bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast cancer in Angola, molecular subtypes: The first preliminary study.
Authors: Santos Lúcio Lara , Miguel Fernando , Lopes Lygia Vieira , Oliveira Julio , Ferreira Eduardo , Lopes Carlos
Published: September 2018

e13075

Background: Women in sub-Saharan African countries, as Angola, are experiencing an increasing burden of aggressive breast cancer. Breast cancer molecular subtypes may enable more accurate diagnoses and support therapeutic decisions, however several studies have suggested that African breast cancers are predominantly hormone receptor poor. We conduct a study, to correlate the clinical pathological profiles and molecular subtypes, according its surrogate immunohistochemistry (IHC) markers, of breast cancer in Luanda, Angola. Methods: From Jan. 2011 to Dec. 30, 2014, 179 consecutive cases of microscopically confirmed invasive breast carcinoma that were evaluable for histology and IHC (ER, PR, HER2, and Ki-67) were classified. However, 21.8% (n = 39) of cases were poorly preserved, therefore it was only possible to study IHC in 140 cases. Results: All patients were female, the median age was 47 years (24-84 years). Invasive ductal carcinoma was the most common type, 91.4% (n = 128), grade 2 (moderately differentiated) was prevalent, 67.1%. Most of the tumours were locally advanced, stage III 65% (n = 91) and stage IV 3.6% (n = 5). In 140 cases studied, 53.2% (n = 74 ) of malignancies were hormone receptors positive, whence 25.7% were luminal A like, 19.3% luminal B like/ HER2 negative, 7.9% luminal B like/HER2 positive, 15.7% HER2 positive and 31,4% were triple-negative. Conclusions: Woman with breast cancer in Luanda-Angola were caracterized by advance stage and younger age at diagnosis of disease. The two predominant molecular subtypes are triple negative and luminal A like. Therefore, determining the molecular subtype using surrogate IHC markers has important treatment and prognostic implications for Angola women with breast cancer.
Tissue trauma and the subsequent risk of soft tissue sarcoma of the extremity: A population based case-control study in Sweden.
Authors: Olsson Hakan Lars , Wagner Philippe
Published: September 2018

e13088

Background: Soft tissue sarcomas (STS) are a rare group of heterogeneous tumors that may occur in the extremities. Little is known of their etiologies and only a handful putative risk factors have been identified. Studies as well as case reports have connected soft tissue tumors to events of physical trauma. There is mounting evidence of inflammation as both an initiator and promotor of tumorigenesis, as well progression. Moreover, as the physiological response of tissue repair and regeneration is mediated through inflammation, it is not unlikely that physical injury may cause and/or contribute to tumor initiation, promotion and/or progression, not least when the subsequent inflammation becomes chronic. Methods: We conducted a matched case control study in a total population in the South of Sweden 1988-2009, collecting 249 cases to examine the risk of STS of the extremities (STSE) following exposure to physical trauma such as accidental injury and/or surgery. Results: Having been exposed to surgery or injury from accidents to any part of the body both increased the risk of STSE, OR 2.1 (1.5 – 3) and 1.5 (1.1 – 2.1), respectively. Adjusting for potential confounders yielded ORs of 2.4 (1.6 – 3.6) and 1.4 (1.00 – 2.00). Surgery related odds ratios (SOR) varied with STSE histological subtype, from 1.2 to 4.2. UPS/MFH, Leiomyosarcoma and Liposarcoma showed significantly elevated SORs that were significantly greater than for remaining subtypes (P = 0.029). The accident related odds ratio (AOR) varied from 0.8 to 3.5, being significantly elevated for Leiomyo- and Liposarcoma, and the AOR of the two combined was significantly greater than remaining subtypes (P = 0.045). Analyzing surgery or accidental injury to a given part of the body and the subsequent STSE risk in the same location showed the SOR to be 4.13 (1.87 – 9.15) and the AOR was 2.29 (1.21 – 4.32). Conclusions: The population attributable risk of having had surgery was 37% (20 – 53%) and accidental injury was 13% (2 – 24%). Combined, the PAR was 43% (25 – 57%), indicating that tissue trauma may be an important contributing factor in sarcomagenesis of the extremities.
Prevalence of germline TP53 p.R337H mutation in Brazilian young breast cancer patients.
Authors: Fortes Fernanda Paschoal , Tonhosolo Renata , Jbili Rima , Santiago Karina Miranda , Andrade Kelvin , Nobrega Amanda Franca , Achatz Maria Isabel Isabel
Published: September 2018

e13101

Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS), a disease that predisposes carriers to a wide variety of early onset tumors. Pre-menopausal breast cancer is the most frequent tumor found in carriers. In Southern and Southeastern Brazil, a germline TP53 mutation in exon 10, p.R337H, was diagnosed in 0,3% of the population due to a founder effect, a prevalence that is substantially higher than other LFS mutations. Methods: In this study we investigated the prevalence of the p.R337H TP53 germline mutation in 287 young female breast cancer patients (diagnosed before the age of 40) at A. C. Camargo Cancer Center, Sao Paulo, Brazil. DNA was extracted from saliva and Sanger sequencing of exon 10 was performed. All patients were consented. Results: The p.R337H TP53 mutation was present in 1.74% (5/287). Family history of cancer was present in three cases although it did not fulfill LFS clinical criteria. Conclusions: The identification of germline p.R337H mutation in this cohort strengthen the role of TP53 mutations in the early onset of breast cancer in pre-menopausal cancer in Brazil.
Clinical implementation of a comprehensive targeted amplicon sequencing system for cancer in Japan.
Authors: Hayashi Hideyuki , Tanishima Shigeki , Mori Ryo , Okamura Yasunobu , Amano Toraji , Kinoshita Ichiro , Komatsu Yoshito , Akita Hirotoshi , Nishihara Hiroshi
Published: September 2018

e13115

Background: The development of clinical sequence systems in hospitals is a critical issue in Japan, especially for medical oncology, as multiplex gene profiling enables precision medicine for cancer. We have launched an in-house clinical sequencing system,“CLHURC” to perform exhaustive targeted exome sequencing for patients with all types of cancer, as an outpatient service. We have analyzed the clinical utility of this system. Methods: Genomic DNA was extracted from tumor tissues and peripheral blood sera of 81 patients with different stages of cancer, during April-December 2016. The top five types of primary cancer were pancreas (16%), colorectal (16%), breast (10%), stomach (9%), and lung (6%). We performed a targeted amplicon exome sequencing for 160 cancer-related genes. The sequencing data was analyzed using an original bioinformatics pipeline within three days, and we identified cancer-specific somatic gene alterations such as SNV (Single Nucleotide Variation), Ins (Insertion)/Del (Deletion), and CNV (Copy Number Variation). The primary endpoints were the detection rates of potential actionable and druggable genes. The secondary endpoints were the detection rates of incidental germline variants and the period from initial visit to elucidation of the results to the patients. Results: Actionable and druggable gene alterations were detected in 90% (73/81) and 51% (41/81) of the subjects, respectively. Druggable gene alterations were frequently detected in BRCA1/2 (11/41), PIK3CA (9/41), AKT1/2 (6/41), TSC1 (5/41), and PTEN (5/41). Surprisingly, incidental germline variants were detected in 31% (25/81) of the patients, and were found in BRCA1/2 (5/25), APC (5/25), and TSC1(3/25), among others. The median period of examination was 21 days (10-66 days). Twelve out of the 81 patients (15%) were treated with therapeutic agents, based on the results of our clinical sequencing. Conclusions: We have established a robust in-house clinical sequencing system, “CLHURC,” and have initiated the development of precision medicine for cancer in Japan. Our novel clinical sequencing system could improve individualized medicine against cancer throughout Japan and Asia.
AWARE: Randomized study of an EMR-based intervention targeting hereditary cancer (CA) risk awareness in peri-op CA patients (pts).
Authors: Hall Michael J. , Handorf Elizabeth , Chertock Yana , Keleher Cindy A , Siemon Mark , Rubin Stephen C. , Sigurdson Elin R. , Uzzo Robert , Savage Michelle , Daly Mary Beryl
Published: September 2018

e13119

Background: Pts having CA surgery have high information needs related to diagnosis, stage, and what caused their CA. Direct EMR access via web portals has grown, and offers a novel means to integrate supplemental health information into the e-chart, such as relevant genetic risk of CA. The AWARE trial (Advancing Web-based Medical Record Access and Risk Evaluation for Cancer Patients) studied the impact of providing personalized pathology (pPATH) and pers/fam history (PFHx) summaries enhanced with information about genetic CA risk and risk assessment. Methods: Peri-op CA pts completed baseline and 3-mo follow-up surveys. Pts randomized to enhanced (E) arm received pPATH & PFHx summaries with embedded tailored info about genetic CA risk and relevant high-risk features. Unenhanced (U) arm got pPATH & PFHx only. Use of summaries and 2 “Genetic risk: Learn more” links was tracked. Outcomes-Primary: awareness, knowledge (of genetic CA risk); Secondary: perceived risk, use of “Learn more” links, intentions/actions toward risk assessment--were stratified by genetic risk factors reported at baseline (0-1, 2+) & use of “Learn more” links. Results: 171 pts consented; men (p = 0.003) & non-White (p = 0.02) were more likely to decline the study. Overall 149 (87%) were randomized & eligible to use AWARE: 109 (73%) logged in, 120 (81%) completed follow-up. Predictors of AWARE use: White race (p < 0.05), sib w/CA (p < 0.05), and use intention (p = 0.005). Reporting 2+ genetic risk factors at baseline predicted use of pPATH, PFHx, and “Learn more” (all p < 0.001). Awareness increased overall (p < 0.002), but between arm changes in primary outcomes were not significant. E arm (vs U) was borderline more likely to seek risk assessment (32% v 18%, p = 0.09), with impact stronger in pts reporting baseline 0-1 (p = 0.035) vs 2+ risk factors (p = 0.7). Among E arm pts who used “Learn more” links, intentions (p = 0.054) & behaviors (p = 0.035) to seek risk assessment increased. Conclusions: AWARE increased genetic risk awareness overall, but primary outcomes were not met. Usage data and secondary outcomes highlight potential for EMR-based interventions to positively impact preventive behaviors toward genetic risk assessment.
TG6002: A novel oncolytic and vectorized gene pro-drug therapy approach to treat glioblastoma.
Authors: Idbaih Ahmed , Erbs Philippe , Foloppe Johann , Chneiweiss Hervé , Kempf Juliette , Homerin Michel , Schmitt Charlotte , Nguyen Them Ludovic , Delattre Jean-Yves
Published: September 2018

e13510

Background: Glioblastoma (GBM) is an incurable disease challenging innovations for significant therapeutic progress. TG6002 is a vaccinia virus that replicates mainly in tumor cells after deletion of genes coding for thymidine kinase and ribonucleotide reductase. TG6002 alsoexpresses the yeast-originated gene FCU1 encoding cytosine deaminase and uracilphosphoribosyltransferase that transforms the pro-drug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluoro-uridilyl monophosphate (5-FUMP), respectively. The proof of this ‘suicide gene’ concept has been demonstrated in man, using a non-replicative vaccinia virus hosting the FCU1gene (Husseini F et al, ASCO 2012). TG6002 mechanism of action then associates oncolysis of tumor cells, immune reaction against released tumor antigens and local chemotherapy. Methods: Prior to initiating clinical development, the anti-tumor activity of the TG6002/5-FC combination was investigated, using U-87MG human GBM cell line and patient-derived cell lines (PDCL). Results: The growth of U-87MG subcutaneous tumors implanted in nude mice was inhibited by systemic administration of TG6002 with or without 5-FC. Mice treated with TG6002 only survived significantly longer than controls; this survival benefit was not modified by addition of 5-FC to TG6002. In contrast, in an orthotopic brain tumor model, mice survived significantly longer when treated intravenously by TG6002 alone, and oral 5-FC added a significant survival benefit. In this model, TG6002 was found in the brain of xenografted mice but not in that of control mice without tumor, indicating a tumor-specific replication of TG6002. PDCL were also exposed in vitro to TG6002. Evidences of virus replication and tumor cells death were detected. In addition, TG6002 exhibited a synergistic cytotoxic effect when combined with temozolomide in this model, suggesting a potential interest for clinical development of this combination. Conclusions: Taken together, our results support initiation, in recurrent GBM patients, of a phase 1 clinical trial testing TG6002 safety in combination with 5-FC, as a first step toward investigation of clinical efficacy of this therapeutic combination in GBM.
BBI608-201GBM: A phase Ib/II clinical study of napabucasin (BBI608) in combination with temozolomide (TMZ) for adult patients with recurrent glioblastoma (GBM).
Authors: Mason Warren P. , de Robles Paula , Borodyansky Laura , Hitron Matthew , Ortuzar Waldo Feliu , Khan Waheed , Xu Bo , Li Wei , Li Youzhi , Li C J
Published: September 2018

e13525

Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Pre-clinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. PK studies demonstrated napabucasin penetration in the murine orthotopic GBM model. Methods: A phase Ib/II open-label, multi-center study in pts with GBM at first recurrence who have not received bevacizumab, was performed to determine safety and preliminary activity of napabucasin administered orally at 480mg BID po in combination with TMZ 150mg/m²/day po; days 1 through 5 of each 28 day cycle, until disease progression or unacceptable toxicity. A 6-patient safety cohort was planned to evaluate the occurrence of DLT during the first 28 days of combination treatment with napabucasin and TMZ. 4 additional patients have been enrolled under the RP2D expansion phase. Results: 11 pts have been enrolled to date; no DLT was observed in the safety cohort and the RP2D of the combination is 480 mg BID for napabucasin. The safety profile was consistent with that of each agent as monotherapy and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Two patients requested to withdraw treatment due to concurrent conditions and AE s. 9 patients were evaluable by RANO; Disease Control Rate was observed in 5 patients (55.5%) of which 4 achieved PR (44.4%) and 1 achieved SD (11.1%). The Overall response rate was 44.4% in the evaluable patients. Conclusions: This phase Ib/II study demonstrated that napabucasin at 480 mg BID can be safely combined with temozolomide at full dose and showed encouraging anti-tumor activity in patients with recurrent Glioblastoma. Clinical trial information: NCT02315534. [Table: see text]
A phase I study of safety and pharmacokinetics of NanoBB-1-Dox in patients with advanced solid tumors.
Authors: Filon Olga , Krivorotko Petr , Kobyakov Grigory , Razjivina Viktoria , Maximenko Olga , Gelperina Svetlana , Kreuter Joerg
Published: September 2018

e13537

Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m2) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentrations were measured immediately before the infusion, and 2 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 168 h after the infusion. Results: The PK analysis demonstrated that AUC0-t of doxorubicin after the NanoBB-1-Dox infusion increased in parallel with the dose level from 121.7 to 2054.4 h x ng/ml. T1/2 varied from 45 to 75 h without dose dependence. NanoBB-1-Dox was well tolerated without dose limiting toxicity even at the highest dose of 90 mg/m2, so the MTD was not achieved. The most common AEs included leukopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, and alopecia. In general, the AE rate and intensity increased with the dose level reaching the maximum at a dose of 90 mg/m2. Only hematological AEs were severe according to CTCAE 4.03. No SAEs were reported. Conclusions: NanoBB-1-Dox after a single i.v. infusion in patients with advanced solid tumors is well tolerated and is characterized by a non-linear PK profile. NanoBB-1-Dox will be investigated in a phase II study in patients with GBM as a second line therapy. [Table: see text]
Blood trypsin proteinases as a new additional test in differential diagnosis of brain tumors.
Authors: Kozlova Larisa , Frantsiyants Elena Mikhaylovna , Tkalya Lyudmila Dmitriyevna , Rostorguev Eduard Evgenevich , Atmachidi Dmitriy P. , Kavickij Sergey E. , Kuznetsova Natalya S. , Porksheyan David H.
Published: September 2018

e13543

Background: Activation of trypsin-type proteinases in cancer is a proven fact. Activity of enzymes synthesized and secreted by a malignant tumor is generally not controlled by endogenous inhibitors. Benign tumors do not come into metabolic conflict with the carrier body, at least prior to their possible malignant transformation. The purpose of the study was to analyze changes in activity of trypsin proteinases (ATP) in the blood plasma of patients to determine possible application of the parameter as an additional test in the differential diagnosis of brain tumors. Methods: The blood plasma of 164 patients was studied: 37 benign brain tumors, 74 primary glioblastomas (G) and 53 brain metastases (MTS) from breast cancer. ATP was determined before treatment using the U-2900 UV Solutions double-beam spectrophotometer (USA). The results were compared to the values in 39 healthy donors (N). The data were processed using the Statistica 10 program. Results: ATP did not differ from N in 37 of 164 patients (22.6%). After removal of the brain tumors, histological examination of surgical material showed benign brain tumors in all 37 cases. ATP in 74 of 164 patients (45.1%) exceeded N by 3.8-5.3 times (on average 4.4±0.3). Histological examination after removal of the brain tumors showed primary G in all 74 cases. ATP was 5.9-9.4 times higher than N (on average 7.3±0.5) in 53 of 164 patients (32.3%). Histological examination after removal of the brain tumors showed MTS in all 53 cases. Conclusions: ATP value similar to N indicates a benign tumor. ATP increase by 3.8-5.3 times shows the presence of a primary malignant tumor. ATP increase by 5.9-9.4 times supposes MTS.
Bevacizumab for the treatment of radiation necrosis in melanoma patients.
Authors: Glitza Isabella Claudia , Amaria Rodabe Navroze , D'Souza Neil Mark , Jiang Wen , Li Jing
Published: September 2018

e13548

Background: Radiation necrosis (RN) can be a late complication of radiotherapy for CNS malignancy, often associated with neurological morbidity. High dose corticosteroids or surgical resection have been the standard of care treatment (tx), but protracted steroid course can lead to significant side effects and surgery is not always feasable. While there is evidence that the anti-VEGF antibody bevacizumab (Bev) can be effective for RN in other cancer types, evidence supporting its use for RN in melanoma patients (pts) is lacking, due to known risk of spontaneous bleeding in melanoma brain metastasis (MBM) and increased bleeding risk with Bev. Methods: We retrospectively identified 6 melanoma pts who received Bev for RN, and demographics, systemic and radiation tx history were obtained. Diagnosis of RN was established by MRI in all pts, and pathology confirmed RN in one pt. Results: Description of the 6 pts identified are shown in Table 1. Conclusions: We present 6 melanoma pts who developed RN after CNS radiation and who were treated with 2-6 doses of Bev. None of these pts developed bleeding, and all pts experienced improvement in symptoms and quality of life, with concurrent improvement of imaging in 5 pts. Our series suggests that in selected melanoma pts Bev may be a safe and effective treatment for RN for MBM and should be evaluated in a prospective setting. [Table: see text]
ADR-201: A novel cytotoxic drug-conjugate for pancreatic cancer.
Authors: Ricigliano Mark , Cooper Brandon , Bartlett Andrew , Yu Kenneth H.
Published: September 2018

e14018

Background:Standard of care treatment for pancreatic adenocarcinoma (PDAC) consists of FOLFIRINOX or gemcitabine with nab-paclitaxel used in either the front-line or 2nd line treatment. There is no consensus for 3rd line treatment. We previously demonstrated that Mitomycin C (M) and Cisplatin (C) as viable 3rdline treatment options with broad use limited by toxicity. To address the toxicity issues with the prolonged use of M and C, we developed a novel cytotoxic drug conjugate ADR-201 (A), as a treatment option for metastatic PDAC . Methods: (A) is a cytotoxic drug conjugate formed from the APIs of Mitomycin C (M) and Cisplatin (C) conjugated with an amine-to-sulfhydryl crosslinker with a soluble polyethylene glycol (PEG) spacer arm to reduce steric hindrance. In order to conjugate C, the molecule was thiolated prior to crosslinking with a maleimide functional group. In cytotoxic assays, MiaPaca-2 cells were treated with 17uM of A and cell viability was measured at 48hrs, 72hrs and 96hrs. In thin layer chromatography (TLC) A, M and C were spotted at the origin with 0.5uL of 17uM, 10mM and 10mM respectively. Cell cultures comprising circulating tumor and invasive cells (CTICs) obtained from PDAC patients (n = 12) were treated with 17uM of A and cell viability was measured at 72hrs. Results: In TLC, A showed marked solubility in polar neutral solvent EtOAc /hexane (20:80) compared to the polar compounds M and C with Rf values 0.38:1.0:1.0 respectively. In cytotoxic assays with MiaPaca-2 cells, serial dilutions of A at 17uM, 8.5uM and 3.4uM demonstrated a 30%, 11% and 6% reduction in cell viability at 72hrs. In 24 CTIC cultures, A reduced cell viability between treatment v control groups by an average -26%. (range -31% - 0%, paired t-test, p-value = 0.013, ). Conclusions: Improvements in solubility and cytotoxic activity at low dose levels compared to single agents M and C should translate to enhanced permeability and retention (EPR) in tumor tissue with corresponding reduced toxicity.
Evaluation of PFS ratio in patients with cancer enrolled in early-phase clinical trials: A single center, retrospective analysis.
Authors: Watson Sarah , Bonnet Clement , Menis Jessica , Michot Jean-Marie , Hollebecque Antoine , Massard Christophe , Soria Jean-Charles , Postel-Vinay Sophie , Paoletti Xavier
Published: September 2018

