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

194s Developmental Therapeutics—Experimental Therapeutics
3084 General Poster Session (Board #18B), Mon, 8:00 AM-12:00 PM
Phase I and pharmacokinetic study of farletuzumab in solid tumors.
Presenting Author: Yasutsuna Sasaki, Saitama Medical University International
Medical Center, Saitama, Japan
Background: Farletuzumab (F) is a humanized monoclonal antibody against
folate receptor � (FRA). Expression of FRA is reported to be 90% and 40%
in ovarian cancer (OC) and gastric cancer (GC), respectively. The purpose of
the study is to assess tolerability, pharmacokinetic profile and preliminary
antitumor effect in solid tumors. Methods: Patients with OC or FRA
expressing solid tumor who are resistant to standard treatments are eligible
in the study. After pharmacokinetic (PK) run-in, F was administered by IV
injection repeating every week until disease progression. PK profile was
analyzed on day1 to day 10 in PK run-in and on day 22 to 29 in cycle 1.
Dose limiting toxicities (DLTs) were defined as G4 hematological and G3/4
non-hematological toxicities by NCI-CTCAE. Dose escalation was planed in
4 cohorts (50, 100, 200 and 400mg/m2 ). Results: Sixteen patients (14 OC
and 2GC) received F infusion. Neither DLTs nor G3/4 toxicities were
reported in all cohorts. As adverse events, G1/2 infusion reaction (44%),
headache (44%), cytokine release syndrome (38%), nausea (31%) and
appetite loss (31%) were observed and medically managed. AUC and
Cmax.were increased dose-dependently and linear PK profiles were identified
with median clearance between 6.02 and 10.54 mL/hr/m2 in each
cohort. No tumor shrinkage was recorded, but long-term disease stabilization
for 22� mos. and 10� mos. were observed in one patient with clear
cell OC (100mg/m2 ) and one patient with GC (400 mg/m2 ), respectively.
No cumulative toxicities were observed in these 2 patients. Conclusions:
The toxicities of F in Japanese patients were manageable with similar PK
profile as compared with the US population (Konner et al. Clin Cancer Res
2010: 16; 5288-95). Long term disease stabilization is observed in
subpopulation of clear cell OC and GC.
3086 General Poster Session (Board #18D), Mon, 8:00 AM-12:00 PM
Associating retinal drug exposure and retention with the ocular toxicity
profiles of Hsp90 inhibitors. Presenting Author: Dan Zhou, Synta Pharmaceuticals
Corporation, Lexington, MA
Background: In clinical trials certain Hsp90 inhibitors, including AUY922,
SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal
dysfunction; others, including ganetespib and 17-AAG, have not. Previous
animal toxicology experiments have suggested that retinal changes may be
linked to photoreceptor degeneration or cell death. Here histopathologic
changes and/or exposure profiles of Hsp90 inhibitors with or without
clinical reports of ocular toxicity were evaluated to understand the observed
differences in toxicity profile between agents in this class. Methods: We
reviewed visual symptoms among subjects administered ganetespib, a
potent Hsp90 inhibitor currently in phase II trials; evaluated retinal
morphology in rats and cyno monkeys given ganetespib; and compared
TUNEL-positive photoreceptors and drug exposure profiles in the retina of
rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s
retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing.
Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both
drugs induced marked photoreceptor cell death (increased TUNEL-positive
cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow
elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min
remained in the retina). In contrast, and consistent with an absence of
clinical visual changes, 17-AAG at the maximum tolerated dose did not
elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h
post-dose, 94% of 17-AAG had been eliminated from the retina, resulting
in a low R/P ratio). Ganetespib given by 1-hour IV infusion on days 1 and 15
of four 21-day cycles did not cause histopathological changes in the retina
of rats or cynos. This finding is consistent with very low rate (~3%) of
drug-related visual symptoms observed among over 300 subjects to date
that received ganetespib in the clinic. Conclusions: Unlike AUY922 and
17-DMAG, ganetespib is not associated with ocular toxicity in humans,
primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit
visual disorders when associated with high retina/plasma exposure ratio
and lower retinal elimination rate.
