A Study of Selumetinib in Patients With Kaposi's Sarcoma

Cancer is a leading cause of death in individuals living with human immunodeficiency virus (HIV), and Kaposi's sarcoma (KS) remains the commonest HIV-associated cancer. KS is caused when individuals become infected with both HIV and another virus, Human herpesvirus-8 (HHV-8). Laboratory studies have shown that HHV-8 can stimulate biological pathways within KS lesions which promotes their growth. Selumetinib targets these pathways and may therefore be a useful new therapy for KS. Phase I of this trial aims to identify the best dose for the use of selumetinib and investigate the effects of selumetinib treatment on the anti-viral treatment HIV patients receive to control HIV infection. Phase II of this trial will investigate how well selumetinib works as a treatment for KS at the best dose determined in phase I.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Histologically confirmed KS.
* Measurable disease according to ACTG criteria.
* Evidence of disease progression in the past 6 months. No anti-cancer treatment within one month prior to commencing trial treatment.
* Progressive cutaneous or nodal KS not requiring chemotherapy OR progressive KS following cytotoxic chemotherapy.
* Adequate haematological function:

  * Haemoglobin ≥ 9 g/dL
  * Absolute neutrophil count ≥ 1.5 x 10 9/L
  * Platelets ≥ 100 x 10 9/L
* Adequate hepatic function:

  * Serum bilirubin ≤ 1.5 x upper limit of normal (ULN), except if the patient is established on the anti-retroviral drug atazanavir (no upper limit) and has aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 x ULN
  * ALT ≤ 2.5 x ULN
  * AST ≤ 2.5 x ULN
* Adequate renal function:

  * Serum creatinine clearance \> 50 ml/min (Cockcroft-Gault formula or 24 hour urine collection).
* Left ventricular function \>50% normal
* Age ≥ 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* For selumetinib, women of child bearing age and child bearing potential MUST have a negative pregnancy test prior to study entry AND be using an adequate contraception method, which must be continued while on treatment and for at least 4 weeks after the study treatment has ended.
* Male patients must agree to use an effective contraception method while on treatment and for at least 16 weeks after the study treatment has ended (barrier contraception is recommended for all individuals living with HIV).
* Written informed consent

Exclusion Criteria:

* HIV viral load \> 200 copies/ml.
* Any previous treatment with a Ras, Raf or MEK inhibitor.
* Active opportunistic infections.
* Known hepatitis B, hepatitis C.
* Clinical evidence of uncontrolled hypertension (systolic BP \> 150 mmHg or diastolic BP \> 90 mmHg on 2 readings ≥ 1 hour apart).
* Clinical evidence of heart failure (New York Heart Association ≥Class II).
* Clinical evidence of atrial fibrillation (heart rate \> 100 bpm) or unstable ischaemic heart disease (MI within 6 months prior to starting treatment or angina requiring the use of nitrates \> once weekly).
* Major surgery within 4 weeks prior to starting selumetinib.
* Evidence of any psychological, familial, sociological or geographical condition potentially hampering protocol compliance.
* Clinical judgement by the Investigator that the patient should not participate in the study.
* Refractory nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption.
* Treatment with any investigational product within 28 days of registration
* Pregnant or breast-feeding women.
* Japanese ethnicity.

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