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Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of GSK2857916

This study is currently recruiting participants.
Verified October 2017 by GlaxoSmithKline
Sponsor:
ClinicalTrials.gov Identifier:
NCT02064387
First Posted: February 17, 2014
Last Update Posted: October 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
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).

Condition Intervention Phase
Multiple Myeloma Drug: GSK2857916 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of the Antibody Drug Conjugate GSK2857916 in Subjects With Relapsed/Refractory Multiple Myeloma and Other Advanced Hematologic Malignancies Expressing BCMA

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of participants with adverse events (AEs) following single and repeat dose administration [ Time Frame: Up to approximately 480 days ]
    AEs will be collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy or transfer to hospice

  • Change from Baseline in vital sign parameters following single and repeat dose administration. [ Time Frame: Baseline (screening) and up to approximately 480 days ]
    Vital sign parameters include: systolic and diastolic blood pressure, temperature, and pulse rate

  • Change from Baseline clinical laboratory parameters following single and repeat dose administration. [ Time Frame: Baseline (screening) and up to approximately 480 days ]
    Laboratory parameters include: hematology, clinical chemistry, urinalysis and additional parameters as needed.


Secondary Outcome Measures:
  • Composite of PK parameters following single dose intravenous (IV) administration of GSK2857916 [ Time Frame: Up to 448 days ]
    GSK2857916 and cys Monomethyl auristatin F (cys-mc MMAF) PK parameters include: area under the concentration-time curve (AUC), maximum plasma drug concentration (Cmax), time to Cmax (tmax), clearance (CL), volume of distribution at steady state (Vss), and terminal half life (t1/2). PK parameters will be assessed from plasma and urine samples collected over a period of time

  • Composite of PK parameters following repeat dose IV administration of GSK2857916 [ Time Frame: Up to 448 days ]
    GSK2857916 and cys-mc MMAF PK parameters include: AUC, Cmax, tmax, CL, Vss and trough plasma concentration (Ctrough). PK parameters will be assessed from plasma and urine samples collected over a period of time.

  • Incidence of anti-drug antibody (ADA) following single and repeat dose administration of GSK2857916 [ Time Frame: Up to 448 days ]
    Blood, bone marrow, and tumor tissue samples will be collected during this study and analyzed pre and post GSK2857916.

  • ADA titre following single and repeat dose administration of GSK2857916 [ Time Frame: Up to 448 days ]
    Blood, bone marrow, and tumor tissue samples will be collected during this study and analyzed pre and post GSK2857916.

  • Overall Response Rate (ORR) following single and repeat dose administration of GSK2857916 as measure of clinical activity with MM [ Time Frame: Up to approximately 480 days ]
    The percentage of subjects achieving confirmed partial response or better (>=PR) will be assessed

  • Clinical benefit rate (CBR) following single and repeat dose administration of GSK2857916 as measure of clinical activity [ Time Frame: Up to approximately 480 days ]
    The percentage of subjects with PR or better or minimal response (MR) will be assessed. Subjects with MR will include,>=25% but <49% reduction of serum M protein and reduction in 24 hour urine M protein by 50-89%, which still exceeds 200 mg per 24 hour; 25-49% reduction in the size of soft tissue plasmacytomas if present at baseline; no increase in size or number of lytic bone lesions

  • Percentage of subjects with lymphoma achieving PR or complete response (CR) [ Time Frame: Up to approximately 480 days ]
    PR is defined as Regression of measurable disease and no new sites; CR is defined as the disappearance of all evidence of disease


Estimated Enrollment: 85
Study Start Date: July 29, 2014
Estimated Study Completion Date: June 3, 2019
Estimated Primary Completion Date: June 3, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Schedule 1 Part 1
Participants will receive GSK2857916 intravenously over 60 minutes (one dose) every 3 weeks (21 day cycle) for a maximum of 16 cycles.
Drug: GSK2857916
A clear or opalescent solution for IV infusion with unit dose strength of 20 mg/mililiter (mL) for multiple dose levels.
Experimental: Schedule 2 Part 1
Participants may receive GSK2857916 intravenously over 60 minutes (one dose) once weekly for three consecutive weeks followed by 1 week of rest (28 day cycle) for a maximum of 16 cycles.
Drug: GSK2857916
A clear or opalescent solution for IV infusion with unit dose strength of 20 mg/mililiter (mL) for multiple dose levels.
Experimental: Schedule 1 Part 2
Participants will receive the dose and schedule of GSK2857916 evaluated in Part 1 that is selected for further evaluation in Part 2 for up to 16 cycles.
Drug: GSK2857916
A clear or opalescent solution for IV infusion with unit dose strength of 20 mg/mililiter (mL) for multiple dose levels.
Experimental: Schedule 2 Part 2
Participants may receive the dose and schedule of GSK2857916 evaluated in Part 1 that is selected for further evaluation in Part 2 for a maximum of 16 cycles.
Drug: GSK2857916
A clear or opalescent solution for IV infusion with unit dose strength of 20 mg/mililiter (mL) for multiple dose levels.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02064387


Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02215
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Michigan
GSK Investigational Site Terminated
Ann Arbor, Michigan, United States, 48109
United States, Missouri
GSK Investigational Site Terminated
Saint Louis, Missouri, United States, 63110
United States, New York
GSK Investigational Site Recruiting
New York, New York, United States, 10065
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, North Carolina
GSK Investigational Site Recruiting
Chapel Hill, North Carolina, United States, 27599-7600
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Pennsylvania
GSK Investigational Site Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Texas
GSK Investigational Site Completed
Dallas, Texas, United States, 75390-8565
United States, Washington
GSK Investigational Site Recruiting
Seattle, Washington, United States, 98109
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Canada, British Columbia
GSK Investigational Site Completed
Vancouver, British Columbia, Canada, V5Z 1M9
Canada, Ontario
GSK Investigational Site Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United Kingdom
GSK Investigational Site Recruiting
London, United Kingdom, NW1 2BU
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Terminated
Manchester, United Kingdom, M20 4BX
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02064387     History of Changes
Other Study ID Numbers: 117159
First Submitted: February 13, 2014
First Posted: February 17, 2014
Last Update Posted: October 11, 2017
Last Verified: October 2017

Keywords provided by GlaxoSmithKline:
Multiple Myeloma
BCMA expressing Lymphomas

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases