AIDS-associated Kaposi's sarcoma MedDRA version: 18.1 Level: PT Classification code 10023286 Term: Kaposi's sarcoma AIDS related System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Selumetinib
Product Code: AZD6244
Pharmaceutical Form: Capsule
Sponsors
Sheffield Teaching Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •HIV positive and established on a HAART regimen for = 3 months. •Histologically confirmed KS. •Measurable disease according to ACTG criteria. •Evidence of disease progression in the past 6 months. •Progressive cutaneous or nodal KS not requiring chemotherapy OR progressive KS following cytotoxic chemotherapy. •Adequate haematological function: o Haemoglobin = 9 g/dL o Absolute neutrophil count = 1.5 x 10 9/L o Platelets = 100 x 10 9/L •Adequate hepatic function: o 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 AST and ALT levels = 2.5 x ULN o ALT = 2.5 x ULN o AST = 2.5 x ULN •Adequate renal function: o Serum creatinine clearance > 50 ml/min (Cockcroft-Gault formula or 24 hour urine collection). •Left ventricular function >50% normal •Age = 18 years. •World Health Organisation (WHO0 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 Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: •HIV viral load > 200 copies/ml. •Active opportunistic infections. •Active hepatitis B, hepatitis C. Any prior exposure to MEK, Ras, or Raf inhibitors or history of hypersensitivity to selumetinib, or any excipient agents. • Any unresolved toxicity > CTCAE Grade 2 from previous anti-cancer therapy, except for alopecia • Cardiac conditions as follows: o Uncontrolled hypertension (BP =150/95 mmHg despite medical therapy) o Left ventricular ejection fraction 100 bpm on ECG at rest o Symptomatic heart failure (NYHA grade II-IV) o Prior or current cardiomyopathy o Severe valvular heart disease o Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy) o Acute coronary syndrome within 6 months prior to starting treatment •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. Ophthalmological conditions as follows: o Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure) o Current or past history of central serous retinopathy or retinal vein occlusion •Treatment with any investigational product within 28 days of registration •Pregnant or breast-feeding women. Due to higher PK exposure, patients of Asian ethnicity may be at a higher risk of adverse events with selumetinib treatment. Selumetinib is not contra-indicated in patients of Asian ethnicity, but the potential increased risk of toxicity should be considered and included as part of the discussion with the patient prior to receiving informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish the safety and dose of selumetinib in combination with HAART and to establish evidence of whether AIDS-associated KS lesions respond to (i.e. get smaller with) selumetinib in combination with HAART.; Secondary Objective: To investigate how selumetinib in combination with HAART moves around the body (pharmacokinetics - drug levels of selumetinib, HAART, and HIV viral load and CD4 counts). To assess the toxicity of selumetinib in combination with HAART. To monitor any effects that selumetinib has on the body (pharmoacodynamics - serum levels of angiogenic biomarkers, levels of pERK in tumour tissue, changes in peripheral blood mononuclear cells). To measure progression free survival at 6 months from commencing treatment. ; Primary end point(s): The primary outcome in phase I is the safety and appropriate dosage of selumetinib in combination with HAART. For determining Maximum Tolerated Dose (MTD), defined as the highest dose producing one or less dose limiting toxicity (DLT), DLTs will be assessed during Cycle 1 in Phase I only, (i.e. up to the time of Cycle 2 day 1 assessment). This will be assessed by toxicity using CTCAE v 4.0 criteria. The primary outcome in phase II is the best tumour response rate with disease assessment based on AIDS Clinical Trials Group Oncology Committee criteria. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints are: - Toxicity - Progression free survival at 6 months after commencing treatment - Percentage inhibition of pERK in tumour tissue - Downstream proteins, apoptotic pathways and adaptive changes to other MAPK pathways - Percentage changes in serum angiogenic markers - Percentage changes in HIV-viral load and CD4 count ;Timepoint(s) of evaluation of this end point: Progression free survival will be measured for 6 month afters completion of treatment. Other secondary endpoints will be met during the treatment. | — |
Countries
United Kingdom
Contacts
Public ContactDr. Gillian L McNab
CRCTU University of Birmingham
Outcome results
None listed