Results from a phase I study of VLX1570 for patients with relapsed/refractory multiple myeloma

The discovery of proteasome inhibitors (PIs) was a significant landmark in the treatment of multiple myeloma (MM) and other plasma cell dyscrasias. Bortezomib, carfilzomib and ixazomib are all PIs used routinely to treat patients with MM and work by inhibiting the 20S proteasome subunit.^1,2 Myeloma cells are particularly sensitive to proteasome inhibition, but resistance to these agents remains a hurdle. In light of this, agents targeting alternative proteasomal sites and pathways are being pursued.¹

Prior to degradation, proteins undergo conformational and physical changes so to facilitate entry in to the tightly gated 20S subunit. Deubiquitinase (DUBs) act at the 19S subunit to remove bulky ubiquitin side chains that hinder protein entry into the degradation site. The small molecule agent, VLX1570, inhibits the activity of DUBs, thereby expediting the accumulation of ubiquitin conjugates and, ultimately, causing cell death. A number of pre-clinical studies have highlighted the anti-tumor effect of VLX1570 in orthotopic and xenograft models of MM, lymphoma and Ewing sarcoma. Furthermore, VLX1570 has demonstrated activity in MM cells derived from patients with bortezomib-resistant disease.¹

Eric K Rowinsky, Vivolux AB, Uppsala, SE, and co-investigators aimed to characterize the safety, tolerability, and pharmacokinetic profile of VLX1570 in patients with relapsed and/or refractory (R/R) MM (RRMM). The results of the phase I study (NCT02372240) were recently published in Investigational New Drugs and we hereby present a summary of the safety and efficacy data.¹

Study design

• Primary objective: determine the maximum tolerated dose (MTD) and recommended phase II dose of VLX-1570
• Secondary objectives: characterize the adverse event (AE) and safety profile, pharmacokinetic behavior and evaluate preliminary anti-cancer activity

Patient eligibility

• Adult patients with RRMM (N = 15) following treatment with ≥ 1 immunomodulatory drug (IMiD®), and ≥ 1 PI were enrolled from five sites across the United States and Finland
• Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and measurable disease defined as ≥ 1 of:
  • Serum monoclonal protein ≥ 0.5 g/dL
  • Urine monoclonal protein > 200 mg / 24 hours and/or
  • Serum immunoglobulin free light chain (FLC) > 10 mg/dL and abnormal kappa/lambda FLC ratio (reference range, 0.26–1.65)
• Median patient age was 65 years (range: 46–78)
• Patients received an average of five prior therapies, but this ranged from 2–14
• 93% had received at least two prior PIs and 100% were double refractory to a PI and IMiD

Treatment

• Of the 15 enrolled patients, one patient withdrew from the study due to significant neutropenia prior to VLX1570 treatment; the dosing cohorts for the remaining 14 patients are illustrated in Table 1
  • Patients received a pre-medication regimen of:
    • Dexamethasone 20 mg oral/intravenous (IV)
    • H₁-histamine antagonist (diphenhydramine 50 mg oral/IV or equivalent)
    • H₂-antagonist (cimetidine 300 mg oral/IV, ranitidine 50 mg oral/IV, or famotidine 20 mg IV)
  • VLX1570 was administered IV over 10–30 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle

Table 1. Dose escalation schedule of VLX1570

DLT, dose-limiting toxicity
Cohort number	Number of patients enrolled	Dose level	Dose (mg/kg)	Number of treated patients	Number of cycles	Number of patients with DLT
1	4	1 2 3	0.05 0.15 0.30	4 4 4	4 4 8	0 0 0
2	8	3 4	0.30 0.60	8 3	8 8	0 0
3	2	5 6	1.2 2.0	2 -	2 -	2 -

Results

Safety

• Cohorts 1 and 2:
  • Three patients from each cohort were evaluable for toxicity
  • The remaining patients were withdrawn from the study due to progressive disease
  • Minimal adverse events (AEs) were observed, those possibly related to the study drug included grade 1–2 fatigue, rash, nausea, and anemia
  • No dose-limiting toxicities (DLTs) were reported
• Cohort 3:
  • Both patients developed fatal pulmonary toxicity within days of receiving two doses of VLX-1570 at 1.2 mg/kg (Table 2)

Table 2. Serious adverse events observed in patients in cohort 3

Auto-SCT, autologous stem cell transplant; CT, computerized tomography; FLC, free light chain; PIs, proteasome inhibitors, SAEs, severe adverse events *In both patients, multi-organ failure occurred on Day 10
	Patient one	Patient two
Age, years	58	75
Sex	Female	Male
Previous treatments	Four PIs Auto-SCT	PIs: bortezomib and carfilzomib Daratumumab Auto-SCT
SAEs	Severe pulmonary event, with cough, fever, dyspnea, hypoxia, diffuse bilateral ground glass opacities on CT. Transfusion-dependent anemia and thrombocytopenia	Progressively worsening dyspnoea, hypoxia and cough with bilateral lung infiltrates on CT. Transfusion-dependent anemia, thrombocytopenia
Treatment	Broad spectrum antibiotics, antifungals and high-dose corticosteroids	Mechanical ventilation, broad-spectrum antibiotics, high-dose corticosteroids
Endpoint*	Multi-organ failure and death	Multi-organ failure and death

 Efficacy

• Anti-myeloma effects were observed at doses ≥ 6 mg/kg however the two study deaths occurred at a dose of 1.2 mg/kg leading to study termination before efficacy could be elucidated further
• One patient in cohort 2 demonstrated improved functionality as well as a reduction in various MM indicators, consistent with stable disease, following four cycles of VLX1570, one at 0.30 mg/kg and three at 0.60 mg/kg

Conclusions

VLX1570 showed modest anti-myeloma effects in patients with RRMM however at doses where potential anti-tumor effects were beginning to be noted, two study-related deaths due to severe lung toxicity occurred and resulted in discontinuation of the trial.

The authors note that the formulation of VLX1570 may have contributed to the severe lung toxicity, though the components are not known to cause such effects. A rat model of VLX1570-induced lung toxicity has been developed which is being used to understand the mechanisms of VLX1570-induced lung toxicity with an aim of identifying DUB inhibitors with a higher specificity for tumor cells than lung tissue.

Due to the unique mechanism of action, the ability of DUB inhibitors to overcome PI resistance, and modest efficacy, further efforts to develop and assess these novel agents in MM are justified.