Combination Chemotherapy With or Without Gemtuzumab Ozogamicin or Tipifarnib in Treating Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

A Programme of Treatment Development for Older Patients With Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Genetic: gene expression analysis; Drug: arsenic trioxide; Genetic: mutation analysis; Drug: cytarabine; Drug: daunorubicin hydrochloride; Genetic: DNA methylation analysis; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: azacitidine; Drug: busulfan; Other: diagnostic laboratory biomarker analysis; Drug: melphalan; Biological: alemtuzumab; Genetic: cytogenetic analysis; Other: immunologic technique; Drug: gemtuzumab ozogamicin; Drug: tipifarnib; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Drug: clofarabine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 2000
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Hereford, United Kingdom, HR1 2ER
    • Hereford Hospitals
  • Slough, Berkshire, United Kingdom, SL2 4HL
    • Wexham Park Hospital
  • Surrey, United Kingdom, KT2 7QB
    • Kingston Hospital
  • England
    • Basingstoke, England, United Kingdom, RG24 9NA
      • Basingstoke and North Hampshire NHS Foundation Trust
    • Bath, England, United Kingdom, BA1 3NG
      • Royal United Hospital
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Birmingham, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
    • Blackpool, England, United Kingdom, FY3 8NR
      • Blackpool Victoria Hospital
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Bradford, England, United Kingdom, BD9 6RJ
      • Bradford Royal Infirmary
    • Brighton, England, United Kingdom, BN2 5BE
      • Sussex Cancer Centre at Royal Sussex County Hospital
    • Burton-upon-Trent, England, United Kingdom, DE13 0RB
      • Queen's Hospital
    • Bury St. Edmunds, England, United Kingdom, IP33 2QZ
      • West Suffolk Hospital
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital
    • Canterbury, England, United Kingdom, CT1 3NG
      • Kent and Canterbury Hospital
    • Carshalton, England, United Kingdom, SM5 1AA
      • St. Helier Hospital
    • Cheltenham, England, United Kingdom, GL53 7AN
      • Gloucestershire Oncology Centre at Cheltenham General Hospital
    • Chester, England, United Kingdom, CH2 1UL
      • Countess of Chester Hospital
    • Chesterfield, England, United Kingdom, S44 5BL
      • Chesterfield Royal Hospital
    • Chichester, England, United Kingdom, P019 4SE
      • Saint Richards Hospital
    • Coventry, England, United Kingdom, CV2 2DX
      • Walsgrave Hospital
    • Croydon, England, United Kingdom
      • Mayday University Hospital
    • Derby, England, United Kingdom, DE1 2QY
      • Derbyshire Royal Infirmary
    • Doncaster, England, United Kingdom, DN2 5LT
      • Doncaster Royal Infirmary
    • Dorchester, England, United Kingdom, DT1 2JY
      • Dorset County Hospital
    • Dudley, England, United Kingdom, DY1 2HQ
      • Russells Hall Hospital
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Gillingham Kent, England, United Kingdom, ME7 5NY
      • Medway Maritime Hospital
    • Harrogate, England, United Kingdom, HG2 7SX
      • Harrogate District Hospital
    • Harrow, England, United Kingdom, HA1 3UJ
      • Northwick Park Hospital
    • Hemel Hempstead, England, United Kingdom, HP2 4AD
      • Hemel Hempstead General
    • High Wycombe, England, United Kingdom
      • Wycombe General Hospital
    • Hull, England, United Kingdom, HU3 2KZ
      • Hull Royal Infirmary
    • Ipswich, England, United Kingdom, IP4 5PD
      • Ipswich Hospital
    • Isleworth, England, United Kingdom, TW7 6AF
      • West Middlesex University Hospital
    • Kettering, Northants, England, United Kingdom, NNI6 8UZ
      • Kettering General Hosptial
    • Kidderminster Worcestershire, England, United Kingdom, DY11 6RJ
      • Kidderminster Hospital
    • Kilmarnock, England, United Kingdom, KA2 OBE
      • Crosshouse Hospital
    • Leeds, England, United Kingdom, LS1 3EX
      • Leeds General Infirmary
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L9 7AL
      • Aintree University Hospital
    • Liverpool, England, United Kingdom, L7 8XP
      • Royal Liverpool University Hospital
    • London, England, United Kingdom, SW17 0QT
      • St. George's Hospital
    • London, England, United Kingdom, EC1A 7BE
      • Saint Bartholomew's Hospital
    • London, England, United Kingdom, WC1E 6AU
      • University College Hospital - London
    • London, England, United Kingdom, SE18 4QH
      • Queen Elizabeth Hospital - Woolwich
    • London, England, United Kingdom, NW1 2QG
      • UCL Cancer Institute
    • London, England, United Kingdom, SE13 6LH
      • University Hospital Lewisham
    • London, England, United Kingdom, SE5 8RX
      • King's College Hospital
    • Maidstone, England, United Kingdom, ME16 9QQ
      • Maidstone Hospital
    • Manchester, England, United Kingdom, M20 4BX
      • Christie Hospital
    • Manchester, England, United Kingdom, M13 9WL
      • Manchester Royal Infirmary
    • Manchester, England, United Kingdom, M31 3SL
      • Trafford General Hospital
    • Melrose, England, United Kingdom, TD6 9BS
      • Borders General Hospital
    • Norfolk, England, United Kingdom, NR31 6LA
      • James Paget Hospital
    • Nottingham, England, United Kingdom, NG5 1PB
      • Nottingham City Hospital
    • Plymouth, England, United Kingdom, PL6 8DH
      • Derriford Hospital
    • Prescot Merseyside, England, United Kingdom, L35 5DR
      • Whiston Hospital
    • Reading, England, United Kingdom, RG1 5AN
      • Berkshire Cancer Centre at Royal Berkshire Hospital
    • Saint Leonards-on-Sea, England, United Kingdom, TN37 7RD
      • Conquest Hospital
    • Salford, England, United Kingdom, M6 8HD
      • Hope Hospital
    • Salisbury, England, United Kingdom, SP2 8BJ
      • Salisbury District Hospital
    • Sheffield, England, United Kingdom, S1O 2JF
      • Royal Hallamshire Hospital
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Southport, England, United Kingdom, PR8 6PN
      • Southport and Formby District General Hospital
    • Stafford, England, United Kingdom, ST16 3SA
      • Staffordshire General Hospital
    • Sunderland, England, United Kingdom, SR4 7TP
      • Sunderland Royal Hospital
    • Sutton, England, United Kingdom, SM2 5PT
      • Royal Marsden - Surrey
    • Swindon, England, United Kingdom, SN3 6BB
      • Great Western Hospital
    • Taunton Somerset, England, United Kingdom, TA1 5DA
      • Taunton and Somerset Hospital
    • Torquay, England, United Kingdom, TQ2 7AA
      • Torbay Hospital
    • Truro, Cornwall, England, United Kingdom, TR1 3LJ
      • Royal Cornwall Hospital
    • Uxbridge, England, United Kingdom, UB8 3NN
      • Hillingdon Hospital
    • West Bromwich, England, United Kingdom, B71 4HJ
      • Sandwell General Hospital
    • Wirral, England, United Kingdom, CH49 5PE
      • Arrowe Park Hospital
    • Worcester, England, United Kingdom, WR5 1DD
      • Worcester Royal Hospital
    • Worthing, England, United Kingdom, BN11 2DH
      • Worthing Hospital
    • York, England, United Kingdom, Y031 8HE
      • Cancer Care Center
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Airdrie, Scotland, United Kingdom, ML6 0JF
      • Monklands General Hospital
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Ninewells Hospital
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Edinburgh Cancer Centre at Western General Hospital
    • Falkirk, Scotland, United Kingdom, FK1 5QE
      • Falkirk and District Royal Infirmary
    • Glasgow, Scotland, United Kingdom, G11 6NT
      • Western Infirmary
    • Glasgow, Scotland, United Kingdom, G4 0SF
      • Royal Infirmary - Castle
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Southern General Hospital
    • Glasgow, Scotland, United Kingdom, G42 9TY
      • Victoria Infirmary
    • Inverness, Scotland, United Kingdom, 1V2 3UJ
      • Raigmore Hospital
    • Kirkcaldy, Scotland, United Kingdom, KY2 5AH
      • Victoria Hospital
    • Paisley, Scotland, United Kingdom
      • Royal Alexandra Hospital
    • Wakefield, Scotland, United Kingdom, WF1 4DG
      • Pinderfields General Hospital
    • Wakefield, Scotland, United Kingdom, WF1 4DG
      • Dorset Cancer Centre
  • Wales
    • Bangor, Wales, United Kingdom, LL57 2PW
      • Ysbyty Gwynedd
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
    • Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
      • Glan Clwyd Hospital
    • Swansea, Wales, United Kingdom, SA2 8QA
      • South West Wales Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Acute myeloid leukemia (AML) meeting the following criteria:

