Thyroid CancerPhase 2NCT04554680
Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Re-differentiation Therapy
A Phase 2 study testing dabrafenib and trametinib in people with Thyroid Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
Progressive and metastatic thyroid cancer patients, who no longer respond to radioactive iodine (RAI), are currently treated with long term tyrosine kinase inhibitors to control tumor growth. Read more about this study
- Who is it for?
- Ages 21 to 99 years
- Conditions the study is for
- Thyroid Cancer
- What is being tested?
- dabrafenib and trametinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteSingapore
- Study dates
- 30 Dec 2020to Apr 2022
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participants must be at least 21 years of age on the day of signing informed consent.
- The participant (or legally acceptable representative if applicable) provides written consent for the trial.
- Eastern Cooperative Oncology Group (ECOG) performance status < 2
- . The histology of the thyroid carcinoma for inclusion includes any of the following:
- Papillary thyroid carcinoma
- Follicular thyroid carcinoma
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- Hurthle cell carcinoma
- Poorly differentiated thyroid carcinoma
- Patients with a thyroid carcinoma of follicular cell origin with mutation involving MAPK signalling pathway, including BRAFV600E mutation or RAS mutation detected in a Clinical Laboratory Improvement Amendments (CLIA)-certified or US Food and Drug Administration-approved assay.
- The patients need to fulfil one of the following criteria for RAI-refractory disease (Tuttle et al, 2019;):
- No 131-I uptake is present on a diagnostic 131-I scan
- No 131-I uptake is present on a 131I scan performed several days after 131-I therapy
- 131-I uptake is only present in some but not other tumor foci
- DTC metastasis(es) progress despite 131-I uptake
- DTC metastasis(es) progress despite a cumulative 131-I activity of >600 mCi
- The metastatic tumoral lesion should have no RAI uptake on therapeutic or diagnostic radioiodine scan performed before enrolment. Alternatively, the RAI-avid metastatic lesion should not show size reduction (either remained stable in size or progressed) despite RAI therapy >6 months before study entry.
- The disease should be measurable based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
- Adequate haematological, renal and liver function defined as:
- Absolute neutrophil count (ANC) ≥ 1.5 ×109/L.
- Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin ≥ 9.0 g/dl is acceptable).
- Platelets ≥ 75 ×109/L.
- Total bilirubin ≤2.5 x institutional upper limit of normal (unless due to Gilbert's disease).
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal.
- Serum creatinine ≤ 1.5 x institutional upper limit of normal.
- Prothrombin time (PT) within the normal range for the institution.
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 months after the last dose of dabrafenib and trametinib. Contraception has to be continued for 6 months after radioactive iodine if this were to be administered. Barrier method of contraception is preferred as dabrafenib may decrease serum estrogen and progestin concentrations.
- Female patients of childbearing potential are required to have a negative serum pregnancy test within 14 days prior to the first dose of study medication.
- A male participant must agree to use a contraception during the treatment period and for at least 4 months days after the last dose of dabrafenib and trametinib (and radioactive iodine if administered), and refrain from donating sperm during this period.
Who cannot join
- Patients will not be recruited if they meet the following criteria:
- Anaplastic thyroid carcinoma
- Exceeded cumulative I-131 treatment dose of >600mCi
- Treatment with I-131 therapy 6 months before study treatment.
- G6PD deficiency due to risk of haemolytic anaemia with dabrafenib
- Had received prior systemic anti-cancer therapy, including investigational agents within 2 weeks prior to randomisation.
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- Had received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities.
- Patients who have not recovered from adverse events related to prior therapy for cancer to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 grade 2 or less, except for alopecia.
- Patients with a history of other active malignancy requiring cancer treatment.
- Patients with uncontrolled brain metastases. Patients who are on a stable dose of corticosteroids for more than 1 week or off corticosteroids for 2 weeks prior to study enrolment can be enrolled.
- On concurrent prohibitive drugs such as enzyme-inducing anti-epileptic drugs. [Refer to section 3.7 (concomitant treatment) for list of medications that require closer monitoring.]
- Patients with a known history of retinal vein occlusion, central serous retinopathy, uncontrolled glaucoma or ocular hypertension.
- Patients with class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- Corrected QT (QTc) interval greater than or equal to 480 msecs (>= 500 msec for subjects with Bundle Branch Block).
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- Pregnant women and nursing women are excluded from this study because dabrafenib has the potential for teratogenic or abortifacient effects. In embro-fetal developmental studies in rats, developmental toxicities including reduced fetal body weight, embryo-lethality, cardiac ventricular septal defect malformations, delayed skeletal development and variation in thymic shape have been observed.
