Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5)

Overview

B-cell maturation antigen (BCMA) is a target present on tumor cells in participants with multiple myeloma. Belantamab mafodotin (GSK2857916); is an antibody-drug conjugate (ADC) containing humanized anti-BCMA monoclonal antibody (mAb). This is a phase I/II, randomized, open-label, platform study designed to evaluate the effects of belantamab mafodotin in combination with other anti-cancer drugs in participants with relapsed/refractory multiple myeloma. The Platform design incorporates a single master protocol, where multiple treatment combinations, as sub-studies, will be evaluated simultaneously.

Full Title of Study: “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) – DREAMM 5”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Sequential Assignment
  • Primary Purpose: Treatment
  • Masking: None (Open Label)
• Study Primary Completion Date: February 21, 2025

Interventions

• Drug: Belantamab mafodotin
  • Belantamab mafodotin will be administered
• Drug: GSK3174998
  • GSK3174998 will be administered
• Drug: Feladilimab
  • feladilimab will be administered.
• Drug: Nirogacestat
  • Nirogacestat will be administered
• Drug: Dostarlimab
  • Dostarlimab will be administered.
• Drug: Isatuximab
  • Isatuximab will be administered
• Drug: Lenalidomide
  • Lenalidomide will be administered
• Drug: Dexamethasone
  • Dexamethasone will be administered
• Drug: Pomalidomide
  • Pomalidomide will be administered

Arms, Groups and Cohorts

• Experimental: Belantamab mafodotin+GSK3174998 dose exploration (Sub-study 1)
• Experimental: Belantamab mafodotin+feladilimab dose exploration (Sub-study 2)
• Experimental: Belantamab mafodotin+nirogacestat dose exploration(Sub-study 3)
• Experimental: Belantamab mafodotin+dostarlimab dose exploration(Sub-study 4)
• Experimental: Belantamab mafodotin+isatuximab dose exploration (Sub-study 5)
• Experimental: Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone dose exploration (Sub-study 6)
• Experimental: Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone dose exploration (Sub-study 7)
• Active Comparator: Belantamab mafodotin monotherapy cohort expansion
• Experimental: Belantamab mafodotin+GSK3174998 cohort expansion (Sub-study 1)
• Experimental: Belantamab mafodotin+ feladilimab cohort expansion (Sub-study 2)
• Experimental: Belantamab mafodotin+ nirogacestat cohort expansion (Sub-study 3)
• Experimental: Belantamab mafodotin+ dostarlimab cohort expansion (Sub-study 4)
• Experimental: Belantamab mafodotin+ isatuximab cohort expansion (Sub-study 5)
• Experimental: Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone cohort expansion (Sub-study 6)
• Experimental: Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone cohort expansion (Sub-study 7)

Clinical Trial Outcome Measures

Primary Measures

• DE Phase: Number of participants achieving dose limiting toxicities (DLT)
  • Time Frame: Up to 12 months
  • An event is considered to be a dose DLT if the event occurs within the first 21 days of treatment and meets the dose limiting toxicity criteria.
• DE Phase: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
  • Time Frame: Up to 12 months
  • AEs and SAEs will be collected.
• DE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters
  • Time Frame: Up to 12 months
  • Blood and urine samples will be collected to evaluate hematology, clinical chemistry and urinalysis lab parameters.
• CE Phase: Number of participants achieving Overall Response Rate (ORR)
  • Time Frame: Up to 36 months
  • ORR is defined as the percentage of participants with a Partial response (PR) or better, according to the International Myeloma Working Group (IMWG) Response Criteria.

Secondary Measures

• DE Phase: Number of participants achieving ORR
  • Time Frame: Up to 12 months
  • ORR is defined as the percentage of participants with PR or better, according to the IMWG Response Criteria.
• CE Phase: Number of participants achieving Clinical Benefit Rate (CBR)
  • Time Frame: Up to 36 months
  • CBR is defined as the percentage of participants with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.
• DE Phase: Number of participants achieving Partial Response (PR)
  • Time Frame: Up to 12 months
  • Number of participants with PR according to IMWG criteria will be analyzed.
• CE Phase: Number of participants achieving PR
  • Time Frame: Up to 36 months
  • Number of participants with PR according to IMWG criteria will be analyzed.
• DE Phase: Number of participants achieving Very Good Partial Response (VGPR)
  • Time Frame: Up to 12 months
  • Number of participants with VGPR according to IMWG criteria will be analyzed.
• CE Phase: Number of participants achieving VGPR
  • Time Frame: Up to 36 months
  • Number of participants with VGPR according to IMWG criteria will be analyzed.
• DE Phase: Number of participants achieving Complete Response (CR)
  • Time Frame: Up to 12 months
  • Participants with CR according to IMWG criteria will be analyzed.
• CE Phase: Number of participants achieving CR
  • Time Frame: Up to 36 months
  • Participants with CR according to IMWG criteria will be analyzed.
• DE Phase: Number of participants achieving stringent Complete Response (sCR)
  • Time Frame: Up to 12 months
  • Participants with sCR according to IMWG criteria will be analyzed.
• CE Phase: Number of participants achieving sCR
  • Time Frame: Up to 36 months
  • Participants with sCR according to IMWG criteria will be analyzed.
• DE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of belantamab mafodotin.
• CE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of belantamab mafodotin.
• DE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of GSK3174998.
• CE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of GSK3174998.
• DE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of feladilimab.
• CE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of feladilimab.
• DE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of nirogacestat.
• CE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of nirogacestat.
• DE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of dostarlimab.
• CE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of dostarlimab.
• DE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples will be collected for concentrations of isatuximab.
• CE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples will be collected for concentrations of isatuximab.
• DE Phase: Concentration of anti-drug antibodies (ADAs) against belantamab mafodotin when administered in combination with anti-cancer treatments
  • Time Frame: Up to 12 months
  • Blood samples for concentrations for ADAs will be collected.
• CE Phase: Concentration of ADAs against belantamab mafodotin when administered in combination with anti-cancer treatments
  • Time Frame: Up to 36 months
  • Blood samples for concentrations for ADAs will be collected.
• DE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples for concentrations for ADAs will be collected.
• CE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples for concentrations for ADAs will be collected.
• DE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples for concentrations for ADAs will be collected.
• CE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples for concentrations for ADAs will be collected.
• DE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples for concentrations for ADAs will be collected.
• CE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples for concentrations for ADAs will be collected.
• DE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 12 months
  • Blood samples for concentrations for ADAs will be collected.
• CE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin
  • Time Frame: Up to 36 months
  • Blood samples for concentrations for ADAs will be collected.
• DE Phase: Number of participants with adverse events of special interest (AESI) for belantamab mafodotin
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for belantamab mafodotin
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with AESI for GSK3174998
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for GSK3174998
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with AESI for Feladilimab
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for Feladilimab
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with AESI for Nirogacestat
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for Nirogacestat
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with AESI for Dostarlimab
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for Dostarlimab
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with AESI for Isatuximab
  • Time Frame: Up to 12 months
  • AESIs will be collected.
• CE Phase: Number of participants with AESI for Isatuximab
  • Time Frame: Up to 36 months
  • AESIs will be collected.
• DE Phase: Number of participants with abnormal ocular findings on ophthalmic examination
  • Time Frame: Up to 12 months
  • Ophthalmic examination will assess abnormal findings.
• CE Phase: Number of participants with abnormal ocular findings on ophthalmic examination
  • Time Frame: Up to 36 months
  • Ophthalmic examination will assess abnormal findings.
• CE Phase: Number of participants achieving Progression-free survival (PFS)
  • Time Frame: Up to 36 months
  • 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)
  • Time Frame: Up to 36 months
  • 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)
  • Time Frame: Up to 36 months
  • 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: Number of participants achieving Overall survival (OS)
  • Time Frame: Up to 36 months
  • OS is defined as the time from randomization until death due to any cause.
• CE Phase: Number of participants with AEs and SAEs
  • Time Frame: Up to 36 months
  • AEs and SAEs will be collected.
• CE Phase: Number of participants with AEs leading to discontinuation
  • Time Frame: Up to 36 months
  • Number of participants with AEs leading to discontinuation will be evaluated.
• CE Phase: Number of participants with dose reduction or delay
  • Time Frame: Up to 36 months
  • Number of participants with dose reduction or delay will be evaluated.
• CE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters
  • Time Frame: Up to 36 months
  • Blood and urine samples will be collected to evaluate hematology, clinical chemistry and urinalysis lab parameters.

Participating in This Clinical Trial

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 immunodilating 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 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 DNA undetectable during screening. – Participants who are currently receiving physiological doses oral steroids (<10 mg/day), inhaled steroids or ophthalmalogical steroids. Inclusion Criteria Specific to Sub-study 6 and 7: – Participants with contraception requirements specific to Sub-study 6 and 7 respectively. – 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. Additional Exclusion Criteria for Sub-study 1 and Sub-study 2: – Participants with autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. – Exclusion for a recent (within the past 6 months) history of symptomatic pericarditis. Additional Exclusion Criteria for Sub-study 3, 6 & 7: – 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. Additional Exclusion Criteria for Sub-study 4: – Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). – Participants who have received prior therapy with an anti-programmed death-1 (anti-PD-1), anti-PD-1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent. – Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Use of inhaled steroids, local injection of steroids, and steroid eye drops are allowed. Additional Exclusion Criteria for Sub-study 5: – 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. Additional Exclusion Criteria for Sub-study 6 and 7: – 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 antithrombolitic prophalaxis, Additional Exclusion Criteria for Sub-study 6: – Participants who discontinued prior treatment with lenalidomide due to intolerable adverse events Additional Exclusion Criteria for Sub-study 7: – Participants who discontinued prior treatment with pomalidomide due to intolerable adverse events

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • GlaxoSmithKline
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • GSK Clinical Trials, Study Director, GlaxoSmithKline
• Overall Contact(s)
  • US GSK Clinical Trials Call Center, 877-379-3718, GSKClinicalSupportHD@gsk.com