bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I dose finding study of AZD8931, an inhibitor of EGFR, HER2, and HER3 signaling, alone or in combination with paclitaxel in Japanese patients.
Authors: Fujisaka Yasuhito , Kurata Takayasu , Tsurutani Junji , Okamoto Wataru , Hayashi Hidetoshi , Kawakami Hisato , Shin Eisei , Hayashi Nobuya , Nakagawa Kazuhiko 
Published: March 2020

e13501 Background: AZD8931 is an equipotent, reversible inhibitor of signaling by EGFR, HER2 and HER3. Methods: This open-label, multiple-dose cohort study (NCT01003158) was conducted in Japan to evaluate the safety, tolerability and PK of ascending doses of AZD8931 alone (starting dose 40 mg bd) in patients (pts) with advanced solid malignancies and AZD8931 in combination with paclitaxel (P; 90 mg/m2on days 1, 8 and 15 of a 28-day cycle) in pts with advanced breast cancer. Results: Between Jan 2010 and Apr 2012,17 pts were treated; 11 with AZD8931 monotherapy (40/60/80 mg bd [n=3/4/4]) and 6 with AZD8931 40 mg bd plus P. Median (range) duration of exposure to AZD8931 was 42.5 (22–238) and 79.5 (53–244) days for monotherapy and combination therapy, respectively. No DLTs were observed (in the DLT evaluation period) and therefore the MTD was not confirmed for AZD8931 alone or with P. The most frequent AEs (all grades) with AZD8931 monotherapy were diarrhea, paronychia, rash pustule and dry skin (each n=8) and with combination therapy were diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n=4). Throughout the study grade ≥3 AEs were reported for 1, 2 and 4 pts in the 40 mg, 60 mg and combination groups, respectively. One serious AE was reported each in the 40 mg (grade 3 intervertebral disc protrusion) and combination (grade 2 infectious pneumonia) groups; neither was considered related to study treatment. One pt in the combination therapy part discontinued due to an AE of grade 1 pneumonia. AZD8931 was rapidly absorbed (median tmax 1–2 hours), well distributed, had moderate clearance (31–39 L/h) and a t½ of 12 hours. There was no suggestion of a PK interaction between AZD8931 and P. One pt on AZD8931 80 mg bd (primary stomach cancer) and another receiving AZD8931 plus P (advanced breast cancer) had an unconfirmed and confirmed PR, respectively (duration of responses 42 and 172 days, respectively) demonstrating preliminary efficacy. Conclusions: Although a MTD was not confirmed for AZD8931, based on overall incidence of AEs of rash and diarrhea in the 80 mg group, doses up to 60 mg bd as monotherapy and 40 mg bd combined with P are the recommended doses for evaluation in Japanese pts. Clinical trial information: NCT01003158.
A phase I study of EMD 525797, a novel humanized monoclonal antibody to human integrin alpha v, in Japanese patients with solid tumor.
Authors: Doi Toshihiko , Fuse Nozomu , Bando Hideaki , Kojima Takashi , Watanabe Morihiro , Yoshino Takayuki , Ohtsu Atsushi 
Published: March 2020

