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A Prospective, Multi-Centre Trial of TKI Redifferentiation Therapy in Patients With RAIR Thyroid Cancer (I-FIRST Study)
This prospective, multi-centre, open label, non-randomised phase II trial aims restore radioiodine sensitivity in patients with NRAS or BRAFV600E mutant refractory thyroid cancer. Participants will be treated with Trametinib +/- Dabrafenib tyrosine kinase inhibitors for a period of 30 days, restoration of sensitivity will be monitored using 18F-FDG-PET \& I-124 PET imaging.
Study details:
This is a prospective, non-randomised, multi-centre study which will be conducted at 10 sites around Australia. Adult patients (18+ years) with radioiodine refractory differentiated thyroid cancer with BRAF V600E or NRAS mutant RECIST 1. 1 evaluable tumours will be eligible to participate.
. All eligible patients will undergo a 18F-FDG PET/CT scan during the registration period (day -28), followed by T4 withdrawal and low iodine diet. T3 will be administered after T4 withdrawal and for up to 10 days prior to the 124I dose to minimise symptoms of hypothyroidism.
The first 124I dose will be administered orally at a dose of 40 MBq (1. 08 mCi) on day -5 with a 18FDG-PET performed on the same day. Patients will then have 124I-PET imaging and bloods at 24 hrs (+/- 6 hrs) post-dose, with a second imaging time-point up until 120 hours post- 124I dose.
The initial 124I study (pre-TKI) will serve as a baseline for the second 124I-PET (day 24, after 23 days of TKI), and demonstrate changes in NIS expression and radioiodine uptake as a result of TKI treatment. Patients will then commence a total of 30 days of treatment with the MEK TKI trametinib (for NRAS mutant tumours) or the MEK and BRAF V600E TKI combination of trametinib and dabrafenib (for BRAF V600E mutant tumours). Patients will then have a further 18F-FDG PET/CT scan and 124I dose on day 23, and scans for dosimetry (124I-PET) at 24 hrs (+/- 6 hrs) post-dose (day 24), with a second imaging time-point up until 120 hours post-124I administration.
If at least one lesion shows uptake on 124I scans consistent with \> 20Gy / 6GBq (3. 3Gy/GBq) 131I administered (based on the 24-hour scan), then 131I treatment will be administered on day 29. The dose of 131I administered will be fixed at 6 GBq (150 mCi) to allow for evaluation of dose response.
TKI treatment will continue until the day after 131I treatment is given (total 30 days). Follow-up staging (CT) will occur every 3 months for the first 24 months, then every 6 months until progression, and 18F-FDG PET at 6 and 12 months. Non-stimulated thyroglobulin (Tg) will also be measured at 3, 6, 9 and 12 months, and evaluated as a percentage change from baseline.
QoL and health economic data will be collected in all patients going on study. Overall survival will be obtained by long-term follow-up. Central review of tumour mutations, 124I PET dosimetry, staging (RECIST) and 18F-FDG PET (PERCIST) will be performed.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 18 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2022-07-14
Primary completion: 2024-12-30
Study completion finish: 2025-12-30
Study type
TREATMENT
Phase
PHASE2
Trial ID
NCT05182931
Intervention or treatment
DRUG: Dabrafenib 75 MG
DRUG: Trametinib 2 MG
Conditions
- • Thyroid Cancer
Find a site
Closest Location:
Austin Health
Research sites nearby
Select from list below to view details:
Austin Health
Heidelberg, Victoria, Australia
Royal North Shore Hospital
Sydney, New South Wales, Australia
Royal Brisbane and Women's Hospital
Brisbane, Queensland, Australia
Royal Adelaide Hsopital
Adelaide, South Australia, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Participant Group/Arm | Intervention/Treatment |
---|---|
EXPERIMENTAL: BRAFv600E mutant radioiodine refractory thyroid cancer
| DRUG: Dabrafenib 75 MG
|
EXPERIMENTAL: RAS mutant radioiodine refractory thyroid cancer
| DRUG: Trametinib 2 MG
|
What is the study measuring?
Primary outcome
Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
---|---|---|
Progression free survival as assessed by RECIST 1.1 criteria at 6 months in participants who proceed to I131 treatment | Radioiodine refractory thyroid cancer patients able to proceed to 131I treatment will be assessed by RECIST 1.1 criteria. | At 6 months following day 1. |
Progression free survival as assessed by RECIST 1.1 criteria at 12 months in participants who proceed to I131 treatment | Radioiodine refractory thyroid cancer patients able to proceed to 131I treatment will be assessed by RECIST 1.1 criteria. | At 12 months following day 1. |
Secondary outcome
Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
---|---|---|
Progression free survival as assessed by RECIST 1.1 criteria at 6 months in all participants and a control population (SELECT study) | To assess PFS by RECIST v1.1 at 6 in radioiodine-refractory thyroid cancer patients able to proceed to 131I treatment following TKI redifferentiation therapy, 1. compared to those who do not proceed to 131I treatment. 2. compared to a control population (from the SELECT study). | At 6 months following day 1. |
Progression free survival as assessed by RECIST 1.1 criteria at 12 months in all participants and a control population (SELECT study) | To assess PFS by RECIST v1.1 at 12 months in radioiodine-refractory thyroid cancer patients able to proceed to 131I treatment following TKI redifferentiation therapy, 1. compared to those who do not proceed to 131I treatment. 2. compared to a control population (from the SELECT study). | At 12 months following day 1. |
Objective response rate by RECIST 1.1 criteria in all treated participants | To assess objective response (CR/PR/SD) in all treated participants from time of enrolment until 18 months or PD. | 0-18 months or at PD |
Overall survival of treated participants | To confirm the overall survival of participants receiving treatment on study via Kaplan-Meier estimation. | From date of enrolment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years. |
Quantification of treatment related toxicities according to CTCAE V5.0 | Quantification of treatment related toxicities according to CTCAE V5.0 | From day -27 until 30 days following last dose [up to max 60 days]. |
Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment. | Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment. | From day -5 until day 30 on study. |
Evaluation of response to treatment by percent change from baseline of non-stimulated thyroglobulin. | Evaluation of response to treatment by percent change from baseline of non-stimulated thyroglobulin. | Day 0; 3, 6, 9, 12 months in participants without radiological progression. |
Evaluation and comparison of quality of life as measured by response to EORTC-QLQ-C30 in participants on study. | Evaluation of QOL in participants who proceed to I131 treatment compared with participants who proceed to follow up only by EORTC-QLQ-C30. Scores are from 0-100 with participant reported quality of live improving with a higher score. | Day -29, 1, 29; 3, 6, 9, 12 months. |
Evaluation and comparison of QOL as measured by response to EQ-5D-5L in participants on study. | In participants who proceed to I131 treatment compared with follow up only by EQ-5D-5L. Five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems to extreme problems. | Day -29, 1, 29; 3, 6, 9, 12 months. |
Evaluation and comparison of QOL as measured by response to Kessler Psychological Distress Scale (K10) in participants on study. | In participants who proceed to I131 treatment compared with follow up only by responses to the Kessler Psychological Distress Scale (K10). This is a 10-item questionnaire yielding a global measure of distress based on questions about anxiety and depressive symptoms. 5 levels ranging from none of the time to all of the time, higher level responses correspond with greater reported distress. | Day -29, 1, 29; 3, 6, 9, 12 months. |
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