Determine the fraction of RAI-R thyroid cancer patients who are eligible for I-131 therapy after 6- or 12-week lenvatinib treatment to an extent that clinically meaningful tumour radiation doses [Gy] can be safely delivered with acceptable I-131…
ID
Source
Brief title
Condition
- Endocrine neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Fraction of RAI-R thyroid cancer patients who are eligible for I-131 therapy
after 6- or 12-week lenvatinib treatment to an extent that clinically
meaningful tumour radiation doses [Gy] can be safely delivered with acceptable
I-131 activities [MBq] as determined by I-124 dosimetry of both lesions and
healthy organs at risk.
Secondary outcome
• Extent of RAI uptake and retention at baseline and after 6- or 12-week
lenvatinib
• Optimal duration of lenvatinib treatment (6 weeks or 12 weeks) for maximum
redifferentiation to occur.
• Agreement between expected absorbed dose per lesion predicted by I-124 PET/CT
dosimetry and actual absorbed dose per lesion determined by intra-therapeutic
I-131 SPECT/CT dosimetry in patients in which I-131 therapy is warranted.
• Metabolic and biochemical treatment response using F-18 FDG PET and
unstimulated (TSH-suppressed) thyroglobulin levels, respectively.
• Overall survival, best objective response and progression free survival.
• Incidence and severity of toxicities according to CTCAE 5.0.
• Quality of life
An explorative endpoint of this study is to evaluate alterations at the
transcriptional and translational level in biopted tumour lesions before and
after lenvatinib treatment and to determine whether treatment response is
related to genetical profiles.
Background summary
Radioactive I-131 therapy is a mainstay therapy in advanced differentiated
thyroid cancer (DTC), thereby offering substantial survival and palliative
benefits to the patient. Its effectiveness is correlated with the ability of
cancer tissue to take up and retain radioiodine (RAI) after which the tissue*s
structure is damaged by the emission of short-pathlength beta particles. The
sodium iodide symporter (NIS) plays a pivotal role in the uptake and retention
of RAI. About two-third of patients with distant metastases will develop
RAI-refractory (RAI-R) thyroid cancer, characterized by an affected expression
of NIS and poor response to I-131 therapy or patients reaching the maximum
recommended cumulative dose of more than 22.2 GBq. Management of these patients
is a considerable challenge in clinical practice and the disease is therefore
associated with a poor overall prognosis. Currently, multi-tyrosine kinase
inhibitors (TKIs) like lenvatinib and sorafenib are recommended treatment
options of progressive, locally advanced or metastasized RAI-R DTC, but have
variable side-effects and a modest effect on progression-free survival.
A potential alternative way to achieve disease control in RAI-R thyroid cancer
is to re-sensitize tumours to RAI using redifferentiation agents such as
multi-tyrosine kinase inhibitors (TKIs) like lenvatinib and subsequently employ
RAI therapy. The direct antitumour activity of these multikinase inhibitors is
based on the inhibition of angiogenesis and cell growth via molecular pathways
that are also involved in the regulation of NIS. The ability to enhance RAI
uptake and retention has already been observed for TKIs selumetinib,
vemurafenib and dabrafenib. In contrast, sorafenib showed disappointing results
regarding renewed RAI uptake and retention. In this pilot study, we will
evaluate the ability of lenvatinib to increase NIS expression and RAI uptake
and retention to halt resistance to I-131 therapy in RAI-R thyroid cancer.
Study objective
Determine the fraction of RAI-R thyroid cancer patients who are eligible for
I-131 therapy after 6- or 12-week lenvatinib treatment to an extent that
clinically meaningful tumour radiation doses [Gy] can be safely delivered with
acceptable I-131 activities [MBq] as determined by I-124 dosimetry of both
lesions and healthy organs at risk.
Study design
This is a single-centre open label phase II study evaluating the effect of
lenvatinib treatment for restoring radioiodine uptake and retention in RAI-R
thyroid cancer to warrant I-131 therapy. 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. Besides that, patients undergo F-18 FDG
PET/CT and a biopsy is performed. An additional biopsy is performed after 6
weeks of lenvatinib treatment. 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 and to assess expected absorbed lesion doses and
the MTA. Patients will undergo subsequent I-131 therapy if a clinically
meaningful lesion dose is expected with the MTA of I-131. For all patients
eligible for I-131 therapy, lenvatinib is discontinued prior to administration
of I-131 and post-therapeutic I-131 SPECT dosimetry will be performed for dose
verification. 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 who are not eligible for I-131
therapy, will continue lenvatinib treatment at the discretion of the treating
physician. Patients will be followed up according to current guidelines for a
total of 9 months after the start of lenvatinib treatment. Metabolic and
biochemical response will be assessed using F-18 FDG PET/CT and Tg levels,
respectively.
Intervention
I-124 dosimetry
Study burden and risks
Patients who will be included in this study have advanced thyroid cancer with
poor prognosis and a lack of effective treatment options. Although RAI-R
thyroid cancer may show slow progression in the beginning of disease, the
progression accelerates towards the end of disease. Therefore, most of these
patients are showing a high disease-related mortality. Short-course treatment
with lenvatinib is expected to redifferentiate RAI-R thyroid cancer to an
extent that I-131 therapy becomes feasible in 60% of patients. There is a
common agreement among leading physicians that redifferentiation is the best
option for RAI-R DTC patients which has been published in several peer-reviewed
reviews and articles. Additionally, the dosimetry approach used in this study
is going to prevent patients who are not likely to benefit from I-131 therapy
from palliative treatment with high activities of RAI. Determining the MTA in
patients will avoid life-threatening side-effects of I-131 therapy, which is
still not taken into account in administering an activity following the current
empirical approach. Since most patients already had several I-131 treatments,
the cumulative radiation-related toxicities become of importance. Investigating
the extent of redifferentiation after lenvatinib treatment, i.e. increased or
renewed RAI uptake and retention, and determining the effective and safe I-131
activity that can be administered to the patient comes at the cost of
additional 6-14 blood drawings and whole body counting procedures, 2-3
administrations of I-124, up to 2 administrations of F-18 FDG and a total of
5-7 PET/CT scans (instead of routinely performed contrast-enhanced whole body
CT scans every 12 weeks). Additionally, an extra biopsy is performed during
lenvatinib treatment. To verify the delivery of I-131 to lesions and critical
structures, a total of 3 post-therapeutic SPECT/CT scans will be performed
which requires only one extra visit to the hospital as patients are expected to
have a mandatory hospital admission of 4-5 days after I-131 administration.
We believe that the advantages significantly outweigh the additional visits to
the hospital to undergo these scans (with accompanying radiation burden), blood
drawings, whole-body retention measurements and the biopsy. A substantial
amount of patients is likely to benefit from this study, at least to slow down
tumour progression significantly. The major risk for patients in this study
lies in the medication. Lenvatinib is well known to have side effects. As we
aim to apply short-term treatment of either 6 or 12 weeks, the toxicity burden
to patients is expected to be reduced in comparison to standard-of-care
long-term lenvatinib treatment. Since most of the side effects are reversible,
we do not expect severe side effects which cannot be treated symptomatically or
locally during short-term lenvatinib treatment. No cumulative toxicities have
been described by the sequential combination of short-term application of other
TKIs and RAI.
Albinusdreef 2
Leiden 2332 BA
NL
Albinusdreef 2
Leiden 2332 BA
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following 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:
o Metastatic lesions that are not RAI-avid on a diagnostic or intra-therapeutic
RAI scan performed prior to enrolment in the current study
o 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:
o 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)
o 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:
o Absolute neutrophil count >=1.5 * 10^9/L
o Hemoglobin >=9 g/dL (5.6 mmol/L)
o Platelets >=100 *10^9/L
• Adequate liver function with
o Albumin >=25 g/L
o Total bilirubin <1.5x institutional upper limit of normal (ULN) with an
exception for patients with Gilbert*s syndrome
o 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 post-menopausal 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
intra-uterine 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:
o Clinically relevant arrhythmias
o Acute coronary syndromes, severe/unstable angina
o 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.
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL75169.058.20 |