    • De novo or secondary AML
    • No acute promyelocytic leukemia
  • High-risk myelodysplastic syndromes (> 10% marrow blasts; refractory anemia with excess blasts-2)
  • No blast transformation of chronic myeloid leukemia
• Patients ≤ 60 years of age may be eligible provided they are considered unfit for clinical trial MRC-AMLI5

PATIENT CHARACTERISTICS:

• Not pregnant or nursing
• AST and ALT ≤ 2 times upper limit of normal (ULN) (for patients receiving gemtuzumab ozogamicin)
• Bilirubin ≤ 2 times ULN (for patients receiving gemtuzumab ozogamicin)
• Creatinine normal (for patients receiving clofarabine)
• No other concurrent active malignancy except basal cell carcinoma

PRIOR CONCURRENT THERAPY:

• No prior cytotoxic chemotherapy for AML

  • Hydroxyurea or similar low-dose therapy to control WBC count prior to initiation of intensive therapy allowed
• No concurrent enzyme anticonvulsants, including phenytoin, phenobarbital, primidone, carbamazepine, or oxcarbazepine (for patients receiving tipifarnib)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Overall survival
Achievement of complete remission and reasons for failure
Duration of remission, relapse rates, and deaths
Hematological and nonhematological toxicity
Supportive care requirements (and other aspects of health economics)

Collaborators and Investigators

• Sponsor: The University of New South Wales

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: March 27, 2007
• First Submitted That Met QC Criteria: March 27, 2007
• First Posted (Estimate): March 30, 2007

Study Record Updates

• Last Update Posted (Estimate): August 26, 2013
• Last Update Submitted That Met QC Criteria: August 23, 2013
• Last Verified: August 1, 2008

More Information

Terms related to this study

• Keywords: refractory anemia with excess blasts; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); secondary acute myeloid leukemia; childhood myelodysplastic syndromes; untreated adult acute myeloid leukemia; adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult acute basophilic leukemia; adult acute eosinophilic leukemia; adult erythroleukemia (M6a); adult pure erythroid leukemia (M6b)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Clofarabine; Melphalan; Azacitidine; Fludarabine; Fludarabine phosphate; Arsenic Trioxide; Cytarabine; Daunorubicin; Tipifarnib; Busulfan; Gemtuzumab; Alemtuzumab
• Other Study ID Numbers: CDR0000526121; UHW-AML16; EU-20677; ISRCTN11036523; EUDRACT-2005-002846-14; MREC-CU106