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

186s Developmental Therapeutics—Experimental Therapeutics
3052 General Poster Session (Board #14B), Mon, 8:00 AM-12:00 PM
Phase I dose-escalation study to evaluate the safety, pharmacokinetics,
and pharmacodynamics of CEP-9722 (a PARP1-2 inhibitor) as singleagent
and in combination with temozolomide in patients with advanced
solid tumors (NCT00920595). Presenting Author: Mario Campone, Institut
de Cancérologie de l’Ouest - René Gauducheau, Centre de Recherche en
Cancérologie, Saint Herblain-Nantes, France
Background: Poly-ADP-ribose (PAR) polymerases (PARPs) are essential in
cellular processing of DNA damage via the base excision repair pathway.
CEP-9722, an orally available PARP1-2 inhibitor, demonstrated singleagent
antitumor activity and synergy with temozolomide (TMZ) in xenograft
models. This phase I study evaluated the pharmacokinetics, pharmacodynamics,
and the maximum tolerated dose (MTD) of CEP-9722 in monotherapy
and combination with TMZ. Methods: Adult patients with advanced
solid tumors were enrolled in cohorts of 3-6 patients to receive a 14-day
cycle of CEP-9722 (days 1-5), followed by 28-day cycles of CEP-9722
(days 1-5) plus TMZ (150 mg/m2 days 1-5). The dose of CEP-9722 was
150 mg/day in the first cohort and was escalated depending on the
occurrence of dose-limiting toxicities (DLTs) during cycles 1 and 2. The
safety, pharmacokinetics, and pharmacodynamics (PAR levels in peripheral
blood mononuclear cells) of CEP-9722 were analyzed. Results: Overall,
26 patients (18F,8 M) 18 to 71 years of age were enrolled in 5 cohorts of
3-9 patients and treated with CEP-9722 at 150-1000 mg/day. The MTD of
CEP-9722 in combination with TMZ (150 mg/m2 ) was reached at 1000
mg/day. The recommended dose was 750 mg/day. A total of 9 patients were
treated at the recommended dose. DLTs were observed in 2 patients during
cycle 1 (1 grade 3 myositis at 750 mg/day and 1 grade 3 asthenia at 1000
mg/day) and 2 patients during cycle 2 (1 grade 3 asthenia at 300 mg/day
and 1 persistent grade 2 weight loss at 1000 mg/day). Overall during this
study, 4 grade 3 treatment-related adverse events were observed. The
pharmacokinetics showed high intra- and inter-patient variability at all
doses. The pharmacodynamic analysis demonstrated PARP inhibition at all
doses, but the high inter- and intra-patient variability prevented any
conclusion regarding a dose / PARP inhibition relationship. Conclusions:
TheMTD of CEP-9722 when administered with TMZ was 1000 mg days 1-5
and the combination CEP-9722/TMZ was well tolerated. In addition, a
clear signal of PARP inhibition was demonstrated.
3054 General Poster Session (Board #14D), Mon, 8:00 AM-12:00 PM
A phase I study of chronically dosed, single-agent veliparib (ABT-888) in
patients (pts) with either BRCA 1/2-mutated cancer (BRCA�), platinumrefractory
ovarian cancer, or basal-like breast cancer (BRCA-wt). Presenting
Author: Shannon Leigh Huggins-Puhalla, University of Pittsburgh
Cancer Institute, Magee-Womens Hospital, Pittsburgh, PA
Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2.
Preclinically, PARP inhibitors have activity in tumors with defective
homologous recombination (HR), particularly those that are BRCA�.
Reduced levels of BRCA expression have been observed in ovarian cancer
and basal-like breast cancer, which share genotypic and phenotypic
similarities with BRCA� cancers. We postulated that these tumors types
may be similarly sensitive to single-agent PARP inhibition. This study
sought to establish the maximum tolerated dose (MTD), dose limiting
toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and
preliminary efficacy of chronically-dosed veliparib. Methods: A3�3 dose
escalation phase I trial was performed. Nine dose levels (DL) were planned,
and dose escalation started at 50 mg BID to a maximum of 500 mg BID.
Veliparib was administered orally continuously on a 28 day cycle. Results:
63 pts have been enrolled to date. Thirty-eight were BRCA� (20 ovary, 12
breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube,
endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the
following dose levels: BRCA�: gr. 2 thrombocytopenia at 50 mg BID;
BRCA�: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at
400 mg BID. The MTD has not been determined and 500 mg BID is
presently enrolling. Notable toxicities have included low-grade fatigue and
nausea. PK was linear and non-saturable with t½of5h.Thenumber of
cycles administered ranged from 1- 15, median 2. In BRCA� pts, there
were 2 partial responses (breast, ovarian) and 10 pts had evidence of
prolonged SD � 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7
pts with SD� 4 months. Correlative studies, including assessment of PAR
inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib
is tolerable on a continuous oral dosing schedule with evidence of
anti-tumor activity seen in BRCA� and BRCA-wt tumors. A mandatory
biopsy expansion cohort is planned at the recommended phase II dose,
which will allow further insights regarding efficacy and mechanisms of
resistance to PARP inhibition.
