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

Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00454480
• Other study ID #: CDR0000526121
• Secondary ID: UHW-AML16EU-2067
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: March 27, 2007
• Last updated: August 23, 2013
• Start date: August 2006

Study information

• Verified date: August 2008
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unspecified
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2000
• Est. primary completion date: August 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Allocation: Randomized, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Biological:
• alemtuzumab

Drug:
• arsenic trioxide

• azacitidine

• busulfan

• clofarabine

• cytarabine

• daunorubicin hydrochloride

• fludarabine phosphate

• gemtuzumab ozogamicin

• melphalan

• tipifarnib

Genetic:
• DNA methylation analysis

• cytogenetic analysis

• gene expression analysis

• mutation analysis

Other:
• diagnostic laboratory biomarker analysis

• immunologic technique

Procedure:
• allogeneic hematopoietic stem cell transplantation

• nonmyeloablative allogeneic hematopoietic stem cell transplantation

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen	Scotland
United Kingdom	Monklands General Hospital	Airdrie	Scotland
United Kingdom	Ysbyty Gwynedd	Bangor	Wales
United Kingdom	Basingstoke and North Hampshire NHS Foundation Trust	Basingstoke	England
United Kingdom	Royal United Hospital	Bath	England
United Kingdom	Birmingham Heartlands Hospital	Birmingham	England
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	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	University Hospital of Wales	Cardiff	Wales
United Kingdom	St. Helier Hospital	Carshalton	England
United Kingdom	Gloucestershire Oncology Centre at Cheltenham General Hospital	Cheltenham	England
United Kingdom	Countess of Chester Hospital	Chester	England
United Kingdom	Chesterfield Royal Hospital	Chesterfield	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	Ninewells Hospital	Dundee	Scotland
United Kingdom	Edinburgh Cancer Centre at Western General Hospital	Edinburgh	Scotland
United Kingdom	Royal Devon and Exeter Hospital	Exeter	England
United Kingdom	Falkirk and District Royal Infirmary	Falkirk	Scotland
United Kingdom	Medway Maritime Hospital	Gillingham Kent	England
United Kingdom	Royal Infirmary - Castle	Glasgow	Scotland
United Kingdom	Southern General Hospital	Glasgow	Scotland
United Kingdom	Victoria Infirmary	Glasgow	Scotland
United Kingdom	Western Infirmary	Glasgow	Scotland
United Kingdom	Harrogate District Hospital	Harrogate	England
United Kingdom	Northwick Park Hospital	Harrow	England
United Kingdom	Hemel Hempstead General	Hemel Hempstead	England
United Kingdom	Hereford Hospitals	Hereford
United Kingdom	Wycombe General Hospital	High Wycombe	England
United Kingdom	Hull Royal Infirmary	Hull	England
United Kingdom	Raigmore Hospital	Inverness	Scotland
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	Victoria Hospital	Kirkcaldy	Scotland
United Kingdom	Leeds General Infirmary	Leeds	England
United Kingdom	Leicester Royal Infirmary	Leicester	England
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Royal Liverpool University Hospital	Liverpool	England
United Kingdom	King's College Hospital	London	England
United Kingdom	Queen Elizabeth Hospital - Woolwich	London	England
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	UCL Cancer Institute	London	England
United Kingdom	University College Hospital - London	London	England
United Kingdom	University Hospital Lewisham	London	England
United Kingdom	Maidstone Hospital	Maidstone	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Manchester Royal Infirmary	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	Royal Alexandra Hospital	Paisley	Scotland
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	Glan Clwyd Hospital	Rhyl, Denbighshire	Wales
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	Wexham Park Hospital	Slough, Berkshire
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	Kingston Hospital	Surrey
United Kingdom	Royal Marsden - Surrey	Sutton	England
United Kingdom	South West Wales Cancer Institute	Swansea	Wales
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	Dorset Cancer Centre	Wakefield	Scotland
United Kingdom	Pinderfields General Hospital	Wakefield	Scotland
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

Sponsors (1)

Lead Sponsor	Collaborator
The University of New South Wales

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival			No
Primary	Achievement of complete remission and reasons for failure			No
Primary	Duration of remission, relapse rates, and deaths			No
Primary	Hematological and nonhematological toxicity			Yes
Primary	Supportive care requirements (and other aspects of health economics)			No