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32P - Clinical correlation between different CKIT exon mutations and clinical outcome imatinib mesylate treatment in gastrointestinal stromal tumor (GIST) patients (ID 71)

Presentation Number
32P
Lecture Time
18:30 - 18:30
Speakers
  • G. Zakaria
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • G. Zakaria
  • N. Allahloubi
  • A. Bahnasy
  • O. Khorshid

Abstract

Background

The clinical behavior of GISTs is highly variable. This study aims at detection of different histo-pathological tumor features and correlation with different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status.

Methods

This is a retrospective study that included all cases diagnosed as GIST who presented to NCI from 2005 to 2017, The following data were collected from the patient’s files: age, gender, tumor site, size, mitotic rate, histological grade, capsular rupture, risk stratification by Joensuu criteria, treatment setting, date of start and end of treatment, dose and toxicity. KIT mutation was assessed on tumor tissues of all patients; clinical correlation between different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status, was done.

Results

Eighty-nine cases of GIST presented to NCI in the period September 2005 to January 2017. Median age at diagnosis was 48 years old with a median follow up of 22 months. More than 75% of the patients had positive C-KIT mutation, while it was negative in 24.7 % of the patients. C-kit positive mutations were significantly associated with tumors more than 5 cm, high mitosis, and with high tumor risk stratification by Joensuu criteria in more than fifty percent of the patients. Exon 9 mutations had poor ORR (55.6 %) compared to those with exon 11(67.6%) (P = 0.33), with the latter having PFS of 55 months compared 120 months for exon 9 mutations, (P = 0.002). No statistically difference in OS was observed with exon 9 (70 months) compared to exon 11 mutations (77 months) (P = 0.55).

Conclusions

C-kIT-positive mutation per-se is an independent poor risk factor, associated with more aggressive tumor features whereas response to imatinib was affected by exon mutations with exon 11 having a tendency for better ORR, compared to exon 9 mutation, with the latter having longer PFS compared with exon 11, with no statistically difference in OS with exon 9 compared to exon 11 mutations.

Legal entity responsible for the study

NCI.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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9P - Safety profile and therapeutic efficacy of one cycle of [177Lu]prostate-specific membrane antigen (PSMA) in end stage metastatic castration-resistant prostate cancer patients with low performance status (ID 79)

Presentation Number
9P
Lecture Time
17:40 - 17:45
Speakers
  • M. Gupta
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
17:30 - 18:00
Authors
  • M. Gupta
  • P. Choudhury
  • S. Rawal
  • H. Goel
  • V. Talwar
  • K. Dutta
  • A. Singh

Abstract

Background

Prostate cancer patients with distant metastasis have poor prognosis and develop resistance to all standard drugs at various time intervals. Therapeutic options which can alleviate symptoms and prolong survival are required for these patients. [177Lu]prostate-specific membrane antigen ([177Lu]PSMA) is a novel drug based on a theranostic concept. Here, we have presented the safety and efficacy profile of one cycle of [177Lu]PSMA in metastatic castration-resistant prostate cancer (mCRPC) patients who have exhausted all standard therapeutic options.

Methods

Twenty two patients treated with at least first line anti-androgens and docetaxel were treated with one cycle of [177Lu]PSMA therapy on a compassionate basis. Haemoglobin, total leukocyte counts, platelets and serum creatinine for toxicity profile while prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, visual analogue scale (VAS) and analgesic quantification scale (AQS) for therapeutic efficacy were recorded pre and 8 weeks post therapy. Wilcoxon signed-rank and ANOVA tests were used for statistical analysis.

Results

Partial response (PR), stable disease (SD) and progressive disease (PD) for PSA were seen in 5 (22.7%), 13 (59.1%) and 4 (18.2%) patients, respectively, treated with mean 6.88GBq dose of [177Lu]PSMA. 8/22 (36.4%) patients showed ≥ 30% drop in PSA. Grade 3 haemoglobin toxicity was seen in 5/22 (22.7%) patients. No patient developed grade 4 haemoglobin toxicity. No patients had grade 3 or 4 leukocytopenia or thrombocytopenia. Wilcoxon signed-rank test showed statistically significant (p < 0.05) difference in pre- and post-treatment ECOG, VAS, AQS scores while it was not significant for PSA (P > 0.05). ANOVA test showed a statistically significant difference in mean doses of [177Lu]PSMA used in the three PSA response groups while the difference was non-significant for other variables.

