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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Refer arm description
Refer arm description
Royal North Shore Hospital
Sydney, New South Wales, Australia
RECRUITINGRoyal Brisbane and Women's Hospital
Brisbane, Queensland, Australia
RECRUITINGRoyal Adelaide Hsopital
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.
Time frame: 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.
Time frame: At 12 months following day 1.
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).
Time frame: 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).
Time frame: 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.
Time frame: 0-18 months or at PD
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Adelaide, South Australia, Australia
Eastern Health
Box Hill, Victoria, Australia
NOT_YET_RECRUITINGMonash Health
Clayton, Victoria, Australia
RECRUITINGAustin Health
Heidelberg, Victoria, Australia
RECRUITINGAlfred Hospital
Prahran, Victoria, Australia
NOT_YET_RECRUITINGSir Charles Gairdner Hospital
Perth, Western Australia, Australia
RECRUITINGPeter MacCallum Cancer Centre
Melbourne, Australia
RECRUITINGOverall survival of treated participants
To confirm the overall survival of participants receiving treatment on study via Kaplan-Meier estimation.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Day -29, 1, 29; 3, 6, 9, 12 months.