Annals of Oncology

abstracts
141P
Identification of baseline parameters associated with the
inter-individual variability in cytidine deaminase serum activity,
a key enzyme in the metabolism of pyrimidine analogue
R. Cohen 1 , L-H. Preta 2 , A. Bessone 3 , C. Narjoz 3 , I. Nicolis 4 , D. Desaulle 4 ,
E. Curis 4 , A. Cessot 1 , O. Huillard 1 , A. Thomas-Schoemann 2 , M. Vidal 2 ,
F. Goldwasser 5 , J. Alexandre 5 , B. Blanchet 6
1 Medical Oncology, Paris Descartes University, Cochin - Port Royal Hospital,
AP-HP, Paris, France, 2 Laboratory of Toxicology and Pharmacology, Paris
Descartes University, Cochin - Port Royal Hospital, AP-HP, Paris, France, 3 Service
de Biochimie, Hopital European George Pompidou, Paris, France, 4 Laboratoire de
Biomathématiques et Informatique, Département de Santé Publique et
Biostatistiques, EA 4064, Faculté de Pharmacie Université Paris Descartes, Paris,
France, 5 Department of Medical Oncology, Cochin Hospital, Paris Descartes
University, APHP, CARPEM, CERTIM, Hôpital Cochin, Paris, France, 6 Laboratory
of Toxicology and Pharmacology, Immunomodulatory Therapies Multidisciplinary
Study Group (CERTIM), Paris Descartes University, Cochin - Port Royal Hospital,
AP-HP, Paris, France
Background: Cytidine deaminase (CDA) catabolizes gemcitabine and cytosine
arabinoside and its serum activity (CDA-A) has been associated with efficacy and
toxicity of both treatments. CDA is mainly produced by hepatocytes and neutrophils.
Our objective was to identify pretreatment patients (pts) characteristics that may
contribute to the large inter-individual variability in CDA-A.
Methods: From December 2014 to November 2015, all consecutive pts were
prospectively included into this single-center study. CDA-A in serum was assayed
using a standardized spectrophotometric method. Biological, clinical characteristics
and 5 common single nucleotide polymorphisms in the CDA gene (-451g > a, -92a > g,
-33delc, 79a > c, 435t > c) were analyzed according to pretreatment CDA-A. Written
consent was obtained from all patients. Univariate and multivariate statistical analysis
were performed on log-transformed CDA-A with significance level of 0.05.
Results: 275 pts (male: 61%) were analyzed. Median age was 66.2 years. Main primary
tumor locations were lung (19%), prostate (11%) and urinary tract (10%). Median
CDA-A was 4.08 u/mg protein (range 1.53-15.49). The inter-individual variability in
CDA-A was large (43%). 49 pts (18%) had high CDA-A (> 6 U/mg). In univariate
analysis, high CDA-A was associated with absolute neutrophil count (ANC) (p < 10 −16 ),
C-reactive protein level (p = 10 −7 ), malnutrition (p = .014), altered ECOG performance
status (p = .0003) and -33delC genotype (p = .0152). In multivariate analysis, only ANC
was independently associated with CDA-A (p < 10 −9 ). Finally, this correlation between
CDA-A and ANC (Pearson coefficient >0.5) was also observed over the treatment course
with gemcitabine (at least 3 sampling occasions per patient; n = 6).
Conclusions: Our results show for the first time an association between the
pretherapeutic number of neutrophils and CDA activity, suggesting a CDA release
from neutrophils. However, it explains only a small part of inter-individual variability
in CDA-A. Therefore, CDA-A assessment in serum remains of interest to identify pts
with high risk of toxicity or low efficacy under pyrimidine analogues.
Legal entity responsible for the study: Paris Descartes University, Cochin - Port Royal
Hospital, AP-HP
Funding: None
Disclosure: F. Goldwasser: Honoraria: Fresenius Kabi, Boehringer Ingelheim, Bayer,
Pfizer Consulting or Advisory Role: Fresenius Kabi, Bayer. Travel, accomodation:
Bayer, Novartis, AsrtaZeneca, Roche Glycart. All other authors have declared no
conflicts of interest.
142P
Development of an ELISA to detect tumor-associated antigen
tNASP in urine
O. Alekseev 1 , J. Vaughn 2 , B. Taylor 2 , L. Barba 2 , J. Greiner 2 , C. Dickson 2 ,
C. Anderson 2 , J. Fullmer 2 , Z. Vaskalis 3
1 Physiology and Pathophysiology, Campbell University, Buies Creek, NC, USA,
2 Campbell University, Buies Creek, NC, USA, 3 School of Osteopathic Medicine,
Campbell University, Buies Creek, NC, USA
Background: Tumor-associated antigens (TAAs) are proteins that elicit a humoral
immune response when their expression is elevated in tumor progression. tNASP is
one of two splice variants of Nuclear Autoantigenic Sperm Protein. In addition to its
normal testicular expression, it is also aberrantly expressed in cancer cells. We have
previously demonstrated that immunohistochemical detection of tNASP has high
diagnostic sensitivity and specificity in ovarian cancer. We have discovered that tNASP
is also aberrantly expressed in prostate cancer cells and tissues. In the current study, we
developed an ELISA to detect specific anti-tNASP serum antibodies as well as tNASP
protein in urine for early diagnosis of prostate cancer.
Methods: tNASP protein expression was assayed by immunohistochemistry (IHC) in
prostate cancer biopsy samples from different disease stages, using affinity-purified goat
anti-tNASP serum, which specifically recognizes only tNASP protein. A recombinant
tNASP-specific fragment was used as bait to produce a standard curve for detection of
anti-tNASP antibodies by ELISA. Serum and urine samples from patients with prostate
cancer, and otherwise healthy control patients, were obtained from the Tissue
Procurement Facility of the University of North Carolina at Chapel Hill, Roswell Park
Cancer Institute, and Fox Chase Cancer Center. Correlation between serum
anti-tNASP antibody levels, urine tNASP protein level and Prostate Specific Antigen
(PSA) was analyzed by Spearman’s coefficient.
Results: ELISA measurements demonstrated a significant increase in tNASP protein
levels in the urine of prostate cancer patients, as compared to control group urine.
Spearman’s rank correlation demonstrated that the concentration of anti-tNASP
antibodies and tNASP levels in urine co-varied with PSA levels. Urine tNASP protein
was detected by ELISA with anti t-NASP antibody as bait, whereas anti-tNASP
antibodies were not detected in urine samples.
Conclusions: Combined detection of serum anti-tNASP antibody and urine tNASP
protein could be used for diagnosis of prostate cancer and has the potential to improve
early diagnostic confidence.
Legal entity responsible for the study: This study was supported by Campbell
University School of Osteopathic Medicine, North Carolina, 27506, USA. Associate
Professor Oleg Alekseev, MD, PhD is a principal investigator on this project.
Funding: This study was funded by School of Osteopathic Medicine of the Campbell
University (CUSOM). Principal investigator Dr. Oleg Alekseev is a full-time faculty in
CUSOM and research activity is his duty along with teaching.
Disclosure: All authors have declared no conflicts of interest.
143TiP
Annals of Oncology
A biomarker-guided first-in-human trial of subcutaneous
ALM201 in patients with solid tumours
A. El-Helali 1 , R. Plummer 2 , G. Jayson 3 , V. Coyle 1 , C. Rogers 3 ,M.D’Arcangelo 2 ,D.
M. Graham 1 ,Y.Drew 2 , A. Clamp 3 , J. McCann 4 , A. McCavigan 5 , L. Knight 5 ,
N. McCabe 5 , K. Keating 5 ,R.Dyer 6 , T. Harrison 6 , P. Harkin 5 , T. Robson 7 ,
R. Kennedy 1 , R. Wilson 1
1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast,
UK, 2 Medical Oncology, Sir Bobby Robson Cancer Trials Research Centre,
Northern Centre for Cancer Care, Newcastle upon Tyne, UK, 3 Medical Oncology,
The Christie NHS Foundation Trust, Manchester, UK, 4 Cancer Research Forum,
Northern Ireland Cancer Research Consumers Forum, Belfast, UK, 5 Almac
Diagnostics, Almac Group, Craigavon, UK, 6 Almac Discovery, Almac Group,
Craigavon, UK, 7 School of Pharmacy, Queen’s University Belfast, Belfast, UK
Background: ALM201 is a 23-amino acid peptide derived from FKPB-L, a human
endogenous protein with inherent anti-angiogenic activity. ALM201 is active after
internalisation via CD44 into the cell, where it binds to tubulin and prevents
microtubule formation. Preclinical studies have demonstrated that ALM201 is a potent
inhibitor of migration, invasion and new blood vessel formation but has no effects on
cell cycle or proliferation. It was very well tolerated in pre-clinical toxicology studies.
