Annual Meeting Proceedings Part 1 - American Society of Clinical ...

166s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2597 General Poster Session (Board #8F), Mon, 8:00 AM-12:00 PM
Clinical pharmacologic considerations for the phase II/III dose/regimen of
the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib):
Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety
relationships. Presenting Author: Karthik Venkatakrishnan, Clinical Pharmacology,
Millennium Pharmaceuticals, Inc., Cambridge, MA
Background: MLN8237, an oral selective AAK inhibitor, is primarily
metabolized by multiple glucuronidation enzymes including the polymorphic
UGT1A1. Phase 1 studies included comprehensive PK and PD
sampling. We report integrated PK, PD, and PK-safety analyses in support
of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies
in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or
d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2
studies contributed to population PK modeling. PD endpoints included
mitotic index (MI) in skin and chromosome alignment and spindle
bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses
evaluated relationships between MLN8237 PK parameters and DLTs
(N�86) or CNS adverse events (AEs; n�134) in 2 phase 1 studies. Results:
MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment
model with first order absorption. Covariate analyses did not
reveal significant effects of age, body size, sex, UGT1A1 genotype, or
creatinine clearance (�30 mL/min). Exposure-related increases in skin MI
and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by
MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean
steady-state exposures (48,200 nM.hr) were comparable to those associated
with �50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr).
Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d
1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic
regression relating MLN8237 AUC to DLT rate estimated a DLT probability
of 8% (95% CI 3-20%). Similar analyses identified Cmax rather than AUC as
the predictor of CNS AEs, supporting BID dosing in adults to reduce peak
concentrations while preserving total systemic exposure. Conclusions:
MLN8237 exhibits dose-linear PK independent of age, body size, mild or
moderate renal impairment, or UGT1A1*28 polymorphism. Exposures
achieved at or near 50 mg BID are expected to result in tumor AAK
inhibition, supporting a pharmacologically active dose range for future
clinical development.
2599 General Poster Session (Board #8H), Mon, 8:00 AM-12:00 PM
Effects of metformin and sulfonylureas on overall and colorectal cancerspecific
mortality. Presenting Author: Susan Spillane, Trinity College
Dublin, Dublin, Ireland
Background: Preclinical studies have suggested a role for metformin in the
treatment of colorectal cancer (CRC). Associations between metformin
versus sulfonylurea exposure and mortality (all-cause and colorectal cancer
specific) are assessed in this population-based study of patients with a
diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland
records were linked to prescription claims data and used to identify a cohort
of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From
this cohort, 2 patient groups were identified and compared for outcomes -
those who received a prescription for metformin �/- a sulfonylurea (MET) or
a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC
diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI)
were estimated using Cox proportional hazards models adjusted for age,
sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin
or statin exposure. Analyses were repeated stratifying by stage and site.
Results: 5,617 patients with stage I-IV CRC were identified, of whom 369
received a prescription for metformin or a sulfonylurea in the 90 days pre
diagnosis (median follow-up 1.6 years; MET: n�257; SUL: n�112). In
adjusted analyses metformin exposure was associated with a 28% lower
risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95%
CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific
mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in
colon cancer, metformin exposure was associated with a significant
one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95)
and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI
0.40-1.02). No mortality benefit was observed for rectal cancer. The
association between metformin exposure and reduced mortality was strongest
for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-
0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions:
Pre-diagnosis metformin exposure in CRC patients was associated with a
significant reduction in mortality relative to sulfonylurea exposure. This
benefit was greatest in patients with colon cancer and early stage disease.
2598 General Poster Session (Board #8G), Mon, 8:00 AM-12:00 PM
Docetaxel pharmacogenetics: The influence of RXR� and HNF4� genetic
variations on docetaxel disposition in Asian nasopharyngeal carcinoma
patients. Presenting Author: Sin Chi Chew, Division of Medical Sciences,
National Cancer Centre, Singapore
Background: The transactivations of the metabolism enzymes (CYP3A4/5)
and efflux transporters (ABCB1/ABCC2) involved in docetaxel disposition
are regulated by the orphan nuclear receptors such as PXR, CAR, RXR� and
HNF4�. This study aimed to explore the associations between the genetic
variations present in the genes encoding the orphan nuclear receptors,
RXR� and HNF4�, on docetaxel disposition. Methods: The DNAs from
healthy Chinese, Malay and Indian subjects (n�56 each) were screened for
RXR� and HNF4� SNPs in exons and intronic/exonic boundaries by direct
sequencing. The high frequency SNPs (�1%) were profiled in a cohort of
local nasopharyngeal cancer patients (n�54). Genotypic-phenotypic correlations
were conducted using Mann-Whitney U-test and Kruskal-Wallis
test. Results: Eighty-eight and sixty-nine SNPs were identified from the
healthy screening of RXR� and HNF4�, respectively, across 3 populations.
A total of 30 and 35 high frequency SNPs in RXR� and HNF4�,
respectively, were profiled in the patients. Six RXR� SNPs [IVS2�33G�A
(rs2234753), IVS7�70A�G (rs1536475),*846G�A (rs4240711),
*�4458G�A (rs3132291), *�4768C�A (rs4842196) and *�4988A�G
(rs4842198)] and 6 HNF4� SNPs [-728A�C (rs1800963), IVS2-
278A�G (rs55934816), IVS6�141A�G (rs6103731), IVS7-88T�C
(rs2273618), IVS9–145T�C (rs3746574) and IVS9-67C�G
(rs3746575)] were significantly associated with higher clearance and
lower AUC0-� and/or Cmax of docetaxel (P�0.05). Conversely, HNF4� SNP
[IVS9�354G�T (rs3818247)] was associated with lower clearance and
higher AUC0-� and Cmax of docetaxel (p�0.05). A high linkage pattern was
observed among the abovementioned RXR� SNPs except for IVS2�33G�A
(rs2234753) (D’�0.74). Similarly, HNF4� SNPs were found to be highly
linked, except for -728A�C (rs1800963) (D’�0.62). Conclusions: The
results highlight the contributions of RXR� and HNF4� pharmacogenetics
in influencing the inter-individual variability in docetaxel disposition in
Asian nasopharyngeal patients.
2600 General Poster Session (Board #9A), Mon, 8:00 AM-12:00 PM
Antibody-dependent cell-mediated cytotoxicity (ADCC) evolution under
treatment by cetuximab and links with treatment outcome in colorectal
cancer (CRC) patients. Presenting Author: Marco Carlo Merlano, St. Croce
General Hospital, Cuneo, Italy
Background: ADCC plays a role in antitumor activity of IgG1 mAb by
inducing immune cell-mediated lysis of tumor cells. We evaluated ADCC
ability before and under cetuximab-based treatment and examined its
impact on treatment outcome. Methods: 29 patients (17 men, 12 women,
median age 72, range 51-84) with metastatic wild-type KRAS CRC treated
with chemotherapy (irinotecan or Folfiri) plus cetuximab were prospectively
enrolled. ADCC ex-vivo was measured before starting treatment and every 2
months during treatment (1 to 7 measurements/patient, 12 patients with
�2 measurements). 400 000 purified Natural Killer cells (CD3- CD56�)
from patients were incubated with 10 000 target cells (CAL166 cancer cell
line expressing EGFR) and 10 �g/ml cetuximab (triplicates). Cytotoxicity
was measured by the LDH-release assay. ADCC was expressed as the % of
lyzed target cells. Gene polymorphisms of Fc� receptors FCGR2a
(131Arg�His) and FCGR3a (158Phe�Val) were analyzed (Allelic Discrimination
assay). Results: The feasibility rate of ADCC measurement was 88%.
ADCC basal values ranged between 30% and 100% (mean 62%, median
66%). Basal ADCC was not influenced by patient gender. A tendency for an
increased ADCC basal value was observed in younger patients: median was
76% in the 6 patients � 60 vs 56% in the 23 patients over 60 years-old (p
� 0.031). FCGR2A and FCGR3A gene polymorphisms were not linked to
basal ADCC. The evolution of individual ADCC ability before treatment and
2 months later revealed a significant drop in ADCC following treatment
initiation (intra-patient comparison, n�18, p�0.006), with an absolute
median drop of 19%. This decrease was not sustained over time and
intra-patient comparison between basal value and 4-month measurement
was not significant. 25 patients were assessable for survival (11 deaths).
Basal ADCC values were not related to survival. Conclusions: A new
generation of mAb is currently being developed with the aim to amplify
ADCC. Present data illustrate the feasibility of ADCC measurement in
mAb-treated patients and reveal an initial drop in ADCC under treatment
that may reflect the variable chemotherapy-induced impact on host
immunity.
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