Study to Investigate Alternative Dosing Regimens of Belantamab Mafodotin in Participants With Relapsed or Refractory Multiple Myeloma
- Registration Number
- NCT05064358
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
This study aims to evaluate alternative dosing regimens of single-agent belantamab mafodotin in participants with relapsed or refractory multiple myeloma (RRMM) to determine if an improved overall benefit/risk profile can be achieved by modifying the belantamab mafodotin dose, schedule, or both.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 177
- Participant must be 18 years of age inclusive at the time of signing the informed consent form (ICF).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Histologically or cytologically confirmed diagnosis of MM and a. Has undergone stem cell transplant or is considered transplant ineligible, and b. Has failed at least 3 prior lines of anti-myeloma therapies, including an anti-cluster of differentiation (CD)38 antibody (e.g., daratumumab) alone or in combination and is refractory to an immunomodulatory agent (e.g., lenalidomide, pomalidomide) and a proteasome inhibitor (e.g., bortezomib, ixazomib, carfilzomib).
- France specific: participants have failed at least 4 prior lines of anti-myeloma therapies
- Participant has measurable disease per modified IMWG criteria.
- Life expectancy of at least 6 months, in the opinion of the investigator.
- Male and female participants agree to abide by protocol-defined contraceptive requirements.
- Participant is capable of giving signed informed consent.
- Participant meets country-specific inclusion criteria described in the protocol.
- Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes), or active plasma cell leukemia at the time of screening.
- Current corneal epithelial disease, except nonconfluent superficial punctate keratitis (SPK).
- Evidence of active mucosal or internal bleeding.
- Presence of an active renal condition.
- Any serious and/or unstable pre-existing medical condition, psychiatric disorder, or other conditions that could interfere with the participant's safety, obtaining informed consent, or compliance with the study procedures.
- Malignancies other than the disease under study, except for any other malignancy from which the participant has been disease free for >2 years and, will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy (MM). Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
- Evidence of cardiovascular risk as per the protocol criteria.
- Pregnant or lactating female.
- Active infection requiring antibiotic, antiviral, or antifungal treatment.
- Known human immunodeficiency virus (HIV) infection, unless the criteria in protocol can be met.
- Hepatitis B and C will be excluded unless the criteria in protocol can be met.
- Cirrhosis or current unstable liver or biliary disease.
- Alanine aminotransferase (ALT) >2.5× upper limit of normal (ULN).
- Total Bilirubin >1.5×ULN.
- Systemic anti-MM therapy within <=14 days or 5 half-lives, whichever is shorter.
- Systemic therapy with high dose steroids within <=14 days before the first dose of study treatment.
- Prior allogenic stem cell transplant.
- Prior treatment with a monoclonal antibody <=30 days before the first dose of study treatment. Use of monoclonal antibodies for serious conditions unrelated to multiple myeloma, such as COVID, may be permitted.
- Prior treatment with an anti-B cell maturation antigen (BCMA) targeted therapy or hypersensitivity reactions to any components of the study treatment.
- Treatment with an antibody-drug conjugate.
- Participant has received any major surgery <=4 weeks before the first dose of study treatment. An exception may be allowed for bone stabilizing surgery.
- Inadequate bone marrow reserve or organ functions as demonstrated by any of the following: a. Absolute neutrophil count <1.0×10^9/L, b. Hemoglobin <8 gram/deciliter (g/dL), c. Platelet count <50×10^9/L, d. Spot urine (albumin/creatinine ratio) >500 milligram/gram (mg/g), e. Estimated glomerular filtration rate (eGFR) <30 milliliter per minute per 1.73 meter square (mL/min/1.73m^2).
- UK specific: a. Absolute neutrophil count <1.5×10^9/L, c. Platelet count <75×10^9/L
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 5: Participants receiving belantamab mafodotin at DL4 with alternative dose modification Belantamab mafodotin - Cohort 1: Participants receiving belantamab mafodotin at dose level (DL) 1 Belantamab mafodotin - Cohort 2: Participants receiving belantamab mafodotin at DL 2 Belantamab mafodotin - Cohort 3: Participants receiving belantamab mafodotin at DL 3 Belantamab mafodotin - Cohort 4: Participants receiving belantamab mafodotin at DL 4 Belantamab mafodotin -
- Primary Outcome Measures
Name Time Method Percentage of Participants With Grade ≥2 Corneal Events Assessed by Keratopathy Visual Acuity (KVA) Scale Up to 29.5 months The KVA scale is based on the evaluation of corneal changes using slit lamp examination. This scale provides a standardized approach for evaluating the relationship between corneal health and visual acuity. KVA scale is defined as Grade 0: No keratopathy, normal visual acuity with no corneal abnormalities; Grade 1: Mild changes to the cornea with no significant loss in visual acuity; Grade 2: Moderate corneal changes with noticeable visual acuity reduction; Grade 3: Severe corneal changes with substantial visual acuity impairment; Grade 4: Very severe corneal changes leading to significant vision loss. Higher grade indicates greater severity of corneal events.
- Secondary Outcome Measures
Name Time Method Number of Participants With Corneal Events up to Week 16 Up to week 16 The number of participants with corneal events were assessed using KVA scale. The KVA scale provides a standardized approach for evaluating the relationship between corneal health and visual acuity. KVA scale is defined as Grade 0: No keratopathy, normal visual acuity with no corneal abnormalities; Grade 1: Mild changes to the cornea with no significant loss in visual acuity; Grade 2: Moderate corneal changes with noticeable visual acuity reduction; Grade 3: Severe corneal changes with substantial visual acuity impairment; Grade 4: Very severe corneal changes leading to significant vision loss. Higher grade indicates greater severity of corneal events.
Incidence Rate of Corneal Events by Grade (KVA Scale) Up to 152 weeks Incidence rate of corneal events is defined as the percentage of participants with corneal events by grade according to the KVA scale. The KVA scale provides a standardized approach for evaluating the relationship between corneal health and visual acuity. KVA scale is defined as Grade 0: No keratopathy, normal visual acuity with no corneal abnormalities; Grade 1: Mild changes to the cornea with no significant loss in visual acuity; Grade 2: Moderate corneal changes with noticeable visual acuity reduction; Grade 3: Severe corneal changes with substantial visual acuity impairment; Grade 4: Very severe corneal changes leading to significant vision loss. Higher grade indicates greater severity of corneal events.
Exposure Adjusted Incidence Rate of Corneal Events as Per CTCAE Grade Up to 152 weeks Exposure adjusted incidence rate of corneal events is defined as the number of participants with corneal events divided by the total exposure time for all participants at risk in the treatment group. Incidence rate for corneal events was assessed using Common Terminology Criteria for Adverse Events (CTCAE). Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grades indicate greater severity. The number of participants with Grades 3,4, and 5 are presented.
Median Duration of All the Dose Delays Up to 152 weeks Median duration of dose delays is defined as the median duration in time of all the dose delays in the respective treatment group. Duration of delays is defined as period from the expected start date of dose to actual start date of current dose.
Percentage of Participants Requiring Dose Reduction, Dose Interruption/Delay, Permanent Treatment Discontinuation Due to Corneal Events Up to 152 weeks The percentage of participants that required dose reduction, dose interruption/delay, permanent treatment discontinuation due to corneal events were evaluated using KVA Scale. KVA scale is defined as Grade 0: No keratopathy, normal visual acuity with no corneal abnormalities; Grade 1: Mild changes to the cornea with no significant loss in visual acuity; Grade 2: Moderate corneal changes with noticeable visual acuity reduction; Grade 3: Severe corneal changes with substantial visual acuity impairment; Grade 4: Very severe corneal changes leading to significant vision loss. Higher grade indicates greater severity of corneal events.
Cumulative Incidence of Grade 2 or Above Corneal Events (KVA Scale) At 3 months, 6 months, 9 months and 12 months Cumulative incidence of Grade 2 or above corneal events is defined as the percentage of corneal events of Grade 2 or above, as assessed using the KVA scale, within a specific time interval. KVA scale is defined as Grade 0: No keratopathy, normal visual acuity with no corneal abnormalities; Grade 1: Mild changes to the cornea with no significant loss in visual acuity; Grade 2: Moderate corneal changes with noticeable visual acuity reduction; Grade 3: Severe corneal changes with substantial visual acuity impairment; Grade 4: Very severe corneal changes leading to significant vision loss. Higher grade indicates greater severity of corneal events.
Toxicity Index (TI) Up to 152 weeks Toxicity Index is a composite score derived from the severity grades of adverse events (AEs) reported during the study, based on the Common Terminology Criteria for Adverse Events (CTCAE). A participant's score is calculated as a function of the ordered toxicity grades, represented in descending order by sequence, on a scale of 0-6, where 0 represents no toxicity and 6 represents the highest toxicity. CTCAE grades are defined as follows: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe or medically significant but not immediately life-threatening), Grade 4 (Life-threatening consequences), and Grade 5 (Death related to AE). Higher grades indicate greater toxicity severity.
Duration of Corneal Events of Grade 2 or Above Up to 152 weeks Duration of corneal events is defined for each participant as the sum of duration of all the corneal AEs. The duration is defined as time from onset of any corneal events (KVA scale) of Grade 2 or above to the first time resolution to baseline, Grade 1 or below. It required at least one day gap between the resolution of all events from first occurrence to the onset of next occurrence.
Percentage of Time on Study With Grade 2 or Above Corneal Events Up to 152 weeks It is defined as the percentage of time that a participant has corneal events out of the total time that a participant is on the study. Time with corneal events is defined as time from onset of any corneal events (KVA scale) of Grade 2 or above to the first-time resolution to baseline, Grade 1 or below.
Number of Participants With Change in Best Corrected Visual Acuity Test (BCVA) Scores Baseline (Day 1) and up to 152 weeks Change in BCVA is defined as change in logarithm of the minimum angle of resolution (logMAR) units compared with baseline or the first visit after the cataract surgery. BCVA score was calculated based on the Logarithm of the Minimum Angle of Resolution (logMAR score). Any change from baseline categories is presented for right and left eyes. No change/improved vision is defined as a change from baseline \<0.1; a possible worsened vision is defined as a change from baseline \>=0.1 to \<=0.3; a definite worsened vision is defined as a change from baseline \>0.3 logMAR score. Improvement in BCVA is represented by a reduction in logMAR score from baseline, while worsening in BCVA is represented by an increase in logMAR score from baseline.
Objective Response Rate (ORR) Up to 152 weeks ORR was defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, very good partial response \[VGPR\], complete response \[CR\] and stringent complete response \[sCR\]), according to the International Myeloma Working Group (IMWG) Response Criteria. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 h; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h.
Percentage of Participants With a Confirmed VGPR or Better (i.e., VGPR, CR, and sCR) Up to 152 weeks Percentage of participants with a confirmed VGPR or better defined as percentage of participant with confirmed VGPR, CR, and sCR, according to the 2016 IMWG response criteria. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component \<100 mg/24 h.
Time to Response (TTR) Up to 152 weeks TTR defined as the time between the date of randomization and the first documented evidence of response (PR or better), among participants who achieve a response (i.e., confirmed PR or better), according to the 2016 IMWG response criteria. PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h.
Duration of Response (DoR) Up to 152 weeks DoR defined as the time from first documented evidence of PR or better until disease progression (PD) among responders according to the 2016 IMWG response criteria or death due to any cause. PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h. PD= Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>= 0.5 g/dL; Serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; Urinary M-protein (absolute increase must be \>= 200 mg per 24 h).
Time to Progression (TTP) Up to 152 weeks TTP defined as the time from randomization until the earliest date of documented PD or death due to PD, according to the 2016 IMWG response criteria. PD= Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>= 0.5 g/dL; Serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; Urinary M-protein (absolute increase must be \>= 200 mg per 24 h).
Progression Free Survival (PFS) Up to 152 weeks PFS defined as the time from randomization until the earliest date of documented PD, according to the 2016 IMWG response criteria, or death due to any cause. PD= Increase of 25% from lowest confirmed response value in 1 or more of the following criteria: Serum M-protein with absolute increase of \>= 0.5 g/dL; Serum M-protein increase \>= 1 g/dL if the lowest M-component was \>=5 g/dL; Urinary M-protein (absolute increase must be \>= 200 mg per 24 h).
Overall Survival (OS) Up to 152 weeks OS defined as the time from randomization until the date of death due to any cause.
Percentage of Participants With AEs Up to 152 weeks An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. AEs were coded using the standard Medical Dictionary for Regulatory Activities (MedDRA).
Percentage of Participants Requiring Dose Reduction, Dose Interruption/Delay, Permanent Treatment Discontinuation Due to Any AEs Up to 152 weeks Percentage of participants requiring dose reduction, dose interruption/delay, permanent treatment discontinuation due to any AEs were presented. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. AEs were coded using the standard MedDRA.
Number of Participants With Worst-Case Hematology Results by Maximum Grade Increase Post-Baseline Relative to Baseline Up to 152 weeks Blood samples were collected for the analysis of hematology parameters. The parameters were graded according to CTCAE grades. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grades indicate greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Any worst-case post baseline increases in grade 1/2/3 to a grade of 4 are presented.
Number of Participants With Worst-Case Clinical Chemistry Results by Maximum Grade Increase Post-Baseline Relative to Baseline Up to 152 weeks Blood samples were collected for the analysis of clinical chemistry parameters. The parameters were graded according to CTCAE grades. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grades indicate greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Any worst-case post baseline increases in grade 1/2/3 to a grade of 4 are presented.
Number of Participants With Post-baseline Positive Anti-drug Antibodies (ADAs) Against Belantamab Mafodotin Baseline (Day 1) and up to 152 weeks Serum samples collected for the analysis of the presence of ADAs using validated immunoassays. All samples were tested in screening assay, and positive samples were further characterized for antibody titers. Baseline was defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits.
Titers of ADAs Against Belantamab Mafodotin Up to 152 weeks Serum samples collected for the analysis of the presence of ADAs using validated immunoassays. All samples were to be further tested in screening assay, and positive samples were further to be characterized for antibody titers.
Maximum Observed Concentration (Cmax) for Belantamab Mafodotin Antibody-drug Conjugate (ADC) Cycle(C)1 Day(D) 1 Pre-dose, End of Infusion (EOI), Start of Infusion (SOI) + 2 hours (H); C1D2 SOI+24H; C1D4; C1D8-15 Plasma samples were collected for PK analysis for belantamab mafodotin antibody-drug conjugate (ADC).
Concentration at 21 Days for Belantamab Mafodotin ADC At 21 days Plasma samples were collected for PK analysis for belantamab mafodotin ADC.
Average Concentration Over 21 Days (Cavg) for Belantamab Mafodotin ADC C1 D1 Pre-dose, EOI, SOI + 2H; C1D2 SOI+24H; C1D4; C1D8-15, D21 Plasma samples were collected for PK analysis for belantamab mafodotin ADC.
Area Under the Concentration-time Curve (AUC) (0-504h) of Belantamab Mafodotin ADC C1 D1 Pre-dose, EOI, SOI + 2H; C1D2 SOI+24H; C1D4; C1D8-15, D21 Plasma samples were collected to determine the area under the concentration-time curve (AUC) (0-504h) of Belantamab mafodotin ADC.
Clearance (CL) for Belantamab Mafodotin ADC C1 D1 Pre-dose, EOI, SOI + 2H; C1D2 SOI+24H; C1D4; C1D8-15 Plasma samples were collected for PK analysis for belantamab mafodotin ADC.
Half-life (t1/2) of Belantamab Mafodotin ADC C1 D1 Pre-dose, EOI, SOI + 2H; C1D2 SOI+24H; C1D4; C1D8-15 Plasma samples were collected for PK analysis of Belantamab mafodotin ADC
Steady-state Volume of Distribution (Vss) for Belantamab Mafodotin ADC C1 D1 Pre-dose, EOI, SOI + 2H; C1D2 SOI+24H; C1D4; C1D8-15 Plasma samples were collected for PK analysis for belantamab mafodotin ADC.
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Stoke-on-Trent, United Kingdom
GSK Investigational Site🇬🇧Stoke-on-Trent, United Kingdom