bluuebunny/crossref_metadata_2025 huggingface dataset:
An evaluation of phase I clinical trial designs of chemotherapeutic agents tested on solid tumors and approved in last 10 years.
Authors: Deshmukh Chetan Dilip , Divekar Ganesh , Bondarde Shailesh Arjun , Jain Minish Mahendra , Prabhash Kumar
Published: March 2020

e13127

Background: Phase I trials are performed with the aim of finding the maximum tolerated dose and often start with a very low dose that is subsequently escalated based on the toxicity seen. As a result patients treated on these trials often receive doses of chemotherapeutic agents that are frequently either below or above the biologically active level, thus reducing their chances for therapeutic benefit or increasing chances for toxicity. This evaluation was undertaken to determine how phase I trials are currently conducted and to correlate phase I doses tested with MTD and marketed doses. Methods: Published phase I trials of 16 chemotherapeutic agents tested on solid tumors and approved in last 10-years were identified by searching the Medline database and reviewed to determine methodology employed, cohorts taken to complete the trial, definition of dose limiting toxicity (DLT), number of cohorts treated below MTD, relation between MTD and marketed dose and DLT (dose limiting toxicity). Results: Twenty-three published trials involving 891 patients were identified. These trialsused the standard method of enrolling cohorts of patients at increasing dose levels and observing toxic effects to determine next dose.. Of these 15 used traditional dose escalation, 6 used accelerated titration, 2 used continual reassessment method. Six trials that used accelerated titration method of dose escalation, 2 were used to test cytotoxic agent (5 trials) while 1 tested targeted therapy. Sixty five cohorts were treated below MTD. Average number of cohorts required to complete trial were 6.2. Nineteen trials defined MTD as a dose below DLT dose while 4 trials defined MTD being DLT. Five of 23 trials were completed with-out reaching MTD. Marketed dose for these 16 chemotherapeutic agents was 0 to 50% lower than MTD. DLT reported was myelosupression, fatigue, rash, hypertension or diarrhea. Conclusions: These results show the need for methods to reduce cohorts to reduce number of patients recruited at doses significantly lower than MTD and complete the trials rapidly so that effective agents can be marketed sooner.
Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model.
Authors: Yamashita-Kashima Yoriko , Shu Sei , Harada Naoki , Fujimoto-Ouchi Kaori
Published: March 2020

e13502

Background: The efficacy and safety of T-DM1 combined with pertuzumab in HER2-positive breast cancer is currently being investigated in a phase III clinical trial (MARIANNE). Anti-HER2 therapy with T-DM1 combined with pertuzumab in HER2-positive gastric cancer is of great interest. In a previous study in a HER2-positive gastric cancer xenograft model, T-DM1 in combination with pertuzumab demonstrated enhanced antitumor activity compared with each agent alone, and potentiated ADCC and apoptosis activity (AACR, 2011). In this study, we investigated the mechanisms underlying the enhanced activity observed with these two drugs. Methods: The binding of T-DM1 to cell surface HER2 was measured in a HER2-positive human gastric cancer cell line (NCI-N87) by flow cytometry using Alexa Fluor 647-labeled T-DM1. The phosphorylation status of HER signaling molecules was assessed by Western blot, and cellular localization of T-DM1 was determined by fluorescence microscopy using labeled T-DM1 in the presence/absence of pertuzumab. Results: Binding of T-DM1 to cell surface HER2 was significantly increased in the presence of pertuzumab. Concomitant treatment with T-DM1 and pertuzumab led to a reduction of phosphorylated (p)EGFR or pHER3 in EGF or heregulin-stimulated cells, respectively, resulting in suppression of downstream pERK or pAkt pathways. Fluorescence microscopy revealed that pertuzumab facilitated the internalization of HER2-bound T-DM1 from the cell surface into the cytoplasm. Conclusions: Results suggest that the enhanced antitumor activity observed with the combination of T-DM1 and pertuzumab may be attributed to 1) increased binding of T-DM1 to HER2, which could potentially augment ADCC and diminish downstream HER2-signaling, and 2) increased T-DM1 internalization into the cytoplasm, which may potentiate tumor cell death caused by DM1. These results suggest that T-DM1 in combination with pertuzumab may provide clinical benefit for patients with HER2-positive gastric cancer.
Clinical and safety data of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer (MBC).
Authors: Mundhenke Christoph , Schem Christian , Bauerschlag Dirk Olaf , Weigel Marion T. , Wenners Antonia Sophie , Schaefer Fritz Werner , Tiemann Katharina , Hanson Sven , Muth Mathias , May Christoph , Jonat Walter , Maass Nicolai
Published: March 2020

e13503

Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated > 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study >28 days (“ITT>28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication >6 months, 15.2% > 12 months (mean 133 days, 15-617 days). Within “ITT>28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.
A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.
Authors: Lim Joline Sijing , Dimitrov Todor , Yong Kol Jia , Gao Chong , Tenen Daniel G , Chai Li
Published: March 2020

e13505

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.
Glycosylation and cancer: A potential target for therapeutic intervention.
Authors: Baldwin Gouri , O'Sullivan Brendan , Desai Anant , Gourevitch David , Woodman Ciaran , Taniere Philippe , Johnson Philip James
Published: March 2020

e13507

Background: Aberrant glycosylation is a hallmark of cancer progression. Altered expression of glycosyltransferases and molecular facilitators within the ER and Golgi apparatus contributes to these changes. The tetraspanin are a family of molecular facilitators, expression of which have been shown to either promote or suppress cancer progression. CD151, a member of this family, modulates the glycosylation of its partner, the α3β1 integrin, affecting the integrin’s affinity towards its laminin ligand. Methods: We have characterised the glycosylation characteristics of CD151 and CD63 using glycosylation inhibitors and glycosidases to explore their patho-physiological role. Results: Inhibition of glucosidaseI/II resulted in the downregulation of CD151 and its partners, α3β1 and α6β1 integrins. 3D cell culture of the glioblastoma cell line (U87MG) in the presence of the inhibitor restrained its dendrite-like invasive growth. Similarly, the migration potential of the breast cancer cell line, MDA-MB-231, towards Lm332 decreased by 90% upon glycosylation inhibitor treatment. Since brain tumours have been shown to have elevated expression of α3β1 and Laminin332 our results suggest that glycosylation inhibitors might have a potential for investigation of therapeutic agents. Glyco-analysis of CD63 in MDA-231 cells indicated the presence of phosphomannosylated(PM) group, which might contribute to its role in lysosomal targeting. Compared to MDA-231, U87MG cells showed markedly reduced PM of CD63. Increased sialylation has previously been identified as a signature for brain metastasis in MDA-231 cells. Accordingly, comparison of CD63 in high and low sialylated populations of MDA-231 showed, upon sorting, showed similarity between the highly sialylated population of MDA-231 and U87MG. Conclusions: Using glycosylation inhibitors, we have identified a novel use for these compounds in down-regulating two major cancer associated integrins, α3β1 and α6β1. We have also uncovered a previously unknown glycomodification of CD63, phosphomannosylation which may affect the metastatic potential of cancer cells. Both findings suggest a potential for glycosylation inhibitors as part of cancer therapy.
Pilot study on antitumor efficacy of intravenously applied synergistic combinations of salicylic acids in patients with advanced solid tumors.
Authors: Drevs Joachim , Spangenberger Holger , Jenny Matthias , Mueller-Huebenthal Jonas , Kamijo Izumi , Kreutz Werner
Published: March 2020

e13508

Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Using this differentiation a new therapy method has been developed for targeted chemotherapy. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of diflunisal, paraaminosalicylic acid (PAS) and aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance. Methods: A total of 30 patients (n=30) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of diflunisal and aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response. Results: Out of 30 patients treated 4 patients suffered from colorectal cancer, 11 from breast cancer, 2 from ovarian cancer, 2 from lung cancer, 2 from gastric cancer, 2 from glioblastoma, 1 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 1 from pancreatic cancer, 1 from choledochus cancer, 1 from prostate cancer, respectively. Side effects related to the therapy have been fatigue (6,7%), nausea (13,3%), tinnitus (10%), hypertension (6,7%), dyspnea (3,3%) and burning sensation in tumor areas (3,3%). Out of 30 patients treated, until today 14 were evaluable for metric response, 12 for metabolic and 13 for tumor marker response assessment. For tumor marker follow up 2 patientis (6,7 %) had a CR, 6 (20 %) a PR, 4 (13,3 %) a SD of > 3 month and 1 (3,3 %) a PD. For metric follow up 0 patients (0 %) had a CR, 6 (20 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. For metabolic follow up 1 patients (3,3 %) had a CR, 3 (10 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. Conclusions: This pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous salicylic acids in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study will be performed.
Serum VEGF in patients (PTS) receiving bevacizimab (BEV) for early-stage breast cancer (ESBC): ICORG 08-10.
Authors: O'Donovan Norma , Canonici Alexandra , Parker Imelda , O'Shea Tanya , Moulton Brian , Gullo Giuseppe , Kennedy John , Tryfonopoulos Dimitrios , Walsh Naomi , Crown John
Published: March 2020

e13520

Background: Approximately 30% of pts with ESBC develop metastasis despite apparently curative loco-regional therapy. Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), may promote metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant in ESBC, but there are no validated biomarkers, and the effect on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results: VEGF concentration was determined in serum samples from 65 patients. Three pts (5%) had no detectable VEGF at 0, 6 and 12 months. The median level of serum VEGF in the remaining 62 patients was 325.4 ± 244 pg/ml. These 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p<0.001 and 9 ± 43.9 pg/ml, p<0.001 respectively). However, no significant change in VEGF levels were observed at 12 months compared to 6 months (median 0 ± 60.3 pg/ml, p=0.704). Conclusions: Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months.
Recombinant adenoviral human p53 gene intracavity infusion in treatment of malignant pleural effusions and peritoneal effusions.
Authors: Hu Yi
Published: March 2020

e13521

Background: Malignant pleural or peritoneal effusion adversely affects patients' quality of life. Once the effusions formed it is difficult to control. This report showed intra-cavity infusion of recombinant adenoviral human p53 gene (rAd-p53) was very effective for controlling malignant pleural or peritoneal effusion. Methods: Twenty-seven patients, 15 males and 12 females with a median age of 59 years old , were included this study. The malignant pleural effusions, consisting of 13 patients, were caused by primary lung cancers (12 cases) and breast cancer (1 case), and 14 cases of peritoneal effusions were caused by gastric cancer (5 cases), ovarian cancers (3 cases), primary live cancer (2 cases), pancreatic cancer (2 cases), esophageal cancer (1 case) and bile duct cancer (1 case). The rAd-p53 intra-cavity infusion was given after removing most of fluids. For intra-chest cavity infusion 2×1012 viral particles (VP) of rAd-p53 diluted into 200 ml of saline solution, and for intra-abdominal cavity infusion 4×1012 VP of rAd-p53 diluted into 500 ml of saline solution, were given weekly for 3 weeks. Results: A total of 3 cases, 2 with pleural effusion and 1 with peritoneal effusion achieved a complete response (CR), and 10 cases (7 pleural effusions and 3 peritoneal effusions) had a partial response (PR). The overall response rate is 48.1%. The CR was defined as the complete disappearance of pleural or peritoneal fluid and negative cytologic findings for >4 weeks, and the PR is defined as a decrease over 50% of the fluid without the need of drainage and negative cytologic findings for >4 weeks. The fluids in 8 cases with peritoneal effusions decreased by over 30% but less than 50%. The associated symptoms relieved in 23 patients (85.2%). There were no serious side effects observed except for self-limited fever found in all the cases. Conclusions: For some patients with malignant pleural or peritoneal effusions, Intra-cavity infusion of rAd-p53 is effective and safe controlling treatment.
Analysis of GTV artifacts in all phases of four dimensional CT for peripheral lung cancer based on three-dimensional CT assisted with active breathing control.
Authors: Qi Huanpeng , Li Jianbin , Zhang Yingjie , Shao Qian
Published: March 2020

e13524

Background: To analysis artifacts of the gross tumor volume (GTV) and correlated affecting factors in all phases of four dimensional CT (4DCT) for peripheral lung cancer based on three dimensional CT (3DCT) assisted with active breathing control. Methods: After respiratory trainning sufficiently, nineteen patients with peripheral lung cancer underwent 3DCT (CTFB) and 4DCT simulation scans during free breathing and underwent 3DCT simulation scans in end inspiration hold (CTEIH) and end expiration hold (CTEEH) assisted with active breathing control. By comparing GTVEIH and GTVEEH, to choose the reference GTV (GTVref) used to calculate artifacts of GTV in all phases of 4DCT. To calculate delineation error based on re-delineating GTV in one phase of 4DCT , to calculate the relative deviations (Devref) between the size of GTV delineated based on CTFB (GTVFB) and GTVref and between the size of GTV delineated based on all phases of 4DCT , and GTVref respectively, and to determine the cutoff of GTV size according to the relevance of the maximum relative deviation (Devmax) and the delineation error when artifacts occurred. Results: GTVEIH was chosen as the GTVref, the delineation error was 10.2%, for 15 of 19 patients Devmax was larger than delineation error (Z=-2.938, p=0.003). Devmax was larger than delineation error when the mean GTV size was not larger than 6.355 cm3. A significant negative correlation was found between GTVEIH and CVGTV (r=-0.68, p=0.002) and between GTVEIH and Devmax (r=-0.691, p=0.001). The maximum median Devref of GTV size was GTVFB with 17.83% (-16.10~105.88%); The maximum one throughout the 4DCT was GTV30 with 17.20% (-6.64~102.05%) and the minimum one was GTV80 with 4.14% (-18.18~132.53%). The Devref of the size of GTVFB (r=0.520, p=0.022), GTV20 (r=0.545, p=0.016), GTV30 (r=0.617, p=0.005), GTV70 (r=0.542, p=0.017), GTV80 (r=0.576, p=0.01) and GTV90 (r=0.478, p=0.039). Conclusions: The GTVs in each phase of 4DCT for the peripheral lung cancer all had artifacts,the sizes of the artifacts in 30% and 60% phases were larger, the other were relatively smaller. The size of artifacts correlated significantly with the tumor motion in the CC direction.
A pilot study of temsirolimus and body composition.
Authors: Rodrigues Heloisa Veasey , Parsons Henrique Afonseca , Janku Filip , Naing Aung , Wheler Jennifer J. , Tsimberidou Apostolia Maria , Kurzrock Razelle
Published: March 2020

