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

February 18, 2019 updated by: Sheffield Teaching Hospitals NHS Foundation Trust

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).

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Brighton, United Kingdom, BN2 5BE
        • Brighton and Sussex University Hospitals
      • Glasgow, United Kingdom, G12 0YN
        • Beatson West of Scotland Cancer Centre
      • London, United Kingdom, NW3 2QG
        • Royal Free Hospital
      • London, United Kingdom, SW10 9NH
        • Chelsea & Westminster Hospital
      • Manchester, United Kingdom, M20 4BX
        • The Christie Hospital
      • Sheffield, United Kingdom, S10 2SJ
        • Sheffield Teaching Hospitals NHS Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Selumetinib treatment
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.
Drug: Selumetinib

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.

Other Names:
  • AZD6244

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity of Selumetinib in Combination with HAART
Time Frame: 3.5 years
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.
3.5 years
Objective Response Rate to Selumetinib Treatment
Time Frame: 3.5 years
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.
3.5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peripheral Blood Mononuclear Cell (PBMC) Sub-study
Time Frame: 3.5 years

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.
3.5 years
Number of Completed Cycles
Time Frame: 3.5 years
Upon patients discontinuing trial treatment, the number of cycles of Selumetinib treatment in combination with HAART that patients received will be recorded.
3.5 years
HIV Viral Load and CD4 Count
Time Frame: 3.5 years
HIV control will be monitored through assessment of HIV-1 viral load and CD4 cell counts throughout the trial.
3.5 years
HAART Drug Levels
Time Frame: 2 years
HAART drug pharmacokinetics will be assessed to discover the effects of selumetinib on HAART drug metabolism (during phase I only).
2 years
Selumetinib and Metabolite Serum Levels
Time Frame: 2 years
The pharmacokinetics of selumetinib and its metabolites will be assessed to discover the effects of HAART on selumetinib metabolism (during phase I only).
2 years
Serum Angiogenic Biomarkers Levels
Time Frame: 3.5 years

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.
3.5 years
Progression Free Survival
Time Frame: 3.5 years
Progression free survival will be assessed for 6 months from commencing selumetinib treatment for each patient using ACTG criteria.
3.5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sheffield Teaching Hospitals NHS Foundation Trust

Collaborators

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

Investigators

  • Principal Investigator: Mark Bower, Professor, Chelsea & Westminster Hospital, London
  • Principal Investigator: Diana Ritchie, Dr., Beatson West of Scotland Cancer Centre, Glasgow
  • Principal Investigator: Sarah Westwell, Dr., Royal Sussex County Hospital, Brighton
  • Principal Investigator: Michael Leahy, Dr, The Christie Hospital, Manchester
  • Principal Investigator: Robin Young, Dr, West Park Hospital, Sheffield
  • Principal Investigator: Grant Stewart, Dr, Royal Free Hospital NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 15, 2012

Primary Completion (Actual)

September 30, 2015

Study Completion (Actual)

December 20, 2017

Study Registration Dates

First Submitted

August 17, 2012

First Submitted That Met QC Criteria

December 14, 2012

First Posted (Estimate)

December 19, 2012

Study Record Updates

Last Update Posted (Actual)

February 20, 2019

Last Update Submitted That Met QC Criteria

February 18, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STH16059
  • 2011-003099-35 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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