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

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

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

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Fludarabine; Drug: Topotecan; Drug: Cytarabine

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • A Coruña, Spain
    • Hospital Juan Canalejo
  • Avila, Spain
    • Hospital Ntra. Sra. de Sonsoles
  • Badalona, Spain
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Barcelona, Spain
    • Centro Medico Teknon
  • Barcelona, Spain
    • Hospital Sant Pau
  • Burgos, Spain
    • Hospital General Yague
  • Cadiz, Spain
    • Hospital de Jerez
  • Lugo, Spain
    • Complejo Hospitalario Xeral-Calde
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • Hospital Clinico Universitario San Carlos
  • Málaga, Spain
    • Hospital Virgen de la Victoria
  • Tarragona, Spain
    • Hosptal Joan XXIII
  • Tortosa, Spain
    • Hospital Verge de la Cinta
  • Valladolid, Spain
    • Hospital Rio Hortega
  • Zaragoza, Spain
    • Hospital Clinico Lozano Blesa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To treat with the combination FLAT patients with acute myeloid leukaemia that they present a primary resistance	one month
•To treat with the combination FLAT a relapse in the first 12 months after reach the first CR with standard treatment	one month
To treat with combination FLAT patients can't receive the standard treatment due any cause	one month

Secondary Outcome Measures

Outcome Measure	Time Frame
Improve the interval free survival and global survival	one year
To avoid the toxicities produced by other chemotherapy in this type of patients	4 months
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

Collaborators and Investigators

• Sponsor: PETHEMA Foundation
• Investigators: Study Chair: Bueno Javier, Dr, Hospital Vall d'Hebron; Principal Investigator: Sanchez Eva, Dr, Hospital Vall d'Hebron

Publications and helpful links

General Publications

• Bishop JF. The treatment of adult acute myeloid leukemia. Semin Oncol. 1997 Feb;24(1):57-69.
• Stone RM. Treatment of acute myeloid leukemia: state-of-the-art and future directions. Semin Hematol. 2002 Jul;39(3 Suppl 2):4-10. doi: 10.1053/shem.2002.35977.
• Lister TA, Rohatiner AZ. The treatment of acute myelogenous leukemia in adults. Semin Hematol. 1982 Jul;19(3):172-92. Review.
• 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. doi: 10.1056/NEJM199812033392301.
• 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. doi: 10.1016/s0140-6736(86)92674-7.
• 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. No abstract available.
• 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. doi: 10.3109/10428199709059682.
• Germann UA. P-glycoprotein--a mediator of multidrug resistance in tumour cells. Eur J Cancer. 1996 Jun;32A(6):927-44. doi: 10.1016/0959-8049(96)00057-3. No abstract available.
• 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. doi: 10.1200/JCO.1989.7.8.1071.
• Nussler 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.
• 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.
• 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.
• 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. No abstract available.
• Frewin RJ, Johnson SA. The role of purine analogue combinations in the management of acute leukemias. Hematol Oncol. 2001 Dec;19(4):151-7. doi: 10.1002/hon.686.
• 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. doi: 10.1200/JCO.1997.15.1.44.
• Sierra J, Brunet S, Granena A, Olive T, Bueno J, Ribera JM, Petit J, Besses C, Llorente A, Guardia R, Macia J, Rovira M, Badell I, Vela E, Diaz de Heredia C, Vivancos P, Carreras E, Feliu E, Montserrat E, Julia 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. doi: 10.1200/JCO.1996.14.4.1353.
• 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. doi: 10.1056/NEJM199410063311402.
• 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. doi: 10.1200/JCO.1996.14.9.2511.

Helpful Links

• Spanish association of Haematology

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Study Completion (Actual): April 1, 2007

Study Registration Dates

• First Submitted: June 1, 2007
• First Submitted That Met QC Criteria: June 19, 2007
• First Posted (Estimate): June 20, 2007

Study Record Updates

• Last Update Posted (Estimate): November 18, 2008
• Last Update Submitted That Met QC Criteria: November 17, 2008
• Last Verified: November 1, 2008

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Multi Drug Resistance
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Fludarabine; Cytarabine; Topotecan
• Other Study ID Numbers: LAMR 2003; FLAT