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

150s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2533 Poster Discussion Session (Board #21), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Effect of age on the pharmacokinetics of busulfan (Bu): An alliance study.
Presenting Author: Jan Hendrik Beumer, University of Pittsburgh Cancer
Institute, Pittsburgh, PA
Background: Older acute myeloid leukemia (AML) and myelodysplastic
syndrome (MDS) patients (pts) have been excluded from myeloablative
regimens including agents such as busulfan because of the potential for
non-disease related morbidity and mortality. Busulfan, often used as part of
myeloablative regimens, is cleared in part by glutathione–S-transferase and
CYP3A4. We hypothesized that busulfan clearance (BuCL) in the elderly
(� 60 years) would be reduced compared to that in young patients
(� 60 years), thus potentially explaining differences in tolerability.
Methods: AML and MDS pts in three CALGB bone marrow transplant studies
across a wide age range (17-74) were treated with a conditioning regimen
using IV busulfan, dosed at 12.8 mg/m2 in CALGB studies 10503 and
19808 and 6.4 mg/m2 in CALGB 100103. Blood samples were collected
for determination of busulfan plasma pharmacokinetics (PK). Plasma
busulfan was quantitated by LC-MS. BuCL was determined using noncompartmental
modeling, and normalized to actual (ABW), ideal (IBW) and
corrected (CBW) body weight (kg). Differences between age groups were
examined using the Wilcoxon rank sum test. Results: A total of 185 pts were
accrued and signed consent, of which 174 provided useable PK data.
Twenty-nine pts �60 years old (median age 66.3) had a significantly higher
mean BuCL vs those � 60 years old (median age 49.8); BuCL 263 vs 186
mL/min, p�0.0002; BuCL/ABW 3.22 vs 2.34 mL/min/kg, p�0.0001;
BuCL/IBW 3.63 vs 2.91 mL/min/kg, p�0.0035; BuCL/CBW 3.50 vs 2.70
mL/min/kg, p�0.0005. Inter-patient variability in clearance (CV%) was up
to 47% in the elderly and up to 48% in young patients. Phenytoin use, a
potential confounder, did not affect BuCL, regardless of weight normalization
(p�0.74). Conclusions: Contrary to our hypothesis, BuCL is significantly
higher in pts �60 years old compared to younger patients and does
not explain the previously reported increase in Bu toxicity observed in the
elderly.
2535 Poster Discussion Session (Board #23), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus
epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced
or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Presenting Author: Min Zhu, Amgen Inc., Thousand Oaks, CA
Background: R is an investigational, fully human monoclonal antibody to
hepatocyte growth factor/scatter factor (HGF/SF), the only known MET
receptor ligand. In a double-blind, placebo-controlled, phase 2 trial of 121
pts with G/EGJ cancer, R (7.5 or 15 mg/kg) � ECX showed trends for
improved overall survival (OS) and progression-free survival (PFS) compared
to ECX alone (placebo, P). Methods: E-R analyses were performed
using pharmacokinetic (PK), biomarker, efficacy, and safety data. A
population PK model was used to evaluate covariate effects (eg, demographics,
ECX, and MET status) on R PK and predict individual R exposure
(trough steady-state Cmin [C]). The effect of C on OS/PFS was evaluated
with Kaplan-Meier estimates and Cox proportional hazards models. Covariate
effects for OS/PFS were evaluated with multivariate analysis. The
relationships between adverse events of interest (AEs), lab values, and C
were analyzed with descriptive statistics and linear regression models.
Results: R showed linear PKs that were unaffected by ECX or MET levels.
Pts who received R � ECX were divided into low C (C L ) and high C (CH )
groups by the median C (94 �g/mL). Median PFS was 4.2, 4.5, and 6.9
months in the P, CL , and CH groups; median OS was 8.9, 9.5, and 13.3
months. Improved OS/PFS in CH and improved PFS in CH and CL groups (vs
P) were seen after adjusting for baseline covariates. Pts with tumors that
expressed high MET levels (METHigh : � 50% cells positive) showed greater
improvement in OS in the CH vs CL group. No improvement in OS was seen
in METLow pts (CH and CL groups) compared to placebo (see Table). No
relationship was seen between R exposure and AEs or lab values.
Conclusions: Higher R exposure was associated with improved OS/PFS in
METHigh pts without increased toxicity, supporting further study of R � ECX
in G/EGJ cancer.
C group N
Median OS -
mo (80% CI)
Adjusted HR
(95% CI) p value
METHigh P 11 5.7 (4.5,10.4) - -
CL 14 9.3 (8.0, 11.1) 0.50 (0.18, 1.39) 0.183
CH 13 13.4 (13.3, NE) 0.12 (0.03, 0.45) 0.002
METLow P 17 NE (8.5, NE) - -
CL 15 8.6 (4.9, 9.9) 2.39 (0.90, 6.33) 0.081
CH 20 11.6 (7.8, 12.5) 1.52 (0.59, 3.95) 0.389
NE: Not estimable.
2534 Poster Discussion Session (Board #22), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
A first-in-human, phase I safety and pharmacokinetic study of genz-
644282, a non-camptothecin topoisomerase I inhibitor, in patients with
advanced solid tumors. Presenting Author: Hyo S. Han, H. Lee Moffitt
Cancer Center & Research Institute, Tampa, FL
Background: The approved topoisomerase I (TopI) inhibitors (irinotecan and
topotecan) are camptothecin derivatives. The lactone ring structure of
camptothecins negatively impacts their clinical potential.Genz-644282 is
a novel non-camptothecin that induces TopI-DNA cleavage complexes at
similar as well as unique genomic positions; that are more persistent. This
study was designed using a pharmacokinetic-pharmacodynamic (PK-PD)
model to predict the maximum tolerated dose (MTD). Methods: A PK-PD
relationship of Genz-644282 to inhibit tumor growth was derived (Simeoni,
Can Res 2004). Using an accelerated titration design, cohorts of 1, 3 or 6
patients received 3 weekly doses of Genz-644282 on a 28 day schedule
starting with 0.5 mg/m2 . After MTD on the 28 day schedule was exceeded,
21 day schedule was initiated. Results: 49 patients (N�44 data available:
26M :18F) were dosed. Tumor types were colorectal (15), breast (5), small
cell lung (SCLC 3), non-small cell lung (4), others (17). As predicted from
the PK-PD model 8 cohorts were evaluated on the 28 day schedule before
defining the MTD. The MTD was 8 mg/m2 and 9 mg/m2 for the 28 day and
21 day schedules, respectively. Dose limiting toxicities that determined the
MTD were: gr 4 thrombocytopenia (n�2); gr 2 thrombocytopenia (n�1)
and gr 4 neutropenia (n�1) both of which resulted in �72h delays in
initiating cycle 2. Treatment emergent adverse events (�10%) were
nausea (45%), fatigue (39%), anorexia (32%), anemia (27%), vomiting
(23%), thrombocytopenia (18%), diarrhea (16%), dehydration (16%),
hyperglycemia (16%), cough (16%), dyspnea (14%), depression (11%)
and hyponatremia (11%). Efficacy data suggest 2 responders with SCLC (1
minor response;1 complete response), and 2 patients (breast, gastric) with
stable disease (� 6 months). PK data show a Genz-644282 half-life of
approximately 50 h, a linear dose-exposure relationship, and no accumulation
in between doses. Conclusions: Genz-644282 is a non-camptothecin
TopI inhibitor in phase I development with ongoing expansion phase. The
emerging pk, efficacy and safety data are suggestive of a distinct clinical
profile of Genz-644282 from the camptothecins.
2536 Poster Discussion Session (Board #24), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Pharmacological interactions of TKIs with the P-gp drug transport protein.
Presenting Author: Sandra Roche, NICB, Dublin City University, Dublin,
Ireland
Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug
transport proteins. P-gp is a transporter with two important roles in cancer
drug therapy. If overexpressed in tumour cells it can cause drug resistance.
However, P-gp, expressed in tissues as part of normal drug clearance
mechanisms, is also involved in termination of drug action. Hence,
TKI-mediated interactions with P-gp have significant therapeutic consequences.
Methods: P-gp over-expressing cancer cell lines were used to
determine the inhibitor or substrate status of tyrosine kinase inhibitors
(erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib).
Cell proliferation assays in combination with a potent P-gp inhibitor, or
P-gp substrate were also employed. Findings were augmented using
LC-MS-based quantitation of cellular levels of target drugs. Results: We
summarise our findings of four distinct interactions with P-gp among
various TKIs. Some agents have little interaction at conventional doses;
others can act as P-gp inhibitors without being substrates; substrates
without being inhibitors or substrates which also prevent the actions of the
transporter.Eachof the investigated TKIs has a distinct relationship with
P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is
a substrate but not an inhibitor, while pazopanib has little interaction with
P-gp. Other agents also have an effect on or are affected by P-gp to varying
amounts with some of these interactions likely to be suprapharmacological.
Conclusions: P-gp protein has important roles both in resistance and drug
toxicology, hence, a clear understanding of the interaction of emerging
drugs with this transporter is vital. Agents which are inhibitors of P-gp may
have applications in drug resistance circumvention but may also greatly
exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics;
conversely the activity of P-gp substrate TKIs may be reduced by
tumour overexpression of the transporter. Hence in vitro screening of
TKI-transporter interactions may identify putative TKI resistance mechanisms,
help guide the development of combination schedule trials and/or
reducing unwanted treatment side effects.
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