e13534

Background: Body weight and composition play a role in cancer etiology, prognosis and treatment response. Temsirolimus is an mTor inhibitor that can cause weight loss. Therefore, we analyzed weight, body composition changes and outcome in patients treated with temsirolimus. Methods: Sixteen patients with advanced solid tumors who participated in a trial with temsirolimus were studied; body composition was evaluated utilizing computerized tomography (CT) images. Sarcopenia was defined (CT-based criteria) as skeletal muscle index lower than 38.5cm2/m2 for women and 52.4cm2/m2 for men. Results: Five of 16 patients (31%) were men; median age, 60 years. There were no overall significant changes in weight, body mass index and body composition parameters after two months. Baseline sarcopenia was present in 44% (7/16) of patients. Fatigue, anemia, hyperglycemia and hyperlipidemia were common. Baseline sarcopenia and body composition did not correlate with worse toxicity or treatment outcome. However, there was significantly greater loss in the composite body fat content for patients with grade 3 or 4 toxicities versus those with grade 1 and 2 toxicities (p=0.007). There was a trend towards loss of body fat content for progressors versus those with stable disease/partial response (SD/PR)(p=0.08), and loss of body muscle content for the SD/PR group versus progressors (p=0.07). Conclusions: Patients with higher grade toxicities had a greater loss of body fat content, and patients with SD/PR showed a trend to loss of body muscle content as compared to those with progression, suggesting an end-organ metabolic effect of temsirolimus.
Phase II trial of bevacizumab (B) and ixabepilone (Ix) for advanced non-squamous NSCLC progressive after first-line therapy.
Authors: Sanborn Rachel E. , Mack Philip C , Beckett Laurel
Published: March 2020

e13550

Background: Ix is a semisynthetic epiothilone analog which inhibits mitosis through microtubule stabilization, with activity in multiple tumor types. Weekly dosing may have less toxicity. B improves survival in combination with carboplatin and paclitaxel for previously untreated non-squamous NSCLC. The use of B in the salvage setting has not been extensively studied. Methods: Non-randomized, open-label, single arm phase II trial of B, 10 mg/kg iv every 2 weeks and Ix, 20 mg/m2 iv weekly for 3 out of 4 weeks. An initial lead-in phase of 6 patients (pts) treated with B and Ix (16 mg/m2 iv weekly for 3 out of 4 weeks) was planned. Pts with advanced non-squamous NSCLC progressive after 1 or 2 lines of therapy are eligible, prior erlotinib is allowed, ECOG 0-1. Prior B is allowed. Pts are treated for a maximum of 6 28-day cycles, with staging every 2 cycles. Pts with response or stable disease may continue on maintenance B for up to 1 year. Primary endpoint is progression free survival, with secondary endpoints ORR, OS, toxicity, and correlative studies to assess potential predictors of response. Correlative studies include evaluations of tumor and plasma levels of VEGF, PDGF, sICAM, bFGF, and IL-8, with hypothesis that lower levels of tumor or plasma levels will correlate with improved outcomes. VEGF and IL-8 polymorphisms will be measured, as will tumor expression of Aurora B, survivin, Ki-67, hyperphosphorylation of BCL2, and overexpression of Tau. Total accrual goal is 46 pts. Results: To date, the first 6 pts for the run-in phase have been accrued. 2 pts required dose reduction in the first 2 cycles (Gr 2 thrombocytopenia, Gr 3 ALT elevation; 1 each). Max treatment cycles: 9 (Range, 2-9). 2 pts had disease progression after 2 cycles and were discontinued from study. Toxicity in the first 2 cycles is primarily hematologic, with related Gr 2 toxicity of thrombocytopenia, anemia, lymphopenia (1 each). Gr 3 lymphopenia occurred in 2 pts. Gr 3 hyperglycemia occurred in 2 pts, attributed to steroid premeds. Conclusions: With 2 pts requiring dose reduction with the run-in dose, Ix will not be increased as previously planned and the ongoing dose for the phase II study will be 16 mg/m2. Accrual to the phase II portion will continue.
MK-0646 (MK), insulin growth factor 1 receptor (IGF-1R) antibody combined with pemetrexed (P) and cisplatin (C) in stage IIIb or IV metastatic nonsquamous lung cancer (NSQL).
Authors: Huang Chao Hui , Kelly Karen , Williamson Stephen K. , Neupane Prakash , Taylor Sarah A. , Allen Ace , Wick Jo , Van Veldhuizen Peter J.
Published: March 2020

