A Study of Selumetinib in Patients With Kaposi's Sarcoma (SCART)

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).

University of Birmingham, AstraZeneca, Thermo Fisher Scientific, Inc, Cancer Research UK, University of Sheffield

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.

Phase I is a dose-finding study to discover the maximum tolerated dose of selumetinib in combination with HAART. Phase II will consider the efficacy of selumetinib for treating Kaposi's sarcoma at the recommended phase II dose discovered in phase I.

The treatment schedule requires selumetinib to be taken either once daily at the same time each day or twice daily approximately 12 hours apart. Selumetinib should be taken with water at least 2 hours after a meal and 1 hour before the next meal. Selumetinib capsules will be administered in a continuous 21 day cycle (6 cycles), unless disease progression occurs. For phase I there were 4 potential dosing levels: Level -1 - 50mg once daily (od) (50mg daily total) Level 1 (starting dose level for phase I) - 50mg bi-daily (bd) (100mg daily total) Level 2 - 75mg bd (150mg daily total) Level 3 - 100mg bd (200mg daily total) Phase I has been completed and identified 75mg bd as the recommended phase II dose. Phase II has begun and is utilising a dose of 75mg bd of selumetinib.

The primary objective of phase I of this study is to identify a safe dose for Selumetinib in combination with HAART (called the recommended phase II dose) for use in an expanded phase II cohort. The recommended phase II dose will be elucidated using a dose-escalation algorithm which will be used to allocate patients to cohorts at a given dose level or expand the numbers of patients allocated to a given dose level dependent on the previous occurrence of specifically pre-defined toxicities (according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) called dose limiting toxicities. Dose limiting toxicities will only be recorded in phase I to obtain a recommended phase II dose. However, all toxicities/adverse events will be recorded throughout both phase I and II of the trial according to CTCAE version 4.0.

Objective response rate to treatment will be assessed using the AIDS Clinical Trials Group (ACTG) Oncology Committee Documentation of Disease and Definition of Response criteria. This will be the primary measure of efficacy to test the null hypothesis that the recommended phase II dose will produce an objective response in less than 10% of patients. The alternative hypothesis that the recommended phase II dose will produce an objective response in more than 30% of patients will also be tested.

Effects of selumetinib treatment on PBMCs will be assessed by isolating these cells and subjecting them to the following analyses: - Levels of pERK, downstream targets c-fos and c-myc and key apoptotic proteins Bad and Bcl-2 will be assessed by Western blotting of lysed viable PBMCs. PBMCs will be challenged with Toll-like Receptor (TLR) 4 and 9 agonists and production of Interleukins (ILs) including IL-1β, IL-6, IL-10 and IL-12 alongside type 1 interferon and tumor necrosis factor alpha (TNFα) will be measured by cytometric bead array of culture supernatants. PBMC reactive oxygen species production and cell survival assessment will be measured flow cytometry.

Upon patients discontinuing trial treatment, the number of cycles of Selumetinib treatment in combination with HAART that patients received will be recorded.

HIV control will be monitored through assessment of HIV-1 viral load and CD4 cell counts throughout the trial.

HAART drug pharmacokinetics will be assessed to discover the effects of selumetinib on HAART drug metabolism (during phase I only).

The pharmacokinetics of selumetinib and its metabolites will be assessed to discover the effects of HAART on selumetinib metabolism (during phase I only).

Pharmacodynamic effects of Selumetinib in combination with HAART will be assessed by: - Quantification of serum concentrations of angiogenic markers including serum Angiopoietin 2 (Ang-2), IL-6 and Vascular Endothelial Growth Factor (VEGF) as analysed via Enzyme-Linked Immunosorbent Assay (ELISA). Analysis of tissue biopsies for pERK levels in tumour tissues and other downstream markers including c-fos, c-myc, apoptotic markers (e.g. Bad and Bcl-2) and for adaptive changes in Phosphoinositide 3-kinase (PI3K), Akt and other Mitogen-Activated Protein Kinase (MAPK) pathways such as c-Jun N-terminal kinase (JNK) and p38.

Progression free survival will be assessed for 6 months from commencing selumetinib treatment for each patient using ACTG criteria.

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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