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

TPS3113 General Poster Session (Board #21G), Mon, 8:00 AM-12:00 PM
First-in-human phase I clinical trial of QBI-139, a human ribonuclease
variant, in solid tumors. Presenting Author: Laura E. Strong, Quintessence
Biosciences, Inc., Madison, WI
Background: RNA has been recognized as a drug target for cancer therapy,
as evidenced by the ongoing clinical trials of RNAi and antisense therapies.
An alternative approach that circumvents the delivery and stability issues of
RNAi and antisense is to harness the activity of naturally occurring enzymes
that degrade RNA. Variants of human ribonucleases (RNase) have been
generated with diminished binding to their natural inhibitor inside cells,
which allows the new proteins to kill cancer cells. QBI-139, a variant that
retains 95% sequence identity to a naturally occurring RNase, has
demonstrated efficacy as both a single agent and in combination against
multiple tumor types in in vivo models of human cancer. A first in human
phase I trial was designed and initiated for QBI-139. Methods: Since
QBI-139 showed efficacy against multiple cancers in model systems, a first
in human phase I trial was designed for patients with advanced solid
tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion
once weekly for a cycle of three weeks. In the absence of disease
progression or unacceptable toxicity, treatment can continue on the twenty
one day cycle. The trial is a standard 3�3 design with cohorts of three to six
patients receiving escalating doses of QBI-139 until the maximum tolerated
dose (MTD) and/or recommended phase II dose is determined. The
inclusion/exclusion criteria are typical for the patient population. Forty
three patients have been treated to date (January 2012) without identification
of dose limiting toxicity. The starting dose in the clinical trial was 3
mg/m2 while the most recently completed cohort was treated with a dose of
50.4 mg/m2 . Dose escalation is ongoing. The primary outcome is to
evaluate the toxicity and tolerability of QBI-139 in patients with advanced
refractory solid tumors. This information will allow for identification of the
maximum tolerated dose. Clinical exposure levels are being monitored by
measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139
will be measured using RECIST criteria. Since QBI-139 demonstrated
broad efficacy in model systems, another outcome of the phase I trial may
be identification of the indications for the next stage of clinical development.
TPS3115 General Poster Session (Board #22A), Mon, 8:00 AM-12:00 PM
BARIS: A phase I trial to evaluate the safety and tolerability of combined
BIBF 1120 and RAD001 in solid tumors and to determine the maximum
tolerated dose (MTD) of the combination. Presenting Author: Matthias
Scheffler, Lung Cancer Group Cologne, Center for Integrated Oncology,
University Hospital Cologne, Cologne, Germany
Background: Simultaneious inhibition of several signallingpathways involved
in angiogenesis as well as in tumor cell growth regulation by kinase
inhibitor combination therapy may increase therapeutic efficacy. Here we
evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and
the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120in a phase I
trial in advanced solid tumors.In addition we use DCE-MRI for early
identification of patients with benefit from BIBF 1120. Methods: This is an
open-label, monocentric phase I trial with three dosage arms in a classical
�3�3� design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg
BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be
administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF
1120 will be given. There is no interindividual dose escalation, and the
enrollment of the patients will be performed sequentially. Eligible are all
patients with relapsed or refractory advanced/metastatic solid tumors
(UICC stage IV) and an ECOG performance state of 0-1 for whom no further
standard therapies are available and who have predefined adequate organ
functions. All patients will start with a 2-week run-in phase of 2 x 200 mg
BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging
(DCE-MRI) scans will be performed at baseline staging, on day 3 and day
14. On day 14, there will also be 12 hours-pharmacokinetic (PK)
assessment. Combination therapy within the forementioned dosage arms
starts on day 15. After two weeks of combination therapy, on day 29, a
DCE-MRI scan and 12-hours PK will be performed. Restaging for the
evaluation of the efficacy will be performed on day 57. The safety of this
combination will be assessed throughout the complete therapy phase using
CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed
until day 42. Patients who experience clinical benefit (i.e., response
or stable disease) on day 57 with adequate tolerability of the combination
will further receive the medication, as long as the benefit lasts. The trial is
registered under NCT01349296 (clinicaltrials.gov). Recruitment in arm A
has started in February 2012.
Developmental Therapeutics—Experimental Therapeutics
201s
TPS3114 General Poster Session (Board #21H), Mon, 8:00 AM-12:00 PM
Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus
in patients with solid, endometrial, and ovarian cancers. Presenting Author:
Hye Sook Chon, H. Lee Moffitt Cancer Center & Research Institute, Tampa,
FL
Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is
a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and
oral formulations. PI3K/AKT/mTOR signalling is associated with resistance
to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts
AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin
(PC) have broad activity including endometrial, ovarian, and many
cancers. mTOR inhibition with PC has synergistic and additive effects in
solid tumors. A common defect in endometrioid ca is mutation of PTEN,
causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS
over hormonal therapy of metastatic endometrial cancer in a randomized
phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]).
In 35 patients in a phase II study of RIDA, there were 7.7% partial response
(PR) and 58% with stable disease with median duration 6.6 months
(Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca
ultimately develops a phenotype resistant to taxanes that may be overcome
with mTOR inhibition. RIDA may therefore potentiate the response of
endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts)
with advanced solid ca and measureable disease and up to 3 prior therapies
received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of
each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered
orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA
cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics
(PD) are collected. More than 1 anticipated DLT of thrombocytopenia or
neutropenia in the latter part of the cycle shifts the escalation of RIDA to an
alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design
until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1
endometrial, 1 urethral ca. The second cohort of an alternate schedule has
been filled and evaluation continues. Further characterization of tolerability,
efficacy, and PD are planned at the MTD in the phase IB expansion
cohorts of 15 ovarian/15 endometrial cancers.
TPS3116 General Poster Session (Board #22B), Mon, 8:00 AM-12:00 PM
A dose escalation, single arm, phase Ib/II combination study of BEZ235
with everolimus to determine the safety, pharmacodynamics, and pharmacokinetics
in subjects with advanced solid malignancies including glioblastoma
multiforme. Presenting Author: Mohamad Adham Salkeni, University
of Cincinnati Cancer Institute, Cincinnati, OH
Background: Downregulation of a number of signaling pathways, including
the mammalian target of rapamycin (mTOR) pathway, has been demonstrated
to be efficacious in a large range of solid tumors such as breast,
colon, endometrial, glial and hepatocellular carcinoma (HCC). However, we
find that rapamycins lead to suppression of a negative feedback loop from
S6 Kinase 1 (S6K1) to Protein Kinase B (PKB), leading to hyperactivation
of PKB. In pre-clinical studies using a mouse model of carcinogen-induced
HCC, we have demonstrated that combining BEZ235 (a potent and highly
selective reversible ATP site competitive inhibitor of PI3K and mTOR) with
everolimus (an allosteric inhibitor of mTOR) synergizes to inhibit tumor
growth. BEZ235, an orally administered agent, has demonstrated preliminary
antitumor activity in a first-in-human phase I study. The current study
will evaluate this combination in patients with a variety of solid malignancies
that includes glioblastoma multiforme (GBM). Methods: This study is
divided into a phase 1b portion designed to determine safety of increasing
doses of the combination, with extensive pharmacokinetics, pharmacodynamics
and pharmacogenomics analysis; and a phase 2 portion that
includes both solid tumors and GBM based on predominance of the mTOR
and PI3K deregulation in these tumors, to determine preliminary antitumor
activity and the recommended dose for phase 2 studies. We will also
integrate biomarker assessment for gene expression products of the mTOR
downstream pathway such as eukaryotic initiation factor 4E binding protein
(4EBP1) and S6 kinase (S6K). The phase 1b portion has started accruing.
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