Lenvatinib in Locally Advanced Invasive Thyroid Cancer

A Phase 2 Study of Neoadjuvant Lenvatinib in Locally Advanced Invasive Thyroid Cancer

This research is being done to evaluate the safety and efficacy of neoadjuvant lenvatinib on surgical outcomes of patients with invasive extrathyroidal differentiated thyroid cancer (DTC).

This research study involves a study drug called lenvatinib

Study Overview

• Status: Recruiting
• Conditions: Advanced Cancer; Differentiated Thyroid Cancer
• Intervention / Treatment: Drug: LENVATINIB

Detailed Description

This is a multicenter, phase II, open-label study examining the effect of neoadjuvant lenvatinib being given to patients with extrathyroidal differentiated thyroid cancer (DTC) prior to surgery to remove cancerous tumors (thyroidectomy).

- The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

• This research study involves a study drug called lenvatinib.
• It is anticipated that 30 people will participate in the study.

The U.S. Food and Drug Administration (FDA) has not approved lenvatinib for the specific disease of extrathyroidal differentiated thyroid cancer (DTC) but it has been approved for other uses.

Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gregory Randolph, MD; Phone Number: 617-573-4115; Email: Gregory_Randolph@MEEI.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital Cancer Center
      • Contact: Gregory Randolph, MD; Phone Number: 617-573-4115; Email: Gregory_Randolph@MEEI.harvard.edu
      • Principal Investigator: Gregory Randolph, MD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Richard Wong, MD; Phone Number: 212-639-7638
      • Principal Investigator: Richard Wong, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Nadia L. Busaidy, MD, FACP, FACE; Email: nbusaidy@mdanderson.org
      • Principal Investigator: Nadia L. Busaidy, MD, FACP, FACE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years of age at the time of informed consent and willing and able to provide written informed consent for the trial.

• Adult participants who are either initially diagnosed with locally advanced thyroid neoplasm or have experienced persistent or recurrent thyroid and/or cervical nodal recurrent DTC (participants with M1 disease are allowed, AJCC 8th edition stage I-IVb)), including:

  • a. Papillary thyroid carcinoma (PTC) - classical and variants

    • 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
  • b. Follicular thyroid carcinoma (FTC)
  • c. Hürthle cell carcinoma
  • d. Poorly differentiated thyroid carcinoma
  • e. Cytologically confirmed thyroid neoplasm, Bethesda 3, 4 and 5

• Evidence of extrathyroidal extension and/or locally invasive disease and deemed at risk for R2 resection by treating team on clinical and/or fiberoptic examination and/or radiographic evaluation in the primary or recurrent setting. Evidence of "at risk for R2 resection" includes:

  • a. Vocal cord paralysis by fiberoptic examination
  • b. Extrathyroid and/or extranodal extension on CT or MRI, including tracheal and/or laryngeal cartilage invasion, esophageal involvement, and/or involvement of perithyroid muscles (e.g. strap, sternocleidomastoid, inferior constrictor muscles) or bone involvement
  • c. Extension into the mediastinum with visceral and/or vascular involvement
  • d. Involvement of the carotid artery or other major vessel by 180 degrees or more (exclusive of complete encasement)
  • e. Other factors that make the participant to be "at risk for R2 resection" may be allowed, after discussion with the study's principal investigator.
• Measurable disease by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 and no medical contraindication to surgery.

• Adequately controlled blood pressure.

  • Blood pressure ≤150/90 with or without antihypertensive medications at screening

• Adequate end-organ function (including bone marrow, coagulation, renal, liver and cardiac) 28 days prior to the study registration as defined below:

  • leukocytes ≥3,000/mcL
  • absolute neutrophil count ≥1,500/mcL
  • platelets ≥100,000/mcL
  • total bilirubin ≤1.5 x institutional upper limit of normal, unless attributed to Gilberts syndrome
  • AST/ALT/Alk Phos ≤3 x institutional upper limit of normal
  • INR ≤1.5 x institutional upper limit of normal
  • creatinine within normal institutional limits OR

  • creatinine clearance ≥30 mL/min per Cockcroft-Gault formulation

    • The cycle 1 day 1 labs need to re-meet eligibility criteria for treatment
• Ability to swallow pills.
• Females must not be lactating or pregnant at baseline (as documented by a negative betahuman chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-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.
• Note: 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 must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation.

Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after.

Exclusion Criteria:

• Diagnosis of medullary thyroid carcinoma or anaplastic (undifferentiated) thyroid carcinoma.

• Radiographically identified following findings:

  • intraluminal airway tumor
  • complete carotid encasement/infiltration
• Active hemoptysis (bright red blood ≥ 1/2 teaspoon) or other uncontrolled bleeding within 21 days prior to the study registration.
• Arterial/venous thromboembolic events in the last 12 months Treatment within 30 days prior to study registration with anticoagulant or antiplatelet therapy, apart from aspirin 81 mg daily.
• Prior radiotherapy to the neck.
• Prior treatment with lenvatinib or other VEGFR-directed therapy, including sorafenib.
• Known metastasis to central nervous system.
• Females who are pregnant or breastfeeding.
• If > 1 + proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1g/24 h will be ineligible.
• Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of study drug.
• Active infection requiring treatment.
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment.
• Prolongation of corrected QT interval (QTc) to > 480 ms as demonstrated by a repeated ECG or any clinically significant ECG abnormality
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lenvatinib.
• Any medical or other condition that in the opinion of the investigators would preclude participant's participation in a clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LENVATINIB; Study procedures include screening for eligibility and study treatment, evaluations, and follow up visits; Lenvatinib will be administered orally daily at a predetermined dose for 2, 4, or 6 cycles, dependent on response. 1 cycle is 28 days.; Surgery per standard of care will follow lenvatinib treatment.	Drug: LENVATINIB; Orally; Other Names: Lenvima

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall R0/R1 resection rate	Evaluate the overall R0/R1 resection rate, as defined by proportion of patients who undergo successful thyroidectomy with clear (R0) or microscopically positive surgical margins (R1).	112 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resection rate of R0	Evaluate R0 resection rates in each of 4 pre-specified extrathyroidal anatomic target interfaces: R0=no cancer cells seen microscopically at the resection margin	112 Days
Resection rate of R1	Evaluate R1 resection rates in each of 4 pre-specified extrathyroidal anatomic target interfaces: R1 cancer cells present microscopically at the resection margin (microscopic positive margin)	112 Days
Change in Surgical complexity and morbidity score (SCMS)	The Thyroid Neck Group Morbidity Complexity Scoring and MGH/MEE-MSK-MD Anderson (MMM) Surgical Morbidity Complexity Score (SMCS) are incorporated, specifying on scale with 5 levels of complexity and morbidity of the surgery [mild (level 0), moderate (level 1), severe (level 2), very severe (level 3), and unresectable (level 4)]. The surgical morbidity/complexity scores will be collected at enrollment, prior to surgery, and based on intraoperative findings. The change in SCMS will be reported as the median SCMS value. Determined by structures requiring resection, the score takes into account preoperatively radiographically defined structures judged to be requiring resection with surgical complexity of the given resection/potential for complications, and expected patient morbidity/change of function from the resection.	112 Days
Primary surgery response rate	Evaluate the response rate (RR) prior to primary surgery based on Response Evaluation Criteria in Solid Tumors version 1.1	112 Days
Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v 5.0	CTCAE version 5	Up to 18 months
Unresectable to resectable conversion rate	The conversion rate will be summarized as frequency (%) -- Determined by structures requiring resection, the RGS takes into account preoperatively radiographically defined structures judged to be requiring resection with surgical complexity of the given resection/potential for complications, and expected patient morbidity/change of function from the resection.	112 Days

Collaborators and Investigators

• Sponsor: Massachusetts Eye and Ear Infirmary
• Collaborators: Eisai Inc.
• Investigators: Principal Investigator: Gregory Randolph, MD, Massachusetts Eye and Ear Infirmary (MEEI)

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: March 24, 2020
• First Submitted That Met QC Criteria: March 24, 2020
• First Posted (Actual): March 25, 2020

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Advanced Cancer; Differentiated Thyroid Cancer
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Lenvatinib
• Other Study ID Numbers: 19-524

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No