bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly cisplatin and docetaxel in borderline resectable head and neck squamous cell carcinoma (HNSCC).
Authors: Mendez Eduardo , Rodriguez Cristina P. , Kao Michael , Harbison Richard A. , Martins Renato G. , Futran Neal D. , Santana-Davila Rafael , Chow Laura Quan Man 
Published: September 2018

6034 Background: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability. In TP53-deficient tumors (via mutation or HPV inactivation), inhibiting WEE1 with AZD1775 can lead to unrestrained mitosis and cell death. We conducted a Phase I clinical trial of AZD1775 in combination with chemotherapy to define the toxicity profile, establish the maximal tolerated dose (MTD) and assess preliminary efficacy in borderline resectable HNSCC. Methods: Stage III/IVB HNSCC deemed borderline resectable by a multidisciplinary team were enrolled in a phase 1, 3 + 3 design to evaluate escalating doses of AZD1775 starting at 125 mg PO BID x 2.5 days alone as lead-in and in combination with cisplatin (25mg/m2) and docetaxel (35 mg/m2) for three additional weeks. Tumors were sequenced with UWOncoPlex (262 cancer genes); HPV status assessed via p16 IHC; toxicities graded with CTCAE v. 4.04; responses measured via RECIST 1.1 and through pathologic assessment when available. Trial is open but primary endpoints were met. Results: Eleven patients were screened; 10 enrolled and were evaluable for toxicities. The most common Grade ≥ 2 toxicities were diarrhea (4), fatigue (4), neutropenia (3) and nausea (3). The drug-limiting toxicity was Grade 3 diarrhea (2). The MTD was established at 150mg PO BID x 2.5 days, alone and in combination with neoadjuvant cisplatin and docetaxel. Two patients were HPV+/TP53wt, 1 was HPV+/ TP53 mut; 6 were TP53mut/HPV-; 1 was TP53 wt/HPV-. Seven out 10 patients had a response. Two patients dropped out after the first week with AZD1775, one due to an allergic reaction to docetaxel and another due to non-compliance. Eight completed neoadjuvant therapy and 7 of those converted to surgery: 2 had pathologic CRs (both HPV+/TP53wt); 4 had PR (all TP53 mutants); 1 (TP53wt/HPV-) had a PR by RECIST, but SD by pathology and 1 had PD. Conclusions: AZD1775 is safe and tolerable in combination with neoadjuvant cisplatin and docetaxel. Results show this combination to have promising anti-tumor efficacy in borderline resectable HNSCC with TP53 deficiency, and merits further investigation with the established MTD as the recommended Phase II dose. Clinical trial information: NCT02508246.
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor, in advanced adenoid cystic carcinoma.
Authors: Cote Gregory Michael , Edenfield William Jeffery , Laurie Scott Andrew , Chau Nicole Grace , Becerra Carlos , Spira Alexander I. , Li Youzhi , Li Wei , Hitron Matthew , Li Chiang 
Published: September 2018

6036 Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib demonstrated safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors. Cancer stemness pathways have been implicated in adenoid cystic carcinoma (ACC). An RP2D expansion cohort was opened for patients with ACC. Methods: Pts with metastatic, unresectable ACC for whom systemic therapy was indicated were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 110 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines. Results: 14 pts with ACC were enrolled. Prior treatments included surgery and radiation in all pts (100%), while 57% (n = 8) had received prior systemic therapy (average 2 prior lines, range 1 to 4). Treatment with amcasertib was well tolerated, with grade 3 diarrhea reported in 1 patient and no related grade 4 AEs. The disease control rate (DCR, proportion with stable disease at 8-weeks, partial response, or complete response per RECIST) was 86% (n = 12) with prolonged disease control (≥ 6 months) achieved in 57% (n = 8) patients. At 12 months, 79% of pts were alive. Median overall survival (mOS) was 28.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced ACC who received treatment with amcasertib. Long term follow-up demonstrates prolonged duration of disease control and that a majority of pts in this cohort have survived beyond 2 years. Further clinical evaluation of amcasertib in pts with ACC is warranted. Clinical trial information: NCT01781455.
Phase I study of the anti-HGF monoclonal antibody (mAb), ficlatuzumab, and cetuximab in cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Duvvuri Umamaheswar , Ferris Robert L. , Ohr James , Gooding William E. , Kim Seungwon , Johnson Jonas Talmadge , Grandis Jennifer R. , Stabile Laura P. 
Published: September 2018

6038 Background: Cetuximab, an anti-EGFR mAb, is approved for R/M HNSCC but only a minority benefits. Activation of cMet, the receptor for hepatocyte growth factor (HGF), overcomes EGFR inhibition in preclinical models and high serum HGF is associated with resistance in patients (pts). We conducted a phase I trial evaluating the combination of cetuximab and ficlatuzumab, an IgG1 anti-HGF mAb, in pts with cetuximab-resistant, R/M HNSCC. Methods: In this Narayana k-in-a-row phase I design, cetuximab 500 mg/m2 was administered every 2 weeks. Ficlatuzumab dose tiers were 10 mg/kg (tier 1) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based on cumulative dose-limiting toxicities (DLT). The recommended phase II dose (RP2D) was set at tier 2 if no DLTs were observed after 8 enrolled pts; expansion continued to n = 12. Key eligibility criteria: R/M HNSCC; recurrence within 6 months of cetuximab-radiation or progression during/within 6 months of palliative cetuximab; ECOG PS 0-1. Candidate biomarkers included serum Veristrat, a proteomic classifier in lung cancer where “good” predicts benefit from anti-EGFR therapy and “poor” indicates resistance and poor prognosis. Results: From Sept 2015–June 2016, 12 pts were enrolled and treated. Primary site: 1 oral cavity; 3 oropharynx (1 p16+); 2 hypopharynx; 5 larynx; 1 external auditory canal. Platinum-refractory: 11/12. Veristrat: 8 poor; 4 good. Three pts were treated at tier 1 and 9 at tier 2. No DLTs were observed. Grade 3 adverse events included: edema (1), hypoalbuminemia (1), infection (2), thromboembolic event (2). Median PFS and OS at RP2D were 6.0 mos (90% CI = 2.0 mos–not reached) and 8.2 mos (90% CI = 2.7 mos–not reached), respectively. Response rate was 17% (90% CI = 0–28%): 2/12 partial response (PR); 1/3 at 10 mg/kg; 1/9 at 20mg/kg. Clinical benefit rate (PR + stable disease) was 67%. Veristrat was not associated with PFS. Conclusions: The RP2D is cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks. This well-tolerated combination demonstrated promising activity in pts with poor prognosis, cetuximab-resistant R/M HNSCC. Phase II testing is justified. Clinical trial information: NCT02277197.
A retrospective cohort study of PD-L1 expression in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SUPREME-HN).
Authors: Pai Sara I. , Cohen Ezra , Lin Derrick , Fountzilas George , Kim Edward S. , Mehlhorn Holger , Baste Neus , Clayburgh Daniel , Lipworth Loren , Resteghini Carlo , Shara Nawar , Fujii Takashi , Zhang Jun , Stokes Michael , Lawrence David , Khaliq Asud , Melillo Giovanni , Shire Norah 
Published: September 2018

6040 Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. Targeting the PD-1/PD-L1 axis has resulted in clinically meaningful antitumor activity and improved overall survival (OS) in R/M HNSCC patients. Tumoral PD-L1 expression correlates with response to blocking PD-1/PD-L1 antibodies. We investigated the prognostic value of PD-L1 expression in R/M HNSCC patients. Methods: Archival tumor samples from R/M HNSCC patients diagnosed between March 2011 and June 2015 at 12 institutions in 6 countries were stained for PD-L1 and clinic-demographic data were abstracted from medical records. Tumoral PD-L1 protein expression was assessed with the validated Ventana SP263 assay and scored as high (≥25% of tumor cells [TC]) or low/negative ( < 25% of TC). Extracted data included demographic and tumor characteristics, treatment patterns, and clinical outcomes. Descriptive analyses were conducted and survival estimated by the Kaplan-Meier method. OS was defined from the diagnosis index date of R/M disease to time of death. Results: As ofSeptember 26, 2016 (interim analysis), data were available for 143 patients of whom 138 were eligible for analysis. Median age was 62.0 years (range, 28.0−88.0), 76.8% were male, and 84.0% were white. PD-L1 protein expression was high in 43 patients (31.2%), low/negative in 91 (65.9%), and unknown in 4 (2.9%). Median OS (8.2 vs. 8.8 months; P = 0.94) and progression-free survival (PFS) from the start of first-line (6.0 vs. 5.6 months; P = 0.29) or second-line therapy (7.1 vs. 1.8 months; P = 0.11) did not significantly differ between PD-L1 high and low/negative patients, respectively. There were no significant differences in OS based on PD-L1 status within subgroups defined by age, race, tobacco or alcohol use, primary tumor site, performance status, metastatic disease at diagnosis, or treatment with platinum-based chemotherapy. Conclusions: Interim analyses indicate that PD-L1 status is not associated with OS or PFS in R/M HNSCC patients.
Two-year clinical outcomes of de-intensified chemoradiotherapy for low-risk HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Chera Bhishamjit S. , Amdur Robert J , Tepper Joel E. , Qaqish Bahjat F. , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Zanation Adam M , Hackman Trevor , Zevallos Jose , Patel Samip , Sheets Nathan Christopher , Weissler Mark Christian , Mendenhall William M. 
Published: September 2018

6044 Background: We here-in report 2 year cancer control outcomes from a prospective phase II clinical trial evaluating de-intensified chemoradiotherapy (CRT) for patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: T0-T3, N0-N2c, M0, HPV or p16 positive, and minimal smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m2). Patients neither received induction chemotherapy nor definitive surgery. The primary study endpoint was pathologic complete response rate (pCR) based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Secondary endpoint measures included 2 year local control (LC), regional control (RC), cause specific survival (CSS), distant metastasis free survival (DMFS), and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: Forty-four patients enrolled and the median f/u was 36 months (range 5-53 months, 93% with > / = 1 year, 88% > / = 2 years). We have previously reported the pCR to be ~ 86%. Two year LC, RC, CSS, DMFS, and OS are the following: 100%, 100%, 100%, 100%, and 95%. All 6 patients who had pathological partial responses are alive with no evidence of disease with a median f/u of 34 months (range 9-48 months). Two patients have died (stroke and glioblastoma). Mean pre and 2-year post EORTC QOL scores were: Global 80/82 (lower worse), Swallowing 11/10 (higher worse), Dry Mouth 16/54, and Sticky Saliva 6/33. 39% of patients required a feeding tube (none permanent) for a median of 15 weeks (5 - 22 weeks). Mean pre and 2 year post PRO-CTCAE (1 to 4 scale, higher worse) scores were: Swallowing 0.4/0.8 and Dry mouth 0.4/1.8. There were no > / = Grade 3 late adverse events. Conclusions: The 2-year clinical outcomes with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatin are excellent in favorable risk OPSCC with evidence of better preservation of quality of life as compared to standard therapies. Clinical trial information: NCT01530997 .
Cellular immune biomarkers to prognosticate for survival to adoptive T-cell therapy in advanced nasopharyngeal cancer.
Authors: Toh Han Chong , Hopkins Richard , Ching Qian Ting , AU Veonice Bijin , WU Lynn Xue , Chia Whay-Kuang , Lee Bernett , WANG Who-Whong , Podinger Michael , Wee Joseph , Ng Joanna , Shuen Timothy , Connolly John E. 
Published: September 2018

6047 Background: We have published a Phase II clinical trial in 35 advanced incurable stage 4c NPC patients employing upfront first line chemo-immunotherapy of four cycles of gemcitabine and carboplatin, followed by six cycles of adoptive transfer autologous EBV-specific cytotoxic T lymphocytes (CTL). The 2- and 3-year overall survival rates were 62.9 and 37.1% respectively, which represent the best reported survival outcome for first-line treatment of advanced NPC when compared to historical clinical trials. Methods: From this Phase II trial, we completed serial multiple deep immune phenotyping analyses including flow cytometry, nanostring, and multiplex ELISA assays. We then investigated how these factors influence and determine successful therapy using 2-year survival rates. Results: Longitudinal modular transcriptome analysis of patient PBMCs revealed significant increases in T cell, NK, and B cell modules post chemotherapy within the 2-year survivor group. Administration of CTLs restored expression of lymphocyte transcripts in the non-survivor group at 2-weeks post infusion. However, as immunotherapy proceeded, 2-year survivors displayed significant increases in multiple lymphocyte module associated transcripts. These immune correlates were associated with increased IFN-γ and decreased myeloid chemokine concentrations in peripheral sera during immunotherapy in 2-year survivors. Longitudinal immunophenotyping of patient PBMCs at serial timepoints showed that 2-year survivors displayed significant decreased amounts of monocytic myeloid-derived suppressor cells (mMDSCs), compared to non-survivors after chemotherapy, which subsequently determined successful CTL immunotherapy survival benefit. Conclusions: This is the first report in human cancer patients that successful adoptive T cell immunotherapy correlates with lower mMDSCs following chemotherapeutic preconditioning. We have also identified potential prognostic immune biomarkers that effectively predicts efficacy of CTL immunotherapy, following upfront combination chemotherapy, and thus survival. Lymphodepletion with chemotherapy appears to be vital for adoptive T cell therapy efficacy.
Intact APM and PD-1:PD-L1 pathway upregulation in HIV-infected head and neck cancer patients.
Authors: Pai Sara I. , Lee J. Jack , Carey Thomas E. , Westra William H. , Ferrone Soldano , Moore Charles , Shin Dong Moon , Ferris Robert L. 
Published: September 2018

