Clinical Trials /

A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Subjects With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody

NCT03525678

Description:

Multiple myeloma (MM) is an incurable malignancy and accounts for 1 percentage of all cancers and for 10% of all hematologic malignancies. Subjects with relapsed/refractory multiple myeloma (RRMM) will be included in this study, to evaluate the efficacy and safety of GSK2857916 monotherapy. Subjects will be treated with GSK2857916 monotherapy until disease progression or unacceptable toxicity and will be followed for Progression Free Survival (PFS) and Overall survival (OS). The subjects will be randomized to receive either frozen GSK2857916 at the dose of 2.5 milligram per kilogram (mg/kg) or 3.4 mg/kg Intravenous (IV). There will be an independent cohort of subjects who will receive a lyophilized configuration of GSK2857916. Approximately 155 subjects will be enrolled in the study of which 130 subjects will be enrolled to receive frozen GSK2857916 and 25 subjects will be enrolled in the independent lyophilized drug product cohort. The subjects who discontinued from the study other than Progressive disease (PD), disease evaluation will continue to be performed at 3-week intervals until confirmed PD, death, start of a new anticancer treatment, withdrawal of consent, or end of the study whichever occurs first.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Subjects With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody
  • Official Title: A Phase II, Open Label, Randomized, Two-Arm Study to Investigate the Efficacy and Safety of Two Doses of the Antibody Drug Conjugate GSK2857916 in Participants With Multiple Myeloma Who Had 3 or More Prior Lines of Treatment, Are Refractory to a Proteasome Inhibitor and an Immunomodulatory Agent and Have Failed an Anti-CD38 Antibody (DREAMM 2)

Clinical Trial IDs

  • ORG STUDY ID: 205678
  • SECONDARY ID: 2017-004810-25
  • NCT ID: NCT03525678

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
GSK2857916 frozenSubjects receiving frozen 2.5 mg/kg GSK2857916
GSK2857916 lyophilizedSubjects receiving lyophilized GSK2857916

Purpose

Multiple myeloma (MM) is an incurable malignancy and accounts for 1 percentage of all cancers and for 10% of all hematologic malignancies. Subjects with relapsed/refractory multiple myeloma (RRMM) will be included in this study, to evaluate the efficacy and safety of GSK2857916 monotherapy. Subjects will be treated with GSK2857916 monotherapy until disease progression or unacceptable toxicity and will be followed for Progression Free Survival (PFS) and Overall survival (OS). The subjects will be randomized to receive either frozen GSK2857916 at the dose of 2.5 milligram per kilogram (mg/kg) or 3.4 mg/kg Intravenous (IV). There will be an independent cohort of subjects who will receive a lyophilized configuration of GSK2857916. Approximately 155 subjects will be enrolled in the study of which 130 subjects will be enrolled to receive frozen GSK2857916 and 25 subjects will be enrolled in the independent lyophilized drug product cohort. The subjects who discontinued from the study other than Progressive disease (PD), disease evaluation will continue to be performed at 3-week intervals until confirmed PD, death, start of a new anticancer treatment, withdrawal of consent, or end of the study whichever occurs first.

Trial Arms

NameTypeDescriptionInterventions
Subjects receiving frozen 2.5 mg/kg GSK2857916ExperimentalSubjects will be randomized in 1:1 ratio to receive either 2.5 or 3.4 mg/kg frozen liquid GSK2857916. Subjects will administer frozen liquid GSK2857916 via infusion pump for once in every 3 weeks.
  • GSK2857916 frozen
Subjects receiving frozen 3.4 mg/kg GSK2857916ExperimentalSubjects will be randomized in 1:1 ratio to receive either 2.5 or 3.4 mg/kg frozen liquid GSK2857916. Subjects will administer frozen liquid GSK2857916 via infusion pump for once in every 3 weeks.
  • GSK2857916 frozen
Subjects receiving lyophilized GSK2857916ExperimentalSubjects in lyophilized arm will receive lyophilized GSK2857916 once lyophilized configuration becomes available and enrollment has been completed for frozen liquid arms.
  • GSK2857916 lyophilized

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects 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.

