A Study of Combination Chemotherapy & Surgical Resection in the Tx of Adrenocortical Cancer: Mitotane & Continuous Infusion Doxorubicin, Vincristine & Etoposide w/the P-glycoprotein Antagonist, Tariquidar (XR9576), Before & After Surgical Resection
Adrenocortical cancer (ACC) is a rare tumor that is optimally treated with surgical
resection. However, many patients present with unresectable disease and relapses are common
after surgical resection creating a need for more effective systemic therapies. Several
investigators have reported responses to a variety of chemotherapy agents, without a clear
improvement in overall survival. A possible explanation for these disappointing results is
the high levels of expression of P-glycoprotein (Pgp) seen in a majority of adrenocortical
cancers. Pgp, a membrane protein that can function as a drug efflux pump lowering the
intracellular concentrations of various drugs, has been implicated as a mechanism of drug
A prior National Cancer Institute (NCI) study (referred to as MAVE) tried to improve
response rates by using a combined modality approach with chemotherapy and surgery. Prior
in vitro studies had shown that mitotane inhibited Pgp and that continuous exposure to
doxorubicin and vincristine was more effective at overcoming Pgp-mediated resistance than
the same drugs given on an intermittent schedule. The MAVE study used daily oral mitotane
with infusional doxorubicin, vincristine, and etoposide prior to tumor resection in patients
with resectable or potentially resectable tumors. The results showed an overall response
rate of 19% (including minor responses), and an overall median survival of 13.5 months.
These results were similar to those reported with previous regimens in adrenocortical cancer
(ACC). A possible explanation for the failure to achieve a higher response rate may be that
mitotane was unable to inhibit Pgp. Although the serum levels of mitotane achieved in
patients had been shown to block Pgp in vitro, inhibition of Pgp in patients was not
accomplished, as documented by a validated surrogate assay using Pgp-expressing CD56+ cells
and the Pgp substrate, rhodamine. Thus the question of whether Pgp inhibition would improve
response rates remains unanswered.
This trial will attempt to answer the latter question by using an agent, tariquidar
(XR9576), which has been proven to inhibit Pgp in humans with minimal toxicity alone or in
combination with chemotherapy. Tariquidar will be used with the regimen from the prior
MAVE study in an effort to improve response rates and overall survival in patients with ACC
whose options at this time are limited.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Percentage of Participants With a Partial or Complete Response
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is defined as the disappearance of all signs and symptoms of tumor for a period of at least 4 weeks. Partial response is defined as at least a 30% decrease in the sum of the longest diameter of all measured lesions lasting for a period of 4 weeks.
Every 6 weeks for up to a year
Antonio Fojo, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
|National Cancer Institute (NCI)||Bethesda, Maryland 20892|