Multiple Treatment Session Study to Assess GSK2398852 Administered Following and Along With GSK2315698
Condition: Amyloidosis
MeSH terms: Amyloidosis
Intervention: GSK2315698 (CPHPC); GSK2398852 (anti-SAP mAb)
Intervention description: 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; Up to 1200mg, IV divided over days 1 and 3. Number of cycles: up to 6. Dose level adjusted based on tolerability.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
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

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