Phase 2
N=152
A Trial of Lenvatinib (E7080) in Subjects With Iodine-131 Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 Milligram (mg) Daily Will Provide Comparable Efficacy to a 24 mg Starting Dose, But Have a Better Safety Profile
Thyroid Cancer
Bottom Line
View on ClinicalTrials.gov: NCT02702388 ↗Enrolled (actual)
152
Serious AEs
40.1%
Results posted
Jan 2021
Primary outcome: Primary: Objective Response Rate (ORR) as of Week 24 (ORR24wk) — 57.3; 40.3 percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Lenvatinib (Drug); Lenvatinib matching placebo (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Eisai Inc.
- Primary completion
- Dec 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Objective Response Rate (ORR) as of Week 24 (ORR24wk) |
57.3; 40.3 | — |
| PRIMARY Percentage of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) in the First 24 Weeks |
61.3; 57.1 | — |
| SECONDARY Progression-free Survival (PFS) |
NA; 24.4 | — |
| SECONDARY PFS After Next Line of Treatment (PFS2) |
NA; NA | — |
| SECONDARY Number of Participants With TEAE and Serious Adverse Events (SAEs) |
75; 76; 26; 35 | — |
| SECONDARY Time to Treatment Discontinuation Due to an Adverse Event (AE) |
NA; NA | — |
| SECONDARY Number of Dose Reductions |
17; 20; 20; 13; 13; 8 | — |
| SECONDARY Time to First Dose Reduction |
15.3; 24.1 | — |
| SECONDARY Model Predicted Apparent Total Clearance (CL/F) Following Oral Dosing of Lenvatinib |
6.408; 6.243 | — |
| SECONDARY Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib |
3747; 3370 | — |
| SECONDARY Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroglobulin Levels |
— | — |
| SECONDARY Parameter Estimates From the Population Pharmacokinetic/Pharmacodynamic (PK/PD) Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Thyroid-Stimulating Hormone (TSH) Levels |
— | — |
| SECONDARY Baseline Level Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and Vascular Endothelial Growth Factor (VEGF), Soluble Tie-2, Angiopoietin-2 (Ang-2) and Fibroblast Growth Factor-23 (FGF23) Levels |
0.370; 14.6; 3.36; 0.0990 | — |
| SECONDARY Mean Residence Time (MRT) Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels |
58.3; 354; 173; 265 | — |
| SECONDARY Hill Coefficient Estimates From the Population PK/PD Model Describing the Relationship Between Lenvatinib Exposure (AUC) and VEGF, Soluble Tie-2, Ang-2 and FGF23 Levels |
1.00; 0.313; 4.27; 1.00 | — |
| SECONDARY Parameter Estimates From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2 |
0.00249; 0.0877; 0.268; -0.0220; -0.0146 | — |
| SECONDARY Lenvatinib Mean AUC Resulting in 50% of the Emax (EC50) Estimate From the PK/PD Model for Tumor Growth Inhibition and Serum Biomarkers Tie-2 and Ang-2 |
1760 | — |
| SECONDARY Scale Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS |
0.00700; 0.0000935 | — |
| SECONDARY Shape Factor Estimate for Final Parametric Time to Event PK/PD Model for PFS |
1.36; 2.19 | — |
| SECONDARY Lenvatinib AUC Exposure Effect Estimate for Final Parametric Time to Event PK/PD Model for PFS |
0.00111 | — |
| SECONDARY Predicted Percent Change in Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS |
-0.0523 | — |
| SECONDARY Baseline Tumor Size Estimate for Final Parametric Time to Event PK/PD Model for PFS |
-0.00547 | — |
| SECONDARY Input Rate Indirect Effect Model Estimate From Base/Final PK/PD Blood Pressure Model |
2.76 | — |
| SECONDARY Drug Effect on Systolic and Diastolic Input Rate Estimates From Base/Final PK/PD Blood Pressure Model |
12.0; 21.1 | — |
| SECONDARY Number of Participants With Weight Decrease Stratified by AUC Quartile (Q) Group |
82; 20; 29; 4; 75; 17 | — |
| SECONDARY Number of Participants With Hypertension Stratified by AUC Quartile (Q) Group |
54; 14; 37; 30; 0; 48 | — |
| SECONDARY Number of Participants With Proteinuria Stratified by AUC Quartile (Q) Group |
104; 12; 13; 6; 92; 7 | — |
| SECONDARY Number of Participants With Fatigue Stratified by AUC Quartile (Q) Group |
75; 27; 30; 3; 81; 32 | — |
| SECONDARY Number of Participants With Diarrhea Stratified by AUC Quartile (Q) Group |
55; 39; 35; 6; 53; 45 | — |
| SECONDARY Number of Participants With Nausea Stratified by AUC Quartile (Q) Group |
88; 32; 14; 1; 79; 36 | — |
| SECONDARY Number of Participants With Vomiting Stratified by AUC Quartile (Q) Group |
106; 19; 7; 3; 100; 21 | — |
| SECONDARY Change From Baseline in the Health-Related Quality of Life (HRQoL) Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS) |
0.8; 0.8; -0.1; 0.0; -0.1; -0.1 | — |
| SECONDARY Change From Baseline in the HRQoL Assessed by Functional Assessment of Cancer Therapy-General (FACT-G) Total Score |
81.1; 77.8; -3.0; -1.3; -4.5; -3.8 | — |
Summary
This is a multicenter, randomized, double-blind study being conducted as a postmarketing requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has a better safety profile in participants with radioiodine-refractory differentiated thyroid cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.
Eligibility Criteria
Inclusion Criteria
- Participants must have histologically or cytologically confirmed diagnosis of one of the following differentiated thyroid cancer (DTC) subtypes:
- Papillary thyroid cancer (PTC)
- Follicular variant
- Variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, oxyphil, Warthin's-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated)
- Follicular thyroid cancer (FTC)
- Hurthle cell
- Clear cell
- Insular
- Measurable disease meeting the following criteria and confirmed by central radiographic review:
- At least 1 lesion of greater than or equal to (>=)1.0 centimeter (cm) in the longest diameter for a non-lymph node or >=1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) using computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1 target lesion and it is a non-lymph node, it should have a longest diameter of >=1.5 cm.
- Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
- Participants must show evidence of disease progression within 12 months (an additional month will be allowed to accommodate actual dates of performance of screening scans, that is, within less than or equal to ) 600 millicurie (mCi) or 22 gigabecquerels (GBq), with the last dose administered at least 6 months prior to study entry.
- Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection, will be eligible if they have remained clinically stable, asymptomatic, and off steroids for one month.
- Participants must be receiving thyroxine suppression therapy and thyroid stimulating hormone (TSH) should not be elevated (TSH should be =30 mL/min per the Cockcroft and Gault formula.
- Adequate bone marrow function:
- Absolute neutrophil count (ANC) >=1500/mm^3 (>=1.5*10^3/uL)
- Platelets >=100,000/mm^3 (>=100*10^9/L)
- Hemoglobin >=9.0 g/dL
- Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) 3*ULN (in absence of liver metastases) or >5*ULN (in presence of liver metastases) AND the participant also is known to have bone metastases, the liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of total alkaline phosphatase.
- Males or females age >=18 years at the time of informed consent.
- Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of B-hCG. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
- All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing).
- Females of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least 1 month after finishing treatment. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (example, total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the ent
Data sourced from ClinicalTrials.gov (NCT02702388). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.