Poor recruitment

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.

BACKGROUND AND RATIONALE

HIV AND KS

The prevalence of HIV in the United Kingdom (UK) is rising with about 83,000 living with HIV and 7,000 new cases per annum (pa). At diagnosis a third of patients have severe immune-suppression with a cluster of differentiation 4 (CD4) positive cell count less than 200/mm3 (HPA, 2009), which is associated with opportunistic infections and an increase in various tumours. Cancer is a leading cause of death in individuals living with HIV, and KS remains the commonest AIDS-associated malignancy. In a UK prospective cohort followed in the Highly Active Anti-Retroviral Therapy (HAART) era, 5.5% of HIV positive patients developed KS (Stebbing et al., 2006).

KS is associated with co-infection with HIV and human herpesvirus-8 (HHV-8). Patients typically present with multi-focal cutaneous disease often with associated lymphoedema. Extra-cutaneous disease commonly involves the gastrointestinal tract, lung, liver and spleen. For early KS, initiation of HAART may be sufficient to control the disease and radiotherapy is of benefit for localised disease (Di Lorenzo et al., 2007). Currently the only alternative for progressive localised disease is cytotoxic chemotherapy.

Cytotoxic chemotherapy with liposomal anthracycline or taxanes, is indicated in patients with widespread cutaneous KS, extensive oral disease or symptomatic visceral involvement (Bower et al., 2008). Pegylated liposomal doxorubicin (PLD) 20mg/m2 q 3 weeks as first-line therapy in combination with HAART is reported to give tumour response in 55% of patients and median progression free survival (PFS) of 22 weeks (Cooley et al., 2007). Second-line therapy with low dose paclitaxel (100mg/m2 q 2 weeks) is reported to give a response rate of 56% with median PFS of 39 weeks (Tulpule et al., 2002). However the majority of patients' progress despite chemotherapy and new treatment alternatives are required.

JUSTIFICATION FOR DESIGN

Selumetinib has been tested in a number of phase I and phase II trials as both monotherapy and combined with cytotoxic chemotherapy in patients with advanced solid malignancies. A toxicity profile and recommended dose has been established in these patients. Selumetinib has not been tested in combination with HAART. No significant interactions are predicted between Selumetinib and HAART however a phase I study is required to investigate the pharmacokinetic effects of combining these drugs. In particular we wish to establish that Selumetinib will not reduce the efficacy of HAART.

This trial is an open-label multi-centre phase I/II study to investigate the use of selumetinib as a potential treatment for HIV-associated KS. Phase I is an accelerated dose finding study with dosing commencing at 1 dose level below that recommended for monotherapy or in combination with cytotoxic chemotherapy. The aims of phase I are to identify a maximum tolerated dose (MTD) for selumetinib in patients on HAART whilst proving selumetinib does not reduce the efficacy of HAART. Phase II aims to provide evidence of the efficacy of selumetinib as a treatment for KS. Evidence of efficacy will be assessed via objective response rate to treatment and will be used to develop a protocol for a future randomised phase II/III study.

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.