3085 General Poster Session (Board #18C), Mon, 8:00 AM-12:00 PM
Phase IB study of an all-oral chemotherapy regimen, tesetaxel plus
capecitabine, in patients with advanced solid tumors. Presenting Author:
Michael Gary Martin, The West Clinic, Memphis, TN
Background: Tesetaxel is a novel oral taxane that is not a substrate for
P-glycoprotein, does not cause hypersensitivity, and may cause less
neurotoxicity. The anticancer activity of tesetaxel exceeds other taxanes in
various cell lines and xenografts. Phase II studies showed overall response
rates [ORRs] of 50% and 38% in patients (pts) treated for 1st- and 2nd-line breast cancer, respectively, and 20% in pts with 2nd-line gastric cancer.
Neutropenia was dose-limiting, and the maximally tolerated dose (MTD)
was 27 mg/m2 once every 3 weeks. Capecitabine, an oral fluoropyrimidine,
is commonly used for treatment of breast and gastric cancer. While the
approved capecitabine dose is 2500 mg/m2 /day x 14 days, most pts are
unable to sustain treatment at this dose due to hand-foot syndrome (HFS).
A prior PK study suggested that short courses of tesetaxel could be
combined with capecitabine at the recommended MTDs of both drugs with
non-overlapping adverse events (AEs) (Cancer Chemother Pharmacol.
68:1565, 2011). We conducted a phase IB study of the tesetaxel/
capecitabine regimen in pts using lower doses of capecitabine to confirm a
tolerable combination dose for extended treatment. Methods: Eligibility
included: solid tumor treated with � 1 line of chemotherapy; no prior
taxane exposure; adequate organ function; ECOG PS � 1. Pts received
tesetaxel 27 mg/m2 on Day 1 and capecitabine 1500-2000 mg/m2 /day (in
divided doses on Days 1-14) every 3 weeks. Results: To date, 10 pts have
been treated. AEs were largely Grade 1-2 (83%) and consistent with those
for each drug as a single agent. Grade 3-4 neutropenia occurred in 3 pts
(30%) and HFS in 4 (40%). Tesetaxel dose reduction was required in 1 pt
for neutropenia; capecitabine dose reduction was required in 3 pts (30%)
(2 for hand-foot syndrome, 1 for diarrhea). Comprehensive toxicity data will
be presented. Conclusions: This combination of all-oral chemotherapy is
generally well-tolerated, although lower than maximally approved doses of
capecitabine are required, similar to other regimens that employ this agent.
AEs are largely non-overlapping, which suggests this combination may be
clinically useful in pts with advanced breast and gastric cancer.
3087 General Poster Session (Board #18E), Mon, 8:00 AM-12:00 PM
Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of
the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
Presenting Author: Khanh Do, National Cancer Institute, Bethesda, MD
Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor
of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site
resulting in down-regulation of key oncoproteins (HER2 and ERK). In
xenograft models AT13387 produced tumor growth inhibition on a QD x 2
dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic
(PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4.
Methods: Adult patients (pts) with advanced cancers progressing following
standard therapy; ECOG � 2; adequate organ function. One pt cohorts for
first three dose levels (DLs, 20, 40, 80 mg/m2 ), planned 3�3 design at DL
4 (120 mg/m2 ). PK evaluations on C1D1 and C1D15. Mandatory tumor
biopsies in expansion cohort at MTD for HER2� tumors (baseline, C1D17)
to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by
IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2,
D15, D16) assessed by Western blot; serum markers of cell death, M30
and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12
pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior
therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma
(1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr �
2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7),
QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision
disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1
pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional;
T1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (� 1.5
fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed.
M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70
(1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose
(� DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data
indicate that AT13387 QD x2iswell tolerated and produces a sustained
induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and
obtain further tumor biopsies for assessment of drug effect. Optional
Indium-labeled trastuzumab scan will be used to evaluate drug effect on
HER2 levels in pts with HER2 expressing tumors.
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