.0%/25.0% in R-HNSCC and 7.7%/61.5% in R/LA-HNNSCC. At a median follow up of 18.8 months (range 9.2–29.0), 1-year PFS and OS by investigator assessment were 70.6% and 100%, respectively. The data for antitumor activity is still immature and will be further updated. Conclusions: AB-BNCT for R-HNSCC and R/LA-HNNSCC demonstrated an acceptable safety profile and a promising antitumor activity.