3053 General Poster Session (Board #14C), Mon, 8:00 AM-12:00 PM
Phase I study of sequential sapacitabine and seliciclib in patients with
advanced solid tumors. Presenting Author: Geoffrey Shapiro, Dana-Farber
Cancer Institute, Boston, MA
Background: Sapacitabine is an orally administered nucleoside analogue;
the active metabolite CNDAC generates ss DNA breaks that are converted to
ds DNA breaks (DSB) during subsequent replication, resulting in cell death
if unrepaired. CNDAC-induced DSB repair is dependent on homologous
recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of
CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via
compromise of HR protein activation and transcriptional inhibition of HR
components. This phase I study evaluates sequential sapacitabine and
seliciclib. Methods: Dose escalation was conducted in patients with
incurable solid tumors and adequate organ function with sapacitabine
b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days
(d8-10) followed by 11 days of rest. At least 3 patients were evaluated per
dose level. MTD was the highest dose level at which less than one-third of at
least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to
assess DNA damage following sapacitabine (d8 vs pre-treatment) and
further augmentation of DNA damage after seliciclib (d11 vs d8). Results:
27 patients were treated. The MTD and RP2D is sapacitabine 50 mg
b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations
and neutropenia. The most frequent adverse events (all cycles,
regardless of causality) included anorexia, fatigue, abdominal pain, dizziness,
nausea, anemia, neutropenia, creatinine elevation, hyperglycemia,
hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia,
the majority mild to moderate in intensity. Skin biopsies showed a
2.3-fold increase in H2AX staining post-sapacitabine (n�16; p�0.007)
and a further 0.58-fold increase post-seliciclib (n�12; p�0.069). Two
confirmed PRs occurred in patients with pancreatic and breast cancer, both
BRCA mutation carriers. SD as best response �/� 12 weeks was observed
in 6 additional patients, including one BRCA mutation carrier with ovarian
cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and
seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier
status may be a potential biomarker for response across multiple tumor
types.
3055 General Poster Session (Board #14E), Mon, 8:00 AM-12:00 PM
Using proton MRSI to predict response to vorinostat treatment in recurrent
GBM. Presenting Author: Hyunsuk Shim, Emory University, Atlanta, GA
Background: A major impediment to the development of new therapies for
glioblastoma (GBM) is a lack of biomarkers indicating response. Epigenetic
modifications are now recognized as a frequent occurrence in the early
phases of tumorigenesis, playing a central role in tumor development.
Epigenetic alterations differ significantly from genetic modifications in that
they may be reversed by ‘‘epigenetic drugs’’ such as histone deacetylase
inhibitors (HDACis). As a promising new modality for cancer therapy, the
first generation of HDACi is currently being tested in phase I/II clinical
trials. Methods: GBM alterations from therapy with HDACis, such as
vorinostat (SAHA), include tumor redifferentiation/cytostasis rather than
tumor size reduction limits the utility of traditional imaging methods such
as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates
various metabolite levels in tumor and normal brain, allowing characterization
of metabolic processes in live tissue. Results: In our preclinical model,
MRS detected metabolic response to SAHA after only 3 days of treatment:
reduced alanine and lactate and elevated myo-inositol, N-acetyl aspartate
and creatine; each returning toward normal brain levels. This led to our
clinical study of MRSI to evaluate the metabolic response of recurrent
GBMs to SAHA � temozolomide. After only 7 days of SAHA treatment,
MRSI can distinguish metabolic responders (normalization/restoration of
tumor metabolites towards normal brain-like metabolism) from nonresponders
(no significant change in tumor metabolites). Our initial cohort
(n�6) consists of 3 responders and 3 non-responders with highly significant
differences in their change in metabolite levels (p � 0.001).
Conclusions: Our results provide exciting insights into the mechanisms by
which HDACi exerts its effect on GBMs. Tumor cells have increased
biosynthetic needs requiring reprogramming of cellular metabolism. This
creates increased energy demands, making tumor cells even more vulnerable
to interventions targeting their metabolism. HDACi may induce
redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI
provides a novel modality to predict response to HDACi-containing combination
therapy in GBM.
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