Adrenal Cortex Neoplasms Clinical Trial
Official title:
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
This study will examine the safety and effectiveness of treating adrenocortical cancer with
combination chemotherapy using doxorubicin, vincristine, and etoposide in addition to the
drugs mitotane and tariquidar and, when possible, surgery. Adrenocortical cancer cells have
a large amount of a protein called P-glycoprotein that "pumps" anti-cancer drugs out of the
cells, decreasing their effectiveness. Continuous infusions of doxorubicin, vincristine, and
etoposide may improve chemotherapy results by blocking the P-glycoprotein pump, as may use
of tariquidar, an experimental drug that is known to block the P-glycoprotein pump.
Patients 18 years of age and older with adrenocortical cancer that has recurred, spread, or
cannot be treated surgically may be eligible for this study. Candidates will be screened
with a medical history and physical examination; review of pathology slides; blood tests;
electrocardiogram (EKG); imaging tests, including computed tomography (CT) of the chest,
abdomen and pelvis; chest x-ray; and possibly a bone scan or other imaging tests needed to
evaluate the cancer, urine studies, and an echocardiogram. Also, a biopsy (removal of a
small sample of tumor tissue) may be required if a specimen is not available to confirm the
cancer.
Participants will undergo the following tests and procedures:
- Tumor biopsy. Before starting chemotherapy, a small piece of tumor is removed to study
the P-glycoprotein pump and to determine the tumor genetics.
- Blood draw. Blood is drawn before treatment begins to establish baseline levels for
future blood tests.
- Central venous catheter placement. A specially trained physician places a plastic tube
into a major vein in the chest. The tube is used to give the study drugs and other
medications and to withdraw blood samples. It can stay in the body for months or be
removed after each treatment is completed. The tube placement is done under a local
anesthetic in the radiology department or operating room.
- Chemotherapy. Treatment cycles are 21 days. Doxorubicin, vincristine, and etoposide are
given through the central venous catheter by an infusion pump continuously over 96
hours starting day 1 of each cycle. The dose of these drugs may be increased or
decreased from cycle to cycle, based on side effects. Mitotane is given in pill form
starting day 1 of cycle 1 and is taken every day throughout the entire study. The
mitotane dose is gradually increased as long as the side effects are tolerable.
Tariquidar is given through the central venous catheter as a 30-minute infusion on days
1 and 3 of every cycle. The tariquidar dose remains the same throughout the study.
Treatment will continue for two cycles after all the cancer is gone, or until surgery
is done to remove some or all of the remaining cancer, or, if surgery is not an option,
until the cancer has grown to where it is defined as progressive disease.
- Nuclear scans. A nuclear scan is done before treatment begins and again on day 1 or day
3 of the first treatment cycle after administration of tariquidar to evaluate the P
glycoprotein response to treatment.
- Computed tomography (CT) scans. These scans are done every two treatment cycles to
follow disease progress.
- Surgery. Surgery to remove areas of cancer may be considered at any point during the
study (including before beginning treatment), if it is deemed beneficial. Treatment
with the study drugs will begin or resume after surgery. The length of treatment will
depend on the response to treatment before the surgery and on whether there is any
cancer remaining after the surgery.
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
resistance.
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.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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