e14025

Background: Progression-free survival ratio (PFSr) has been proposed as a direct evaluation of treatment benefit in advanced cancer patients, based on the hypothesis that the natural history of cancer is accelerating and therefore successive lines of treatments become less efficient over time. Consequently, PFS at line +2 (PFS2) is expected to be shorter than PFS at line +1 (PFS1), whereas a PFS2/PFS1 ratio > 1.3 might reflect treatment benefit. However, this hypothesis has been poorly documented, especially in the context of early phase trials where determining treatment benefit is becoming key. We therefore proposed to evaluate PFSr in a large cohort of cancer patients enrolled in early phase clinical trials at Gustave Roussy Drug Development Department. Methods: Patients enrolled in at least two phase 1 studies for advanced solid tumors or lymphomas were retrospectively identified. Demographical, clinical and therapeutic data were collected. Time to progression (PFS) was measured from treatment initiation to progression, using radiological evaluations. Patients who had gone off-trial for reasons other than progression were censored. PFSr was defined as the ratio of the PFS under line 2 divided by the PFS under line 1 and might be censored in presence of censored PFS2. Ratio distribution in this population was estimated using Kaplan Meier. Calibration of the ratio was proposed for hypothesis testing. The influence of therapeutic class and combination versus monotherapy was studied via non parametric Gehan-Wilcoxon tests or Mick tests. Results: 212 patients enrolled between 2009 and 2016 in at least two phase 1 clinical trials were included, corresponding to 113 different clinical trials. PFSr distribution was described and correlated with demographical, clinical and therapeutic data. The relevance of the usual 1.3 PFSr cut-off to determine treatment benefit was evaluated. Final analysis results will be presented at the time of the congress. Conclusions: This study, one of the first to establish PFSr in a large cohort of patients treated in early phase clinical trials, provides guidelines for using PFSr to assess the impact of treatment sequences in advanced cancer patients.
A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors.
Authors: Diab Adi , Tannir Nizar M. , Bernatchez Chantale , Haymaker Cara L. , Bentebibel Salah E , Curti Brendan D. , Wong Michael K.K. , Gergel Ivan , Tagliaferri Mary Ann , Zalevsky Jonathan , Hoch Ute , Aung Sandra , Imperiale Michael , Cho Daniel C. , Tykodi Scott S. , Puzanov Igor , Kluger Harriet M. , Hurwitz Michael E. , Hwu Patrick , Sznol Mario
Published: September 2018

e14040

Background: NKTR-214 is a CD-122-biased agonist that targets the IL-2 pathway and is designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T regulatory cells within the tumor microenvironment. In a phase 1 monotherapy trial, pts treated with NKTR-214 demonstrated a substantial increase in CD8+ T and NK cells within the tumor microenvironment even when pretreated with multiple prior immunotherapeutic agents (abstract submitted). Based on this biomarker data and a favorable safety profile, a trial combining NKTR-214 and nivolumab was initiated. Methods: This is an on-going phase 1/2 study of NKTR-214 plus nivolumab in Pts with either melanoma (Mel), NSCLC, renal, bladder, or TNBC. Pts who are immunotherapy naïve or checkpoint therapy relapse/refractory are being studied separately. NKTR-214 and nivolumab are administered IV on a q2w or q3w schedule. Cohort 1 received NKTR-214 0.006 mg/kg q3w with nivolumab 240 mg q2w. Blood and tumor tissue were collected to measure immune activation using flow cytometry, immunohistochemistry, T cell clonality and gene expression analyses. Results: As of February 7, 2017, 5 Pts have been treated with the combination and all Pts were naïve to checkpoint inhibitors. There have been no dose limiting toxicities, no drug-related or immune related grade 3-5 adverse events (TRAEs) and no Pts have discontinued treatment. The most common TRAEs were pruritis and rash. Radiographic scans were available for 2 Pts. On treatment, Pt 1 with Mel had a mixed radiographic response at 1st scan, a ~40% decrease in LDH and a robust tumor immune cell infiltrate at week 3 the majority being newly proliferating CD8+ T cells expressing PD-1. Pt 2 with Mel had an unconfirmed complete response per RECIST 1.1 after 6 weeks of treatment; follow up tumor response data will be presented. Conclusions: Preliminary data demonstrate that NKTR-214 and nivolumab combination therapy is well tolerated with early evidence of clinical activity. Updated safety, pharmacokinetics, tumor response and biomarker data will be presented. Clinical trial information: NCT02983045.
A phase I study to evaluate the pharmacokinetics of a new oncology nce, apatinib mesylate tablets, with and without food following single and multiple doses in healthy subjects.
Authors: Pesco Koplowitz Luana , Koplowitz Barry , Park Cheol Hee , McGinn Arlo N.
Published: September 2018

e14049

Background: Apatinib Mesylate (YN968D1) is a selective inhibitor of VEGFR-2 being developed for the treatment of advanced gastric cancer. Objectives: 1. Evaluate single- and multiple-dose PKs 2. Evaluate food effect on bioavailability 3. Evaluate dose-proportionality 4. Determine CYP3A4 and 2C19 metabolic effects on the PKs Methods: Single ascending-dose (SAD), open-label, crossover of 2 oral doses of apatinib mesylate tablets (100 mg and 250 mg, [81 mg and 201 mg apatinib]) in healthy male and female volunteers with a minimum 3-day washout between dosing, plus a multiple ascending-dose (MAD), open-label, crossover study of the same doses. Both doses were administered with and without food in a crossover for the SAD and MAD parts. PK blood samples were collected for each dosing period. Subjects were genotyped for CYP3A4 and CYP2C19. WinNonlin 6.4 used for analysis. Results: 24 male and female subjects completed the SAD study section. They were extensive or intermediate metabolizers of CYP2C19, and 23/24 were normal metabolizers of CYP3A4. 22 male and female subjects completed the MAD study section. Most were extensive, intermediate or ultra-rapid metabolizers of CYP2C19; 21/22 subjects were normal metabolizers of CYP3A4. Conclusions: For the 100 mg dose in the SAD and MAD parts of the study, there was no significant food effect. For the 250 mg dose in SAD and MAD parts, food appeared to increase bioavailability by 20–30% in the SAD part, and 30–40% in the MAD part. Noncompartmental PK analysis of the SAD and MAD showed medium tmaxvalue delayed at 2 doses when apatinib was administered with food. Compartmental PK analysis showed food delayed initiation in absorption and reduced first order absorption rate constant. Dose proportionality was confirmed only for the AUC0-∞ value from the SAD-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. Visual inspection of the effect of CYP2C19 genotype on the clearance of apatinib did not show correlation. Inspection of CYP3A4 genotype on the calculated clearance values was tenuous given the intermediate metabolizers (N = 1), compared to extensive metabolizers.
Results of bevacizumab biosimilar compared with RMP for the treatment of metastatic colorectal cancer.
Authors: Roca Enrique Luis , Vinnyk Yuriy , Bondarenko Igor , Shparyk Yaroslav V. , Bariani Giovanni Mendonca , Abdalla Kathia , Franke Fábio , Cruz Felipe , Romera Alvaro , Bhamare Sulabhchandra , Sudalaiandi Suresh , Ostwal Vikas S. , Shah Pradeep , Rahuman Sajeed , Cubillo Antonio , Huerga Camino , Paravisini Alexandra , Fernandez Francisco Javier , Millan Susana
Published: September 2018

e14065

Background: BEVZ92 has being developed as a proposed biosimilar approved reference medicine product (RMP). BEVZ92 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to RMP. The aim of this study was to demonstrate pharmacokinetics (PK) similarity of BEVZ92 to RMP, in combination in combination with FOLFOX or FOLFIRI, as first-line treatment in patients with mCRC (NCT02069704). Methods: PK analysis for multiple dose studies was conducted, as per guidelines, measuring the total exposure area under the concentration-time profile (AUC0-336) at cycle 1, and to the end of the dosing interval at steady-state (AUCss) at cycle 7. PK similarity was achieved if 90% confidence interval (CI) for the test-to-reference ratios of AUC0-336h and AUCss were within 80.00–125.00% bioequivalence acceptance window. Secondary endpoints included other PK parameters, safety profile, immunogenicity and objective response rate (ORR). Results: A total of 142 patients were randomized and treated. Bevacizumab serum concentrations showed a ratio (90% CI) of geometric means for BEVZ92 and RMP were 99.4% (90.5%-109%) and 100% (90.2%–112%) for AUC0-336h and AUCss, respectively. All secondary PK endpoints which include Cmax, Ctrough, Tmax, t1/2, Kel, CL, Vd, and RA-AUC were also similar between the two arms. The ORR was 45% (95% CI, 33% to 57%) for BEVZ92, and 52% (95% CI, 40% to 64%) for RMP. Immunogenicity results showed a low incidence in the anti-drug antibodies de novo development and similar between both arms. Safety profile in terms of nature, frequency and severity was similar to the RMP and according to what is expected given the underlying disease and concurrent use of chemotherapy. Conclusions: These study results confirm the bioequivalence of BEVZ92 and the RMP in a real and common clinical setting, and translates the high similarity demonstrated in the in vitro and in vivo characterization into the clinical outcomes such as efficacy, immunogenicity and safety profile. Clinical trial information: NCT02069704.
Combined treatment of apatinib with docetaxel in non-small-cell lung cancer mice and its material basis of pharmacokinetics.
Authors: Zhou Fang , Feng Siqi , Zhang Jingwei , Aa Jiye , Wang Guangji
Published: September 2018

