Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide...Modakafusp alfa is an immunocytokine that targets interferons to CD38+ cells. It has demonstrated single agent activity in relapsed/refractory MM in the phase 1 setting.
Follow-up analyses of the correlation of biomarkers with clinical response are in progress and will be presented. Further clinical trials are underway (iinnovate-2, NCT05556616; iinnovate-3, NCT05590377) to evaluate moda's novel immune activating mechanism in combination with standard of care anti-myeloma therapies.
1 year ago
Clinical • P1/2 data • PD(L)-1 Biomarker • IO biomarker
Both patients had hemodialysis & eculizumab while inpatient & are continuing on hemodialysis on an outpatient basis. Both patients were recently started on carfilzomib & modakafusp alfa, a relatively new phase I/II clinical trial. Case reports of aHUS/TMA from carfilzomib do exist, however. We conclude that it is reasonable to perform genetic testing prior to initiating treatment with modakafusp alfa +/- carfilzomib, to mitigate the risk of aHUS/TMA as seen in our two patients.
As moda and daratumumab (dara) do not bind to the same epitope, they may have complementary mechanisms of action; furthermore, moda has been shown to increase CD38 expression on immune and MM cells. In the phase 2 iinnovate-1 extension study (NCT03215030), pts are randomized to receive moda 120 mg or 240 mg every four weeks to define the single-agent dose with the optimal benefit/risk profile in pts with ≥3 prior lines of therapy (LoT) who are at least triple-class refractory (to an IMiD, a PI, and an anti-CD38 mAb)...In group 1, moda is combined with lenalidomide (len) as post-transplant maintenance therapy... The ongoing iinnovate-1-2-3 studies are assessing the optimal dose of moda as a single agent and as part of doublet and triplet combinations with SOC agents for different MM pt populations, including those with high unmet medical needs.
iinnovate-3 (NCT05590377) is a phase 1/2a study to evaluate the safety, tolerability, and preliminary efficacy of moda in combination with dara SC...Two dose levels of moda in combination with dara will be selected for phase 2a optimal dose finding in pts who have received 1–3 prior lines and are refractory to lenalidomide and sensitive (non-refractory) or naïve to an anti-CD38 mAb... The iinnovate-1-2-3 studies plan to determine the optimal dose of moda as a single agent and in doublet and triplet combinations with SOC agents for different MM pt populations, including pts with the highest unmet medical needs. Interferon alpha, Multiple myeloma, Innate Immunity, Cancer immunotherapy
As dexamethasone (dex) is part of standard of care in MM, but could counteract the immune activation elicited by modakafusp, additional cohorts at 0.4 mg/kg Q3W and 1.5 mg/kg Q4W in combination with 40 mg dex QW were opened. Conclusions Modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging anti-myeloma activity at 1.5 mg/kg Q4W, independent of peripheral blood immune cell CD38 expression. A randomized phase 2 study to compare fixed-dose levels of 120 and 240 mg (equivalent to 1.5 and 3.0 mg/kg) Q4W and to define the single-agent dose with the optimal benefit/risk profile is currently enrolling.
This important MoA also results in improved efficacy of daratumumab or elotuzumab in short-term cytotoxicity assays. Our findings warrant clinical investigation of combining modakafusp alfa with NK cell-exploiting immunotherapies.
2 years ago
IO biomarker
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CD69 (CD69 Molecule) • SLAMF7 (SLAM Family Member 7)
Furthermore, modakafusp alfa binds to a different epitope on CD38 than the currently approved anti-CD38 therapeutic mAbs, daratumumab and isatuximab. Modakafusp alfa (TAK-573) is a novel candidate for the treatment of RRMM, which has shown promising anti-myeloma activity in heavily pretreated pts, including anti-CD38 mAb-refractory pts and those who have received an anti-CD38 mAb in their most recent line of treatment. A Q4W dosing schedule of modakafusp alfa is feasible and the optimal dose and potential combinations are being explored.
TAK-573 binds to a site on CD38 that is distinct from the binding sites of currently available therapeutic antibodies, and therefore does not compete for binding with daratumumab or isatuximab. TAK-573 is a clinically and pharmacologically active molecule that mediates IFNAR pathway modulation and leads to myeloma responses. Additional biomarker data is being collected to further refine the MOA, which will inform the recommended phase 2 dose, optimal schedule of administration, and rational development of TAK-573.
Proposed Mechanism of Action of TAK-573 Conclusions These preliminary biomarker data indicate that TAK-573 is a pharmacologically active molecule that mediates its effect through IFNAR pathway modulation. Additional data are being collected to further refine the mechanism of action (Image 1), which will inform the recommended phase 2 dose and optimal schedule of administration for the development of TAK-573.
4 years ago
Clinical • IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD38 (CD38 Molecule) • GZMB (Granzyme B) • IFNAR1 (Interferon (alpha, beta and omega) receptor 1)
Proposed Mechanism of Action of TAK-573 Conclusions These preliminary biomarker data indicate that TAK-573 is a pharmacologically active molecule that mediates its effect through IFNAR pathway modulation. Additional data are being collected to further refine the mechanism of action (Image 1), which will inform the recommended phase 2 dose and optimal schedule of administration for the development of TAK-573.
4 years ago
Clinical • IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD38 (CD38 Molecule) • GZMB (Granzyme B) • IFNAR1 (Interferon (alpha, beta and omega) receptor 1)
Administration of mCD38-mATT induced broad immunomodulation and antitumor responses, alone and in combination with SOC agents in immunocompetent mouse models, highlighting the impact of this agent on CD38+ cells, both tumor and immune. These results support further investigation of combination therapies in the ongoing clinical evaluation of TAK-573 in a Phase 1 trial in patients with relapsed refractory MM.