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

188s Developmental Therapeutics—Experimental Therapeutics
3060 General Poster Session (Board #15B), Mon, 8:00 AM-12:00 PM
A phase I study of EP-100, a luteinizing hormone releasing hormone
(LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with
advanced refractory LHRH- receptor (R)-expressing tumors. Presenting
Author: Ramesh K. Ramanathan, Virginia G. Piper Cancer Center at
Scottsdale Healthcare/TGen, Scottsdale, AZ
Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated
to an 18 aa cytolytic peptide. Selective targeting in LHRH-R
expressing cells occurs via direct binding to the extracellular membrane
receptor followed by disruption of the membrane by the cytolytic peptide
portion. A first in human, phase I study was performed. Methods: Eligible
pts had adequate organ function and LHRH-R tumor expression, as
determined by IHC. EP-100 was given IV (30-60 min) weekly x3for
cohorts 1- 6 (n�20 at 0.6 - 5.2 mg/m2 ) and then twice weekly x3for
cohorts 7- 11 (n�18 at 7.8 - 40 mg/m2 ) with a week break. The
pharmacokinetic profile of EP-100 and antibody production against EP-
100 was determined by a validated HPLC/MS and ELISA respectively.
Potential activity of EP-100 on the pituitary gonadotropes was determined
by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue
obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37
were enrolled (female 76%) and treated. The LHRH-R expression rate in
breast was 81% (N�21) and in ovarian cancer 56% (n�18). Most pts had
breast (n� 16, 42%) ovary (n�7,18%), colon (n�4, 11%) or uterine
(n�3, 8%) cancer. Pts were treated in a 3 � 3 standard dose escalation
scheme. Doses were escalated 100% in the absence of a grade 2 drug
related toxicity. MTD was not reached at the highest dose level of 40
mg/m2 . Only one DLT occurred, a grade 2 increase in ALT/AST. The only
other drug-related toxicity was a self limited infusion-related skin reaction
(grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean
half life ranged from 7.1 � 3.8 min to 15.9 � 3.6 min. Best response was
stable disease for �12 weeks in 5 pts. In 3 pts rapid, sustained decreases
in LH/FSH levels were noted. Antibody production against EP-100 was
absent in all pts. Conclusions: The study has completed accrual, the phase
II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well
tolerated and not antigenic/immunogenic. Preclinical studies indicated
synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus
paclitaxel in ovarian cancer is planned.
3062 General Poster Session (Board #15D), Mon, 8:00 AM-12:00 PM
Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer
patients responding to therapy. Presenting Author: Maria Alsina, Molecular
Therapeutics Research Unit, Vall d’Hebron University Hospital, Barcelona,
Spain
Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised
of lipid nanoparticle-formulated small interfering RNAs targeting
vascular endothelial growth factor (VEGF)-A and kinesin spindle protein
(KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks
was well-tolerated and showed evidence of anti-VEGF pharmacology and
antitumor activity. Methods: Patients treated on the phase I trial with stable
disease (SD) or better after 4 months (8 doses) were eligible to continue on
an extension study until disease progression. Main objectives included
continued evaluation of safety/tolerability and assessment of disease
response. Results: Seven of 37 patients (18.9%) evaluable for response
went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of
5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had
progressed after one or more prior therapies. Tumor types included head
and neck squamous cell carcinoma, angiosarcoma, endometrial cancer,
renal cell carcinoma (RCC, N�2), and pancreatic neuroendocrine tumor
(PNET, N�2). At the time of enrollment, 6 had SD and one (endometrial
cancer with multiple liver metastases) had an unconfirmed partial response
(PR). The average length of time on treatment (including phase I and
extension studies) was 9.5 months (range 5-19). As of January 2012, 3
patients remain on study, including the endometrial cancer patient with an
ongoing PR who has had �80% tumor regression after 19 months of
treatment at 0.7 mg/kg and two patients with RCC and PNET with
continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other
patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and
5.5 months, respectively, for adverse events that included fatigue or
elevated alkaline phosphatase. A decrease in spleen volume, likely an
on-target effect and not associated with any adverse events, occurred to a
greater degree on the extension study than on the phase I trial and was most
pronounced in patients receiving � 12 doses. Conclusions: ALN-VSP02 has
preliminary activity against endometrial cancer, RCC and PNET and a
favorable safety profile that permits chronic dosing. Phase II trials are
warranted in these and other VEGF-overexpressing tumors.