e13551

Background: IGF-1R regulates cell growth, proliferation and apoptosis. Adenocarcinoma and never smokers have higher expression of IGF-1R and it is associated with worse survival. MK is a humanized monoclonal antibody that targets IGF-1R. P has higher activity in NSQL. We initiated a randomized phase II trial to evaluate the combination of P and C +/- MK in NSQL. Methods: Eligibility criteria: untreated NSQL stage IIIB or IV, ECOG 0 or 1, measurable disease, adequate organ function and no other intercurrent illness. Standard B12 and folic acid were given. P at 500mg/m2 and C at 75mg/m2 IV were given every 3 weeks. MK was given at the dose of 10mg/kg IV weekly on days 1, 8 and 15 of every 3 week cycle in the experimental group. The patients had radiographic assessment after every 2 cycles and treated for a maximum of 6 cycles if there was either response or stable disease. The primary objective of the study was to estimate the individual response rate of standard and experimental arm. IRB reviewed and approved the study at participating institutions. Results: From 1/2009 to 2/2011, the study accrued 26 patients, 16 male, 10 female, median age 59 yo. 14 patients were treated with PC and 12 patients were treated with PC +MK. In the PC arm we observed 2 partial responses (PR), 7 stable disease (SD), 3 had progression (PD) and 2 were not evaluable (NE). In the MK arm there were 3 PRs, 4 SD, 4 PD and 1 NE. In both arms, hematologic adverse events(AE) observed were: grade 3 neutropenia(5), hemoglobin (3), febrile neutropenia (2), platelet (2) leukopenia (1), lymphopenia (1); grade 4 platelet (2), hemoglobin (1); Grade 3 non-hematological AE were: hyperglycemia (4) and 1 occurrence each of hearing deficit, pain in extremity, hyponatremia, urinary tract infection, fatigue, dyspnea, laboratory, hypokalemia, esophageal stenosis, hypoxia, dysphagia and muscle weakness; Grade 4 hypoxia and hyperglycemia. The study was closed due to termination of funding. Conclusions: PC with MK had a similar response rate to PC. There was a higher rate of hyperglycemia in the MK group. Identification of a response predictive marker would be critical in order to continue the study of this agent.
The inhibition of p21 on irradiation-induced apoptosis in EL-4 cells.
Authors: Yan Feng-qin , Wang Jian-qiu , Fu Shi-bo , Wang Fang-zheng , Fu Zhen-fu , Ju Gui-zhi
Published: March 2020

e13558

Background: To elucidate the effect of p21 on ionizing radiation-induced apoptosis in EL-4 cells. Methods: In EL-4 cells, RT-PCR, immunocytochemistry and flow cytometry (FCM) were used to analyze the changes in the expression of p21 with time and doses caused by ionizing radiation; RNAi was used to silence the expression of p21 in EL-4 cells; FCM was applied to analyze the distribution of cell cycle,the number of the chromosome and the apoptosis in wild or p21-silencing EL-4 cells exposed to X-rays. Results: In EL-4 cells, p21 protein level was markedly increased at 8 ~ 72 h after exposure in 4.0 Gy of X-ray in vitro (p<0.01), as well as exposed in 1.0 ~ 4.0 Gy of X-ray at 24 h in vitro (p<0.05). Results of time-course experiments showed that, in EL-4 cells exposed to 4.0 Gy X-rays, the percentage in G0/G1 phase increased while that in S phase decreased, significantly different with the sham-irradiated groups (p<0.05), during 8-48h after exposure; the percentage of diploid cells increased significantly during 8-48 h (p<0.01), and the percentage of tetraploid and octoploid cells decreased significantly at 2 h and 8 h (p<0.05); the percentage of apoptosis during 2-72 h increased significantly (p<0.05-p<0.01). Compared with wild EL-4 cells, in p21-silencing EL-4 cells, the distribution of cell cycle had no apparent difference; the percentage of diploid cells decreased significantly and the percentage of octoploid cells increased significantly (p<0.01); the percentage of apoptosis increased significantly (p<0.05). Conclusions: p21 inhibited the apoptosis induced by ionizing radiation in EL-4 cells.
Phase I clinical, pharmacokinetic, and pharmacodynamic study of CG200745, a histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors.
Authors: Kim Kyu-Pyo , Hong Yong Sang , Ahn Jin-Hee , Lee Jae-Lyun , Bae Kyun-Seop , Kim Tae Won
Published: March 2020

e13560

Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.
Expression of eIF4E relevant biomarkers detected in circulating tumor cells from metastatic NSCLC and prostate cancer patients using antibody-independent ApoStream technology.
Authors: Wu Weiguo , Woo Jacky , Melnikova Vladislava O. , Pace Margaret , Gupta Vishal , Jouravleva Elena , Anderes Kenna Lynn , Ackermann Elizabeth J. , Kwoh T. Jesse , Davis Darren W.
Published: March 2020

