SG301, a Novel Anti-CD38 Monoclonal Antibody, in Patients with Relapsed/Refractory Multiple Myeloma: A First-in-Human, Multicentre, Phase 1 Trial

Background: Anti-CD38 monoclonal antibody-containing regimens have changed the treatment paradigm for patients with multiple myeloma (MM). SG301 is a novel humanized IgG1-kappa monoclonal antibody that binds CD38 via a unique epitope distinct from that of other anti-CD38 antibodies including daratumumab and isatuximab. Comparing with daratumumab, SG301 exhibits enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. Meanwhile, SG301 does not induce complement dependent cytotoxicity (CDC) which is suspected to contribute to the toxicities, especially the infusion related reactions (IRR). In the in vivo studies, SG301 demonstrated superior anti-tumor activity when compared to daratumumab. Methods: This is a first-in-human, multicenter, open label Phase 1 study to evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of SG301 in relapsed/refractory multiple myeloma (RRMM) patients. This study consists of a dose-escalation part (phase 1a) and a dose-expansion part (phase 1b). The patients who had been treated with proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) previously and be relapsed/refractory to prior therapies would be eligible to the study. In the dose escalation part (phase 1a), the eligible patients were treated with SG301 at doses of 0.005, 0.05, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 16.0 mg/kg in ascending order. SG301 was administered intravenously once weekly for the first 8 weeks, then every 2 weeks onwards until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed over first 28 days following the first infusion. The selected dosage of SG301 for phase 1b were 4.0, 8.0, and 12.0 mg/kg, respectively, based on the PK, PD (CD38 receptor occupancy), safety and efficacy data. DLTs and adverse events (AEs) were assessed per NCI-CTCAE v5.0. Tumor response was assessed according to IMWG 2016 criteria in the efficacy-evaluable population (all subjects receiving at least 1 cycle of treatment and 2 post dose evaluations). PD markers include CD38 receptor occupancy, isotypes of immunoglobin, and immune cell phenotyping. Results: As of March 7, 2024, 61 RRMM patients were enrolled in the trial, with 23 in phase 1a and 38 in phase 1b. Median age was 64 years (range 42-78). Subjects have received a median of 4 prior treatment regimens (range 1-10). All subjects were relapsed or refractory to both PIs and IMiDs. The maximum tolerated dose was not reached, and no DLTs were observed. The most frequent (≥20%) treatment related AEs (TRAEs) were leukopenia (37.7%), neutropenia (34.4%), IRR (26.2%), and thrombocytopenia (26.2%). All IRRs were grade 1/2 and mainly occurred during the first infusion. ≥5% grade 3 or higher TRAEs were lung infection (16.4%), lymphopenia (8.2%), neutropenia (8.2%), and thrombocytopenia (6.6%). There was 1 grade 4 TRAE (thrombocytopenia) and no grade 5 TRAE occurred. Serious adverse reactions were reported in 6 subjects (9.8%) with lung infections, and one of them also experienced urinary tract infections and diarrhea. 1 subject discontinued treatment due to AEs, which was grade 3 lung infection related to SG301. As for anti-tumor efficacy, partial response (PR) or better response started to be observed through 2 mg/kg and above dose levels. Among the 13 efficacy-evaluable subjects without extramedullary multiple myeloma who received SG301 at 8 mg/kg (the recommended phase 2 dose), overall response rate was 30.8%, ≥ very good partial response (VGPR) rate was 23.1%. Median duration of response (DoR) was not reached yet. As of data cutoff (median follow up of 8.4 months), except for one VGPR subject in the 8 mg/kg dose group who had disease progression (remission lasting for about 7 months), all other responders are still under remission and continuing treatment, with the longest one having been in remission for about 17.5 months. Occupancy of CD38 receptor increased with increasing doses. SG301 8 mg/kg and above can keep the target occupancy saturated (≥90%). Conclusion: SG301 is an innovative anti-CD38 antibody targeting unique epitope. The monotherapy with SG301 was well tolerated with favorable hematological toxicities and IRR. SG301 8 mg/kg demonstrated preliminary promising clinical efficacy with the target occupancy continuously saturated. Further studies are ongoing and planned.