Targeted Alpha Therapy Using Astatine (At-211) Against Differentiated Thyroid Cancer

Study Overview
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Brief Summary
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Single intravenous administration of TAH-1005 is performed in patients with differentiated thyroid cancer (papillary cancer, follicular cancer) who cannot obtain therapeutic effect with standard treatment or who have difficulty in implementing and continuing standard treatment. The safety, pharmacokinetics, absorbed dose, and efficacy will be evaluated to determine the recommended dose for Phase II clinical trial.

Detailed Description
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Radioactive iodine (I-131) has long been used clinically for patients with metastatic differentiated thyroid cancer. However, some patients are refractory to repetitive I-131 treatment, despite the targeted regions showing sufficient iodine uptake. In such patients, beta-particle therapy using I-131 is inadequate and another strategy is needed using more effective radionuclide targeting the sodium/iodide symporter (NIS). Astatine (At-211) is receiving increasing attention as an alpha-emitter for targeted radionuclide therapy. At-211 is a halogen element with similar chemical properties to iodine. Alpha particles emitted from At-211 has higher linear energy transfer as compared to beta particles from I-131 and exert a better therapeutic effect by inducing DNA double strand breaks and free radical formation. Thus, targeted alpha therapy using At-211 is highly promising for the treatment of advanced differentiated thyroid cancer.

Official Title
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Phase I Investigator-initiated Clinical Trial in Patients With Differentiated Thyroid Cancer (Papillary Cancer, Follicular Cancer) by the Targeted Alpha Therapy Drug TAH-1005 ([211At] NaAt) (Alpha-T1 Study)

Conditions
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Thyroid Cancer

Intervention / Treatment
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* Drug: Targeted alpha therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with differentiated thyroid cancer (papillary cancer, follicular cancer) after total thyroidectomy who meet the following conditions (1) resistance to standard treatment or (2) difficulty in continuing standard treatment (1) Patients who are refractory to standard treatment such as 131I-NaI treatment Insufficient therapeutic effect after 3 or more 131I-NaI treatments. 131I-NaI treatment resistance and difficulty in performing or continuing tyrosine kinase inhibitor (TKI) treatment (2) Patients who have difficulty continuing standard treatment such as 131I-NaI treatment Ablation for residual thyroid or 131I-NaI treatment for relapsed / metastatic lesions has been performed, but relapsed / metastatic lesions were observed at the time of participation in this study, and 131I-NaI is the standard treatment. If it is difficult to continue treatment or if local radiation therapy (including addition) is not indicated (if it is not 131I-NaI treatment resistant, TKI treatment is not indicated). Patients aged 18 years or older at the time of consent acquisition Patients with stable general condition with PS (Performance status) of 0 to 2 in ECOG (Eastern Cooperative Oncology Group) Patients who can be expected to survive for 6 months or more, judging from clinical symptoms and medical examination findings Patients with no or controlled brain metastases with symptoms Patients with no clinically significant abnormal findings in electrocardiogram, respiratory rate, and blood oxygen saturation within 30 days before registration Patients whose laboratory values within 30days before the enrollment are within the range specified in the protocol Patients who thoroughly listened to the explanation of the clinical trial, agreed to the examination, visit during the observation period and follow-up survey, contraception during the clinical trial period, etc. according to the clinical trial protocol, and signed the consent document. Exclusion Criteria: Patients who need fertility preservation Pregnant or potentially pregnant women, lactating patients Patients with active double cancer (simultaneous double cancer and ectopic double cancer with a disease-free period of 5 years or less) Patients who received other investigational or unapproved drugs within 5 weeks prior to enrollment Patients who received chemotherapy, immunotherapy or radiation therapy within 8 weeks prior to enrollment in this study Patients with uncontrollable active infections HBsAg positive, HCV antibody positive or HIV antibody positive patients Patients with mental illness or psychiatric symptoms who are judged to be difficult to participate in clinical trials Other patients who are judged to be inappropriate by the investigator, etc.

Ages Eligible for Study
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Maximum 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment group<br> | Drug: Targeted alpha therapy<br>* Single intravenous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related adverse events as assessed by CTCAE v5.0 | Type, severity, frequency of occurrence and duration of adverse events | From the start of iodine restriction to 6 months after administration | 
| Dose Limiting Toxicity | Toxicity is defined as one or more of the following items for which a causal relationship with the investigational drug cannot be ruled out. Grade 3 * hematological toxicity that lasts for 7 days or more Hematological toxicity of Grade 4 * or higher regardless of duration Febrile neutropenia regardless of duration Thrombocytopenia with bleeding tendency or requiring platelet transfusion Anemia requiring red blood cell transfusion Neutropenia with infection Non-hematological toxicity of Grade 3 * or higher that does not improve with symptomatic treatment and lasts for 7 days or longer. However, the following are excluded. Abnormal laboratory test values that are not clinically significant Toxicity that can be controlled to Grade 2 * or less with maximum supportive care Due to exacerbation of the underlying disease (*: Grade specified in CTCAE v.5.0J COG version) | within 4 weeks after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure | Systolic and diastolic blood pressure (mmHg) | within 4 weeks after administration | 
| Heart rate | Pulse (bpm) | within 4 weeks after administration | 
| Blood oxygen saturation | Percutaneous oxygen saturation (%) | within 4 weeks after administration | 
| Respiratory rate | Respiratory rate (times/min) | within 4 weeks after administration | 
| Body temperature | Body temperature (°C) | within 4 weeks after administration | 
| Body weight | Weight (kg) | within 4 weeks after administration | 
| Symptoms and examination findings | Subjective symptoms and medical examination findings | within 4 weeks after administration | 
| Hematological examination | White blood cell count (/μL), red blood cell count (×10^4/μL), hemoglobin (g/dL), hematocrit (%), platelet count (×10^4/μL) | within 4 weeks after administration | 
| Blood biochemical test | Total protein (g/dL), albumin (g/dL), total bilirubin (mg/dL), AST (U/L), ALT (U/L), ALP (U/L), γ-GTP (U/L), LDH (U/L), total cholesterol (mg/dL), triglyceride (mg/dL), uric acid (mg/dL), BUN (mg/dL), creatinine (mg/dL), CK (U/L), Na (mmol/L), K (mmol/L), Cl (mmol/L), Ca (mmol/L), CRP (mg/dL) | within 4 weeks after administration | 
| Urinalysis | Urinary protein, urine sugar, urineous blood, urobilinogen (qualitative test) | within 4 weeks after administration | 
| 12-lead ECG | Presence or absence of abnormal findings in waveform | within 4 weeks after administration | 
| Pharmacokinetic parameters 1) | AUC (Area under the plasma concentration versus time curve, Bq·min/mL) | until 24 hours after administration | 
| Pharmacokinetic parameters 2) | AUC / D (Area under the plasma concentration versus time curve divided by injected dose, min/mL) | until 24 hours after administration | 
| Pharmacokinetic parameters 3) | Cmax (Peak plasma concentration, Bq/mL) | until 24 hours after administration | 
| Pharmacokinetic parameters 4) | Cmax / D (Peak plasma concentration divided by injected dose, /mL) | until 24 hours after administration | 
| Pharmacokinetic parameters 5) | Tmax (Time to maximum plasma concentration, min) | until 24 hours after administration | 
| Pharmacokinetic parameters 6) | T1 / 2 (Time from Tmax to half of maximum plasma concentration, min) | until 24 hours after administration | 
| Pharmacokinetic parameters 7) | CL (Clearance, L/hr/kg) | until 24 hours after administration | 
| Pharmacokinetic parameters 8) | Vss (Volume of distribution in steady state, L/kg) | until 24 hours after administration | 
| Excretion 1) urinary | Urine volume (mL) and radioactivity (Bq): Radioactivity and volume will be combined to report radioactivity concentration (Bq/mL). | until 24 hours after administration | 
| Excretion 2) fecal | Stool weight (g) and radioactivity (Bq): Radioactivity and weight will be combined to report radioactivity concentration (Bq/g). | until 24 hours after administration | 
| Excretion 3) exhaled | Exhaled volume (mL) and radioactivity (Bq): Radioactivity and volume will be combined to report radioactivity concentration (Bq/mL). | until 24 hours after administration | 
| Radioactivity concentration in major organs | Changes in radioactivity concentration (Bq/mL) in major organs over time: Whole-body imaging (planar and SPECT/CT) is performed to evaluate the distribution in the body at 1 hour, 3 hours, 24 hours after the administration. | until 24 hours after administration | 
| Residence time of major organs | Residence time (hr) of each organ | until 24 hours after administration | 
| Absorbed dose of major organs | Absorbed dose (mGy / MBq) of each organ | until 24 hours after administration | 
| Preliminary effectiveness assessment 1) | Evaluation of treatment effect on CT images by referring to the Revised RECIST guideline (version 1.1): CR (Complete response), PR (Partial response), SD (Stable disease), or PD (Progressive disease) | 3 and 6 months after administration | 
| Preliminary effectiveness assessment 2) | Evaluation of uptake change in diagnostic [131I] NaI scans: CR , PR, SD, or PD | 3 and 6 months after administration | 
| Preliminary effectiveness assessment 3) | Evaluation of changes in tumor markers: blood thyroglobulin (ng/mL) | 3 and 6 months after administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Targeted alpha therapy, Astatine (At-211)