Multiple Myeloma
Conditions
Keywords
Belantamab Mafodotin, Nirogacestat, Pomalidomide, Dexamethasone, GSK2857916, Multiple myeloma
Brief summary
The primary purpose is to determine the safety and tolerability of belantamab mafodotin in combination with nirogacestat, pomalidomide, and dexamethasone and to establish the recommended Phase 2 dose for 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).
Interventions
DRUGBelantamab mafodotin
Belantamab mafodotin will be administered.
DRUGNirogacestat
Nirogacestat will be administered.
DRUGPomalidomide
Pomalidomide will be administered.
DRUGDexamethasone
Dexamethasone will be administered.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 ophthalmalogical steroids. * Participants with platelets value for Adequate Organ System Function is ≥75 × 10\^9/L.
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 uncontrolled small and/or large intestinal disease. * Participants with uncontrolled skin disease. * Participants with any condition causing hypophosphatemia, hypokalemia or hypomagnesemia which is refractory to electrolyte replacement. * Participants with previous administration of a gamma secretase inhibitor. * Participants with concomitant administration of a strong CYP3A4 inhibitor or inducer. * Participants with active or history of venous thromboembolism within the past 3 months. * Participants with evidence of active mucosal or internal bleeding. * Participants with contraindications to or are unwilling to undergo protocol-required anti-thrombotic prophylaxis or unable to tolerate antithrombotic prophylaxis. * Participants who discontinued prior treatment with pomalidomide due to intolerable adverse events.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DE Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | Up to 28 days | 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 5.0). |
| DE Phase: Number of Participants With Adverse Events (AEs) | Up to approximately 137 weeks | 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. |
| DE Phase: Number of Participants With Worst-Case Hematology Results by Maximum Grade Increase Post - Baseline Relative to Baseline | Baseline (Day 1) and up to 137 weeks | Blood samples were collected for the analysis of hematology parameters. The laboratory parameters were graded according to CTCAE version 5. 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. |
| DE Phase: Number of Participants With Worst-Case Chemistry Results by Maximum Grade Increase Post - Baseline Relative to Baseline | Baseline (Day 1) and up to 137 weeks | Blood samples were collected for the analysis of chemistry parameters. The laboratory parameters were graded according to CTCAE version 5. G1: mild; G2: moderate; 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. CPK = creatine kinase. |
| CE Phase: Overall Response Rate (ORR) | Up to 137 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DE Phase: Overall Response Rate (ORR) | Up to 137 weeks | 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. |
| CE Phase: Clinical Benefit Rate (CBR) | Up to 137 weeks | 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 defined as \>= 25% but \< 49% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 50-89%. |
| DE Phase: Percentage of Participants Achieving Stringent Complete Response (SCR), Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR) | Up to 137 weeks | Partial Response \[PR\], Very Good Partial Response \[VGPR\], Complete Response \[CR\], and stringent Complete Response \[sCR\] as 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. |
| CE Phase: Percentage of Participants Achieving SCR, CR, VGPR and PR | Up to 137 weeks | Partial Response \[PR\], Very Good Partial Response \[VGPR\], Complete Response \[CR\], and stringent Complete Response \[sCR\] as assessed by the investigator per IMWG (2016). 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. |
| DE Phase: Plasma Concentrations of Belantamab Mafodotin Antibody-Drug Conjugate (ADC) | Predose, end of infusion (EOI), and 2 hours postdose on Cycle 1 Day 1, anytime sample at Cycle 1 Day 4, 8, 29; Predose and EOI on Day 1 of Cycle 2, 4, 6, 9, 12; Predose on Cycle 18 Day 1; and at end of treatment (~137 weeks) | Blood samples were collected for PK analysis of belantamab mafodotin Antibody-Drug Conjugate (ADC). |
| CE Phase: Plasma Concentrations of Belantamab Mafodotin Antibody-Drug Conjugate (ADC) | Up to 137 weeks | Blood samples were to be collected for PK analysis of Belantamab Mafodotin Antibody-Drug Conjugate (ADC). |
| DE Phase: Plasma Concentration of Belantamab Mafodotin Total Antibody | Predose, end of infusion (EOI), and 2 hours postdose on Cycle 1 Day 1, anytime sample at Cycle 1 Day 4, 8, 29; Predose and EOI on Day 1 of Cycle 2, 4, 6, 9, 12; Predose on Cycle 18 Day 1; and at end of treatment (~137 weeks) | Blood samples were collected for PK analysis of Belantamab mafodotin total antibody. |
| CE Phase: Plasma Concentration of Belantamab Mafodotin Plasma Total Antibody | Up to 137 weeks | Blood samples were to be collected for PK analysis of Belantamab mafodotin plasma total antibody. |
| DE Phase: Plasma Concentrations of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF) | Predose, end of infusion (EOI), and 2 hours postdose on Cycle 1 Day 1, anytime sample at Cycle 1 Day 4, 8, 29; Predose and EOI on Day 1 of Cycle 2, 4, 6, 9, 12; Predose on Cycle 18 Day 1; and at end of treatment (~137 weeks) | Blood samples were collected for PK analysis of belantamab mafodotin cys- monomethyl auristatin-F (cys-mcMMAF). |
| CE Phase: Plasma Concentrations of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF) | Up to 137 weeks | Blood samples were to be collected for PK analysis of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF) |
| DE Phase: Nirogacestat Concentration When Administered in Combination With Belantamab Mafodotin | Predose, 30 mins, 1 hour, 2 hours, and 4 hours post dose on Cycle 1 Day -2; Predose on Cycle 1 Day 1, 4, 8; Predose, 30 mins, 1 hour, 2 hours, and 4 hours post dose on Cycle 2 Day 1 | Blood samples were collected for PK analysis of Nirogacestat when administered orally in combination with belantamab mafodotin. |
| CE Phase: Nirogacestat Concentration When Administered in Combination With Belantamab Mafodotin | Up to 137 weeks | Blood samples were to be collected for PK analysis of Nirogacestat when administered orally in combination with belantamab mafodotin. |
| DE Phase: Number of Participants With Post-baseline Positive Anti-drug Antibodies (ADAs) Against Belantamab Mafodotin | Up to 137 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. |
| CE Phase: Number of Participants With Post-baseline Positive ADAs Against Belantamab Mafodotin | Up to 137 weeks | Serum samples were to be collected for the analysis of the presence of ADAs using validated immunoassays. All samples were to be tested in screening assay, and positive samples were to be further characterized for antibody titers. |
| DE Phase: Titer of ADAs Against Belantamab Mafodotin | Up to 137 weeks | Serum samples were collected for the analysis of the presence of ADAs using validated immunoassays. All samples were further tested in screening assay, and positive samples were further characterized for antibody titers. |
| CE Phase: Titer of ADAs Against Belantamab Mafodotin | Up to 137 weeks | 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. |
| DE Phase: Number of Participants With Adverse Events of Special Interest (AESI) | Up to 137 weeks | 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. Adverse Events of Special Interest (whether serious or non serious) were collected. |
| CE Phase: Number of Participants With AESI | Up to 137 weeks | 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. Adverse Events of Special Interest (whether serious or non serious) were to be collected. |
| DE Phase: Number of Participants With Any Corneal Events by Maximum Grade as Per CTCAE Grade | Up to 137 weeks | 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 version (v) 5.0. |
| CE Phase: Number of Participants With Any Corneal Events by Maximum Grade as Per CTCAE Grade | Up to 137 weeks | The corneal events were 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 version (v) 5.0. |
| CE Phase: Progression-free Survival (PFS) | Up to 137 weeks | 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. |
| CE Phase: Duration of Response (DoR) | Up to 137 weeks | 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. |
| CE Phase: Time to Response (TTR) | Up to 137 weeks | 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). |
| CE Phase: Overall Survival (OS) | Up to 137 weeks | OS is defined as the time from randomization until death due to any cause. |
| CE Phase: Number of Participants With AEs and SAEs | Up to 137 weeks | 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. |
| CE Phase: Number of Participants With AEs Leading to Discontinuation | Up to 137 weeks | 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. Number of participants with AEs leading to discontinuation were to be evaluated. |
| CE Phase: Number of Participants With Dose Reduction or Delay | Up to 137 weeks | Number of participants with dose reduction or delay were to be evaluated. |
| CE Phase: Number of Participants With Clinically Significant Changes in Hematology Lab Parameters | Up to 137 weeks | 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: 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. |
| CE Phase: Number of Participants With Clinically Significant Changes in Clinical Chemistry Lab Parameters | Up to 137 weeks | 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. |
Countries
Brazil, Canada, France, Mexico, Norway, Poland, South Korea, Sweden
Participant flow
Recruitment details
This is a sub-study of the master study NCT04126200. The study was planned to include two phases - Dose Escalation (DE) and Cohort Expansion (CE) and no participants from this sub study were enrolled in CE phase as CE Phase was not initiated due to business strategic reason.
Pre-assignment details
The results presented are based on the data cut-off date of 17 Apr 2025. Those participants still benefiting from study drug in the opinion of their treating physician continued to receive study drug in Post Analysis Continuation of Treatment (PACT) phase and their safety data will be provided within a year of study completion.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 67.1 YEARS STANDARD_DEVIATION 11.92 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 12 / 14 |
Outcome results
None listed