Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

NCT ID: NCT00504764

Last Updated: 2014-10-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2014-10-31

Brief Summary

Summary Acute promyelocytic leukemia is defined by a characteristic morphology (AML FAB M3/M3v), by the specific translocation t(15;17) and its molecular correlates (PML/RARa and RARa/PML). Thereby it can be separated from all other forms of acute leukemia.

By all-trans retinoic acid in combination with chemotherapy cure rates of 70 to 80% can be reached. On average, about 10% of patients still die in the early phase of the treatment and about 20 to 30% relapse. Molecular monitoring of the minimal residual disease (MRD) by qualitative nested RT-PCR and quantitative REAL-time PCR of PML/RARa allows to follow the individual kinetics of MRD and to identify patients with an imminent hematological relapse.

A standardized treatment for patients with relapsed APL has not yet been established. With arsenic trioxide (ATO) monotherapy remission rates over 80% were achieved and long-lasting molecular remissions are described. The drug was mostly well tolerated. ATO exerts a dose dependent dual effect on APL blasts, apoptosis in higher and partial differentiation in lower concentrations. ATO was also successfully administered before allogeneic and autologous transplantation. ATO is approved for the treatment of relapsed and refractory APL in Europe and in the USA.

After remission induction, there are several options for postremission therapy Previous studies shows that risk of relapse is higher in patients treated with ATO postremission in monotherapy , than in other that receive ATO plus chemotherapy or transplantation (TPH). Also, compared with chemotherapy, ATO induction and consolidation has a favorable impact in posterior response to transplantation. It is due to a low toxicity or a best quality of remission to TPH. It seems better, for these reasons, the intensification with TPH (autologous or allogenic) in patients with relapsed APL treated with ATO. For another hand, patients no candidates to TPH can be treated with ATO combined with other active agents in APL, as ATRA, anthracyclines o Mylotarg

Detailed Description

Induction ATO 0.15 mg/kg/día IV in continuous perfusion 1-2 hours/day until complete response (CR) or maximum of 60 days.

Oral hydroxyurea treatment (initial dose 2 g/day)is recommended in patients with leucocyte counts at relapse >10x109/L or in the two first weeks of induction.

Isolated molecular relapsed patients will be treated with ATO (same dose) 5 days at week, during 6 weeks.

Consolidation ATO 0.15 mg/kg/día IV 5 days at week, during 5 weeks, combined with oral ATRA 45 mg/m²/day during the same 5 weeks.

Post-consolidation therapy TPH (autologous or allogenic) in candidate patients. In case of molecular remission, is recommended autologous-TPH.

Patients no candidates to auto-TPH or alo-TPH, should will follow treatment with ATO cycles + ATRA +/- Mylotarg.

1. Option Alo-TPH If PCR post-consolidation is negative is recommended auto-TPH. However, if alo-TPH is decided, it will be done immediately without preceding chemotherapy.

If PCR post-consolidation is positive, should done alo-TPH.

2. Option Auto-TPH If PCR post-consolidation is negative it will be administered one cycle of MTZ + Ara-C follow by auto-TPH.

In cas of failure: a) if patient has autologous stem cells preserved (PCR negative) are suitable for auto-TPH; b) patients with HLA-compatible donor who are suitable for allogenic stem cell transplantation should be transplanted; c) Patients who are not eligible for allogenic or autologous transplantation, receive various cycles with ATO + ATRA combined or not with Mylotarg.

If PCR post-consolidation is positive and patient is eligible for allogenic TPH, should be done a allogenic TPH.

If patient is no eligible for allogenic TPH or dont has compatible donor, will be administrate one cycle of MTZ + Ara-C and collect stem cells. Autologous transplantation will be done if after this cycle, a molecular remission is obtained. No molecular remission or no enough stem cells collection, patient follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

3. ATO + ATRA combined or no with Mylotarg Patients no eligible to autologous TPH or allogenic TPH follows treatment with subsequent cycles of ATO + ATRA combined or no with Mylotarg.

If Mylotarg is no possible, treatment will be with subsequent cycles of ATO + ATRA.

ATO + ATRA + Mylotarg: Mylotarg 6 mg/m2 day 1, ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15. Doses of mylotarg should be reduced to 3 mg/m2 in patients aged over 60 years. Administration of 3 cycles with a month interval, follow of 3 to 6 cycles of ATO + ATRA without Mylotarg. After, ATRA 45 mg/m2/d 15 days every 3 months until complete two years of maintenance.

ATO + ATRA: ATO 0.15 mg/kg days 1 to 5 and 8 to 12, and ATRA 45 mg/m2/d days 1 to 15, every 29 days. Administration of 9 cycles, and followed by ATRA 45 mg/m2/d during 15 days every 3 months until complete two years of maintenance.

Conditions

Acute Promyelocytic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

Arsenic Trioxide

Induction ATO 0.15 mg/kg/day IV until CR or a maximum of 60 days In isolated molecular relapse ATO will be administered at same dose, 5 days a week, during 6 weeks.

Consolidation ATO 0.15 mg/kg/day IV 5 days week, during 5 weeks

Intervention Type: DRUG

Autologous Transplantation

Autologous Transplantation

Intervention Type: PROCEDURE

Allogenic Transplantation

Allogenic Transplantation

Intervention Type: PROCEDURE

ATRA

Consolidation: ATRA 45 mg/m²/day oral during 5 weeks

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• ECOG ≤ 3.
• Patients in first or subsequent hematological or molecular relapse of APL
• Persistence of a positive PCR (positive PCR after 3 consolidation cycles of first line therapy).
• Diagnostic measures Confirmation of relapse by RT-PCR of PML/RARa, cytogenetics, FISH or positive PGM3.
• Age over 18 years (No upper age limit)
• Informed consent of the patient

Exclusion Criteria

• ECOG 4.
• Heart failure NYHA grade III and IV.
• Renal or hepatic failure WHO grade ³III
• Positive HIV.
• Psychological dysfunction
• Associated active neoplasia
• Pregnancy.
• Arsenic Hypersensibility.
• QTc-interval prolonged over 460 msec before therapy (normal electrolytes, no other drugs prolonging the QT-interval )

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PETHEMA Foundation

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sanz Miguel Angel, Dr

Role: STUDY_CHAIR

Hospital La Fe

Esteve Jordi, Dr

Role: STUDY_CHAIR

Hospital Clinic of Barcelona

Montesinos Pau, Dr

Role: STUDY_CHAIR

Hospital General Universitario de Valencia

Locations

Hospital General de Alicante

Alicante, Alicante, Spain

Hospital Ntra. Sra. Sonsoles

Ávila, Avila, Spain

Hospital Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, Barcelona, Spain

Hospital del Mar

Barcelona, Barcelona, Spain

Hospital Valle Hebrón

Barcelona, Barcelona, Spain

Hospital de Mataró

Mataró, Barcelona, Spain

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, Spain

Hospital general de Castellón

Castelló, Castellón, Spain

Hospital Puerta del Mar

Cadiz, Cádiz, Spain

Complejo Hospitalario Reina Sofía

Córdoba, Córdoba, Spain

Hospital Virgen de las Nieves

Granada, Granada, Spain

Hospital Médico Quirúrgico Ciudad de Jaén

Jaén, Jaen, Spain

Hospital Juan Canalejo

A Coruña, La Coruña, Spain

Complejo Hospitalario Universitario de Santiago

Santiago de Compostela, La Coruña, Spain

Hospital Arnau de Vilanova

Lleida, Lleida, Spain

Hospital de Alcorcón

Alcorcón, Madrid, Spain

Clínica La Concepción

Madrid, Madrid, Spain

Clínica Puerta de Hierro

Madrid, Madrid, Spain

Hospital Clínico San Carlos de Madrid

Madrid, Madrid, Spain

Hospital General Universitario Gregorio Marañón, Madrid

Madrid, Madrid, Spain

. Hospital Clínico Universitario Virgen de la Victoria

Málaga, Málaga, Spain

Clínica Universitaria de Navarra

Pamplona, Navarre, Spain

Hospital del Río Carrión

Palencia, Palencia, Spain

Hospital Son Dureta

Palma de Mallorca, Palma de Mallorca, Spain

Hospital Son Llàtzer

Palma de Mallorca, Palma de Mallorca, Spain

Hospital Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital Joan XXIII

Tarragona, Tarragona, Spain

Hospital Verge de la Cinta

Tortosa, Tarragona, Spain

Hospital Clínic

Valencia, Valencia, Spain

Hospital General Universitario

Valencia, Valencia, Spain

Hospital La Fe

Valencia, Valencia, Spain

Complejo Hospitalario Xeral-Cies

Vigo, Vigo, Spain

Hospital Clínico Lozano Blesa

Zaragoza, Zaragoza, Spain

Complejo Hospitalario Universitario de Albacete

Albacete, , Spain

Fundación Hospital Alcorcón

Alcorcón, , Spain

Hospital de la Ribera

Alzira, , Spain

Hospital Clinic

Barcelona, , Spain

Basurtuko Ospitalea

Basurto, , Spain

Hospital de Cruces

Bilbao, , Spain

Complejo Hospitalario de Cáceres

Cáceres, , Spain

Hospital Donostia

Donostia / San Sebastian, , Spain

Hospital General de Elda

Elda, , Spain

Hospital de Fuenlabrada

Fuenlabrada, , Spain

Hospital General de Guadalajara

Guadalajara, , Spain

Area Hospitalaria Juan Ramón Jimenez

Huelva, , Spain

Hospital de San Jorge

Huesca, , Spain

Hospital de Jerez de la Frontera

Jerez de la Frontera, , Spain

Hospital General de Lanzarote

Lanzarote, , Spain

Complejo Hospitalario León

León, , Spain

Complexo Hospitalario Xeral-Calde

Lugo, , Spain

Clínica Moncloa

Madrid, , Spain

Clínica Puerta de Hierro

Madrid, , Spain

Clínica Rúber

Madrid, , Spain

Fundación Jiménez Díaz

Madrid, , Spain

Hospital 12 de Octubre

Madrid, , Spain

Hospital Central de la Defensa

Madrid, , Spain

Hospital de la Princesa

Madrid, , Spain

Hospital Doce de Octubre

Madrid, , Spain

Hospital la Paz

Madrid, , Spain

Althaia, Xarxa Asistencial de Manresa

Manresa, , Spain

Fundación Hospital Sant Joan de Déu de Martorell

Martorell, , Spain

Hospital de Mérida

Mérida, , Spain

Hospital de Móstoles

Móstoles, , Spain

Hospital General Morales Meseguer

Murcia, , Spain

Hospital de Gran Canaria Doctor Negrín

Palma de Gran Canaria, , Spain

Hospital Verge del Toro

Palma de Mallorca, , Spain

Complejo Hospitalario de Pontevedra_Hospital Montecelo

Pontevedra, , Spain

Complejo Hospitalario de Pontevedra_Hospital Provincial

Pontevedra, , Spain

Corporació Sanitaria Parc Taulí

Sabadell, , Spain

Hospital de Sagunto

Sagunto, , Spain

Hospital Clínico de Salamanca

Salamanca, , Spain

Clínica Sant Camil

Sant Pere de Ribes, , Spain

Hospital Universitario de Canarias

Santa Cruz de Tenerife, , Spain

Hospital General de Segovia

Segovia, , Spain

H.U. Virgen del Rocio

Seville, , Spain

Hospital Nuestra Señora del Prado

Toledo, , Spain

Fundación Instituto Valenciano de Oncología

Valencia, , Spain

Hospital Dr. Peset

Valencia, , Spain

Hospital Francesc de Borja

Valencia, , Spain

Hospital Clínico de Valladolid

Valladolid, , Spain

Hospital Comarcal Pius de Valls

Valls, , Spain

Comarcal de Vinaros

Vinaròs, , Spain

Hospital Txagorritxu

Vitoria-Gasteiz, , Spain

Hospital de Galdakao

Vizcaya, , Spain

Hospital Miguel Servet

Zaragoza, , Spain

Countries

Spain

Related Links

http://www.aehh.org

Spanish association of Haematology

Other Identifiers

LAP-R2007

Identifier Type: -

Identifier Source: org_study_id