Clinical trial NCT00488709: Fludarabine, Cytarabine, Topotecan in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: FLAT: Fludarabine, Cytarabine and Topotecan in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Multi Drug Resistance
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
First posted: 2007-06-20
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: To treat with the combination FLAT patients with acute myeloid leukaemia that they present a primary resistance
timeFrame: one month
measure: •To treat with the combination FLAT a relapse in the first 12 months after reach the first CR with standard treatment
timeFrame: one month
measure: To treat with combination FLAT patients can't receive the standard treatment due any cause
timeFrame: one month
Secondary outcomes:
measure: Improve the interval free survival and global survival
timeFrame: one year
measure: To avoid the toxicities produced by other chemotherapy in this type of patients
timeFrame: 4 months
measure: 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
timeFrame: 6 months
Other outcomes:
Locations:
city: A Coruña
country: Spain
facility: Hospital Juan Canalejo
city: Avila
country: Spain
facility: Hospital Ntra. Sra. de Sonsoles
city: Badalona
country: Spain
facility: Hospital germans Trias i Pujol
city: Barcelona
country: Spain
facility: Centro Médico Teknon
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Burgos
country: Spain
facility: Hospital General Yagüe
city: Cadiz
country: Spain
facility: Hospital de Jerez
city: Lugo
country: Spain
facility: Complejo hospitalario Xeral-Calde
city: Madrid
country: Spain
facility: Hospital Clínico Universitario San Carlos
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Málaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Tarragona
country: Spain
facility: Hosptal Joan XXIII
city: Tortosa
country: Spain
facility: Hospital Verge de la Cinta
city: Valladolid
country: Spain
facility: Hospital Rio Hortega
city: Zaragoza
country: Spain
facility: Hospital Clinico Lozano Blesa
Study officials:
affiliation: Hospital Vall d'Hebron
name: Bueno Javier, Dr
role: STUDY_CHAIR
affiliation: Hospital Vall d'Hebron
name: Sanchez Eva, Dr
role: PRINCIPAL_INVESTIGATOR
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