6058 Background: HIV-infected individuals have a higher incidence of oral infection with human papillomavirus (HPV) and possibly a higher incidence of head and neck cancer (HNC). Whether this observation reflects defects in the ability of this Òimmune-compromisedÓ patient population to mount sufficient tumor specific immune responses and/or reflects activation of immune escape mechanisms is not known. To address this question, we investigated the expression of HLA class I antigen processing machinery (APM) components and PD-1:PD-L1 pathway activation in HIV(+) HNC patients. Methods: 62 HIV(+) HNC patients diagnosed between 1991-2011 from five tertiary care referral centers in the United States and matched HIV(-) HNC controls were identified. HLA class I APM component, PD-1, and PD-Ll expression were analyzed by immunohistochemical staining. Clinical data was abstracted from the medical records. Results: 44 of 62 (71%) HIV(+) HNC cases were matched based on gender, age ( < 10 years), and anatomic sub-site to HIV(-) HNC patients. There was no significant difference between the cases and controls in HLA-A, HLA-B/C, LMP2, and TAP1, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1. HLA-A, HLA-B/C, and LMP2 expression was significantly correlated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = 0.004, p = 0.026, and p = 0.006, respectively) but not in the HIV(-) controls. Similarly, HLA-A expression was also significantly associated with PD-L1 expression only in the HIV(+) HNC cases (p = 0.029). Conclusions: No defects were detected in the expression of the HLA class I APM components tested. PD-1:PD-L1 pathway was found to be upregulated in both HIV(+) and HIV(-) HNC patients. Our data suggest that recently approved anti-PD-1 immunotherapy should not exclude HIV(+) patients.
Optima: A phase II dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancers.
Authors: Melotek James , Seiwert Tanguy Y. , Blair Elizabeth A. , Karrison Theodore G. , Agrawal Nishant , Portugal Louis , Gooi Zhen , Stenson Kerstin , Brisson Ryan J. , Arshad Saba , Dekker Allison , Kochanny Sara , Saloura Vassiliki , Spiotto Michael T. , Villaflor Victoria Meucci , Haraf Daniel J. , Vokes Everett E. 
Published: September 2018

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or > 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p < .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.
Prognostic factors associated with benefit to post-operative chemotherapy: A National Cancer Data Base analysis.
Authors: Geiger Jessica Lyn , Woody Neil McIver , Reddy Chandana A. , Koyfman Shlomo A. , Joshi Nikhil Purushottam , Bodmann Joanna , Harr Bridgett Ann , Ives Denise I. , Ferrini Jodi , Burkey Brian , Scharpf Joseph , Lamarre Eric , Prendes Brandon , Lorenz Robert , Adelstein David J. 
Published: September 2018

6072 Background: Addition of chemotherapy to adjuvant radiation (RT) confers an OS benefit and is recommended in HNSCC patients with nodal extracapsular extension (ECE) and positive surgical margins based on pooled data. The purpose of this study is to retrospectively evaluate a larger patient data set in an attempt to confirm this observation and to assess current patterns of practice. Methods: The National Cancer Data Base (NCDB) was queried to identify patients with HNSCC who were treated with primary definitive surgery followed by adjuvant RT between 2004 and 2012. For patients treated with surgery and post-operative RT with or without chemotherapy, the effect of the systemic therapy on OS was explored using multivariable Cox proportional hazards modeling and stratified by patient and disease factors. Results: 6,351 patients were identified meeting study criteria; 3157 patients (49.7%) received adjuvant RT alone, and 3194 patients (50.3%) received adjuvant chemoradiotherapy (CRT). An increase in chemotherapy usage was observed over time (6% of patients in 2004; 16% in 2012). No difference was seen in OS by use of CRT (median OS 8.3 years in patients without CRT vs. 9.4 years in patients with CRT, p = 0.0893). On multivariate analysis OS was improved in younger patients, patients with less co-morbidity, oropharynx, lower T and lower N. OS was also improved in patients given chemotherapy if either ECE or positive surgical margins were present (HR 1.166, p = 0.0438) but not in those with negative surgical margins and no ECE (HR 1.037, p = 0.5888). Nonetheless, chemotherapy was given to 38% of post-operative patients without these risk factors and not given to 35% of patients with risk factors. Conclusions: This NCDB analysis confirms an OS benefit with addition of chemotherapy to post-operative RT in HNSCC patients with ECE or positive surgical margins but not in patients without these risk factors, consistent with current guidelines. National practice patterns, however, do not mirror these recommendations. These results are subject to limitations of retrospective analysis of a large database and further studies are needed to better elucidate high risk factors benefiting from intensifying adjuvant therapy.