CO43923: A Platform Study Evaluating the Safety and Efficacy of Multiple Treatment Combinations in Patients with Multiple Myeloma

Background: Multiple myeloma (MM) remains an incurable disease, with almost all patients eventually relapsing after initial therapy. Patients with relapsed/refractory MM require novel treatment options that are able to deliver deep and durable responses in later lines of therapy to improve treatment outcomes and prolong survival. Combination regimens that target disease-associated proteins and pathways are an important part of the treatment of MM. Novel immunotherapies, including immunomodulatory agents, bispecific antibodies, and chimeric antigen receptor T-cell therapies, have shown promising anti-myeloma activity as monotherapies, with preliminary data suggesting that regimens that combine these agents could further improve patient outcomes (Ghosh et al. Leuk Lymphoma 2018; Cohen et al. J Clin Invest 2019; Costa et al. Blood 2019; Raje et al. N Engl J Med 2019; Caraccio et al. Front Immunol 2020; Cohen et al. Blood 2020; Jagannath et al. Blood 2021; Martin et al. Curr Med Res Opin 2021). CO43923 is a Phase Ib/II platform study that will evaluate novel treatment combinations with new molecular entities and/or marketed products with differing mechanisms of action in individual substudies to identify early signals and establish proof-of-concept clinical data in patients with MM. The study is designed with the flexibility to open additional treatment substudies as new treatments become available and to close existing treatment substudies that demonstrate unacceptable toxicity or minimal clinical activity. Concurrent non-interventional substudies will collect patient level data on standard-of-care (SOC) MM therapies and aim to capture the heterogeneity of the patient population and treatment patterns across regions in a prospective and standardized fashion. An extensive collaboration program and a preclinical/translational platform will also be put in place to better understand the biology of the disease, its evolution, and emerging mechanisms of treatment resistance. This will in turn inform the combinatory strategy for the active treatment arms within the platform.

Study design and methods: CO43923 is a platform study composed of a Master Protocol and several independent substudies. The platform has no defined therapeutic backbone regimen, nor population of interest within MM, and substudies can be run with drugs in the Roche/Genentech portfolio and/or SOC therapies based on scientific rationale and an ever-evolving treatment landscape. The study has been designed to be fit for purpose and flexible in its development. The Master Protocol outlines general information for the study, while the substudies provide specific details and requirements for the individual treatment combinations. Most substudies will be signal-seeking Phase Ib studies that will generate safety and preliminary efficacy data on treatment combinations and will include a dose-escalation phase to ensure optimal dosing; this will be followed by an expansion phase to better characterize the overall safety profile. An optional Phase II study will be initiated for select combinations only and will use either a single-arm design or a randomized design with a comparator. Some substudies will be non-interventional and hence will not administer active treatments but rather collect patient-level data. The first active substudy will explore the combination of cevostamab, a T-cell engaging bispecific antibody targeting FcRH5 on myeloma cells and CD3 on T cells, and lenalidomide as a post-transplant maintenance therapy in patients with MM with high-risk cytogenetic features who experience a partial response (PR) or better after induction. The treatment arm is composed of a preliminary (dose-escalation) phase followed by an expansion phase. Patients must have completed an induction therapy and achieved a PR or better, have undergone an autologous stem cell transplant within 100 days of first dosing in the study, and have been shown to have one or more high-risk cytogenetic features at diagnosis (t(4;14), t(14;16), del(17p), or 1q gain). Further substudies are already planned and anticipated to be approved in the near future.

Sheikh:Roche: Current Employment. Patil:Roche/Genentech: Current Employment, Current equity holder in publicly-traded company. Wehrman:Pharmacovigilance consultant with LBC Pharmaceutical professionals on whose behalf I consulted at Adamas Pharma from Apr 2018 until Jul 2021, when I began consulting at Genentech. I was hired as a FTE at Genentech and started as an FTE on 18 Jul 2022.: Ended employment in the past 24 months; I own publicly traded mutual funds in my investment account (none are Genentech or Roche): Current equity holder in publicly-traded company; Genentech: Current Employment. Sideri:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Ruppert:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Yu:Genentech/Roche: Current Employment; Pfizer: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Pfizer, Roche: Current equity holder in publicly-traded company. Yan:Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Bhatti:Roche: Current Employment. Pogeza:Roche Pharma: Current Employment, Current holder of stock options in a privately-held company. Nouet:Roche Pharma: Current Employment.