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

3040 General Poster Session (Board #12F), Mon, 8:00 AM-12:00 PM
First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor
sulfatinib in patients with advanced solid tumors. Presenting Author:
Jian-Ming Xu, Cancer Center, 307 Hospital, Academy of Military Medical
Science, Beijing, China
Background: Sulfatinib is a highly selective oral small molecule tyrosine
dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and
fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo
inhibitory effects on a variety of human tumor xenografts. Methods: This
phase I dose-escalation study were to determine the maximum tolerated
dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile,
and preliminary antitumor activity, and to assess potential pharmacodynamics
(PD) markers of sulfantinib when given orally in continuous cycles of 28
days, until disease progression or unacceptable toxicity. Results: Forty one
patients (pts) have been enrolled and treated with doses of 50-300mg once
or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and
93% gastrointestinal tumors. Common adverse events (AEs) included
fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and
elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3
coagulation disorders, upper gastrointestinal bleeding and impaired liver
function were observed in the 50 and 265mg qd and 150mg bid cohorts,
respectively. MTD has not been reached and the dose escalation is ongoing.
Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or
longer, including liver and neuroendocrine cancer, GIST and solidpseudopapillary
tumor of pancreas. A patient with GIST had SD of 9
months at 265mg qd. There was a significant decrease in soluble VEGFR2
level and increase in FGF23 level after 4-week treatment comparing to the
baseline at 265 mg or higher daily doses, indicating inhibition of both
VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly
absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and
AUC displayed dose-proportional increases and no obvious accumulation
occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to
300 mg per day and demonstrated preliminary anti-tumor activity, especially
in liver cancer and GIST. PD marker analysis indicates dual inhibition
of VEGFR and FGFR. PK data suggests good dose proportionality in
exposure without marked drug accumulation.
3042^ General Poster Session (Board #12H), Mon, 8:00 AM-12:00 PM
Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced
solid tumor patients. Presenting Author: Shawn D. Spencer, SAIC-
Frederick, National Cancer Institute at Frederick, Bethesda, MD
Background: CD105 is an endothelial cell membrane receptor highly
expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal
antibody that inhibits angiogenesis and tumor growth by endothelial
cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced
solid tumors and normal organ function were treated with escalating
doses of intravenously administered TRC105 and assessed for safety and
pharmacokinetics (PK). PK parameters for determining dose-linearity were
estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg
and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg
weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was
dose-limiting at 15 mg/kg weekly and was associated with TRC105
accumulation in serum from target saturation. Preliminary evidence of
activity was observed with 21 of 45 evaluable patients progression-free at 2
months, including two ongoing responders. The AUC-single dose relationship
of TRC105 revealed supra-proportionality in serum exposure at 15
mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power
model revealed a nonlinear pharmacokinetic process (log[AUC] �
0.125*Dose�2.67, r2 � 0.92, ANOVA p�0.0035). The steady state
volume of distribution was low (� 5.40 L/70kg) indicating TRC105 was
confined to the vasculature with a low capacity target (i.e., low relative
abundance) making it susceptible to saturation. The post-infusion Cmax
however was linearly related to dose (r � 0.85) which suggested the
nonlinearity in clearance was attributed to target-mediated disposition. The
nonlinear disposition in the presence of low distribution indicated TRC105
bound avidly to endothelial cells. Concentrations expected to saturate
CD105 binding were achieved continuously at 15 mg/kg dosed every 2
weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the
accumulation factor at 56 days was 1.77-fold over single doses on C1D1.
Conclusions: TRC105 clearance decreased above the MTD resulting in drug
accumulation and hypoproliferative anemia with weekly dosing. The
nonlinearity in clearance was attributed to saturating target-mediated
disposition, consistent with binding to proliferating endothelial cells.
Developmental Therapeutics—Experimental Therapeutics
183s
3041 General Poster Session (Board #12G), Mon, 8:00 AM-12:00 PM
Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI)
x-82 in patients (pts) with advanced solid tumors. Presenting Author:
Kathleen N. Moore, Sarah Cannon Research Institute/University of Oklahoma
Health Sciences Center, Oklahoma City, OK
Background: VEGFR TKIs have shown benefit in the treatment of various
tumor types. Side effects of the TKIs have affected the duration of therapy
pts can tolerate, as well as the combinability with chemotherapy. X-82 is a
highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and
limited tissue accumulation designed to minimize side effects while
maintaining target effect. Methods: Pts with advanced solid tumors were
enrolled using an accelerated titration scheme followed by 3�3 dose
escalation design. X-82 was administered orally once daily (QD) or twice
daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and
blood-based biomarkers were evaluated. Results: 16 pts were treated across
8 dose levels: 20 (n�1), 40 (n�1), 80 (n�1), 160 (n�1), 300 (n�2), 400
mg QD (n�3), 140 mg BID (n�3) and 200 mg BID (n�4). The most
common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2),
nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting
(2 G1). G2 hypertension, resolved with treatment, was experienced by 1
patient. No � G3 related AEs have been reported. Dose proportional
exposure was observed with doses up to 160 mg QD, and BID dosing
cohorts were added. At 160 mg QD X-82 has plasma concentrations �100
ng/mL for at least 12 hours, the desired exposure predicted preclinically.
Preliminary blood biomarker data (n�8) shows �25% decrease in VEGFR1
in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg
cohorts. Efficacy has also been noted, including 1 confirmed complete
response lasting 24� weeks (pancreatic adenocarcinoma), and 6 pts with
stable disease lasting 8� weeks (range 12.1�, 38.3� weeks), including
the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a
well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while
inhibiting target receptors. No MTD has yet been defined, though preliminary
biomarker data are encouraging and clinical efficacy has been noted.
3043 General Poster Session (Board #13A), Mon, 8:00 AM-12:00 PM
A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic
castration resistant prostate cancer (mCRPC). Presenting Author: Fatima
H. Karzai, Medical Oncology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD
Background: Pre�clinical and clinical evidence demonstrates an important
role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane
protein expressed on the surface of proliferating vascular endothelial
cells. The expression of CD105 is required for the formation of new blood
vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal
antibody that binds to human CD105 (endoglin). It inhibits angiogenesis
and tumor growth through inhibition of endothelial cell proliferation,
antibody-dependent cellular cytotoxicity, and induction of apoptosis. The
primary objective is to evaluate safety and identify the maximum tolerable
dose (MTD) of TRC105. Secondary objectives include the assessment of
TRC105 pharmacokinetics, PSA response rate, evaluation of progression
free survival (PFS), overall response rate (ORR) and overall survival (OS).
Methods: Patients with an ECOG performance status (PS) � 2, progressive
mCRPC and either chemotherapy-naïve or post-docetaxel treatment were
eligible. Six cohorts of patients, on escalating dose levels, receive TRC105
intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks
(cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week
cycle. Response is assessed with imaging studies every 2 months for the
first four months and then every 3 months thereafter. Results: Sixteen
patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87),
median ECOG PS is 1 (range 0�2), median Gleason score is 8 (range
6�10), median on�study PSA is 147.5 (range 0.1-3373), and median
number of prior (non-hormonal) therapies is 3 (range 0�6). Median time on
study is 16 weeks (range 8-28 weeks). One patient experienced a dose
limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were
seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12
patients with measurable soft tissue disease achieved stable disease for at
least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two
weeks with early evidence of clinical activity in mCRPC. An additional
cohort (6), with dosage of 20 mg/kg, is currently under investigation.
Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of
this study.
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