Clinical trial NCT03044353: Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698
Official title: A Multiple Treatment Session, Open Label Phase 2 Clinical Study of GSK2398852 Administered Following and Together With GSK2315698 in Cohorts of Patients With Cardiac Amyloidosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-02-07
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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
* LV mass on CMR \> 200 grams (g) Inclusion Criteria for Group 1
* Transthyretin amyloid (ATTR) cardiomyopathy (CM)
* Subjects with a diagnosis of hereditary ATTR amyloidosis should have a known amyloidogenic transthyretin (TTR) mutation demonstrated by genotyping AND is recognised to be primarily associated with cardiomyopathy AND one of the following: Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarised light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis.

Or Scintigraphy: 99m\^Tc-DPD with Grade 2 cardiac uptake or 99m\^Tc-PYP with either Grade 2 or 3 cardiac uptake.

* Subjects with a diagnosis of wild type ATTR-CM must be negative by genotyping and have one of the following: Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarised light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis OR Scintigraphy 99m\^Technetium-dicarboxypropane diphosphonate (99m\^Tc-DPD) with Grade 2 cardiac uptake or 99m\^ Technetium-pyrophosphate (99m\^Tc-PYP) with Grade 2 or 3 cardiac uptake.
* Clinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months preceding screening

Inclusion Criteria for Group 2

* Subject medically diagnosed with AL amyloidosis that has required chemotherapy or an autologous stem cell transplant based upon:

AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic identification of AL amyloid fibril type, in subjects with definite monoclonal gammopathy in whom causative mutations of all known relevant amyloidogenic genes have been excluded

* Clinically stable in NYHA class 2 or 3 for the 3 months preceding screening
* \>=6 months after completing any line of chemotherapy, or after autologous stem cell transplantation, and having attained either a very good partial response (VGPR) or a complete response (CR), and without the need for haematological maintenance therapies

Inclusion Criteria for Group 3

* Newly diagnosed AL amyloidosis based upon:

AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic identification of AL amyloid fibril type in subjects with definite monoclonal gammopathy in whom causative mutations of all known relevant amyloidogenic genes have been excluded

* Mayo stage II or IIIa
* Confirmed free light chain complete response (CR) during the first three cycles of first-line chemotherapy where at least the first cycle has been with cyclophosphamide, bortezomib, dexamethasone (CyBorD).

Exclusion Criteria:

* 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)
* Uncontrolled hypertension during screening
* Alanine transaminase ALT \>3x upper limit of normal (ULN) AND bilirubin \>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* Peripheral oedema at Screening that in the opinion of the Prinicpal Investigator (PI) or designee might prevent adequate absorption of subcutaneously administered CPHPC
* Urine dipstick positive (\>1+) for blood during screening with investigation indicating glomerular haematuria. If other causes are identified, subjects may be enrolled on resolution of the abnormality
* Presence of any co-morbid or an uncontrolled medical condition (e.g. 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 patient
* 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
* Unwillingness or inability to follow the procedures outlined in the protocol
* Use of GSK2315698 (CPHPC), or participation in a separate clinical trial involving CPHPC within 3 months of screening
* Any prohibited concomitant medication as per protocol within 28 days of Screening
* Donation of blood or blood products in excess of 500 mL within 84 days of screening
* Lactating females
* Poor or unsuitable venous access
* 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.
* History of sensitivity to any of the study medications, or metabolite thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation CARDIAC MAGNETIC RESONANCE (CMR) SCANNING
* Orthopnoea of sufficient severity to preclude supine scanning as determined at screening
* Contraindication to magnetic resonance imaging (MRI) contrast agents
* Inability to fit inside scanner due to body size (girth)
* Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to:

  * Intracranial aneurysm clips (except Sugita) or other metallic objects
  * Intra- orbital metal fragments that have not been removed
  * Pacemakers or other implanted cardiac rhythm management/monitoring devices and non-MR conditional heart valves
  * Inner ear implants
  * History of claustrophobia

    99m\^TC-PYP OR 99mTC-DPD BONE TRACER RADIOSCINTOGRAPHY
* Orthopnoea of sufficient severity to preclude supine scanning as determined at Screening
* Previous allergic reaction to radioisotope bone tracers
* Previous inclusion in a research protocol involving nuclear medicine, positron emission tomography (PET) or radiological investigations with significant radiation burden (a significant radiation burden being defined as 10 mSv in addition to natural background radiation, in the previous 3 years).

Exclusion Criteria for Group 1

Has any of the following:

* Fulfilment of diagnostic criteria for AL amyloidosis
* TTR polyneuropathy and / or intracranial TTR involvement including ophthalmological disease
* Non-amyloidosis related chronic liver disease (with the exception of Gilbert's syndrome or clinically asymptomatic gallstones)
* Platelet count \< 125x10\^9 / L

Exclusion criteria for Group 2

* Chronic liver disease or current active liver or biliary disease not attributable to amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).

Exclusion criteria for Group 3

* Chronic liver disease or current active liver or biliary disease not attributable to amyloidosis (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Platelet count \< 75x10\^9 /L

Primary outcomes:
measure: Change From Baseline in Left Ventricular (LV) Mass Over Time up to 8-week Follow-up
timeFrame: Baseline (Day -1) and Session 2 Day 24, Session 3 Day 24, Session 4 Day 24, Session 5 Day 24, 8 Weeks Follow-up
measure: Number of Participants With Any On-treatment Adverse Events (AEs)
timeFrame: Up to 56 days after the last dosing session (up to 265 days)
measure: Number of Participants With Any Serious Adverse Events (SAEs)
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormal Hematology Values
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormal Clinical Chemistry Values
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormal Urinalysis Results
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormal Urinalysis Results for Character Parameters
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Body Temperature Shifts From Baseline Relative to Potential Clinical Importance (PCI) Criteria
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Shifts From Baseline Relative to PCI Criteria
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Pulse Rate Shifts From Baseline Relative to PCI Criteria
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormalities During Cardiac Monitoring
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants for Which Unscheduled Echocardiography (ECHO) Was Performed for Safety Reasons
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Skin Rashes
timeFrame: Up to 56 days after the last dosing session (up to 265 days)
measure: Number of Participants With Skin Rashes Classified Using CTCAE
timeFrame: Up to 56 days after the last dosing session (up to 265 days)
Secondary outcomes:
measure: Number of Participants With Abnormalities in Histopathological Examination of Skin Biopsies
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormalities in Immunohistochemical Examination of Skin Biopsies
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormalities in Histopathological Examination of Blood Biomarkers
timeFrame: Up to the end of study (Up to 369 days)
measure: Number of Participants With Abnormalities in Immunohistochemical Examination of Blood Biomarkers
timeFrame: Up to the end of study (Up to 369 days)
measure: Change From Baseline in Plasma Cytokines Over Time
timeFrame: 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
measure: Change From Baseline in Fluid Phase Complement Marker-Complement 3 (C3) Over Time
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
measure: Change From Baseline in Fluid Phase Complement Marker-Complement 4 (C4) Over Time
timeFrame: Baseline (Day -1) and Day 2, Day 5, Day 6
measure: Change From Baseline in Fluid Phase Complement Marker-Total Complement (CH50) Over Time
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
measure: Change From Baseline in Inflammatory Biomarkers Over Time
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 1 (predose, 2,4,8 hours), Day 2, Day 3 (predose, 2,4,8 hours), Day 5, Day 6
measure: Maximum Concentration (Cmax) of GSK2398852
timeFrame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
measure: Time Associated With Cmax (Tmax) of GSK2398852
timeFrame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC 0-t) of GSK2398852
timeFrame: Session 1 to 6: Day 1 (Pre-dose, 6, 8, 12 hour), Day 2, Day 3 (Pre-dose and at 6 hour), Day 4, Day 7 and Day 11
measure: Cmax of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
timeFrame: Day 1: Pre-dose; Day 2 (pre-dose and 2 hours post-dose); Day 3: Pre-dose in each session (each session of 24 days)
measure: Tmax of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
timeFrame: Day 1: Pre-dose; Day 2: pre-dose and 2 hours post-dose; Day 3: Pre-dose in each session (each session of 24 days)
measure: AUC 0-t of GSK2315698 for Newly Diagnosed Mayo Stage II/IIIa AL Amyloidosis Participants
timeFrame: Day 1: Pre-dose; Day 2 (pre-dose and 2 hours post-dose); Day 3: Pre-dose in each session (each session of 24 days)
measure: Change From Baseline in Global Longitudinal Strain (GLS) by CMR
timeFrame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in GLS by ECHO
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in LV Twist Over Time
timeFrame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Stroke Volume (SV) by CMR
timeFrame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in SV by ECHO
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Left Ventricular Ejection Fraction (EF) by CMR
timeFrame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Left Ventricular EF by ECHO
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Left Ventricle End Diastolic Volume (EDV) by CMR
timeFrame: Baseline (Day -1) and Session 2 to 5: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Left Ventricle End Diastolic Volume (EDV) by ECHO
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
measure: Change From Baseline in Ratio of Mitral Peak Velocity of Early Filling to Early Diastolic Mitral Annual Velocity (E/e' Ratio)
timeFrame: Baseline (Day -1) and Session 1 to 6: Day 24; 8 week follow-up; 6 months follow-up
Other outcomes:
Locations:
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: