Thyroid Cancer
Conditions
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to compare the progression free survival, overall response rate (ORR) and safety of participants treated with lenvatinib 24 mg by continuous once daily oral dosing versus placebo. The study is conducted in 3 phases: a Prerandomization Phase (screening and baseline period), a Randomization Phase (double-blind treatment period), and an Extension Phase (Optional Open Label (OOL) Lenvatinib Treatment Period and a follow-up period).
Detailed description
Randomization Phase: Participants will receive blinded study drug (lenvatinib/placebo) in 2:1 ratio until documentation of disease progression (confirmed by independent imaging review), development of unacceptable toxicity, or withdrawal of consent. After having completed the primary analysis, subjects treated with lenvatinib who have not experienced disease progression may request to continue open label lenvatinib at the same dose, according to the clinical judgment of the investigator. Participants who discontinue treatment for any reason other than disease progression will be followed in the Randomization Phase until disease progression or start of another anticancer treatment; these participants then enter the Extension Phase for survival follow-up. Extension Phase: Participants in the placebo arm who have disease progression confirmed by IIR could request to enter the OOL Lenvatinib Treatment Period and receive lenvatinib treatment. Participants will receive lenvatinib treatment until disease progression (investigator's assessment), development of intolerable toxicity, or withdrawal of consent. Participants who had disease progression during the Randomization Phase and did not enter the OOL Lenvatinib Treatment Period and all participants who discontinued lenvatinib treatment in the OOL Lenvatinib Treatment Period will enter the follow-up period. Participants will be followed for survival, and all anticancer treatments will be recorded until the time of death.
Interventions
DRUGLenvatinib
Lenvatinib 24 mg (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously. Dose interruptions or reductions were allowed for subjects who experienced treatment-related toxicity.
DRUGPlacebo
Matching placebo (two 10-mg and one 4-mg lenvatinib matched capsules) taken orally once daily, continuously.
Sponsors
Eisai Inc.
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
1. Histologically or cytologically confirmed diagnosis of one of the following DTC subtypes: Papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC). 2. Measurable disease according to (RECIST 1.1) and confirmed by central radiographic review. 3. 131 I-refractory/resistant disease. 4. Evidence of disease progression within 12 months prior to signing informed consent (+1 month screening window). 5. Prior treatment with 0 or 1 vascular endothelial growth-factor (VEGF) or vascular endothelial growth-factor receptors (VEGFR) targeted therapy. 6. Adequate renal, liver, bone marrow, and blood coagulation function, as defined in the protocol.
Exclusion criteria
1. Anaplastic or medullary carcinoma of the thyroid 2. 2 or more prior VEGF/ VEGFR-targeted therapies 3. Received any anticancer treatment within 21 days or any investigational agent within 30 days prior to the first dose of study drug. Inclusion criteria for OOL Lenvatinib Treatment Period : Participants were eligible for lenvatinib treatment in the OOL Lenvatinib Treatment Period if the met the following criteria: 1. Placebo-treated participants in the Randomization Phase who had progressive disease (PD) confirmed by IIR, and who requested treatment with lenvatinib. 2. Participants who continued to satisfy specified inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years | PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years | ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR. |
| Overall Survival (OS) | Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years | Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time. |
| Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve | Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Denmark, France, Germany, Italy, Japan, Poland, Portugal, Romania, Russia, South Korea, Spain, Sweden, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 117 investigative sites in Europe, North America, Asia Pacific, Japan, and Latin America from 17 March 2011 to 19 March 2019.
Pre-assignment details
A total of 612 participants were screened for entry into the study. Of these 612 participants, 220 participants were screening failures and 392 participants were randomly assigned to receive either lenvatinib or placebo in a 2:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Randomization Phase: Lenvatinib 24 mg Participants received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. | 261 |
| Randomization Phase: Placebo Participants received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent. | 131 |
| Total | 392 |
Baseline characteristics
| Characteristic | Randomization Phase: Lenvatinib 24 mg | Randomization Phase: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 10.57 | 61.5 years STANDARD_DEVIATION 10.09 | 61.9 years STANDARD_DEVIATION 10.4 |
| Sex: Female, Male Female | 136 Participants | 56 Participants | 192 Participants |
| Sex: Female, Male Male | 125 Participants | 75 Participants | 200 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 | 161 / 261 | 13 / 16 | 62 / 85 | 15 / 30 |
| other Total, other adverse events | 259 / 261 | 118 / 131 | 84 / 85 | 29 / 30 |
| serious Total, serious adverse events | 171 / 261 | 31 / 131 | 62 / 85 | 16 / 30 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions.
Time frame: Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Lenvatinib 24 mg | Progression Free Survival (PFS) | 18.3 months |
| Randomization Phase: Placebo | Progression Free Survival (PFS) | 3.6 months |
99% CI: [0.14, 0.31]
Secondary
Overall Response Rate (ORR)
ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR.
Time frame: Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomization Phase: Lenvatinib 24 mg | Overall Response Rate (ORR) | 64.8 percentage of participants |
| Randomization Phase: Placebo | Overall Response Rate (ORR) | 1.5 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time.
Time frame: Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
Population: The full analysis set (Intent-to-Treat Analysis Set) included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Lenvatinib 24 mg | Overall Survival (OS) | NA months |
| Randomization Phase: Placebo | Overall Survival (OS) | NA months |
Secondary
Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve
Time frame: Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose
Population: The PK analysis set included all the participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomization Phase: Lenvatinib 24 mg | Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve | 3490 nanogram*hour per milliliter (ng*h/mL) |