Medullary Thyroid CarcinomaPhase 1/2NCT00923247
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)
A Phase 1/2 study testing Bortezomib and Vandetanib in people with Medullary Thyroid Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Medullary Thyroid Carcinoma
- What is being tested?
- Bortezomib and Vandetanib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Feb 2009to 9 Dec 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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)
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Medullary Thyroid Carcinoma
- Being tested
- Bortezomib, Vandetanib
- Keywords
- Vandetanib, Bortezomib, Medullary Thyroid, Proteasome Inhibitor, Cancer, Solid Tumor, Thyroid Cancer, Medullary Thyroid Cancer
- Medical subject headings
- Carcinoma, Medullary, Neoplasms, Thyroid Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BortezomibDrug
Also called Velcade
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
VandetanibDrug
Also called Caprelsa
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
| Study group | Role | What they receive |
|---|---|---|
| Phase 1 - vandetanib and bortezomib | Experimental | Patients will be treated with vandetanib and bortezomib to find the maximally tolerated dose Receives: Drug: Bortezomib; Drug: Vandetanib |
| Phase 2 B - vandetanib alone | Active comparator | Patients will be treated with vandetanib alone. Receives: Drug: Vandetanib |
| Phase 2 A - vandetanib and bortezomib at the MTD | Active comparator | Patients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study Receives: Drug: Bortezomib; Drug: Vandetanib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 4 months
Secondary outcomes (13)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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."
Measured: Cycle 3 day 1 (an average of 60 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2009 (estimated)
- Study start19 Feb 2009
- Primary completion1 Apr 2016
- Study completion9 Dec 2016
Why it stopped: Terminated due to slow accrual,primary endpoint reached \& investigator left NIH.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Medullary Thyroid CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Ravi A. Madan, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Ravi A Madan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00923247
- Sponsor's protocol ID
- 090089
- Other IDs
- 09-C-0089
- Status last verified
- Nov 2018
- First submitted
- 17 Jun 2009
- Last updated
- 29 Nov 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
PubMed 16684987Truong T, Rougier Y, Dubourdieu D, Guihenneuc-Jouyaux C, Orsi L, Hemon D, Guenel P. Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999). Eur J Cancer Prev. 2007 Feb;16(1):62-70. doi: 10.1097/01.cej.0000236244.32995.e1.
PubMed 17220706Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006 Jan;16(1):47-53. doi: 10.1089/thy.2006.16.47.
PubMed 16487013Del Rivero J, Edgerly M, Ward J, Madan RA, Balasubramaniam S, Fojo T, Gramza AW. Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer. Oncologist. 2019 Jan;24(1):16-e14. doi: 10.1634/theoncologist.2018-0452. Epub 2018 Oct 8.
PubMed 30297385
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT00923247
- Acronym / sponsor ID
- 090089
- Conditions
- Medullary Thyroid Carcinoma
- Keywords
- Vandetanib, Bortezomib, Medullary Thyroid, Proteasome Inhibitor, Cancer, Solid Tumor, Thyroid Cancer, Medullary Thyroid Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Terminated due to slow accrual,primary endpoint reached \& investigator left NIH.
- Enrolment
- 22 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 19 Feb 2009 (actual)
- Primary completion
- 1 Apr 2016 (actual)
- Study completion
- 9 Dec 2016 (actual)
- First posted
- 18 Jun 2009 (estimated)
- Results
- Posted 17 May 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Phase 1 - vandetanib and bortezomib | Experimental | Drug: Bortezomib, Drug: VandetanibPatients will be treated with vandetanib and bortezomib to find the maximally tolerated dose |
| Phase 2 B - vandetanib alone | Active comparator | Drug: VandetanibPatients will be treated with vandetanib alone. |
| Phase 2 A - vandetanib and bortezomib at the MTD | Active comparator | Drug: Bortezomib, Drug: VandetanibPatients will be treated with vandetanib and bortezomib at the maximally tolerated dose (MTD) of the Phase I study |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BortezomibAlso: VelcadeThis 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 | Drug | Phase 1 - vandetanib and bortezomib, Phase 2 A - vandetanib and bortezomib at the MTD |
| VandetanibAlso: CaprelsaThis 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 | Drug | Phase 1 - vandetanib and bortezomib, Phase 2 A - vandetanib and bortezomib at the MTD, Phase 2 B - vandetanib alone |
Primary outcome
Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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).
13 secondary outcomes
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
Time frame: 2-3 years
Progression Free Survival (PFS)
Time frame: 2-3 years
Number of Participants With Adverse Events
Time frame: Date treatment consent signed to date off study, approximately 7 years and 9 days
Number of Participants With Tumor Biomarker Calcitonin (CTN) Response
Time frame: 4 weeks
Number of Participants With Tumor Biomarker Carcinoembryonic Antigen (CEA) Response
Time frame: 4 weeks
Percentage of Participants With a Change in Frequency in Tumor-Related Diarrhea Compared to Baseline
Time frame: 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
Time frame: Baseline, and for a period of at least 4 weeks post study drug administration
Maximum Bortezomib Plasma Concentration Normalized to Dose (Cmax/D)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: Cycle 3 day 1 (an average of 60 days); and Pre-dose and 1, 2, 4, 6, 8, 10, and 24 hours post dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 16684987Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10;295(18):2164-7. doi: 10.1001/jama.295.18.2164.
- Background: PubMed 17220706Truong T, Rougier Y, Dubourdieu D, Guihenneuc-Jouyaux C, Orsi L, Hemon D, Guenel P. Time trends and geographic variations for thyroid cancer in New Caledonia, a very high incidence area (1985-1999). Eur J Cancer Prev. 2007 Feb;16(1):62-70. doi: 10.1097/01.cej.0000236244.32995.e1.
- Background: PubMed 16487013Burgess JR, Tucker P. Incidence trends for papillary thyroid carcinoma and their correlation with thyroid surgery and thyroid fine-needle aspirate cytology. Thyroid. 2006 Jan;16(1):47-53. doi: 10.1089/thy.2006.16.47.
- Results publication: PubMed 30297385Del Rivero J, Edgerly M, Ward J, Madan RA, Balasubramaniam S, Fojo T, Gramza AW. Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer. Oncologist. 2019 Jan;24(1):16-e14. doi: 10.1634/theoncologist.2018-0452. Epub 2018 Oct 8.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ravi A Madan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Bortezomib and Vandetanib in people with Medullary Thyroid Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 May 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I: Maximum Tolerated Dose (MTD) of Daily Oral Vandetanib (time frame: 80 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00923247, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2018.