e13562

Background: Enumeration of circulating tumor cells (CTCs) is used clinically to monitor disease progression and has previously been shown to be an independent biomarker for predicting survival of metastatic breast, prostate, and colorectal cancer patients. Molecular characterization of CTCs is rapidly emerging as a minimally invasive approach to interrogate the genotype and phenotype of cancers. However, the use of EpCAM-based enrichment platforms relies on the expression of EpCAM thus limiting the type of tumor cells that can be recovered. ApoStream, is a novel, antibody-independent, dielectrophoretic field-flow fractionation based technology that recovers CTCs from cancer patient blood samples. Methods: A side-by-side comparison of EpCAM dependent CellSearch and ApoStream was performed for CTC enumeration in NSCLC and prostate cancer patients. A multiplexed immunofluorescent assay was developed for CTC (cytokeratin+/CD45-/DAPI+ cells) enumeration. CTCs recovered by ApoStream were evaluated for the expression of multiple eIF4E pathway biomarkers using quantitative laser scanning cytometry (LSC). Results: ApoStream isolated a significantly greater number of CTCs in both NSCLC and prostate cancer patients (NSCLC: range 9-1037, mean=407 by ApoStream versus a range of 30-340, mean=118 by CellSearch , p<0.05; prostate cancer: range 12-3490, mean=1472 by ApoStream versus a range of 16-2155, mean=502 by CellSearch , p<0.05). The eIF4E protein expression in CTCs was positively correlated with the CTC count. A trend toward correlation between the eIF4E protein expression level and the expression levels of Cyclin D1, Survivin and Bcl-2 was observed. Conclusions: The ApoStream platform recovers higher numbers of CTCs from the blood of metastatic NSCLC and prostate cancer patients compared to the EpCAM-dependent CellSearch platform. CTCs recovered by ApoStream are suitable for downstream molecular analyses paving the way for broader applications in translational cancer research.
ERCC1, p16, and Ki-67 immunohistochemichal expression as predictive and prognostic markers in head and neck squamous cell carcinoma treated with platin-based induction chemotherapy: Staining with the two anti-ERCC1 antibodies (8F1 and FL-297) was compared.
Authors: Roussel Helene , Housset Martin , Tournat Helene , Ravel Patrice , Hans Stephane , Bruneval Patrick , Badoual Cecile
Published: March 2020

e13578

Background: Head and neck squamous cell carcinoma (HNSCC) treatment had undergone important changes, in particular due to the organ preservation and the advent of chemotherapy, particularly using platinum. The excision repair cross-complementation group 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and has been associated with resistance to platinum-based chemotherapy. The purpose of this study was to evaluate the role of ERCC1expression with p16 and Ki-67 as predictive markers in the response to platin-based induction chemotherapy and as prognostic markers in patients with HNSCC. Methods: 208 patients treated from 2000 to 2006 by an induction chemotherapy regimen for HNSCC were included retrospectively. ERCC1 (8F1 and FL297 clone), p16 and Ki-67 staining were performed on paraffin-embedded tumor tissue collected before chemotherapy. We assessed response to treatment, progression-free survival (PFS) and overall survival (OS). Results: Respectively, 68% (142/208 patients) and 81.5% (163/200 patients) of HNSCC showed low expression of 8F1 and FL297 ERCC1. No correlation was found between the two clones (p=0.1). There was no correlation between the expression of 8F1 ERCC1, FL297 ERCC1 and Ki-67 and the response to induction chemotherapy, OS or PFS. However, in the subgroup of 129 patients treated with induction cisplatin-5FU chemotherapy, a low expression of 8F1 ERCC1 was significantly associated with a better response (p=0.027). Over expression of p16, found in 34.5% of cancers of the oropharynx was significantly correlated with a better OS (p=0.0007) and a better PFS (p = 0.01). Conclusions: These results suggest that ERCC1 expression might be a useful predictive marker of HNSCC in patients treated by cisplatin-based chemotherapy. The 8F1 ERCC1 clone appears to be the best for immunohistochemical analysis; clone FL297 did not show any association with treatment response and survival. Independently, our study confirms the prognostic value of the over expression of p16 in carcinoma of the oropharynx.
Comprehensive preclinical testing for neuroblastoma using orthotopic xenografts of a patient tumor.
Authors: Federico Sara Michele , Stewart Elizabeth , Brennan Rachel Christine , Bradley Cori , Wang Fan , Freeman Burgess B. , Stewart Clinton F. , Wu Jianrong , Dyer Michael A.
Published: March 2020

e13584

Background: Neuroblastoma is an aggressive malignancy that accounts for 15% of pediatric cancer deaths. There are limited well characterized neuroblastoma models for use in preclinical trials. We characterized a human neuroblastoma orthotopic xenograft, performed comprehensive preclinical studies, and evaluated the pharmacokinetics of drugs targeting the PI3K pathway. Methods: Tumor tissue (MAST3) was obtained from a 2 year old with stage IV metastatic MYCN amplified neuroblastoma. Using ultrasound guidance, MAST3 cells were injected into the para-adrenal space of nod-scid mice. Tumors were monitored for growth with routine ultrasound and passaged. The initial patient tumor (MAST3) and tumor from each passage were extensively analyzed including: histology, electron microscopy (EM), gene expression profiling, single nucleotide polymorphism (SNP ) microarrays, whole genome sequencing (WGS), and spectral karyotyping (SKY). Using this orthotopic xenograft model, a randomized preclinical trial was conducted to evaluate the response to standard chemotherapeutic agents. Pharmacokinetic studies of oral BEZ-235, BKM-120, OSI-906 and everolimus were conducted. Results: Analysis of the histology, EM, gene expression profiling, SNP microarrays, WGS, and SKY showed minimal variability between the MAST3 tumor and the passaged tumors in the orthotopic xenografts. Notably, MAST3 metastasized to the liver, lung and spleen in vivo. Administering standard chemotherapeutic agents every 3 weeks for a total of 6 courses, we observed a significant response in 40% of treated mice. Further ongoing preclinical trials will evaluate the comparative efficacy of IGFR/PI3K/mTOR molecular targeted therapies. Conclusions: We developed the first well characterized neuroblastoma orthotopic xenograft. Our comprehensive characterization of this xenograft indicates that it retains many of the molecular, cellular and genetic properties of the primary lesion. A preclinical trial using standard chemotherapeutic agents has provided a valuable baseline for comparison with novel therapeutics and will inform our selection of the most promising agents to move into clinical trials.
Phase I study of everolimus in combination with fluvastatin and zoledronic acid in patients with solid tumours.
Authors: Lemech Charlotte Rose , Fontela Antoinette , Arkenau Hendrik-Tobias , Chin Melvin T.M. , Li Sandra , Liauw Winston S. , Thomas David , De Souza Paul L.
Published: March 2020

