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

182s Developmental Therapeutics—Experimental Therapeutics
3036 General Poster Session (Board #12B), Mon, 8:00 AM-12:00 PM
Response of nonenhancing regions in glioblastoma to VEGF-signaling
inhibitor cediranib correlates with tumor infiltration. Presenting Author:
Summer A. Fakhro, Martinos Center for Biomedical Imaging, Massachusetts
General Hopital, Charlestown, MA
Background: Antiangiogenic therapy has limited direct antitumor effect in
glioblastoma (GBM). Mainly its benefits may derive from anti-permeability
and anti edema effects. In GBMs treated with cediranib we found that
regions on MRI that are suggestive of being vasogenic edema, according to
Diffusion Tensor Imaging (DTI) data, experience a greater decrease in
volume than non-enhancing regions suggestive of being tumor infiltrated.
Methods: Thirty-four newly diagnosed GBM patients were scanned on
3Tesla Siemens at two pre-therapy time points (2 days apart). Patients were
treated with cediranib, standard radiation and temozolomide. Due to
technical difficulties, 4 patients were left out of the analysis. Diffusion
images were acquired with TR�7500ms, TE�84ms and b-values 0 and
700s/mm2 in 42 directions. A board certified radiologist determined the
extent of abnormality on FLAIR and T1-weighted post contrast images.
Non-enhancing regions (NER) were determined by subtracting the T1
enhancing area and any necrosis from the FLAIR abnormality. Volume of
NERs was observed at baseline and day 47 of treatment. Mean Apparent
Diffusion Coefficient (ADC) and mean Fractional Anisotropy (FA) of the
NER were used to represent extent of tumor burden. Tumor Infiltration
Index (TII), a measure based on comparing DTI metrics in metastatic
tumors to GBM, was also derived. Twelve patients with metastatic cancer to
the brain who underwent the same imaging and analysis pretreatment were
used. High FA and low ADC and TII represent areas with more tumor
burden. Results: There was a significant correlation between mean FA in the
NERs at baseline and the percent volume reduction of the NER at day 47
(rho�0.45, p�0.02). Similarly, ADC and TII were correlated with percent
volume reduction in the NER. Conclusions: DTI metrics have been used in
GBMs to measure tumor infiltration. We found volume reduction of NERs to
be inversely correlated to tumor burden. Thus, glioma patients with greater
vasogenic edema may benefit from a different treatment paradigm than
patients with lower vasogenic edema.
% Volume reduction of NER at day 47 vs
ADC mean FA mean TII mean
Spearman correlation (rho) -0.33 0.45 -0.44
p-value 0.083 0.015 0.017
3038 General Poster Session (Board #12D), Mon, 8:00 AM-12:00 PM
Phase I study of safety and pharmacokinetics of fruquintinib, a selective
inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with
advanced solid tumors. Presenting Author: Jin Li, Fudan University
Shanghai Cancer Center, Shanghai, China
Background: Fruquintinib is a novel oral small molecule compound discovered
and developed by Hutchison MediPharma that selectively inhibits
vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has
demonstrated potent inhibitory effects on multiple human tumor xenografts.
This first-in-human study is conducted to assess the maximum
tolerated dose (MTD) and dose-limiting toxicity (DLT), safety and tolerability,
pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib.
Methods: This phase I study used the 3�3 design for dose-escalation
of fruquintinib given once daily (QD) in 28-day cycles in patients with solid
tumors who had failed standard therapies. Endpoints included safety, PK,
and preliminary efficacy measurements. Results: To date 16 patients were
enrolled in 5 dose cohorts of 1-6 mg QD, with age 42-69 yr, 44% male,
ECOG 0-1 and all heavily pretreated. Tumor types included 9 colorectal, 3
lung, 3 breast, and 2 gastric (one patient with bi-primary carcinoma of
breast and colon). The most common adverse events included hypertension
(50%), proteinuria (43.8%), hand-foot syndrome (HFS 43.8%), diarrhea
(31.2%), and hoarseness (25%). Grade 3/4 AEs were diarrhea (25%), HFS
(12.5%), thrombocytopenia (6.2%), and hyperbilirubinemia (6.2%). Three
DLTs were observed: 2 grade 3 HFS both at 6mg and 1 grade 3
hyperbilirubinemia at 4mg. PK analysis showed good and rapid absorption
followed by slow terminal elimination with a half-life of approximately 37
hours which was consistent across all dose groups. Both Cmax and AUC
exhibited good dose proportionality over the studied dose range with low
inter-patient variability following single and multiple doses. Among 8
evaluable patients, 2 (1 colorectal and 1 gastric) had confirmed partial
response for more than 4 months; 5 had stable disease, including 3 SDs of
3-8 months. Conclusions: Fruquintinib was well tolerated at doses up to 4
mg QD to date and demonstrated excellent pharmacokinetic properties.
Encouraging clinical activity was observed. Further clinical studies are
warranted and under planning.
3037 General Poster Session (Board #12C), Mon, 8:00 AM-12:00 PM
Phase I study of vandetinib in combination with gemcitabine and oxaliplatin
in advanced solid malignancies. Presenting Author: Peng Wang,
University of Pittsburgh Cancer Institute, Pittsburgh, PA
Background: Vandentinib (VAN) is a tyrosine kinase inhibitor with activity
against vascular endothelial growth factor receptor-2 (VEGFR-2) and 3
(VEGFR-3) as well as epidermal growth factor receptor (EGFR) and RET
(‘rearranged during transfection’). Combinations of VEGFR kinase inhibitors
and cytotoxic agents have been studied with interest, but have been
associated with increased toxicity. This phase I trial evaluated the safety,
tolerability and maximum tolerated dose of VAN in combination with
gemcitabine (GEM) and oxaliplatin (OX). Methods: Subjects with advanced
solid malignancy, � 2 prior regimens with adequate hematologic, hepatic
and renal function were eligible. GEM and OX were administered intravenously
at 1000 mg/m2 and 85 mg/m2 respectively every 14 days. VAN was
administered orally at two dose levels: level 1 (200 mg) and level 2 (300
mg) once daily continuously. After a maximum of 6 cycles of GEMOX,
non-progressing patients were allowed to continue VAN until progression or
intolerance. A dose level was determined to be tolerable if �2 DLTs out of 6
evaluable subjects were observed. Response was assessed by restaging
scan after every 2 cycles. Results: A total of 20 subjects were enrolled in the
study; 15 male, 5 female. Median age 62 years (47-68). Nine subjects
were enrolled on dose level 1 and 11 subjects on dose level 2. One subject
in dose level 1 experienced a deep venous thrombosis in cycle 1 deemed a
DLT. Thrombocytopenia (worst-grade 3) as well as diarrhea and rash
(worst-grade 2) were observed in several patients, without dose-limiting
toxicity in cycle 1. Reversible posterior leukoencephalopathy was observed
in 1 subject following abrupt self-discontinuation of an antihypertensive
mediation. The recommended phase 2 dose was established as GEM
(1000mg/m2 ) OX (85mg/m2 ) and VAN (300mg). One subject with refractory
small cell lung cancer had a confirmed partial response, and 10
subjects (pancreas-7, bladder-2 and biliary-1) achieved stable disease
�12 weeks. Conclusions: VAN in combination with GEM/OX was well
tolerated at full doses of each of the 3 agents. Preliminary anti-tumor
activity seen in refractory solid tumors supports further evaluation of this
regimen.
3039 General Poster Session (Board #12E), Mon, 8:00 AM-12:00 PM
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met
and VEGFR: Dose-escalation phase I study. Presenting Author: Christian K.
Kollmannsberger, British Columbia Cancer Agency, Vancouver, BC, Canada
Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer
greater anti-tumor activity than inhibiting either target alone. MGCD265
has broad anti-tumor effects in preclinical models. Methods: Patients (pts)
with advanced malignancies were enrolled in this Phase I, open-label, dose
escalating study using the classic 3�3 study design. MGCD265 was
administered every day over a 21-day cycle. The aim of this study is to
determine the safety profile including the maximum tolerated dose and the
dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK),
pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265
were also evaluated. Results: As of January 10, 2012, 56 patients were
enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old).
MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a
favorable safety profile. The DLTs (n�1 for each event) captured were:
grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation,
grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily
doses � 250 mg/m2 . Additional � grade 3 drug-related adverse events
(observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and
elevated alkaline phosphatase (n�1 for each event). Two schedules of
MGCD265 were tested sequentially: once (QD) and twice daily (BID),
respectively. Increasing the dose frequency to BID increased the exposure
of MGCD265 by ~ 2 fold at steady state. To date, the exposure (Cmax) attained at steady state with the BID schedule was ~20 fold higher than the
IC50 for Met and VEGFR inhibition and was also above the plasma
exposures associated with efficacy in the Met-sensitive xenograft model
(MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles).
Conclusions: The safety profile of MGCD265 continues to be favorable in
this Phase I dose escalating study. While no evidence of objective
responses have been noted to date, several pts have had prolonged SD.
Dose escalation is ongoing.
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