High grade serous ovarian cancer (HGSOC) is a disease of clinical unmet need, and the
role of anti-angiogenics in HGSOC remains a critical area of investigation. The 63-gene
AADx biomarker (Gourley et al, ASCO 2014) identifies a sub-group of HGSOC with
significant up-regulation of angiogenic genes and a worse outcome from conventional
platinum-based chemotherapy. In our trial, we wish to investigate ALM201 in this
AADx-selected “Angiogenic” HGSOC population.
Trial design: This phase I trial employs an accelerated dose-escalation design with
single patient cohorts, later moving to a standard 3 + 3 design, and will explore 6 dose
levels. Patients will have histologically confirmed advanced solid tumours, in which use
of an antiangiogenic is reasonable. The dose expansion cohort will recruit 36 patients
and treat them with the recommended phase II dose (RP2D). They will have relapsed
advanced HGSOC with a tumour classified as angiogenic by the AADx signature. This
companion diagnostic will utilise a pre-enrolment FFPE tumour sample. Patients will
receive ALM201 once daily as a subcutaneous injection on days 1-5, 8-12, and 15-19
every 21 days. The primary objectives are to determine the safety, tolerability and
RP2D of ALM201. Secondary objectives are to determine the pharmacokinetic profile
and preliminary antitumor activity of ALM201 overall and in the biomarker-selected
HGSOC population. Exploratory objectives are to assess relevant tumour biomarkers
and the pharmacodynamic activity of ALM201. This trial commenced recruitment in
July 2015, with 10 patients currently enrolled across the first 6 dose levels.
Clinical trial identification: EudraCT No: 2014-001175-31
Legal entity responsible for the study: Almac Discovery
Funding: Almac Discovery
Disclosure: V. Coyle: Research funding and site PI: Onyx/Amgen. Travel and
accommodation expense covered by sanofi and BM. C. Rogers: consulting/advisory
role for AstraZeneca. Y. Drew: Honoraria: AstraZeneca and Clovis Oncology.
Consulting and advisory role: AstraZeneca and Clovis Oncology. A. Clamp: Consulting
and advisory role: Astra Zeneca. Speakers Bureau: Astra Zeneca and Roche. Research
funding: Astra Zeneca, Clovis Oncology, Array Biopharma, AB bioscience and
Amgen. A. McCavigan: Employee of Almac Diagnostics. L. Knight: Employee of Almac
group. N. McCabe: Employee of Almac group. Research funding from ALmac
group. K. Keating: Employed by Almac diagnostics. Research funded by Almac
Diagnostics. Hold patent and royalties in ALmac diagnostics. Travel and expenses
covered by Almac Diagnostics. R. Dyer: Almac discovery employee, holds patent/
royalties through Almac Discovery. Travel/accommodation expenses covered by Almac
Discovery. T. Harrison: Employee of Almac Discovery, research funded by Almac
Discovery. P. Harkin: Employment: Almac Diagnostics. Research funded by Almac
Diagnostics. Patent and royalties held and received by Almac Diagnostics. T. Robson:
Research funding: Almac Discovery. Patent/royalties held with Almac
Discovery. R. Kennedy: Employee of Almac Diagnostics. Patent and royalties held with
Almac Diagnostics. R. Wilson: Honoraria, Advisory roles and travel expenses from
Sanofi, Merck Serono, Amgen and Sirtex. All other authors have declared no conflicts
of interest.
vi42 | abstracts Volume 27 | Supplement 6 | 2016