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
National University Hospital
Singapore
Samantha, Peiling Yang, MBBS, MRCP, (+65) 6779 5555, mdcyp@nus.edu.sg
Samantha, Peiling Yang, MBBS, MRCP
About this study
Official title: Phase II Clinical Trial in Radioactive Iodine-Refractory Advanced Thyroid Carcinoma Evaluating BRAF & MEK Blockade Therapy for Re-differentiation- Applying a Novel Time-Dependent Concept
Progressive and metastatic thyroid cancer patients, who no longer respond to radioactive iodine (RAI), are currently treated with long term tyrosine kinase inhibitors to control tumor growth. The investigators will study the effect of short term oral anti-cancer drug combination, called dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), in improving thyroid cancer RAI absorption that can potentially lead to tumor shrinkage response. To assess for suitability, participant's thyroid cancer tissue taken at the time of surgery will be tested for DNA changes, such as BRAFV600E, RAS, or MEK mutations.
Based on experimental studies, the response to these medications could occur within 1 week of treatment. So in the study, the investigators will find out whether participant's cancer would respond to 1 week of treatment with these medications rather than the 1 month duration of treatment in previous re-differentiation clinical trials. After 1 week of treatment with dabrafenib and trametinib, iodine absorption I-124 PET-CT scan will predict if the cancer will respond to RAI. If iodine absorption is insufficient on the scan, treatment with dabrafenib and trametinib will be continued for a total of 4 weeks. Then iodine absorption response of participant's cancer will be assessed on I-124 PET-CT scan again. If the iodine absorption is good at 1 week or 4 weeks, the investigators will treat the participant with thyroid cancer using RAI.
The 1-week treatment regime can potentially save cost, avoid drug toxicity with prolonged treatment, and prevent drug resistance that can occur with longer treatment period.
- Conditions
- Thyroid Cancer
- Being tested
- dabrafenib and trametinib
- Keywords
- Thyroid carcinoma, re-differentiation, radioactive iodine - refractory
- Medical subject headings
- Thyroid Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
dabrafenib and trametinibDrug
Participants will receive systemic therapy in the form of oral tablet dabrafenib 150mg twice a day \& oral tablet trametinib 2mg once a day for 1 or 4 weeks.
Pre- \& post-systemic therapy assessment of tumor iodine absorption is done using I-124 PET CT scan. Participants are prepared for this scan with intramuscular injection of thyrogen 0.9mg on 2 consequent days, followed by I-124 PET-CT scan over the next 3 days for tumoral lesional dosimetry.
Participants are then started on systemic therapy for 1 week, followed by I-124 PET-CT scan. If at least one tumor site can attain adequate dosimetry, RAI (I-131) treatment under thyrogen stimulation will be considered. Systemic therapy will be stopped 3 days after I-131.
If after 1 week of systemic therapy, tumors do not reach dosimetry criteria, participants will be continued on systemic therapy for a total of 4 weeks duration, followed by I-124 PET-CT scan. If tumor can attain adequate dosimetry, I-131 treatment will be considered.
| Study group | Role | What they receive |
|---|---|---|
| Treatment Group | Experimental | Patients with progressive, metastatic or locally advanced, unresectable radioiodine (RAI)-refractory thyroid cancer of follicular cell origin with mutation involving MAPK signalling pathway, including BRAFV600E mutation or RAS mutation. Receives: Drug: dabrafenib and trametinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
The proportion of participants attaining at least one tumor lesion with lesional dosimetry of >=2000 cGy with I-131 dose of =<300 mCi.
The primary endpoint can be considered attained in both groups of participants:
- those that attain target lesional dosimetry after 1 week of therapy
- those that attain target lesional dosimetry after 4 weeks of therapy
Measured: 1 month after start of dabrafenib and trametinib
Secondary outcomes (4)
Progression-free survival and overall survival
Measured: From the start of assessment until study completion, an average of 2 years
Best tumor response as assessed by RECIST criteria
Measured: From the start of assessment until study completion, an average of 2 years
Change in serum thyroglobulin level after radioactive iodine (RAI) treatment compared to baseline, pre-treatment level
Measured: 6 months after RAI treatment
The proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0
Measured: From the start of assessment until study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Sep 2020
- Study start30 Dec 2020
- Primary completionDec 2021 (estimated)
- Study completionApr 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Thyroid CancerStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Singapore General Hospital
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04554680
- Sponsor's protocol ID
- TY01/04/20
- Other IDs
- 2020/00309
- Status last verified
- Aug 2020
- First submitted
- 29 Aug 2020
- Last updated
- 5 Mar 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Clinical Trial in Radioactive Iodine-Refractory Advanced Thyroid Carcinoma Evaluating BRAF & MEK Blockade Therapy for Re-differentiation- Applying a Novel Time-Dependent Concept
- ClinicalTrials.gov ID
- NCT04554680
- Acronym / sponsor ID
- TY01/04/20
- Conditions
- Thyroid Cancer
- Keywords
- Thyroid carcinoma, re-differentiation, radioactive iodine - refractory
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- Singapore General Hospital
- Study start
- 30 Dec 2020 (actual)
- Primary completion
- Dec 2021 (estimated)
- Study completion
- Apr 2022 (estimated)
- First posted
- 18 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Progressive and metastatic thyroid cancer patients, who no longer respond to radioactive iodine (RAI), are currently treated with long term tyrosine kinase inhibitors to control tumor growth. The investigators will study the effect of short term oral anti-cancer drug combination, called dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), in improving thyroid cancer RAI absorption that can potentially lead to tumor shrinkage response. To assess for suitability, participant's thyroid cancer tissue taken at the time of surgery will be tested for DNA changes, such as BRAFV600E, RAS, or MEK mutations.
