Browsing Over 138 Presentations
Presentation of the TAT 2019 Honorary Award (ID 3)
- A. Adjei
- A. Adjei
Introduction (ID 92)
- L. Ellis
- L. Ellis
Q&A (ID 212)
- J. De Bono
- E. Calvo
- J. De Bono
- E. Calvo
Session DOI (ID 215)
Immuno-oncology combination in patients with pre-existing molecular alteration (EGFR ALK BRAF and other) (ID 27)
- M. Gutierrez
- M. Gutierrez
Phase I trial of RO5126766 a MEK-RAF inhibitor in solid tumours and myeloma driven by RAS driven cancers (ID 51)
- U. Banerji
- U. Banerji
7O - Phase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL) (ID 127)
- A. Hollebecque
- 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.
28P - Simultaneous unbiased and absolute quantification of a 500 protein panel in pancreatic cancer plasma using HRM mass spectrometry (ID 192)
- H. Yu
- H. Yu
- J. Vowinckel
- C. Escher
- D. Heinzmann
- N. Dupuis
Abstract
Background
Recent studies have demonstrated of utility of quantifying circulating proteins for early disease detection, prediction of therapeutic response, and treatment monitoring. Although the utility is clear, standardization of measurement methods for a large number of proteins from plasma remains challenging. Here, plasma proteins are detected using hyper-reaction monitoring (HRM) mass spectrometry in samples from normal and pancreatic cancer subjects. The data is acquired and analyzed simultaneously with unbiased label-free quantification of all proteins and absolute quantification of proteins from a > 500-protein panel constructed from stable-isotope standard (SIS) peptides.
Methods
Plasma samples from subjects with Stage IV pancreatic cancer (PC, n = 6) and age matched healthy donors (n = 15) were prepared for mass spectrometry. Prior to analysis, a panel of SIS peptides, covering 582 plasma proteins, was spiked into each sample. All samples were acquired using nano-flow liquid chromatography with separation over a one-hour gradient coupled online to a Thermo Scientific Q Exactive HF mass spectrometer. Protein data was extracted using Spectronaut (Biognosys) and statistical analysis was conducted to identify disease associated biomarker candidates.
Results
Analysis of the PQ500 panel enabled absolute quantification of 282 proteins across all samples. Univariate statistical testing identified 29 candidate proteins (27 up- and 2 down-regulated; q-value > 0.05 and fold change > 1.5). Key dysregulated proteins include CRP, SAA1, and C9. With unbiased, label-free quantification, 414 proteins were quantified, with 87 significantly regulated. In addition to the acute phase protein candidates identified in the PQ500 panel, 12 adhesion related protein candidates were identified (e.g. TLN1, MYH9, TPM4), 9 of which were decreased in PC. Notably, membrane associated ICAM1 and VCAM1, both potential therapeutic targets, were increased in PC.
Conclusions
Combining PQ500 with unbiased label-free quantification enables comprehensive characterization of the plasma proteome, while at the same time providing absolute quantification for a large subset of well annotated, clinically relevant proteins.
Legal entity responsible for the study
Biognosys AG, Schlieren, Switzerland.
Funding
Biognosys AG, Schlieren, Switzerland.
Disclosure
H. Yu, J. Vowinckel, C. Escher, D. Heinzmann, N. Dupuis: Employee: Biognosys AG.
Epigenetic dysregulation in hematological malignancies (ID 18)
- O. Bernard
- O. Bernard
Introduction (ID 41)
- G. Shapiro
- G. Shapiro
Development of Cyclin-Dependent Kinase Inhibitors: A Brief History and Future Directions (ID 202)
- G. Shapiro
- G. Shapiro
18P - Choline transporter-like protein 1 (CTL1/SLC44A1) is a therapeutic target molecule for prostate cancer therapy (ID 115)
- M. Inazu
- 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.