Treatment to restore radioiodine sensitivity in thyroid cancer patients

A Prospective, Multi-Centre Trial of TKI Redifferentiation Therapy in Patients With RAIR Thyroid Cancer (I-FIRST Study)

This study is testing if a combination of two drugs can help people with certain types of thyroid cancer become more sensitive to radioiodine treatment.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Olivia Newton-John Cancer Research Institute (Academic / other)
• Drugs / interventions: radiation, Trametinib
• Locations: 9 sites (Sydney, New South Wales and 8 other locations)
• Trial ID: NCT05182931 on ClinicalTrials.gov

What this trial studies

This prospective, multi-centre trial aims to restore radioiodine sensitivity in patients with radioiodine refractory differentiated thyroid cancer harboring NRAS or BRAF V600E mutations. Participants will receive treatment with Trametinib and/or Dabrafenib for 30 days, with their response monitored through advanced imaging techniques including 18F-FDG-PET and I-124 PET. The study will evaluate changes in NIS expression and radioiodine uptake as a result of the treatment. It is conducted across 10 sites in Australia, focusing on adult patients with specific genetic mutations.

Who should consider this trial

Good fit: Ideal candidates are adults over 18 with radioiodine refractory differentiated thyroid cancer and documented NRAS or BRAF V600E mutations.

Not a fit: Patients without NRAS or BRAF V600E mutations or those with thyroid cancer that is not radioiodine refractory may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve the management and outcomes for patients with refractory thyroid cancer.

How similar studies have performed: Other studies have shown promise in using targeted therapies for similar mutations in thyroid cancer, indicating potential for success in this approach.

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.

Where this trial is running

Sydney, New South Wales and 8 other locations

• Royal North Shore Hospital — Sydney, New South Wales, Australia (Recruiting)
• Royal Brisbane and Women's Hospital — Brisbane, Queensland, Australia (Recruiting)
• Royal Adelaide Hsopital — Adelaide, South Australia, Australia (Recruiting)
• Eastern Health — Box Hill, Victoria, Australia (Not_yet_recruiting)
• Monash Health — Clayton, Victoria, Australia (Recruiting)
• Austin Health — Heidelberg, Victoria, Australia (Recruiting)
• Alfred Hospital — Prahran, Victoria, Australia (Not_yet_recruiting)
• Sir Charles Gairdner Hospital — Perth, Western Australia, Australia (Recruiting)
• Peter MacCallum Cancer Centre — Melbourne, Australia (Recruiting)

Study contacts

• Study coordinator: Kylie Wilkie

Conditions Thyroid Cancer; Radioiodine refractory; BRAF600E mutant; RAS mutant