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

3064 General Poster Session (Board #15F), Mon, 8:00 AM-12:00 PM
Microarray genomic expression (MAGE)-based therapy for heavily pretreated
patients with metastatic solid tumors. Presenting Author: Joseba
Rebollo, Plataforma de Oncología, USP-Hospital San Jaime, Torrevieja,
Spain
Background: Oligonucleotide-MAGE assay to identify tumor targets and
potential active drugs based on molecular profiling in chemotherapy
resistant/refractory (R/R) patients with metastatic solid tumors. A potential
clinical benefit has been observed by Von Hoff et al (JCO 2010;20:4877-
83). Methods: Patients (pts) with R/R metastatic solid tumors were
included in the study. Pathology confirmed fresh-frozen biopsies were
obtained and molecular profiling oligonucleotide-MAGE (Agilent Whole
Human Genome 4x44K) results, confirmed whenever possible by IHC, were
used to identify potential therapy targets. Results were discussed and
offered to pts and the response evaluated using RECIST criteria. OS and
PFS were measured from the beginning of therapy. All pts signed informed
consent. Results: From August 2010 we performed 70 procedures in 69
pts. No complications derived from the biopsy were observed. Thirty pts did
not follow therapeutic recommendations and 9 pts are too early to evaluate.
Thirty procedures from 29 pts are clinically evaluable. Ten pts were male
and 19 female, with a median (M) age of 57 years (range 41-70). Seven pts
had breast cancer, 5 NSCLC, 5 pancreas, 4 CRC, 2 ovary and one each of
gastric, parotid gland, biliary tree, head and neck, esophagus and gallbladder
cancers, respectively. The M previous treatments were 3 (range 1 to
�6). Oligonucleotide-MAGE assay confirmed resistance in 82% of drugs
previously used. AMof3conventional (range 0-5) and 2 experimental
(range 0-4) potentially active drugs were identified. Partial response was
observed in 7 (26.9%), stable disease �2 months in 12 (46.1%) and
progression in 7 (26.9%) pts. Four pts were not evaluable. MPFS was 4
months (95%CI: 1.815-6.185), MOS was 6 months (95%CI: 3.4-8.6) and
1-year projected OS was 21%. Conclusions: We confirmed that it is possible
to identify new potentially active drugs in heavily pretreated solid tumor pts
with oligonucleotide-MAGE assay. Therapy based on these drugs showed to
be active in one fourth of treated pts. These assays might be also integrated
in early tumor stages to aid in the selection of chemotherapy drugs, and for
this reason deserve further studies. Updated results will be presented.
3066 General Poster Session (Board #15H), Mon, 8:00 AM-12:00 PM
Feasibility to obtain a chemogram in circulating tumorigenic cells to guide
further treatments in refractory solid tumors. Presenting Author: Antonio
Cubillo, START-Madrid, Centro Integral Oncológico Clara Campal, Madrid,
Spain
Background: Circulating tumorigenic cells (CTCs) may be responsible for
tumor progression, represent a new source of information of tumor biology,
avoiding unnecessary biopsies. Gene-expression analysis (GEA) of CTCs
could guide anti-cancer therapies in patients with refractory solid tumors.
Methods: Pts �18y ECOG PS 0-2 with advanced refractory solid tumors
were recruited. Twelve ml blood samples were collected from each pt and
processed for isolation of CTCs using a novel cell adhesion assay (Vita-Cap,
Vitatex Inc., Stony Brook, NY) following the manufacturer protocol. Total
RNA was extracted with RNeasy Mini Kit (Qiagen Inc.) and GEA was
performed with Affymetrix GeneChip Human Genome U133 Plus 2.0 array.
The CEL file obtained for each pt sample was used in a gene-set expression
analysis (GSEA) to determine the enrichment profile of the pt sample to a
pre-determined set of 12 PGx-modeled drugs created from the GI50 data of
the NCI-60 cell lines. The drug with the highest Normalized Enrichment
Score (NES) obtained from the GSEA was selected as the most sensitive.
The NES for each drug was standardized and rank-ordered according to
Sensitive/Intermediate/Resistant categories to generate a nominal chemosensitivity
profile for the pt. This generates a comprehensible report called
chemogram (ChG). We assessed preliminary efficacy in pts treated based
on ChG. Results: ChG was obtained in 74/75 pts (57% male/43% female,
median age 57y [20-81]) Tumor’s type was GI 67% (CRC n�18;
pancreatic n�18; gastric n�6; cholangiocarcinoma n�7), NSCLC 14%,
breast 8%, sarcoma 8%, others 3%. Median of 2 previous lines of therapy
[range 1-12]. ECOG PS was 1 in 56%. Average RNA/pt 2.4 ng/�l (95% CI
1.5-3.4) Median time to obtain the report from blood extraction was 4 wks
[range 2-7] Pts treated after the ChG were 37 (49%), of them 25 (69%)
based on ChG recommended drug. In patients treated with ChG sensitive
drugs, PFSratio � 1.3 (PFS on therapy after ChG/PFS on prior therapy) was
24%, and 3 partial responses (12%) were observed. Conclusions: It is
feasible to generate a sensitivity drug profiling on CTCs which shows
preliminary activity and merits further studies.
Developmental Therapeutics—Experimental Therapeutics
189s
3065 General Poster Session (Board #15G), Mon, 8:00 AM-12:00 PM
High concordance for MammaPrint 70 genes by RNA next generation
sequencing. Presenting Author: Lorenza Mittempergher, Netherlands Cancer
Institute (NKI-AVL), Amsterdam, Netherlands
Background: The development of new biomarkers often requires fresh
frozen (FF) samples. Recently we showed that microarray gene expression
data generated from FFPE material are comparable to data extracted from
the FF counterpart, including known signatures such as the 70-gene
prognosis signature (Mittempergher L et al., 2011). As described by Luo et
al (2010) RNA profiling using next generation sequencing (RNA-Seq) is
now applicable to archival FFPE specimens. Methods: Technical performance
and the comparison between the RNA-Seq 70-gene read-out and
the MammaPrint test (Glas et al., 2006) is evaluated in a series of 15
patients (11/15 with matched FFPE/FF material). RNA-Seq was carried out
using minor adjustments of the Illumina TruSeq RNA preparation method.
RNA sequencing libraries were prepared starting from 100ng of total RNA.
Next, the DSN (Duplex-Specific Nuclease) normalization process was used
to remove ribosomal RNA and other abundant transcripts (Luo et al, 2010).
The libraries were paired-end sequenced on the Illumina HiSeq 2000
instrument with multiplexing of 4 libraries per lane. The resulting sequences
were mapped to the human reference genome (build 37) using
TopHat 1.3.1(Trapnell et al., 2009). The HTSeq-count tool was used to
generate the total number of uniquely mapped reads for each gene. Results:
Between 14% and 45% of the total number of reads were assigned to
protein-coding genes. The minimum coverage per 1000bp of CDS was 38
reads. The 70 MammaPrint genes were successfully mapped to the
RNA-Seq transcripts. We calculated the Pearson correlation coefficient
between the centroids of the original good prognosis template (van’t Veer et
al., 2002) and the 70-gene read count determined by RNA-Seq of each
sample. Predictions based on the 70-gene RNA-Seq data showed a high
agreement with the actual MammaPrint test predictions (�90%), irrespective
of whether the RNA-seq was performed on FF or FFPE tissue.
Conclusions: New generation RNA-sequencing is a feasible technology to
assess diagnostic signatures.
3067 General Poster Session (Board #16A), Mon, 8:00 AM-12:00 PM
ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results
from a first-in-human phase I study. Presenting Author: Carla D. Kurkjian,
University of Oklahoma Health Sciences Center, Oklahoma City, OK
Background: ME-143, a second generation isoflavone-derived compound,
specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting
in prompt apoptosis via pleotrophic caspase activation. A first generation
compound, phenoxodiol (PXD), showed promising phase II activity
with cisplatin in ovarian cancer. ME-143 is broadly active against human
cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than
PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/
kg) showed no STD level. The only significant findings were dose dependent
hypospermia and testicular atrophy in rats. We report clinical and PK
results from the first-in-human phase I study. Methods: A 3�3 dose
escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg
IV over 30 minutes weekly times 3, followed by a 1 week break, and then
continuous weekly dosing in patients with advanced solid tumors. Dense
PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240,
300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first
treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each
of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62).
Five patients have discontinued protocol therapy, all due to PD. No DLT’s
have been observed. Related AE’s include grade 1: myalgia (1), anorexia
(1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2:
fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table
below. Conclusions: ME-143 appears to be well tolerated when administered
IV. Preliminary PK data suggest that drug levels achieve target
concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/
mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts,
including the final pharmacokinetic analysis and planned phase II dose,
will be presented.
Day 1 Day 15
Dose
2.5mg/kg 5.0mg/kg 2.5mg/kg 5.0mg/kg
Cmax (mg/mL)
T1/2 (hr)
AUC0-t (mg*hr/mL)
CL (L/hr)
2.18
4.12
2.93
69.73
8.65
6.95
9.92
37.30
3.55
4.36
3.53
56.18
5.31
5.55
7.29
41.52
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