Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of GSK2857916
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: GSK2857916
Intervention description: A clear or opalescent solution for IV infusion with unit dose strength of 20 mg/mililiter (mL) for multiple dose levels.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 79.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Multiple Myeloma; BCMA expressing Lymphomas

Summary:

      This study will assess the safety, pharmacokinetic (PK), pharmacodynamic (PD) and the
      therapeutic potential of GSK2857916 in subjects with multiple myeloma (MM) and lymphomas that
      express B cell maturation antigen (BCMA). The hypothesis is that GSK2857916 can be safely
      administered to subjects with MM and with BCMA positive malignancies at doses where target
      engagement can be demonstrated. This study will determine if adequate target engagement of
      BCMA receptors translates into clinical benefit for subjects with MM and BCMA positive
      lymphomas. The study will consists of two parts: a Part 1 dose escalation phase and a Part 2
      expansion phase for safety, tolerability, PK, PD, and clinical activity testing. The study
      will enroll a total of approximately 80-95 subjects with relapsed/refractory MM or
      BCMA-expressing hematologic malignancies. The maximum dose to be administered in this trial
      will not exceed 5 milligram/kilogram(mg/kg).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Provide signed written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  Male or female, 18 years or older (at the time consent is obtained)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Part 1/dose escalation; Histologically or cytologically confirmed diagnosis of
             Multiple Myeloma in a subject who fulfills all of the following: has undergone stem
             cell transplant, or is considered transplant ineligible, has been pretreated with at
             least the 3 following classes of anti-myeloma drugs: alkylators, proteasome inhibitors
             and immunomodulators, has demonstrated progression on, or within 60 days of completion
             of the last therapy.

        Part 2 /MM cohort; Histologically or cytologically confirmed diagnosis of: Multiple Myeloma
        in a subject who fulfills all of the following: has undergone stem cell transplant, or is
        considered transplant ineligible, has been pretreated with at least the 3 following classes
        of anti-myeloma drugs: alkylators, proteasome inhibitors and immunomodulators, has
        demonstrated progression on, or within 60 days of completion of the last therapy, and has
        measurable disease with at least one of the following: serum M-protein >=0.5 gram
        (g)/decilitre (dL) (>=5 g/Litre (L)), urine M-protein >=200 milligram (mg)/24hour (h).

        Serum free light chain (FLC) assay: Involved FLC level >=5 mg/dL (>=50 mg/L) and an
        abnormal serum FLC ratio (<0.26 or >1.65) and biopsy proven plasmacytoma (should be
        measured within 28 days of Screening Visit).

          -  Part 2/Other BCMA positive Hematologic Malignancies cohort: Subject with one of the
             following lymphomas: Diffuse Large B-cell Lymphoma (DLBCL) or follicular lymphoma (FL)
             that exhibits positive BCMA expression on tumor cells as determined by a central
             laboratory using a validated Immunohistochemistry (IHC) assay. Eligible subjects with
             BCMA positive malignancies must also fulfill the prior treatment requirements as
             follows: DLBCL: at least 2 prior lines of systemic therapy containing at least one
             line of chemo-immunotherapy with anti-CD20 antibody, and either has undergone stem
             cell transplant or is considered transplant ineligible. FL: at least 2 prior lines of
             systemic therapy.

          -  Subjects with a history of autologous stem cell transplant are eligible for study
             participation provided the following eligibility criteria are met: transplant was >
             100 days prior to study enrolment, no active infection; subject meets the remainder of
             the eligibility criteria outlined in the study protocol.

          -  Adequate organ system functions as defined below Absolute neutrophil
             count>=1.0x10^9/L, hemoglobin>=8.0 g/dL, platelet>=50x10^9/L, international normalized
             ration (INR) <=1.5, Partial thromboplastin time <=1.5xupper limit of normal (ULN),
             total bilirubin <=1.25xULN, alanine aminotransferase and aspartate
             aminotransferase<=1.5 X ULN, serum creatinine or calculated creatinine
             clearance<1.2XULN >=60 mL/min for Part 1;>=50 mL/minute (min) for Part 2 if data
             supports loosening criteria, Albuminuria<=500 mg/24h, left ventricular ejection
             fraction >=50%, Troponin<=1xULN, Calcium<=1.1xULN

          -  A female subject is eligible to participate if she is of: Non-childbearing potential
             or women of childbearing potential must have a negative serum pregnancy test within 72
             hours of first dose of study treatment and agree to use effective contraception during
             the study and for 60 days following the last dose of study treatment.

          -  Men with a female partner of childbearing potential must have either had a prior
             vasectomy or agree to use effective contraception from the time of first dose of study
             until 60 days after the last dose of study treatment to allow for clearance of any
             altered sperm

          -  All prior treatment-related toxicities (defined by National Cancer Institute- Common
             Toxicity Criteria for Adverse Events, version 4) must be <=Grade 1 at the time of
             enrollment except for alopecia, and grade 2 neuropathy.

        Exclusion Criteria:

          -  Systemic anti-tumor therapy within 14 days, or plasmapheresis within 7 days prior to
             the first dose of study drug

          -  Use of an investigational drug within 14 days or five half-lives, whichever is
             shorter, preceding the first dose of study drug. Prior treatment with a monoclonal
             antibody within 30 days of receiving the first dose of study drug.

          -  History of an allogeneic stem cell transplant. Subjects with a history of an
             autologous stem cell transplant are NOT excluded if they meet inclusion criteria
             related to history of autologous stem cell transplant.

          -  Presence of active renal condition (infection, requirement for dialysis or any other
             condition that could affect subject's safety). Subjects with isolated proteinuria
             resulting from MM are eligible, provided they fulfil the inclusion criteria related to
             organ system function.

          -  Evidence of active mucosal or internal bleeding

          -  Any major surgery within the last four weeks.

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
             conditions (including lab abnormalities) that could interfere with subject's safety,
             obtaining informed consent or compliance to the study procedures.

          -  Known active infection requiring antibiotic treatment

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal or cardiac disease

          -  Subjects with previous or concurrent malignancies are allowed only if the second tumor
             is not contributing to the subject's illness. The subject must not be receiving active
             therapy, other than hormonal therapy for this disease and the disease must be
             considered medically stable for at least 2 years.

          -  Evidence of cardiovascular risk including any of the following: QT interval
             corrected>=470 millisecond, evidence of current clinically significant uncontrolled
             arrhythmias, history of myocardial infarction, acute coronary syndromes (including
             unstable angina), coronary angioplasty, or stenting or bypass grafting within six
             months of Screening, Class III or IV heart failure as defined by the New York Heart
             Association functional classification system, uncontrolled hypertension, subjects with
             intra-cardiac defibrillators or permanent pacemakers, abnormal cardiac valve
             morphology (>=grade 2) documented by echocardiogram (subjects with grade 1
             abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects
             with moderate valvular thickening should not be entered on study.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to GSK2857916 or any of the components of the study treatment.

          -  Pregnant or lactating female.

          -  Known human immuno virus infection.

          -  Subjects with positive test for Hepatitis B surface (HBS-Ag) or Hepatitis B core
             (HBc)antigen

          -  Subjects with positive test for hepatitis C (HCV) infection are excluded regardless of
             viral load. If hepatitis C antibody test is positive, a confirmatory polymerase chain
             reaction (PCR) or Recombinant immunoblot assay (RIBA) test should be performed. If the
             PCR or RIBA test is negative, subject is eligible for this trial

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
             per investigator's assessment).

          -  Current corneal disease or a history of corneal disease.