A Study of Belantamab Mafodotin to Investigate Safety, Tolerability, Pharmacokinetics, Immunogenicity and Clinical Activity in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)

GlaxoSmithKline6 enrolled

Overview

Multiple myeloma (MM) is a neoplastic plasma cell disorder that is characterized by osteolytic bone lesions, anemia, hypercalcemia and renal failure. belantamab mafodotin was well tolerated in previous studies with at least one dose of belantamab mafodotin in heavily pre-treated participants with relapsed/refractory multiple myeloma (RRMM). This aim of the study is to explore safety, pharmacokinetics (PK), tolerability, immunogenicity and clinical activity of belantamab mafodotin monotherapy in Chinese participants with RRMM who have received at least 2 prior line of anti-myeloma therapy including an alkylator, a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). This study will include two dose cohorts 2.5 milligram per kilogram (mg/kg) and 3.4 mg/kg. A maximum of 12 participants will be enrolled, 6 each for 2.5 mg/kg cohort and 3.4 mg/kg cohort based on 3+3 design. Participants will be treated until disease progression, intolerable toxicity, end of study or informed consent withdrawal.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Multiple Myeloma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Provide signed written informed consent, which includes compliance with requirements and restrictions listed in the consent form. * Male or female, 18 years or older (at the time consent is obtained). * Eastern Cooper Oncology Group (ECOG) performance status of 0-2. * Histological or cytologically confirmed diagnosis of MM as defined according to IMWG criteria and a) Has undergone stem cell transplant or transplant is considered not feasible by local assessment, b) Has failed at least 2 prior lines of anti-myeloma treatments, containing all of the following classes of drugs: alkylating agent, IMID and PI, c) In addition, eligible participant needs to be refractory to an IMiD (i.e.,lenalidomide or pomalidomide), and to a proteasome inhibitor (i.e., bortezomib, ixazomib or carfizomib) as defined by International Myeloma Working Group (IMWG) criteria, d) Participants who failed with cluster of differentiation38 (CD38) antibody (i.e., daratumumab) in previous clinical trials can also be considered to include if they meet the remainder of inclusion criteria in this protocol. * Has measurable disease with at least one of the following: a) Serum M-protein greater than or equal to 0.5 grams per deciliter (g/dL) (5 g/L) , b) Urine M-protein greater than or equal to 200 mg/24hour, c) Serum Free light chain (FLC) assay: Involved FLC level greater than or equal to10 mg/dL (greater than or equal to 100 mg/L) and an abnormal serum free light chain ratio (less than 0.26 or greater than 1.65) * Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a) Transplant was greater than 100 days prior to study enrolment, b) No active infection(s), c) Participant meets the remainder of the eligibility criteria outlined in this protocol. * Adequate organ system functions. * Female Participants: 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 participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is 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 less than 1 percent 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. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. * Male Participants: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 140 days: Refrain from donating sperm, plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. or Must agree to use contraception/barrier as detailed below: Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of less than 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 5.0 must be less than or equal to Grade 1 at the time of enrolment except for alopecia and Grade 2 peripheral neuropathy. Exclusion Criteria: * Systemic anti-myeloma therapy within less than 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 (SCT). * 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 B-cell maturation antigen (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 participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria. * 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. * Malignancies other than disease under study are excluded, except for any other malignancy from which the participant 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: a) corrected QT internal Fridericia (QTcF) interval greater than equal to 480 milliseconds (msecs), b) Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block, c) History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within three months of Screening, d) Class III or IV heart failure as defined by the New York Heart Association functional classification system, e) Uncontrolled severe hypertension, e.g. 170/110. * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin, or any of the components of the study intervention. * 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 intervention). * 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 intervention.

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention.

Time frame: Up to 24 months and 21 days

Number of Participants With Serious Adverse Events (SAEs)

An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; important medical events that may jeopardize the participant or may require medical or surgical intervention; is associated with liver injury and impaired liver function.

Time frame: Up to 24 months and 21 days

Number of Participants With Dose Limited Toxicities (DLTs)

An event was considered DLT if it occurred within 21 days of treatment and met any of the following criteria within same period: * Any Grade (Gr.) 3 or greater non-hematologic toxicity as described in NCI-CTCAE Version 5.0, other than corneal events that persists for \>48 hours despite supportive treatment or leads to hospitalization. * Hematologic toxicity such as Gr. 3 or greater febrile neutropenia lasting \>48 hours despite adequate treatment (Gr. 3 defined as absolute neutrophil count (ANC) \<1000/millimeter cube (mm\^3) at a single temperature \>38.3 degree celsius or a sustained temperature \>=38 degree celsius for more than 1 hour) and, Gr. 4 thrombocytopenia defined as platelet count \<25000/mm\^3 with clinically significant bleeding, or if platelet transfusion is required. * Gr. 4 per the corneal grading scale. * Liver toxicity meeting pre-specified by GSK liver stopping criteria.

Time frame: Day 1 to day 21 of cycle 1

Secondary Outcomes

Area Under the Plasma Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC[0-t]) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis. AUC\[0-t\] was calculated using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.

Time frame: Pre-dose (within 30 minutes prior to start of infusion), end of infusion (EOI), 2, 4, 8 and 24 hours post start of infusion (HPS) on day 1, anytime on day 2, 4, 8, 15 and 22 of cycle 1 (each cycle is of 21 days)

AUC[0-t] of Belantamab Mafodotin Total Antibody

AUC[0-t] of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Time frame: Pre-dose (within 30 minutes prior to start of infusion), end of infusion (EOI), 2, 4, 8 and 24 hours post start of infusion (HPS) on Day 1, anytime on Day 2, 4, 8, 15 and 22 of Cycle 1 (each cycle is of 21 days)

Area Under the Concentration-time Curve During the Dosing Interval (AUC[0-tau]) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

AUC[0-tau] of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Area Under the Concentration-time Curve From Time 0 to 168h (AUC[0-168]) of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Up to 168 hours

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-infinity]) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

AUC[0-infinity] of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

AUC[0-infinity] of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Observed Plasma Concentration at the End of Infusion (CEOI) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Pre-dose (within 30 minutes prior to start of infusion) on day 1 of cycle 2, 4, 6, 9 and 12 (each cycle is of 21 days)

CEOI of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Pre-dose (within 30 minutes prior to start of infusion) on day 1 of cycle 2, 4, 6, 9 and 12 (each cycle is of 21 days)

CEOI of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Pre-dose (within 30 minutes prior to start of infusion) on day 1 of cycle 2, 4, 6, 9 and 12 (each cycle is of 21 days)

Maximum Observed Concentration (Cmax) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis. Maximum observed plasma concentration, determined directly from the concentration-time data for each cycle.

Cmax of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis. Maximum observed plasma concentration, determined directly from the concentration-time data for each cycle.

Cmax of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis. Maximum observed plasma concentration, determined directly from the concentration-time data for each cycle.

Time to Reach Maximum Observed Concentration (Tmax) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Tmax of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Tmax of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Last Time Point Where the Concentration is Above the Limit of Quantification (Tlast) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Tlast of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Tlast of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Systemic Clearance (CL) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

CL of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Systemic Clearance Normalized by Body Weight (CL/Weight) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

CL/Weight of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Volume of Distribution at Steady State (Vss) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Vss of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Volume of Distribution at Steady State Normalized by Body Weight (Vss/Weight) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Vss/Weight of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Apparent Terminal Half-life (t1/2) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

t1/2 of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

t1/2 of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Trough Concentration Prior to the Next Dose for Each Cycle (Ctrough) of Belantamab Mafodotin Antibody-drug Conjugate (ADC)

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Pre-dose (within 30 minutes prior to start of infusion) on day 1 of cycle 1, 3, 5, 8 and 11 (each cycle is of 21 days)

Ctrough of Belantamab Mafodotin Total Antibody

Blood samples were collected at indicated time points for pharmacokinetic analysis of belantamab mafodotin. PK parameters were analyzed using standard non-compartmental analysis.

Time frame: Pre-dose (within 30 minutes prior to start of infusion) on day 1 of cycle 1, 3, 5, 8 and 11 (each cycle is of 21 days)

Number of Participants With Abnormal Vital Signs

Abnormal vital signs were defined as any abnormal findings in the vital signs parameters (temperature, blood pressure and pulse rate).

Time frame: Up to 21 months

Number of Participants With Worst- Case Grade Changes Post-baseline in Hematology Parameter: Hemoglobin, Lymphocytes, Neutrophils, Platelets, Leukocytes

Blood samples were collected at indicated time points to assess change from baseline in hemoglobin, lymphocytes, neutrophils, platelets, leukocytes. Worst case grade increase from baseline grade was provided for all the hematology tests that were gradable by National Cancer Institute Common Terminology Criteria (NCI CTCAE, Version 5.0, 2017). Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE. Data for any participants with worst-case grade changes (Increase to Grade 3 or Increase to Grade 4) post-baseline were presented. Baseline was defined as latest pre-dose assessment (day 1) with a non-missing value, including those from unscheduled visits.

Time frame: Baseline (day 1) and up to 21 months

Number of Participants With Worst- Case Grade Changes Post-baseline in Clinical Chemistry Parameters

Blood samples were collected at indicated time points to assess change from baseline in albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatine kinase, gamma glutamyl transferase, potassium, lactate dehydrogenase, magnesium. Worst case grade (G) increase from baseline grade was provided for all the chemistry tests that were gradable by National Cancer Institute Common Terminology Criteria (NCI CTCAE, Version 5.0, 2017). Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE. Data for any participants with worst-case grade changes (Increase to Grade 3 or Increase to Grade 4) post-baseline were presented. Baseline was defined as latest pre-dose assessment (day 1) with a non-missing value, including those from unscheduled visits.

Time frame: Baseline (day 1) and up to 21 months

Percentage of Participants With Objective Response Rate (ORR)

ORR was defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., very good partial response \[VGPR\], complete response \[CR\] and stringent complete response \[sCR\]) as assessed by International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma 2016. PR=response greater than or equal to (\>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to less than (\<) 200 mg per 24 hours. CR=negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow aspirates. sCR=complete response below plus normal free light chain (FLC) ratio and absence of clonal plasma cells in bone marrow by immunohistochemistry or 8-color, 2 tube multiparametric flow cytometry. VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-component level \<100 mg/24 h.

Time frame: Up to 21 months

Number of Participants With Anti-drug Antibodies (ADAs) Against Belantamab Mafodotin

Serum samples were analyzed for the presence of anti-belantamab mafodotin antibodies by a validated electro chemiluminescent immunoassay. All samples were tested in a screening assay to identify potentially positive samples.

Time frame: Up to 24 months and 21 days

Titers of ADAs Against Belantamab Mafodotin

Samples were analyzed for the presence of anti-belantamab mafodotin antibodies by a validated electro chemiluminescent immunoassay. All samples were tested in a screening assay to identify potentially positive samples. Screened positive was further characterized for the antibody titer values.

Time frame: Up to 24 months and 21 days

Change From Baseline in Ocular Surface Disease Index (OSDI) Total Score

The OSDI instrument measures vision-related function. The total OSDI score was calculated as (sum of scores for all questions answered\*100) divided by (total number of questions answered\*4). The 12 items questionnaire assessed ocular symptoms, visual-related functioning and environmental triggers. Scores ranged from 0 to 100, with higher scores indicating a worse status. Baseline was defined as latest pre-dose assessment (day 1) with a non-missing value, including those from unscheduled visits.

Time frame: Baseline (day 1) Up to 24 months and 21 days

A Study of Belantamab Mafodotin to Investigate Safety, Tolerability, Pharmacokinetics, Immunogenicity and Clinical Activity in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes