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)

INTERVENTION: Selumetinib, Orally bioavailable, selective inhibitor of MEK 1/2, inhibiting the phosphorylation of ERK 1/2 Patients will undergo 6 x 21‐day (3‐weekly) cycles of treatment. There is a screening visit following by visits every at the end of every cycle. In Phase I during cycle 1 there are weekly visits. Visits involve clinical examination, periodic clinical photographs of lesions, haematology/biochemistry, blood samples taken for translational studies. CT, ECHO or Multi Gated Acquisition Scan (MUGA). Ophthalmologic exam will occur during screening. Further assessments of this nature will only be performed if judged clinically necessary. Patients will have a follow‐up visit every 12 weeks for 12 months to record changes in lesions by clinical photographs. CONDITION: Topic: National Cancer Research Network, Infection; Subtopic: Sarcoma, Infection (all Subtopics); Disease: Soft Tissue, Infectious diseases and microbiology ; Cancer ; Kaposi's sarcoma PRIMARY OUTCOME: Objective response rates; Timepoint(s): Phase I and II SECONDARY OUTCOME: 1. HAART Drug Levels; Timepoint(s): Phase I; 2. HIV control; Timepoint(s): Phase I and II; 3. Number of selumetinib cycles completed; Timepoint(s): Phase I and II; 4. PBMC Sub‐study; Timepoint(s): Phase I and II; PD measures of selumetinib in combination with HAART; Timepoint(s): Phase I and II; 5. Progression free survival rate; Timepoint(s): Phase I and II ‐ 6 months post ccompletion of study; 6. Selumetinib and metabolite serum levels; Timepoint(s): phase I; 7. Toxicity; Timepoint(s): Phase I and II INCLUSION CRITERIA: 1. Human immunodeficiency virus (HIV) positive and established on a HAART regimen for >=3 months 2. Histologically confirmed KS 3. Measurable disease according to AIDS Clinical Trials Group (ACTG) criteria 4. Evidence of disease progression in the past 6 months, without anticancer treatment since progression 5. Progressive cutaneous or nodal KS not requiring chemotherapy or progressive KS following cytotoxic chemotherapy 6. Adequate haematological function: 6.1. Haemoglobin = 9 g/dL 6.2. Absolute neutrophil count = 1.5 x 10 9/L 6.3. Platelets = 100 x 10 9/L 7. Adequate hepatic function: 7.1. Serum bilirubin = 1.5 x upper limit of normal (ULN) 7.2. Alanine aminotransferase (ALT) = 2.5 x ULN 7.3. Aspartate aminotransferase (AST) = 2.5 x ULN 8. Adequate renal function: 8.1. Serum creatinine clearance > 50 ml/min (Cockcroft‐Gault formula or 24 hour urine collection) 8.2. Left ventricular function >50% normal 9. Age = 18 ye