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

NCT05182931 | Unknown Phase 2 DMC

• 1 other identifier: ONJ2021-006
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 9

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.

Conditions

Thyroid Cancer

Keywords

Radioiodine refractory; BRAF600E mutant; RAS mutant

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (10)

• Progression free survival as assessed by RECIST 1.1 criteria at 6 months in all participants and a control population (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)

  At 12 months following day 1.

• Objective response rate by RECIST 1.1 criteria in all treated participants

  0-18 months or at PD

• Overall survival of treated participants

  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

  From day -27 until 30 days following last dose [up to max 60 days].

Study Arms (2)

BRAFv600E mutant radioiodine refractory thyroid cancer

EXPERIMENTAL

Prior to commencing interventional treatment, participants will commence a low iodine diet and undergo thyroxine withdrawal and commence T3 replacement from day -27. On day -5 they will receive an oral dose of 124I (40MBq/1.08 mCi) with imaging at 24 hours (+/-6) post dose and a second imaging assessment within 120 hours. Participants will receive Dabrafenib (oral, 150mg BD) and Trametinib (oral, 2mg OD) from day 1-30. A second oral dose of I124 will be administered at day 24 followed by imaging at the same interval as baseline. Participants achieving \>20Gy tumour uptake of I124 will be administered 6GBq (3.3Gy/GBq) 131I, I131 wb scan and SPECT/CT will be performed within 24 hours and at hospital discharge. Participants who do not achieve \>20Gy tumour update of I-124 will move into follow up. Follow up will occur every 12 weeks for 12 months.

Drug: Dabrafenib 75 MG; Drug: Trametinib 2 MG

RAS mutant radioiodine refractory thyroid cancer

EXPERIMENTAL

Prior to commencing interventional treatment, participants will commence a low iodine diet and undergo thyroxine withdrawal and commence T3 replacement from day -27. On day -5 they will receive an oral dose of 124I (40MBq/1.08 mCi) with imaging at 24 hours (+/-6) post dose and a second imaging assessment within 120 hours. Participants will receive Trametinib (oral, 2mg OD) from day 1-30. A second oral dose of I124 will be administered at day 24 followed by imaging at the same interval as baseline. Participants achieving \>20Gy tumour uptake of I124 will be administered 6GBq (3.3Gy/GBq) 131I, I131 wb scan and SPECT/CT will be performed within 24 hours and at hospital discharge. Participants who do not achieve \>20Gy tumour update of I-124 will move into follow up. Follow up will occur every 12 weeks for 12 months.

Drug: Trametinib 2 MG

Interventions

Dabrafenib 75 MG DRUG

Refer arm description

Also known as: Tafinlar

BRAFv600E mutant radioiodine refractory thyroid cancer

Trametinib 2 MG DRUG

Refer arm description

Also known as: Mekinist

BRAFv600E mutant radioiodine refractory thyroid cancer; RAS mutant radioiodine refractory thyroid cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically-confirmed differentiated (including poorly differentiated) thyroid cancer that is either locally advanced or metastatic.
• Age \> 18 years.
• Life expectancy \> 12 weeks.
• Documented radiological progression by RECIST 1.1 in last 12 months.
• Radioiodine refractory (at least one of):
• one measurable lesion without radioiodine uptake on 131I scan,
• 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
• cumulative treatment with \>24 GBq (600 mCi) of 131I.
• 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.
• NRAS or BRAF V600E mutation tested by NGS in a NATA accredited laboratory or by recognised sequencing platform.
• ECOG 0-1.
• Informed consent.
• Adequate haematological and biochemical parameters:
• Haemoglobin ≥ 9g/dL
• Neutrophils ≥ 1.5 x 109/L

You may not qualify if:

• Anaplastic thyroid cancer.
• Suitable for curative surgery or radiotherapy.
• Other anti-cancer (including TKI) therapy in prior 6 weeks.
• 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.
• 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.
• Pregnancy, breastfeeding or unwilling to use contraception in those of child-bearing age.
• Significant medical condition that would prevent compliance with study procedures.
• History of retinal vein occlusion or retinopathy.
• Iodine-containing contrast scan within 8 weeks of planned 124I scan.

Sponsors & Collaborators

• Olivia Newton-John Cancer Research Institute: lead
• Royal North Shore Hospital: collaborator
• Austin Health: collaborator
• Sir Charles Gairdner Hospital: collaborator
• Monash Health: collaborator
• Peter MacCallum Cancer Centre, Australia: collaborator
• Royal Brisbane and Women's Hospital: collaborator
• Eastern Health: collaborator
• The Alfred: collaborator
• Royal Adelaide Hospital: collaborator

Study Sites (9)

Royal North Shore Hospital

Sydney, New South Wales, Australia

RECRUITING

Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4029, Australia

RECRUITING

Royal Adelaide Hsopital

Adelaide, South Australia, Australia

RECRUITING

Eastern Health

Box Hill, Victoria, 3128, Australia

NOT YET RECRUITING

Monash Health

Clayton, Victoria, 3168, Australia

RECRUITING

Austin Health

Heidelberg, Victoria, 3084, 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

MeSH Terms

Conditions

Thyroid Neoplasms

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Study Officials

• Andrew M Scott, MD, FRACP

  Austin Health

  STUDY CHAIR

Central Study Contacts

Kylie Wilkie

CONTACT

+61394963573; trials@onjcri.org.au

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants with BRAF V600E mutant thyroid cancer will receive Dabrafenib + Trametinib; Participants with RAS mutant thyroid cancer will receive Trametinib alone.

Study Record Dates

• First Submitted: November 23, 2021
• First Posted: January 10, 2022
• Study Start: July 14, 2022
• Primary Completion: December 30, 2024
• Study Completion: December 30, 2025
• Last Updated: October 31, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (9)