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

200s Developmental Therapeutics—Experimental Therapeutics
TPS3109 General Poster Session (Board #21C), Mon, 8:00 AM-12:00 PM
Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic
breast cancer: A phase II clinical trial with ER imaging correlates.
Presenting Author: Hannah M. Linden, University of Washington, Seattle,
WA
Background: Endocrine refractory,Indolent, soft tissue, and bone dominant
metastatic breast cancer is a clinical problem, for which alternatives to
chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have
shown pre-clinical promise in estrogen receptor-modulation and restoring
sensitivity to endocrine manipulation, suggesting potential clinical benefit.
HDACi restore ER expression in ER-negative cells which are then sensitive
to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive
cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL,
and could have a beneficial role in restoring ER-signaling in endocrineresistant
tumors. We hypothesized that HDACi therapy could restore
sensitivity to aromatase inhibitor (AI) therapy, in patients with prior
progression on AI, and allow continued endocrine therapy. Recent data
suggest clinical benefit of Tamoxifen and vorinostat given continuously
(Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior
work has shown the feasibility of monitoring regional ER expression and
ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging
(Linden 2011) providing a biomarker to interrogate the molecular target.
Methods: Patients with metastatic breast cancer with prior clinical benefit
from endocrine manipulation who progressed on AI therapy are eligible.
Patients must be off ER blocking therapies, and functionally postmenopausal.
Baseline FES and FDG PET are performed and patients receive
investigational vorinostat treatment at 400 mg po BID for 2 weeks followed
by serial FES and FDG PET to assess the impact of vorinostat on ER
expression and tumor metabolism. Patients are retreated on their prior AI as
a single agent for 6 weeks, followed by paired FES and FDG and clinical
assessment. Patients with clinical benefit may continue on treatment: 2
weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until
progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.
TPS3111 General Poster Session (Board #21E), Mon, 8:00 AM-12:00 PM
A phase I and pharmacologic study of MM-111, a bispecific HER2/HER3
antibody fusion protein, in combination with multiple treatment regimens
in patients with advanced HER2-positive solid tumors. Presenting Author:
Donald A. Richards, Texas Oncology-Tyler, Tyler, TX
Background: The HER2/HER3 oncogenic heterodimer is a potent HER
receptor pairing with respect to strength of interaction, receptor tyrosine
phosphorylation, and downstream signaling through mitogen activated
protein kinase and phosphoinositide-3 kinase pathways. MM-111 is a novel
bispecific antibody fusion protein that inhibits ligand activated HER3
signaling through abrogation of ligand binding specifically in HER2
overexpressing tumors. In preclinical models of HER2� solid tumors,
MM-111 inhibits ligand-induced HER3 phosphorylation, cell cycle progression,
and tumor growth. HER2 is a well-established target of anticancer
agents such as trastuzumab and lapatinib, specifically in breast and gastric
tumors. Preclinical data demonstrate that MM-111 potentiates the antitumor
activity of both trastuzumab and lapatinib and this phase I study seeks
to determine if MM-111 can be safely used in combination with various
standard of care HER2 targeting regimens, namely; (1) trastuzumab,
cisplatin and, capecitabine, (2) trastuzumab and lapatinib, and (3)
trastuzumab and paclitaxel. Methods: This is a multi-arm phase I, open
label, multicenter, dose-escalation study of MM-111 in an add-on design
that evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of
MM-111 in combination. Each arm is designed to run as a separate phase I
study to address safety and tolerability of each combination. For eligibility,
patients are required to have documented advanced HER2-positive cancer,
with adequate bone marrow, hepato-renal and cardiac function. The dose
escalation for each arm utilizes a standard “3 � 3” design with MM-111
dosed initially at a moderate dose of 10 mg/kg and escalated up to 20
mg/kg to identify a phase II dose in combination with each regimen. Once
the maximum tolerated dose or phase II dose is identified, expansion
cohorts will accrue to further evaluate these combinations. The flexibility of
the design allows additional combinations arms to be added. Key exploratory
analyses will include an evaluation of safety, PK, and efficacy as
evidenced by best overall response and duration of response.
