A study of selumetinib in patients with Kaposi’s sarcoma
Research type
Research Study
Full title
Phase I/II study of oral MEK inhibitor Selumetinib (AZD6244 Hyd-Sulphate) in Combination with Highly Active Anti-Retroviral Therapy (HAART) in AIDS-associated Kaposi’s sarcoma (KS).
IRAS ID
82708
Contact name
Robin Young
Contact email
Sponsor organisation
Sheffield Teaching Hospitals NHS Foundation Trust
Eudract number
2011-003099-35
Duration of Study in the UK
5 years, 10 months, 30 days
Research summary
Summary of Research
Cancer is a leading cause of death in individuals living with HIV, and Kaposi's sarcoma (KS) remains the commonest HIV-associated cancer. KS results from co-infection with HIV and another virus, HHV-8. Laboratory studies have shown that HHV-8 viral proteins stimulate intracellular signalling pathways within KS lesions which promotes their growth. Selumetinib targets these signalling pathways and may therefore be a useful new therapy for KS.SCART is a national multi-centre study. The objectives of the SCART trial are to determine a safe and tolerable dose for selumetinib in combination with HIV anti-retroviral therapy, and to determine whether selumetinib reduces KS lesions in HIV positive patients.
Summary of Results
In the SCART clinical trial (ISRCTN24921472), patients with human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS) were treated with a drug, Selumetinib (AZD6244), in addition to their usual Highly Active Anti-Retroviral Therapy (HAART). HAART is used to treat patients infected with HIV. Selumetinib inhibits MEK 1/2, an important enzyme (a protein that acts on other molecules changing their structure and activity) that regulates cell growth and division and is overactive in many cancers including KS. The combination of Selumetinib with HAART had not been tested before or in KS, so this phase I/II trial was trying to work out a safe dose of Selumetinib to give to patients with HIV-associated KS who take HAART and to assess effectiveness.Between 15-Jun-2012 and 29-Apr-2015, 19 patients, were recruited to SCART from four hospitals across the United Kingdom: Sheffield, Brighton, London, and Manchester. Recruitment to the SCART Trial was very difficult due to the rarity of KS, but also because several potential patients declined study entry due to their concerns about the risk of experiencing additional side effects with Selumetinib on top of those of HAART. As a result, a decision to close the trial to recruitment was made on 31st December 2016.
Of the 19 patients recruited, 13 entered the phase I part of the trial with five patients receiving 50mg Selumetinib twice a day. Four of these patients received enough treatment to be considered evaluable, and none of these patients experienced serious side effects. Eight patients then received a dose of 75mg Selumetinib twice a day, six of these patients received enough treatment to be considered evaluable, of which one patient experienced a serious side effect. The dose of 75mg Selumetinib twice a day was then carried forward to the phase II part of the trial and a further six patients received this dose. Therefore, a total of 12 patients received the phase II dose of 75mg Selumetinib twice a day.
In the phase II part of the trial, the primary outcome measure was to look at how effective the new combination was in controlling the patient’s KS following up to six cycles of treatment. Only one patient achieved a partial response i.e., their KS had reduced in size by >50%. Eight patients recorded stable disease and two patients reported their disease got worse. Due to the limited amount of response data, no further analyses were feasible.
There were few serious (grade 3 or 4) side effects, but all patients experienced multiple non-serious (grade 1 or 2) side effects, and six of the 16 evaluable patients discontinued treatment before completing the planned six cycles of treatment. This suggested that these numerous side effects were not acceptable to patients. Therefore, in hindsight the lower dose of Selumetinib of 50 mg twice a day may have been a more acceptable dose to test in the phase II part of the trial.
Importantly, HIV remained controlled in all patients within the SCART trial, with the number of immune cells increasing overall during Selumetinib treatment.In conclusion, no definitive answer on the effectiveness of Selumetinib in combination with HAART in patients with HIV-associated KS can be drawn. Unfortunately, due to the rarity of KS, further investigation of Selumetinib is unlikely in this disease.
REC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
11/YH/0373
Date of REC Opinion
10 Nov 2011
REC opinion
Further Information Favourable Opinion