A Study of Selumetinib in Patients With Kaposi's Sarcoma

NCT01752569 | Terminated Phase 1 DMC

• 2 other identifiers: STH160592011-003099-35
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

AIDS-related Kaposi's Sarcoma

Keywords

HIV; Kaposi's sarcoma; Anti-retroviral therapy; HAART; AIDS

Outcome Measures

Primary Outcomes (2)

• Toxicity of Selumetinib in Combination with HAART

  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

  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 Outcomes (7)

• Peripheral Blood Mononuclear Cell (PBMC) Sub-study

  3.5 years

• Number of Completed Cycles

  3.5 years

• HIV Viral Load and CD4 Count

  3.5 years

• HAART Drug Levels

  2 years

• Selumetinib and Metabolite Serum Levels

  2 years

Study Arms (1)

Selumetinib treatment

EXPERIMENTAL

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

Interventions

Selumetinib DRUG

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.

Also known as: AZD6244

Selumetinib treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sheffield Teaching Hospitals NHS Foundation Trust: lead
• University of Birmingham: collaborator
• AstraZeneca: collaborator
• Thermo Fisher Scientific, Inc: collaborator
• Cancer Research UK: collaborator
• University of Sheffield: collaborator

Study Sites (6)

Brighton and Sussex University Hospitals

Brighton, BN2 5BE, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Chelsea & Westminster Hospital

London, SW10 9NH, United Kingdom

Location

The Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, S10 2SJ, United Kingdom

Location

Related Publications (14)

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  PMID: 18390968 BACKGROUND

• Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, Desar IM, Timmer-Bonte JN, Eckhardt SG, Lewis KD, Brown KH, Cantarini MV, Morris C, George SM, Smith PD, van Herpen CM. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010 Mar 1;16(5):1613-23. doi: 10.1158/1078-0432.CCR-09-2483. Epub 2010 Feb 23.

  PMID: 20179232 BACKGROUND

• Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, Tebbutt NC. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012 Jun;30(3):1216-23. doi: 10.1007/s10637-011-9687-4. Epub 2011 May 19.

  PMID: 21594619 BACKGROUND

• Bower M, Collins S, Cottrill C, Cwynarski K, Montoto S, Nelson M, Nwokolo N, Powles T, Stebbing J, Wales N, Webb A; AIDS Malignancy Subcommittee. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Med. 2008 Jul;9(6):336-88. doi: 10.1111/j.1468-1293.2008.00608.x. No abstract available.

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• Cooley T, Henry D, Tonda M, Sun S, O'Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi's sarcoma. Oncologist. 2007 Jan;12(1):114-23. doi: 10.1634/theoncologist.12-1-114.

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• Krown SE, Metroka C, Wernz JC. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 1989 Sep;7(9):1201-7. doi: 10.1200/JCO.1989.7.9.1201.

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• Sharma-Walia N, Krishnan HH, Naranatt PP, Zeng L, Smith MS, Chandran B. ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol. 2005 Aug;79(16):10308-29. doi: 10.1128/JVI.79.16.10308-10329.2005.

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• Tulpule A, Groopman J, Saville MW, Harrington W Jr, Friedman-Kien A, Espina BM, Garces C, Mantelle L, Mettinger K, Scadden DT, Gill PS. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer. 2002 Jul 1;95(1):147-54. doi: 10.1002/cncr.10634.

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• Vart RJ, Nikitenko LL, Lagos D, Trotter MW, Cannon M, Bourboulia D, Gratrix F, Takeuchi Y, Boshoff C. Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res. 2007 May 1;67(9):4042-51. doi: 10.1158/0008-5472.CAN-06-3321.

  PMID: 17483315 BACKGROUND

• Wang HW, Trotter MW, Lagos D, Bourboulia D, Henderson S, Makinen T, Elliman S, Flanagan AM, Alitalo K, Boshoff C. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet. 2004 Jul;36(7):687-93. doi: 10.1038/ng1384. Epub 2004 Jun 27.

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Related Links

• Health Protection Agency "HIV in the United Kingdom" Report 2009

MeSH Terms

Conditions

AIDS-related Kaposi sarcoma; Sarcoma, Kaposi; Acquired Immunodeficiency Syndrome

Interventions

AZD 6244

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2012
• First Posted: December 19, 2012
• Study Start: June 15, 2012
• Primary Completion: September 30, 2015
• Study Completion: December 20, 2017
• Last Updated: February 20, 2019

Record last verified: 2019-02

Locations

GB (6)