Clinical trial NCT05182931: A Prospective, Multi-Centre Trial of TKI Redifferentiation Therapy in Patients With RAIR Thyroid Cancer (I-FIRST Study)
Official title: A Prospective, Multi-Centre Trial of TKI Redifferentiation Therapy in Patients With RAIR Thyroid Cancer (I-FIRST Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Thyroid Cancer
Keywords: Radioiodine refractory
BRAF600E mutant
RAS mutant
Lead sponsor: Olivia Newton-John Cancer Research Institute
Sponsor class: OTHER
Collaborators: name: Royal North Shore Hospital
name: Austin Health
name: Sir Charles Gairdner Hospital
name: Monash Health
name: Peter MacCallum Cancer Centre, Australia
name: Royal Brisbane and Women's Hospital
name: Eastern Health
name: The Alfred
name: Royal Adelaide Hospital
First posted: 2022-01-10
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants with BRAF V600E mutant thyroid cancer will receive Dabrafenib + Trametinib; Participants with RAS mutant thyroid cancer will receive Trametinib alone.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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: Inclusion Criteria:

1. Histologically-confirmed differentiated (including poorly differentiated) thyroid cancer that is either locally advanced or metastatic.
2. Age \> 18 years.
3. Life expectancy \> 12 weeks.
4. Documented radiological progression by RECIST 1.1 in last 12 months.
5. Radioiodine refractory (at least one of):

   1. one measurable lesion without radioiodine uptake on 131I scan,
   2. at least one measurable lesion that had progressed by RECIST criteria within 12 months of 131I therapy despite 131I avidity at time of treatment, or
   3. cumulative treatment with \>24 GBq (600 mCi) of 131I.
6. At least one evaluable lesion as per RECIST v1.1 that has not been treated with local radiation therapy within 3 months prior to the first dose of TKI. Irradiated lesions can only be included as an evaluable lesion if it has shown radiological progression as per RECIST v1.1 on subsequent imaging following irradiation.
7. NRAS or BRAF V600E mutation tested by NGS in a NATA accredited laboratory or by recognised sequencing platform.
8. ECOG 0-1.
9. Informed consent.
10. Adequate haematological and biochemical parameters:

    1. Haemoglobin ≥ 9g/dL
    2. Neutrophils ≥ 1.5 x 109/L
    3. Platelets ≥ 100 x 109/L
    4. INR ≤ 1.4
    5. Serum Creatinine ≤ 1.3 x ULN
    6. Estimated Creatinine Clearance ≥ 30 ml/min (by Cockcroft Gault Formula)
    7. Serum ALT and AST ≤ 2.5 x ULN
    8. Serum Total Bilirubin ≤ 1.5 x ULN.
    9. TSH suppression \<0.1mU/L or otherwise consistent with 2015 ATA Guidelines on Thyroid Cancer

Exclusion Criteria:

1. Anaplastic thyroid cancer.
2. Suitable for curative surgery or radiotherapy.
3. Other anti-cancer (including TKI) therapy in prior 6 weeks.
4. Concurrent malignancy other than non-melanoma skin cancer. Prior malignancies treated with curative intent and no evidence of recurrence in past three years may be allowed upon discussion with the medical monitor.
5. Unstable brain metastasis. Treated or non-treated brain metastasis are allowed if neurologically stable, asymptomatic, on a stable steroid dose for a period of 2 weeks, and not anticipated to require any intervention during the trial treatment period. If treated with radiation or surgery, any related AE's should have recovered to ≤ grade 1 prior to enrolment on trial.
6. Pregnancy, breastfeeding or unwilling to use contraception in those of child-bearing age.
7. Significant medical condition that would prevent compliance with study procedures.
8. History of retinal vein occlusion or retinopathy.
9. Iodine-containing contrast scan within 8 weeks of planned 124I scan.

Primary outcomes:
measure: Progression free survival as assessed by RECIST 1.1 criteria at 6 months in participants who proceed to I131 treatment
timeFrame: At 6 months following day 1.
measure: Progression free survival as assessed by RECIST 1.1 criteria at 12 months in participants who proceed to I131 treatment
timeFrame: At 12 months following day 1.
Secondary outcomes:
measure: Progression free survival as assessed by RECIST 1.1 criteria at 6 months in all participants and a control population (SELECT study)
timeFrame: At 6 months following day 1.
measure: Progression free survival as assessed by RECIST 1.1 criteria at 12 months in all participants and a control population (SELECT study)
timeFrame: At 12 months following day 1.
measure: Objective response rate by RECIST 1.1 criteria in all treated participants
timeFrame: 0-18 months or at PD
measure: Overall survival of treated participants
timeFrame: 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.
measure: Quantification of treatment related toxicities according to CTCAE V5.0
timeFrame: From day -27 until 30 days following last dose [up to max 60 days].
measure: Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment.
timeFrame: From day -5 until day 30 on study.
measure: Evaluation of response to treatment by percent change from baseline of non-stimulated thyroglobulin.
timeFrame: Day 0; 3, 6, 9, 12 months in participants without radiological progression.
measure: Evaluation and comparison of quality of life as measured by response to EORTC-QLQ-C30 in participants on study.
timeFrame: Day -29, 1, 29; 3, 6, 9, 12 months.
measure: Evaluation and comparison of QOL as measured by response to EQ-5D-5L in participants on study.
timeFrame: Day -29, 1, 29; 3, 6, 9, 12 months.
measure: Evaluation and comparison of QOL as measured by response to Kessler Psychological Distress Scale (K10) in participants on study.
timeFrame: Day -29, 1, 29; 3, 6, 9, 12 months.
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hsopital
state: South Australia
city: Box Hill
country: Australia
facility: Eastern Health
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Prahran
country: Australia
facility: Alfred Hospital
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
Study officials:
affiliation: Austin Health
name: Andrew M Scott, MD, FRACP
role: STUDY_CHAIR
References: