BMS-214662 in Treating Patients With Advanced Solid Tumors
Study Details
Study Description
Brief Summary
Phase I trial to study the effectiveness of BMS-214662 in treating patients who have advanced solid tumors. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
PRIMARY OBJECTIVES:
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To establish the maximum tolerated dose (MTD) and identify the dose limiting toxicities (DLT) of the investigational agent BMS-214662 when escalated to a 24-hour continuous intravenous infusion every 7 days for 3 consecutive weeks to patients with solid tumors who have failed curative or survival prolonging therapy or for who no such therapies exist.
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To establish and assess the safety of an appropriate dose for Phase II studies.
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To characterize the pharmacokinetics of BMS-214662 in patients when escalated to a 24-hour continuous IV infusion.
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To assess the extent and duration of farnesyltransferase inhibition in peripheral blood mononuclear cells and other relevant surrogate markers of pharmacological activity.
SECONDARY OBJECTIVES:
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To describe any preliminary evidence of antitumor activity. II. To establish pharmacodynamic relationships for the pharmacological effect of the drug upon surrogate markers of activity and host toxicity.
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To compare the toxicity profiles for the 1 hour IV infusion and 24 hr continuous IV infusion administration schedules, assuming that the 24 hr infusion schedule is feasible.
OUTLINE: This is a dose-prolongation, dose-escalation study.
Single patient cohorts receive BMS-214662 IV over escalating periods of 2, 4, 8, 16, and 24 hours weekly for 3 weeks followed by 1 week of rest. If no patient experiences dose-limiting toxicity (DLT), dose escalation proceeds in the single patient cohorts.
Treatment repeats every 4 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Individual patient cohorts may increase their duration of BMS-214662 infusion in subsequent courses to the current duration safely reached.
Beginning with the infusion level at which DLT is first encountered by a single patient, cohorts of 3-6 patients receive escalating doses of BMS-214662 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. An additional cohort of 10 patients is treated at the MTD.
Patients are followed for at least 4 weeks.
PROJECTED ACCRUAL: A total of 20-40 patients will be accrued for this study within 9-12 months.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (BMS-214662) Single patient cohorts receive BMS-214662 IV over escalating periods of 2, 4, 8, 16, and 24 hours weekly for 3 weeks followed by 1 week of rest. If no patient experiences DLT, dose escalation proceeds in the single patient cohorts. Treatment repeats every 4 weeks for at least 2 courses in the absence of disease progression or unacceptable toxicity. Individual patient cohorts may increase their duration of BMS-214662 infusion in subsequent courses to the current duration safely reached. Beginning with the infusion level at which DLT is first encountered by a single patient, cohorts of 3-6 patients receive escalating doses of BMS-214662 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. An additional cohort of 10 patients is treated at the MTD. |
Drug: BMS-214662
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose (MTD) of BMS-214662, based on the National Cancer Institute Common Toxicity Criteria (NCI CTC) v2.0 [Up to 28 days]
- Adverse events, based on the NCI CTC v2.0 [Up to 5 years]
- Plasma concentration-time profile of BMS-214662 when given as a continuous IV infusion escalating to 24 hr [Up to 48 hours]
Secondary Outcome Measures
- Determination whether the pharmacokinetic behavior is linear as dose is escalated [Up to 48 hours]
- Determination of dose that provides potentially effective level of systemic exposure to the drug as indicated by information from preclinical studies [Up to 48 hours]
- Interpatient variability in the steady state plasma concentration (C^ss) and other pharmacokinetic variables in patients treated at the MTD peak [Up to 48 hours]
- Correlations between pharmacokinetic variables and pretreatment laboratory values, toxicity, and indications of biological response (farnesyltransferase activity) [Up to 48 hours]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Metastatic or inoperable malignancy, other than leukemia or a primary CNS tumor, for which there is no known curative or survival prolonging palliative therapy, or failure of these therapies
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Life expectancy >= 2 months
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ECOG performance status 0-1
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ANC >= 1,500/mm^3
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Platelets >= 100,000/mm^3
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SGOT and SGPT =< 2.5 times the upper limit of normal (ULN)
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Total bilirubin =< ULN
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Serum creatinine =< ULN
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Calculated or measured creatinine clearances (Cockcroft-Gault formula) >= 50 ml/minute
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= 3 weeks since major surgery
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= 4 weeks since chemotherapy or radiation therapy
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No uncontrolled serious medical or psychiatric illness
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Women of childbearing potential must not be pregnant or lactating; all women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L of beta-HCG) within 72 hr prior to receiving the study medication; BMS 214662 has antiproliferative effects which may be harmful to the developing fetus or nursing infant
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Fertile males and females must use adequate contraception
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Signed informed consent
Exclusion Criteria:
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Any history of clinically significant atrial or ventricular arrhythmias, any history of second or third degree heart block, or prolonged QTc interval (greater than 450 ms) on electrocardiogram
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Active brain metastases including evidence of cerebral edema by CT scan or MRI, or progression from prior imaging study, any requirement for steroids, or clinical symptoms of/from brain metastases
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Received any drugs within 7 days prior to receiving study drug therapy, which are known to be substrates of cytochrome P450-3A4 (CYP3A4)
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Patients should not receive concurrent therapy with known CYP3A4 substrates while on study and for at least 1 week following the last dose of BMS-214662; this is due to the CYP3A4 inhibitory potential of BMS-214662; a representative list of commonly prescribed known CYP3A4 substrates includes: terfenadine, astemizole, triazolam, midazolam, cisapride, bepridil, rifabutin, simvastatin, lovastatin, and propafenone
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Patients receiving therapy with BMS-214662 should not receive concomitant therapy with NSAIDs or other potentially nephrotoxic medications for at least 2 days before and after administration of BMS-214662
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Patients with known pre-existing renal disease are not eligible
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Joseph Eder, Dana-Farber Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2013-00032
- 00-003
- U01CA062490
- CDR0000068170