A Study of Selumetinib in Patients With Kaposi's Sarcoma
NCT ID: NCT01752569
Last Updated: 2019-02-20
Study Results
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Basic Information
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TERMINATED
PHASE1/PHASE2
19 participants
INTERVENTIONAL
2012-06-15
2017-12-20
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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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.
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.
Interventions
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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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
18 Years
ALL
No
Sponsors
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University of Birmingham
OTHER
AstraZeneca
INDUSTRY
Thermo Fisher Scientific, Inc
INDUSTRY
Cancer Research UK
OTHER
University of Sheffield
OTHER
Sheffield Teaching Hospitals NHS Foundation Trust
OTHER
Responsible Party
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Principal Investigators
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Mark Bower, Professor
Role: PRINCIPAL_INVESTIGATOR
Chelsea & Westminster Hospital, London
Diana Ritchie, Dr.
Role: PRINCIPAL_INVESTIGATOR
Beatson West of Scotland Cancer Centre, Glasgow
Sarah Westwell, Dr.
Role: PRINCIPAL_INVESTIGATOR
Royal Sussex County Hospital, Brighton
Michael Leahy, Dr
Role: PRINCIPAL_INVESTIGATOR
The Christie Hospital, Manchester
Robin Young, Dr
Role: PRINCIPAL_INVESTIGATOR
West Park Hospital, Sheffield
Grant Stewart, Dr
Role: PRINCIPAL_INVESTIGATOR
Royal Free Hospital NHS Foundation Trust
Locations
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Brighton and Sussex University Hospitals
Brighton, , United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, , United Kingdom
Royal Free Hospital
London, , United Kingdom
Chelsea & Westminster Hospital
London, , United Kingdom
The Christie Hospital
Manchester, , United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
Sheffield, , United Kingdom
Countries
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References
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Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008 May 1;26(13):2139-46. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
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.
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.
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.
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.
Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, Di Trolio R, De Placido S, Dezube BJ. Management of AIDS-related Kaposi's sarcoma. Lancet Oncol. 2007 Feb;8(2):167-76. doi: 10.1016/S1470-2045(07)70036-0.
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.
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.
Stebbing J, Sanitt A, Nelson M, Powles T, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi's sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006 May 6;367(9521):1495-502. doi: 10.1016/S0140-6736(06)68649-2.
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.
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.
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.
Xie J, Ajibade AO, Ye F, Kuhne K, Gao SJ. Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways. Virology. 2008 Feb 5;371(1):139-54. doi: 10.1016/j.virol.2007.09.040. Epub 2007 Oct 26.
Yang X, Gabuzda D. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. J Virol. 1999 Apr;73(4):3460-6. doi: 10.1128/JVI.73.4.3460-3466.1999.
Related Links
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Health Protection Agency "HIV in the United Kingdom" Report 2009
Other Identifiers
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2011-003099-35
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
STH16059
Identifier Type: -
Identifier Source: org_study_id
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