A Targeted Ph I/II Trial of ZD6474 (Vandetanib; CAPRELSA) Plus the Proteasome Inhibitor, Bortezomib (Velcade ), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Ca (MTC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib
研究概览
简要总结
Background:
- The combination of anti-cancer drugs vandetanib (given orally) and bortezomib (given intravenously) has not been used in humans. However, both drugs have been studied separately. Bortezomib has been approved by the U.S. Food and Drug Administration (FDA) for treating multiple myeloma and mantle cell lymphoma, while vandetanib is still under investigation pending FDA approval.
- Both bortezomib and vandetanib are under investigation for use in treating certain kinds of cancer. Researchers hope that the combination of these two drugs will be more effective than either of them alone.
Objectives:
- To determine if the combination of vandetanib and bortezomib will decrease the amount of the cancer and, if it does, to determine how long the response will last.
- To determine any side effects that may occur with this combination of treatments.
- To determine what doses of each drug are well tolerated and safe when given together.
- To study genetic mutations in tumors to better understand how tumors grow and how these drugs interact with the tumor.
Eligibility:
- Patients 18 years of age and older with solid tumors that cannot be surgically removed and have either recurred or shown further growth. The tumor(s) must be able to be evaluated by X-ray, MRI (magnetic resonance imaging), and CT (computerized tomography) scanning.
- Patients who have been diagnosed with medullary thyroid cancer will participate in Phase II of the study.
Design:
- Tumor samples may be taken at the start of the study for research purposes.
- Phase I: Patient groups will be treated on an outpatient basis with vandetanib and bortezomib, given at increasing doses over four different levels to determine the maximum tolerated dose calculated by height and weight:
- Doses will be given on Days 1, 4, 8, and 11 for each 28-day cycle.
- Two additional levels (Level 1A and Level 1B) may be included in the study, depending on side effects at various levels.
- Phase II: Patients with medullary thyroid cancer will be divided into two groups, with two patients in Group A for every one patient in Group B. No placebo will be involved in this study.
- Group A: Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose of the Phase I study.
- Group B: Patients will be treated with bortezomib alone.
- A second tumor sample may be taken. In patients with thyroid cancer, the second biopsy will be done at the 6-week evaluation (approximately 42 days after beginning). In patients with cancer other than thyroid cancer, the second biopsy will be obtained on Day 4 of either the first or second cycle, after the bortezomib infusion.
- The effects of the drugs will be studied through blood samples and CT scans taken during and after various drug cycles.
详细描述
Background:
- Vandetanib (CAPRELSA; ZD6474) potently inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), and shows additional inhibitory activity at sub-micromolar concentrations against the Rearranged during Transfection (RET) receptor, Flt-4 and EGF receptor tyrosine kinases.
- Clinical trials have shown that vandetanib is active against medullary thyroid carcinomas (MTCs), but the activity is characterized by partial responses of variable duration, underscoring the need to develop active combinatorial regimens.
- Bortezomib (PS-341, Velcade ), a proteasome inhibitor, has been reported to have several putative mechanisms of action and it is likely that its toxicity is mediated by affecting more than one pathway or target. Bortezomib is reported to inhibit the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathway and regulate NF-kappaB-dependent expression of several other inhibitors of apoptosis.
- In vitro studies have shown bortezomib to be active against a broad range of thyroid cancer cell lines. Given this activity of bortezomib and the role of the proteasome in regulating diverse cellular pathways, this study proposes to combine bortezomib with vandetanib to treat patients with advanced solid tumors with a focus on patients with MTC.
Objectives:
- To assess the activity of vandetanib plus bortezomib in adults with MTC, using Response Evaluation Criteria in Solid Tumors (RECIST) and tumor biomarkers including carcinoembryonic antigen (CEA) and calcitonin as endpoints.
- To assess the safety and tolerance of vandetanib plus bortezomib in dose-seeking cohorts.
- To compare the combination bortezomib plus vandetanib versus vandetanib alone in adults with MTC by assessing the response rate and progression-free survival
- In exploratory analyses: (a) examine the correlation between genotype and response to therapy in patients with MTC, (b) examine the extent, if any, of rearranged during transfection (RET) inhibition in patients with MTC following the administration of vandetanib; and (c) examine the effect, if any, of bortezomib on microtubules.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Phase 1 - vandetanib and bortezomib
Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dose
干预措施: Bortezomib (Drug)
Phase 1 - vandetanib and bortezomib
Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dose
干预措施: Vandetanib (Drug)
Phase 2 B - vandetanib alone
Patients will be treated with vandetanib alone.
干预措施: Vandetanib (Drug)
Phase 2 A - vandetanib and bortezomib at the MTD
Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study
干预措施: Bortezomib (Drug)
Phase 2 A - vandetanib and bortezomib at the MTD
Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study
干预措施: Vandetanib (Drug)
结局指标
主要结局
Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib
时间窗: 80 days
A maximum tolerated dose for vandetanib will be determined if dose limiting toxicity is observed in 2 or more patients at one of the dose levels being evaluated. The MTD will be the dose level immediately preceding the dose level at which DLT (e.g. defined as neutrophil count below 1000/ µL (grade 3) on 2 consecutive measurements drawn at least 72 hours OR a single neutrophil count below 500/µL occurred. Platelet count below 50,000 µL (grade 3) on 2 consecutive measurements drawn at least 72 hours apart OR a singe platelet count below 25,000/µL. A platelet transfusion administered when platelet count is below 50,000/µL is dose limiting thrombocytopenia, unless the transfusion is being administered for peri-operative coverage.
Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Bortezomib
时间窗: 80 days
A maximum tolerated dose for bortezomib will be determined if dose limiting toxicity is observed in 2 or more patients at one of the dose levels being evaluated. The MTD will be the dose level immediately preceding the dose level at which DLT (e.g. defined as neutrophil count below 1000/ µL (grade 3) on 2 consecutive measurements drawn at least 72 hours OR a single neutrophil count below 500/µL occurred. Platelet count below 50,000 µL (grade 3) on 2 consecutive measurements drawn at least 72 hours apart OR a singe platelet count below 25,000/µL. A platelet transfusion administered when platelet count is below 50,000/µL is dose limiting thrombocytopenia, unless the transfusion is being administered for peri-operative coverage.
Phase 2: Tumor Response in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib
时间窗: 4 months
Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.
Phase 2: Progression Free Survival in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib
时间窗: 4 months
Progression free survival is defined as the duration of time from start of treatment to time of progression. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of one or more new lesions or unequivocal progression of existing non-target lesions. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
次要结局
- Percentage of Participants With a Change in Frequency in Tumor-Related Diarrhea Compared to Baseline(Baseline, and for a period of at least 4 weeks post study drug administration)
- Progression Free Survival (PFS)(2-3 years)
- Number of Participants With Adverse Events(Date treatment consent signed to date off study, approximately 7 years and 9 days)
- Number of Participants With Tumor Biomarker Calcitonin (CTN) Response(4 weeks)
- Number of Participants With Tumor Biomarker Carcinoembryonic Antigen (CEA) Response(4 weeks)
- Response Rate (Complete Response (CR) + Partial Response (PR) of Adults With a Diagnosis of MTC Treated With Either of Two Regimens: (1) Daily Oral Vandetanib and Bortezomib or (2) Daily Oral Vandetanib(2-3 years)
- Percentage of Participants With a Change in Consistency in Tumor-Related Diarrhea Compared to Baseline(Baseline, and for a period of at least 4 weeks post study drug administration)
- Maximum Bortezomib Plasma Concentration Normalized to Dose (Cmax/D)(Cycle 1 day 1, and cycle 3 day 1 (an average of 61 days); and Pre-dose, 1, 2,4, 6, 8, 10 and 24 hours post dose)
- Area Under the Bortezomib Plasma Concentration Versus Time Curve From Time Zero to Infinity/Dose (AUCinf/D)(Cycle 1 day 1, and cycle 3 day 1 (an average of 61 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose)
- Terminal Half-Life (T1/2) of Bortezomib(Cycle 1 day 1, and cycle 3 day 1 (an average of 61 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose)
- Total Systemic Clearance (CL) of Bortezomib(Cycle 1 day 1, and cycle 3 day 1 (an average of 61 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose)
- Bortezomib Volume of Distribution (Vss)(Cycle 1 day 1, and cycle 3 day 1 (an average of 61 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose)
- Comparison of Steady State Vandetanib Exposure With Relevant Literature Values(Cycle 3 day 1 (an average of 60 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose)
研究者
Ravi A. Madan, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)