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Annals of Oncology
and fluids, is known to play an important role in tumor biology. CD26 is frequently
highly expressed on multiple cancer cell types, especially mesothelioma and renal cell
carcinoma (RCC). In addition to its role in proteolysis via the DPPIV activity, CD26
also acts as a receptor involved in T-cell co-stimulation and immune regulation.
Preclinical evaluations of YS110 have demonstrated anti-tumor effects in cancer cell
lines and xenografts expressing the CD26 antigen without significant side effects in
toxicology studies (up to 100 mg/kg as single dose or 30 mg/kg for 5 weekly doses in
cynomolgus monkeys).
Phase I design and endpoints: The ongoing YSCMA-EU-0001 trial is a Phase I/II
study of YS110 escalating dose administered intravenously once every 2 weeks for 3
doses (Days 1, 15, 29). Patients must have progressive locally advanced inoperable
and/or metastatic histologically confirmed solid tumors, refractory to prior standard
therapies, with confirmed CD26 + tumor expression (≥ 20% of the tumor cells by
central IHC evaluation). The primary endpoint is to determine the Maximum
Tolerated Dose/Recommended Dose of YS110 and the pattern of DLTs. Secondary
endpoints are the determination of the PK/PD parameters (i.e. analysis of cytokine
release, immunophenotyping, circulating DPPIV activity and sCD26 antigen level).
Preliminary antitumor efficacy is evaluated by RECIST1.1 criteria at Day 43. Patients
demonstrating objective response or stable disease receive additional treatment cycles.
Status of the study: As of May 1 st 2012, 22 patients (13 mesothelioma, 9 RCC) have
been treated with 3 bi-weekly infusions over 29 days at 0.1, 0.4, 1 and 2 mg/kg. Based
on PK data for them, the next cohort of 3 patients will be dosed at 2 mg/kg with
weekly infusions over 29 days starting in May 2012. Safety, PK/PD, and preliminary
efficacy data will be presented.
Disclosure: T. Podoll: Compensated employment position : President of Y\\’s
Therapeutics Compensated Consultant role. I. Miyashita: Compensated Employment
role: Director Kissei Pharmaceuticals Co, Ltd. Y. Kaneko: Compensated employment
role : managing board of directors Y’s AC Stock ownership: Y’s AC. C. Morimoto:
Compensated Consultant role : Kissei Pharmaceuticals Co, Ltd Stock ownership: Y’s
Therapeutics Honororia: Kissei Pharmaceuticals Co, Ltd Research funding: Y’s
Therapeutics. All other authors have declared no conflicts of interest.
499P INCIDENCE AND RELEVANCE OF PROTEINURIA IN
BEVACIZUMAB (BV)-TREATED PATIENTS (PTS): POOLED
ANALYSIS FROM RANDOMIZED CONTROLLED TRIALS (RCTS)
R. Lafayette 1 , B. McCall 2 , N.F. Li 3 , L. Chu 4 , P. Werner 5 , A. Das 6 , R.J. Glassock 7
1 Nephrology, Stanford Glomerular Disease Center, Stanford, CA, UNITED
STATES OF AMERICA, 2 Product Development, Oncology, Genentech, Inc.,
South San Francisco, CA, UNITED STATES OF AMERICA, 3 Biostatistics,
Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA,
4 Global Product Development Biometrics, Genentech, Inc., South
San Francisco, CA, UNITED STATES OF AMERICA, 5 Statistical Programming
and Analysis (spa), F. Hoffmann-La Roche AG, Basel, SWITZERLAND, 6 PDCO,
Genentech, Inc., South San Francisco, CA, UNITED STATES OF AMERICA, 7 The
David Geffen School of Medicine, UCLA, Laguna Niguel, CA, UNITED STATES
OF AMERICA
Background: Proteinuria (PU) is a recognized adverse event with BV treatment (tx);
however it is not known if BV-related PU is associated with clinical outcomes. This
analysis was undertaken to define the relationship between PU with BV tx and
sequelae, including changes in kidney function.
Methods: A pooled safety database, comprising 22 phase 2/3 RCTs of BV across
tumor types, was used to characterize PU events. Analysis pools were created based
on data availability in individual studies. Raw and time-adjusted PU rates and data
on the association between PU and arterial thromboembolic events (TEs), venous
TEs, and infection were derived from Pool 1 (17 RCTs; n = 14,548). Data from Pool
2 (8 RCTs; n = 9,158) were used to estimate the association between lab-reported PU
and changes in kidney function based on serum creatinine (sCr) levels. Severity of
kidney function change was categorized using the RIFLE classification for acute
kidney injury (AKI). Potential predictors of PU were also assessed.
Results: In Pool 1, the incidence rate of any-grade (gr) PU was 8.2% (733/8917) and
4.6% (257/5631) in BV and control pts, respectively; gr ≥3 PU occurred in 1.4% and
0.2%, respectively. Pts developing PU had a numerically increased rate of any-gr
infection irrespective of tx (driven mostly by urinary tract infection); however, no
association was found between PU and TEs (arterial or venous). In Pool 2, PU gr
and tx appeared to slightly shift the rate of post-baseline AKI (Table). Evaluated risk
factors (age, sex, history of hypertension or diabetes) were not found to be
significantly predictive for gr ≥3 PU.
Conclusions: The use of laboratory events and pooled data confirm a modest
increase in PU with BV tx. The development of PU in BV-treated pts was associated
with a modest increase in the risk of infection, but not TEs, and a trend toward a
decrease in kidney function. Whether these associations are causal cannot be
determined by this analysis.
Tx group
BV (n =
5098)
No BV (n =
3186)
Worst
post-BL gr
of PU a
Pts without
PU at BL,
n
Worst post-BL kidney function (RIFLE
classification), n (%)
Normal Risk b
Injury c
Failure d
0 2960 2277 (76.9) 585 (19.8) 66 (2.2) 25 (0.8)
1 1381 1021 (73.9) 307 (22.2) 31 (2.2) 20 (1.4)
2 562 391 (69.6) 137 (24.4) 18 (3.2) 14 (2.5)
3 59 34 (57.6) 19 (32.2) 4 (6.8) 2 (3.4)
0 2144 1736 (81.0) 349 (16.3) 39 (1.8) 18 (0.8)
1 769 618 (80.4) 123 (16.0) 19 (2.5) 9 (1.2)
2 166 124 (74.7) 32 (19.3) 7 (4.2) 3 (1.8)
3 2 1 (50.0) 1 (50.0) — —
a CTCAE grade. No patients had gr 4 PU.
b Increased sCR ×1.5 or estimated creatinine clearance (eCrCl) decrease >25%.
c Increased sCr ×2 or eCrCl decrease >50%.
d Increased sCr ×3, eCrCl decrease >75% or sCr ≥4 mg/dL.
Note: missing values for each row are not shown.
BL, baseline.
Disclosure: B. McCall: Dr. McCall is an employee of and holds stock options in
Genentech, Inc. N.F. Li: Dr. Li is an employee of and holds stock options in
Genentech, Inc. L. Chu: Ms. Chu is an employee of and holds stock options in
Genentech, Inc. P. Werner: Dr. Werner is an employee of F. Hoffmann-La Roche
Ltd. A. Das: Dr. Das is an employee of and holds stock options in Genentech, Inc. R.
J. Glassock: Dr. Glassock is a consultant to Genentech. All other authors have
declared no conflicts of interest.
500P THE LEEDS FORMULA: A NEW, MORE ACCURATE AND
WIDELY APPLICABLE FORMULA FOR ESTIMATING RENAL
FUNCTION, ACCOUNTING FOR VARIABILITY IN CREATININE
ASSAY MEASUREMENT
F. Collinson 1 , W. Gregory 1 , C. Twelves 2 , C. Handforth 3 , M. Bosomworth 4 ,
G. Hall 3
1 Clinical Trials Research Unit, University of Leeds, Leeds, UNITED KINGDOM,
2 Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine & St
James’s Institute of Oncology, Leeds, UNITED KINGDOM, 3 St James’s Institute
of Oncology, St James’s University Hospital, Leeds, UNITED KINGDOM, 4 Blood
Sciences, St James’s University Hospital, Leeds, UNITED KINGDOM
Introduction: Many formulae are used to estimate renal function, but none account
for the significant variation in creatinine (Cr) measurement between the 26 assays
currently used in the UK. The UK National External Quality Assessment Service has
published assay-specific Cr adjustors, but the calculated ’standardised Cr’ (SCr)
dangerously overestimates GFR when used in formulae such as Cockroft and Gault
(C&G) and Wright (W). We aimed to develop a simple formula to accurately
estimate GFR in oncology patients, using easily available patient characteristics and
the SCr, hence accounting for inter-assay variation.
Methods: Isotopic GFR (iGFR) was measured using Tc 99m DTPA clearance. Serum
Cr was measured using the O’Leary Jaffe assay and from this SCr derived. Clinical
parameters (age, sex, height, weight, SCr, urea and albumin) were used in regression
modelling (STATA) to investigate the relationship of individual parameters with
iGFR. From this a novel formula was derived to estimate iGFR (the Leeds formula).
This formula was then prospectively validated on a second cohort of patients.
Results: In the discovery set 423 oncology patients were included with a range of
malignancies, a median age of 49 (range 18-91) years and serum Cr between 50-130
µmol/l who underwent iGFR measurement between 1/4/06 and 31/3/09. A model
incorporating SCr, age, sex, height, weight, urea and albumin predicted iGFR
(median calculated GFR 92 ml/ min, range 25-217; r 2 of 0.74) more accurately than
alternative established GFR formulae e.g. C&G and W formulae (r 2 0.4-0.6) .
Prospective validation on a separate cohort of oncology patients (496 patients
between 1/4/09 and 31/3/11) validated the Leeds formula with an r 2 of 0.71 for
correlation with iGFR.
Conclusions: The Leeds formula uses readily available clinical information to
estimate GFR more precisely than existing formulae and has the advantage of being
applicable to Cr results from any laboratory provided the assay type is known. Many
oncologists do not appreciate the resultant effect of inter-Cr assay variability on
estimated renal function (GFR) and hence chemotherapy dosing.
Disclosure: All authors have declared no conflicts of interest.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds395 | ix171