e13510 Background: Integrin alpha v, in association with several integrin beta subunits, plays critical roles in migration, invasion, proliferation, and survival of both tumor and endothelial cells and represents an attractive target for cancer treatment. EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting integrin alpha v. Methods: The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in Japanese patients with advanced solid tumors, treated with intravenous infusions of 250, 500, 1000, or 1500 mg of EMD 525797 (given over 1 h), who received 3 doses (weeks 1, 3, and 5) before response assessment during week 6. Thereafter, patients without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 4 weeks and safety was monitored until 31 days after the last administration of EMD 525797. Results: A total of 27 patients were treated. Regarding the primary site of disease, 17 patients had colorectal cancer, 3 pancreatic cancer, 2 gastrointestinal stromal tumors (GIST), 1 esophageal cancer, 1 gastric cancer, 1 rectal carcinoid, 1 cholangiocarcinoma, 1 hepatocellular carcinoma, and 1 leiomyosarcoma. Twenty-five patients (92.6%) experienced treatment-emergent adverse events (TEAEs); nausea (25.9%), headache (22.2%), pyrexia (22.2%), stomatitis (22.2%), and vomiting (22.2%) were the most common. None of these TEAEs was greater than grade 3 by NCI-CTCAE version 4.0 and no DLT was observed. Fourteen (51.9%) of the TEAEs were possibly related to EMD 525797. Two patients, 1 with GIST and 1 with rectal carcinoid, had longer than expected exposure time (>84 days). EMD 525797 showed a non-linear PK profile. Distribution volume and clearance after EMD 525797 administration did not show apparent ethnic difference considering body weight influence. Conclusions: EMD 525797 was well tolerated in Japanese patients. The safety profile in Japanese patients was comparable to the results from Caucasian patients. In some patients EMD 525797 treatment duration was longer than expected. Clinical trial information: NCT01327313.
Induction of autophagy across multiple tumor types through irreversible HER tyrosine kinase blockade.
Authors: Gwin William Rayford , Liu Leihua , Zhao Sumin , Xia Wenle , Spector Neil 
Published: March 2020

e13517 Background: Human epidermal growth factor receptor (HER) receptor tyrosine kinases play a key role in solid tumor oncogenesis. Despite broad expression of HER receptors in solid tumors, HER targeted therapies have not shown significant improvement in survival, calling into question the value of wild-type HER receptors as therapeutic targets. Here we found that an irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, but not similar HER TKIs, induced morphologic changes in ovarian, TNBC, and prostate cancer cell lines consistent with induction of autophagy. Methods: SKOV3 (ovarian), OVCAR8 (ovarian), HBL-100 (TNBC), and LAPC4 (prostate) cancer cells were treated with lapatinib, gefitinib, CI-1033, afatinib, and neratinib (0.5mM-2.5mM). The activation state of HER2, EGFR, HER3, Akt, Erk, p70S6, 4EBP1, and Ulk1 was determined by Western blot analysis (WB) at various time points of neratinib treatment. LC3 was analyzed by immunofluorescence (IF) microscopy and WB. Analysis of proliferation, apoptosis, and cell cycle were performed using WST-1, annexin V, and PI staining, respectively. Results: Neratinib, but not similar HER TKIs, induced marked cytoplasmic vacuolization in tumors. The conversion of LC3-I to LC3-II in neratinib-treated cells was consistent with induction of autophagy. Moreover, PI3K/Akt, MAPK/Erk1/2 and mTORC1 signaling cascades were inhibited in neratinib-treated cells, and were associated with the inhibition of phospho-Ulk1, a key step in autophagy initiation. Treatment with neratinib alone resulted in G1 cell cycle arrest. Importantly, the combination of neratinib and chloroquine, an autophagy inhibitor, induced a statistically significant inhibition of cellular proliferation (p <0.01) and increased apoptosis compared to treatment with either drug alone. Conclusions: Our data suggest that more effective inhibition of wild-type HER receptors, can lead to mTORC1 inhibition, which in turn triggers autophagy. Here, autophagy appears to protect cells rather than inducing apoptosis. Consequently, targeting both HER receptors and autophagy represents an attractive therapeutic strategy to treat tumors expressing wild-type HER receptors.
BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.
Authors: Salkeni Mohamad Adham , Rixe Olivier , Abdel Karim Nagla , Ogara Sue , Feiler Monica , Moorthy Ganesh , Mercer Carol A , Thomas Hala , Desai Pankaj B , Fathallah Hassana , Kozma Sara , Thomas George , Morris John Charles 
Published: March 2020

e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.
Phase I expansion study of sunitinib and bevacizumab in patients with advanced solid malignancies.
Authors: Mittal Kriti , Koon Henry B. , Elson Paul , Triozzi Pierre L. , Dowlati Afshin , Borden Ernest C. , Rini Brian I. 
Published: March 2020

