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

202s Developmental Therapeutics—Experimental Therapeutics
TPS3117 General Poster Session (Board #22C), Mon, 8:00 AM-12:00 PM
A phase I study determining the safety and tolerability of combination
therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212,
a MEK inhibitor, in advanced solid tumors enriched with patients with
advanced differentiated thyroid cancer. Presenting Author: Shabina Roohi
Ahmed, The Johns Hopkins University School of Medicine, Baltimore, MD
Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway,
especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the
development of many different types of cancers, including breast, colorectal,
melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is
the most common endocrine malignancy, but there is currently no approved
therapy for advanced radioiodine-resistant disease. In DTC xenograft
models, vertical inhibition of this pathway, achieved by targeting the
vascular endothelial growth factor receptor (VEGFR) and MEK, has shown
greater clinical efficacy than with either agent alone. Pazopanib (P) is a
small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3,
PDGFR-�, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC
from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months
in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly
selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al.
reported an ORR of 81% in BRAF mutant melanoma patients when G was
combined with a RAF inhibitor. Methods: A phase I, open label, dose
escalation trial with P�G is currently accruing pts with advanced malignancies.
The study is a standard 3�3 design with an expansion cohort of 25 pts
with advanced DTC for correlative endpoints and PK studies. Pts will be
treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held
constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD.
Eligibility includes advanced solid tumor, good end organ function and
performance status, and PD within 6 months in the expansion cohort. The
primary objective is to determine the safety and tolerability of the
combination and determine the MTD. Secondary objectives include assessing
preliminary efficacy as defined by RECIST criteria and PFS, and
exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for
changes in signaling through p-ERK. RAS and RAF mutation sites will be
sequenced in order to correlate with PD endpoints and disease response.
Currently, DL1 has accrued with no DLTs.
TPS3118 General Poster Session (Board #22D), Mon, 8:00 AM-12:00 PM
Phase lb combination trial of a MEK inhibitor, pimasertib (MSC1936369B),
and a PI3K/mTOR inhibitor, SAR245409, in patients with locally advanced
or metastatic solid tumors. Presenting Author: Jeffrey R. Infante,
Sarah Cannon Research Institute, Nashville, TN
Background: The PI3K/mTOR and MAPK signaling pathways are frequently
aberrantly activated in tumors and interact to promote growth and resistance
to treatment. Simultaneous inhibition of both pathways may enhance
antitumor activity. This trial investigates the combination of pimasertib, a
highly selective MEK1/2 inhibitor, and SAR245409, a dual PI3K/mTOR
inhibitor (ClinicalTrials.gov NCT01390818). Maximum tolerated dose
(MTD) when administered once daily (qd) as a single agent to solid tumor
patients (pts) is 90 mg for both compounds. Methods: Pts with advanced
solid tumors characterized by frequent alterations of the MAPK or PI3K/
mTOR pathways (pancreatic, thyroid, colorectal, non-small cell lung,
endometrial, renal, breast, ovarian and melanoma) and/or with identified
alterations in genes activating these pathways, adequate performance
status and organ function, and no retinal disease are eligible for entry. The
primary objective of the trial is to determine the MTD of the combination
therapy. Secondary objectives include: safety, pharmacokinetics (PK),
pharmacodynamics (PD), biomarker identification and antitumor efficacy
(response rate via RECIST v1.1). Both compounds are dosed together qd
continuously in 21 day cycles. The study uses a classical 3 � 3 design, with
modified Fibonacci (decreasing increments) dose escalation based on
occurrence of dose-limiting toxicities (DLTs). In parallel with dose escalation,
more pts may be enrolled in already tested lower dose level (DL)
cohorts to further evaluate PK, PD, safety and antitumor activity. After MTD
confirmation, additional pts may be enrolled in up to 4 disease-specific
cohorts based on scientific rationale, and observed preclinical and clinical
activity signals. As of January 25th 2012, 20 pts have been treated. No
DLTs have been reported.
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