scholarly journals Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer

2021 ◽  
Author(s):  
Tadashi Watabe ◽  
Kazuko Kaneda-Nakashima ◽  
Kazuhiro Ooe ◽  
Yuwei Liu ◽  
Kenta Kurimoto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Thyroid Cancer ◽  
Single Dose ◽  
General Condition ◽  
Blood Test ◽  
Differentiated Thyroid Cancer ◽  
Targeted Alpha Therapy ◽  
Evaluation Point ◽  
Alpha Therapy

Abstract Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

scholarly journals Prophylactic prednisolone for the prevention of early and intermediate adverse effects of radioactive iodine therapy in patients with thyroid cancer: study protocol for a single-centre, phase II/III, randomized, double-blinded, placebo-controlled clinical trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Umesh Jayarajah ◽  
Mahilal Wijekoon ◽  
Sanjeewa A. Seneviratne
Keyword(s):  
Quality Of Life ◽  
Clinical Trial ◽  
Thyroid Cancer ◽  
Adverse Effects ◽  
Differentiated Thyroid Cancer ◽  
Radioactive Iodine ◽  
Oral Prednisolone ◽  
Single Centre ◽  
Double Blinded

Abstract Background Radioactive iodine (RAI) therapy is the standard adjuvant treatment for differentiated thyroid cancer (i.e. papillary and follicular). RAI is associated with troublesome early, intermediate and late adverse effects. Although glucocorticoids are used for the management of these adverse effects, there is little evidence regarding the effectiveness of prophylactic glucocorticoids to prevent these complications. This trial will evaluate the efficacy of a short course of prophylactic glucocorticoids in the prevention of adverse effects of RAI treatment in patients with differentiated thyroid cancer. Methods A phase II/III, single-centre, randomized, double-blinded, placebo-controlled, parallel-arm clinical trial will be conducted. Patients with differentiated thyroid cancer who are referred to RAI therapy at the National Cancer Institute, Sri Lanka, will be randomized into two arms consisting of 200 patients each. The experimental group will receive prophylactic oral prednisolone 0.5 mg/kg and omeprazole 20 mg single dose 6 h before RAI therapy followed by oral prednisolone 0.5 mg/kg and omeprazole 20 mg daily for 3 days. The control group will receive oral placebo and omeprazole 20 mg single dose 6 h before RAI therapy followed by oral placebo and omeprazole 20 mg daily for 3 days. Clinically significant adverse effects assessed as related to RAI as well as prednisolone therapy and the quality of life parameters will be compared between the two groups. Discussion If proven beneficial, this intervention can be incorporated into the standard practice to reduce early and intermediate adverse effects of RAI for thyroid cancer with a potential improvement of quality of life. Trial registration Sri Lanka Clinical Trials Registry SLCTR/2020/009. Registered prospectively on 23 February 2020. Items of the WHO Trial Registration Data Set are provided in the supplementary file.

scholarly journals Targeted Alpha Therapy Trial in Bangladesh: Promise for Advanced MUC1 – Expressing Tumors

2018 ◽  
Vol 19 (1) ◽  
pp. 43-50
Author(s):  
Lutfun Nisa ◽  
Kamila Afroj Quadir ◽  
Shamim MF Begum ◽  
Raihan Hussain ◽  
Mizanul Hasan
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Advanced Technology ◽  
Current Status ◽  
Targeted Alpha Therapy ◽  
Cancer Management ◽  
Tolerance Dose ◽  
Maximum Tolerance ◽  
Alpha Therapy

Introduction: Targeted alpha therapy (TAT) is a new experimental therapy that targets cancer cells and tumor capillary endothelial cells through intravenous injection of an alpha immuneconjugate (AIC). The AIC is formed by labeling the cancer targeting vector (monoclonal antibody) with alpha emitting radioisotopes using a bifunctionalchelator. The monoclonal antibody (MAb) is raised against antigens (e.g. MUC1) over-expressed on the surface of certain cancer cells. There are several centers notably in Europe, the US and Australia that are actively involved in TAT clinical trials of different cancers using a variety of techniques, alpha emitters and MAbs. Observations from their cumulative experience suggest that TAT is safe and effectivebut needs further trials for practical acceptance. Especially critical is the issue of maximum tolerance dose (MTD) which needs to be established for maximum target kill. Bangladesh has the infrastructure to conduct aTAT clinical trial and can significantly add to the growing pool of data for advanced treatment of cancers through collaborative involvement in targeted alpha therapy research.Objective: The aim of the article is to present a general overview of targeted alpha therapy and to discuss the feasibility of a TAT clinical trial in Bangladesh in the context of current cancer management situation in the country.Method: Literature review of significant publications was done to obtain an update of the current status of targeted alpha therapy. Relevant issues of TAT are presented for a theoretical basis of the technology. Next, the methodology of a proposed clinical trial is discussed, together with the practicability of its introduction in Bangladesh.Conclusion: Implementation of TAT clinical trial will help to develop an advanced technology and build- up skilled manpower in Bangladesh.It will optimize the key parameters of targeted alpha therapy, i e stability and specific activity of the alpha-conjugate and establish the maximum tolerance dose for the AIC. If the clinical trial is successful, it can change the prognosis of many end-stage cancers. Patients in Bangladesh with advanced MUCI expressing tumors of the breast, ovary, pancreas and prostate can have some measure of hope with stability of the disease.Bangladesh J. Nuclear Med. 19(1): 43-50, January 2016

scholarly journals Assessment of Gonadal Function Following Single Dose of Radioiodine Therapy in Differentiated Thyroid Cancer Patients of Reproductive Age

2018 ◽  
Vol 19 (2) ◽  
pp. 92
Author(s):  
Md Sunny Anam Chowdhury ◽  
Sadia Sultana ◽  
Md Abdul Awal ◽  
Suraya Sarmin ◽  
Mohammad Simoon Salekin
Keyword(s):  
Thyroid Cancer ◽  
Single Dose ◽  
Differentiated Thyroid Cancer ◽  
Reproductive Age ◽  
Age Group ◽  
Gonadal Function ◽  
Male Patients ◽  
The Mean ◽  
Reproductive Age Group

<p><strong>Objective</strong>: This interventional study has undertaken to assess the gonadal function of differentiated thyroid cancer (DTC) patients within reproductive age group following single dose of radioactive iodine (131I) therapy/ablation.</p><p><strong>Patients and Methods:<em> </em></strong>A total of 69 patients (25 male and 44 female) of DTC were included in this study, those were referred for 131I ablation after total thyroidectomy. Following RAI, these patients were followed-up three times at three months interval.  The usual I-131 dose was 75 or 100 m Ci for ablation of thyroid residues and 150 mCi for treatment of nodal metastasis. All the patients were interviewed about menstrual (female only) and reproductive history and investigated of the level of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone of male patients and FSH, LH, estradiol (E<sub>2</sub>) of female patients before administration of  131I and three, six and nine months after therapy.</p><p><strong>Result</strong>: In this study all of the 25 (100.0%) male patients showed high FSH level after three months of therapy. The mean± SD FSH level of male patients was found significantly (p-0.001) higher (15.59±7.53 IU/L) after three months of therapy than the pretherapy (4.85±2.57 IU/L) level.  The mean± SD of FSH level was significantly declining in six months and nine months of follow up. The mean± SD of LH hormone level of these patients was found 6.1±3.67 IU/L in pretherapy which was significantly increased to 7.67±4.33 IU/L after three months. The mean LH level was 7.20±3.98 IU/L at six months follow up and 7.3±3.5IU/L after nine months. The differences of LH level between 3 months to 6 months and 6 months to 9 months are not statistically significant. No significant change was observed in testosterone level throughout the study period. In female, five patients developed irregular menstruation (changed duration of cycle or lighter amount), three patients developed amenorrhea associated with hot flashes within six months of 131I administration. Biochemical study of the patients with amenorrhoea showed markedly elevated serum FSH, LH level and declined E<sub>2 </sub>level. The FSH, LH levels of the two patients with amenorrhea became normal within study period and one patient had persistent amenorrhea at 9 months. E<sub>2</sub> level raised slowly.</p><p><strong>Conclusion</strong>: A single dose of radio-iodine (131I) therapy causes impairment of gonadal function of male patients within reproductive age group. In case of female patients the effect is insignificant. The effect is usually reversible and gonadal function of the patients restores within the study period.</p><p>Bangladesh J. Nuclear Med. 19(2): 92-97, July 2016  </p>

Increased Uptake of At-211 in Thyroid Gland by the Preparation with Ascorbic Acid for Targeted Alpha Therapy of Thyroid Cancer

2019 ◽  
Vol 50 (4) ◽  
pp. S75
Author(s):  
Kazuhiro Ooe ◽  
Tadashi Watabe ◽  
Kazuko Kaneda-Nakashima ◽  
Yuwei Liu ◽  
Yoshifumi Shirakami ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Thyroid Cancer ◽  
Thyroid Gland ◽  
Targeted Alpha Therapy ◽  
Alpha Therapy

Encorafenib and binimetinib with or without nivolumab in treating patients with metastatic radioiodine refractory BRAF V600 mutant thyroid cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS6085-TPS6085
Author(s):  
Matthew H. Taylor ◽  
Rom S. Leidner ◽  
Richard Bryan Bell ◽  
Bernard Fox ◽  
Hong Xiao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Multikinase Inhibitors ◽  
Braf Mutant

TPS6085 Background: Differentiated thyroid cancer is the most common endocrine malignancy and has a high frequency of actionable molecular aberrations including BRAF V600E mutations (45%), RET fusions (10%), and NTRK fusions ( < 2%). FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers). Previous phase II clinical trials showed clinical efficacy with first and second generation BRAF inhibitors in patients with BRAF mutant RR-DTC. BRAF inhibitors have not yet been FDA approved for treatment of BRAF mutant RR-DTC. Effective therapeutic options for patients with BRAF mutant RR-DTC remains an important unmet clinical need. BRAF mutant thyroid cancers often show elevated expression of PD-L1. Additionally, BRAF inhibition results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib plus binimetinib with or without nivolumab in patients with BRAF mutant metastatic RR-DTC. Encorafenib and binimetinib are highly selective and potent oral inhibitors of BRAF and MEK, respectively. Nivolumab is a potent inhibitor of the immune co-inhibitory receptor programmed cell death protein 1 (PD-1). Methods: This is a phase II, single institution, open-label, randomized clinical trial evaluating the combinations of (Arm 1) encorafenib 450 mg/day + binimetinib 45 mg twice daily and (Arm 2) encorafenib 450 mg/day + binimetinib 45 mg twice daily + nivolumab 480 mg I.V. every 4 weeks in patients with metastatic BRAF mutant RR-DTC. The trial will enroll 20 patients in each arm and treatment will be given in 28 day cycles for up to 2 years. Eligible patients must have metastatic/unresectable BRAF mutant RR-DTC, an ECOG performance status of 0-1 and adequate bone marrow, liver and kidney function. Patients with CNS metastases are included if the metastases have been treated and remained stable or are asymptomatic and ≤10 mm in diameter. Patients may be systemic therapy naïve or have previously been treated with multikinase inhibitors. Prior therapy with BRAF, MEK or immune checkpoint inhibitors is exclusionary. The primary endpoint is confirmed objective response rate (ORR) determined by RECIST v1.1 with restaging imaging every 12 weeks. Secondary endpoints include progression free survival, overall survival, and safety/tolerability (CTCAE v5.0). Arms 1 and 2 will be evaluated independently and are not powered for direct comparison. The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary. This clinical trial is in progress and 3 patients have been enrolled. Clinical trial information: NCT04061980.

scholarly journals Prophylactic prednisolone for the prevention of early and intermediate adverse effects of radioactive iodine therapy in patients with thyroid cancer: study protocol for a single centre, phase II/III, randomized, double blinded, placebo controlled clinical trial

2020 ◽  
Author(s):  
Umesh Jayarajah ◽  
Mahilal Wijekoon ◽  
Sanjeewa Seneviratne
Keyword(s):  
Quality Of Life ◽  
Clinical Trial ◽  
Thyroid Cancer ◽  
Adverse Effects ◽  
Differentiated Thyroid Cancer ◽  
Radioactive Iodine ◽  
Oral Prednisolone ◽  
Single Centre ◽  
Double Blinded

Abstract BackgroundRadioactive iodine (RAI) therapy is the standard adjuvant treatment for differentiated thyroid cancer (i.e. papillary and follicular). RAI is associated with troublesome early, intermediate and late adverse effects. Although glucocorticoids are used for the management of these adverse effects, there is little evidence regarding the effectiveness of prophylactic glucocorticoids to prevent these complications. This trial will evaluate the efficacy of a short course of prophylactic glucocorticoids in the prevention of adverse effects of RAI treatment in patients with differentiated thyroid cancer.MethodsA phase II/III, single centre, randomized, double blinded, placebo controlled, parallel arm clinical trial will be conducted. Patients with differentiated thyroid cancer who are referred to RAI therapy at the National Cancer Institute, Sri Lanka will be randomised into two arms consisting of 200 patients each. The experimental group will receive prophylactic oral prednisolone 0.5mg/kg and omeprazole 20mg single dose 6 hours before RAI therapy followed by oral prednisolone 0.5mg/kg and omeprazole 20mg daily for 3 days. The control group will receive oral placebo and omeprazole 20mg single dose 6 hours before RAI therapy followed by oral placebo and omeprazole 20mg daily for 3 days. Clinically significant adverse effects assessed as related to RAI as well as prednisolone therapy and the quality of life parameters will be compared between the two groups.DiscussionIf proven beneficial, this intervention can be incorporated into the standard practice to reduce early and intermediate adverse effects of RAI for thyroid cancer with a potential improvement of quality of life. Trial registrationRegistration ID: Sri Lanka Clinical Trials Registry: SLCTR/2020/009 Registered prospectively on 23 February 2020. Url: https://slctr.lk/trials/slctr-2020-009

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