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

GlaxoSmithKline (GSK)

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Multiple Myeloma

Treatments: Drug: GSK3174998; Drug: Pomalidomide; Drug: Nirogacestat; Drug: Dostarlimab; Drug: Feladilimab; Drug: Lenalidomide; Drug: Isatuximab; Drug: Belantamab mafodotin; Drug: Dexamethasone

Study type: Interventional

Funder types: Industry

Identifiers

NCT04126200

208887

2023-509550-55-00 (EU Trial (CTIS) Number)

Details and patient eligibility

About

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.

Enrollment: 208 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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 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 and7:

• 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.
• Participants with Known 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/mL b) CD4+ T-cell (CD4+) counts >= 350 cells/microliter (µL) c) No history of AIDS-defining opportunistic infections within the last 12 months in which case the participant would be eligible for CE Phase only.

For patients receiving nirogacestat, HIV drugs that are strong 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.

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 and 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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208 participants in 15 patient groups

Belantamab mafodotin+GSK3174998 dose exploration (Sub-study 1)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: GSK3174998

Belantamab mafodotin+feladilimab dose exploration (Sub-study 2)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Feladilimab

Belantamab mafodotin+nirogacestat dose exploration(Sub-study 3)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Nirogacestat

Belantamab mafodotin+dostarlimab dose exploration(Sub-study 4)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Dostarlimab

Belantamab mafodotin+isatuximab dose exploration (Sub-study 5)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Isatuximab

Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone dose exploration (Sub-study 6)

Experimental group

Treatment:

Drug: Dexamethasone

Drug: Belantamab mafodotin

Drug: Lenalidomide

Drug: Nirogacestat

Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone dose exploration (Sub-study 7)

Experimental group

Treatment:

Drug: Dexamethasone

Drug: Belantamab mafodotin

Drug: Nirogacestat

Drug: Pomalidomide

Belantamab mafodotin monotherapy cohort expansion

Active Comparator group

Treatment:

Drug: Belantamab mafodotin

Belantamab mafodotin+GSK3174998 cohort expansion (Sub-study 1)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: GSK3174998

Belantamab mafodotin+ feladilimab cohort expansion (Sub-study 2)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Feladilimab

Belantamab mafodotin+ nirogacestat cohort expansion (Sub-study 3)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Nirogacestat

Belantamab mafodotin+ dostarlimab cohort expansion (Sub-study 4)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Dostarlimab

Belantamab mafodotin+ isatuximab cohort expansion (Sub-study 5)

Experimental group

Treatment:

Drug: Belantamab mafodotin

Drug: Isatuximab

Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone cohort expansion (Sub-study 6)

Experimental group

Treatment:

Drug: Dexamethasone

Drug: Belantamab mafodotin

Drug: Lenalidomide

Drug: Nirogacestat

Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone cohort expansion (Sub-study 7)

Experimental group

Treatment:

Drug: Dexamethasone

Drug: Belantamab mafodotin

Drug: Nirogacestat

Drug: Pomalidomide