Conclusions

We conclude that [177Lu]PSMA therapy delivers adequate pain palliation in all end-stage mCRPC patients and it has a potential to become an effective therapeutic option in properly selected patients.

Legal entity responsible for the study

Manoj Gupta.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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11P - Photosensitizer-based multimodal nanocomposites as a theranostic agent for near infrared (NIR)-guided cancer-targeting synergistic chemo-phototherapy (ID 85)

Presentation Number
11P
Lecture Time
18:25 - 18:25
Speakers
  • T. Ponraj
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • T. Ponraj
  • R. Vivek
  • M. Paulpandi1
  • K. Vimala
  • A. Vasanthakumar
  • S. Kannan

Abstract

Background

Many therapeutic methods existing for conventional cancer therapy have not been successful in achieving ideal outcomes or have noticeable side effects from off-targeting cytotoxicity. The photosensitizer-based cancer treatment approach has attracted great attention. Chemotherapy (CT), photodynamic therapy (PDT), and photothermal therapy (PTT), called combination treatments. In a single system could be potential solutions to address the above mentioned adverse effects in conventional therapy. Multimodal nanocomposites (NCs) are being used to achieve with innovative and noninvasive enhanced targeting synergistic anticancer phototherapy.

Methods

We prepared spherical-like titanium dioxide nanoparticles TiO2NPs by the water in oil emulsification method, obtaining a novel theranostic nanocomplex FA-ICG-Qtn@PVPylated-TiO2NPs. Nanocomplex (NCs) were characterized by various physicochemical techniques including UV via spectroscopy, TEM, DLS, FTIR, MTT, AO/EtBr, DAPI, cell cycle arrest, ROS, mitochondrial membrane potential loss, Western blot, RT-PCR, Histopathology, and immunohistochemistry. Studies were performed both in vitro/in vivo.

Results

The resulting TiO2NPs achieved high drug loading in combination with low leakage at physiological pH, and minimal toxicity toward healthy cells. To assist drug delivery, we have prepared FA-ICG-Qtn@PVPylated-TiO2NPs containing Qtn with high loading efficiency (35.2% w/w) as a novel drug delivery system. The NCs are taken up via FR endocytosis by MCF-7 cells and can generate intracellular reactive oxygen species (ROS) in order to increase mitochondrial membrane potential loss (MMPL) and enable release of cytochrome-c, followed by dysregulation of Bcl-xL into the cytosol and activation of caspase-7 to induce cancer cell apoptosis. These NCs can be utilized to improve cancer nanotherapy by induction of apoptosis in vitro. After intravenous in vivo direction of FA-ICG-Qtn@PVPylated-TiO2NPs NCs could significantly accumulate in the tumour-bearing Balb/c mice, and effectively inhibit the tumor growth after 808 nm laser irradiation as confirmed by the cancer cell killing studies in vivo.

Conclusions

The present thermal/pH-coupling controlled and targeted drug delivery system paves the way for the next generation of nanotherapeutics working toward a potential proficient targeted anticancer treatment.

Legal entity responsible for the study

Department of Zoology, Bharathiar University, Coimbatore.

Funding

Has not received any funding.

Disclosure

C. Massard: Consultant/Advisory fees: Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion; Principal/sub-Investigator of Clinical Trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc, Tioma Therapeutics, Inc., Xencor; Research Grants: Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied): Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. All other authors have declared no conflicts of interest.

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33P - Proteomic analysis of UKF-NB-4 cells reveals a stimulatory activity of MT-3 on cellular senescence and apoptosis (ID 88)

Presentation Number
33P
Lecture Time
18:30 - 18:30
Speakers
  • M. Merlos Rodrigo
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • M. Merlos Rodrigo
  • H. Buchtelova
  • V. Strmiska
  • A. Jimenez Jimenez
  • I. Casal
  • V. Adam
  • Z. Heger

Abstract

Background

Metallothioneins (MTs) family is a intracellular and cysteine-rich proteins with a high affinity to metals. MT-3 could play important neuromodulatory and neuroprotective roles. MT-3 has been also found up-regulated in a number of cancers. Neuroblastoma (Nbl) is a cancer is the most common extra-cranial solid tumour of childhood. The main aim was to provide novel insights into the molecular mechanisms of hMT-3 up-regulation and to elucidate the effects beneath the MT-3 up-regulation in Nbl cells.

Methods

To increase the expression of MT-3 Nbl (UKF-NB-4) cells were transiently transfected with a plasmid containing MT-3 gene (pcDNA3.1-GFP-hMT-3-TOPO). Separations of tryptic digests were carried out on an Easy-nLC 1000 nano system. MS analysis was performed using a Q-Exactive MS. The mass spectrum *.raw file was searched against the human SwissProt 57.15 database using MASCOT search engine (version 2.3, Matrix Science).

Results

The efficiency of transfection analysed through a fluorescence of GFP tag expressed at the C-terminus of MT-3 showed more 70% transfection efficiency for both constructed plasmids (mock and MT-3). From the total of common proteins in dataset (hMT-3 vs. mock), 176, 20 and 1244 proteins were quantitatively identified with up-regulation, down-regulation, and no significant differences between hMT-3 and mock treatments. Noteworthy, the bioinformatical analyses revealed the exclusive expression (induced by MT-3) and up-regulation proteins of a number of proteins affecting biological pathways related to mitotic cell cycle, cellular responses to stress, positive regulation of proteolysis, negative regulation of cell cycle and programmed cell death.

Conclusions

Our proteomic data shed some light on the proteins involved in inducing senescence and apoptosis in tested Nbl cells with up-regulated MT-3. Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. Cellular senescence and apoptosis are among those mechanisms. Further experiments will be performed to functionally verify these data to provide novel insights into the Nbl biology. These might be useful to develop novel therapeutic protocols utilizing MT-3 as prognostic biomarker or therapeutic target.

Legal entity responsible for the study

Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ.

Funding

European Research Council (ERC) under the European Uniońs Horizon 2020 Research and Innovation Programme (grant agreement No. 759585).

Disclosure

All authors have declared no conflicts of interest.

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22P - Therapeutic potential of connective tissue growth factor (CTGF) in triple-negative breast cancer (ID 104)

Presentation Number
22P
Lecture Time
18:25 - 18:25
Speakers
  • H. Kim
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • H. Kim
  • S. Son

Abstract

Background

Matricellular proteins are a subset of extracellular matrix (ECM) proteins which are dynamically expressed and serve many regulatory roles. Among matricellular proteins, the CCN family, a group of secreted proteins are known to regulate cell adhesion, migration, proliferation, differentiation, apoptosis, survival, senescence, and gene expression. Connective tissue growth factor (CTGF), also known as CCN2, is a member of the CCN family. CTGF is known to have many roles in biological processes such as cell proliferation, migration, adhesion, and angiogenesis.

Methods

To investigate the function of CTGF in triple-negative breast cancer cells (TNBC), we silenced CTGF in TNBC cell lines using short hairpin RNA. Knockdown of CTGF was verified by western blot, qPCR, and immunostaining. The effect of CTGF knockdown on TNBCs was examined by cell proliferation assay, adhesion assay, migration assays, metabolism assays, and cell cycle analysis.

Results

Knockdown of CTGF decreased cell proliferation, adhesion, migration, glucose uptake, ATP production and lactate production. Since CTGF is a secreted protein, we gave recombinant human CTGF (rhCTGF) to the cells and found that rhCTGF induced activation of the Src/FAK/MAPK pathway and led to expression of proteins related to cell cycle progression. Also, when CTGF-specific antibodies were given to the cells, they expressed cytotoxicity by neutralizing the extracellular CTGF and decreasing CTGF-mediated signalling.

Conclusions

We suggest that the secreted CTGF mediates tumor cell progression via modulation of cell proliferation, adhesion, migration and metabolism and could possess a potential for being a therapeutic target.

Legal entity responsible for the study

Hanyang University.

Funding

National Research Foundation of Korea.

Disclosure

All authors have declared no conflicts of interest.

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10P - Safety profile of epigenetic therapies in early phase trials: Do epidrugs deserve specific drug development processes? (ID 105)

Presentation Number
10P
Lecture Time
18:25 - 18:25
Speakers
  • L. Leroy
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • L. Leroy
  • T. Satar
  • C. Baldini
  • P. Martin-Romano
  • A. Hollebecque
  • J. Michot
  • V. Ribrag
  • C. Massard
  • X. Paoletti
  • S. Postel Vinay

Abstract

Background

Targeting the epigenome has demonstrated efficacy in hematological malignancies, and results of recent phase 1 (P1) trials have shown promising activity in solid tumors. The number of novel epidrugs is increasing exponentially, with several first-in-class, first-in-human selective compounds now evaluated in P1 trials. Accurate knowledge of their safety profile and toxicity management beyond cycle 1 is essential to appropriate P2 dose recommendation.

Methods

All patients (pts) with hematologic or solid tumors enrolled in at least one epidrug P1 trial at Gustave Roussy Drug Development Department were retrospectively analysed. Baseline pts characteristics, treatment-related adverse events (AEs) – type, grade, date of occurrence, duration, resolution - toxicity management (medication, dose modification) and outcome were collected.

Results

A total of 243 pts (43,6% hematologic, 23,1% non-Hodgkin lymphoma (NHL), 33,3% solid tumors excluding NHL) were included in 15 epidrug monotherapy P1 trials between Jan 2010 and March 2017; 62% were male; median age was 65 yo and median treatment duration was 119 days; 1980 treatment cycles and 335 AEs were analysed: 118 (35%) (64 G1-2; 54 G3-4) and 217 (65%) (114 G1-2; 103 G3-4) AEs occurred during and after cycle 1 (C1; DLT period), respectively; 58% of AEs were hematological toxicities. The risk of G3-4 toxicity for hematologic pts was 15% and 11% during and after C1 respectively, and was 12% and 18% for solid tumors excluding NHL, and was 29% and 24% for pts with NHL. DLT occurred in 10 pts (4%). Dose reduction occurred in 15% of pts, after a median duration of 21 treatment days. Temporary and definitive treatment interruption for toxicity occurred in 21% and 9% of pts, respectively; 87% of these occurred after C1.

Conclusions

In P1 trials of epidrugs, 65% of high-grade AEs occur after cycle 1 and 42% are non-haematological toxicities. More pts with NHL than pts with solid tumors (excluding NHL) or hematological malignancies present their first severe AE during C1. The dose recommendation process may require fine-tuning according to each pt population. Like molecularly targeted or immune therapies, epidrugs have distinct toxicity profile requiring specific attention in their development process.

Legal entity responsible for the study

Gustave Roussy Institut.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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23P - Matricellular protein CCN3/NOV regulates tumorigenesis in triple-negative breast cancer (ID 109)

Presentation Number
23P
Lecture Time
18:25 - 18:25
Speakers
  • S. Son
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • S. Son
  • H. Kim
  • I. Shin

Abstract

Background

CCN3(NOV) is a matricellular protein belonging to the CCN family and is known to be involved in various cellular signaling processes including tumorigenesis. Previous studies have shown that CCN3 can promote cell migration in sarcoma, glioblastoma, prostate and renal cancer cells. In-silico analysis using the TCGA database shows CCN3 was highly amplified in breast cancer patients especially in TNBC (triple-negative breast cancer) patients. Accordingly, we confirmed that the expression of CCN3 is up-regulated in the TNBC cell lines. Based on these findings, it was thought that CCN3 would participate in TNBC tumorigenesis.

Methods

We generated CCN3 knockdown TNBC cell lines by using shRNA. Proliferation assays and wound healing assay were performed to check the phenotype changes in the established cell line, and western blotting and RT-qPCR were used to monitor changes in intracellular protein expression. In addition, in-silico analysis using the TCGA database confirmed gene sets affected by CCN3 expression.

Results

We identified that CCN3 knockdown cell lines exhibited decreased proliferation, migration ability and colony-forming ability compared with control cell lines. Then we performed immunoblotting to find altered signaling by CCN3 knockdown. Phosphorylation level of FAK and EGFR were decreased in CCN3 knockdown cell lines.

Conclusions

We have shown that CCN3 can be involved in proliferation and migration ability in TNBC cell lines. We thought that this regulation may involve EGFR, which is known to be overexpressed in TNBC, or phosphorylation of FAK through integrin signaling. This study shows that CCN3 expressed in TNBC affects tumorigenesis of TNBC and may be used as a possible molecular therapeutic candidate to target TNBC.

Legal entity responsible for the study

Hanyang University.

Funding

National Research Foundation Korea.

Disclosure

All authors have declared no conflicts of interest.

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18P - Choline transporter-like protein 1 (CTL1/SLC44A1) is a therapeutic target molecule for prostate cancer therapy (ID 115)

Presentation Number
18P
Lecture Time
18:25 - 18:25
Speakers
  • M. Inazu
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • M. Inazu
  • I. Saiki
  • H. Uchino
  • T. Yamanaka

Abstract

Background

Prostate cancer is one of the most common types of cancer in men. Choline is an essential component of cell membrane phospholipids and is metabolized and internalized into cells by choline kinase, an enzyme that is overexpressed in certain tumors, such as prostate cancer. Two choline tracers are available for clinical use, which are labeled either with 11C-choline or with 18F-choline. These choline PET tracers that target cell membrane metabolism have influenced prostate cancer imaging, particularly in biochemical relapse, and are therefore FDA approved for use in patients with recurrent disease. However, the uptake system for choline and the functional expression of choline transporters in prostate cancer are not totally understood.

Methods

We examined [3H]choline uptake in the prostate cancer cell line LNCaP, which depends on androgen. Cells were cultured in RPMI 1640 medium supplemented with 10 % fetal bovine serum and grown at 37 °C in 5% CO2. The CellTiter-Glo Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells. The Caspase-Glo 3/7 assay reagent was used for caspase detection in treated cells.

Results

[3H]Choline uptake is mediated by a single Na+-independent and intermediate-affinity transport system. Choline transporter-like protein 1 (CTL1) and CTL2 mRNA are highly expressed. CTL1 and CTL2 immunoreactivity were recognized in the plasma membrane and intracellular compartments, respectively. The anticancer drugs, flutamide, and bicalutamide inhibited cell viability and [3H]choline uptake in a concentration-dependent manner. The correlations between the effect of both anticancer drugs for cell viability and [3H]choline uptake were significant. The caspase-3/7 activity significantly increased by flutamide and bicalutamide. Furthermore, both flutamide and bicalutamide decreased the expression level of CTL1 in LNCaP cells.

Conclusions

These results suggest that CTL1 are functionally expressed in prostate cancer cells and are also involved in abnormal proliferation. Identification of this CTL1-mediated choline transport system provides a potential new target for prostate cancer therapy.

Legal entity responsible for the study

Tokyo Medical University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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34P - Impact of treatment with bilastine for PD-1/PD-L1 inhibitors induced rash (ID 125)

Presentation Number
34P
Lecture Time
18:30 - 18:30
Speakers
  • T. Hirata
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • T. Hirata

Abstract

Background

PD-1/PD-L1 inhibitors are novel anti-cancer agents for various tumors. PD-1/PD-L1 inhibitors induced rash occurred in 20% to 30%. The therapy for rash includes anti-histamine and corticosteroid. Bilastine is a non-sedating second-generation H1-antihistamine. Bilastine showed the efficacy for urticaria, prurigo and cutaneous pruritus. However, its effectiveness for PD-1/PD-L1 inhibitors induced rash is unknown. The objective of this retrospective study was to evaluate the efficacy of bilastine for PD-1/PD-L1 inhibitors induced rash.

Methods

We identified 224 patients who received PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab) at the Kure Medical Center from September 2014 to October 2018. PD-1/PD-L1 inhibitors induced rashes were observed in 84 patients (37.5%). They were classified into 4 groups on the basis of the systemic antihistamine and topical corticosteroid therapy: the (1) bilastine and corticosteroid group (n = 18), (2) another anti-histamine and corticosteroid group (n = 22), (3) bilastine group (n = 20); and (4) another antihistamine group (n = 24). Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 4.0). This study was approved by the Kure Medical Center IRB.

Results

The bilastine and corticoegsteroid group had significantly shorter the median duration of topical corticosteroids and antihistamine than the another antihistamine and corticosteroid group (p<0.01). Bilastine group had significantly shorter the period of systemic medications than the another antihistamine group (p<0.01). The incidence of adverse events was observed as follows, somnolence in 3% (1/38), headache 3% (1/38) and dizziness in 3% (1/38) in the bilastine and corticosteroid group and bilastine group. There were no serious adverse events.

Conclusions

Bilastine treatment reduced the need for topical corticosteroids use and shortened the period of topical corticosteroids for PD-1/PD-L1 inhibitors induced rash with acceptable safety profiles. Bilastine may be more effective than another antihistamine for PD-1/PD-L1 inhibitors induced rash.

Legal entity responsible for the study

Taizo Hirata.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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7O - Phase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (ID 127)

Presentation Number
7O
Lecture Time
11:25 - 11:40
Speakers
  • A. Hollebecque
Location
Amphithéâtre Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
11:00 - 12:15
Authors
  • A. Hollebecque
  • J. De Bono
  • R. Plummer
  • N. Isambert
  • P. Martin-Romano
  • E. Baudin
  • S. Mora
  • E. Filvaroff
  • M. Lamba
  • Z. Nikolova

Abstract

Background

CC-90011 is a potent, selective, reversible oral inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-proliferative activity against cancer cells in vitro and in patient-derived xenograft models.

Methods

CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).

Results

As of September 4, 2018, 50 pts were enrolled. All had advanced solid tumors except 1 pt with R/R NHL; 26 pts had neuroendocrine neoplasms (NENs). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The non-tolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. The median age was 61 y (range, 22–75), 52% were male, and pts had received a median of 3 (range, 1–4) prior systemic anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (16%) and neutropenia (8%; occurring in the context of thrombocytopenia at the highest doses). Serious AEs occurred in 40% of pts; 6% were treatment-related. Peak plasma concentrations occurred 2-4 h post-dose and average terminal half-life was ∼60 h; exposure was dose proportional. PD analysis showed decreased CgA and MMD in response to CC-90011, correlating with clinical benefit. One pt achieved a complete response (CR) and 22 had stable disease (SD). Prolonged SD ≥ 4 months occurred in 7 pts, 5 with bronchial NEN and 2 with prostate NEN.

Conclusions

CC-90011 is well-tolerated with promising antitumor activity in solid tumors and R/R NHL, including a CR and prolonged SD in pts with NENs. PD and PK data showed sufficient target engagement. Taken together, the preliminary clinical data provides the rationale for dose expansion of CC-90011 in pts with NENs.

Editorial acknowledgement

Editorial assistance was provided by Johna Van Stelten, Ph.D., of BioConnections LLC, funded by Celgene Corp.

Clinical trial identification

NCT02875223 and EUDRACT 2015-005243-13.

Legal entity responsible for the study

Celgene Corp.

Funding

Celgene Corp.

Disclosure

A. Hollebecque: Honoraria: Merck Serono; Consultant or advisor: Gritstone Oncology; Travel funding: Amgen. J.S. de Bono: Advisor: AstraZeneca, Genentech, Pfizer, Merck Sharp & Dohme, Bayer, Merck Serono, Janssen, Astellas, Seattle Genetics; Research funds: AZ, Sanofi, Genentech, GSK, Daiichi Sankyo, Taiho Oncology, Merck Serono, Merck Sharp & Dohme, Sierra Oncology; Speaker bureau: AZ. R. Plummer: Honoraria: Novartis, BristolMyers Squibb; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents: with Clovis Oncology; Travel funding: Merck Sharp & Dohme, Bristol Myers Squibb. S. Mora: Travel funding: Celgene; Employment and equity ownership: Celgene. E. Filvaroff: Employee: Celgene; Stock or equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents/royalties: Celgene and Genentech. M. Lamba: Employee, equity ownership, research funding: Pfizer, Celgene; Patents/royalties: Pfizer. Z. Nikolova: Employee, equity ownership, travel funding: Celgene. All other authors have declared no conflicts of interest.

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13P - Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways (ID 129)

Presentation Number
13P
Lecture Time
18:25 - 18:25
Speakers
  • G. Umapathy
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • G. Umapathy
  • J. Van den Eynden
  • D. Cervantes-Madrid
  • J. Szydzik
  • J. Guan
  • R. Palmer
  • B. Hallberg

Abstract

Background

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective.

Methods

In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets.

Results

The phosphoproteomic analysis identified several conserved oncogenic downstream signaling pathways of ALK, similar to those involved in insulin receptor (INSR)/tropomyosin receptor kinase (TRK) and fibroblast growth factor receptor (FGFR) signaling. In addition, signaling events involved in feedback and cross-talk were identified, including modulation of DUSP (dual-specificity phosphatase) family phosphatases. Furthermore, from analysis of the RNA-seq data, several transcription factors were predicted and validated as responsive to ALK signaling, including members of the FOXO (forkhead box O) and ETS (E26 transformation-specific or E-twenty-six) transcription factor families.

Conclusions

Although neuroblastoma is a complex heterogeneous disease, this in-depth investigation of downstream targets of ALK signaling offers future avenues to pursue to inhibit ALK-driven neuroblastoma.

Legal entity responsible for the study

Bengt Hallberg.

Funding

Barncancerfonden.

Disclosure

All authors have declared no conflicts of interest.

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Cocktail and Poster viewing Poster Display session

27P - Detection of genomic alterations in breast cancer (BC) patients with paired plasma and tumour specimens (ID 131)

Presentation Number
27P
Lecture Time
18:25 - 18:25
Speakers
  • Y. Yap
Location
Hall Bordeaux, Palais des Congrès, Paris, France
Date
26.02.2019
Time
18:00 - 18:45
Authors
  • Y. Yap
  • D. Ho
  • R. Ng
  • C. Chan
  • A. Lee
  • I. Tan
  • S. Ng

Abstract

Background

There is increasing interest in the use of circulating tumour DNA (ctDNA) to identify targetable genomic alterations for therapy selection. However, the feasibility of next generation sequencing on ctDNA in BC patients with varying disease burden merits further investigation.

Methods

The cohort of 35 BC patients included 30 metastatic cases with paired primary and metastatic specimens in addition to plasma taken prior to commencement of a new line of palliative systemic therapy (all subtypes), + 5 patients (3 stage III, 2 stage II) about to commence neoadjuvant systemic therapy. DNA from tumour, buffy coat and plasma was sequenced on a 77-gene capture panel customised for BC. Matched tumour/normal samples were processed to discover somatic alterations using a standard GATK pipeline. Plasma samples were processed using unique molecular identifiers to identify potential alterations at low frequency.

Results

Among the entire cohort, 74% (26/35) of patients had mutation(s) in at least 1 gene detected from ctDNA: 60% (3/5) for the neoadjuvant cases, 77% (23/30) for the metastatic cases. The most frequently mutated genes from ctDNA analysis were TP53 (17/35; 49%) and PIK3CA (8/35; 23%), with HER2, HER3, JAK2, NF1, MAGI3 and TSC2 mutations observed in 2 patients each (6%). There was no obvious correlation between detection of ctDNA mutation and disease burden, serum CA-15.3 tumour marker or circulating tumour cell levels using a microfluidic platform. Out of 35 patients, 21(60.0%) had ≥1 concordant mutation via both ctDNA and tumour genotyping. Concordance between the plasma and primary and/or metastatic lesions was observed for 59% (39/66) of the mutations detected in ctDNA. Among the metastatic cases, 14/37(38%) of the concordant mutations were shared between the plasma, primary and metastatic specimens, while 5(14%) were shared between the plasma and the primary only, and 18/37(49%) shared between the plasma and metastatic lesions only.

Conclusions

Detection of genomic alterations from ctDNA is feasible in BC patients, but concordance of mutations in ctDNA is better with the metastatic than the primary lesion. This is likely due to suboptimal quality of DNA from archived tissue, and spatial, temporal heterogeneity.

Legal entity responsible for the study

National Cancer Centre Singapore and Genome Institute of Singapore.

Funding

SingHealth Foundation.

Disclosure

Y.S. Yap: Personal financial interests, honoraria for consultancy and talks, travel support: AstraZeneca, Eisai, Lilly, Novartis, Pfizer, Roche. All other authors have declared no conflicts of interest.

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