Biodistribution of 89Zirconium-labelled GSK2398852 Using PET Imaging

NCT03417830 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2045122017-002665-22
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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

Keywords

miridesap; GSK2315698; 89Zirconium labelled; Positron Emission Tomography; Transthyretin cardiomyopathy; GSK2398852; dezamizumab

Outcome Measures

Primary Outcomes (8)

• Part A- Session 1: Peak Standardized Uptake Values (SUV) in Focal Anatomical Regions of the Heart Following 80-200 mg Dose of Anti-SAP mAb

  SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as blood pool left atrium, blood pool left ventricle, blood pool right ventricle, left ventricle wall - high uptake, left ventricle wall - low uptake, mid septum - high uptake and mid septum - low uptake. Peak SUV values derived from PET images has been presented. All treated population consisted of all participants who received at least one Anti-SAP treatment including 89Zr-GSK2398852.

  Session 1: Days 4, 5, 6 and 8

• Part A- Session 2: Peak SUV in Focal Anatomical Regions of the Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg

  SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. SUV was analyzed for each region of interest such as blood pool left atrium, blood pool left ventricle, blood pool right ventricle, left ventricle wall - high uptake, left ventricle wall - low uptake, mid septum - high uptake and mid septum - low uptake. Peak SUV values derived from PET images has been presented.

  Session 2: Days 3, 4 and 5

• Part B: Peak SUV in Focal Anatomical Regions of the Heart Following 80-200 mg Dose of Anti-SAP mAb

  SUV in focal anatomical regions of the heart was planned to be measured.

  Days 3, 4 and 6

• Part B: Peak SUV in Focal Anatomical Regions of the Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg

  SUV in focal anatomical regions of the heart was planned to be measured.

  Days 3, 4 and 6

• Part A- Session 1: Mean SUV of Whole Heart Following 80-200 mg Dose of Anti-SAP mAb

  SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

  Session 1: Days 4, 5, 6 and 8

• Part A- Session 2: Mean SUV of Whole Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg

  SUV was measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

  Session 2: Days 3, 4 and 5

• Part B: Mean SUV of Whole Heart Following 80-200 mg Dose of Anti-SAP mAb

  SUV of whole heart was planned to be measured.

  Days 3, 4 and 6

• Part B: Mean SUV of Whole Heart Following Anti-SAP mAb Dose Between 200 mg and <=500 mg

  SUV of whole heart was planned to be measured.

  Days 3, 4 and 6

Secondary Outcomes (83)

• Part A- Session 1: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb

  Session 1: Days 4, 5, 6 and 8

• Part A- Session 1: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb: Thyriod Gland-goitre Hotspot

  Session 1: Days 4 and 6

• Part A- Session 2: Mean SUV of Focal Radioactivity Uptake After Anti-SAP mAb Dose Between 200 mg and <=500 mg

  Session 2: Days 3, 4 and 5

• Part B: Mean SUV of Focal Radioactivity Uptake After 80-200 mg Dose of Anti-SAP mAb

  Days 3, 4 and 6

• Part B: Mean SUV of Focal Radioactivity Uptake After Anti-SAP mAb Dose Between 200 mg and <=500 mg

  Days 3, 4 and 6

Study Arms (2)

Subjects with ATTR-CM in Part A

EXPERIMENTAL

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.

Drug: GSK2315698 (CPHPC); Drug: GSK2398852 (unlabeled anti-SAP mAb); Drug: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

Subjects with ATTR-CM in Part B

EXPERIMENTAL

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.

Drug: GSK2315698 (CPHPC); Drug: GSK2398852 (unlabeled anti-SAP mAb); Drug: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

Interventions

GSK2315698 (CPHPC) 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.

Also known as: miridesap

Subjects with ATTR-CM in Part A; Subjects with ATTR-CM in Part B

GSK2398852 (unlabeled anti-SAP mAb) DRUG

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

Also known as: dezamizumab

Subjects with ATTR-CM in Part A; Subjects with ATTR-CM in Part B

89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb) 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 A; Subjects with ATTR-CM in Part B

Eligibility Criteria

• Age: 65 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Uppsala, SE-751 85, Sweden

Location

Related Publications (1)

• 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.

  PMID: 35152886 DERIVED

MeSH Terms

Conditions

Amyloidosis

Interventions

miridesap; dezamizumab

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A of the study will include 3 subjects with ATTR-CM who will participate in two dosing sessions and Part B of the study will include 3 subjects with ATTR-CM who will participate in one dosing session. A single dosing session will constitute treatment with carboxy pyrrolidine hexanoyl pyrrolidine carboxylate (CPHPC), total mass dose (TMD) administration of anti-serum amyloid P (SAP) monoclonal antibody (mAb) consisting of in vivo mixing of a single infusion of unlabeled anti-SAP mAb and a separate infusion of 89Zr-GSK2398852 via a different peripheral venous line, and up to 3 serial PET scanning procedures after administration of 89Zr-GSK2398852.

Study Record Dates

• First Submitted: January 25, 2018
• First Posted: January 31, 2018
• Study Start: April 6, 2018
• Primary Completion: July 20, 2018
• Study Completion: July 20, 2018
• Last Updated: August 29, 2019
• Results First Posted: August 29, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

SE (1)