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

3088^ General Poster Session (Board #18F), Mon, 8:00 AM-12:00 PM
A phase I study of dovitinib (TKI258) in Japanese patients with advanced
solid tumors. Presenting Author: Hiroya Takiuchi, Osaka Medical College,
Osaka, Japan
Background: Dovitinib is a tyrosine kinase inhibitor with demonstrated
inhibitory activity against FGFRs, VEGFRs, and PDGFRs in vivo. Based on
responses observed in renal cell carcinoma, breast cancer, AML, melanoma,
and multiple myeloma in clinical studies in the West, we investigated
dovitinib in Japanese patients (pts). Methods: This multicenter phase
I study determined the maximum tolerated dose (MTD) of dovitinib based
on the occurrence of dose-limiting toxicity (DLT) in Japanese pts with
advanced solid tumors. Following a 2-day pharmacokinetic (PK) run-in
period, dovitinib was administered orally once daily on a 5-days-on/2-daysoff
schedule in 28-day cycles until disease progression or withdrawal. The
planned dose range was 100-600 mg/day. A 2-parameter Bayesian logistic
regression model based on the principle of escalation with overdose control
was used to estimate the MTD. Results: In total, 28 pts received dovitinib:
100 mg (n � 3), 200 mg (n � 3), 300 mg (n � 7), 400 mg (n � 9), and
500 mg (n � 6). The median age was 58.5 years (range, 30-76); 16 of 28
pts (57%) were male. All pts had stage IV disease, with an ECOG
performance status of 0 or 1. Pts completed a median of 3 cycles. One pt is
currently ongoing in the study (peritoneal adenocarcinoma, 400-mg cohort,
cycle 19), 23 discontinued due to disease progression, and 4 discontinued
due to adverse events (AEs). All DLTs were grade 3: anorexia (n � 1; 300
mg), nausea/vomiting (n � 1; 400 mg), liver function disorder (n � 1; 400
mg), and increased alanine transaminase (n � 1; 500 mg). The most
common grade 3/4 AEs (occurring in �10% of pts) suspected to be related
to study drug were lymphopenia (18%), neutropenia (14%), abnormal
hepatic function (14%), decreased white blood cell count (14%), decreased
appetite (14%), and hypertension (14%). Best responses were
confirmed partial response in 1 pt (4%; peritoneal adenocarcinoma,
400-mg cohort), stable disease in 9 pts (32%), and progressive disease in
10 pts (36%). No treatment-related deaths have been reported. Safety and
PK parameters were comparable to those of non-Japanese pts in the global
study. Conclusions: The study has completed enrollment. Dovitinib was
found to be tolerable at doses up to 500 mg, which was declared as the
MTD in Japanese pts.
3090 General Poster Session (Board #18H), Mon, 8:00 AM-12:00 PM
Preclinical activity of the Hsp90 inhibitor, ganetespib, in ALK- and
ROS1-driven cancers. Presenting Author: David A. Proia, Synta Pharmaceuticals
Corporation, Lexington, MA
Background: Ganetespib is a potent inhibitor of heat shock protein 90
(Hsp90) currently being studied in a broad range of clinical trials. Phase II
results with ganetespib demonstrated an encouraging objective response
rate of 50% in non-small cell lung carcinoma (NSCLC) patients whose
tumors contained ALK translocations and had progressed on previous
treatments. To further understand the clinical potential of ganetespib in
ALK-driven cancers, we evaluated its activity in (1) crizotinib-sensitive and
-resistant cancer cells harboring ALK fusions; (2) cells expressing amplified
ALK or ROS1 translocations (a kinase structurally similar to ALK); and (3)
in combination with crizotinib. Methods: H3122 NSCLC cells, which
express EML4-ALK, were treated with ganetespib, crizotinib or the combination,
and cell viability and signaling cascades were assessed. Similar
experiments were done in cells with amplified, constitutively active ALK
(NB-39-nu) or ROS1 kinase fusions (HCC-78, U118MG). To generate a
model of crizotinib resistance, NPM-ALK-expressing BaF3 cells were
exposed to various crizotinib concentrations. Fifteen different ALK kinase
domain substitutions were identified; clonal NPM-ALK/BaF3 cells were
made for each resistance mutation and assayed for sensitivity to ganetespib.
Results: Ganetespib was 50-fold more potent than crizotinib in killing
H3122 cells, and when combined together at sub-lethal doses, displayed
strong synergistic anticancer activity. Ganetespib showed similar potency
in other cells driven by constitutively active ALK or ROS1 kinase fusions,
due to abrogation of their oncogenic kinase activity. All 15 of the
crizotinib-resistant NPM-ALK/BaF3 mutant clones were highly sensitive to
ganetespib (IC50 values ranging from 14-23 nM), including the 7
mutations reported to date in patients with ALK-driven tumors. Conclusions:
Ganetespib effectively inhibits the activity of ALK and ROS1, kinases
associated with several tumor types, resulting in marked single agent
anticancer activity in cells driven by them. Importantly, ganetespib retains
its potency irrespective of the mutational status of ALK. The strong synergy
observed between ganetespib and crizotinib warrants further study.
Developmental Therapeutics—Experimental Therapeutics
195s
3089^ General Poster Session (Board #18G), Mon, 8:00 AM-12:00 PM
Endoxifen for breast cancer: Multiple-dose, dose-escalation study characterizing
pharmacokinetics and safety in metastatic breast cancer patients.
Presenting Author: Ateeq Ahmad, Jina Pharmaceuticals, Inc., Libertyville,
IL
Background: Endoxifen is an active metabolite of tamoxifen, a drug used in
the treatment of breast cancer. To be clinically effective, tamoxifen must
be converted to endoxifen by CYP2D6. Direct administration of endoxifen
would not be subject to pharmacogenetic variations or drug-drug interactions.
Our preclinical studies (Breast Cancer Treat 122, 579-584, 2010)
have validated the concept of using endoxifen for the treatment of breast
cancer. In human (Clin. Pharmacol. Ther. 88, 814-817, 2010), the single
oral doses tested up to 4 mg of endoxifen were safe, well tolerated and
bioavailable. Methods: A multiple-dose escalating study was conducted in 3
cohorts and each cohort had 6 patients (18 metastatic breast cancer
patients). Endoxifen at 3 dose levels (2, 4, or 8 mg) was given once daily for
28 days. Routine laboratory tests, vital signs and electrocardiograms were
measured throughout the study. Blood samples for PK analysis were
collected after 28 days post dose. Endoxifen in plasma samples was
determined using LC-MS/MS. Results: Endoxifen was found to be safe up to
8.0 mg. At steady state, it displays dose-proportional PK with respect to
Cmax and AUC ( see Table below). Conclusions: Multiple daily endoxifen
doses of 4.0-8.0 mg resulted in endoxifen exposures that would be
sufficient for effective therapy. The favorable safety and multiple-dose PK
profile of endoxifen warrants further evaluation of safety and efficacy of
endoxifen in breast cancer patients.
Pharmacokinetics parameters of endoxifen in metastatic breast cancer
patients (n�5) after multiple-dose of 2, 4 or 8 mg of endoxifen tablets.
Parameters (units) 2mg
Mean � SD
4mg 8mg
Tmax (h)*
Cmin ss (ng/mL)
Cmax ss (ng/mL)
AUCtau (ng.h/mL)
PTF (%)
5 (3.0-12.0)
15.7�6.4
24.5 �7.3
445.3 �146.2
50.8�19.0
5 (4.0-6.0)
44.0�11.6
75.9 �18.5
1363.3�396.3
56.5 �17.9
5 (4.0-6.0)
80.4�26.7
134.1�32.1
2322.6�619.8
57.6 �14.6
Cav ss (ng/mL) 18.6 �6.1 56.8 �16.5 96.8�25.8
*Data presented as median (range)
3091 General Poster Session (Board #19A), Mon, 8:00 AM-12:00 PM
Therapy of human solid tumor xenografts with CD74-targeted milatuzumab-
SN-38 immunoconjugates. Presenting Author: David M. Goldenberg,
Center for Molecular Medicine and Immunology, Morris Plains, NJ
Background: CD74 is commonly considered to be an antigen present in
hematopoietic cancers, but it is also expressed in a number of solid tumors.
The humanized anti-CD74 antibody, milatuzumab (hLL1), was previously
shown to have exquisite internalization properties, making it an attractive
carrier for drug delivery. In this study, we evaluated hLL1 conjugates of a
potent topo I inhibitor, SN-38, for treating solid tumors. Methods: Two
hLL1-SN-38 conjugates, possessing either a pH-sensitive linker (‘CL2A’
form) or a cathepsin-B-cleavable linker (�CL2E� form), were examined. In
vitro analyses were carried out in the A-375 human melanoma cell line, and
therapy experiments were performed in female athymic nude mice bearing
established s.c. A-375 or s.c. human pancreatic adenocarcinoma (Capan-1)
xenografts using specified doses (i.p.) at a twice weekly � 4 wks
schedule; animals were sacrificed when tumor volumes (TVs) reached 1
cm3 . Results: Both A-375 and Capan-1 cell lines tested positive for CD74
expression by IHC. In vitro, both SN-38 derivatives liberated free drug at
the same rate when exposed to cathepsin-B at pH 5, while serum stabilities
for CL2A and CL2E forms of the conjugates were ~1dand�10 d,
respectively. In the A-375 melanoma cell line, IC50 for the hLL1-SN-38
conjugates of CL2A and CL2E forms were 5 nM and 34 nM, respectively. In
the aggressive A-375 s.c. model of melanoma, in nude mice (n �8; TV:
0.23 � 0.06 cm3 ) treated with 12.5 mg/kg protein dose (total 1.7 mg/kg
SN-38 eq.) of specific or non-specific SN-38 conjugates of CL2A and CL2E
forms, only hLL1-CL2A-SN-38 conjugate was efficacious (Log-rank:
P�0.009 vs. all controls), with a median survival time of 28 d vs. 10.5 d for
untreated. Likewise, in mice bearing Capan-1 xenografts (n � 8-10;
TV�0.27 � 0.05 cm3 ), two low doses of hLL1-CL2A-SN-38 (12.5 or 5
mg/kg) significantly improved survival in comparison to saline control mice
(p�0.035), whereas the CL2E form and a non-specific control demonstrated
no efficacy. Conclusions: These results indicate the therapeutic
potential of hLL1-CL2A-SN-38 conjugate and the importance of linker
chemistry, and encourage additional testing in other CD74-positive solid
cancers.
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