Cancer-selective targeting of the NF-κB pathway via GADD45β/MKK7 inhibition: Results from the phase I trial of the first-in-class inhibitor, DTP3, in patients with relapsed or refractory multiple myeloma

Abstract

Abstract Background: NF-κB transcription factors are major drivers of multiple myeloma (MM) aetiopathogenesis, malignant cell survival, and therapy resistance. However, developing clinically useful IκB kinase (IKK)/NF-κB inhibitors has not proven possible, due to the preclusive toxicities of systemic NF-κB blockade. To overcome this problem, we developed a targeted approach that disrupts the essential, cancer-specific survival module GADD45β/MKK7 – located downstream of NF-κB – rather than NF-κB itself [PMID:25314077]. This strategy led to the development of the first-in-class GADD45β/MKK7 inhibitor, DTP3, which selectively kills human MM cells via MKK7/JNK-dependent apoptosis ex vivo and in vivo and is not toxic to normal cells [PMID:25314077; PMID:31080744]. Here, we report the results of a Phase I, multi-centre dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of DTP3 monotherapy in patients with relapsed or refractory MM and diffuse large B-cell lymphoma (DLBCL; EudraCT: 2021-004028-13). Methods: Since May 2022, 16 patients provided informed consent, and 14 were enrolled (13 with MM and 1 with DLBCL). At study entry, median age was 64 years, and all patients had progressive disease, after receiving a minimum of 4 previous lines of therapy (median 5.5; range 4–11). Six MM patients (46.15%) had triple-refractory disease, and high-risk features, such as adverse cytogenetics, elevated serum LDH, or extramedullary disease, were present in 8 MM patients (57.1%). Dose escalation followed a 1-patient per dose-level study design, unless a dose-limiting toxicity (DLT) occurred. DTP3 was administered intravenously on days 1, 3, and 5 of each week in 28-day cycles, over an overall range of escalating doses from 0.5 to 67 mg/kg of body weight. The minimum evaluable duration of treatment was 1 cycle, and median treatment duration was 58 days (range 29-142 days). Adverse events (AEs) were graded by CTCAE v5.0 criteria, and clinical responses were assessed by IMWG criteria. PD responses were evaluated by measuring JNK activation and apoptosis in CD138+ plasma cells post-treatment compared to baseline, using flow cytometry. For PK analysis, plasma samples were collected on Cycle 1, Day 1 (C1D1) at baseline up to 24 hours post-dosing and, further, on Cycle 1, Day 6 (C1D5) at baseline up to 4 hours post-dosing. Results: The best observed clinical response was a Very Good Partial Response (VGPR) in the single MM patient treated at 30 mg/kg; stable disease was observed in 6 patients (46.15%), and progressive disease was observed in a further 6 patients (46.15%). Duration of the VGPR was 109 days. The dose was escalated to 45 mg/kg for 4 weeks before treatment discontinuation, due to disease progression. No haematological toxicity was observed in any of the study participants. Grade 3 non-haematological AEs included hypotension and (pre-)syncope in the 2 patients treated at 67 mg/kg, fulfilling the DLT criteria. Grade 3 self-limiting QTc prolongation post-treatment was observed in 2 patients. In total, 42 treatment-related AEs Grade 1-2 were recorded, most commonly dysgeusia and/or perioral dysesthesia (n=15), dizziness (n=6), and QTc interval prolongation (n=6). On the basis of the toxicity data, the Continual Reassessment Method (CRM) identified 45 mg/kg as the Maximum Tolerated Dose (MTD). Mechanistically consistent PD responses of varying degree – i.e., selective induction of JNK activation and apoptosis in MM cells, with no drug-related responses in normal cells – were observed in about 50% of patients. PK analyses demonstrated a favourable clinical profile across patients at doses ranging from 0.5 to 67 mg/kg, confirming linearity of plasma exposure (AUC) and maximum plasma concentration (Cmax) with dose level and no accumulation upon repeated administration. The median plasma half-life was 8.1 hours (range 5.5-11.1 hours). Conclusions: In summary, DTP3 exhibited a favourable PK, PD, safety, and initial efficacy profile upon intravenous administration at doses up to 45 mg/kg. A VGPR was observed in the patient treated at 30 mg/kg, and the cumulative PD and initial efficacy signals suggest broad clinical activity. A Phase IIA dose-expansion study is ongoing to further evaluate the safety and clinical activity of DTP3 in patients with relapsed or refractory MM and DLBCL, alongside development of predictive biomarkers for patient stratification.