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

Primary Purpose

Thyroid Cancer

Status

Recruiting

Phase

Phase 2

Locations

Australia

Study Type

Interventional

Intervention

Dabrafenib 75 MG

Trametinib 2 MG

About this trial

This is an interventional treatment trial for Thyroid Cancer focused on measuring Radioiodine refractory, BRAF600E mutant, RAS mutant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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):
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.
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:
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:

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

BRAFv600E mutant radioiodine refractory thyroid cancer

RAS mutant radioiodine refractory thyroid cancer

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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, compared to those who do not proceed to 131I treatment. compared to a control population (from the SELECT study).

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, compared to those who do not proceed to 131I treatment. compared to a control population (from the SELECT study).

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.

Overall survival of treated participants

To confirm the overall survival of participants receiving treatment on study via Kaplan-Meier estimation.

Quantification of treatment related toxicities according to CTCAE V5.0

Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment.

Evaluation of response to treatment by percent change from baseline of non-stimulated thyroglobulin.

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.

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.

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.

Full Information

NCT ID

NCT05182931

First Posted

November 23, 2021

Last Updated

July 19, 2023

Sponsor

Olivia Newton-John Cancer Research Institute

Collaborators

Royal North Shore Hospital, Austin Health, Sir Charles Gairdner Hospital, Monash Health, Peter MacCallum Cancer Centre, Australia, Royal Brisbane and Women's Hospital, Eastern Health, The Alfred, Royal Adelaide Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05182931

Brief Title

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

Acronym

I-FIRST

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 14, 2022 (Actual)

Primary Completion Date

December 30, 2024 (Anticipated)

Study Completion Date

December 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Olivia Newton-John Cancer Research Institute

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Thyroid Cancer

Keywords

Radioiodine refractory, BRAF600E mutant, RAS mutant

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

BRAFv600E mutant radioiodine refractory thyroid cancer

Arm Type

Experimental

Arm Description

Arm Title

RAS mutant radioiodine refractory thyroid cancer

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Dabrafenib 75 MG

Other Intervention Name(s)

Tafinlar

Intervention Description

Refer arm description

Intervention Type

Drug

Intervention Name(s)

Trametinib 2 MG

Other Intervention Name(s)

Mekinist

Intervention Description

Refer arm description

Primary Outcome Measure Information:

Title

Progression free survival as assessed by RECIST 1.1 criteria at 6 months in participants who proceed to I131 treatment

Description

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.

Title

Progression free survival as assessed by RECIST 1.1 criteria at 12 months in participants who proceed to I131 treatment

Description

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.

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

At 6 months following day 1.

Title

Progression free survival as assessed by RECIST 1.1 criteria at 12 months in all participants and a control population (SELECT study)

Description

Time Frame

At 12 months following day 1.

Title

Objective response rate by RECIST 1.1 criteria in all treated participants

Description

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

Title

Overall survival of treated participants

Description

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.

Title

Quantification of treatment related toxicities according to CTCAE V5.0

Description

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].

Title

Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment.

Description

Quantification of radioiodine uptake in metastatic lesions before and after TKI treatment.

Time Frame

From day -5 until day 30 on study.

Title

Evaluation of response to treatment by percent change from baseline of non-stimulated thyroglobulin.

Description

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.

Title

Evaluation and comparison of quality of life as measured by response to EORTC-QLQ-C30 in participants on study.

Description

Time Frame

Day -29, 1, 29; 3, 6, 9, 12 months.

Title

Evaluation and comparison of QOL as measured by response to EQ-5D-5L in participants on study.

Description

Time Frame

Day -29, 1, 29; 3, 6, 9, 12 months.

Title

Evaluation and comparison of QOL as measured by response to Kessler Psychological Distress Scale (K10) in participants on study.

Description

Time Frame

Day -29, 1, 29; 3, 6, 9, 12 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Platelets ≥ 100 x 109/L INR ≤ 1.4 Serum Creatinine ≤ 1.3 x ULN Estimated Creatinine Clearance ≥ 30 ml/min (by Cockcroft Gault Formula) Serum ALT and AST ≤ 2.5 x ULN Serum Total Bilirubin ≤ 1.5 x ULN. TSH suppression <0.1mU/L or otherwise consistent with 2015 ATA Guidelines on Thyroid Cancer Exclusion Criteria: 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jodie Palmer, PhD

Phone

+61394963573

trials@onjcri.org.au

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Andrew M Scott, MD, FRACP

Organizational Affiliation

Austin Health

Official's Role

Study Chair

Facility Information:

Facility Name

Royal North Shore Hospital

City

Sydney

State/Province

New South Wales

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Roderick Clifton-Bligh, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

Roderick Clifton-Bligh, MBBS

First Name & Middle Initial & Last Name & Degree

Bruce Robinson, MBBS, FRACP

Facility Name

Royal Brisbane and Women's Hospital

City

Brisbane

State/Province

Queensland

ZIP/Postal Code

4029

Country

Australia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David Pattison, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

David Pattison, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

Donald McLeod, MBBS, FRACP

Facility Name

Royal Adelaide Hsopital

City

Adelaide

State/Province

South Australia

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anne Taylor, MBBS

Facility Name

Eastern Health

City

Box Hill

State/Province

Victoria

ZIP/Postal Code

3128

Country

Australia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chris Gillfilan, MBBS

First Name & Middle Initial & Last Name & Degree

Chris Gillfilan, MBBS

Facility Name

Monash Health

City

Clayton

State/Province

Victoria

ZIP/Postal Code

3168

Country

Australia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Mond, MBBS

First Name & Middle Initial & Last Name & Degree

Michael Mond, MBBS, FRACP

Facility Name

Austin Health

City

Heidelberg

State/Province

Victoria

ZIP/Postal Code

3084

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Andrew M Scott, MD, FRACP

First Name & Middle Initial & Last Name & Degree

Andrew M Scott, MBBS, FRACP

Facility Name

Alfred Hospital

City

Prahran

State/Province

Victoria

Country

Australia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Duncan Topliss, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

Duncan Topliss, MBBS, FRACP

Facility Name

Sir Charles Gairdner Hospital

City

Perth

State/Province

Western Australia

Country

Australia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Roslyn Francis, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

Roslyn Francis, MBBS, FRACP

Facility Name

Peter MacCallum Cancer Centre

City

Melbourne

Country

Australia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Annette Lim, MBBS, FRACP

First Name & Middle Initial & Last Name & Degree

Annette Lim, MBBS, FRACP

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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

Thyroid Cancer

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial