A Dose Escalation Study of R115777 (Zarnestra) Combined With Velcade® (PS-341) in Patients With Relapsed Multiple Myeloma.
Overview
- Phase
- Phase 1
- Intervention
- bortezomib
- Conditions
- Refractory Multiple Myeloma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 64
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I)
- Status
- Terminated
- Last Updated
- 12 years ago
Overview
Brief Summary
This phase I/II trial is studying the side effects and best dose of tipifarnib when given together with bortezomib and to see how well they work in treating patients with relapsed multiple myeloma. Tipifarnib and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving tipifarnib together with bortezomib may kill more cancer cells.
Detailed Description
OBJECTIVES: Primary I. Determine the maximum tolerated dose and dose-limiting toxicity of tipifarnib when administered with bortezomib in patients with relapsed multiple myeloma. (Phase I) II. Determine the response rate in patients treated with this regimen. (Phase II) III. Determine the toxicity profile of this regimen in these patients. (Phase II) Secondary I. Determine the progression-free survival of patients treated with this regimen. (Phase II) Tertiary I. Determine whether this regimen overcomes CAM-DR in primary myeloma cells and establish whether ex vivo efficacy predicts a clinical response in these patients. II. Determine if activated Akt predicts clinical resistance and if levels of phosphorylated Akt are reduced by tipifarnib and bortezomib in these patients. III. Determine whether molecular profiles from primary isolates (suspension vs adhered) correlate with clinical response in patients treated with this regimen. OUTLINE: This is a phase I dose-escalation study of tipifarnib followed by a phase II study. Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: Approximately 52-64 patients will be accrued for this study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of multiple myeloma
- •Stage II or III disease
- •Relapsed disease after ≥ 2 prior therapies\*, confirmed by the presence of 1 of the following:
- •New lytic lesion
- •A 25% increase in urine or serum monoclonal protein
- •Patients who received prior bortezomib must have responded to therapy
- •Measurable disease, defined by 1 or more of the following criteria:
- •Serum M-component ≥ 1.0 g/dL by serum protein electrophoresis
- •Urine M-protein excretion \> 200 mg per 24-hour collection, by urine protein electrophoresis
- •Performance status - Karnofsky 60-100%
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (bortezomib, tipifarnib)
Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD.
Intervention: bortezomib
Treatment (bortezomib, tipifarnib)
Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD.
Intervention: tipifarnib
Treatment (bortezomib, tipifarnib)
Phase I: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tipifarnib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive bortezomib as in phase I and tipifarnib as in phase I at the MTD.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I)
Time Frame: Up to day 21
Toxicities, graded according to the NCI CTCAE v3.0 (phase II)
Time Frame: Up to 2 years
Response rate (complete response [CR] + partial response [PR]) determined using the Bladé Response criteria (phase II)
Time Frame: Up to 6 weeks
Exact 95% confidence intervals constructed.
Secondary Outcomes
- Proportion of patients overcoming CAM-DR(Day 11 of course 1)
- Relationship of overcoming CAM-DR and clinical response(Day 11 of course 1)
- Correlation of molecular profiles from primary isolates with clinical response(Day 11 of course 1)
- Progression-free survival (phase II)(Up to 2 years)
- Clinical resistance and levels of phosphorylated Akt(Day 11 of course 1)