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

TPS663 General Poster Session (Board #17B), Sat, 8:00 AM-12:00 PM
A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in
patients with advanced, HER2-positive (HER2�) breast cancer. Presenting
Author: Pamela N. Munster, University of California, San Francisco Helen
Diller Family Comprehensive Cancer Center, San Francisco, CA
Background: Anthracyclines have been an effective backbone of breast
cancer therapies for decades. However, cardiotoxicity issues associated
with free anthracyclines have limited their effective use in the clinic and
led to the exploration of anthracycline-free regimens, particularly with
HER2-positive cancers that require treatment with another cardiotoxic
agent, trastuzumab. While liposomal doxorubicin formulations have succeeded
in reducing cardiotoxicity, they have failed to demonstrate clear-cut
efficacy advantages and can involve other toxicities. To address the safety
and efficacy limitations of currently available anthracyclines, we have
designed a new liposomal formulation, MM-302, that targets doxorubicin
to HER2-overexpressing tumor cells. Antibody fragments that bind to
HER2 without blocking HER2-mediated signaling are coupled to the outer
surface of pegylated liposomal doxorubicin. MM-302 specifically binds and
enters tumor cells overexpressing HER2 with minimal uptake into normal
cells such as cardiomyocytes which express low levels of HER2. This
first-in-human phase I study evaluates the safety of MM-302 in patients
and provides preliminary efficacy data in HER-2� advanced breast cancer
(ABC). Methods: Patients aged � 18 years with histologically confirmed
HER-2� advanced breast cancer that have progressed or recurred on
standard therapy or for which no standard therapy exists who have adequate
performance status, bone marrow reserve, and organ function, are eligible
for the study. Following a standard 3 � 3 dose escalation design, the
maximum tolerated dose (MTD) or maximum feasible dose (MFD) is
determined and up to 25 additional patients with HER-2� ABC will be
enrolled for a planned total of 40-49 patients. The primary endpoint is
determination of the MTD/MFD. Secondary endpoints include determination
of dose-limiting toxicity, adverse event(s), and pharmacokinetic and
immunogenicity profiles of MM-302, as well as overall response and
clinical benefit rates of MM-302. MM-302 is administered intravenously
weekly in 4-week cycles. At the time of this submission, 8 patients have
been enrolled in the dose escalation portion.
TPS665 General Poster Session (Board #17D), Sat, 8:00 AM-12:00 PM
OPTIMA prelim: Optimal personalized treatment of early breast cancer
using multiparameter analysis: Preliminary study. Presenting Author: Rob
Stein, University College London Hospitals, London, United Kingdom
Background: “Multi-parameter” prognostic tests such as Oncotype DX are
increasingly used to identify women with ER �ve HER2 -ve breast cancer
treated with endocrine therapy who are unlikely to benefit meaningfully
from adjuvant chemotherapy. The supporting evidence for predictive
testing is retrospective and is strongest for women with negative nodes.
Randomised trials to validate testing are in progress but more evidence is
needed, especially for node positive disease. There is early evidence that
other multi-parameter tests which are in development have a predictive
utility. Methods: OPTIMA will assess the value of multi-parameter tests in a
UK population. OPTIMA prelim, the feasibility phase, will recruit 300
patients from May 2012 (with a 200 patient bridging extension to the main
study). Eligible patients will have ER �ve HER2 -ve tumours with involved
nodes (pN1-2). Patients will be randomised to the standard arm of both
chemotherapy and endocrine therapy, or to the “test-directed treatment”
arm in which patients will be assigned either the same chemotherapy and
endocrine therapy or endocrine therapy only according to the result of an
Oncotype DX test. OPTIMA prelim has 3 objectives. (1) To establish
whether randomisation to test-directed treatment is acceptable to patients
and clinicians. This will be done through qualitative research with in-depth
interviews with OPTIMA researchers and by recording and analysing
consultations when the trial is discussed with potential participants. (2)
Alternative multi-parameter tests will be evaluated on all patients’ tumours
and their performance will be compared to Oncotype DX using statistical
and cost-effectiveness analysis to select a candidate test(s) appropriate for
NHS use to be evaluated in the main trial. (3) The success of the main trial
depends on efficient tumour sample collection and analysis to avoid
treatment delays. The obstacles to this will be analysed in detail using a
sample tracking database. The main study is an efficacy trial of 2-3 arms
with the same design but uses tests selected in OPTIMA prelim. It will
compare 5-year relapse free survival of test-directed vs. conventional
treatment with a non-inferiority hypothesis.