e13585

Background: Everolimus (E) is an mTOR inhibitor with broad anti-tumour clinical activity. There is preclinical evidence of synergistic activity through the combination of E with fluvastatin (F) and zoledronic acid (ZA). F, an HMG CoA reductase inhibitor, and ZA, a bisphosphonate, have both been shown preclinically to inhibit isoprenylation (addition of hydrophobic molecules) of key signalling proteins with subsequent inhibition of the Ras pathway. We investigate their potential activity further in this open-label phase I trial. Methods: Patients (pts) with advanced solid tumours were treated with escalating doses of E, F and ZA to evaluate safety, clinical activity, pharmacokinetics (PK), pharmacodynamics (PD) and the recommended dose for further study. PK samples were obtained over 24 hrs on day 1 and 8 of cycle 1 and day 1 of cycle 2. Pre- and post-dose PBMCs were analysed for markers of MAPK and PI3K-AKT-mTOR pathways (pERK, pAKT and pS6). Results: Maximum doses of each drug in combination (DL 4) were feasible and no DLTs were observed. Of the 16 pts evaluable [median age=63yrs (range 47-81)], the median number of cycles was 3.8 (range 1-8), with 44% of pts receiving ≥ 4 cycles. Drug related toxicities were mainly G1/2, many within the expected toxicity profile of E, including fatigue (12 pts, 75%), myalgias (9 pts, 56%), anorexia (8 pts, 50%), infection (8pts, 50%), dyspnoea (7pts, 44%), diarrhoea (7 pts, 44%), nausea (7 pts, 44%), peripheral oedema (5 pts, 31%) and mucositis (4 pts, 25%). G3 adverse events were predominantly due to symptoms of disease progression. G1/2 anemia and thrombocytopaenia were the most common haematological toxicities, particularly in DL 3 and 4. 44% of pts achieved stable disease as best response (mean 4.5m [range 3-6m]); including 2 CRC pts (DL 4) and 2 CRPC pts (DL 3 and 4). PK and PD results will be presented in further detail. Conclusions: The combination of E/F/ZA is feasible without any added or overlapping toxicities in this phase 1 study. [Table: see text]
Use of DNA repair proteins translated from biomarker screening to predict overall survival in patients with esophageal cancer treated with oxaliplatin chemotherapy.
Authors: Sharma Ricky A , Macgregor Tom , Gillies Richard , Hatch Stephanie , Swift Lonnie , Humphrey TIM , Chetty Runjan , McHugh Peter J , Middleton Mark R.
Published: March 2020

e13587

Background: Oxaliplatin is first-line chemotherapy for colorectal, gastric, and esophageal cancers. Aim was to identify key determinants of oxaliplatin sensitivity and optimise these biomarkers to select patients for chemotherapy. Methods: High-throughput screening of oxaliplatin sensitivity was performed in a Schizosaccharomyces pombe deletion library of 229 DNA repair strains and Chinese Hamster Ovary (CHO) cell lines with mutations in specific proteins. Biopsies were taken from 50 patients with esophageal cancer, who then received two cycles of oxaliplatin and fluorouracil chemotherapy prior to surgery. Levels of DNA repair proteins were quantified by immunohistochemistry and by qRT-PCR. Results: Twelve lead biomarkers were identified from the preclinical models. In CHO cells, XPF and ERCC1 mutants were approximately 30 times more sensitive than the WT cells (p<0.01). In comparison to WT CHO cells, XPF-deficient cells had prolonged delay in mid-late S-phase after oxaliplatin treatment, and persistence of double strand breaks for at least 48 hours. Modified Comet assay confirmed persistence of inter-strand crosslinks created by oxaliplatin. Cells deficient in DNA polymerase eta (pol eta) also accumulated in S-phase and were 3-fold more sensitive (p<0.01) to oxaliplatin treatment than pol eta-complemented cells. Knockdown of XPF, ERCC1 or pol eta sensitised both oxaliplatin-resistant and oxaliplatin-sensitive HCT116 cells to oxaliplatin. In patients with esophageal cancer, low or absent XPF protein expression predicted complete pathological response to chemotherapy with a sensitivity of 58% and specificity of 72%. Cyclin A protein levels (univariate analysis, p<0.005) and pol eta mRNA levels (multivariate analysis, P<0.005) in pre-treatment esophageal biopsies correlated with overall survival. Conclusions: Results suggest that inter-strand DNA cross-links are the principal cytotoxic lesions created by oxaliplatin. Homologous recombination and damage checkpoint proteins are leading biomarkers for patient selection. In patients with esophageal cancer, XPF and pol eta predict response to oxaliplatin chemotherapy.
Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors.
Authors: Jia Jingquan , Li Haiyan , Dellinger Andrew , Pang Herbert , Russell Karen Bullock , Hurwitz Herbert , Nixon Andrew B.
Published: March 2020

