Evaluation of 177Lu-DOTA-EB-FAPI in Patients With Metastatic Radioactive Iodine Refractory Thyroid Cancer

Study Overview
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Brief Summary
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Increased fibroblast activation protein expression is positively correlated with the dedifferentiation and aggressiveness of thyroid cancer. Radiolabeled fibroblast activation protein inhibitor therapy, also known as radioligand therapy has become a novel treatment for patients with radioactive iodine refractory thyroid cancer and disease progression after first-line treatment. However, a major problem in the therapeutic use of 177Lu-DOTA-FAPI has been its short half-life and fast rate of clearance. This study was designed to evaluate the safety, tolerability, and maximum tolerated dose of a long-lasting radiolabeled fibroblast activation protein inhibitor 177Lu-DOTA-EB-FAPI in mRAIR-TC patients with PD after TKIs treatment.

Detailed Description
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This dose-escalation study will include a maximum of 20 mRAIR-TC subjects with progressive disease after tyrosine kinases inhibitors (TKIs) treatment, with an increased radiotracer uptake in tumors on 68Ga-FAPI-46 PET/CT. The initial dose of 177Lu-DOTA-EB-FAPI is 2.22GBq (60 mCi), and subsequent cohorts receive an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. Treatment is planned for up to 2 cycles, and the time interval between cycles is 6 weeks. The primary endpoint assessed the safety and maximum tolerated dose of 177Lu-DOTA-EB-FAPI used for radioligand therapy in patients with advanced mRAIR-TC. Secondary endpoints included dosimetry and determination of the preliminary treatment efficacy of 177Lu-DOTA-EB-FAPI.

Official Title
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An Open-Label, Non-Randomized, Dose Escalation, Single-Center, Investigator-Initiated Trial to Determine the Safety, Dosimetry, and Preliminary Effectiveness of 177Lu-DOTA-EB-FAPI in Metastatic Radioactive Iodine Refractory Thyroid Cancer Patients With Progressive Disease After Tyrosine Kinase Inhibitors Treatment

Conditions
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Refractory Thyroid Gland Carcinoma, Refractory Thyroid Gland Papillary Carcinoma, Refractory Thyroid Gland Follicular Carcinoma, Refractory Thyroid Gland Hurthle Cell Carcinoma

Intervention / Treatment
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* Drug: 177Lu-DOTA-EB-FAPI 1 radionuclide therapy
* Drug: 177Lu-DOTA-EB-FAPI 2 radionuclide therapy
* Drug: 177Lu-DOTA-EB-FAPI 3 radionuclide therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and willingness to sign a written informed consent document. Age 18 and older Confirmed unresectable or metastatic radioactive iodine refractory thyroid cancer with measurable disease per RECIST (version 1.1) (i.e. at least 1 lesion > 1 cm or lymph node > 1.5 cm in short axis) Progressive disease after TKIs treatment Eastern Cooperative Oncology Group Performance Status ≤ 3 Participant must have completed prior therapy at least 2 weeks (washout period) prior to 68Ga-FAPI-46 PET/CT scan. Any clinically significant toxicity (with the exceptions of hair loss and sensory neuropathy) related to prior therapy resolved below Grade 2 or baseline. Completion of entry into 68Ga-FAPI-46 study and completion of scan Hematologic parameters defined as: Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 Platelet count ≥ 50,000/mm3 Hemoglobin ≥ 8 g/dL Blood chemistry levels defined as: AST, ALT, alkaline phosphatase ≤ 5 times upper limit of normal (ULN) Total bilirubin ≤ 3 times ULN Creatinine ≤ 3 times ULN Able to remain motionless for up to 30-60 minutes per scan Exclusion Criteria: Participant on any chemical anticoagulant including antiplatelet agents (excluding ASA) Participants with Class 3 or 4 NYHA Congestive Heart Failure Clinically significant bleeding within two weeks prior to trial entry (e.g. gastrointestinal bleeding, intracranial bleeding) Pregnant or lactating women Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e. larger than what is required for placement of a central venous access, percutaneous feeding tube, or biopsy) within 28 days prior to study day 1 or anticipated surgery within the subsequent 6 weeks Has an additional active malignancy requiring therapy within the past 2 years Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy Psychiatric illness/social situations that would interfere with compliance with study requirements Cannot undergo PET/CT scanning because of weight limits (350 lbs) INR>1.2; PTT>5 seconds above UNL

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: classic 3+3 dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DOTA-EB-FAPI 1<br>177Lu-DOTA-EB-FAPI A maximum of 2 cycles of 60 mCi (2.22 GBq) 177Lu-DOTA-EB-FAPI, each. Route of administration: Slow intravenous infusion/injection (i.v.) Duration of treatment: 2 cycles, every 6 weeks | Drug: 177Lu-DOTA-EB-FAPI 1 radionuclide therapy<br>* radionuclide therapy using 177Lu-DOTA-EB-FAPI 60 mCi (2.22 GBq) will be performed 6-weekly. A maximum of 2 cycles will be administered.<br>|
| Experimental: 177Lu-DOTA-EB-FAPI 2<br>177Lu-DOTA-EB-FAPI A maximum of 2 cycles of 90mCi (3.33 GBq) 177Lu-DOTA-EB-FAPI, each. Route of administration: Slow intravenous infusion/injection (i.v.) Duration of treatment: 2 cycles, every 6 weeks | Drug: 177Lu-DOTA-EB-FAPI 2 radionuclide therapy<br>* radionuclide therapy using 177Lu-DOTA-EB-FAPI 90 mCi (3.33 GBq) will be performed 6-weekly. A maximum of 2 cycles will be administered.<br>|
| Experimental: 177Lu-DOTA-EB-FAPI 3<br>177Lu-DOTA-EB-FAPI A maximum of 2 cycles of 135 mCi (4.99 GBq) 177Lu-DOTA-EB-FAPI, each. Route of administration: Slow intravenous infusion/injection (i.v.) Duration of treatment: 2 cycles, every 6 weeks | Drug: 177Lu-DOTA-EB-FAPI 3 radionuclide therapy<br>* radionuclide therapy using 177Lu-DOTA-EB-FAPI 135 mCi (4.99 GBq) will be performed 6-weekly. A maximum of 2 cycles will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related adverse events (safety and tolerability) | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Dose-limiting toxicity was defined as any 177Lu-DOTA-EB-FAPI-related AE ≥ grade 3 (G3). | From date of involvement until 6 weeks after the second treatment cycles | 
| To determine the maximum tolerated dose (MTD) | The MTD is the dose level below that which 2 out of 6 subjects in a cohort have DLT | From date of involvement until 6 weeks after the second treatment cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | 68Ga-Fibroblast activation protein inhibitor 46 will be performed for efficacy evaluation by RECIST 1.1. Particularly, 68Ga-FAPI-46 will be performed at baseline, and 6 weeks after each treatment cycle. | baseline, 6 weeks after each treatment cycle | 
| Dosimetry | Dosimetry, measured as absorbed dose in tumor and normal organs (Gy/GBq), was estimated in the first treatment cycle for each patient. | Dosimetry was estimated in the first treatment cycle for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radioactive iodine refractory thyroid cancer, RAIR-TC, radioligand therapy, 177Lu-DOTA-EB-FAPI