Contributions
Abstract: PB1698
Type: Publication Only
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Single-agent belamaf (GSK2857916, BLENREP), a B-cell maturation antigen–targeting antibody-drug conjugate, induced durable responses in patients with RRMM, with a manageable safety profile with 13 months of follow-up (DREAMM-2; NCT03525678). The unique multimodal mechanisms of action (MoAs) of belamaf in combination with MoAs of selected agents, have the potential to achieve synergistic effects in RRMM to further enhance the benefit-risk profile. The DREAMM-5 study (NCT04126200), a platform trial, allows for efficient evaluation of belamaf in combination with other anti-tumor agents, including a humanized wild-type immunoglobulin (Ig)G1 anti-OX40 agonist, an IgG4-inducible T-cell co-stimulator (ICOS) agonist (feladilimab), a gamma-secretase inhibitor (nirogacestat), a humanized programmed cell death (PD)-1 antagonist (dostarlimab), and a humanized wild-type IgG1 CD38 antagonist (isatuximab).
Aims
.
Methods
DREAMM-5 is a Phase I/II study that utilizes a master protocol with separate sub-studies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases, to identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only). The DE phase consists of multiple dosing cohorts with belamaf combinations in which patients are assigned to treatment slots by a predetermined algorithmic approach (N≤10 per cohort). A recommended Phase II dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in the DE phase. At the end of the DE phase, an interim analysis of safety, pharmacokinetic, biomarker, and efficacy data will also be performed for each sub-study treatment combination to determine whether the combination should move forward at the RP2D to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a sub-study, and within a sub-study to either combination treatment or the belamaf monotherapy control arm shared across sub-studies; patients will also be stratified by number of prior therapies. Eligible patients will have RRMM and will have received ≥3 prior therapy lines, which includes a prior immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody; all patients will provide informed consent for participation. The primary objectives of the study are to identify the RP2D (DE phase) and the overall response rate (≥partial response, CE phase), along with safety and tolerability, for each combination treatment.
Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment. Sub-study 5 (combination with isatuximab [Sanofi], CD38 antagonist antibody) will be open to enrollment soon. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination data available.
Results
.
Conclusion
.
Funding: GSK (Study 208887, NCT04126200); belamaf drug linker technology licensed from Seagen Inc; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics and isatuximab produced by and used in collaboration with Sanofi.
Keyword(s): B-cell maturation antigen, Clinical trial, Multiple myeloma
Abstract: PB1698
Type: Publication Only
Session title: Myeloma and other monoclonal gammopathies - Clinical
Background
Single-agent belamaf (GSK2857916, BLENREP), a B-cell maturation antigen–targeting antibody-drug conjugate, induced durable responses in patients with RRMM, with a manageable safety profile with 13 months of follow-up (DREAMM-2; NCT03525678). The unique multimodal mechanisms of action (MoAs) of belamaf in combination with MoAs of selected agents, have the potential to achieve synergistic effects in RRMM to further enhance the benefit-risk profile. The DREAMM-5 study (NCT04126200), a platform trial, allows for efficient evaluation of belamaf in combination with other anti-tumor agents, including a humanized wild-type immunoglobulin (Ig)G1 anti-OX40 agonist, an IgG4-inducible T-cell co-stimulator (ICOS) agonist (feladilimab), a gamma-secretase inhibitor (nirogacestat), a humanized programmed cell death (PD)-1 antagonist (dostarlimab), and a humanized wild-type IgG1 CD38 antagonist (isatuximab).
Aims
.
Methods
DREAMM-5 is a Phase I/II study that utilizes a master protocol with separate sub-studies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases, to identify promising, effective belamaf combinations when compared with a shared single-agent belamaf control arm (CE phase only). The DE phase consists of multiple dosing cohorts with belamaf combinations in which patients are assigned to treatment slots by a predetermined algorithmic approach (N≤10 per cohort). A recommended Phase II dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in the DE phase. At the end of the DE phase, an interim analysis of safety, pharmacokinetic, biomarker, and efficacy data will also be performed for each sub-study treatment combination to determine whether the combination should move forward at the RP2D to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a sub-study, and within a sub-study to either combination treatment or the belamaf monotherapy control arm shared across sub-studies; patients will also be stratified by number of prior therapies. Eligible patients will have RRMM and will have received ≥3 prior therapy lines, which includes a prior immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody; all patients will provide informed consent for participation. The primary objectives of the study are to identify the RP2D (DE phase) and the overall response rate (≥partial response, CE phase), along with safety and tolerability, for each combination treatment.
Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment. Sub-study 5 (combination with isatuximab [Sanofi], CD38 antagonist antibody) will be open to enrollment soon. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination data available.
Results
.
Conclusion
.
Funding: GSK (Study 208887, NCT04126200); belamaf drug linker technology licensed from Seagen Inc; belamaf monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa; nirogacestat gamma-secretase inhibitor produced by and used in collaboration with SpringWorks Therapeutics and isatuximab produced by and used in collaboration with Sanofi.
Keyword(s): B-cell maturation antigen, Clinical trial, Multiple myeloma