Clinical trial NCT00504764: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
Official title: APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Promyelocytic Leukemia
Keywords: Relapsed Acute Promyelocytic Leukemia
Arsenic Trioxide
Lead sponsor: PETHEMA Foundation
Sponsor class: OTHER
First posted: 2007-07-20
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 )

Primary outcomes:
measure: Evaluate the hematological and molecular remission rate after induction and consolidation with ATO
timeFrame: 1 year
measure: Evaluate the induction mortality with ATO in monotherapy
timeFrame: 1 year
measure: Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg
timeFrame: 1 year
Secondary outcomes:
measure: Evaluate kinetics of the MDR of PML/RARa during and after ATO
timeFrame: 2 years
measure: Evaluate the mortality related with postremission treatment
timeFrame: 1 year
measure: Side effects of ATO and the different treatments post-consolidation
timeFrame: 2 years
measure: Overall survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
state: Asturias
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Mataró
country: Spain
facility: Hospital de Mataró
state: Barcelona
city: Castello
country: Spain
facility: Hospital general de Castellón
state: Castellón
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
state: La Coruña
city: Alcorcón
country: Spain
facility: Hospital de Alcorcón
state: Madrid
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
state: Navarra
city: Tortosa
country: Spain
facility: Hospital Verge de la Cinta
state: Tarragona
city: Albacete
country: Spain
facility: Complejo Hospitalario Universitario de Albacete
city: Alcorcón
country: Spain
facility: Fundación Hospital Alcorcón
city: Alicante
country: Spain
facility: Hospital General de Alicante
city: Alzira
country: Spain
facility: Hospital de la Ribera
city: Avila
country: Spain
facility: Hospital Ntra. Sra. Sonsoles
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Valle Hebrón
city: Basurto
country: Spain
facility: Basurtuko Ospitalea
city: Bilbao
country: Spain
facility: Hospital de Cruces
city: Cáceres
country: Spain
facility: Complejo Hospitalario de Cáceres
city: Cádiz
country: Spain
facility: Hospital Puerta del Mar
city: Córdoba
country: Spain
facility: Complejo Hospitalario Reina Sofía
city: Donostia
country: Spain
facility: Hospital Donostia
city: Elda
country: Spain
facility: Hospital General de Elda
city: Fuenlabrada
country: Spain
facility: Hospital de Fuenlabrada
city: Granada
country: Spain
facility: Hospital Virgen de las Nieves
city: Guadalajara
country: Spain
facility: Hospital General de Guadalajara
city: Huelva
country: Spain
facility: Area Hospitalaria Juan Ramón Jimenez
city: Huesca
country: Spain
facility: Hospital de San Jorge
city: Jaen
country: Spain
facility: Hospital Médico Quirúrgico Ciudad de Jaén
city: Jerez de la Frontera
country: Spain
facility: Hospital de Jerez de la Frontera
city: La Coruña
country: Spain
facility: Hospital Juan Canalejo
city: Lanzarote
country: Spain
facility: Hospital General de Lanzarote
city: Leon
country: Spain
facility: Complejo Hospitalario León
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Lugo
country: Spain
facility: Complexo Hospitalario Xeral-Calde
city: Madrid
country: Spain
facility: Clínica La Concepción
city: Madrid
country: Spain
facility: Clínica Moncloa
city: Madrid
country: Spain
facility: Clínica Puerta de Hierro
city: Madrid
country: Spain
facility: Clínica Rúber
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Central de la Defensa
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos de Madrid
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital Doce de Octubre
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón, Madrid
city: Madrid
country: Spain
facility: Hospital la Paz
city: Manresa
country: Spain
facility: Althaia, Xarxa Asistencial de Manresa
city: Martorell
country: Spain
facility: Fundación Hospital Sant Joan de Déu de Martorell
city: Murcia
country: Spain
facility: Hospital General Morales Meseguer
city: Málaga
country: Spain
facility: . Hospital Clínico Universitario Virgen de la Victoria
city: Mérida
country: Spain
facility: Hospital de Mérida
city: Móstoles
country: Spain
facility: Hospital de Móstoles
city: Palencia
country: Spain
facility: Hospital del Río Carrión
city: Palma de Gran Canaria
country: Spain
facility: Hospital de Gran Canaria Doctor Negrín
city: Palma de Mallorca
country: Spain
facility: Hospital Son Dureta
city: Palma de Mallorca
country: Spain
facility: Hospital Son Llàtzer
city: Palma de Mallorca
country: Spain
facility: Hospital Verge del Toro
city: Pontevedra
country: Spain
facility: Complejo Hospitalario de Pontevedra_Hospital Montecelo
city: Pontevedra
country: Spain
facility: Complejo Hospitalario de Pontevedra_Hospital Provincial
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
city: Sagunto
country: Spain
facility: Hospital de Sagunto
city: Salamanca
country: Spain
facility: Hospital Clínico de Salamanca
city: Sant Pere de Ribes
country: Spain
facility: Clínica Sant Camil
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Segovia
country: Spain
facility: Hospital General de Segovia
city: Sevilla
country: Spain
facility: H.U. Virgen del Rocio
city: Tarragona
country: Spain
facility: Hospital Joan XXIII
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Toledo
country: Spain
facility: Hospital Nuestra Señora del Prado
city: Valencia
country: Spain
facility: Fundación Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Clínic
city: Valencia
country: Spain
facility: Hospital Dr. Peset
city: Valencia
country: Spain
facility: Hospital Francesc de Borja
city: Valencia
country: Spain
facility: Hospital General Universitario
city: Valencia
country: Spain
facility: Hospital La Fe
city: Valladolid
country: Spain
facility: Hospital Clínico de Valladolid
city: Valls
country: Spain
facility: Hospital Comarcal Pius de Valls
city: Vigo
country: Spain
facility: Complejo Hospitalario Xeral-Cies
city: Vinaros
country: Spain
facility: Comarcal de Vinaros
city: Vitoria
country: Spain
facility: Hospital Txagorritxu
city: Vizcaya
country: Spain
facility: Hospital de Galdakao
city: Zaragoza
country: Spain
facility: Hospital Clínico Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
Study officials:
affiliation: Hospital La Fe
name: Sanz Miguel Angel, Dr
role: STUDY_CHAIR
affiliation: Hospital Clinic of Barcelona
name: Esteve Jordi, Dr
role: STUDY_CHAIR
affiliation: Hospital General Universitario de Valencia
name: Montesinos Pau, Dr
role: STUDY_CHAIR
References: