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

Sponsor

The University of New South Wales (Other)

Overall Status

Completed

CT.gov ID

NCT00454480

Collaborator

(none)

2,000

Enrollment

Locations

20.8

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes	Biological: alemtuzumab Drug: arsenic trioxide Drug: azacitidine Drug: busulfan Drug: clofarabine Drug: cytarabine Drug: daunorubicin hydrochloride Drug: fludarabine phosphate Drug: gemtuzumab ozogamicin Drug: melphalan Drug: tipifarnib Genetic: DNA methylation analysis Genetic: cytogenetic analysis Genetic: gene expression analysis Genetic: mutation analysis Other: diagnostic laboratory biomarker analysis Other: immunologic technique Procedure: allogeneic hematopoietic stem cell transplantation Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

2000 participants

Allocation:

Randomized

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2006

Actual Primary Completion Date :

Aug 1, 2012

Outcome Measures

Primary Outcome Measures

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) []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

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