          -  Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  Histologically or cytologically confirmed diagnosis of MM as defined according to
             International Myeloma Working Group (IMWG). The subject has undergone stem cell
             transplant or is considered transplant ineligible and has failed at least 3 prior
             lines of anti-myeloma treatments, including an anti-CD38 antibody (example [e.g.],
             daratumumab) alone or in combination, and is refractory to an Immunomodulatory drugs
             (IMiD) (that is [i.e.], lenalidomide or pomalidomide), and to a proteasome inhibitor
             (i.e., bortezomib, ixazomib or carfilzomib).

          -  The subject has measurable disease with at least one of the following: Serum M-protein
             >=0.5 gram per deciliter (g/dL) (>=5 gram per Liter [g/L]); Urine M-protein >=200
             milligram per 24 hours (mg/24h); Serum Free light chain (FLC) assay: Involved FLC
             level >=10 mg/dL (>=100 mg/L) and an abnormal serum free light chain ratio (<0.26 or
             >1.65).

          -  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(s); subjects meets the remainder of
             the eligibility criteria outlined in this protocol.

          -  Subjects with adequate organ system functions as defined follows: Absolute neutrophil
             count (ANC) >=1.0 X 10^9/L; Hemoglobin >=8.0 g/dL; Platelets>= 50 X 10^9/L; Total
             bilirubin <=1.5X Upper limit of normal (ULN). Isolated bilirubin >=1.5xULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35 percent); Alanine
             aminotransferase (ALT) <=2.5X ULN; Estimated glomerular filtration rate (eGFR) >=30
             milliliter per minute per 1.73 meter square (mL/min/m^2); Spot urine
             (albumin/creatinine ratios [spot urine]) < 500 milligram per gram (mg/g) (56 mg per
             millimoles [mg/mmol]); Left ventricular ejection fraction (LVEF) >= 45 percent.

          -  Female subjects: Contraceptive use by men or women should be consistent with local
             regulations regarding the methods of contraception for those participating in clinical
             studies. A female subject is eligible to participate if she is not pregnant or
             breastfeeding, and not a woman of childbearing potential (WOCBP) or is a WOCBP and
             using a contraceptive method that is highly effective (with a failure rate of <1% per
             year), preferably with low user dependency, during the intervention period and for at
             least 80 days after the last dose of study intervention and agrees not to donate eggs
             (ova, oocytes) for the purpose of reproduction during this period. The investigator
             should evaluate the effectiveness of the contraceptive method in relationship to the
             first dose of study intervention. A WOCBP must have a negative highly sensitive serum
             pregnancy test (as required by local regulations) within 72 hours before the first
             dose of study intervention.

          -  Male subjects are eligible to participate if they agree to the following during the
             intervention period and for at least 140 days: Refrain from donating sperm; Be
             abstinent from heterosexual intercourse as their preferred and usual lifestyle
             (abstinent on a long term and persistent basis) and agree to remain abstinent; Agree
             to use a male condom and female partner to use an additional highly effective
             contraceptive method with a failure rate of <1 percent per year as when having sexual
             intercourse with a woman of childbearing potential who is not currently pregnant.

          -  All prior treatment-related toxicities (defined by National Cancer Institute- Common
             Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.03, must be <=Grade 1 at
             the time of enrolment except for alopecia and Grade 2 peripheral neuropathy.

          -  For France only: A subject will be eligible for inclusion in this study only if either
             affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Systemic anti-myeloma therapy within <14 days, or plasmapheresis within 7 days prior
             to the first dose of study drug.

          -  Symptomatic amyloidosis, active 'polyneuropathy, organomegaly, endocrinopathy, myeloma
             protein, and skin changes' (POEMS) syndrome, active plasma cell leukemia at the time
             of screening.

          -  Prior allogeneic stem cell transplant.

          -  Current corneal epithelial disease except mild punctate keratopathy.

          -  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 drugs. Prior BCMA
             targeted therapy.

          -  Evidence of active mucosal or internal bleeding.

          -  Any major surgery within the last four weeks.

          -  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.

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder or other
             conditions (including lab abnormalities) that could interfere with participant's
             safety, obtaining informed consent or compliance to the study procedures.

          -  Current unstable liver or biliary disease per investigator assessment defined by the
             presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
             gastric varices, persistent jaundice, or cirrhosis. Stable chronic liver disease
             (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement
             of malignancy is acceptable if subject otherwise meets entry criteria.

          -  Malignancies other than disease under study are excluded, except for any other
             malignancy from which the subject has been disease-free for more than 2 years and, in
             the opinion of the principal investigators and GSK Medical Monitor, will not affect
             the evaluation of the effects of this clinical trial treatment on the currently
             targeted malignancy (MM).

          -  Evidence of cardiovascular risk including any of the following: Corrected QT interval
             Fridericia (QTcF) interval >=470 milliseconds (msecs); Evidence of current clinically
             significant uncontrolled arrhythmias, including clinically significant ECG
             abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block;
             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 (NYHA); Uncontrolled hypertension.

          -  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.

          -  Active infection requiring antibiotic, antiviral, or antifungal treatment.

          -  Known Human Immunodeficiency Virus (HIV) infection.

          -  Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb
             at screening or within 3 months prior to first dose of study treatment.

          -  Positive hepatitis C antibody test result or positive hepatitis C Ribonucleic acid
             (RNA) test result at screening or within 3 months prior to first dose of study
             treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease
             can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:ORR, defined as the percentage of subjects with a confirmed partial response (PR) or better (that is [i.e.], PR, very good partial response [VGPR], complete response [CR] and stringent complete response [sCR]), according to the 2016 International Myeloma Working Group (IMWG) Response Criteria by Independent Review Committee (IRC).

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:CBR is defined as the percentage of subjects with a confirmed minimal response (MR) or better according to the 2016 IMWG IRC.
Measure:Duration of response (DoR)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:DoR is defined as the time from first documented evidence of PR or better until the earliest date of documented PD per IMWG; or death due to PD occurs among subjects who achieve an overall response, i.e., confirmed PR or better.
Measure:Time to response
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Time to response is defined as the time between the date of first dose and the first documented evidence of response (PR or better).
Measure:Progression free survival
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Progression free survival is defined as the time from first dose until the earliest date of documented disease progression (PD) per IMWG, or death due to any cause.
Measure:Time to progression
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Time to progression is defined as the time from first dose until the earliest date of documented PD per IMWG, or death due to PD.
Measure:Overall survival
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Overall survival is defined as the time from first dose until death due to any cause.
Measure:Number of subjects with abnormal hematology parameters
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Laboratory assessment for hematology parameters will include Platelet count, hemoglobin (Hgb), Red blood cell (RBC) count, hematocrit, reticulocyte count, RBC indices like mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). White blood cell (WBC) count with differential will include neutrophils, lymphocytes, monocytes, eosinophils and basophils.
Measure:Number of subjects with abnormal clinical chemistry parameters
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Laboratory assessment for clinical chemistry parameters will include blood urea nitrogen (BUN), potassium, calcium, sodium, creatinine, glucose, magnesium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline phosphate, total protein, total and direct bilirubin, albumin, uric acid, lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), Creatine kinase (CK), total bicarbonate, albumin/ creatinine ratio, Estimated glomerular filtration rate (eGFR), chloride, and phosphorus.
Measure:Number of subjects with abnormal physical examination parameters
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Physical examination parameters will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities.
Measure:Number of subjects with abnormal systolic blood pressure (SBP) and diastolic blood pressure (DBP) assessment
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:SBP and DBP will be measured after 5 minutes rest.
Measure:Number of subjects with abnormal pulse rate
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Pulse rate will be measured after 5 minutes rest.
Measure:Number of subjects with abnormal body temperature
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:Temperature will be measured after 5 minutes rest.
Measure:Number of subjects with adverse events (AEs), serious AEs (SAEs) and AEs of special interest (AESI)
Time Frame:Up to 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that at any dose may result in death due to PD, is life-threatening, may require hospitalization or prolongation of existing hospitalization, result in persistent disability/incapacity, or may led to any congenital anomaly or birth defect. AESI for GSK2857916 are corneal events, thrombocytopenia and infusion related reactions.
Measure:Number of subjects with abnormal ocular findings
Time Frame:Up to 2 years
Safety Issue:
Description:Ocular examination for the subjects will include procedures for corrected visual acuity, current glasses, pupillary examination, extra ocular muscular movements, intra-ocular pressure, examination of tear film, and examination of cornea.
Measure:Area under the curve (AUC) of GSK2857916
Time Frame:Pre-dose within 30 minutes prior to start of infusion (SOI) and End of Infusion (EOI) on Cycle (C)1; Pre-dose, 2 hours after SOI on C2, C6, C9, and C12 and at EOI; every 6 subsequent cycles at pre-dose and at EOT
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of AUC
Measure:Maximum plasma concentration (Cmax) of GSK2857916
Time Frame:Pre-dose within 30 minutes prior to start of infusion (SOI) and End of Infusion (EOI) on Cycle (C)1; Pre-dose, 2 hours after SOI on C2, C6, C9, and C12 and at EOI; every 6 subsequent cycles at pre-dose and at EOT
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of Cmax
Measure:Time of occurrence of Cmax (Tmax) of GSK2857916
Time Frame:Pre-dose within 30 minutes prior to start of infusion (SOI) and End of Infusion (EOI) on Cycle (C)1; Pre-dose, 2 hours after SOI on C2, C6, C9, and C12 and at EOI; every 6 subsequent cycles at pre-dose and at EOT
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of tmax
Measure:Terminal phase half-life (T1/2) of GSK2857916
Time Frame:Pre-dose within 30 minutes prior to start of infusion (SOI) and End of Infusion (EOI) on Cycle (C)1; Pre-dose, 2 hours after SOI on C2, C6, C9, and C12 and at EOI; every 6 subsequent cycles at pre-dose and at EOT
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of t1/2
Measure:Incidence and titers of anti-drug antibodies (ADAs)
Time Frame:Up to 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of ADAs using electrochemiluminescent immunoassay
Measure:Number of subjects with symptomatic AEs measured by Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:The PRO-CTCAE includes an item library of 124 items representing 78 symptomatic toxicities drawn from the CTCAE. It provides systematic and flexible tool for descriptive reporting of symptomatic treatment side effects in cancer clinical trials.
Measure:Number of subjects with symptomatic AEs measured by National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:The NEI-VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question.
Measure:Number of subjects with symptomatic AEs measured by Ocular Surface Disease Index (OSDI)
Time Frame:Every 3 weeks up to 2 years
Safety Issue:
Description:The OSDI is a 12-item questionnaire designed to assess both the frequency of dry eye symptoms and their impact on vision-related functioning.
Measure:Change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item Core module (EORTC QLQ-C30) score
Time Frame:Every 6 weeks up to 2 years
Safety Issue:
Description:The EORTC QLQ-C30 is a 30-item questionnaire containing both single and multi-item measures. These include five functional scales (Physical, Role, Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a Global Health Status/ Quality-of-Life (QoL) scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). The scores ranges from 0-100, a high score for functional scales and for Global Health Status/QoL represent better functioning ability or Health-Related Quality-of-Life (HRQoL), whereas a high score for symptom scales and single items represents significant symptomatology.
Measure:Change in EORTC QLQ- 20-item Multiple Myeloma module (MY-20) score
Time Frame:Every 6 weeks up to 2 years
Safety Issue:
Description:The EORTC QLQ-MY20 is a supplement to the QLQ-C30 instrument used in subjects with MY. The module comprises 20 questions that address four myeloma-specific HRQoL domains: Disease Symptoms, Side Effects of Treatment, Future Perspective, and Body Image. A high score for Disease Symptoms and Side Effects of Treatment represents a high level of symptomatology or problems, whereas a high score for Future Perspective and Body Image represents better outcomes.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • Relapsed
  • Refractory multiple myeloma
  • Antibody-drug conjugate
  • Patient-Reported Outcome Version of the Common Term Criteria for Adverse Events
  • Quality of Life Questionnaire 20-item Multiple Myeloma module
  • Multiple Myeloma
  • Quality of Life Questionnaire 30-item Core module

Last Updated