Thyroid Cancer
Conditions
Keywords
medullary thyroid cancer, metastatic, thyroid cancer, carcinoma of the thyroid, receptor tyrosine kinase inhibitor, VEGFR, Unresectable locally advanced thyroid cancer
Brief summary
The purpose of this study is to give patients with medullary thyroid cancer either 300mg/day or 150mg/day vandetanib and compare how well each dose affects how their cancer responds. It will also help the investigators understand the side effects of different doses in these patients.
Detailed description
An International, Randomised, Double-Blind, Two-Arm Study To Evaluate The Safety And Efficacy Of Vandetanib 150 And 300mg/Day In Patients With Unresectable Locally Advanced Or Metastatic Medullary Thyroid Carcinoma With Progressive Or Symptomatic Disease
Interventions
DRUG300mg vandetanib
Oral blinded tablets taken once daily. At objective disease progression or 14 months (whichever is earlier), patient may be unblinded to treatment Dosing with unblinded study treatment can continue until 24 months after patient was randomised. At any time dosing may be interrupted for up to 6 weeks due to toxicity. Dosing may restart at a reduced dose (200mg/day). Once reduced, dose increases are not permitted and dosing must stop if further toxicities occur.
DRUG150mg vandetanib
Oral blinded tablets taken once daily. At objective disease progression or 14 months (whichever is earlier), patient may be unblinded to treatment. Patients who have not dose reduced at the time of unblinding may have their dose increased to 300mg Dosing with unblinded study treatment can continue until 24 months after patient was randomised At any time dosing may be interrupted for up to 6 weeks due to toxicity. Dosing may restart at a reduced dose (100mg/day) \[OR 300 reduced to 200mg/day if dose was increased at unblinding.\] Once reduced, dose increases are not permitted and dosing must stop if further toxicities occur.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written consent from Female or male patients aged 18 years and over. Previously confirmed histological diagnosis of unresectable, locally advanced or metastatic, hereditary or sporadic MTC Objective disease progression within the previous 14 months prior to enrolment, and/or * Have one or more symptoms that the Investigator believes to be related to the patient's MTC. * World Health Organisation (WHO) or Eastern Cooperative Oncology Group (ECOG) Performance status 0-2. * Has measurable disease (at least one lesion, not irradiated within 12 weeks of study randomisation, with longest diameter more or equal 10mm (lymph nodes minimum more or equal 15 mm) with CT or MRI). * Lesions must be amenable to accurate and repeat measurement.
Exclusion criteria
* Prior treatment (major surgery, radiation therapy, chemotherapy, or other investigational drugs) received within 28 days before randomization. * Abnormal liver function tests (bilirubin more than 1.5xULRR, and ALT, AST, or ALP more than 2.5xULRR or 5.0xULRR if related to liver metastases). * Significant cardiac conditions or events such as reduced cardiac functions, symptomatic cardiac arrhythmia requiring treatment, congenital long QT syndrome, history of drug-induced QT prolongation, or QTcF correction unmeasurable or more than 450 ms. * Abnormal electrolytes such as potassium, magnesium and calcium, or abnormal organ functions such as decreased creatinine clearance. * For women only - currently pregnant or breast feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) for Vandetanib 150 and 300mg With Responses Determined by the Investigator | Randomisation to week 60 (maximum) | ORR=proportion of patients with a best response of complete or partial response as per Response Evaluation Criteria in Solid Tumors(RECIST)1.1 |
Secondary
| Measure | Time frame |
|---|---|
| Best Objective Response | Randomisation to week 60 (maximum) |
| Duration of Objective Response (RECIST 1.1) by Treatment Arm | Randomization to Week 60 (maximum) |
| Time to Objective Response (RECIST 1.1) by Treatment Arm | Randomization to Week 60 (maximum) |
| Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Randomization to Week 60 (maximum) |
| Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 3 to week 60 (maximum) |
Countries
Czechia, India, Israel, Italy, Netherlands, Poland, Russia, United Kingdom, United States
Participant flow
Recruitment details
From 8 June 2012 to 2 April 2014, 81 participants were randomized by 29 centers in 9 global countries. The study consisted of a double-blind randomized period and an open-label period.
