A Dose Escalation Study of R115777 (Zarnestra) Combined With Velcade® (PS-341) in Patients With Relapsed Multiple Myeloma.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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%
- •More than 8 weeks
- •Platelet count ≥ 100,000/mm^3
- •Absolute neutrophil count ≥ 1,000/mm^3
- •Bilirubin ≤ 2 mg/dL
- •Direct bilirubin ≤ 2 times upper limit of normal (ULN)
- •AST or ALT ≤ 2 times ULN
- •Creatinine ≤ 1.5 times ULN
- •Calcium ≤ 12 mg/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •Able to swallow study medication
- •Capable of following directions regarding study medication, or has a daily caregiver who will be responsible for administering study medication
- •No peripheral neuropathy ≥ grade 2
- •No hypersensitivity to any of the following:
- •Bortezomib
- •Imidazole compounds (e.g., clotrimazole, ketoconazole, miconazole, econazole)
- •No serious medical or psychiatric illness that would preclude study compliance
- •No other life-threatening illness (unrelated to tumor)
- •No other active or invasive malignancy within the past 3 years except for nonmelanoma skin cancer
- •No serious infection
- •No prior allogeneic bone marrow transplantation
- •More than 30 days since prior and no concurrent immunotherapy
- •More than 30 days since prior and no concurrent cytotoxic chemotherapy
- •More than 14 days since prior high-dose corticosteroids
- •No concurrent therapeutic corticosteroids (e.g., > 10 mg prednisone per day)
- •No concurrent hormonal therapy
- •No concurrent antiemetic corticosteroids
- •More than 14 days since prior and no concurrent radiotherapy
- •More than 1 year since prior bortezomib
- •More than 14 days since prior investigational drugs
- •No prior tipifarnib
- •No other concurrent cancer-related treatment
- •No concurrent administration of the following enzyme-inducing anti-epileptic drugs:
- •Phenytoin
- •Phenobarbital
- •Carbamazepine
- •No concurrent magnesium- or aluminum-based antacids within 2 hours before or after tipifarnib administration
- •Concurrent pamidronate or other bisphosphonates allowed
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: bortezomib (Drug)
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.
干预措施: tipifarnib (Drug)
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.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Maximum tolerated dose of tipifarnib as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (phase I)
时间窗: Up to day 21
Toxicities, graded according to the NCI CTCAE v3.0 (phase II)
时间窗: Up to 2 years
Response rate (complete response [CR] + partial response [PR]) determined using the Bladé Response criteria (phase II)
时间窗: Up to 6 weeks
Exact 95% confidence intervals constructed.
次要结局
- 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)