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

3072 General Poster Session (Board #16F), Mon, 8:00 AM-12:00 PM
Effect of MDV3100, a novel androgen receptor signaling inhibitor, on cell
proliferation and tumor size in an apocrine breast cancer xenograft model.
Presenting Author: Sebastián Bernales, Medivation, Inc., San Francisco,
CA
Background: MDV3100, a new androgen receptor (AR) signaling inhibitor,
has demonstrated therapeutic effects in men with post-docetaxel prostate
cancer (AFFIRM). AR is also expressed in the majority of breast cancers.
Molecular profiling of estrogen receptor negative (ER-) breast cancer
classifies this disease into basal and molecular apocrine subtypes. Apocrine
breast cancer represents ~50% of ER- tumors and is characterized by
a steroid response gene signature that includes AR expression. Here we
report the effects of MDV3100 on the growth of the ER-/AR� breast cancer
cell line MDA-MB-453 in tissue culture and in an in vivo xenograft mouse
model. Methods: MDA-MB-453 cells were maintained in 5% complete or
5% charcoal-stripped serum supplemented with dihydrotestosterone (CSS-
DHT). The DHT induced nuclear translocation of AR was determined by
subcellular fractionation followed by western blot. AR target gene expression
was measured by qPCR. To generate a mouse xenograft model, 5-6 wk
old female NOD-SCID-IL2Rgc–/– mice were injected ortotopically with
6x106 MDA-MB-453 cells into the fourth inguinal gland and were administered
exogenous DHT (12.5 mg in a 60 day release pellet) or control pellets.
When tumor size reached 100 mm3 , mice were treated with 10 mg/kg/day
MDV3100 or vehicle (0.5% methocel solution) by oral gavage for 33 days.
Results: Viability of MDA-MB-453 cells treated with 10 uM MDV3100 was
reduced by 10% after 3 days and 27% after 6 days. Treatment with 25 uM
MDV3100 reduced cell viability by 27% after 3 days and 36% after 6 days.
Similar results were obtained when cells maintained in CSS-DHT were
treated with MDV3100. Treatment with MDV3100 blocked DHT-induced
nuclear translocation and concordantly reduced the expression of ARtargets
fatty acid synthase, prolactin receptor, and gross cystic disease
protein-15. In the xenograft model, MDV3100 inhibited tumor growth by
78% as compared to tumors treated with vehicle. Conclusions: MDV3100
reduced cell proliferation in apocrine cell lines. MDV3100 also suppressed
exogenous DHT-induced growth of ER-/AR� tumors in vivo. These results
support the evaluation of MDV3100 as a treatment for apocrine tumors.
3074 General Poster Session (Board #16H), Mon, 8:00 AM-12:00 PM
Targeted therapies for the treatment of non-small cell lung cancer: Bull’s
eye or missed target? Presenting Author: Shakun M. Malik, U.S. Food and
Drug Administration, Silver Spring, MD
Background: Targeted drugs approved for advanced non-small cell lung
cancer (NSCLC) include bevacizumab [(monoclonal antibody directed
against vascular endothelial growth factor-A (VEGF-A)], erlotinib [(an
epidermal growth factor receptor kinase (EGFR) inhibitor)] and crizotinib
[(an anaplastic lymphoma kinase (ALK) inhibitor)]. The development
programs for erlotinib and bevacizumab did not prospectively employ in
vitro diagnostic tests to select patients (pts). Post-hoc exploratory analyses
for bevacizumab based on VEGF-A levels have not identified subgroups with
differential treatment effects: however for erlotinib, pts with activating
EGFR mutations had greater improvement in overall response rates (ORR)
and progression-free survival. Crizotinib is the first targeted therapy for
NSCLC in which pts were selected using an analytically validated investigational
test for ALK translocations. Crizotinib received accelerated approval
on August 26, 2011 for the treatment of pts with locally advanced or
metastatic ALK-positive NSCLC as detected by an FDA-approved test (Vysis
ALK Break Apart FISH Probe Kit) that was approved by FDA on the same
day. Methods: NDA file for crizotinib was examined. Results: Two single arm
trials assessing efficacy of crizotinib monotherapy in ALK positive pts
showed ORR of 61% and 50%. At FDA’s request, a cohort of 23 pts that
tested negative for the ALK translocation evaluated showed ORR of 26%.
Two additional pts had a single assessment and, if confirmed, the response
rate would be 37% in this “marker negative” subgroup. Further exploration
of this subgroup is a postmarketing commitment. Conclusions: Evaluation
of target status (positive or negative) in all pts provides optimal information
to guide clinical practice. As observed with crizotinib, responses may be
observed in the “marker negative” subgroup. This unexpected finding may
reflect the drug’s activity via alternate pathways, selection of a suboptimal
biomarker for assessing ALK activation, or selection of a suboptimal
cut-point for positive/negative. Accurate diagnostic tests will facilitate drug
development with possible greater observed treatment effect and potentially
smaller clinical trials.
