Selumetinib in Combination with Anti Retroviral Therapy in HIV-associated Kaposi sarcoma (SCART): an open-label, multicentre, phase I/II trial.

Abstract

Background: Kaposi sarcoma (KS) is the commonest HIV-associated malignancy. It is caused by co-infection with Kaposi sarcoma herpesvirus (KSHV), which upregulates the MAPK pathway. The aim of the SCART trial was to identify a safe dose for the MEK inhibitor selumetinib in combination with antiretroviral therapy (ART) and to establish evidence of the combination's efficacy.

Methods: SCART was a prospective, single arm, open-label, multi-centre, phase I/II trial, recruiting from four UK centres. Eligible patients were HIV positive, established on an ART regimen ≥ 3 months, had HIV viral load ≤ 200/ml, and had histologically confirmed KS with progressive disease. Phase I primary outcomes were occurrence of dose limiting toxicity (DLT) to determine the maximum tolerated dose/recommended phase II dose (RP2D), and pharmacokinetic assessments of selumetinib and N-desmethyl metabolite. Phase II primary outcome was occurrence of objective response (OR) as defined by AIDS Clinical Trials Group (ACTG) criteria.

Results: Between 15-Jun-2012 and 25-Sep-2018, 19 patients were recruited; three did not start treatment and were not included in the final analysis. Ten eligible patients were treated in phase I and an additional six in phase II. There was one DLT at the 75 mg bd dose, which was deemed to be the RP2D. Of those patients receiving the RP2D (six within phase I, six within phase II), one achieved a partial response (OR 8.3%, 90% confidence interval: 0.4, 33.9). Further to the DLT, two serious adverse reactions, one unrelated serious adverse event (AE), and six non-serious grade 3 AEs were reported, together with 360 AEs graded 1 or 2. No detrimental impact on ART drug levels or HIV viral load were observed, with improvements in CD4 count and evidence of response in Angiopoietin-2 demonstrated.

Conclusions: SCART was closed early due to slow recruitment, partly due to the rarity of KS because of improvements in HIV care, but also due to patients' concerns about experiencing non-serious toxicity additional to those from ART. Although we cannot recommend the use of 75 mg bd selumetinib with ART in patients with HIV-associated KS, studies exploring selumetinib in combination with other agents including anti-angiogenic agents and/or immune checkpoint inhibitors are warranted.

Trial registration: ISRCTN24921472.