Differentiated Thyroid Cancer
Conditions
Keywords
vandetanib, AZD 6474, Differentiated Thyroid Cancer
Brief summary
Primary Objective: To determine the efficacy (as assessed by progression-free survival \[PFS\]) of vandetanib when compared to placebo in participants with differentiated thyroid cancer that is either locally advanced or metastatic who are refractory or unsuitable for radioiodine therapy. Secondary Objectives: * To determine the efficacy of vandetanib when compared to placebo in this participant population as assessed by efficacy variables including duration of response (DOR), objective response rate (ORR), change in tumour size (TS) and overall survival (OS). * To evaluate the pharmacokinetics (PK) of vandetanib in this participant population and potentially investigate any influence of participant demography and pathophysiology on vandetanib PK. * To demonstrate an improvement in time to worsening of pain (TWP) in participants treated with vandetanib when compared to placebo in this participant population. * To evaluate the safety and tolerability of vandetanib treatment in this participant population.
Detailed description
Participants who received vandetanib as randomized treatment were allowed, upon re-consent, to continue on open-label vandetanib if in the opinion of the Investigator the participant received benefit. Placebo participants who experienced disease progression within 60 days of unblinding were offered the option of treatment with open-label vandetanib if, in the Investigator's opinion, such treatment was of clinical benefit to the participant. Approximately 2 years; duration depends on individual participant response.
Interventions
DRUGVandetanib (SAR390530)
Pharmaceutical form: tablet Route of administration: oral
DRUGPlacebo
Pharmaceutical form: tablet Route of administration: oral
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of informed consent to participate in the study as well as provision of informed consent to provide a sample of a previously obtained archival tumor biopsy. * Female or male aged 18 years and older with previously confirmed histological diagnosis of locally advanced or metastatic differentiated (excluding minimally invasive follicular) thyroid cancer not amenable to surgical resection, external beam radiotherapy or local therapy. * Measurable disease defined as at least one lesion, not irradiated within 12 weeks of the date of randomization, that can be accurately measured at baseline. * Participants must have experienced progression within 14 months and be RAI-refractory/resistant or unsuitable for RAI. * Thyroid-stimulating hormone (TSH) suppression below 0.5 mU/L is required. * World Health Organization (WHO) or Eastern Cooperative Oncology Group (ECOG) Performance status 0-2. * Negative pregnancy test (urine or serum) for female participants of childbearing potential.
Exclusion criteria
* Inadequate organ function as defined by: (1) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5\*upper limit of normal (ULN), or greater than 5.0\*ULN if judged by the Investigator to be related to liver metastases. (2) Serum bilirubin greater than 1.5\*ULN. This criterion does not apply to participants with known Gilbert's Disease. (3) Creatinine clearance \<50 mL/min (calculated by Cockcroft-Gault formula). * Risk of prolonged interval between Q and T (QT) on an electrocardiogram (ECG) corrected for heart rate (QTc) as defined by: (1) Current therapy with any medication known to be associated with Torsades de pointes or potent inducers of cytochrome CYP3A4. (2) History of QT prolongation. (3) Congenital long QT syndrome. (4) QT interval corrected for heart rate by the Bazett's method (QTcB) correction unmeasurable or greater than 480 ms on screening ECG. * Previous therapy with approved or investigational tyrosine kinase or anti- vascular endothelial growth factor (VEGF) receptor inhibitors or targeted therapies (e.g. multi-targeted kinase inhibitors such as sorafenib, AMG-706, sunitinib, pazopanib, lenvatinib). * RAI therapy within 12 weeks prior to first dose of study drug, and radiation therapy other than RAI, including external beam, if not completed prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Randomization until disease progression or death, assessed every 12 weeks (up to 22 months) | The PFS was defined as the time (in months) from randomization until the date of first documented disease progression or death (from any cause), whichever came first. Disease progression as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) was defined as: at least a 20% increase and absolute increase of 5 mm in the sum of the longest diameter (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. Analysis was performed by Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36 | Baseline, Week 36 | Tumor size was the sum of the longest diameters of the target lesions. Target lesions were measurable tumor lesions. Baseline was defined as the last evaluable assessment prior to starting treatment. |
| Percentage of Participants With Objective Response | From randomization to the date of first documented tumor progression, or death due to any cause, whichever comes first (maximum duration: up to 42 months) | Objective Response was defined as the percentage (%) of participants with complete response or partial response. Per RECIST 1.1 criteria, complete response was defined as the disappearance of all target lesions since Baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than (\<)10 millimeters (mm). Partial response was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the Baseline sum of diameters. Progressive Disease was defined as at least at least a 20% increase and absolute increase of 5 mm 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. |
| Overall Survival (OS) | From randomization to the date of death due to any cause (maximum duration: up to 42 months) | OS was defined as the time from the date of randomization until death due to any cause. In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. |
| Duration of Response (DOR) | From the date of first response to the date of first documented tumor progression or death due to any cause whichever comes first (maximum duration: up to 42 months) | Duration of response was defined as the time from the date of first documented response until the date of documented progression or death. If participants did not progress following a response, then their DOR used the PFS censoring time. Per RECIST 1.1, progressive disease was defined as at least a 20% increase and absolute increase of 5 mm 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. DOR analysis was performed using Kaplan-Meier method. |
| Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Post-dose on Week 1 to Week 48 | — |
| Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain | From randomization to the date of first assessment of worsening of pain (maximum duration: up to 42 months) | Time to worsening of pain was defined as the time interval from the date of randomization to the date of first assessment of worsening of pain with no evidence of improvement within the next 14 days. Participants rate their worst pain intensity during the past seven days using an 11-point NRS scale, where 0 represents no pain and 10 represents pain as bad as you can imagine. Higher scores indicated greater pain severity. TWP analysis was performed using Kaplan-Meier method. |
Countries
Brazil, China, Czechia, Denmark, France, Italy, Japan, Poland, Russia, Spain, Sweden, United States
Participant flow
Recruitment details
The study was conducted at 60 active centers in 12 countries. A total of 299 participants were screened between 17 September 2013 and 26 September 2014, of which 238 participants were randomized. A total of 235 participants were treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Vandetanib/Vandetanib Participants received Vandetanib 300 mg tablet, orally once daily until disease progression or death, in randomized treatment period (up to maximum of 40 months). Participants who completed the randomized treatment period, were offered the opportunity to continue the same vandetanib treatment in the open label period, if, in the investigator's opinion, they received benefit and if the participant agreed and provided their informed consent to continue the open-label period for up to additional 31 months. | 119 |
| Placebo/Vandetanib Participants received placebo matched to Vandetanib tablet, orally once daily until disease progression or death, in randomized treatment period (up to maximum of 40 months). Participants who completed the randomized treatment period, and experienced disease progression were offered the option of treatment in open-label period with vandetanib, if in the investigator's opinion, such treatment was of clinical benefit to the participant, and if the participant agreed and provided their informed consent to begin open-label vandetanib treatment i.e., 300 mg tablet, orally once daily for up to 31 months. | 119 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-label Period (31 Months) | Adverse Event | 2 | 6 |
| Open-label Period (31 Months) | Death | 0 | 1 |
| Open-label Period (31 Months) | Development of study-specific discontinuation criteria | 1 | 5 |
| Open-label Period (31 Months) | Lost to Follow-up | 1 | 0 |
| Open-label Period (31 Months) | Other than specified above | 9 | 18 |
| Open-label Period (31 Months) | Progressive disease | 4 | 35 |
| Open-label Period (31 Months) | Protocol Violation | 0 | 1 |
| Open-label Period (31 Months) | Withdrawal by Subject | 6 | 8 |
| Randomized Treatment Period (40 Months) | Adverse Event | 22 | 5 |
| Randomized Treatment Period (40 Months) | Death | 1 | 0 |
| Randomized Treatment Period (40 Months) | Development of study-specific discontinuation criteria | 5 | 2 |
| Randomized Treatment Period (40 Months) | Disease progression | 43 | 81 |
| Randomized Treatment Period (40 Months) | Lost to Follow-up | 1 | 1 |
| Randomized Treatment Period (40 Months) | Other than specified above | 24 | 25 |
| Randomized Treatment Period (40 Months) | Protocol Violation | 1 | 0 |
| Randomized Treatment Period (40 Months) | Randomized but not treated | 2 | 1 |
| Randomized Treatment Period (40 Months) | Withdrawal by Subject | 20 | 4 |
Baseline characteristics
| Characteristic | Vandetanib/Vandetanib | Placebo/Vandetanib | Total |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 9.69 | 63.2 years STANDARD_DEVIATION 11.02 | 63.7 years STANDARD_DEVIATION 10.36 |
| Sex: Female, Male Female | 70 Participants | 64 Participants | 134 Participants |
| Sex: Female, Male Male | 49 Participants | 55 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 111 / 117 | 87 / 118 | 9 / 23 | 62 / 74 |
| serious Total, serious adverse events | 37 / 117 | 19 / 118 | 7 / 23 | 24 / 74 |
Outcome results
Primary
Progression-Free Survival (PFS)
The PFS was defined as the time (in months) from randomization until the date of first documented disease progression or death (from any cause), whichever came first. Disease progression as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) was defined as: at least a 20% increase and absolute increase of 5 mm in the sum of the longest diameter (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. Analysis was performed by Kaplan-Meier method.
Time frame: Randomization until disease progression or death, assessed every 12 weeks (up to 22 months)
Population: Intent to treat population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Treatment Period: Vandetanib | Progression-Free Survival (PFS) | 10.0 months |
| Randomized Treatment Period: Placebo | Progression-Free Survival (PFS) | 5.7 months |
Comparison: A multiple testing procedure (MTP) with an alpha-exhaustive recycling strategy was employed to provide adequate control of type I error.p-value: 0.0895% CI: [0.55, 1.03]Log Rank
Secondary
Duration of Response (DOR)
Duration of response was defined as the time from the date of first documented response until the date of documented progression or death. If participants did not progress following a response, then their DOR used the PFS censoring time. Per RECIST 1.1, progressive disease was defined as at least a 20% increase and absolute increase of 5 mm 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. DOR analysis was performed using Kaplan-Meier method.
Time frame: From the date of first response to the date of first documented tumor progression or death due to any cause whichever comes first (maximum duration: up to 42 months)
Population: Analysis was performed on subset of participants with response. Here, '0' in 'overall number of participants' analyzed signifies that no participant in the Placebo/Vandetanib achieved any response, therefore DOR was not analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Treatment Period: Vandetanib | Duration of Response (DOR) | NA months |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of randomization until death due to any cause. In the absence of observation of death, survival time was censored to last date the participant is known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method.
Time frame: From randomization to the date of death due to any cause (maximum duration: up to 42 months)
Population: Analysis was performed on intent-to-treat population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Treatment Period: Vandetanib | Overall Survival (OS) | NA months |
| Randomized Treatment Period: Placebo | Overall Survival (OS) | NA months |
Secondary
Percentage of Participants With Objective Response
Objective Response was defined as the percentage (%) of participants with complete response or partial response. Per RECIST 1.1 criteria, complete response was defined as the disappearance of all target lesions since Baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than (\<)10 millimeters (mm). Partial response was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the Baseline sum of diameters. Progressive Disease was defined as at least at least a 20% increase and absolute increase of 5 mm 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.
Time frame: From randomization to the date of first documented tumor progression, or death due to any cause, whichever comes first (maximum duration: up to 42 months)
Population: Analysis was performed on intent-to-treat population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Treatment Period: Vandetanib | Percentage of Participants With Objective Response | 5.0 percentage of participants |
| Randomized Treatment Period: Placebo | Percentage of Participants With Objective Response | 0 percentage of participants |
Secondary
Randomized Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36
Tumor size was the sum of the longest diameters of the target lesions. Target lesions were measurable tumor lesions. Baseline was defined as the last evaluable assessment prior to starting treatment.
Time frame: Baseline, Week 36
Population: Analysis was performed on intent-to-treat population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36 | 23.29 percent change | Standard Deviation 50.059 |
| Randomized Treatment Period: Placebo | Randomized Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36 | 21.52 percent change | Standard Deviation 25.428 |
Secondary
Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax)
Time frame: Post-dose on Week 1 to Week 48
Population: Number of participants analyzed= participants with available data for the time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 1 | 695.1 ng/ml | Standard Deviation 238.94 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 2 | 846.2 ng/ml | Standard Deviation 288.98 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 4 | 975.7 ng/ml | Standard Deviation 358.33 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 8 | 1043.1 ng/ml | Standard Deviation 395.08 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 12 | 1041.9 ng/ml | Standard Deviation 404.69 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 24 | 1004.9 ng/ml | Standard Deviation 408.34 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 36 | 904.1 ng/ml | Standard Deviation 312.51 |
| Randomized Treatment Period: Vandetanib | Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) | Week 48 | 963.0 ng/ml | Standard Deviation 452.4 |
Secondary
Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain
Time to worsening of pain was defined as the time interval from the date of randomization to the date of first assessment of worsening of pain with no evidence of improvement within the next 14 days. Participants rate their worst pain intensity during the past seven days using an 11-point NRS scale, where 0 represents no pain and 10 represents pain as bad as you can imagine. Higher scores indicated greater pain severity. TWP analysis was performed using Kaplan-Meier method.
Time frame: From randomization to the date of first assessment of worsening of pain (maximum duration: up to 42 months)
Population: Analysis was performed on intent-to-treat population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Treatment Period: Vandetanib | Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain | 5.6 months |
| Randomized Treatment Period: Placebo | Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain | 8.3 months |