3061 General Poster Session (Board #15C), Mon, 8:00 AM-12:00 PM
Improved sorafenib activity on hepatocellular carcinoma in Notch3 silenced
in vivo and in vitro models. Presenting Author: Michele Baglioni,
Department of Clinical Medicine, University of Bologna, and Center for
Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, Bologna,
Italy
Background: Sorafenib is the only approved drug for the treatment of the
advanced stage of HCC. Although its efficacy has been proven with
randomized clinical trials, the clinical benefit seen in overall survival for
advanced HCC patients treated with sorafenib could be improved. New
molecules or combination of novel targeted agents to improve sorafenib
efficacy for advanced stage HCC patients are needed. Notch genes are a
family of receptors involved in many cell fate regulations, their expression
has been found altered in many tumors, including HCC. The aim of this
study was to study the combination of sorafenib and Notch3 signaling
inhibition to improve sorafenib’s therapeutic effect. Methods: HepG2 and
Huh7 cellular models were used for Notch3 stable silencing by retroviral
introduction of specific interfering RNAs Xenograft models in both Notch3
stable shRNA cell lines have been developed using NOD/SCID mice.
Animals bearing tumors were treated with 60 mg/kg of sorafenib for 21
consecutive days. Notch3, p21 and pGSK3�Ser9 protein expression were
also analyzed in 20 human HCCs. Results: Notch3 silencing (shN3) in
HuH7 and HepG2 cell lines treated with sorafenib showed an increase in
cell death (3.8 to 5 fold increase) when shN3 cell lines were compared with
their relative controls (GL2). A difference in tumor growth was observed
between GL2 negative control vs shN3 xenografts in both HepG2 and Huh7
after 21 days of sorafenib treatment. Two tailed student’s t test (shN3 vs
GL2) P�0,04 and P�0,01 for Huh7 and HepG2 respectively. Molecular
investigations have shown the involvement of p21 and GSK3� in the
enhanced response to sorafenib in Notch 3 silenced models. A significant
inverse correlation between Notch3 and pGSK3�Ser9 proteins accumulation
(Spearman �� -0.666) (p � 0.01) and a direct correlation between
Notch3 and p21 proteins expression (Spearman �� 0.681) (p � 0.01) was
found in HCC samples obtained from patients. Conclusion: Our preclincal
findings outline the effect of combined Notch3 inhibition and sorafenib.
The molecular mechanisms responsible for sorafenib induced cell death
associated with Notch3 silencing relays on inhibition of p21/CDKN1A and
GSK3�Ser9 . This study is supported by a grant from Bayer Healthcare, Italy.
3063 General Poster Session (Board #15E), Mon, 8:00 AM-12:00 PM
Evaluation of toxicities of target therapy phase I and II trials on glioblastoma
multiforme patients treated by curative radiotherapy: A metaanalysis.
Presenting Author: Marcos Antonio Santos, Institut Gustave
Roussy, Villejuif, France
Background: An important limitation of the combination of target therapies
(TT) to radiation (RT) is its potentially high level of toxicity. The objective of
this study was to describe and quantify the drug related acute adverse
events presented by patients taking part in phase I and/or phase II trials on
TT combined to curative RT for the treatment of glioblastoma multiforme
(GBM). Methods: A meta-analysis of summary data including all phase I, I/II
and II trials published between 2000 and 2011 on newly diagnosed GBM
patients treated by TT with RT was performed. Pooled incidence rates (IR)
of all and specific toxicities were estimated using a generalized linear
mixed model with fixed and random study effects. The pooled median of
progression-free (PFS) and overall survivals (OS) were also considered.
These results were compared to those obtained by patients receiving
standard treatment (ST). Results: Twenty-one trials (8 phases I, 3 phases
I/II and 10 phases II), testing 9 different drugs, have been selected,
including 915 patients. The median follow-up varied from 1.4 to 34.0
months. The estimated pooled IR of all toxicities was 68.6 [53.5-88.0] per
1000 person-months of follow-up, compared to 20.7 [17.6-24.1] on ST
(p�0.001). The pooled IRs of thrombocytopenia, neutropenia or leucopenia,
fatigue, gastrointestinal events and treatment-related deaths are 11.2
[7.5-16.9], 9.0 [6.1-13.4], 6.4 [4.1-10.0], 5.5 [2.9-10.2] and 3.2
[1.6-6.4], compared to 4.1 [2.8-5.8], 4.9 [3.5-6.6], 4.6 [3.2-6.4], 0.8
[0.3-1.6] and 0.1 [0.0-0.6], respectively, on ST. Median survival times are
7.7 [6.1-9.8] and 13.8 months [11.9-16.1] on TT studies, and 6.9
[5.8-8.2] and 14.6 [13.2-16.8], on ST, for PFS and OS, respectively,
without statistically significant difference (p�0.39 and 0.55). The heterogeneity
among specific toxicities and survival endpoints may be partially
explained by the study design and/or the intake or not of temozolomide.
Conclusions: The use of TT combined to RT represented a significative
increase in severe adverse events in patients with GBM compared to ST,
whereas no significant difference was observed in survival endpoints.
Grants from French Cancer League.
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