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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2601 General Poster Session (Board #9B), Mon, 8:00 AM-12:00 PM
Biomarkers of vincristine neuropathy in Kenyan children. Presenting
Author: Jodi L. Skiles, Riley Hospital for Children, Indiana University
School of Medicine, Indianapolis, IN
Background: In a U.S. population, cytochrome P450 (CYP) 3A5 highexpressers
metabolize vincristine (VCR) more efficiently than lowexpressers
and vincristine-induced peripheral neuropathy (VIPN) is less
common in African-Americans than Caucasians. We test the hypothesis
that more children in Kenya are CYP3A5 high-expressers compared to U.S.
children and as such experience less VIPN. Methods: This study was
conducted in Kenyan children with cancer (n�78) being treated with VCR
at Moi University AMPATH Oncology Institute in partnership with Indiana
University. Saliva Oragene kits for DNA extraction and genotyping were
obtained. Whole blood was collected via finger stick on Whatman protein
saver dried blood spot cards for analysis of VCR concentrations. VIPN was
assessed prospectively using two neuropathy assessment tools (Modified
Total Neuropathy Score (TNS) and National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results:
Compared to 14% in the U.S. sample, 94% of Kenyan subjects are
CYP3A5 high-expressers (p�2.2x10-16 ). Kenyan children have significantly
lower VCR plasma concentrations (11.15ng/ml/mg � 1.051) compared
to US (primarily Caucasian) children (13.26ng/ml/mg � 2.897) one
hour following the administration of VCR (p�0.011). By TNS VIPN
assessment, 71% of Kenyan children developed VIPN compared to 100%
of U.S. children (p�8.8x10-7 ). CYP3A5 high-expresser genotype is associated
with lower TNS VIPN severity scores than low-expresser genotypes
(p�0.006). TNS VIPN assessments show that height is positively correlated
with severity of VIPN (p�0.025). CTCAE VIPN assessments also
showed a positive correlation with height (p�0.036), but did not show any
association with CYP3A5 genotype. Conclusions: Kenyan children are more
likely to be CYP3A5 high-expressers than U.S. children and as such may
metabolize VCR more efficiently. Supporting these data is that Kenyan
children experience significantly less VIPN than U.S. children. CYP3A5
genotype and height are independent predictors of VIPN in Kenyan children
with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for
use in future studies aimed at optimizing VCR dosing strategies.
2603 General Poster Session (Board #9D), Mon, 8:00 AM-12:00 PM
Dovitinib (TKI258): Exploration of pharmacokinetics and pharmacodynamics
(PK/PD) for dose and regimen consideration. Presenting Author: Samira
M. Garonzik, Novartis Pharmaceuticals, East Habover, NJ
Background: Dovitinib is a potent oral inhibitor of Receptor Tyrosine
Kinases with activity against FGFR, VEGFR and PDGFR. The objectives of
this analysis are to describe the PK/PD of dovitinib to characterize the
differences between two different dosing regimens, 400 mg once daily (qd)
or 500 mg 5 days on, 2 days off (int) in terms of exposure and biomarker
response. Methods: PK/PD data from 127 patients receiving dovitinib,
100-600 mg int and 50 – 600 mg qd were available. Duration of therapy
was 15 to 859 days. Plasma concentration-time data � sparse biomarker
(BM) data were available after the first dose and at steady state (SS). Data
was analyzed using non-linear mixed effects modeling to characterize
nonlinearities in PK as well as BM response. VEGF, sVEGFR2 and PDGF
were described by indirect response models and FGF23 was described
using a mechanism based model to characterize acute drop, rebound,
tolerance and increase to a new SS over time. Results: Raw data revealed
prolonged absorption, linear clearance after the first dose, but dose
dependent 2 in clearance at SS (leading to over-proportional accumulation),
and apparent linear clearance at doses below 400 mg qd. 2 exposure
for doses up to 400 mg at SS compared to 1st dose implied auto-induction.
The PK was well described by a 1-compartment (CMT) model with 3 transit
CMTs to characterize absorption lag. Auto-induction and over-proportional
accumulation at SS were modeled as depending on cumulative exposure
through a time-dependent process with half-life of 18 h. In our study,
median (10th –90th percentile) Clearance was 30 (17 – 80) L/h on Day 1,
and 96 (51 – 185) L/h at SS. The model predicted 36%1in VEGF, 18% 2
in sVEGFR2, 82% and 57% 1in PDGF and FGF23 respectively at SS, for
median exposure at a dose of 400 mg qd. Simulations of PK and biomarker
responses were performed for different dosing regiments to assess relative
safety and target effects. Conclusions: The PK/PD model suggests 400 mg
qd may lead to over-proportional accumulation of dovitinib in �5% of
subjects while int dosing minimizes this. 500 mg int may be a more
tolerable regimen while maintaining adequate PD response, and is being
used in the pivotal phase III study for dovitinib in patients with mRCC.
167s
2602 General Poster Session (Board #9C), Mon, 8:00 AM-12:00 PM
Is cigarette smoke associated with increased catabolism of gemcitabine in
patients with advanced solid tumors? Presenting Author: Meaghan Working
O’Malley, University of Michigan Comprehensive Cancer Center, Ann Arbor,
MI
Background: Cigarette smoking can accelerate chemotherapy metabolism
and result in lower plasma concentrations of the chemotherapeutic agent.
Reduced drug levels may lead to undertreatment in smokers and, conversely,
increased treatment-related neutropenia in nonsmokers. Methods:
An IRB-approved retrospective chart review was performed on 151 patients
with solid tumor malignancies who received gemcitabine alone or in
combination with oral chemotherapy agents from July 1, 2009 to June 30,
2011 at the University of Michigan. Using logistic regression, we compared
toxicity, including neutropenia, and smoking history measured in packyears
in smokers vs. nonsmokers to ascertain whether cigarette smoking is
an independent factor predictive of toxicity to gemcitabine. Results: Tumor
types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or
other/unknown primary (15.2%). Most patients had advanced disease
(stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB;
n�107), 77.6% patients had stage III-IV disease. Within the PB cohort,
most patients were “ever” smokers as compared to “never” smokers
(60.7% vs. 39.3%). Logistic regression of this cohort showed that current
smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers
(OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with
higher pack-year history: smokers with �50 pack-years had even less
neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-
1.699]). Further statistical analysis of subgroups was not performed due to
small sample size. Conclusions: Smokers with pancreatobiliary malignancies
receiving gemcitabine had less treatment-related neutropenia as
compared to never smokers, a finding that was more pronounced as
pack-years increased. Decreased toxicity, including neutropenia, may be
due to increased metabolism and drug clearance as a result of smoking.
This may lead to potential undertreatment of smokers and, conversely,
increased treatment-related toxicity in never smokers. A prospective
clinical trial is needed to further elucidate this correlation, and is currently
being designed.
2604 General Poster Session (Board #9E), Mon, 8:00 AM-12:00 PM
A randomized, double-blind, placebo-controlled study to assess the efficacy
and toxicity of subcutaneous ketamine in the management of cancer
pain. Presenting Author: David C. Currow, Flinders University, Adelaide,
Australia
Background: The dissociative anaesthetic ketamine is widely used for
cancer related pain. A Cochrane review concluded that insufficient evidence
was available to support its use in this setting. Methods: This phase
III, multisite, double-blind, dose escalation, placebo, randomised controlled
study aimed to determine whether ketamine, delivered subcutaneously
over three to five days is more effective than placebo, when used in
conjunction with adjuvant therapy in the management of chronic uncontrolled
cancer pain. Ketamine would be considered to be of net benefit if it
provided a reduction in average pain scores by �2/10 points from baseline,
with limited breakthrough analgesia and acceptable toxicity. Results: For
the 185 participants, there was no significant difference between the
proportion of positive outcomes (0.04 (-0.10, 0.18) p�0.55) in the
placebo and intervention arms (response rates 27% (25/92) and 31%
(29/93)). Pain type (nociceptive versus neuropathic) was not a predictor of
response. There was almost twice the incidence of adverse events worse
than baseline in the ketamine group after day 1 (IRR � 1.95 (1.46, 2.61),
p�0.001) and throughout the study. Those receiving ketamine were more
likely to experience a more severe grade of adverse event/day (OR�1.09
(1.00, 1.18), p�0.039). The number needed to treat for one additional
patient to get a positive outcome from ketamine was 25 (6, �). The number
needed to harm, because of toxicity-related withdrawal was 6 (4, 13).
Conclusions: Ketamine does not have net clinical benefit when used as an
adjunct to opioids and standard co-analgesics in cancer pain.
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