e14069

Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has attracted many attentions due to its encouraging anticancer activity in clinic third-line treatment across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer (NSCLC) and colorectal cancer. Its usage in second-line with chemotherapeutic drugs is still under exploration. This study is focus on the antitumor effect of apatinib combined with docetaxel (DTX) on NSCLC and its pharmacokinetic material basis. Methods: Apatinib (150 mg/kg, every day, p.o.) with or without DTX (8 mg/kg, q3d for four times, i.p.) was administered in A549 xenograft nude mice. The antitumor effect, histopathology of important organs and serum transaminases for liver function were detected. The metabolomic changes in serum were profiled by GC/MS and analyzed for the treatment outcome. The effect of apatinib on DTX concentrations in plasma, tumor and other tissues were determined by LC-MS/MS. The expressions of multidrug resistant transporters were detected. Effects of apatinib on the uptake, efflux and subcellular distribution of DTX in A549 cell and A549/DTX (DTX resistant) cell were investigated. Results: Apatinib enhanced the antitumor effect of DTX with alleviated DTX-induced inflammatory cells infiltration in liver and decreased serum transaminases (ALT and AST). Metabolomic results showed that serum endogenic molecules of apatinib and DTX co-treatment mice were closer to that of normal nude mice when compared to the DTX group. Apatinib significantly increased DTX concentration in tumor (up to 1.82 times) without enhancement in serum, heart, liver, lung and kidney. Additionally, apatinib decreased the DTX-induced upregulation of P-glycoprotein in tumor. In vitro, apatinib increased the cell/subcellular accumulation (especially in cytosol) and decreased the efflux of DTX in A549/DTX cells, while apatinib exerted no significant effect on cellular pharmacokinetics of DTX in A549 cells. Conclusions: Apatinib has a potential application prospect in second-line therapy combined with DTX for NSCLC patients, especially for multidrug resistant patients.
Preclinical in vitro and in vivo study of UD-017, a novel highly selective and orally available CDK7 inhibitor, in a variety of cancers.
Authors: Onuma Kazuhiro , Aga Yasuhiro , Ogi Sayaka , Matsushita Takashi , Sunamoto Hidetoshi , Ogawa Ayumi , Tokunaga Yasunori , Ushiyama Shigeru
Published: September 2018

e14086

Background: Cyclin dependent kinase 7 (CDK7) modulates mRNA transcription and some oncogenes are reported to be sensitive to inhibition of transcription in certain cancer cells. CDK7 inhibitors have been considered as an intriguing approach to treat cancers that depend on transcriptional regulation of their oncogenes. We synthesized a novel highly selective CDK7 inhibitor, UD-017, and found that the compound showed antitumor potency in a variety of cancers in vitro and in vivo. We therefore explored underlying mechanisms especially focusing on an oncogenic driver, c-Myc. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated an antiproliferative activity of UD-017 in over 200 multiple types of cancer cell lines including patients-derived cancer cells. We then investigated the correlation between c-Myc expression levels and an antiproliferative activity of UD-017 in cancer cells. Antitumor efficacy of UD-017 was assessed in multiple types of cancer xenograft models and patients-derived xenograft model. We determined whether an intratumoral c-Myc expression levels correlated with in vivo antitumor efficacy of UD-017 in xenograft models. Results: UD-017 inhibited CDK7 enzyme (IC50= 16 nM) highly selectively among the CDKs (over 300-fold) and almost mono-specifically in a panel of 313 kinases assay. In a cellular antiproliferative panel assay, UD-017 broadly inhibited the proliferation of a variety of cancer cells and c-Myc expression levels showed the good correlation with antiproliferative activity. UD-017 showed favorable PK profile and good oral absorbability and showed the potent antitumor activity in multiple types of cancer xenograft models in mice. In correlation with the PK, UD-017 reduced the intratumoral c-Myc mRNA levels time-dependently after dosing of UD-017 in the colorectal cancer xenograft model. Conclusions: We identified a highly selective and orally available CDK7 inhibitor that showed the broad in vitro and in vivo antitumor activity in a variety of cancers, modulating c-Myc as an oncogenic driver. These data support the rationale for further advancing towards clinical development.
Efficacy, maximal tolerated dose, and toxicokinetics of TTC-352 in rats and dogs, a partial ER agonist for metastatic ER+ breast cancer.
Authors: Tonetti Debra A. , Xiong Rui , Zhao Jiong , Gutgesell Lauren , Dudek Arkadiusz Z. , Thatcher Gregory R.
Published: September 2018

e14090

Background: The high prevalence of treatment resistance for estrogen receptor positive (ER+) breast cancer cause more deaths than all other breast cancers, despite the availability of endocrine therapeutics including selective ER downregulators (SERDs). Before tamoxifen, high dose estradiol (E2) delivered clinical efficacy slightly superior to tamoxifen. While recent clinical trials have shown efficacy of low dose E2, unacceptable side effects including vaginal bleeding, endometrial hypertrophy, and the negative perceptions of both patients and physicians limit acceptance. In preclinical models, tamoxifen resistant (TR) breast cancer is sensitive to treatment by E2. TTC-352 is an orally bioavailable selective human ERα partial agonist (ShERPA) designed to mimic E2 in causing tumor regression of TR breast cancer xenografts without uterine proliferation caused by E2 and tamoxifen. Methods: The published preclinical efficacy studies were extended to multiple TR ER+ cell lines in 3D spheroid cell cultures comparing to E2 and the SERD GDC0810. The maximum tolerated dose (MTD) was determined in Sprague-Dawley rats at: 200, 300, 600, 1000 and 2000 mg/kg by oral gavage (N = 3). Animals were observed for 7 days prior to necropsy. A single MTD range finding study was performed in dogs at: 50, 100, and 200 mg/kg TTC-352, administered orally in gelatin capsules. Based on these results, a 7-day repeated dose studies were completed at 30, 100, 300 and 1000 mg/kg/day in rats (3/sex/dose) and 15, 75, and 150 mg/kg (2/sex/dose) in dogs. Results: Growth of three TR ER+ breast cancer cell cultures in 3D was inhibited by TTC-352, which mimicked E2 and was equivalent to GDC0810. In female rats MTD was 1000 mg/kg and TTC-352 was well tolerated following a single oral dose of 200, 300, 600 mg/kg. The oral administration of TTC-352 at doses of 30, 100, and 300 mg/kg/day in rats (both sexes) and 15, 75 or 150 mg/kg/day in dogs (both sexes) for seven days was generally well tolerated. Conclusions: TTC-352 has demonstrated efficacy in preclinical models of TR breast cancer. Completed rat and dog studies indicated favorable tolerability and rapid absorption up to 300 mg/kg/day in rats and 150 mg/kg/day in dogs.
Concordance of tumor cell (TC) and immune cell (IC) staining with Ventana SP142, Ventana SP263, Dako 28-8 and Dako 22C3 PD-L1 IHC tests in NSCLC patient samples.
Authors: Scott Marietta L. , Ratcliffe Marianne J , Sharpe Alan , Barker Craig , Scorer Paul , Rebelatto Marlon , Al-Masri Hytham , Walker Jill
Published: September 2018

e14503

Background: PD-1/PD-L1 directed antibodies are emerging as effective oncology therapeutics with multiple diagnostic PD-L1 tests available for patient segmentation. It is essential to compare these assays to understand the risk if assays are used interchangeably. Previous data showed strong concordance (OPA >85%) of TC PD-L1 expression at multiple clinically relevant cutoffs with the Ventana SP263, Dako 28-8 and 22C3 assays (Ratcliffe et al. Clin Cancer Res 2017; Ratcliffe et al. ESMO 2016 (955PD)). This work supplements previous data with concordance of IC scoring and data from Ventana SP142. Methods: IC PD-L1 IHC expression data were generated from 493 clinical NSCLC biopsy samples stained with Ventana SP263 and Dako 22C3 and 28-8 assays. In addition, consecutive sections from 200 blocks of the 493 samples were later sectioned and stained with SP142 and SP263. Concordance at matched cutoffs between the 4 assays is reported for IC, and concordance between SP263 and SP142 for TC. Results: Strong agreement in IC scoring between the SP263 and 22C3 and 28-8 assays is observed. The SP142 assay showed lower IC concordance and reduced TC PD-L1 staining/concordance vs SP263 (Table). Conclusions: Analytical similarity is shown between the SP263, 28-8 or 22C3 assays when measuring TC or IC PD-L1 expression, with high concordance between patient classification at matching TC cutoffs up to ≥50% or IC up to ≥10%, strengthening the evidence that these 3 assays could be used interchangeably at relevant clinical cutoffs. The SP142 assay shows clear analytical differences in both IC and TC staining. [Table: see text]
Immune response and adverse events to influenza vaccine in cancer patients undergoing PD-1 blockade.
Authors: Laubli Heinz Philipp , Balmelli Cathrin , Kaufmann Lukas , Stanczak Michal , Syedbasha Mohammedyaseen , Vogt Dominik , Mueller Beat , Gautschi Oliver , Stenner Frank , Zippelius Alfred , Egli Adrian , Rothschild Sacha
Published: September 2018

e14523

Background: Cancer patients (pts) are at risk to develop complications when infected with seasonal influenza viruses. Current guidelines propose that pts on PD-1 directed therapies may receive concurrent inactivated influenza immunization if not medically contraindicated. In this observational study, we aimed to assess the vaccine induced immune response and safety of immunotherapy and influenza vaccine. Methods: Metastatic cancer pts treated with at least one dose of either nivolumab or pembrolizumab were vaccinated with a trivalent inactive influenza vaccination between October and November 2015. Partners of the pts were vaccinated and included in our analysis as age-matched controls. Antibody titers against vaccine virus strains were measured by hemagglutination inhibition assay at days 7, 30, 60 and 180. Cytokine/chemokine profile and changes in peripheral immune cells were assessed in cancer pts at the same time points. Immune-related adverse events (irAE) were documented according to CTCAE v4.0. Results: We included 23 pts and 7 age-matched healthy controls. Median time between initiation of PD-1 inhibition and influenza vaccination was 74 days (range, 44-57). 22 pts were treated with nivolumab and 1 pt with pembrolizumab. 16 pts had a diagnosis of non-small cell lung cancer, 3 pts had renal cell carcinoma and 3 pts a malignant melanoma. In total, 12 pts (52.2%) experienced an irAE. 6 pts (26.1%) had grade 3 or 4 (G3/4) irAEs. This frequency seems to be higher than reported in the literature. G3/4 irAEs include colitis (n = 2), encephalitis (n = 1), vasculitis (n = 1), pneumonitis (n = 1), peripheral neuritis (n = 1). There was no major difference over time in the generation of antibody titers against strains in the vaccine. Peripheral leukocyte counts and cytokine/inflammatory chemokine levels were unchanged after vaccination. We did not observe unexpected local toxicities at the injection site. Conclusions: The seasonal influence vaccination reaches a protective range in these pts. Unexpectedly, however, an increased rate of clinically relevant irAEs was observed. Confirmation in a larger population and mechanistic understanding is required.
High baseline lymphocyte count is a predictive biomarker of prolonged time to progression in patients with advanced solid tumors receiving checkpoint inhibitors.
Authors: Maltese Mariangela , Panni Stefano , Lazzarelli Silvia , Brighenti Matteo , Negri Federica , Ratti Margherita , Giganti Maria Olga , Passalacqua Rodolfo
Published: September 2018

e14532

Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.