Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698

NCT03044353 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 2014642016-000276-23
• Study Type: interventional
• Target: 7
• Locations: 2 countries
• Sites: 3

Brief Summary

The study is intended to evaluate whether monthly repeated courses of administration of GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and echocardiography (ECHO), and whether this is associated with an improvement in cardiac function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy. Primary objectives for the study are assessment of reduction in cardiac amyloid load after repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and assessment of safety \& tolerability of repeated administration of Anti-SAP treatment, including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis. This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis. Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a subject in the study is approximately 18 months.

Conditions

Amyloidosis

Keywords

echocardiography (ECHO); skin biopsy; monoclonal anti-serum amyloid p component antibody (anti-SAP mAb); Amyloidosis; cardiac magnetic resonance imaging (CMR); biomarkers; cardiac functional measures; left ventricular mass

Outcome Measures

Primary Outcomes (15)

• Change From Baseline in Left Ventricular (LV) Mass Over Time up to 8-week Follow-up

  Left ventricular mass was measured by Cardiac Magnetic Resonance (CMR) imaging to assess reduction in cardiac amyloid load after repeated administration of anti-SAP treatment. Each CMR imaging session took approximately 45-60 minutes, with a maximum scan time inside of the scanner of 90 minutes. Baseline was considered as the latest assessment prior to first administration of either study drug, i.e. CPHPC or anti-SAP mAb. Change from Baseline was calculated as post-dose visit value minus Baseline value. Safety Population comprised of all participants who received at least one dose of study treatment (any dose of CPHPC \[GSK2315698\] or anti-SAP mAb \[GSK2398852\]).

  Baseline (Day -1) and Session 2 Day 24, Session 3 Day 24, Session 4 Day 24, Session 5 Day 24, 8 Weeks Follow-up

• Number of Participants With Any On-treatment Adverse Events (AEs)

  AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants with any on-treatment AEs are presented.

  Up to 56 days after the last dosing session (up to 265 days)

• Number of Participants With Any Serious Adverse Events (SAEs)

  AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, events associated with liver injury and impaired liver function, or any other situation according to medical or scientific judgment were categorized as SAE. Number of participants with any SAEs during study are presented.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormal Hematology Values

  Blood samples were collected for assessment of hematology parameters, which included platelet count, hemoglobin, hematocrit, erythrocytes, reticulocyte count, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils, leukocytes and basophils. Abnormal laboratory results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormal Clinical Chemistry Values

  Blood samples were collected for assessment of clinical chemistry parameters, which included aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), urea, creatinine, glucose, chloride, creatinine kinase, potassium, sodium, calcium, total carbon dioxide (CO2), urate, total and direct bilirubin, total protein and albumin. Abnormal laboratory results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormal Urinalysis Results

  Urine samples were collected to assess potential of hydrogen (pH), specific gravity, albumin excretion rate, creatinine excretion rate and protein excretion rate. Abnormal urinalysis results are categorized as high, low or normal with respect to their normal ranges. Data for worst case post Baseline is presented. Participants having both High and Low values from Normal Ranges at any post-baseline visits for any parameter was counted in both the High and Low categories.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormal Urinalysis Results for Character Parameters

  Urine samples were collected to assess character parameters which included Cellular Casts, Erythrocytes, Glucose, Ketones, Leukocytes and Occult Blood. Number of participants with abnormal urinalysis results are presented. Data for worst case post Baseline is presented.

  Up to the end of study (Up to 369 days)

• Number of Participants With Body Temperature Shifts From Baseline Relative to Potential Clinical Importance (PCI) Criteria

  Vital signs including body temperature was measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in body temperature from Baseline to worst case post Baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to PCI criteria. PCI criteria for body temperature was: high: \>37.5 degree Celsius; low: not applicable.

  Up to the end of study (Up to 369 days)

• Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Shifts From Baseline Relative to PCI Criteria

  Vital signs including SBP and DBP were measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in SBP and DBP from baseline to worst case post baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to PCI criteria. PCI criteria for SBP was: high: \>180 millimeter of mercury (mmHg); low: \<90 mmHg. PCI criteria for DBP was: high: \>110 mmHg; low: \<30 mmHg.

  Up to the end of study (Up to 369 days)

• Number of Participants With Pulse Rate Shifts From Baseline Relative to PCI Criteria

  Vital signs including pulse rate were measured after participants rested in semi-supine position for at least 5 minutes. Number of participants with shifts in pulse rate from baseline to worst case post baseline relative to PCI criteria have been presented. PCI results were categorized as to high, to low and to normal/no change with reference to its PCI criteria. PCI criteria for pulse rate was: high: \>140 beats per minute (bpm); low: \<35 bpm.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings

  Twelve-lead ECGs were performed during the study using an automated ECG machine. The number of participants with worst case post-Baseline abnormal ECG findings were reported and categorized as abnormal-clinically significant and abnormal-not clinically significant.

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormalities During Cardiac Monitoring

  Lead II telemetry and cardiac monitoring devices were used for electrical cardiac monitoring during the study. The number of participants with worst case post-Baseline abnormalities during cardiac monitoring as per investigator's assessment have been reported and categorized as Abnormal-clinically significant and Abnormal-not clinically significant.

  Up to the end of study (Up to 369 days)

• Number of Participants for Which Unscheduled Echocardiography (ECHO) Was Performed for Safety Reasons

  Echocardiography was performed by a qualified echocardiographer or cardiologist during the study. Number of participants with unscheduled echocardiograms performed for safety reasons have been presented.

  Up to the end of study (Up to 369 days)

• Number of Participants With Skin Rashes

  Skin rash was an event of special interest. Only Rashes that were associated with study drug were categorised as Rash for Common Terminology Criteria for Adverse Events (CTCAE) and are presented. Number of participants with on-treatment skin rash AEs are presented.

  Up to 56 days after the last dosing session (up to 265 days)

• Number of Participants With Skin Rashes Classified Using CTCAE

  Skin rash was an event of special interest. All the events of rashes were graded for their severity using CTCAE version 4.0 . Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening, Grade 5: death. Higher the grade, more severe the symptoms. Only Rashes that were associated with study drug were categorised as Rash for CTCAE and are presented here. Number of participants with skin rashes classified by their maximum grade are presented.

  Up to 56 days after the last dosing session (up to 265 days)

Secondary Outcomes (25)

• Number of Participants With Abnormalities in Histopathological Examination of Skin Biopsies

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormalities in Immunohistochemical Examination of Skin Biopsies

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormalities in Histopathological Examination of Blood Biomarkers

  Up to the end of study (Up to 369 days)

• Number of Participants With Abnormalities in Immunohistochemical Examination of Blood Biomarkers

  Up to the end of study (Up to 369 days)

• Change From Baseline in Plasma Cytokines Over Time

  Baseline (Day -1) and Session 1: Day 1 (predose, 1,3,6 hours), Day 2, Day 3 (predose, 1,3,6 hours), Day 4, Day 5; Session 2 to 6: Day -2, Day 1 (predose, 1,3,6 hours), Day 2, Day 3 (predose, 1,3,6 hours), Day 4, Day 5

Study Arms (3)

Group 1: Cardiac TTR amyloidosis (ATTR-CM) participants

EXPERIMENTAL

Cardiac transthyretin (TTR) amyloidosis (transthyretin amyloid cardiomyopathy \[ATTR-CM\]) participants with mutant genotypes primarily associated with familial amyloidotic cardiomyopathy (FAC) and wild-type TTR will be included. Participants will receive 6 anti-SAP treatments, consisting of carboxy pyrrolidine hexanoyl pyrrolidine carboxylate (CPHPC) followed by anti-SAP monoclonal antibody (mAb) at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC intravenous (IV) infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered intravenous infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 milligrams (mg) (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered as subcutaneous (SC) injection for 11 days from the day of first dose of anti-SAP mAb.

Drug: GSK2315698 (CPHPC); Biological: GSK2398852 (anti-SAP mAb)

Group 2: Post-chemotherapy AL Amyloidosis participants

EXPERIMENTAL

Immunoglobin light chain amyloidosis (AL) participants who attain either a very good partial response (VGPR), or complete response (CR), to systemic chemotherapy (including autologous stem cell transplantation) will be included. Participants will receive 6 anti-SAP treatments, consisting of CPHPC followed by anti-SAP mAb at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC IV infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered IV infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 mg (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered by as SC injection for 11 days from the day of first dose of anti-SAP mAb.

Drug: GSK2315698 (CPHPC); Biological: GSK2398852 (anti-SAP mAb)

Group 3: Newly diagnosed Mayo stage II/IIIa AL participants

EXPERIMENTAL

Newly diagnosed Mayo stage II/IIIa AL participants who attain a free light chain CR during the first 3 cycles of first-line chemotherapy where the first cycle was cyclophosphamide, bortezomib, dexamethasone (CyBorD) will be included. Participants will receive 6 anti-SAP treatments, consisting of CPHPC followed by anti-SAP mAb at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC IV infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered IV infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 mg (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered as SC injection for 11 days from the day of first dose of anti-SAP mAb.

Drug: GSK2315698 (CPHPC); Biological: GSK2398852 (anti-SAP mAb)

Interventions

GSK2315698 (CPHPC) DRUG

20mg/hour, IV (in the vein) for up to 72hours followed by 60mg three times daily subcutaneous injection for 11 days. Number of cycles: up to 6. Dose level and frequency adjusted according to renal function

Group 1: Cardiac TTR amyloidosis (ATTR-CM) participants; Group 2: Post-chemotherapy AL Amyloidosis participants; Group 3: Newly diagnosed Mayo stage II/IIIa AL participants

GSK2398852 (anti-SAP mAb) BIOLOGICAL

Up to 1200mg, IV divided over days 1 and 3. Number of cycles: up to 6. Dose level adjusted based on tolerability.

Group 1: Cardiac TTR amyloidosis (ATTR-CM) participants; Group 2: Post-chemotherapy AL Amyloidosis participants; Group 3: Newly diagnosed Mayo stage II/IIIa AL participants

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
• Male and female.
• Males:
• Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication for a cycle of spermatogenesis following five terminal half-lives after the last dose of study medication. Vasectomy with documentation of azoospermia.
• Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant, Intrauterine device or intrauterine system, Combined Oral Contraceptive or Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches .
• This is an all-inclusive list of those methods that meet the following GlaxoSmithKline (GSK) definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. The GSK definition is based on the definition provided by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
• The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
• Females
• A female subject is eligible to participate if she is not pregnant (as confirmed by a negative Urine human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy.
• Postmenopausal defined as: 60 years old; Twelve(12) months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, \> 45 years, in the absence of hormone replacement therapy (HRT) or medical suppression of the menstrual cycle (e.g. leuprolide treatment) in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and oestradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). Females on HRT and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (As mentioned in study protocol) from 30 days prior to the first dose of study medication and until 3 months after the last dose of study medication.
• The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis

You may not qualify if:

• Cardiomyopathy primarily caused by non-amyloid diseases (e.g. ischemic heart disease; valvular heart disease)
• Interval from the Q wave on the ECG to point T using Fredericia's formula (QTcF) \> 500 millisecond (msec)
• Sustained / symptomatic monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, 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
• N-terminal pro b-type Natriuretic Peptide \[(NT)-proBNP\] \>8500 nanograms (ng)/ Liter (L)
• Glomerular filtration rate (GFR) at Screening \< 40 milliliter (mL)/minute (min)
• Any active and persistent dermatological condition
• Existing diagnosis of any type of dementia
• History of allogeneic stem cell transplantation, prior solid organ transplant, or anticipated to undergo solid organ transplantation, or left ventricular assist device (LVAD) implantation, during the course of the study.
• 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.
• Stroke within 6 months of screening, or transient ischaemic attack (TIA) within 3 months of screening
• Symptomatic, clinically significant autonomic neuropathy which the Principal Investigator (PI) feels will preclude administration of study treatment
• Hypoalbuminaemia (serum albumin \< 30 g/L)

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Boston, Massachusetts, 02115, United States

Location

GSK Investigational Site

Cambridge, CB2 0GG, United Kingdom

Location

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

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 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2016
• First Posted: February 7, 2017
• Study Start: July 10, 2017
• Primary Completion: January 3, 2019
• Study Completion: January 3, 2019
• Last Updated: October 16, 2019
• Results First Posted: October 16, 2019

Record last verified: 2019-09

Locations

GB (2); US (1)