Pre-assignment details
93 participants were screened; 81 participants were randomized to treatment. Participants with objective disease progression within the 14 months on blinded treatment were given the option to continue to receive vandetanib in open-label period for up to 2 years from the time of study entry. Participants were followed for efficacy during the randomized period only. No further efficacy data was collected in open-label period as pre-specified in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Vandetanib 150 mg Oral blinded tablet, taken once daily | 40 |
| Vandetanib 300 mg Oral blinded tablet, taken once daily | 41 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Open-Label Period (Month 14 to 2 Years) | Other | 0 | 0 | 2 | 2 | 1 | 7 |
| Open-Label Period (Month 14 to 2 Years) | Participant Decision | 0 | 0 | 0 | 0 | 0 | 3 |
| Open-Label Period (Month 14 to 2 Years) | Study-specific Withdrawal Criteria | 0 | 0 | 0 | 0 | 0 | 1 |
| Randomized Period (up to 14 Months) | Adverse Event | 1 | 5 | 0 | 0 | 0 | 0 |
| Randomized Period (up to 14 Months) | Condition Under Investigation Worsened | 2 | 3 | 0 | 0 | 0 | 0 |
| Randomized Period (up to 14 Months) | Other | 1 | 2 | 0 | 0 | 0 | 0 |
| Randomized Period (up to 14 Months) | Participant Decision | 1 | 3 | 0 | 0 | 0 | 0 |
| Randomized Period (up to 14 Months) | Study-specific Discontinuation Criteria | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Vandetanib 150 mg | Vandetanib 300 mg | Total |
|---|---|---|---|
| Age, Continuous | 52.2 Years STANDARD_DEVIATION 15.24 | 52.7 Years STANDARD_DEVIATION 15.42 | 52.5 Years STANDARD_DEVIATION 15.24 |
| Age, Customized >=18 to <40 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Customized >=40 to <65 years | 22 Participants | 20 Participants | 42 Participants |
| Age, Customized >=65 to <75 years | 7 Participants | 10 Participants | 17 Participants |
| Age, Customized >=75 years | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 39 Participants | 37 Participants | 76 Participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 25 Participants | 29 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 40 | 6 / 41 | 0 / 5 | 0 / 9 | 1 / 8 | 10 / 39 |
| other Total, other adverse events | 38 / 40 | 40 / 41 | 5 / 5 | 7 / 9 | 7 / 8 | 31 / 39 |
| serious Total, serious adverse events | 9 / 40 | 9 / 41 | 0 / 5 | 4 / 9 | 2 / 8 | 11 / 39 |
Outcome results
Primary
Overall Response Rate (ORR) for Vandetanib 150 and 300mg With Responses Determined by the Investigator
ORR=proportion of patients with a best response of complete or partial response as per Response Evaluation Criteria in Solid Tumors(RECIST)1.1
Time frame: Randomisation to week 60 (maximum)
Population: Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial response (PR), at least a 30% decrease in the sum of diameters of target lesions; ORR = CR + PR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vandetanib 150 mg | Overall Response Rate (ORR) for Vandetanib 150 and 300mg With Responses Determined by the Investigator | 0.20 Proportion of participants |
| Vandetanib 300 mg | Overall Response Rate (ORR) for Vandetanib 150 and 300mg With Responses Determined by the Investigator | 0.29 Proportion of participants |
Secondary
Best Objective Response
Time frame: Randomisation to week 60 (maximum)
Population: Per RECIST v1.1 for target lesions: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of diameters of target lesions; Progressive disease (PD), at least 20% increase in the sum of diameters of target lesions; Stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vandetanib 150 mg | Best Objective Response | Partial response | 8 Participants |
| Vandetanib 150 mg | Best Objective Response | Progressive disease | 9 Participants |
| Vandetanib 150 mg | Best Objective Response | Stable disease | 21 Participants |
| Vandetanib 150 mg | Best Objective Response | Non-evaluable | 2 Participants |
| Vandetanib 150 mg | Best Objective Response | Complete response | 0 Participants |
| Vandetanib 300 mg | Best Objective Response | Non-evaluable | 4 Participants |
| Vandetanib 300 mg | Best Objective Response | Complete response | 1 Participants |
| Vandetanib 300 mg | Best Objective Response | Partial response | 11 Participants |
| Vandetanib 300 mg | Best Objective Response | Stable disease | 23 Participants |
| Vandetanib 300 mg | Best Objective Response | Progressive disease | 2 Participants |
Secondary
Duration of Objective Response (RECIST 1.1) by Treatment Arm
Time frame: Randomization to Week 60 (maximum)
Population: Per RECIST v1.1 for target lesions: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of diameters of target lesions; Progressive disease (PD), at least 20% increase in the sum of diameters of target lesions; Stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib 150 mg | Duration of Objective Response (RECIST 1.1) by Treatment Arm | 9.8 Months |
| Vandetanib 300 mg | Duration of Objective Response (RECIST 1.1) by Treatment Arm | 8.4 Months |
Secondary
Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm
Time frame: Randomization to Week 60 (maximum)
Population: Per RECIST v1.1 for target lesions: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of diameters of target lesions; Progressive disease (PD), at least 20% increase in the sum of diameters of target lesions; Stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 12 | -3.8 % change | Standard Deviation 29.24 |
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 24 | -13.0 % change | Standard Deviation 19.51 |
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 36 | -16.7 % change | Standard Deviation 24.33 |
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 48 | -20.7 % change | Standard Deviation 23.56 |
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Follow-up RECIST assessment | -51.0 % change | Standard Deviation 0 |
| Vandetanib 150 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Disc. of blinded vandetanib | -11.9 % change | Standard Deviation 27.98 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Follow-up RECIST assessment | -11.4 % change | Standard Deviation 67.05 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 12 | -17.5 % change | Standard Deviation 18.24 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 48 | -30.6 % change | Standard Deviation 25.31 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 24 | -24.9 % change | Standard Deviation 22.11 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Disc. of blinded vandetanib | -27.3 % change | Standard Deviation 29.58 |
| Vandetanib 300 mg | Percentage Change From Baseline in Target Lesion Size (RECIST 1.1) by Treatment Arm | Week 36 | -29.1 % change | Standard Deviation 22.96 |
Secondary
Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm.
Time frame: Week 3 to week 60 (maximum)
Population: All patients who received at least 1 dose of vandetanib and for whom quantifiable plasma concentration data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vandetanib 150 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 8 (Day 56) | 510.5 ng/ml | Standard Deviation 206.5 |
| Vandetanib 150 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 24 (Day 168) | 549.7 ng/ml | Standard Deviation 189.62 |
| Vandetanib 150 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 12 (Day 84) | 561.4 ng/ml | Standard Deviation 215.66 |
| Vandetanib 150 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Discontinuation of blinded vandetanib | 536.8 ng/ml | Standard Deviation 225.34 |
| Vandetanib 150 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 3 (Day 21) | 428.6 ng/ml | Standard Deviation 140.71 |
| Vandetanib 300 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Discontinuation of blinded vandetanib | 964.0 ng/ml | Standard Deviation 357.3 |
| Vandetanib 300 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 3 (Day 21) | 786.2 ng/ml | Standard Deviation 243.15 |
| Vandetanib 300 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 8 (Day 56) | 941.0 ng/ml | Standard Deviation 249.4 |
| Vandetanib 300 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 12 (Day 84) | 969.9 ng/ml | Standard Deviation 396.18 |
| Vandetanib 300 mg | Plasma Concentration of Vandetanib in the Bloodstream (Cmax) for Patients by Treatment Arm. | Week 24 (Day 168) | 1017.7 ng/ml | Standard Deviation 330.89 |
Secondary
Time to Objective Response (RECIST 1.1) by Treatment Arm
Time frame: Randomization to Week 60 (maximum)
Population: Per RECIST v1.1 for target lesions: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of diameters of target lesions; Progressive disease (PD), at least 20% increase in the sum of diameters of target lesions; Stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vandetanib 150 mg | Time to Objective Response (RECIST 1.1) by Treatment Arm | 4.2 Months |
| Vandetanib 300 mg | Time to Objective Response (RECIST 1.1) by Treatment Arm | 4.4 Months |