A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)-DREAMM5 - Sub-study 3 - Belantamab Mafodotin and Nirogacestat in Combination
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 106
- 试验地点
- 34
- 主要终点
- DE Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The primary purpose is to determine the safety and tolerability of belantamab mafodotin in combination with nirogacestat 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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
Belantamab mafodotin + Nirogacestat
干预措施: Nirogacestat (Drug)
Belantamab mafodotin + Nirogacestat
干预措施: Belantamab mafodotin (Drug)
结局指标
主要结局
DE Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: 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, was 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 qualified as DLTs. Severity was graded using National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
DE Phase: Number of Participants With Adverse Events (AEs)
时间窗: Up to approximately 253 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
时间窗: Baseline (Day 1) and up to approximately 253 weeks
Blood samples were collected for evaluation of hematology parameters including Anemia (An), Hemoglobin increased (HbI), Lymphocyte count decreased (LyD), Lymphocytes count increased (LyI), Neutrophils count decreased (NeuD), Platelet count decreased (PD), Leukocytosis (LC) and White blood cell decreased (WBCD). The laboratory parameters were graded according to CTCAE v5.0. 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 increases 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
时间窗: Baseline (Day 1) and up to approximately 253 weeks
Blood samples were collected for evaluation of clinical chemistry parameters including Hypoglycemia (HG), Hypoalbuminemia (HA), Creatinine Kinase increased (CPKi), Hyperkalemia (HK), Blood lactate dehydrogenase Increased (BLDi), Hypermagnesemia (HyperM), Hypomagnesemia (HypoM), Hypernatremia (HyperN), Hypercalcemia (HyperC), Hypocalcemia (HypoC) and Chronic Kidney Disease (CKD). 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.
CE Phase: Overall Response Rate (ORR)
时间窗: Up to approximately 253 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.
Dose Exploration (DE) Phase: Number of participants with dose limiting toxicities (DLTs)
时间窗: Up to 21 days
DE Phase: Number of participants with adverse events (AEs)
时间窗: Up to approximately 253 weeks
DE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry, and urinalysis lab parameters
时间窗: Up to approximately 253 weeks
Cohort Expansion (CE) Phase: Overall Response Rate (ORR)
时间窗: Up to approximately 253 weeks
ORR is defined as the percentage of participants with a confirmed Partial response (PR) or better as the best overall response (BOR), according to the International Myeloma Working Group (IMWG) Response Criteria.
次要结局
- CE Phase: Clinical Benefit Rate (CBR)(Up to approximately 253 weeks)
- DE Phase: Overall Response Rate (ORR)(Up to approximately 253 weeks)
- DE Phase: Number of Participants Achieving Stringent Complete Response (SCR), Complete Response (CR), Very Good Partial Response (VGPR) and Partial Response (PR)(Up to approximately 253 weeks)
- CE Phase: Number of Participants Achieving SCR, CR, VGPR and PR(Up to approximately 253 weeks)
- DE Phase: Plasma Concentrations of Belantamab Mafodotin Antibody-Drug Conjugate (ADC)(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, D22, and D29 ; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18 and C30; End of Treatment (approximately 157 weeks))
- CE Phase: Plasma Concentrations of Belantamab Mafodotin Antibody-Drug Conjugate (ADC)(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, and D22 ; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18; End of Treatment (approximately 157 weeks))
- DE Phase: Plasma Concentration of Belantamab Mafodotin Total Antibody(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, D22, and D29; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18 and C30; End of Treatment (approximately 157 weeks))
- CE Phase: Plasma Concentration of Belantamab Mafodotin Plasma Total Antibody(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, and D22; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18; End of Treatment (appoximately 157 weeks))
- DE Phase: Plasma Concentrations of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, D22, and D29; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18 and C30; End of Treatment (approximately 157 weeks))
- CE Phase: Plasma Concentrations of Belantamab Mafodotin Cys- Monomethyl Auristatin-F (Cys-mcMMAF)(PRE-DOSE(PD), END OF INFUSION (EOI), EOI+2 HOURS(H), EOI+ 24H on Day(D) 1 of Cycle (C) 1; ANYTIME on C1 D4, D8, D22 ; PD and EOI on D1 of C2, C4, C6, C9, C12; PD on D1 of C18; End of Treatment (approximately 157 weeks))
- DE Phase: Plasma Concentration of Nirogacestat When Administered in Combination With Belantamab Mafodotin(PRE-DOSE (PD), Post-dose 30 Minutes, 1H, 2H, and 4H on Cycle (C) 1 Day (D) -2; PRE-DOSE (PD), Post-dose 30 Minutes, 1H, 2H, 4H, 8H on C1D1; PD on C1D4 and D8 ; PD, Post-dose 30 Minutes, 1H, 2H, 4H, 8H on C2D1)
- CE Phase: Progression-free Survival (PFS)(Up to approximately 253 weeks)
- CE Phase: Plasma Concentration of Nirogacestat When Administered in Combination With Belantamab Mafodotin(PRE-DOSE (PD), Post-dose 30 Minutes, 1H, 2H, 4H, 8H on C1D1; PD on C1D4 and D8 ; PD, Post-dose 30 Minutes, 1H, 2H, 4H, 8H on C2D1)
- DE Phase: Number of Participants With Post-baseline Positive Anti-drug Antibodies (ADAs) Against Belantamab Mafodotin(C2 D1, C4 D1, C6 D1, C9 D1, C12 D1, C18 D1, C30 D1, End of Treatment (approximately 157 weeks))
- CE Phase: Number of Participants With Post-baseline Positive ADAs Against Belantamab Mafodotin(C2 D1, C4 D1, C6 D1, C9 D1, C12 D1, C18 D1, End of Treatment (approximately 157 weeks))
- DE Phase: Titer of ADAs Against Belantamab Mafodotin(Up to approximately 157 weeks.)
- CE Phase: Titer of ADAs Against Belantamab Mafodotin(C2 D1 and at End of Treatment (approximately 157 weeks))
- DE Phase: Number of Participants With Adverse Events of Special Interest (AESI) for Belantamab Mafodotin(Up to approximately 253 weeks)
- CE Phase: Number of Participants With Adverse Events of Special Interest (AESI) for Belantamab Mafodotin(Up to approximately 253 weeks)
- DE Phase: Number of Participants With Any Corneal Event by Maximum Grade as Per CTCAE Grade(Up to approximately 253 weeks)
- CE Phase: Number of Participants With Any Corneal Event by Maximum Grade as Per CTCAE Grade(Up to approximately 253 weeks)
- CE Phase: Duration of Response (DoR)(Up to approximately 253 weeks)
- CE Phase: Time to Response (TTR)(Up to approximately 253 weeks)
- CE Phase: Overall Survival (OS)(Up to approximately 253 weeks)
- CE Phase: Number of Participants With AEs and SAEs(Up to approximately 253 weeks)
- CE Phase: Number of Participants With AEs Leading to Discontinuation(Up to approximately 253 weeks)
- CE Phase: Number of Participants With Adverse Events Leading to Dose Reduction or Delay(Up to approximately 253 weeks)
- CE Phase: Number of Participants With Worst-case Hematology Results by Maximum Grade Increase Post - Baseline Relative to Baseline(Baseline (Day 1) and up to approximately 253 weeks)
- CE Phase: Number of Participants With Worst-Case Chemistry Results by Maximum Grade Increase Post - Baseline Relative to Baseline(Baseline (Day 1) and up to approximately 253 weeks)
- DE Phase: Overall Response Rate(Up to approximately 253 weeks)
- CE Phase: Clinical Benefit Rate (CBR)(Up to approximately 253 weeks)
- DE Phase: Number of participants achieving Partial Response (PR)(Up to approximately 253 weeks)
- CE Phase: Number of participants achieving PR(Up to approximately 253 weeks)
- DE Phase: Number of participants achieving Very Good Partial Response (VGPR)(Up to approximately 253 weeks)
- CE Phase: Number of participants achieving VGPR(Up to approximately 253 weeks)
- DE Phase: Number of participants achieving Complete Response (CR)(Up to approximately 253 weeks)
- CE Phase: Number of participants achieving CR(Up to approximately 253 weeks)
- DE Phase: Number of participants achieving Stringent Complete Response (sCR)(Up to approximately 253 weeks)
- CE Phase: Number of participants achieving sCR(Up to approximately 253 weeks)
- DE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments(Up to approximately 253 weeks)
- CE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments(Up to approximately 253 weeks)
- DE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin(Up to approximately 253 weeks)
- CE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin(Up to approximately 253 weeks)
- DE Phase: Number of participants with anti-drug antibodies (ADAs) against belantamab mafodotin(Up to approximately 253 weeks)
- DE Phase: Titre of (ADAs) against belantamab mafodotin(Up to approximately 253 weeks)
- CE Phase: Number of participants with ADAs against belantamab mafodotin(Up to approximately 253 weeks)
- CE Phase: Titre of ADAs against belantamab mafodotin(Up to approximately 253 weeks)
- DE Phase: Number of participants with adverse events of special interest (AESI) for belantamab mafodotin(Up to approximately 253 weeks)
- CE Phase: Number of participants with AESI for belantamab mafodotin(Up to approximately 253 weeks)
- DE Phase: Number of participants with AESI for Nirogacestat(Up to approximately 253 weeks)
- CE Phase: Number of participants with AESI for Nirogacestat(Up to approximately 253 weeks)
- DE Phase: Number of participants with abnormal ocular findings on ophthalmic examination(Up to approximately 253 weeks)
- CE Phase: Number of participants with abnormal ocular findings on ophthalmic examination(Up to approximately 253 weeks)
- CE Phase: Progression-free survival (PFS)(Up to approximately 253 weeks)
- CE Phase: Duration of response (DoR)(Up to approximately 253 weeks)
- CE Phase: Time to response (TTR)(Up to approximately 253 weeks)
- CE Phase: Overall survival (OS)(Up to approximately 253 weeks)
- CE Phase: Number of participants with AEs and SAEs(Up to approximately 253 weeks)
- CE Phase: Number of participants with AEs leading to discontinuation(Up to approximately 253 weeks)
- CE Phase: Number of participants with dose reduction or delay(Up to approximately 253 weeks)
- CE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters(Up to approximately 253 weeks)