Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Isatuximab in Participants With RRMM

Phase 2Active Not RecruitingNCT07217184

GlaxoSmithKline30 enrolled

Overview

The primary purpose is to determine the safety and tolerability of belantamab mafodotin in combination with isatuximab, and to establish the recommended Phase 2 dose (RP2D) for the combination treatment to explore in the cohort expansion (CE) phase in participants with RRMM. This study is a sub study of the Master protocol (NCT04126200).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Multiple Myeloma

Interventions

Belantamab mafodotinDRUG

Belantamab mafodotin will be administered.

IsatuximabDRUG

Isatuximab will be administered.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participant must be 18 years of age inclusive or older, at the time of signing the informed consent. * Participants must have histologically or cytologically confirmed diagnosis of Multiple Myeloma (MM), as defined by the IMWG. * Participants having at least 3 prior lines of prior anti-myeloma treatments including an immunomodulating agent (IMID) a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody. * Participants with a history of autologous stem cell transplant are eligible for study participation when, transplant was \>100 days prior to study enrolment and with no active infection(s). * Participants with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, unless ECOG less than equal to (\<=)2 is due solely to skeletal complications and/or skeletal pain due to MM. * Participants with measurable disease defined as at least one of the following: Serum M-protein greater than equal to (\>=)0.5 gram per deciliter (\>=5 gram per liter) or Urine M-protein \>=200 milligrams (mg) per 24 hours or Serum free light chain (FLC) assay: Involved FLC level \>=10 mg per deciliter (\>=100 mg per Liter) and an abnormal serum FLC ratio (\<0.26 or \>1.65). * Participants who have tested positive for Hepatitis B core antibody (HBcAb) can be enrolled if the following criteria are met: Serology result HBcAb+, Hepatitis B surface antigen (HBsAg)-; HBV deoxyribonucleic acid (DNA) undetectable during screening. * Participants who are currently receiving physiological doses oral steroids (\<10 mg/day), inhaled steroids or ophthalmological steroids. Exclusion Criteria: * Participants with current corneal epithelial disease except mild punctate keratopathy. * Participants with evidence of cardiovascular risk. * Participants with known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other mAb. * Participants with active infection requiring antibiotic, antiviral, or antifungal treatment. * Participants with other monoclonal antibodies within 30 days or systemic anti-myeloma therapy within \<14 days. * Participants with prior radiotherapy within 2 weeks of start of study therapy. * Participants with prior allogeneic transplant are prohibited. * Participants who have received prior Chimeric Antigen T cell therapy (CAR-T) therapy with lymphodepletion with chemotherapy within 3 months of screening. * Participants with any major surgery (other than bone-stabilizing surgery) within the last 30 days. * Participants with prior treatment with an investigational agent within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is shorter. * Participants with \>=grade 3 toxicity considered related to prior check-point inhibitors and that led to treatment discontinuation. * Participants who have received transfusion of blood products within 2 weeks before the first dose of study drug. * Participants must not receive live attenuated vaccines within 30 days prior to first dose of study treatment or whilst receiving belantamab mafodotin +- partner agent in any sub-study arm of the platform trial and for at least 70 days following last study treatment. * Participants with 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. * Participants with known human immunodeficiency virus (HIV) infection, unless the participant can meet all criteria: a) established anti-retroviral therapy for at least 4 weeks and HIV viral load\<400 copies/milliliter (mL) b) cluster of differentiation 4 plus (CD4+) T-cell (CD4+) counts \>= 350 cells/microliter (µL) c) No history of Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months in which case the participant would be eligible for CE Phase only. For participants receiving nirogacestat, HIV drugs that are strong Cytochrome P450 3A4 (CYP3A4) inhibitors are prohibited. HIV drugs that are moderate CYP3A4 inhibitors, while permitted, should be co-administered with caution and must be accompanied by nirogacestat dose modifications. * Participants with Severe hypersensitivity to Isatuximab-irfc or to any of its excipients. * Participants with prior treatment with other anti-CD38 monoclonal antibody within 6 months of the first dose of study drug treatment. * Participants with known intolerance or hypersensitivity to infused proteins products, sucrose, histidine, and polysorbate 80.

Locations (19)

GSK Investigational Site

Atlanta, Georgia, United States

GSK Investigational Site

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Dose Expansion (DE) Phase: Number of Participants With Dose Limiting Toxicities (DLT)

Criteria for dose-limiting toxicity (DLT) included hematologic indicators such as Grade 3-5 febrile neutropenia and thrombocytopenia with bleeding. Non-hematologic criteria, excluding corneal toxicity, comprise Grade 3-5 toxicities, with exceptions for manageable nausea, vomiting, or diarrhea, controlled Grade 3 hypertension, and events linked to disease progression. Tumor lysis syndrome (TLS) of Grade 3 or 4, successfully managed within 7 days without end-organ damage, is considered. Corneal toxicity, assessed by the GSK corneal grading scale at Grade 4, is a DLT. Other organ-specific toxicities, notably liver toxicity meeting GSK stopping criteria, also qualify as DLT severity was graded using National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) Version (v) 5.0.

Time frame: Up to 28 days

DE Phase: Number of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.

Time frame: Up to approximately 194 weeks

DE Phase: Number of Participants With Worst-Case Hematology Results by Maximum Grade Increase Post - Baseline Relative to Baseline

Blood samples were collected for the analysis of hematology parameters. The laboratory parameters were graded according to CTCAE v 5.0. Grade 1 (G1): mild; Grade 2 (G2): moderate; Grade 3 (G3): severe; Grade 4 (G4) life-threatening or disabling. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Any worst-case post baseline increase to G1, G2, G3, and G4 are presented. Baseline value was defined as the most recent, non-missing value from a local laboratory prior to the first dose of study treatment. WBC: White blood cells.

Time frame: Baseline (Day 1) and up to approximately 194 weeks

DE Phase: Number of Participants With Worst-Case Chemistry Results by Maximum Grade Increase Post - Baseline Relative to Baseline

Data from ClinicalTrials.gov

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Secondary Outcomes

DE Phase: Overall Response Rate (ORR)

Overall Response Rate (ORR) was defined as the percentage of participants with a confirmed Partial Response (PR) or better as the best overall response (i.e., PR, Very Good Partial Response \[VGPR\], Complete Response \[CR\], and stringent Complete Response \[sCR\]), as assessed by the investigator per international myeloma working group (IMWG) (2016). PR is defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h. VGPR is defined as 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. CR is defined as negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow. sCR is defined as CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

Time frame: Up to approximately 194 weeks

CE Phase: Clinical Benefit Rate (CBR)

Clinical benefit rate was defined as the percentage of participants with a confirmed minimal response (MR) or better according to the IMWG Response Criteria. MR is \>= 25% but \< 49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%.

Time frame: Up to approximately 194 weeks

DE Phase: Percentage of Participants Achieving Stringent Complete Response (SCR), Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR)

Partial Response \[PR\], Very Good Partial Response \[VGPR\], Complete Response \[CR\], and stringent Complete Response \[sCR\] were assessed by the investigator per IMWG (2016). PR defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h. VGPR defined as 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. CR defined as negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow. sCR defined as CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

Time frame: Up to approximately 194 weeks

CE Phase: Percentage of Participants Achieving SCR, CR, VGPR and PR

Partial Response \[PR\], Very Good Partial Response \[VGPR\], Complete Response \[CR\], and stringent Complete Response \[sCR\] was assessed by the investigator per IMWG (2016). PR defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to \<200 mg/24 h. VGPR defined as 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. CR defined as negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND \<5% plasmacytomas in the bone marrow. sCR defined as CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

Time frame: Up to approximately 194 weeks

DE Phase: Plasma Concentrations of Belantamab Mafodotin Antibody-Drug Conjugate (ADC)

Blood samples were collected for PK analysis of belantamab mafodotin Antibody-Drug Conjugate (ADC). Only those participants who were measured and analyzed (i.e., contributed data reported in the table) were included in the Overall Number of Participants Analyzed field. 'Number Analyzed' signifies participants evaluable for the specified timepoints.

Time frame: Predose (PD), end of infusion (EOI), and 2-hour and 24-hour postdose on Cycle 1 Day 1; predose on C1D8, C1D15 and C1D22, anytime samples on C1D8 and C1D22; predose and EOI on Day 1 of Cycles 2, 4, 6, 9 and 12; and end of treatment (~194 weeks).

CE Phase: Plasma Concentration of Belantamab Mafodotin Antibody-Drug Conjugate (ADC)

Blood samples were to be collected for PK analysis of Belantamab Mafodotin Antibody-Drug Conjugate (ADC).

Time frame: Up to approximately 194 weeks

DE Phase: Plasma Concentration of Belantamab Mafodotin Total Antibody

Blood samples were collected for PK analysis of Belantamab mafodotin total antibody.

Time frame: Predose, end of infusion (EOI), and 2-hour and 24-hour on Cycle 1 Day 1; predose and anytime samples on Cycle 1 Days 8 and 22; predose on Cycle 1 Day 15; predose and EOI on Day 1 of Cycles 2, 4, 6, 9, and 12; and end of treatment (~194 weeks).

CE Phase: Plasma Concentration of Belantamab Mafodotin Plasma Total Antibody

Blood samples were to be collected for PK analysis of Belantamab mafodotin plasma total antibody.

Time frame: Up to approximately 194 weeks

DE Phase: Plasma Concentration of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were collected for PK analysis of belantamab mafodotin cys- monomethyl auristatin-F (cys-mcMMAF).

Time frame: Predose, end of infusion (EOI), and 2-hour and 24-hour postdose on Cycle 1 Day 1; predose on Cycle 1 Days 8, 15 and 22, anytime samples on C1D8 and C1D22 ; predose and EOI on Day 1 of Cycles 2, 4, 6, 9 and 12; and end of treatment (~194 weeks).

CE Phase: Plasma Concentration of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Blood samples were to be collected for PK analysis of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)

Time frame: Up to approximately 194 weeks

DE Phase: Isatuximab Concentration When Administered in Combination With Belantamab Mafodotin

Blood samples were collected for PK analysis of Isatuximab when administered intravenously in combination with belantamab mafodotin.

Time frame: Predose on Cycle (C)1 Day (D)1, D8, D15 and D22; predose on C2D1 and C2D15; predose on C3D1 and C3D15; predose on C4D1 and C4D15; predose on C5D1, C6D1, C7D1, C8D1, C9D1 and C10D1; and end of treatment (~194 weeks).

CE Phase: Isatuximab Concentration When Administered in Combination With Belantamab Mafodotin

Blood samples were planned to be collected for PK analysis of isatuximab when administered intravenously in combination with belantamab mafodotin.

Time frame: Up to approximately 194 weeks

DE Phase: Number of Participants With Post-baseline Positive Anti-drug Antibodies (ADAs) Against Belantamab Mafodotin

Serum samples were 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.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With Post-baseline Positive ADAs Against Belantamab Mafodotin

Serum samples were to be 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.

Time frame: Up to approximately 194 weeks

DE Phase: Titer of ADAs Against Belantamab Mafodotin

Time frame: Up to approximately 194 weeks

CE Phase: Titer of ADAs Against Belantamab Mafodotin

Time frame: Up to approximately 194 weeks

DE Phase: Number of Participants With Adverse Events of Special Interest (AESI)

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With AESI

Time frame: Up to approximately 194 weeks

DE Phase: Number of Participants With Any Corneal Events by Maximum Grade as Per CTCAE Grade

The corneal events were graded according to CTCAE version 5. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant. Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Results are presented for number of participants with any corneal events by maximum grade as per CTCAE grade v 5.0.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With Any Corneal Events by Maximum Grade as Per CTCAE Grade

The corneal events were planned to be graded according to CTCAE version 5. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant. Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade. Results were to be presented for number of participants with any corneal events by maximum grade as per CTCAE grade v5.0.

Time frame: Up to approximately 194 weeks

CE Phase: Progression-free Survival (PFS)

PFS is defined as the time from randomization until the earliest date of confirmed progressive disease (PD) per IMWG, or death due to any cause.

Time frame: Up to approximately 194 weeks

CE Phase: Duration of Response (DoR)

DoR is defined as the time from first documented evidence or PR or better until progressive disease per IMWG or death due to progressive disease among participants who achieve confirmed partial response or better.

Time frame: Up to approximately 194 weeks

CE Phase: Time to Response (TTR)

TTR is 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 (confirmed PR or better).

Time frame: Up to approximately 194 weeks

CE Phase: Overall Survival (OS)

OS is defined as the time from randomization until death due to any cause.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With AEs and SAEs

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function. AEs and SAEs were to be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With AEs Leading to Discontinuation

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With Dose Reduction or Delay

Number of participants with dose reduction or delay were to be evaluated.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With Clinically Significant Changes in Hematology Lab Parameters

Blood samples were to be collected for the analysis of hematology parameters. The laboratory parameters were to be graded according to CTCAE version 5.0. Grade 1 (G1): mild; Grade 2 (G2): moderate; Grade 3 (G3: severe or medically significant; Grade 4 (G4): Life-threatening consequences; Grade 5 (G5): Death related to AE. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade.

Time frame: Up to approximately 194 weeks

CE Phase: Number of Participants With Clinically Significant Changes in Clinical Chemistry Lab Parameters

Blood samples were to be collected for the analysis of chemistry parameters. The laboratory parameters were to be graded according to CTCAE version 5.0. G1: mild; G2: moderate; G3: severe or medically significant; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. Higher grade indicates greater severity and an increase in CTCAE grade was defined relative to the Baseline grade.

Time frame: Up to approximately 194 weeks