mezagitamab (TAK-079)

P1, N=23, Completed, Millennium Pharmaceuticals, Inc. | N=58 --> 23 | Phase classification: P1b --> P1

P2, N=41, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting

P1/2, N=27, Terminated, Takeda | Phase classification: P1b/2 --> P1/2 | Active, not recruiting --> Terminated; Enrolment Challenges

P1, N=16, Active, not recruiting, Takeda | Phase classification: P1b --> P1

P1b/2, N=27, Active, not recruiting, Takeda | Recruiting --> Active, not recruiting | N=81 --> 27 | Trial completion date: Aug 2026 --> Nov 2023 | Trial primary completion date: Feb 2025 --> Aug 2023

P1b, N=50, Active, not recruiting, Takeda | Trial completion date: Mar 2023 --> Feb 2024 | Trial primary completion date: Mar 2023 --> Feb 2024

Daratumumab and isatuximab already received FDA approval, and novel agents such as MOR202, TAK079 and TNB-738 undergo clinical trials. Also, novel therapeutics such as SAR442085 aim to outrank the older antibodies against CD38...This review focuses on targeting CD38 in cancer and non-cancerous diseases using antibodies, cell-based therapies and CD38 inhibitors. We also provide a summary of current clinical trials targeting CD38.

P1b/2 | "The ability of TAK-981 to promote activation of macrophages and NK cells provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis; in vivo experiments have demonstrated synergistic activity between TAK-981 and rituximab, and between TAK-981 and the anti-CD38 mAbs daratumumab (dara) (Nakamura SITC 2020) or mezagitamab (meza; TAK-079; Figure 1). The iBOIN design selects the true maximum tolerated dose (if any) with high accuracy by allocating more patients to dose levels with a prior dose-limiting toxicity probability closest to the target of 0.3. This study is currently enrolling patients, with the first patient dosed in May 2021."

Conclusions Chronic treatment with mezagitamab is immunomodulatory in patients with RRMM, which is associated with reductions in tumor burden, subpopulations of B and T regulatory cells, and characterized by conventional NK and T cells exhibiting an activated, proliferative and effector phenotype. The immune landscape changes observed is consistent with the immunologic concept of converting the tumor microenvironment from cold-to-hot and highlights a key mechanistic effect of mezagitamab.

Daratumumab (Dara), a CD38-targeting antibody, can eliminate CD38 immune suppressor cells and is regarded as a standard therapy for MM because of its outstanding clinical efficacy. Other CD38 monospecific antibodies, such as isatuximab, MOR202, and TAK079, showed promising effects in clinical trials...There is convincing evidence that CD38-targeted immunotherapeutics reduce CD38 immune suppressor cells. This result suggests that CD38 can be exploited to treat solid tumors by regulating the immunosuppressive microenvironment.

PFS, with a median FU of 7.5 months at the data-cut off, is not estimable at the RP2 dose. Updated safety and efficacy data will be presented.

TAK-079 monotherapy is safe, generally well tolerated, and active in patients with RRMM through tested doses. Clinical activity occurred early and was durable. With no MTD identified, no IRRs, no significant hematologic toxicity, the RP2 dose is 600 mg.