Clinical trial NCT00454480: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Leukemia
Myelodysplastic Syndromes
Keywords: untreated adult acute myeloid leukemia
de novo myelodysplastic syndromes
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
previously treated myelodysplastic syndromes
refractory anemia with excess blasts
adult acute basophilic leukemia
adult acute eosinophilic 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 erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
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)
adult acute myelomonocytic leukemia (M4)
childhood myelodysplastic syndromes
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-03-30
Enrollment: 2000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Overall survival
measure: Achievement of complete remission and reasons for failure
measure: Duration of remission, relapse rates, and deaths
measure: Hematological and nonhematological toxicity
measure: Supportive care requirements (and other aspects of health economics)
Secondary outcomes:
Other outcomes:
Locations:
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire NHS Foundation Trust
state: England
city: Bath
country: United Kingdom
facility: Royal United Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust
state: England
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: England
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: England
city: Brighton
country: United Kingdom
facility: Sussex Cancer Centre at Royal Sussex County Hospital
state: England
city: Burton-upon-Trent
country: United Kingdom
facility: Queen's Hospital
state: England
city: Bury St. Edmunds
country: United Kingdom
facility: West Suffolk Hospital
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: England
city: Carshalton
country: United Kingdom
facility: St. Helier Hospital
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
state: England
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
state: England
city: Chichester
country: United Kingdom
facility: Saint Richards Hospital
state: England
city: Coventry
country: United Kingdom
facility: Walsgrave Hospital
state: England
city: Croydon
country: United Kingdom
facility: Mayday University Hospital
state: England
city: Derby
country: United Kingdom
facility: Derbyshire Royal Infirmary
state: England
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
state: England
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: England
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Gillingham Kent
country: United Kingdom
facility: Medway Maritime Hospital
state: England
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
state: England
city: Harrow
country: United Kingdom
facility: Northwick Park Hospital
state: England
city: Hemel Hempstead
country: United Kingdom
facility: Hemel Hempstead General
state: England
city: High Wycombe
country: United Kingdom
facility: Wycombe General Hospital
state: England
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
state: England
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
state: England
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
state: England
city: Kettering, Northants
country: United Kingdom
facility: Kettering General Hosptial
state: England
city: Kidderminster Worcestershire
country: United Kingdom
facility: Kidderminster Hospital
state: England
city: Kilmarnock
country: United Kingdom
facility: Crosshouse Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: UCL Cancer Institute
state: England
city: London
country: United Kingdom
facility: University Hospital Lewisham
state: England
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital - Woolwich
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: University College Hospital - London
state: England
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Manchester
country: United Kingdom
facility: Trafford General Hospital
state: England
city: Melrose
country: United Kingdom
facility: Borders General Hospital
state: England
city: Norfolk
country: United Kingdom
facility: James Paget Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Prescot Merseyside
country: United Kingdom
facility: Whiston Hospital
state: England
city: Reading
country: United Kingdom
facility: Berkshire Cancer Centre at Royal Berkshire Hospital
state: England
city: Saint Leonards-on-Sea
country: United Kingdom
facility: Conquest Hospital
state: England
city: Salford
country: United Kingdom
facility: Hope Hospital
state: England
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Southport
country: United Kingdom
facility: Southport and Formby District General Hospital
state: England
city: Stafford
country: United Kingdom
facility: Staffordshire General Hospital
state: England
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Taunton Somerset
country: United Kingdom
facility: Taunton and Somerset Hospital
state: England
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: England
city: Truro, Cornwall
country: United Kingdom
facility: Royal Cornwall Hospital
state: England
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
state: England
city: West Bromwich
country: United Kingdom
facility: Sandwell General Hospital
state: England
city: Wirral
country: United Kingdom
facility: Arrowe Park Hospital
state: England
city: Worcester
country: United Kingdom
facility: Worcester Royal Hospital
state: England
city: Worthing
country: United Kingdom
facility: Worthing Hospital
state: England
city: York
country: United Kingdom
facility: Cancer Care Center
state: England
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
state: Scotland
city: Airdrie
country: United Kingdom
facility: Monklands General Hospital
state: Scotland
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Edinburgh Cancer Centre at Western General Hospital
state: Scotland
city: Falkirk
country: United Kingdom
facility: Falkirk and District Royal Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Western Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Infirmary - Castle
state: Scotland
city: Glasgow
country: United Kingdom
facility: Victoria Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Southern General Hospital
state: Scotland
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
state: Scotland
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
state: Scotland
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
state: Scotland
city: Wakefield
country: United Kingdom
facility: Dorset Cancer Centre
state: Scotland
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clwyd Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: South West Wales Cancer Institute
state: Wales
city: Hereford
country: United Kingdom
facility: Hereford Hospitals
city: Slough, Berkshire
country: United Kingdom
facility: Wexham Park Hospital
city: Surrey
country: United Kingdom
facility: Kingston Hospital
Study officials:
affiliation: University Hospital of Wales
name: Alan K. Burnett, MD, FRCP
role: STUDY_CHAIR
References: