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

168s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2605 General Poster Session (Board #9F), Mon, 8:00 AM-12:00 PM
Vectorized gene therapy of liver tumors: Safety and proof of concept of
TG4023 (MVA-FCU1)/5-FC combination. Presenting Author: Faress Husseini,
Hôpitaux Civils de Colmar, Colmar, France
Background: TG4023 is a non-integrative and non-propagative Modified
Vaccinia virus Ankara (MVA) expressing a chimeric yeast transgene (FCU1)
coding for cytosine deaminase and uracil phosphoribosyl transferase that
transform the pro-drug 5-flucytosine (5-FC) respectively into 5-FU and
5-FUMP in infected cells; these derivatives then diffuse and kill additional
tumor cells (bystander effect). Methods: This phase I study determined
safety and Maximal Tolerated Dose (MTD) of a single intra-tumor injection
of TG4023 combined with a 2-week dosing period of 5-FC 200 mg/kg/day.
Plasma and tumor 5-FC (PK) and 5-FU (PD) concentrations were measured.
Other assessments were tumor response, changes in tumor markers
and immune response. Patient requirements were � 1 injectable primary or
metastatic unresectable liver tumor of 2-5 cm, no treatment option left,
ECOG PS � 2. Consenting patients were allocated to cohorts according to a
3�3 dose-escalating design driven by Dose-Limiting Toxicities (DLTs) and
Data Safety Monitoring Board recommendations. Results: Among 16
enrolled patients (13 colorectal, 1 pancreatic and 1 liver cancers, 1 cancer
of unknown primary) 6 were injected in one tumor with 107 plaque forming
units (pfu) TG4023, 3 with 108 pfu and 7 with 4.108 pfu, using a multiport
needle and ultrasound imaging guidance. 5-FC was given IV the first days
then orally. One DLT (grade 3 transient increase in AST/ALT) was recorded
at 4.108 pfu; other severe adverse events, diarrhea, hypertension, alkaline
phosphatase increase were related to 5-FC; most frequent AEs were
transient fever, asthenia, site injection pain, nausea/vomiting. 5-FU concentrations
in tumor biopsies at Day 8 were 56�30 ng/g and 1.9� 2.6 ng/mL
in plasma. 11/16 injected, 12/23 non-injected target tumors were stable
and 10/16 patients progressed at week 6. One patient had a 3-fold
decrease in CEA and CA 19.9. Conclusions: This study showed that
vectorized gene therapy of liver tumors with TG4023/5-FC combination is
feasible and safe, as supported by a high therapeutic index; MTD for
TG4023 was 4.108 pfu for one injected tumor. A proof of concept of the in
vivo conversion of the pro-drug 5-FC into 5-FU was obtained.
2607 General Poster Session (Board #9H), Mon, 8:00 AM-12:00 PM
Impact of body surface area on efficacy of gefitinib in patients with
non-small cell lung cancer harboring activating epidermal growth factor
receptor mutation. Presenting Author: Eiki Ichihara, Department of Respiratory
Medicine, Okayama University Hospital, Okayama, Japan
Background: Gefitinib is an essential drug for the treatment of non-small
cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)
mutation. Its approved dosage is fixed at 250 mg/body/day without any
adjustment by physical size. On the other hand, most cytotoxic agents are
administered with body surface area (BSA) based dose-adjustment to
reduce the pharmacokinetic inter-patient variability. However, the impact
of BSA on efficacy of gefitinib has not been fully evaluated. We here tried to
clarify this issue using our retrospective cohort. Methods: We reviewed the
medical records of consecutive advanced NSCLC patients harboring EGFR
mutation who underwent gefitinib monotherapy at Okayama University
Hospital from October 2002, when gefitinib was approved in Japan, to
October 2011. Results: A total of 101 patients with EGFR-mutant tumors
who received gefitinib (250 mg/body/day) were included in this study. The
median progression free survival (PFS) of patients with high BSA (�1.5 m2 :
the median value in this cohort) was significantly worse than that of
patients with low BSA (�1.5 m2 ) (10.4 vs. 18.0 months, p � 0.019
log-rank test). The multivariate analysis also showed a significant impact of
BSA on PFS; (hazard ratio of 2.34 with 95% confidence interval of 1.78 -
2.89, p � 0.002). By contrast, such significant association between BSA
and PFS was not observed in cytotoxic chemotherapy (5.4 months vs. 3.7
months, p � 0.49, log lank test). Conclusions: BSA affected PFS in the
gefitinib monotherapy, potentially suggesting the need for appraisal of
BSA-based dose adjustment even in this molecular-target therapy.
2606 General Poster Session (Board #9G), Mon, 8:00 AM-12:00 PM
The role of phase I clinical trials in advanced malignant melanoma:
Retrospective analysis of CTEP-sponsored trials 1995-2011. Presenting
Author: Jason John Luke, Dana-Farber Cancer Institute, Boston, MA
Background: Standard chemotherapy for melanoma is DTIC (RR ~10%).
