Reinducing Radioiodine-sensitivity in Radioiodine-refractory DTC Using Lenvatinib (RESET)

NCT ID: NCT04858867

Last Updated: 2023-10-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-10
• Study Completion Date: 2025-06-01

Brief Summary

This is a single-centre open label phase II study evaluating the effect of lenvatinib treatment for restoring radioiodine uptake and retention in radioiodine-refractory (RAI-R) thyroid cancer to warrant I-131 therapy.

Detailed Description

RAI-R DTC patients starting standard-of-care lenvatinib treatment will be included in this study. Prior to lenvatinib treatment, patients will undergo I-124 PET/CT to quantify RAI uptake and retention at baseline. The first half of the intended sample size (cohort 1) will be treated with lenvatinib for a total of 12 weeks. After 6- and 12-week treatment, patients will undergo I-124 PET/CT dosimetry to evaluate the redifferentiation effect, assess expected absorbed lesion doses and maximum tolerable activity. Results between 6- and 12-week lenvatinib treatment will be compared to select the lenvatinib treatment duration that leads to highest extent of redifferentiation. The next patients (cohort 2) will then receive lenvatinib for either 6 or 12 weeks.

Patients will undergo subsequent I-131 therapy if a clinically meaningful lesion dose is expected and toxicity is deemed acceptable. For all patients eligible for I-131 therapy, lenvatinib is discontinued prior to administration of I-131 and intra-therapeutic I-131 SPECT dosimetry will be performed for dose verification. Patients who are not eligible for I-131 therapy, will continue lenvatinib treatment at the discretion of the treating physician.

Biopsies are performed at baseline and after 6-week lenvatinib treatment to evaluate alterations at the transcriptional and translational level in biopted tumor lesions. Patients will be followed up according to current guidelines for a total of 9 months after initiating lenvatinib treatment. Metabolic and biochemical response will be assessed using F-18 FDG PET/CT and Tg levels, respectively.

Conditions

Differentiated Thyroid Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1

Study procedures

• Lenvatinib during week 1-12
• rhTSH-stimulated I-124 dosimetry at week 0, 6 and 12
• rhTSH-stimulated I-131 therapy at week 13 (if eligible)
• Intra-therapeutic I-131 dosimetry at week 13 (if eligible)
• Biopsy at week 0 and 6
• F-18 FDG PET/CT at week 0, 6, 12, 24 and 36
• Tg levels at week 0, 6, 12, 24 and 36
• QoL assessment at week 0, 6, 12, 24 and 36

Group Type: OTHER

rhTSH-stimulated I-124 dosimetry

Intervention Type: RADIATION

Preparation:

• Low iodine diet 7 days prior to I-124 ingestion until 24 hours post-ingestion
• Thyrogen injections 24 and 48h prior to I-124 ingestion

Procedures following Jentzen et al:

• Ingestion of capsule with 37±10% MBq I-124
• I-124 PET/CT at 24 and 96h post-ingestion
• Blood draws at 2, 24 and 96h post-ingestion
• Whole body counting at 2, 24 and 96h post-ingestion

Intra-therapeutic I-131 dosimetry

Intervention Type: RADIATION

Procedures following EANM guidelines:

• I-131 SPECT/CT at 2, 6, 24, 96 and 144h post-ingestion
• Blood draws at 2, 6, 24, 96 and 144h post-ingestion
• Whole body counting at 2, 6, 24, 96 and 144h post-ingestion

Cohort 2

Study procedures (in case of 12-wk lenvatinib):

• Lenvatinib during week 1-12
• rhTSH-stimulated I-124 dosimetry at week 0 and 12
• rhTSH-stimulated I-131 therapy at week 13 (if eligible)
• Intra-therapeutic I-131 dosimetry at week 13 (if eligible)
• Biopsy at week 0 and 6
• F-18 FDG PET/CT at week 0, 12, 24 and 36
• Tg levels at week 0, 6, 12, 24 and 36
• QoL assessment at week 0, 6, 12, 24 and 36