e13589

Background: Tumor growth and angiogenesis are regulated by multiple cellular pathways, including the VEGF, mTOR, and EGFR pathways. We have previously reported our clinical experience combining Bev, Ev and Erl therapies. Taking advantage of the similarities between tumor growth and wound healing, we conducted a PD analysis of these agents using novel dermal wound angiogenesis assays. Methods: Patients with advanced solid tumors received either 1) Bev-Ev doublet therapy; 2) Bev-Ev-Erl triplet therapy; 3) Ev monotherapy for 14 days followed by addition of Bev-Erl; 4) Erl monotherapy for 14 days followed by addition of Bev-Ev. Full-thickness dermal granulation biopsies were harvested; the phospho (p) and total (t) levels of VEGFR2, EGFR, and S6RP were measured at baseline, end of the monotherapy lead-in period (day 14), and 35 days post doublet or triplet therapy. A dermal wound angiogenesis assay, which quantifies peripheral wound vascularization was also incorporated in the study. Results: 38 pts were evaluable for biomarker analysis. Wilcoxon signed rank tests indicated that both VEGFR2 and S6RP were significantly down-regulated after Bev-Ev-Erl triplet therapy: tVEGFR2 (q=5.1E-05), pVEGFR2 (q=0.01), tS6RP (q=0.007), pS6RP (q=9.7E-04). Levels of tVEGFR2 (q=5.5E-04) and pS6RP (q=6.9E-04) were also found to be significantly down-regulated after Bev-Ev doublet therapy. Ev monotherapy for 14 days led to significant tVEGFR2 down-regulation (q=0.035). No significant changes in EGFR levels were observed in any cohort. Additionally, Bev-Ev-Erl triplet therapy led to a slight decrease in dermal wound vascularization (p=0.098), which positively correlated with changes in tVEGFR2 levels (q=0.008). Conclusions: This is the first investigation evaluating the PD effects of VEGF, mTOR, and EGFR inhibition in a clinical wound-healing model. Our results indicate that targeting of all three pathways is associated with overall down-regulation of both VEGF and mTOR pathways. These data suggest that this dermal wound model can be used to quantify PD markers in evaluating multiple classes of targeted therapies.
Antimetastatic activity of Atu027, a liposomal small interfering RNA formulation, targeting protein kinase N3 (PKN3): Final results of a phase I study in patients with advanced solid tumors.
Authors: Strumberg Dirk , Schultheis Beate , Meyer-Sabellek W , Vank C. , Gebhardt F , Santel A. , Keil O. , Giese K. , Kaufmann J. , Drevs Joachim
Published: March 2020

e13597

Background: Atu027 contains siRNA-lipoplexes, which elicits RNAi mediated suppression on PKN3 in vascular endothelial cells. In various xenograft mouse models, silencing of PKN3 expression and significant inhibition of invasive growth, lymph node and pulmonary metastasis formation was shown. Methods: Atu027 was applied to patients (pts) as a single 4h-infusion with subsequent follow-up for 3 wks. Thereafter pts were treated twice weekly for 4 weeks. In case of SD, pts were treated until PD. Dose escalation was associated with assessment of toxicity, pharmacokinetics (PK), and multiplex biomarker analyses in plasma from treated pts. Results: A total of 33 pts have received Atu027 of 11 dose levels (DL) up to 0.336 mg/kg. No pre-medication was required. No cytokine activation (TNF-α, IL-1β, IFN-γ, IL-6) was observed. In some subjects transient activation of the complement system (C3a, Bb, sC5b-9) was found, but without any clinical relevance. PK-data showed dose-dependent increase in plasma siRNA as well as lipid levels. Among various biomarkers tested, sVEGFR-1 plasma levels decreased significantly upon treatment. Across all dose levels, Atu027 was well-tolerated. Adverse events possibly related to Atu027 were fatigue grade G1 (6pts), hair loss G1 (2pts), sweating G1 (1pt), and abdominal pain G2 (1pt). G3 AEs not considered as DLTs were elevated lipase (2 pts, DL2+DL10) and diarrhea (1 pt, DL5). So far, no DLTs were seen in the last DL. Stable disease after 3 and 6 months was observed in 10 and 3 pts, respectively. Two pts with neuroendocrine cancer had disease stabilization for 9 and 12 months, respectively, including partial regression of pulmonary metastases in 1 pt. Another patient with breast cancer had regression of liver metastases. Conclusions: Atu027 is well-tolerated and anti-metastatic activity has been observed. Soluble VEGFR-1 might serve as a biomarker. So far, 0,336 mg/kg is the recommended dose for further phase II trials.