Many physicians do not refer to phase I due to perceived limited clinical
benefit (CB�CR�PR�SD) and increased toxicity. To understand the
actual experience of melanoma patients (pts) in phase I trials, we analyzed
the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-
2011) and compared them to DTIC. Methods: We queried the CTMS of
CTEP for phase I trials in which advanced melanoma pts were treated.
Trials were separated into targeted (T), chemo (C) and immunotherapy (I).
Pt characteristics, response and toxicity data were collected. Chemotherapy
included chemo with targeted or immunotherapy. Toxicity was drug
related if attributed possibly, probably or definitely to drug. Fisher’s Exact
Test (2-sided p) was used to compare groups. DTIC data was pooled from 6
modern phase III clinical trials (1999-2011). Results: 937 pts (M595:
F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics
included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2
(majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and
toxicity data are shown in the Table. Targeted therapy was associated with
lower RR (p�.01), immuno with lower CB rate (p�.001) and chemo with
higher incidence of G4 toxicity (p�.001) relative to the other groups.
Comparing phase 1 to DTIC, RR and CB were not clinically different (phase
I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was
significantly higher (54% vs. 28%) in phase I (p�.0001). Conclusions:
Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had
similar therapeutic benefit but more toxicity compared to DTIC naïve pts in
modern clinical trials.
All (937) Targeted (182) Chemo (186) Immuno (569)
Response Total % 95% CI Total % 95% CI Total % 95% CI Total % 95% CI
CR � PR 59 6.3 4.8-8.1 4 2.2 0.6-5.5 14 7.5 4.2-12.3 41 7.2 5.2-9.7
SD 192 20.5 59 32.4 53 28.5 80 14.0
CB 251 26.8 24.0-29.8 63 34.6 27.7-42.0 67 36.0 29.1-43.4 121 21.2 18.0-24.9
Not evaluated 61 6.5 15 8.2 16 8.6 30 5.3
PD
Toxicity
625 66.7 104 57.1 103 55.4 418 73.3
G3 G4 G3 G4 G3 G4 G3 G4
% 42.2 12.1 42.3 9.3 46.2 23.7 40.8 9.1
95% CI 39.0-45.4 10.0-14.3 35.0-49.8 5.5-14.5 38.9-53.7 17.8-30.4 36.7-44.9 6.9-11.8
2608 General Poster Session (Board #10A), Mon, 8:00 AM-12:00 PM
Multivariate screening of prognostic factors to identify a novel, simple, and
objective marker to optimize patient selection and predict survival benefit
in early-phase trials. Presenting Author: Chara Stavraka, Imperial College
London, London, United Kingdom
Background: Several prognostic indices have been devised to optimize
patient selection for phase I trials. However, there is no consensus as to the
optimal score and none qualifies as a marker of response. We developed a
simple score through a multivariate screening of individual variables and
compared its performance with existing prognostic scores including the
Royal Marsden, Nijmegen and Prince Margaret Hospital scores. Methods:
We retrospectively analyzed characteristics and outcomes of 120 referrals
to our phase I center (2007 - 2011). Independent predictors for overall
survival (OS) were identified from univariate (Kaplan Meier) and multivariate
(Cox regression) analyses and used to create the Hammersmith Hospital
score (HS). This was compared with the other indices for predicting
progression free survival (PFS), OS and 90 day mortality (90 DM).
Multivariate logistic regression and ROC curves were used to estimate 90
DM and c-index was used to estimate the prognostic ability of the different
indices. Changes in HS following treatment (�HS) were calculated at 6
weeks RECIST in a subset of patients receiving targeted therapies (n� 50).
Results: Median age was 62 years (range: 28 – 80); median OS 4.3 months
(range: 0.2 – 39); 34% male; 25% PS�1. Multivariate screening identified
albumin �35 g/L, lactate dehydrogenase (LDH) �450 U/L and sodium
�135mmol/L as the strongest independent predictors of OS (p�0.05).
These were entered into a 3-point score (HS) that classifies patients as
being at high risk (score 2-3) vs. low risk (score 0-1) of worse OS (HR� 5.8,
p�0.001), PFS (HR� 2.7, p� 0.04) and 90 DM (OR� 5.9, p� 0.001). All
scores predicted for OS on univariate analysis (p�0.05). On multivariate
analysis HS performed best to predict OS (HR� 3.9, p�0.001 C-index
score� 0.71), PFS (HR� 2.6 p� 0.04) and 90 DM with area under the
ROC curve 0.71. �HS independently predicted for OS (p�0.001), with
worsening of the score reflecting poorer OS. Prospective validation is
ongoing. Conclusions: HS is a simple score that outperforms other prognostic
indices. This can be used to select individuals for future studies as well
as an additional marker of response.
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