Study procedures (in case of 6-wk lenvatinib)

• Lenvatinib during week 1-6
• rhTSH-stimulated I-124 dosimetry at week 0 and 6
• rhTSH-stimulated I-131 therapy at week 13 (if eligible)
• Intra-therapeutic I-131 dosimetry at week 13 (if eligible)
• Biopsy at week 0 and 6
• F-18 FDG PET/CT at week 0, 6, 12, 24, 30 and 36
• Tg levels at week 0, 6, 12, 24, 30 and 36
• QoL assessment at week 0, 6, 12, 24, 30 and 36

Group Type: OTHER

rhTSH-stimulated I-124 dosimetry

Intervention Type: RADIATION

Preparation:

• Low iodine diet 7 days prior to I-124 ingestion until 24 hours post-ingestion
• Thyrogen injections 24 and 48h prior to I-124 ingestion

Procedures following Jentzen et al:

• Ingestion of capsule with 37±10% MBq I-124
• I-124 PET/CT at 24 and 96h post-ingestion
• Blood draws at 2, 24 and 96h post-ingestion
• Whole body counting at 2, 24 and 96h post-ingestion

Intra-therapeutic I-131 dosimetry

Intervention Type: RADIATION

Procedures following EANM guidelines:

• I-131 SPECT/CT at 2, 6, 24, 96 and 144h post-ingestion
• Blood draws at 2, 6, 24, 96 and 144h post-ingestion
• Whole body counting at 2, 6, 24, 96 and 144h post-ingestion

Interventions

rhTSH-stimulated I-124 dosimetry

Preparation:

• Low iodine diet 7 days prior to I-124 ingestion until 24 hours post-ingestion
• Thyrogen injections 24 and 48h prior to I-124 ingestion

Procedures following Jentzen et al:

• Ingestion of capsule with 37±10% MBq I-124
• I-124 PET/CT at 24 and 96h post-ingestion
• Blood draws at 2, 24 and 96h post-ingestion
• Whole body counting at 2, 24 and 96h post-ingestion

Intervention Type: RADIATION

Intra-therapeutic I-131 dosimetry

Procedures following EANM guidelines:

• I-131 SPECT/CT at 2, 6, 24, 96 and 144h post-ingestion
• Blood draws at 2, 6, 24, 96 and 144h post-ingestion
• Whole body counting at 2, 6, 24, 96 and 144h post-ingestion

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years at the time of informed consent
• Histologically or cytologically confirmed DTC (including papillary, follicular or Hürthle Cell carcinoma)
• Progressive (biochemical or anatomic) disease for which lenvatinib is started as standard treatment at the discretion of the treating physician
• Measurable disease at baseline imaging (F-18 FDG PET) according to the definition of the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 with at least one lesion ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short axis for a lymph node.
• RAI-R disease on structural imaging, defined as any one of the following:

• Metastatic lesions that are not RAI-avid on a diagnostic or intra-therapeutic RAI scanperformed prior to enrolment in the current study
• RAI-avid metastatic lesions which remained stable in size or progressed according to RECIST 1.1 criteria despite RAI treatment. Absence of response is observed during 6-9 months after high dose I-131 therapy.
• No recent treatment for thyroid cancer:

• No prior I-131 therapy is allowed <6 months prior to initiation of therapy on this protocol (a diagnostic study using <400 MBq of I-131 is not considered 131I therapy)
• No external beam radiation therapy is allowed <4 weeks prior to initiation of therapy on this protocol. (Previous treatment with radiation for any indication is allowed if the investigator judges that the previous radiation does not significantly compromise patient safety on this protocol)
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (or Karnofsky ≥60%)
• Life expectancy ≥3 months
• Ability to swallow and retain orally-administered medication and no clinically significant gastrointestinal abnormalities that may alter absorption
• Creatinine ≤1.5 mg/dL (≤133 µmol/L) or estimated glomerular filtration rate (eGFR) (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) ≥50 mL/min/1.73m2 or 24-hour urine creatinine clearance ≥50 mL/min/1.73m2
• Adequate blood coagulation function as evidenced by an international normalized ratio (INR) ≤1.5
• Adequate bone marrow function with:

• Absolute neutrophil count ≥1.5*10^9 /L
• Hemoglobin ≥9 g/dL (5.6 mmol/L)
• Platelets ≥100*10^9 /L
• Adequate liver function with

• Albumin ≥25 g/L
• Total bilirubin <1.5x institutional upper limit of normal (ULN) with an exception for patients with Gilbert's syndrome
• Aspartate aminotransferase and alanine aminotransferase ≤3x institutional ULN (≤5x ULN if subject has liver metastases)
• Negative pregnancy test within 7 days prior to starting the study for premenopausal women. Women can be included without pregnancy test if they are either surgically sterile or have been postmenopausal for ≥1 year.
• Sexually active women of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 6 months after the last study treatment administration.Sexually active males patients must agree to use condom during the study and for at least 6 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception. Effective methods of contraception are defined as those, which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intrauterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
• Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol

Exclusion Criteria

• Concomitant or previous malignancies within the last 3 years. Patients are eligible for this study if they have been disease-free of the previous malignancy for at least 3 years, have a history of completely resected non-melanoma skin cancer and/or have indolent secondary malignancies.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• Evidence of cardiovascular risk including any of the following:

• Clinically relevant arrhythmias
• Acute coronary syndromes, severe/unstable angina
• Symptomatic congestive heart failure
• Use of other investigational drugs within 28 days preceding the first dose of treatment in this study or during the study
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lenvatinib and/or to Thyrotropin alfa (human recombinant thyrotropin) or other known contents of the two drugs.
• Inability to follow a low iodine diet or requiring medication with high content in iodide (e.g. amiodarone)
• Patients who received iodinated intravenous contrast as part of a radiographic procedure within 6-8 weeks of study registration. Patients are eligible for this study if urinary iodine analysis reveals that the excess iodine has been adequately cleared after the last intravenous contrast administration
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant, lactating or breast feeding women
• Any medical or other condition that in the opinion of the investigator(s) would preclude the participation in a clinical study
• Unwillingness or inability to comply with study and follow-up procedures

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

HW Kapiteijn

Medical Oncologist, Associate Professor Research and Treatment of Rare Cancers

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ellen Kapiteijn, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

LUMC

Dennis Vriens, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

LUMC

Locations

Leiden University Medical Center

Leiden, South Holland, Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Maaike Dotinga, MSc

Role: CONTACT

M.Dotinga@lumc.nl

+31715263695

Dennis Vriens, MD, PhD

Role: CONTACT

D.Vriens@lumc.nl

+31715299703

Facility Contacts

Ellen Kapiteijn, MD, PhD

Role: primary

H.W.Kapiteijn@lumc.nl

+31715263206

Maaike Dotinga, MSc

Role: backup

M.Dotinga@lumc.nl

+31715263695

References

Dotinga M, Vriens D, van Velden F, Heijmen L, Nagarajah J, Hicks R, Kapiteijn E, de Geus-Oei LF. Managing radioiodine refractory thyroid cancer: the role of dosimetry and redifferentiation on subsequent I-131 therapy. Q J Nucl Med Mol Imaging. 2020 Sep;64(3):250-264. doi: 10.23736/S1824-4785.20.03264-1.

Reference Type: BACKGROUND

PMID: 32744039 (View on PubMed)

Dotinga M, Vriens D, van Velden FHP, Stam MK, Heemskerk JWT, Dibbets-Schneider P, Pool M, Rietbergen DDD, de Geus-Oei LF, Kapiteijn E. Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial. Diagnostics (Basel). 2022 Dec 14;12(12):3154. doi: 10.3390/diagnostics12123154.

Reference Type: BACKGROUND

PMID: 36553163 (View on PubMed)

Other Identifiers

P20.096

Identifier Type: -

Identifier Source: org_study_id