Fludarabine, Cytarabine, Topotecan in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Acute Myeloid Leukemia Clinical Trial

— FLAT  

Official title:

FLAT: Fludarabine, Cytarabine and Topotecan in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00488709
• Other study ID #: LAMR 2003
• Secondary ID: FLAT
• Status: Completed
• Phase: Phase 4
• First received: June 1, 2007
• Last updated: November 17, 2008
• Start date: May 2003
• Est. completion date: April 2007

Study information

• Verified date: November 2008
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The study is designed with drugs used frequently in the treatment of AML, but with a new combination less toxic,and effective in AML multidrug resistant.

Justification:

• The AML patients with primary resistance or relapsed in the first 12 months after CR, have second line chemotherapy low response rate .

• These patients with AML with primary resistance or relapse, that reach remission after a rescue treatment, have an interval free survival and a global survival very short

• Probably the resistance to the treatments is in relation to different forms expression of the MDR.

• Complete remission is considered valid evaluation, because every patient who should obtain a CR can be considered to be eligible for a possible curative treatment: Ara-C administration to high doses or the TPH treatment

Description:

It is a protocol opened, multicentric, led to end to increase a) the rate of complete responses, b) the duration of the response, c) the free survival of disease and d) the global survival.

The included subjects will be patients with primary or secondary AML that they have not achieved the CR after the standard treatment with an anthracycline or derivative associated with Ara-C or have relapsed in the first 12 months after having achieved the RC. Also patients with AML that, for any reason, they could not receive the standard treatment with anthracycline and Ara-C, will be included

Cycle of induction. The patients will be treated by FLAT according to the following scheme:

• FLUDARABINE, 30 mg/m2 i.v. (In 1 hour) on the 1st to 4.

• CITARABINE, 2 g/m2 i.v. (In 4 hours), four hours after finishing the fludarabine, on the 1st to 4.

• TOPOTECAN, 1,5 mg/m2 i.v. (In 4 hours), four hours after finishing the cytarabine, on the 1st to 4.

When the patient starts recovering the hematological counts, and providing that has not blasts in the peripheral blood (SP), he will become a medullar revision (MO):

• If MO presents severe hypocellularity without blasts,no therapeutic measurement will take and there will repeat revisions weekly and MDR's study up to the CR or the blasts appearance.

• If in MO persist blasts (>5 %) but have diminished less than 50 % of the initial number, the induction will be continued by the FLAT's second shift.

• If in MO persists more than 50 % of blasts of the initial number, the patient goes out of the protocol and it will be treated as an agreement by the criterion of the center.

The patients who have managed to enter CR will receive a cycle of consolidation as soon as possible and always within 2 months from the day in which they received first FLAT's dose. The cycle of consolidation consists of another FLAT's scheme to the same doses.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: April 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subjects of 18 years of age or major, with diagnosis of primary or secondary AML, confirmed cytologically, that fulfill one of the following conditions:

• Do not reach a CR after the conventional treatment.

• Relapse in the first 12 months after a CR. During remission, patients can have be treated by a transplant. The relapse is defined as the presence of blasts in peripheric blood or the presence of >5 % of blasts in MO.

• Not participation in a clinical trial.

2. ECOG < o = 2

3. Considered suitable patients for an intensive chemotherapy

4. Informed consent

Exclusion Criteria:

1. Pelvic or spinal radiotherapy in 4 weeks before the incorporation in the protocol.

2. Acute promyelocytic leukaemia

3. First line chemotherapy for AML which has contained fludarabine or topotecan.

4. Active or chronic hepatitis or hepatic cirrhosis.

5. Positivity known to the virus of the human immunodeficiency (HIV)

6. Pregnant or breastfeeding patients.

7. Patients with deterioration of the functions hepatic or renal, defined for the following values base them of laboratory:

• AST or ALT >2,5 times the top limit of the normality of the center (LSNC)

• Alkaline phosphatase >2,5 times the LSNC

• Total bilirubin value >2 times the LSNC

• Creatinine value >2 times the LSNC after a suitable hydration

8. Precedents of intervention of major surgery in 2 weeks before the incorporation in the protocol.

9. Patients with disease serious or not controlled (for example not controlled diabetes, infection, hypertension, etc.).

10. Patients who have received other cytotoxic drugs (except hydroxyurea to reduce the leucocytosis) as treatment of the current relapse or of the resistance, in 4 weeks before the protocol.

11. Patients with hypersensitivity known to someone of the drugs of the protocol.

12. Patients treated previously with growth factors with purposes of sensibilization.

13. Patients with psychological, intellectual or sensitive dysfunction that can reduce his capacity of comprehension and fulfillment of the protocol.

14. Patients treated before with FLAT.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Topotecan

• Fludarabine

• Cytarabine

Locations

Country	Name	City	State
Spain	Hospital Juan Canalejo	A Coruña
Spain	Hospital Ntra. Sra. de Sonsoles	Avila
Spain	Hospital germans Trias i Pujol	Badalona
Spain	Centro Médico Teknon	Barcelona
Spain	Hospital Sant Pau	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital General Yagüe	Burgos
Spain	Hospital de Jerez	Cadiz
Spain	Complejo hospitalario Xeral-Calde	Lugo
Spain	Hospital Clínico Universitario San Carlos	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Virgen de la Victoria	Málaga
Spain	Hosptal Joan XXIII	Tarragona
Spain	Hospital Verge de la Cinta	Tortosa
Spain	Hospital Rio Hortega	Valladolid
Spain	Hospital Clinico Lozano Blesa	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Country where clinical trial is conducted

Spain, 

References & Publications (18)

3. Lister TA, Rohatiner AZS. The treatment of adult acute leukaemia in adults. Sem Hematol 1982; 19:172

Bennett CL, Smith TJ, Weeks JC, Bredt AB, Feinglass J, Fetting JH, Hillner BE, Somerfield MR, Winn RJ. Use of hematopoietic colony-stimulating factors: the American Society of Clinical Oncology survey. The Health Services Research Committee of the American Society of Clinical Oncology. J Clin Oncol. 1996 Sep;14(9):2511-20. — View Citation

Bishop JF. The treatment of adult acute myeloid leukemia. Semin Oncol. 1997 Feb;24(1):57-69. Review. — View Citation

Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998 Dec 3;339(23):1649-56. — View Citation

Del Poeta G, Venditti A, Aronica G, Stasi R, Cox MC, Buccisano F, Bruno A, Tamburini A, Suppo G, Simone MD, Epiceno AM, Del Moro B, Masi M, Papa G, Amadori S. P-glycoprotein expression in de novo acute myeloid leukemia. Leuk Lymphoma. 1997 Oct;27(3-4):257-74. — View Citation

Frewin RJ, Johnson SA. The role of purine analogue combinations in the management of acute leukemias. Hematol Oncol. 2001 Dec;19(4):151-7. Review. — View Citation

Germann UA. P-glycoprotein--a mediator of multidrug resistance in tumour cells. Eur J Cancer. 1996 Jun;32A(6):927-44. Review. — View Citation

Hendricks CB, Rowinsky EK, Grochow LB, Donehower RC, Kaufmann SH. Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. Cancer Res. 1992 Apr 15;52(8):2268-78. — View Citation

Keating MJ, Kantarjian H, Smith TL, Estey E, Walters R, Andersson B, Beran M, McCredie KB, Freireich EJ. Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol. 1989 Aug;7(8):1071-80. — View Citation

Leoni F, Ciolli S, Nozzoli C, Santini V, Fanci R, Rossi Ferrini P. Fludarabine, cytarabine and topotecan (FLAT) as induction therapy for acute myeloid leukemia in the elderly: a preliminary report. Haematologica. 2001 Jan;86(1):104. — View Citation

Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E 3rd. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994 Oct 6;331(14):896-903. — View Citation

Michelutti A, Michieli M, Damiani D, Melli C, Ermacora A, Grimaz S, Candoni A, Russo D, Fanin R, Baccarani M. Effect of fludarabine and arabinosylcytosine on multidrug resistant cells. Haematologica. 1997 Mar-Apr;82(2):143-7. — View Citation

Nüssler V, Pelka-Fleischer R, Zwierzina H, Nerl C, Beckert B, Gieseler F, Diem H, Ledderose G, Gullis E, Sauer H, Wilmanns W. P-glycoprotein expression in patients with acute leukemia-clinical relevance. Leukemia. 1996 Jul;10 Suppl 3:S23-S31. — View Citation

Rees JK, Gray RG, Swirsky D, Hayhoe FG. Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial. Lancet. 1986 Nov 29;2(8518):1236-41. — View Citation

Seiter K, Feldman EJ, Halicka HD, Traganos F, Darzynkiewicz Z, Lake D, Ahmed T. Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia. J Clin Oncol. 1997 Jan;15(1):44-51. — View Citation

Sierra J, Brunet S, Grañena A, Olivé T, Bueno J, Ribera JM, Petit J, Besses C, Llorente A, Guardia R, Macía J, Rovira M, Badell I, Vela E, Díaz de Heredia C, Vivancos P, Carreras E, Feliu E, Montserrat E, Julía A, Cubells J, Rozman C, Domingo A, Ortega JJ. Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation. J Clin Oncol. 1996 Apr;14(4):1353-63. — View Citation

Stone RM. Treatment of acute myeloid leukemia: state-of-the-art and future directions. Semin Hematol. 2002 Jul;39(3 Suppl 2):4-10. Review. — View Citation

Vey N, Keating M, Giles F, Cortes J, Beran M, Estey E. Effect of complete remission on survival in patients with acute myelogenous leukemia receiving first salvage therapy. Blood. 1999 May 1;93(9):3149-50. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To treat with the combination FLAT patients with acute myeloid leukaemia that they present a primary resistance		one month
Primary	•To treat with the combination FLAT a relapse in the first 12 months after reach the first CR with standard treatment		one month
Primary	To treat with combination FLAT patients can't receive the standard treatment due any cause		one month
Secondary	Improve the interval free survival and global survival		one year
Secondary	To avoid the toxicities produced by other chemotherapy in this type of patients		4 months
Secondary	To determine the existing association between the response to the treatment with FLAT and the expression of Multi Drug Resistance (MDR) in the acute myeloid leukaemia		6 months

External Links

•   Pethema Foundation web
•   Spanish association of Haematology