Tumor resistance to anti-cancer drugs is a major problem in cancer treatment. Studies have
found that a protein (P-glycoprotein) on some cancer cells pumps chemotherapy drugs out of
the cells, reducing treatment effectiveness. In laboratory tests, an experimental drug
called XR9576, has blocked pumping by this protein. It is being used in this study to try
to increase the amount of the anti-cancer drug vinorelbine, in cancer cells. Vinorelbine
has been shown in several clinical trials to be effective against some advanced cancers,
including breast, lung and ovarian, and is one of the drugs pumped out of tumor cells by
Patients with cancer 18 years and older may be eligible for this study. Candidates will be
screened with tests that may include blood and urine tests, electrocardiogram,
echocardiogram, CT scans, X-rays, and nuclear medicine studies. A tumor biopsy may be done
for diagnostic or research purposes.
Study participants will undergo tumor imaging with the radioactive drug Tc-99m Sestamibi.
This drug accumulates in tumor cells and is eliminated from them in much the same way that
some cancer drugs are eliminated from cells. The drug is injected into a vein and a series
of pictures are taken with a gamma camera. After this baseline scan, patients will receive
a dose of XR9576 and undergo a second scan 24 hours later. The scan will show whether
XR9576 affects the accumulation and elimination of Sestamibi in tumor cells. This procedure
may provide a way to monitor cancers for evidence of chemotherapy resistance and show if
XR9576 can improve the effectiveness of therapy.
At least 10 days after the baseline and XR9576 scans, patients will begin the first of 3 or
more 21-day cycles of vinorelbine treatment. On days 1 and 8 of each cycle, patients will
receive a 30-minute infusion of XR9576 intravenously (through a vein) followed by
vinorelbine, infused over a 6- to 10-minute period. (In some patients, XR9576 will be
administered before only one of the two vinorelbine dosages.)
Physical examination, blood tests, and other procedures may be done periodically to monitor
Intrinsic and acquired drug resistance remain major obstacles in the treatment of cancer.
Accumulating evidence indicates that in some malignancies P-glycoprotein can confer
resistance, and that its reversal can improve therapeutic outcome. Clinical trials
investigating P-glycoprotein antagonists have been hampered by the occurrence of
unpredictable pharmacokinetic interactions, which have required dose reductions of the
chemotherapeutic agents to avert excessive toxicity. XR9576 is a new P-glycoprotein
antagonist that is more potent, has prolonged activity, and is potentially devoid of
significant pharmacokinetic interactions. This phase I study seeks to identify the safety
of XR9576 administration in combination with vinorelbine and determine the extent, if any,
of a pharmacokinetic interaction between these two drugs. Clinical responses will also be
Age greater than or equal to 18 years.
Histologic or cytologic confirmation of cancer, for which there is no known standard
therapy capable of extending life expectancy.
Performance status ECOG 0-2.
Life expectancy of 3 months or greater.
Platelet count greater than or equal to 90,000/mL.
Absolute granulocyte count (AGC) greater than or equal to 1,000/mL.
Serum creatinine less than or equal to 1.5 mg/dl (or if greater than 1.5, measured
creatinine clearance greater than or equal to 50 mL/min).
SGPT and SGOT less than or equal to 2.5 times normal limit, and bilirubin less than or
equal to 1.5 times normal limit (in patients with clinical evidence of Gilbert's disease,
less than or equal to 3 times normal limit).
2 weeks from prior radiation or chemotherapy and recovery from associated toxicities such
that they meet eligibility criteria. Hormonal therapy may be taken up to the time of
No serious intercurrent medical illness.
Bidimensionally measurable disease by radiographic means or physical examination; or
relevant tumor markers (i.e. CA-125 and PSA greater than or equal to 2 times upper limit
The ability to understand and willingness to sign a written informed consent form, and to
comply with the protocol.
No pregnant or nursing women; or women of childbearing potential unless using effective
contraception as determined by the patient's physician.
No history of another malignancy; specifically, no patients with a non-skin malignancy or
with melanoma within the past 5 years; no concomitant malignancy that has not been
curatively treated. However, cancer survivors who have undergone potentially curative
therapy for a prior malignancy at least 5 years before enrollment is considered, and are
deemed at low risk for recurrence by their treating physicians.
No patients with current or a history of CNS metastases.
No patients who are a poor medical risk because of other non malignant systemic disease or
active, uncontrolled infection.
No HIV seropositive patients.
No prior vinorelbine therapy.