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Brief Title: Combination Chemotherapy With or Without Gemtuzumab Ozogamicin or Tipifarnib in Treating Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes
Official Title: A Programme of Treatment Development for Older Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome
Study ID: NCT00454480
Brief Summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab ozogamicin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with gemtuzumab ozogamicin or tipifarnib may kill more cancer cells. PURPOSE: This randomized phase II/III trial is studying different combination chemotherapy regimens to compare how well they work when given with or without gemtuzumab ozogamicin or tipifarnib in treating patients with acute myeloid leukemia or high-risk myelodysplastic syndromes.
Detailed Description: OBJECTIVES: Primary (patients considered fit for intensive treatment) * Compare the efficacy and toxicity of daunorubicin hydrochloride and cytarabine (DA) vs daunorubicin hydrochloride and clofarabine (DClo) as induction therapy in older patients with acute myeloid leukemia or high-risk myelodysplastic syndromes. * Assess the value of gemtuzumab ozogamicin when given in combination with DA or DClo during course 1 of induction therapy. * Compare a total of two vs three courses of treatment in patients who achieve at least partial remission (\< 15% blasts) after course 1 of induction therapy. * Compare the use of demethylation maintenance therapy comprising azacitidine vs no maintenance therapy in these patients. * Assess the value of reduced-intensity allogeneic stem cell transplantation as consolidation in patients with matched donors. Primary (patients considered unfit for intensive treatment) * Compare the efficacy and toxicity of low-dose cytarabine with vs without gemtuzumab ozogamicin in these patients. * Compare the efficacy and toxicity of low-dose cytarabine with vs without arsenic trioxide in these patients. * Compare the efficacy and toxicity of low-dose cytarabine vs low-dose clofarabine in these patients. Secondary * Evaluate the relevance of the presence of a cytogenetic abnormality in the bone marrow of patients in morphological remission. * Correlate molecular detection of FLT3 and RAS mutation, genetic signature, and resistance protein status with response to treatment. * Evaluate methods of minimal residual disease monitoring. * Correlate gene methylation status with treatment with maintenance azacitidine. OUTLINE: This is a randomized, controlled, factorial design, prospective, multicenter study. Patients are stratified according to age (\< 60 years vs 60-64 years vs 65-69 years vs 70-74 years vs ≥ 75 years), performance status, WBC count (0-9.9,000/mm³ vs 10-49.9,000/mm³ vs 50-99.9,000/mm³ vs ≥ 100,000/mm³), and type of disease (de novo acute myeloid leukemia \[AML\] vs secondary AML vs high-risk myelodysplastic syndromes). Patients receive treatment according to disease status (fit for intensive treatment vs unfit for intensive treatment). * Intensive treatment (for patients considered fit for intensive treatment): * Induction therapy: Patients are randomized to 1 of 4 treatment arms. * Arm I: For course 1, patients receive daunorubicin hydrochloride (DH) IV over 1 hour on days 1, 3, and 5 and cytarabine IV twice daily on days 1-10. For course 2, patients receive DH as in course 1 and cytarabine IV twice daily on days 1-8. Courses are 4 weeks in duration. * Arm II: Patients receive DH IV over 1 hour on days 1, 3, and 5 and clofarabine IV over 1 hour on days 1-5. Treatment repeats every 4 weeks for 2 courses. * Arm III: For course 1, patients receive DH IV over 1 hour on days 1, 3, and 5, cytarabine IV twice daily on days 1-10, and gemtuzumab ozogamicin (GO) IV over 2 hours on day 1. For course 2, patients receive DH as in course 1 and cytarabine IV twice daily on days 1-8. Courses are 4 weeks in duration. * Arm IV: For course 1, patients receive DH and clofarabine as in arm II and GO as in arm III. For course 2, patients receive DH and clofarabine as in arm II. Courses are 4 weeks in duration. Patients who fail to achieve partial remission (PR) or complete remission (CR) after course 1 but achieve CR after course 2 receive a third course of chemotherapy comprising DH IV over 1 hour on days 1 and 3 and cytarabine IV twice daily on day 1-5. Patients then proceed to randomization for maintenance therapy. Patients who achieve PR or CR after course 1 and are in CR after course 2 are randomized to receive or not receive a third course of chemotherapy (as above). Patients then proceed to randomization for maintenance therapy. Patients who have an HLA-matched donor may proceed to nonintensive allogeneic stem cell transplantation (ASCT). * Nonintensive ASCT: Patients receive a nonintensive allograft comprising 1 of 2 mini-allograft protocols. * Protocol 1: Patients receive fludarabine on days -9 to -5, busulfan on days -3 and -2, and alemtuzumab on days -5 to -1. Patients undergo ASCT on day 0. * Protocol 2: Patients receive fludarabine on days -7 to -3, melphalan on day -2, and alemtuzumab on days -8 to -4. Patients undergo ASCT on day 0. * Maintenance Therapy: Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive azacitidine subcutaneously (SC) once daily on days 1-5. Treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. * Arm II: Patients do not receive maintenance therapy. * Nonintensive treatment (for patients considered unfit for intensive treatment): Patients are randomized to 1 of 4 treatment arms. * Arm I: Patients receive low-dose cytarabine (LDC) SC twice daily on days 1-10. * Arm II: Patients receive LDC as in arm I and GO IV over 2 hours on day 1. * Arm III: Patients receive low-dose clofarabine IV over 1 hour once daily on days 1-5. * Arm IV: Patients receive LDC as in arm I and arsenic trioxide IV over 1-2 hours on days 1-5, 9, and 11. Treatment in all arms repeats every 4-6 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Bone marrow is collected at diagnosis and examined for characterization of FLT3 and RAS mutations by immunophenotyping, gene expression by DNA microarray, and cytogenetic analysis. Blood samples are collected at baseline and after 18, 36, and 54 weeks of treatment for assessment of gene methylation status. After completion of study therapy, patients are followed at 6 and 12 months and then annually thereafter. PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.
Minimum Age:
Eligible Ages: CHILD, ADULT, OLDER_ADULT
Sex: ALL
Healthy Volunteers: No
Basingstoke and North Hampshire NHS Foundation Trust, Basingstoke, England, United Kingdom
Royal United Hospital, Bath, England, United Kingdom
Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust, Birmingham, England, United Kingdom
Birmingham Heartlands Hospital, Birmingham, England, United Kingdom
Blackpool Victoria Hospital, Blackpool, England, United Kingdom
Royal Bournemouth Hospital, Bournemouth, England, United Kingdom
Bradford Royal Infirmary, Bradford, England, United Kingdom
Sussex Cancer Centre at Royal Sussex County Hospital, Brighton, England, United Kingdom
Queen's Hospital, Burton-upon-Trent, England, United Kingdom
West Suffolk Hospital, Bury St. Edmunds, England, United Kingdom
Addenbrooke's Hospital, Cambridge, England, United Kingdom
Kent and Canterbury Hospital, Canterbury, England, United Kingdom
St. Helier Hospital, Carshalton, England, United Kingdom
Gloucestershire Oncology Centre at Cheltenham General Hospital, Cheltenham, England, United Kingdom
Chesterfield Royal Hospital, Chesterfield, England, United Kingdom
Countess of Chester Hospital, Chester, England, United Kingdom
Saint Richards Hospital, Chichester, England, United Kingdom
Walsgrave Hospital, Coventry, England, United Kingdom
Mayday University Hospital, Croydon, England, United Kingdom
Derbyshire Royal Infirmary, Derby, England, United Kingdom
Doncaster Royal Infirmary, Doncaster, England, United Kingdom
Dorset County Hospital, Dorchester, England, United Kingdom
Russells Hall Hospital, Dudley, England, United Kingdom
Royal Devon and Exeter Hospital, Exeter, England, United Kingdom
Medway Maritime Hospital, Gillingham Kent, England, United Kingdom
Harrogate District Hospital, Harrogate, England, United Kingdom
Northwick Park Hospital, Harrow, England, United Kingdom
Hemel Hempstead General, Hemel Hempstead, England, United Kingdom
Wycombe General Hospital, High Wycombe, England, United Kingdom
Hull Royal Infirmary, Hull, England, United Kingdom
Ipswich Hospital, Ipswich, England, United Kingdom
West Middlesex University Hospital, Isleworth, England, United Kingdom
Kettering General Hosptial, Kettering, Northants, England, United Kingdom
Kidderminster Hospital, Kidderminster Worcestershire, England, United Kingdom
Crosshouse Hospital, Kilmarnock, England, United Kingdom
Leeds General Infirmary, Leeds, England, United Kingdom
Leicester Royal Infirmary, Leicester, England, United Kingdom
Royal Liverpool University Hospital, Liverpool, England, United Kingdom
Aintree University Hospital, Liverpool, England, United Kingdom
Saint Bartholomew's Hospital, London, England, United Kingdom
UCL Cancer Institute, London, England, United Kingdom
University Hospital Lewisham, London, England, United Kingdom
Queen Elizabeth Hospital - Woolwich, London, England, United Kingdom
King's College Hospital, London, England, United Kingdom
St. George's Hospital, London, England, United Kingdom
University College Hospital - London, London, England, United Kingdom
Maidstone Hospital, Maidstone, England, United Kingdom
Manchester Royal Infirmary, Manchester, England, United Kingdom
Christie Hospital, Manchester, England, United Kingdom
Trafford General Hospital, Manchester, England, United Kingdom
Borders General Hospital, Melrose, England, United Kingdom
James Paget Hospital, Norfolk, England, United Kingdom
Nottingham City Hospital, Nottingham, England, United Kingdom
Derriford Hospital, Plymouth, England, United Kingdom
Whiston Hospital, Prescot Merseyside, England, United Kingdom
Berkshire Cancer Centre at Royal Berkshire Hospital, Reading, England, United Kingdom
Conquest Hospital, Saint Leonards-on-Sea, England, United Kingdom
Hope Hospital, Salford, England, United Kingdom
Salisbury District Hospital, Salisbury, England, United Kingdom
Royal Hallamshire Hospital, Sheffield, England, United Kingdom
Southampton General Hospital, Southampton, England, United Kingdom
Southport and Formby District General Hospital, Southport, England, United Kingdom
Staffordshire General Hospital, Stafford, England, United Kingdom
Sunderland Royal Hospital, Sunderland, England, United Kingdom
Royal Marsden - Surrey, Sutton, England, United Kingdom
Great Western Hospital, Swindon, England, United Kingdom
Taunton and Somerset Hospital, Taunton Somerset, England, United Kingdom
Torbay Hospital, Torquay, England, United Kingdom
Royal Cornwall Hospital, Truro, Cornwall, England, United Kingdom
Hillingdon Hospital, Uxbridge, England, United Kingdom
Sandwell General Hospital, West Bromwich, England, United Kingdom
Arrowe Park Hospital, Wirral, England, United Kingdom
Worcester Royal Hospital, Worcester, England, United Kingdom
Worthing Hospital, Worthing, England, United Kingdom
Cancer Care Center, York, England, United Kingdom
Aberdeen Royal Infirmary, Aberdeen, Scotland, United Kingdom
Monklands General Hospital, Airdrie, Scotland, United Kingdom
Ninewells Hospital, Dundee, Scotland, United Kingdom
Edinburgh Cancer Centre at Western General Hospital, Edinburgh, Scotland, United Kingdom
Falkirk and District Royal Infirmary, Falkirk, Scotland, United Kingdom
Western Infirmary, Glasgow, Scotland, United Kingdom
Royal Infirmary - Castle, Glasgow, Scotland, United Kingdom
Victoria Infirmary, Glasgow, Scotland, United Kingdom
Southern General Hospital, Glasgow, Scotland, United Kingdom
Raigmore Hospital, Inverness, Scotland, United Kingdom
Victoria Hospital, Kirkcaldy, Scotland, United Kingdom
Royal Alexandra Hospital, Paisley, Scotland, United Kingdom
Dorset Cancer Centre, Wakefield, Scotland, United Kingdom
Pinderfields General Hospital, Wakefield, Scotland, United Kingdom
Ysbyty Gwynedd, Bangor, Wales, United Kingdom
University Hospital of Wales, Cardiff, Wales, United Kingdom
Glan Clwyd Hospital, Rhyl, Denbighshire, Wales, United Kingdom
South West Wales Cancer Institute, Swansea, Wales, United Kingdom
Hereford Hospitals, Hereford, , United Kingdom
Wexham Park Hospital, Slough, Berkshire, , United Kingdom
Kingston Hospital, Surrey, , United Kingdom
Name: Alan K. Burnett, MD, FRCP
Affiliation: University Hospital of Wales
Role: STUDY_CHAIR