Developmental Therapeutics—Experimental Therapeutics
3073 General Poster Session (Board #16G), Mon, 8:00 AM-12:00 PM
Inhibition of autophagy: Phase I safety, tolerability, and pharmacokinetics
(PK) of hydroxychloroquine (H) in combination with vorinostat (V) in
patients with advanced solid tumors. Presenting Author: Devalingam
Mahalingam, Institute for Drug Development, Cancer Therapy and Research
Center, University of Texas Health Science Center at San Antonio,
San Antonio, TX
Background: The histone deacetylase (HDAC) inhibitor V has pleiotropic
effects, and induces both apoptosis and autophagy. As autophagy can
promote cancer cell survival, we hypothesized that inhibiting autophagy
would enhance the anti-cancer activity of V. Our pre-clinical studies
showed that inhibition of autophagy using H significantly increased the
pro-apoptotic effects of V. The primary objective of this NCI-funded study
was to determine the maximum tolerated dose (MTD) of H in combination
with V in patients (pts) with advanced solid tumors. Methods: Pts with ECOG
PS 0-2 and adequate organ function received PO V 300-400 mg QD and H
400-1000 mg QD in 21d cycles. 3�3 dose escalation. Dose limiting
toxicities (DLTs) � non-hem toxicity � grade (Gr) 3 or hem toxicity � Gr 4
in the first 2 cycles. PBMCs were analyzed for autophagic changes at
baseline, week 1 � 6. PKs done on cycle 1.Tumor biopsies were performed
at baseline and post-cycle 2 on 3 pts at MTD. Results: 31 pts enrolled, 27
evaluable for DLT. No DLT was observed in cohort 1 (300 mg V/400 mg H)
or cohort 2 (400 mg V/400 mg H). In cohort 3 (400 mg V/600 mg H) 1/6
pts experienced a DLT of Gr 3 fatigue. Cohort 4 (400 mg V/800 mg H) 3/6
pts had DLT of Gr 3 fatigue, and 1 had a Gr 2 seizure. Expansion of cohort 3
resulted in no further DLTs. 10 pts got the MTD. Treatment-related
toxicities were mostly Gr 1- 2: nausea/vomiting (10 pts), diarrhea (7),
fatigue (5), anorexia (4), weight loss (3), anemia (4), elevated creatinine
(4) and thrombocytopenia (2). Gr 3 toxicities were fatigue (4), anemia,
thrombocytopenia and neutropenia (1 each). No drug-related deaths or Gr
4 toxicities were noted. One pt (RCC) had a confirmed PR (cohort 2 active
on cycle 32) and 2 pts with CRC had prolonged SD (�4 cycles). PK analysis
indicated dose-proportional exposure for H. Changes from baseline in
biomarkers of autophagy and HDAC inhibition were observed in PBMC and
primary tumors with therapy. Conclusions: Recommended dose is V 400
and H 600 mg QD. Dose-dependent fatigue was observed with the
combination, but well tolerated at the MTD without any further increase in
toxicities compared to V alone. Analyses of PK-PD interactions are
underway.
3075 General Poster Session (Board #17A), Mon, 8:00 AM-12:00 PM
Translational assessment of the efficacy of CPI-613 against pancreatic
cancer in animal models versus patients with stage IV disease. Presenting
Author: Avi S. Retter, Eastchester Center for Cancer Care, Bronx, NY
Background: CPI-613 is a novel agent that selectively targets the altered
mitochondrial enzymes of tumor cells, causing apoptosis, necrosis, and
autophagia. Results assessing clinical efficacy of CPI-613 translated from
animal tumor xenograft models to patients with stage IV pancreatic cancer
are presented. Methods: Efficacy of CPI-613 was tested in mice with
pancreatic tumor xenografts generated by inoculation of BxPC-3 human
pancreatic tumor cells. The safety and efficacy of CPI-613 (70-320
mg/m2 ), when used in combination with gemcitabine (1,000 mg/m2 ), was
assessed in patients with stage IV pancreatic cancer. Results: In the animal
pancreatic tumor xenograft model (n�10/grp), CPI-613 (25 mg/kg, IV, 1x
weekly for 4 weeks) suppressed tumor growth by ~100%, when compared
to vehicle. The positive control, gemcitabine (50 mg/kg, IV, 1x weekly for 4
weeks), suppressed tumor growth by only ~50%. Median overall survival in
tumor-bearing mice treated with CPI-613 was ~240 days, which was
significantly longer than those with gemcitabine or vehicle treatments (~65
and ~50 days, respectively). In 6 humans with stage IV pancreatic cancer
(Table), the CPI-613�gemcitabine combination was well-tolerated. In
those without prior chemotherapy before participating in the clinical trial
(first three patients in the table), the CPI-613�gemcitabine combination
prolonged survival that correlated with the dose of CPI-613. Conclusions:
CPI-613 exhibits efficacy against pancreatic cancer in animal models,
which is translational to patients with stage IV disease.
Patients with stage IV pancreatic cancer.
ID# Sex Age Race/ethnicity
Chemotherapy prior to
study participation
CPI-613 dose a
(mg/m 2 )
191s
Survival b
(months)
1-106 M 52 Hispanic None 70 4.1
1-110 F 65 Caucasian None 150 7.5
1-113 F 77 African American None 190 �22 (still alive)
1-107 M 63 Caucasian Gemcitabine 105 9.8
1-111 F 76 African American 5-FU; gemcitabine;
FOLFOX � transferrinlaced
oxaliplatin
150 11.3
2-107 M 65 Caucasian Gemcitabine � erlotinib;
Xenoda � oxaliplatin
320 �10
Abbreviations: f � female; ID � identification; M � male; mo � month. a CPI-613 was given in
combination with gemcitabine (1,000 mg/m 2 ). b Survival was measured since the start of first
chemotherapy the patient received.
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