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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Adults age 18 and older with unresectable, recurrent or metastatic solid tumors, including MTC. Disease must be evaluable by RECIST. Design: 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 maximum tolerated dose (MTD)/dose limiting toxicity (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.

Official Title
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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)

Conditions
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Medullary Thyroid Carcinoma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Vandetanib


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Pathologic confirmation of cancer by the Laboratory of Pathology, National Cancer Institute (NCI) Phase I: Diagnosis of recurrent, metastatic or primary unresectable solid tumor that does not have curative standard treatment. Phase II: Diagnosis of recurrent, metastatic or primary unresectable medullary thyroid cancer (MTC). Measurable disease at presentation: Either by Response Evaluation Criteria in Solid Tumors (RECIST) or by measurement of serum markers (calcitonin, carcinoembryonic antigen (CEA), prostate specific antigen (PSA) or cancer antigen 125 or carbohydrate antigen 125 (CA-125) in the dose-finding portion of the study; with disease measurable by RECIST required only in the phase II cohort. A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status 0 1. Age greater than or equal to 18 years Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the case of nitrosourea) prior to enrollment date; unless the last therapy consisted of an oral agent whose average half life is known to be less than 48 hours in which case only 2 weeks need to have elapsed. Regardless of the therapy, any toxicity greater than Common Terminology Criteria in Adverse Events (CTCAE) grade 1 from previous anti-cancer therapy must have been resolved. Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol with the exception of palliative radiotherapy and there must be sites of measurable disease that did not receive radiation. Organ and marrow function as defined: total bilirubin less than 1.5 times the upper limit of reference range (ULRR), unless the patient meets the criteria for Gilbert's Syndrome alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) all three less than 2.5 times the upper limit of the reference range (ULRR), or less than 5 times the ULRR if judged by the investigator to be related to liver metastases serum creatinine less than 1.5 times the ULRR or creatinine clearance greater than or equal to 30 mL/minute (calculated by Cockcroft-Gault formula or measured in a timed urine collection) serum calcium below the CTCAE grade 1 upper limit (11.5mg/dL or 2.9 mmol/L). In cases where the serum calcium is below the normal range, the calcium adjusted for albumin is calculated and substituted for the measured value. serum potassium greater than the lower limit of normal (LLN) and less than 5.5 mmol/L. serum magnesium greater than the LLN and less than 3.0 mg/dL or 1.23 mmol/L. absolute neutrophil count greater than or equal to 1000/mm(3) platelet count greater than or equal to 100,000/mm(3) Prothrombin time (PT) less than or equal to 4 seconds above ULN and partial thromboplastin time (PTT) less than or equal to 10 seconds above ULN. Ability to understand and sign an informed consent document. Provision of informed consent prior to any study-related procedures Negative pregnancy test for women of childbearing potential Ability and willingness to follow the guidelines of the clinical protocol including visits to National Cancer Institute (NCI), Bethesda, Maryland for treatment and follow up visits. Because the effects of chemotherapy on the developing human fetus are potentially harmful, female patients must be one year post-menopausal, surgically sterile, or using an acceptable method of contraception during and continued after the last dose of study medications (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation). Male patients must be surgically sterile or using an acceptable method of contraception during their participation in this study. Contraceptive use will continue for at least four months after the last dose of study medication. EXCLUSION CRITERIA: Patients with cancer potentially curable by surgical excision alone or patients who have not received therapy that might be considered standard and potentially curable. Evidence of severe or uncontrolled systemic disease or any concurrent condition including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, unstable hypertension, seizure disorder, or psychiatric illness which in the Investigators opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Untreated brain metastases (or local treatment of brain metastases within the last 6 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic toxicities. During Phase II enrollment: Prior therapy with vandetanib. Women who are currently pregnant or breast-feeding, due to the possible adverse effects on the developing fetus and infants. The presence of a second malignancy within the last 2 years, other than squamous cell carcinoma of the skin or in situ cervical cancer because it will complicate the primary objective of the study. Cancer survivors who have been free of disease for at least two years can be enrolled in this study. - There is one other exception to the exclusion of secondary malignancies: multiple endocrine neoplasia type 2 (MEN2) patients with concurrent medullary thyroid cancer and pheochromocytoma may be enrolled at the discretion of the Principal Investigator. Patients with evidence of a bleeding diathesis that cannot be corrected with standard therapy or factor replacement. Any unresolved toxicity greater than CTCAE grade 1 (except alopecia) from previous anticancer therapy. Patients with grade 1 neuropathy will be evaluated on a case by case basis for entry into study. Baseline conditions will be taken into consideration. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy. Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease greater than or equal to 2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. History of arrhythmia (multifocal premature ventricular contractions PVCs, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation controlled on medication is not excluded. History (within the last 6 months) or presence of stroke/cerebrovascular accident. Corrected QT interval (QTc) prolongation with other medications. If the medication can be discontinued and an alternative medication started that does not cause QTc prolongation, the patient would be eligible. If no alternative medication is available and the medication cannot be discontinued for medical reasons, then the patient would not be eligible. Congenital long Q wave, T wave (QT) syndrome, or 1st degree relative with unexplained sudden death under 40 years of age. Presence of left bundle branch block (LBBB). QTc with Bazett's correction that is not measurable, or greater than or equal to 480 msec on screening electrocardiogram (ECG). (Note: If a patient has a QTc interval greater than or equal to 480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be less than 480 msec in order for the patient to be eligible for the study). Patients who are receiving a drug that has a risk of QTc prolongation are excluded if QTc is greater than or equal to 460 msec. Concurrent medication that may cause QTc prolongation or induce Torsades de Pointes: Those medications in Group One will not be allowed. Those medications in Group Two will be allowed. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg) Currently active (uncontrolled) diarrhea greater than or equal to CTCAE Grade 2 that may affect the ability of the patient to absorb the vandetanib or tolerate diarrhea. Antidiarrhea medications are allowed in patients with chronic diarrhea. Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John's Wort) of cytochrome P450 3A4 (CYP3A4) function. Major surgery within 4-weeks, or incompletely healed surgical incision before starting study medications. Biopsies, port placements, and dental work are examples of acceptable (nonmajor) surgery within the 4 week time frame. Inability to take oral medications for whatever reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - vandetanib and bortezomib<br>Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dose | Drug: Bortezomib<br>* This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 & 11 every 28 days in adults<br>* Other names: Velcade;Drug: Vandetanib<br>* This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 & 11 every 28 days in adults<br>* Other names: Caprelsa;|
| Active Comparator: Phase 2 B - vandetanib alone<br>Patients will be treated with vandetanib alone. | Drug: Vandetanib<br>* This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 & 11 every 28 days in adults<br>* Other names: Caprelsa;|
| Active Comparator: Phase 2 A - vandetanib and bortezomib at the MTD<br>Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study | Drug: Bortezomib<br>* This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 & 11 every 28 days in adults<br>* Other names: Velcade;Drug: Vandetanib<br>* This study is designed to assess the safety, tolerance and activity of daily oral vandetanib and bortezomib on days 1, 4, 8 & 11 every 28 days in adults<br>* Other names: Caprelsa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib | 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. | 80 days | 
| Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Bortezomib | 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. | 80 days | 
| Phase 2: Tumor Response in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib | 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. | 4 months | 
| Phase 2: Progression Free Survival in Adults With a Diagnosis of Medullary Thyroid Cancer (MTC) Treated With Daily Oral Vandetanib and Bortezomib | 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). | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Comparison of response between cohorts 1, 2A and 2B was to be determined by computed tomography scan reviews using 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. | 2-3 years | 
| Progression Free Survival (PFS) | Progression free survival is defined as the duration of time from start of treatment to time of progression. Comparison of PFS between cohorts 1, 2A and 2B was to be assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). 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. | 2-3 years | 
| Number of Participants With Adverse Events | Here is the number of participants with adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0. For the detailed list of adverse events see the adverse event module. | Date treatment consent signed to date off study, approximately 7 years and 9 days | 
| Number of Participants With Tumor Biomarker Calcitonin (CTN) Response | Calcitonin was measured by the biomarker response criteria. Complete response (CR) is normalization (≤ upper limit of normal) of CTN level following treatment, confirmed with a repeat CTN level at least 4 weeks apart. Partial response (PR) is a ≥50% decrease in the CTN level relative to the baseline level, confirmed with a repeat CTN level at least 4 weeks apart. Progressive disease is a ≥50% increase in the CTN relative to the baseline level, confirmed with a repeat CTN level at least 4 weeks apart. Stable disease is <50% increase or decrease in CTN level relative to the baseline level. | 4 weeks | 
| Number of Participants With Tumor Biomarker Carcinoembryonic Antigen (CEA) Response | Carcinoembryonic Antigen (CEA) was measured by the biomarker response criteria. Complete response (CR) is normalization (≤ upper limit of normal) of CEA level following treatment, confirmed with a repeat CEA level at least 4 weeks apart. Partial response (PR) is a ≥50% decrease in the CEA level relative to the baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Progressive disease is a ≥50% increase in the CEA relative to the baseline level, confirmed with a repeat CEA level at least 4 weeks apart. Stable disease is <50% increase or decrease in CEA level relative to the baseline level. | 4 weeks | 
| Percentage of Participants With a Change in Frequency in Tumor-Related Diarrhea Compared to Baseline | Complete response is an average of 0-2 formed stools per day for a period of at least 4 weeks. partial response is a ≥50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks. No response is criteria for CR or PR not met. Only patients with a stool frequency of ≥5/day and a stool consistency of watery will be evaluable for clinical response. | Baseline, and for a period of at least 4 weeks post study drug administration | 
| Percentage of Participants With a Change in Consistency in Tumor-Related Diarrhea Compared to Baseline | Baseline stool consistency (formed, loose or partially formed, watery) will be the consistency most frequently observed during a 7-day period immediately prior to starting vandetanib. Complete response (CR) is an average of 0-2 formed stools per day for a period of at least 4 weeks. Partial response (PR) is a ≥50% decrease in the average stool frequency relative to baseline and a change in stool consistency from watery to loose (partially formed) for a period of at least 4 weeks. No response is criteria for CR or PR not met. Only patients with a stool frequency of ≥5/day and a stool consistency of watery will be evaluable for clinical response. | Baseline, and for a period of at least 4 weeks post study drug administration | 
| Maximum Bortezomib Plasma Concentration Normalized to Dose (Cmax/D) | Geometric mean for Bortezomib pharmacokinetic (PK) parameters both before (cycle 1 day 1) and during steady-state Vandetanib (cycle 3 day 1; exposures are dose normalized). Bortezomib plasma concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification (LLOQ) of 1 ng/mL. Only measured concentrations above the LLOQ were used in the calculation of PK parameters. The maximum plasma concentration (Cmax) was recorded as observed values. | 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) | The area under the concentration-time curve (AUC) extrapolated to infinity (AUCinf) was calculated using the linear up-log down trapezoidal method via extrapolation of AUC(LAST) (AUC to the last quantifiable time point) by dividing C(LAST) (the last measurable drug concentration, typically at 24 hour post-dose) by the rate constant of the terminal phase, lambda z. This constant was determined from the slope of the terminal phase of the concentration-time curve using weighted least-squares as the estimation procedure. | 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 | The time it takes for the measured concentration of the drug to drop by half. | 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 | Total systemic clearance = dose/area under curve extrapolated to infinity (AUCinf.). This measurement represents the rate at which plasma is systematically cleared of drug. | 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) | Vss represents the volume into which the drug distributes into once given to the patient at steady-state. This volume parameter provides a measure of where in the body the drug is going, based on fluid volume. | 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 | Because vandetanib PK exposure was only measured during a single 8-hr window during daily dosing, the only comparison to assess the effect of bortezomib is to compare these values to published literature. | Cycle 3 day 1 (an average of 60 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vandetanib, Bortezomib, Medullary Thyroid, Proteasome Inhibitor, Cancer, Solid Tumor, Thyroid Cancer, Medullary Thyroid Cancer