TPS3110 General Poster Session (Board #21D), Mon, 8:00 AM-12:00 PM
Design of a phase I clinical trial with PNT2258, a novel DNA interference
oligonucleotide (DNAi), in patients with advanced solid tumors. Presenting
Author: Drew Warren Rasco, South Texas Accelerated Research Therapeutics,
LLC, San Antonio, TX
Background: With the knowledge that Bcl-2 facilitates drug resistance and
cell survival, a DNA interference (DNAi) strategy was applied to silence
Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic
mRNA targeting (antisense, RNAi, and miRNA targets) as it targets
genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a
novel single-stranded 24-base unmodified DNA designed to bind to an
upstream region of the Bcl-2 promoter. The drug product (PNT2258) is
PNT100 encapsulated in a specialized pH tunable liposome and is being
assessed for safety and tolerability in a phase I trial. PNT2258 avoids the
toxicities associated with modified oligonucleotides and double-stranded
RNAs; since the liposome formulation is anionic and contains no surface
spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated
marked single agent activity in a diffuse large cell lymphoma, and
therapy potentiation when combined with either rituximab in Daudi-
Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An openlabel,
single-arm, first-in-man phase I dose-escalation study of PNT2258
in patients with advanced solid tumors was designed to evaluate safety,
tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics
of PNT2258 to recommend a dose for phase II studies. In this
phase I study, pharmacodynamic effects of PNT2258 will be evaluated
through analyses of soluble serum and plasma markers and peripheral
blood mononuclear cells. Patients will receive PNT2258 as an intravenous
infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each
21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with
PNT2258 administered to one patient per cohort and dose-escalation will
proceed by dose-doubling in each successive cohort until a dose level of 64
mg/m2 is attained, provided no dose-limiting toxicities are observed in
cycle 1. Thereafter, dose escalations shall proceed at 33% increments of
the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions
of up to six patients per cohort as needed. The ten planned dose cohorts
have been completed with all patients enrolled.
TPS3112 General Poster Session (Board #21F), Mon, 8:00 AM-12:00 PM
A phase I trial of riluzole and sorafenib in patients with advanced solid
tumors and melanoma. Presenting Author: Janice M. Mehnert, Cancer
Institute of New Jersey, New Brunswick, NJ
Background: Metabotropic glutamate receptor 1 (GRM1) has been identified
as a potential therapeutic target in melanoma. Over 60% of human
melanomas express this cell surface glutamate receptor and excitation of
GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole,
an oral GRM1 blocking agent, results in growth arrest of melanoma cells in
vitro and in vivo. We previously reported that administration of riluzole to
melanoma patients suppressed activity of the PI3K/AKT and MAPK
pathways in paired tumor samples (Yip Clin Cancer Res 2009). In
preclinical studies, the efficacy of riluzole was attenuated in melanoma
cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase
inhibitor, enhanced the effect of riluzole on these cells. The combination of
riluzole and sorafenib was additive or synergistic in both BRAF mutant and
BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a
xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase
I trial to test the combination of riluzole with sorafenib in patients with solid
tumors and advanced melanoma. Methods: The primary objective of this
trial is identification of the maximum tolerated dose (MTD). An expansion
cohort at the MTD is planned for patients with advanced melanoma to
examine the correlation of clinical or radiographic response with signaling
through the MAPK and PI3K/AKT pathways and with GRM1 receptor status
of individual tumors. Eligible patients must have advanced solid tumors
(phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor
(expansion cohort) and ECOG PS � 2. Riluzole will be administered at 100
mg twice daily combined with sorafenib beginning at 200 mg daily and
escalating in subsequent cohorts at 200 mg increments. Correlative
studies: Tumors will be assessed for BRAF and NRAS mutational status.
Pretreatment tumor blocks will be examined for GRM1 receptor status by
immunohistochemistry. Pre and post treatment levels of pERK and pAKT
will be measured in paired tumor samples to assess effects of treatment on
MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will
be performed. Progress: Accrual to three cohorts is complete without DLT.
Accrual to the final planned cohort is in progress.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.