Based on experimental studies, the response to these medications could occur within 1 week of treatment. So in the study, the investigators will find out whether participant's cancer would respond to 1 week of treatment with these medications rather than the 1 month duration of treatment in previous re-differentiation clinical trials. After 1 week of treatment with dabrafenib and trametinib, iodine absorption I-124 PET-CT scan will predict if the cancer will respond to RAI. If iodine absorption is insufficient on the scan, treatment with dabrafenib and trametinib will be continued for a total of 4 weeks. Then iodine absorption response of participant's cancer will be assessed on I-124 PET-CT scan again. If the iodine absorption is good at 1 week or 4 weeks, the investigators will treat the participant with thyroid cancer using RAI.
The 1-week treatment regime can potentially save cost, avoid drug toxicity with prolonged treatment, and prevent drug resistance that can occur with longer treatment period.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment Group | Experimental | Drug: dabrafenib and trametinibPatients with progressive, metastatic or locally advanced, unresectable radioiodine (RAI)-refractory thyroid cancer of follicular cell origin with mutation involving MAPK signalling pathway, including BRAFV600E mutation or RAS mutation. |
Who may qualify
- Ages
- 21 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (30 listed)
- Participants must be at least 21 years of age on the day of signing informed consent.
- The participant (or legally acceptable representative if applicable) provides written consent for the trial.
- Eastern Cooperative Oncology Group (ECOG) performance status < 2
- . The histology of the thyroid carcinoma for inclusion includes any of the following:
- Patients with a thyroid carcinoma of follicular cell origin with mutation involving MAPK signalling pathway, including BRAFV600E mutation or RAS mutation detected in a Clinical Laboratory Improvement Amendments (CLIA)-certified or US Food and Drug Administration-approved assay.
Key exclusion criteria (16 listed)
- Anaplastic thyroid carcinoma
- Exceeded cumulative I-131 treatment dose of >600mCi
- Treatment with I-131 therapy 6 months before study treatment.
- G6PD deficiency due to risk of haemolytic anaemia with dabrafenib
- Had received prior systemic anti-cancer therapy, including investigational agents within 2 weeks prior to randomisation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| dabrafenib and trametinibParticipants will receive systemic therapy in the form of oral tablet dabrafenib 150mg twice a day \& oral tablet trametinib 2mg once a day for 1 or 4 weeks. Pre- \& post-systemic therapy assessment of tumor iodine absorption is done using I-124 PET CT scan. Participants are prepared for this scan with intramuscular injection of thyrogen 0.9mg on 2 consequent days, followed by I-124 PET-CT scan over the next 3 days for tumoral lesional dosimetry. Participants are then started on systemic therapy for 1 week, followed by I-124 PET-CT scan. If at least one tumor site can attain adequate dosimetry, RAI (I-131) treatment under thyrogen stimulation will be considered. Systemic therapy will be stopped 3 days after I-131. If after 1 week of systemic therapy, tumors do not reach dosimetry criteria, participants will be continued on systemic therapy for a total of 4 weeks duration, followed by I-124 PET-CT scan. If tumor can attain adequate dosimetry, I-131 treatment will be considered. | Drug | Treatment Group |
Primary outcome
The proportion of participants attaining at least one tumor lesion with lesional dosimetry of >=2000 cGy with I-131 dose of =<300 mCi.
Time frame: 1 month after start of dabrafenib and trametinib
The primary endpoint can be considered attained in both groups of participants: * those that attain target lesional dosimetry after 1 week of therapy * those that attain target lesional dosimetry after 4 weeks of therapy
4 secondary outcomes
Progression-free survival and overall survival
Time frame: From the start of assessment until study completion, an average of 2 years
Best tumor response as assessed by RECIST criteria
Time frame: From the start of assessment until study completion, an average of 2 years
Change in serum thyroglobulin level after radioactive iodine (RAI) treatment compared to baseline, pre-treatment level
Time frame: 6 months after RAI treatment
The proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: From the start of assessment until study completion, an average of 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Mar 2021.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing dabrafenib and trametinib in people with Thyroid Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 30 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Samantha, Peiling Yang, MBBS, MRCP ((+65) 6779 5555, mdcyp@nus.edu.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The proportion of participants attaining at least one tumor lesion with lesional dosimetry of >=2000 cGy with I-131 dose of =<300 mCi. (time frame: 1 month after start of dabrafenib and trametinib). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2021.