e13521 Background: The vascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) and the VEGF receptor (VEGFR) inhibitor sunitinib are efficacious agents in many malignancies. This combination has been previously evaluated in phase I studies of advanced solid tumors. In addition to renal cell carcinoma (RCC), objective responses in the previous phase I occurred in melanoma and adrenal carcinoma. An expansion phase of the phase I study was undertaken primarily to obtain further safety data in these tumor types. Methods: Patients (pts) with metastatic solid tumors with ECOG performance status 0-1 were enrolled on a phase I trial of sunitinib (37.5 mg daily weeks 1-4) and Bev (5 mg/kg iv on days 1, 15 and 29) of a 6 week cycle. Responses were assessed by CT scans performed at baseline and every 12 weeks based on RECIST criteria v1.0. Results: Twenty-two pts were enrolled (10 males, 12 females; median age 58 years) in the expansion cohort. Tumor types included melanoma (11), RCC (5), adrenal cancer (5) and angiosarcoma (1). Prior systemic treatment included chemotherapy (41%) and immunotherapy (27%). Common all grade toxicities included fatigue (77%), hypertension (73%), thrombocytopenia (68%), nausea (59%) and oral mucositis (55%). Grade 3 or higher toxicities occurred in 15 pts (68%); including hypertension (41%), thrombocytopenia (23%) and fatigue (14%). Seven pts developed hemorrhagic events, all grade 1 or 2. Two pts experienced grade 4 thrombocytopenia, 3 RCC pts developed grade 1 thrombotic microangiopathy (TMA); while 1 melanoma patient developed decreased haptoglobin (grade 1) with associated thrombocytopenia (grade 4) and schistocytes consistent with TMA. A median of 2 cycles were completed (range, 1-8). Best response in 19 evaluable pts included partial response 21% (4/19; melanoma (2), adrenal (1), and RCC(1)); stable disease 21% (4/19) and progressive disease 58% (11/19). Overall, 6 pts (31.5%) had measurable reduction in tumor burden. Conclusions: The safety profile of Bev plus sunitinib in melanoma and adrenal carcinoma pts is similar to the previously evaluated toxicities in RCC pts. Although reversible, combined VEGF and VEGFR inhibition may lead to microangiopathy even in non-RCC pts. Clinical trial information: NCT00357318.
Effect of ABTL0812, a safe dual inhibitor of mTORC1/C2 and dihydrofolate reductase, on gemcitabine and docetaxel cytotoxicity in pancreatic and lung cancer cells.
Authors: Alfon Jose , Espadaler Jordi , Garcia Jose A , Domenech Carles , Lizcano Jose M 
Published: March 2020

e13526 Background: We have previously described that ABTL0812 has oral anticancer properties. The action is exerted through a mechanism of action involving the inhibition of mTORC1 and mTORC2 (mammalian target of rapamycin) pathways and dihydrofolate reductase (DHFR) expression. Administration of ABTL0812 reduced tumor volume similarly or more than standards of care (SOC) in A549 or MiaPaca2 xenografts in mice. Moreover, a 28-day rat toxicity study has shown very low toxicity (NOAEL=500 mg/Kg) good bioavailability and pharmacokinetic linearity, suggesting a broad therapeutic window. A FiM phase I clinical trial in patients with advanced cancer is scheduled to start in June 2013. Methods: Cellular assays were performed in A549 lung adenocarcinoma, and MiaPaca-2 pancreatic carcinoma cells. Cell proliferation was carried out by bromodeoxyuridine (BrdU) incorporation, cell viability by MTT, and protein expression and phosphorylation by immunoblotting. Cellular apoptosis was assessed both by caspase 3 immunoblot and Hoechst 3342 nuclear staining and quantification of nuclei; and autophagy by LC3-II lipidation assay in immunoblots. All studies were performed with ABTL0812 either alone or in combination with SOC. Results: ABTL0812 potentiated the cytotoxic effects of gemcitabine and docetaxel in MiaPaCa-2 and A549 cancer cells, respectively. In MTT assays, the IC50’s of gemcitabine and docetaxel decreased 7 and 80 times in MiaPaca-2 and A549 cells, respectively, when cells were co-incubated with non-cytotoxic ABTL0812 concentrations. Analysis of the activity (Chou and Talalay’s method) revealed that ABTL0812 synergizes with gemcitabine and docetaxel to promote cytotoxicity. We also present data showing the effects of gemcitabine and docetaxel on the molecular targets of ABTL0812 such as Akt and ribosomal S6 phosphorylation, DHFR expression and cellular autophagy. Conversely, we also show the effects of ABTL0182 on cellular apoptosis induced by gemcitabine and docetaxel. Conclusions: ABTL0812 synergistically potentiates the cytotoxic effect of gemcitabine and docetaxel in pancreatic and lung cancer cell models.
Outcome analyses of patients with metastatic cervical cancers in a phase I clinic.
Authors: Hou Ming-Mou , Liu Xiaochun , Wheler Jennifer J. , Naing Aung , Hong David S. , Bodurka Diane C. , Schmeler Kathleen M. , Tsimberidou Apostolia Maria , Janku Filip , Zinner Ralph , Piha-Paul Sarina Anne , Lu Karen H. , Wolff Robert A. , Kurzrock Razelle , Fu Siqing 
Published: March 2020

e13534 Background: Patients with metastatic cervical cancers have a poor prognosis and few effective therapies available. Thus, access to a phase I trial may provide a viable option. Methods: Outcomes of 54 consecutive patients with metastatic cervical cancers seen in a phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 12/31/2012 were reviewed in accordance with the MD Anderson IRB guidelines. Results: The 54 patients included Caucasians (n=34, 63%), Hispanics (n=9, 17%), African Americans (n=7, 13%), and others (n=4, 7%). Pathological diagnoses were squamous cell carcinoma (n=33, 60%), adenocarcinoma (n=12, 22%), adenosquamous (n=3, 6%), poorly differentiated carcinoma (n=2, 4%), small cell carcinoma (n=2, 4%), clear cell carcinoma (n=1, 2%), and melanoma (n=1, 2%). Initial staging was as follows: I (n=16, 30%), II (n=11, 20%), III (n=11, 20%), and IV (n=16, 30%). Prior treatment included surgery (n=23, 43%), radiotherapy (n=41, 76%), and systemic chemotherapy (n=54, 100%) including one regimen (n=30, 55%), two (n=15, 28%) and more (n=9, 17%). At their initial visit to the phase I clinic, the median age was 47 years. The majority of patients had ECOG PS 0-1 (n=45, 83%), and MDACC prognostic scores 0-1 (n=48, 89%). Almost all the 54 referred patients were enrolled into a phase I trial (n=52, 96%). Initial phase I trials these patients had received led to one CR, five PR, and 12 SD ≥ 6 months (CR/PR/SD≥6 months=35%). Of the patients who progressed on their first protocols, 11 patients (21%) were enrolled into a second protocol, leading to 36% of PR/SD≥6 months (n=4). Among those enrolled into a third (n=4) and a fourth (n=1) study, no CR/PR/SD≥6 months was achieved. The median overall survival in these 54 referred patients was 10.6 months. Among 36 patients who underwent molecular marker studies, 15 were found to harbor PIK3CA mutations and/or PTEN loss (42%) and achieved 60% of CR/PR/SD≥6 months (3 PR and 6 SD≥6 months). Conclusions: Aberrant PI3K pathway was frequently identified in advanced cervical cancers, and the high rate of CR/PR/SD≥6 months was observed in these patients treated under a phase I trial, suggesting that phase I trials, especially mutation matched regimens, may provide potential benefits to these patients.
DNA repair suppression and effect of cisplatin in mesothelioma and lung cancer cell lines.
Authors: Røe Oluf D. , Chen Wu , Zhi Xiaofei , Chen Duan , Chen Yijiang 
Published: March 2020

e13542 Background: Recently we characterized a gene profile with overexpressed DNA double strand repair systems in mesothelioma versus normal tissue, where homologous recombination (HR) and non-homologous end joining (NHEJ) were prominent systems overexpressed. They play a role in resistance to the DNA damaging agent cisplatin, the backbone of both mesothelioma and lung cancer treatment. We hypothesized that inhibition of these systems could increase the effect of cisplatin. Methods: Cisplatin and two natural compounds A and B inhibiting HR and NHEJ respectively were tested as single treatment and various combinations in mesothelioma (MSTO-211H), parental (A549) and cisplatin resistant lung cancer cells (A549/DDP) were the dose-response and time-response was determined. Sterile MTT (0.5mg/ml) was added at 37°C for 4h, then removed and DMSO added for 10 minutes. Spectrometric absorbance at 570nm was measured. The inhibition rate was calculated by the relative inhibition curve. The IC30 doses of cisplatin was combined with IC5 of the experimental compounds to reveal the effects of combining chemotherapy with non-toxic compounds. Results: The IC5 of the experimental compounds A and B were 2μM and 1mM in the MSTO-211H and A549 respectively, and similarly in the A549/DDP cells, 2μM and 0.5mM. The IC30 of cisplatin was 1,5 μg/ml in the MSTO and A549 and 20 μg/ml (13-fold) in the A549/DDP cells.The combination of IC5 of A and B without cisplatin showed a synergic effect of about 50%. IC30 of cisplatin from 24h to 72h without pretreatment showed 20% inhibition at 48h and interestingly the inhibition rate was reduced to 10% at 72h. Pretreatment with A and B for 24h, and then cisplatin for 48h had the same effect as cisplatin together with A and B for 48h, about 30% inhibition. Pretreatment with A and B for 24h, then addition of cisplatin plus A and B for 48h had the strongest effect of >50% inhibition rate. Conclusions: Our results indicate that suppression of HR and NHEJ in both mesothelioma and non-small cell lung cancer cell lines by non-toxic doses increased cisplatin efficacy. The acquired cisplatin resistant A549/DDP remained sensitive to the natural inhibitors. Molecular analyses on DNA damage and apoptosis will be presented at the meeting.
New targeted anti CDK4/6 peptide MM-D37K.
Authors: Bozhenko Vladimir Konstantinovich , Kulinich Tatyana Michailovna , Kudinova Elena Aleksandrovna , Boldyrev Andrey , Solodkij Vladimir Alekseevich 
Published: March 2020

e13545 Background: MM-D37K is a synthetic peptide which consists of p16INK4a-specific inhibitor of complex cyclin D- CDK4 and CDK6 and cell penetrating peptide (CPP) – Antp (Penetratin). We investigated in vitro and in vivo cytotoxic, cytostatic and antitumor activity of MM-D37K. The level of cyclin A, Ki67,bax, bcl-2 and pRb phosphorylation was investigated. Full range of Toxicology tests and Pharmacokinetics experiments in mice, rats and rabbits were performed. Methods: Different cell lines (Jurcat, Raji, A549, MCF-7, Hct-116, Ht-29, HEK293) were incubated with 0.1-100 mM MM-D37K for 24-48 hrs. Proliferation (MTT), DNA-content, cell cycle (flow cytometry) and mRNA level of appropriate proteins (RT PCR) were investigated. In vivo experiments were conducted on xenograft model of HCT116, A-549 at concentration 5 and 10 mg/kg of MM-D37K. Toxicology experiments were made under RF Law and included 3 types of animals. LC-MS MMD37K method of detection in plasma was developed. Results: MM-D37K prevented pRb phosphorilation and proliferation activation in all investigated cell lines. Cell cycle was blocked in G1 phase. Cytostatic effect did not depend on p16 mutation or expression. MM-D37K induced apoptosis in 20-82% of investigated cells at 40 mM with lowest level for MCF-7. LD10 for rats was 100 mg/kg and no deaths were registered for rabbits (highest dose was 50 mg/kg). Concentration of MMD-37K in plasma after 2 min and bolus i.v. injection in dose 10 mg/kg was 72.16±5.64 mcg/ml. Concentration decreased in two phases. 1st – t1/2 = 2.39±0.39 min and for 2nd t1/2=2.39±0.39 hr. Antitumor effects in xenograft model were 53% for A-549 and 67% for HCT116. Conclusions: Our results proved cytotoxic, cytostatic and antitumor effects of MM-D37K in investigated cell lines in vitro and in vivo. Toxicological and pharmacokinetics results allow us recommend for I/IIa Phase clinical trial. (Support: MetaMax Ltd., RFFI, Minpromtorg RF.)