Biodistribution of 89Zirconium-labelled GSK2398852 Using PET Imaging

NCT ID: NCT03417830

Last Updated: 2019-08-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-06
• Study Completion Date: 2018-07-20

Brief Summary

The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.

Conditions

Amyloidosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Subjects with ATTR-CM in Part A

Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part A will participate in two anti-SAP dosing sessions approximately 26 days in duration. The first two subjects in Part A will have up to three 89Zr PET scans, while the remaining subject will undergo up to two 89Zr PET scans.

Group Type: EXPERIMENTAL

GSK2315698 (CPHPC)

Intervention Type: DRUG

GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.

GSK2398852 (unlabeled anti-SAP mAb)

Intervention Type: DRUG

Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.

89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

Intervention Type: DRUG

89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Subjects with ATTR-CM in Part B

Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part B will participate in one anti-SAP dosing session. Subjects will undergo up to two 89Zr PET scans.

Group Type: EXPERIMENTAL

GSK2315698 (CPHPC)

Intervention Type: DRUG

GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.

GSK2398852 (unlabeled anti-SAP mAb)

Intervention Type: DRUG

Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.

89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

Intervention Type: DRUG

89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Interventions

GSK2315698 (CPHPC)

GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.

Intervention Type: DRUG

GSK2398852 (unlabeled anti-SAP mAb)

Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.

Intervention Type: DRUG

89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Intervention Type: DRUG

Other Intervention Names

miridesap; dezamizumab

Eligibility Criteria

Inclusion Criteria

• Subject must be 65 to 80 years of age inclusive, at the time of signing the informed consent.
• Subjects with a diagnosis of ATTR-CM: a) Wild-type ATTR status must be confirmed by genotyping and have one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of Transthyretin amyloidosis (TTR) as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR ii) Scintigraphy Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) with confirmed myocardial uptake. b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. ii) Scintigraphy: 99mTc-DPD with confirmed myocardial uptake.
• Both male and female subjects are eligible to participate. a) Male subjects: A male subject must agree to use contraception during the treatment period and for at least 3 months after the last scan and refrain from donating sperm during this period. b) Female subjects: A female subject is eligible to participate if she is not of childbearing potential.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
• New York Heart Association (NYHA) up to class 3; subjects should be clinically stable for at least 3 months preceding to Screening.

Exclusion Criteria

• Cardiomyopathy primarily caused by non-amyloid diseases (example, ischemic heart disease; valvular heart disease).
• Interval from the Q wave on the ECG to point T using Fredericia's formula (QTcF) >500 milliseconds (msec).
• Sustained (at a rate of >=120 beats per minute for >=30 seconds), or symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at Screening/Baseline cardiac monitoring.
• Systolic blood pressure <=100 millimeters of mercury (mm/Hg) based on triplicate readings at Screening.
• Unstable heart failure defined as emergency hospitalization for worsening, or decompensated heart failure, or syncopal episode within 1 month of screening.
• Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at Screening.
• Estimated Glomerular filtration rate (eGFR) at Screening <50 milliliters per minute (mL/min) calculated using modification of diet in renal disease (MDRD).
• Any active and persistent dermatological condition, which in the opinion of the Investigator and Medical Monitor would preclude safe participation.
• History of allogeneic stem cell transplantation, prior solid organ transplant, or anticipated to undergo solid organ transplantation, or left ventricular assist device (LVAD) implantation.
• Malignancy within last 5 years, except for basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix that has been successfully treated.
• Acute coronary syndrome, or any form of coronary revascularization procedure (including coronary artery bypass grafting [CABG]), within 6 months of screening.
• Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment.
• Uncontrolled hypertension during Screening.
• ALT >3 times upper limit of normal (ULN) OR bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Peripheral edema at Screening that in the opinion of the PI or designee might prevent adequate absorption of subcutaneously administered CPHPC.
• Presence of any co-morbid (example, steroid refractory rheumatoid arthritis), or an uncontrolled medical condition (example, diabetes mellitus), which in the opinion of the investigator would increase the potential risk to the subject. Investigator should liaise with the Medical Monitor where there is uncertainty as to the eligibility of a subject.
• Positive test for hepatitis B, hepatitis C and/or human immunodeficiency virus (HIV) during Screening, or within 3 months prior to first dose of study treatment.
• Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis and exfoliative dermatitis).
• Inability to comprehend and/or understand the study patient information sheet, and/or unwillingness or inability to follow the procedures outlined in the protocol.
• Has any of the following: a) Fulfillment of diagnostic criteria for Amyloid Light-chain (AL) amyloidosis. b) Fulfillment of diagnostic criteria for amyloid A (AA) or non-TTR hereditary amyloidosis.
• ATTR Disease Load: c) Histologically proven or clinically suspected gastrointestinal TTR amyloidosis; d) Diffuse skeletal muscle uptake of 99m(Tc)-DPD on Single-photon emission computed tomography (SPECT) imaging (where available); e) Peripheral neuropathy causing more than mild morbidity (example, walking disability; neuropathic pain affecting activities of daily living); f) Proven or clinically suspected intracranial TTR involvement including ophthalmological disease.
• Non-amyloidosis related chronic liver disease (with the exception of Gilbert's syndrome or clinically asymptomatic gallstones).
• Participation in a separate clinical trial involving CPHPC within 3 months of Screening.
• Any prohibited concomitant medication within referenced timeframe.
• Treatment with another investigational drug, biological agent, or device within 6 months of screening, or 5 half-lives of the study agent, whichever is longer.
• Orthopnea of sufficient severity to preclude supine scanning as determined at Screening.
• Inability to fit inside scanner due to body size (girth).
• History of claustrophobia.
• Contraindication to magnetic resonance imaging (MRI) contrast agents.
• Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to: a) Intracranial aneurysm clips (except Sugita) or other metallic objects; b) Intra-orbital metal fragments that have not been removed; c) Pacemakers or other implanted cardiac rhythm management/monitoring devices and non-magnetic resonance (MR) conditional heart valves; d) Inner ear implants.
• Donation of blood or blood products in excess of 500 milliliters (mL) within 84 days of Screening.
• Poor or unsuitable venous access.

• Minimum Eligible Age: 65 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Uppsala, , Sweden

Countries

Sweden

References

Wechalekar A, Antoni G, Al Azzam W, Bergstrom M, Biswas S, Chen C, Cheriyan J, Cleveland M, Cookson L, Galette P, Janiczek RL, Kwong RY, Lukas MA, Millns H, Richards D, Schneider I, Solomon SD, Sorensen J, Storey J, Thompson D, van Dongen G, Vugts DJ, Wall A, Wikstrom G, Falk RH. Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study. BMC Cardiovasc Disord. 2022 Feb 13;22(1):49. doi: 10.1186/s12872-021-02407-6.

Reference Type: DERIVED

PMID: 35152886 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-002665-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

204512

Identifier Type: -

Identifier Source: org_study_id