A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis

Abstract

Janus kinase 2 (JAK2) inhibitors such as ruxolitinib have become standard-of-care therapy for patients with myeloproliferative neoplasms (MPNs); however, activation of alternate oncogenic pathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has limited durable response as single-agent therapy. With the rationale of targeting both pathways, we conducted a phase I dose escalation trial of pevonedistat in combination with ruxolitinib for the treatment of patients with myelofibrosis (NCT03386214). The primary objective was to assess the safety and tolerability of combination therapy with additional objectives of treatment efficacy and alterations of biomarkers. There were no dose-limiting toxicities observed with most adverse events being limited to grades 1/2. In secondary measures, anemia response was observed in two patients. Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

Keywords: JAK2; MLN4924; NFκB; clinical trial; myeloproliferative neoplasms; pevonedistat; ruxolitinib.

Figure 1.

Outcome measures to study drug combination. (a) Flow chart of patient enrollment and for outcome measure analysis. (b) Spleen volume responses at study end-point relative to baseline assessed by ultrasound. (c) Variant allele frequencies by sequencing panel of peripheral blood mononuclear cells throughout treatment. (d) Plasma levels of pro-inflammatory cytokines throughout drug treatment. (e) Iron parameters in plasma throughout drug treatment.