A Targeted Phase I/II Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade ), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Cancer (MTC)
This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
First received: June 17, 2009
Last updated: August 23, 2014
Last verified: July 2014
- 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.
- 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.
- 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.
- 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.
Medullary Thyroid Carcinoma
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Targeted Ph I/II Trial of ZD6474 (Vandetanib; ZACTIMA) 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)|
Resource links provided by NLM:
U.S. FDA Resources
Further study details as provided by National Institutes of Health Clinical Center (CC):
Primary Outcome Measures:
- Access the activity of vandetanib/bortezomib in patients with solid tumors using RECIST, and in patients with MTC, using RECIST and tumor biomarkers including CEA and CTN. [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Examine correlations between genotype and response to therapy in patients with MTC. [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Examine the extent of RET inhibition in patients with MTC following the administration of vandetanib [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
- Effect of bortezomib on microtubles [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
|Study Start Date:||February 2009|
|Estimated Study Completion Date:||May 2016|
|Estimated Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
Active Comparator: B Phase 2
Patients will be treated with bortezomib alone.
Active Comparator: A Phase 2
Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose of the Phase I study
Phase IDrug: Vandetanib
- 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 toxcitiy is mediated by affecting more than one pathway or target. Bortezomib is reported to inhibit the 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.
- To assess the activity of vandetanib plus bortezomib in adults with MTC, using RECIST and tumor biomarkers including 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 RET inhibition in patients with MTC following the administration of vandetanib; and (c) examine the effect, if any, of bortezomib on microtubules.
- Adults age 18 and older with unresectable, recurrent or metastatic solid tumors, including MTC.
- Disease must be evaluable by RECIST.
- Phase I dose-escalation study followed by randomized phase II trial.
- Maximum total number for planned enrollment: 117 - Dose-seeking cohorts of three to 6 patients until MTD/DLT reached (up to 24 patients) followed by a randomized phase II trial comparing the activity of the combination of bortezomib plus vandetanib with vandetanib alone (2:1 randomization 62 plus 31 equals 93 patients).
- The MTD and DLT will be determined based on toxicities during the first eight weeks of combined therapy.
- Cycle length will be four weeks. Response will be determined by RECIST every 12 weeks.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00923247
Please refer to this study by its ClinicalTrials.gov identifier: NCT00923247
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
Sponsors and Collaborators
|Principal Investigator:||Ann W Gramza, M.D.||National Cancer Institute (NCI)|