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NCT00454480

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

Last Updated: 2013-08-26

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

2000 participants

Study Classification

INTERVENTIONAL

Study Start Date

2006-08-31

Brief Summary

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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

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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.

Conditions

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Leukemia Myelodysplastic Syndromes

Keywords

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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

Study Design

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Allocation Method

Intervention Type PROCEDURE

nonmyeloablative allogeneic hematopoietic stem cell transplantation

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

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)

Eligible Sex

ALL

Accepts Healthy Volunteers

Principal Investigators

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Alan K. Burnett, MD, FRCP

Role: STUDY_CHAIR

University Hospital of Wales

Identifier Source: org_study_id

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

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Interventions

alemtuzumab

arsenic trioxide

azacitidine

busulfan

clofarabine

cytarabine

daunorubicin hydrochloride

fludarabine phosphate

gemtuzumab ozogamicin

melphalan

tipifarnib

DNA methylation analysis

cytogenetic analysis

gene expression analysis

mutation analysis

diagnostic laboratory biomarker analysis

immunologic technique

allogeneic hematopoietic stem cell transplantation

nonmyeloablative allogeneic hematopoietic stem cell transplantation

Eligibility Criteria

Inclusion Criteria

Sponsors

The University of New South Wales

Principal Investigators

Alan K. Burnett, MD, FRCP

Locations

Ysbyty Gwynedd

University Hospital of Wales

Basingstoke and North Hampshire NHS Foundation Trust

Royal United Hospital

Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust

Birmingham Heartlands Hospital

Blackpool Victoria Hospital

Royal Bournemouth Hospital

Bradford Royal Infirmary

Sussex Cancer Centre at Royal Sussex County Hospital

Queen's Hospital

West Suffolk Hospital

Addenbrooke's Hospital

Kent and Canterbury Hospital

St. Helier Hospital

Gloucestershire Oncology Centre at Cheltenham General Hospital

Countess of Chester Hospital

Chesterfield Royal Hospital

Saint Richards Hospital

Walsgrave Hospital

Mayday University Hospital

Derbyshire Royal Infirmary

Doncaster Royal Infirmary

Dorset County Hospital

Russells Hall Hospital

Royal Devon and Exeter Hospital

Medway Maritime Hospital

Harrogate District Hospital

Northwick Park Hospital

Hemel Hempstead General

Wycombe General Hospital

Hull Royal Infirmary

Ipswich Hospital

West Middlesex University Hospital

Kettering General Hosptial

Kidderminster Hospital

Crosshouse Hospital

Leeds General Infirmary

Leicester Royal Infirmary

Royal Liverpool University Hospital

Aintree University Hospital

Saint Bartholomew's Hospital

UCL Cancer Institute

University Hospital Lewisham

Queen Elizabeth Hospital - Woolwich