Phase 1 study of 211At-MABG in patients with pheochromocytoma/parganglioma

JRCT ID: jRCT2021220012

Registered date:17/06/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Pheochromocytoma, paraganglioma
• Date of first enrollment: 03/10/2022
• Target sample size: 18
• Study type: Interventional

Intervention(s)

In-house formulated 3-astatobenzylguanidine (MABG), bound to alpha-emitting radionuclide astatine-211 (211At), is administered to patients with pheochromocytoma/paraganglioma. Follow a 3+3 design, starting with cohort 1.
Dose of investigational new drug
Cohort 1 (0.65 MBq/kg)
Cohort 2 (1.3 MBq/kg)
Cohort 3 (2.1 MBq/kg)

Outcome(s)

• Primary Outcome: Safety (dose limiting toxicity: DLT, maximum tolerated dose: MTD, recommended dose: RD).

Secondary Outcome

1) Radioactive pharmacokinetics (RPK)
2) Rate of discharge of radioactivity into the urine
3) Response rate of urinary catecholamines
4) Objective response rate (ORR)
5) Progression free survival (PFS)
6) Effect of 123I-MIBG scintigraphy on reducing tumour accumulation
7) Quality of life

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

All of the following conditions shall be met.
1) Patients who can give their written consent by the individual
2) Patients with histologically or clinically diagnosed pheochromocytoma, paraganglioma, malignant pheochromocytoma, or malignant paraganglioma
The diagnostic criteria will be in accordance with the "2018 Clinical Practice Guidelines for Pheochromocytoma and Paraganglioma."
3) Patients diagnosed with pheochromocytoma are defined below (refractory pheochromocytoma is defined as those who satisfy any of the following (a) to (c) and are unable to undergo surgical resection or radical external irradiation)
(a) Pheochromocytoma/paraganglioma with a highly localized extension of the primary tumor at first presentation
(b) Malignant pheochromocytoma/malignant paraganglioma with distant metastasis at first presentation
(c) Pheochromocytoma/paraganglioma with local recurrence or distant metastasis despite surgical resection
4) Patients aged 20 years or older
5) Patients with an ECOG Performance status (PS) of 0-2
6) 123I-MIBG aggregation positive as determined by scintigraphy at the screening in one or more target lesions confirmed by CT imaging
7) Patients who meet all of the following criteria with test values at screening
(a) bone marrow function
(1) >= 3,000/microL without administration of granulocyte colony-stimulating factor (G-CSF)
(2) Non-transfusion hemoglobin >= 9.0 g/dL
(3) Non-transfused platelet count >= 10 x 104/mm3
(b) Renal function
(1) Estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73m2
(c) Liver function
(1) AST =< 90 U/L
(2) ALT =< 126 U/L (male), ALT =< 69 U/L (female)
(3) LDH < 666 U/L
(d) Heart function
(1) NYHA Functional class: I or lower
(e) Diabetes/endocrine disease
(1)HbA1c<8.0% (NGSP value)
(f) breathing condition
(1) Atmospheric blood oxygen saturation (SpO2) >= 96%
(g) Patients expected to survive for 3 months or longer
9) Patients who are expected to be independent in eating, excretion, and sleeping during the isolation period in the nuclear medicine ward
10) Patients have not responded to standard therapy (CVD therapy or 131I-MIBG therapy) or who have no other appropriate therapy

Exclude criteria

Exclude patients who meet any of the following criteria:
1) Patients with multiple active cancers
Active multiple cancers here are defined as synchronous double/multiple cancers and metachronous double/multiple cancers with a disease-free interval of 5 years or less. However, lesions equivalent to carcinoma in situ or carcinoma in situ that are judged to be cured by local treatment and have a disease-free period of more than 1 year after cure are not included in active multiple cancers. In addition, the following cancers associated with familial pheochromocytoma are not included in active double/multiple cancers.
(a) Medullary thyroid carcinoma in multiple endocrine neoplasia type 2 (MEN2)
(b) Retinal hemangioblastoma in von Hippel Lindau disease (VHL)
(c) Neurofibromas in neurofibromatosis type 1 (NF1)
2) Patients who are unable to discontinue any drugs that suppress MABG accumulation for a predetermined period
3) Patients who are unable to discontinue alpha-methylparatyrosine for a predetermined period
4) Patients who have undergone surgery, CVD therapy, catheter hepatic artery embolization for liver metastasis, or radiotherapy within 8 weeks prior to enrollment
5) Patients who have received MIBG treatment within 12 weeks prior to enrollment
6) Patients who have developed Grade 2 or higher non-hematological toxicity during or after prior treatment, for which a causal relationship to treatment cannot be ruled out, and who require treatment during the study period
7) Patients who have any of the following infections and require medical treatment during the study period
(a) Hepatitis B virus infection
(b) Hepatitis C virus infection
(c) HIV infection
(d) Other infectious diseases requiring systemic treatment
8) Patients with a disease that requires continuous systemic administration of adrenocortical hormone (prednisone or prednisolone equivalent dose of 10 mg/d or more) or other immunosuppressants and treatment during the study period
9) Patients with a history of uncontrolled catecholamine seizures
10) Patients with a history of fatal arrhythmia or cardiac arrest
11) Patients with uncontrolled symptomatic arrhythmia, thyroid dysfunction, respiratory disease, or pleural effusions and ascites
12) Patients with coronary artery disease, arrhythmia requiring treatment with amiodarone, severe valvular disease, aortic disease, or any disease or condition with bleeding tendency
13) Patients that are pregnant (even if it is determined that there is a possibility of pregnancy by a doctor's interview, the patient will be excluded from this study), within 28 d after delivery, or breast-feeding (including women who have temporarily stopped breast-feeding)
14) Female patients of childbearing potential or male patients with partners of childbearing potential who are unable to agree to contraception for 6 months after drug treatment (any 2 of the following: contraception methods include latex condoms (used by men), oral contraceptives, intrauterine device (IUD) (progesterone-free T type) used in combination; or tubal ligation and vasectomy)
15) Patients participating in other clinical trials within 3 months before the consent date
16) Patients who are judged by the investigator or subinvestigator to be unsuitable for this study for other reasons

Related Information

• Primary Sponsor: Shiga Tohru
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development