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1. Oncologist. 2012 Mar 16. [Epub ahead of print]

A Pharmacodynamic Study of the P-glycoprotein Antagonist CBT-1(R) in Combination
With Paclitaxel in Solid Tumors.

Kelly RJ, Robey RW, Chen CC, Draper D, Luchenko V, Barnett D, Oldham RK, Caluag
Z, Frye AR, Steinberg SM, Fojo T, Bates SE.

Medical Oncology Branch and.

AbstractBackground. This pharmacodynamic trial evaluated the effect of CBT-1® on
efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein
(Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally
administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically.
Laboratory studies showed potent and durable inhibition of Pgp, and in phase I
studies CBT-1® did not alter the pharmacokinetics of paclitaxel or
doxorubicin.Methods. CBT-1® was dosed at 500 mg/m(2) for 7 days; a 3-hour
infusion of paclitaxel at 135 mg/m(2) was administered on day 6. Peripheral blood
mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day
6 prior to the paclitaxel infusion. (99m)Tc-sestamibi imaging was performed on
the same schedule. The area under the concentration-time curve from 0-3 hours
(AUC(0-3)) was determined for (99m)Tc-sestamibi.Results. Twelve patients were
planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3
or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56(+) PBMCs was a
statistically significant 51%-100% lower (p < .0001) with CBT-1®. Among 10
patients who completed imaging, the (99m)Tc-sestamibi AUC(0-3) for liver
(normalized to the AUC(0-3) of the heart) increased from 34.7% to 100.8% (median,
71.9%; p < .0001) after CBT-1® administration. Lung uptake was not
changed.Conclusion. CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and
normal liver to a degree observed with Pgp inhibitors studied in earlier clinical
trials. Combined with its ease of administration and lack of toxicity, the data
showing inhibition of normal tissue Pgp support further studies with CBT-1® to
evaluate its ability to modulate drug uptake in tumor tissue.Discussion. Although
overexpression of ABCB1 and other ABC transporters has been linked with poor
outcome following chemotherapy efforts to negate that through pharmacologic
inhibition have generally failed. This is thought to be a result of several
factors, including (a) failure to select patients with tumors in which ABCB1 is a
dominant resistance mechanism; (b) inhibitors that were not potent, or that
impaired drug clearance; and (c) the existence of other mechanisms of drug
resistance, including other ABC transporters. Although an animal model for Pgp
has been lacking, recent studies have exploited a Brca1(-/-); p53(-/-) mouse
model of hereditary breast cancer that develops sporadic tumors similar to
cancers in women harboring BRCA1 mutations. Treatment with doxorubicin,
docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about
shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene,
the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance
in a subset of these tumors. Treating mice with resistant tumors with olaparib
plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although
results in this animal model support a new look at Pgp as a target, in this era
of "targeted therapies," trial designs that directly assess modulation of drug
uptake, including quantitative nuclear imaging, should be pursued before clinical
efficacy assessments are undertaken. Such assessment should be performed with
compounds that inhibit tissue Pgp without altering the pharmacokinetics of
chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®,
inhibits Pgp-mediated efflux from PBMCs and normal liver.

PMID: 22416063 [PubMed - as supplied by publisher]