Breast Cancer—HER2/ER
TPS664 General Poster Session (Board #17C), Sat, 8:00 AM-12:00 PM
A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase
(PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with
estrogen receptor positive metastatic breast cancer. Presenting Author: Gayathri
Nagaraj, Washington University in St. Louis, St. Louis, MO
Background: PI3K pathway activation plays a crucial role in mediating endocrine
therapy resistance in estrogen receptor positive (ER�) breast cancer. We have
shown previously that BKM120 in combination with fulvestrant induced synergistic
apoptotic cell death in long-term estrogen deprived ER� breast cancer
(LTED) cell line models, supporting the clinical investigation of this combination
in ER� breast cancer. Methods: The study is composed of the dose escalation
cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard
3�3 phase I design is employed to determine the maximum tolerated dose
(MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER�
metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be
enrolled at the MTD to further examine the toxicity profile and preliminary
efficacy of this combination. Steady state concentrations of BKM120 will be
analyzed. Postmenopausal women with ER� MBC and measurable disease per
RECIST are eligible. Pts who are currently taking fulvestrant without disease
progression are eligible. There is no restriction on the number of prior lines of
systemic therapy for metastatic disease in phase IA but � 3 lines is required in
phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on
day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and
d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level
(DL) is DL1 (Table). Correlative studies include assessing PI3K pathway
abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen,
and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin
D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation
(Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor
biopsies collected at baseline and cycle 2 day 1 in consented patients.
Enrollment to DL1 is complete and the study is currently enrolling pts to DL2.
Dose levels for the dose escalation cohort (phase IA).
DL
BKM120 (mg)
PO daily
Dose
Fulvestrant (mg)
Day 1 of each cycle
2 100 500
1 80 500
-1 60 500
47s
TPS666 General Poster Session (Board #17E), Sat, 8:00 AM-12:00 PM
Randomized phase II open-label study of abiraterone acetate (AA) plus
low-dose prednisone (P) with or without exemestane (E) in postmenopausal
women with ER� metastatic breast cancer (MBC) progressing after
letrozole or anastrozole therapy. Presenting Author: Joyce O’Shaughnessy,
Texas Oncology-Baylor Charles A. Sammons Cancer Center and US Oncology,
Dallas, TX
Background: AA plus P treatment in men with metastatic castrationresistant
prostate cancer has demonstrated a survival advantage over P
alone. Circulating adrenal steroids including DHEA and DHEA-sulfate can
stimulate proliferation of breast cancer cell lines in a low-estrogen
environment. Thus, it is hypothesized that depletion of adrenal androgens
as well as estrogens by AA, a potent CYP17 inhibitor, inhibits tumor growth
by disruption of ER-dependent growth signaling. In a previously reported
phase I study of AA in patients (pts) with breast cancer (Basu, ASCO 2011),
2/21 pts who were ER� were on study for � 11 months; 1 had a confirmed
PR and continued on treatment � 14 months. Mechanism-based adverse
event of grade 3/4 hypokalemia occurred in 4 pts and was managed with
potassium supplementation and low dose corticosteroids. Methods: In the
current study, 300 postmenopausal women with ER� Her2- MBC progressing
after letrozole or anastrozole are randomized to either AA 1000 mg � P
5 mg daily or AA � P � E 25 mg daily vs E. Disease must have been
sensitive to a non-steroidal aromatase inhibitor (AI) prior to study entry.
Subjects are stratified by number of prior therapies and by AI use in
adjuvant or metastatic setting. Central review of tissue is required prior to
randomization. Gene expression profiling (GEP) (AR, ER, PR, Her2,
CYP17, Ki-67, CYP 19, and 3-�-HSD) will be performed on FFPE archival
tissue. Pre- and post-treatment circulating tumor cells and fresh tumor
biopsies will also be obtained for GEP in a subset of pts. Primary endpoint is
PFS. Secondary endpoints are OS, ORR, patient reported outcomes,
changes in endocrine markers, and PK characterization of AA and E.
Subjects randomized to E may crossover to AA � P at time of disease
progression. One interim analysis is scheduled after 50% of PFS events
have occurred. After review of interim data, the Data Review Committee will
make recommendations regarding study continuation. 23pts from 45
active sites have been randomized as of January 24,2012. (ClinicalTrials.
gov Identifier: NCT01381874)
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