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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2537^ Poster Discussion Session (Board #25), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Pharmacogenetic study in metastatic colorectal cancer (CRC) patients
receiving third-line panitumumab-irinotecan: A GERCOR ancillary study.
Presenting Author: Marie-Christine Etienne-Grimaldi, Centre Antoine-
Lacassagne, Nice, France
Background: Test the predictive value of gene polymorphisms potentially
linked to panitumumab and irinotecan pharmacodynamics. Methods: 45
patients with metastatic CRC refractory to standard therapy were enrolled
in this ancillary pharmacogenetic study as part of a phase II trial that
included 63 patients. Inclusion required wild-type KRAS tumor status
(codons 12-13, analyses performed in each center). After inclusion, central
KRAS re-assessment was performed (codons 12-13-59-61) and 9 patients
over 45 were found to carry a KRAS mutation. Patients received panitumumab
(6 mg/kg, day 1) associated with irinotecan (180 mg/m2 , day 1),
Q2W until disease progression or unacceptable toxicity. Analyzed polymorphisms
on blood DNA were : EGFR (CA repeats in intron 1, -216G�T,
-191C�A), EGF (61A�G), CCND1 (870A�G), UGT1A1 (*28). Results:
Cutaneous toxicity imputable to panitumumab i.e. folliculitis and paronychia
was not linked to EGFR, EGF or CCND1 polymorphisms. Diarrhea
(12 grade 1, 13 grade 2, 8 grade 3) was linked to CCND1 polymorphism:
22% grade 2-3 in AA patients vs 63% in AG�GG patients (p � 0.007). As
expected, neutropenia (6 grade 1, 4 grade 2, 5 grade 3) was more frequent
in patients bearing the *28 allele of UGT1A1 gene (33% grade 2-3 vs 5%
in *1/*1, p � 0.020). In these 45 patients, response rate, progression-free
survival and overall survival (OS) were only significantly related to reassessed
KRAS status. Of note, a tendency for a longer OS was observed in
patients bearing the *28 allele of UGT1A1 gene (p � 0.091, analysis
adjusted for KRAS). Interestingly, the frequency of KRAS mutation was
higher in patients with long CA repeats in EGFR gene intron 1: 54.5% i.e. 6
mutated patients among the 11 patients with both alleles �17 vs 10.5%
i.e. 2 mutated patients among the 19 patients with intermediary alleles vs.
6.7% i.e. 1 mutated patient among the 15 patients with both alleles �17
(p � 0.004). Conclusions: Present data indicate that A870 allele of CCND1
gene (40% AA patients) may protect from diarrhea induced by panitumumab-irinotecan.
Also, these results report an original relationship
between EGFR polymorphism in intron 1 and KRAS mutation status that
merits further confirmation.
2539 General Poster Session (Board #1B), Mon, 8:00 AM-12:00 PM
Phase Ib study of plitidepsin (APL) with gemcitabine (GEM) in refractory
solid tumors and lymphoma patients. Presenting Author: Mark N. Stein,
Cancer Institute of New Jersey, New Brunswick, NJ
Background: Combination chemotherapy (CT) regimens may improve the
outcome of patients with advanced metastatic disease. APL (a marinederived
cyclodepsipeptide) is a cytotoxic agent that induces apoptosis by
JNK-pathway activation and increased oxidative stress; it has also shown
anti-angiogenic properties in vitro. GEM has a different mechanism of
action and toxicity profile from APL, making this combination appropriate
for clinical testing. Moreover, APL has been shown pre-clinically to
potentiate the anti-tumor effect of GEM. Methods: Patients with ECOG-PS
� 1 received escalating doses of APL/GEM (1.8/750, 1.8/1000, 2.4/1000
and 3.0/1000 mg/m2 ) on days 1, 8 and 15 every four weeks. The primary
objective was to determine of the maximum tolerated dose (MTD) and the
recommended dose (RD) for APL/GEM. Secondary objectives included
characterization of safety profile, pharmacokinetics (PK) and anti-tumor
activity of APL/GEM. Results: 34 patients were included and 33 treated (23
solid tumors and 11 lymphomas) with a median age of 59 years (r: 28–86),
median prior CT lines 3 (r:1-7) and a median of 2 cycles (r:1-12). Relative
dose intensity was 66.7% (r: 37.7-85.7%) and 80.9% (r: 56.1-100.6%)
for APL and GEM, respectively. The MTD was 3.0/1000 mg/m2 ,as2/6
patients experienced dose limiting toxicities (DLTs) [grade (G) 4 thrombocytopenia
and 2 missed doses due to G2 ALT/AST]. The RD was 2.4/1000
mg/m2 , with no patients experiencing DLTs. Adverse events (AEs) were
mainly G 1-2 anemia, thrombocytopenia and ALT/AST increase. Six
patients with solid tumors had stable disease (SD) � 3 months, one patient
with NK T-cell lymphoma had a complete response, a patient with Hodgkin
disease (HD) had a partial response and three other patients with HD had
SD � 3 months with tumor decrease at the RD. No relevant drug-drug
interaction was observed for the dose levels tested. Conclusions: APL/GEM
at the RD can be safely combined. Objective responses were observed in
patients with HD and NK T-Cell lymphoma. Further studies of this
combination in lymphoma are warranted.
151s
2538 General Poster Session (Board #1A), Mon, 8:00 AM-12:00 PM
A mismatch between methods and objectives in phase I drug development:
Statistical limitations and personalized medicine—A California Cancer
Consortium (CCC) study. Presenting Author: Paul Henry Frankel, City of
Hope, Duarte, CA
Background: Patient variation in drug response and toxicity impacts all
phases of drug development. While detailed sample-size calculations and
analysis based on statistical methodology are critical for addressing
variation in late stage trials, phase I studies pose unique and largely
unsolved challenges related to variability. Changes in patient selection
during the study, small sample-sizes and large patient variation in toxicity
are exactly the kind of problems that statistical methods cannot address in
small, isolated phase I studies, regardless of apparent mathematical rigor.
We have documented these problems via a physician survey. Methods: A
10-question anonymous survey was sent to 670 oncologists at National
Comprehensive Cancer Network (NCCN) and CCC institutions via an online
survey. 19 % (126/670) of the oncologists polled responded. 78/126
(62%) specialized in Medical Oncology. The number of years in practice
varied from 2-45 yrs with a median of 17 yrs. Results: a) 66% of all
respondents stated that non-DLT toxicities on one dose level would impact
their patient selection on the following dose level, conflicting with the
assumption of random patient selection implicit in simulations used in
evaluating statistical designs. b) Only 13% stated a desire to target a
non-heme toxicity as high as 20% grade 3, while 87% desired a 10% or
less grade 3 rate; c) More than half the respondents would prefer not to
escalate if 3/3 patients experienced grade 2 LFTs; d) 82% of the
respondents thought the appropriate target toxicity differed for patients
depending on their potential for becoming a surgical candidate, furthering
the need for personalized dosing. Conclusions: Statistical methods in phase
I trials are unable to address many of the salient features of phase I study
conduct and investigator goals. We will present several approaches we have
initiated to address these limitations, and present future plans to help
produce a more reliable estimate of a recommended dose. Supported in
part by NCI grants U01CA062505, N01-CM-62209, and NCCN data
collection assistance.
2540 General Poster Session (Board #1C), Mon, 8:00 AM-12:00 PM
Prediction of early death among patients (pts) enrolled in phase I trials:
Development and validation of a new model based on platelet count and
albumin level. Presenting Author: Anne Ploquin, Centre Oscar Lambret,
Lille, France
Background: Selecting pts with “sufficient life expectancy” for phase I
oncology trials remains challenging. The Royal Marsden Model (RMM;
Arkenau, JCO 2009) identified high-risk pts as those with �2 of: albumin
(ALB) �35g/l; LDH �ULN; more than 2 metastatic sites. The RMM was
assessed in 1845 pts treated in phase I trials by members of the European
New Drug Development Network (ENDDN). The present study aimed to
develop an alternative prognostic model using a different methodology and
to compare its performance with the RMM. Methods: The primary endpoint
was 90-day mortality rate (90-DMR). The new model was developed from
the ENDDN database using CHAID, an exploratory non-parametric data
analysis method evaluating the relationship between a dependent variable
(90-DMR) and possible predictive variables through a decision-tree analysis.
The ROC characteristics and calibration of both methods were then
validated in the independent EORTC Database (n�341 pts). Results: The
CHAID method identified low and high-risk groups with 90-DMR of 9.5% vs
37.5%. High-risk pts had ALB�33g/L or ALB�33g/L but platelet count
�400.000/mm3 . Applying both models to the validation dataset; the rates
of correctly-classified pts were 0.86 [CI-95% 0.82-0.90] vs. 0.67 [CI-95%
0.60-0.74], with the CHAID model and RMM respectively. The CHAID
model had higher specificity (0.90 vs. 0.65), but lower sensitivity (0.36 vs.
0.93) than the RMM. Discriminative slopes were similar for the CHAID
model and RMM (19.4% and 19.3%, respectively). The negative predictive
value (NPV; correct identification of pts surviving 90 days) was similar for
the CHAID model and RMM (0.94 [0.91-0.97] and 0.99 [0.94-1.00]
respectively). Calibration, assessed by the Brier score, was slightly better
with the CHAID model (0.001 and 0.098, respectively). Conclusions: In
selecting pts for phase I trials arguably an important criterion is NPV; the
CHAID model and RMM provided a similar high level of NPV but the CHAID
model gave a better rate of correctly-classified patients. Both models
improved the screening process and reduce the attrition rate in phase I
trials.
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