Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Acute Promyelocytic Leukemia Clinical Trial

Official title:

APL-R2007: Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00504764
• Other study ID #: LAP-R2007
• Status: Completed
• Phase: Phase 4
• First received: July 19, 2007
• Last updated: October 27, 2014
• Start date: July 2007
• Est. completion date: October 2014

Study information

• Verified date: October 2014
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: October 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 )

Study Design

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

Related Conditions & MeSH terms

• Acute Promyelocytic Leukemia
• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

Drug:
• 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

Procedure:
• Autologous Transplantation
Autologous Transplantation
• Allogenic Transplantation
Allogenic Transplantation

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

Locations

Country	Name	City	State
Spain	Complejo Hospitalario Universitario de Albacete	Albacete
Spain	Fundación Hospital Alcorcón	Alcorcón
Spain	Hospital de Alcorcón	Alcorcón	Madrid
Spain	Hospital General de Alicante	Alicante
Spain	Hospital de la Ribera	Alzira
Spain	Hospital Ntra. Sra. Sonsoles	Avila
Spain	Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Valle Hebrón	Barcelona
Spain	Basurtuko Ospitalea	Basurto
Spain	Hospital de Cruces	Bilbao
Spain	Complejo Hospitalario de Cáceres	Cáceres
Spain	Hospital Puerta del Mar	Cádiz
Spain	Hospital general de Castellón	Castello	Castellón
Spain	Complejo Hospitalario Reina Sofía	Córdoba
Spain	Hospital Donostia	Donostia
Spain	Hospital General de Elda	Elda
Spain	Hospital de Fuenlabrada	Fuenlabrada
Spain	Hospital Virgen de las Nieves	Granada
Spain	Hospital General de Guadalajara	Guadalajara
Spain	Area Hospitalaria Juan Ramón Jimenez	Huelva
Spain	Hospital de San Jorge	Huesca
Spain	Hospital Médico Quirúrgico Ciudad de Jaén	Jaen
Spain	Hospital de Jerez de la Frontera	Jerez de la Frontera
Spain	Hospital Juan Canalejo	La Coruña
Spain	Hospital General de Lanzarote	Lanzarote
Spain	Complejo Hospitalario León	Leon
Spain	Hospital Arnau de Vilanova	Lleida
Spain	Complexo Hospitalario Xeral-Calde	Lugo
Spain	Clínica La Concepción	Madrid
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 Clínico San Carlos de Madrid	Madrid
Spain	Hospital de la Princesa	Madrid
Spain	Hospital Doce de Octubre	Madrid
Spain	Hospital General Universitario Gregorio Marañón, Madrid	Madrid
Spain	Hospital la Paz	Madrid
Spain	. Hospital Clínico Universitario Virgen de la Victoria	Málaga
Spain	Althaia, Xarxa Asistencial de Manresa	Manresa
Spain	Fundación Hospital Sant Joan de Déu de Martorell	Martorell
Spain	Hospital de Mataró	Mataró	Barcelona
Spain	Hospital de Mérida	Mérida
Spain	Hospital de Móstoles	Móstoles
Spain	Hospital General Morales Meseguer	Murcia
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Hospital del Río Carrión	Palencia
Spain	Hospital de Gran Canaria Doctor Negrín	Palma de Gran Canaria
Spain	Hospital Son Dureta	Palma de Mallorca
Spain	Hospital Son Llàtzer	Palma de Mallorca
Spain	Hospital Verge del Toro	Palma de Mallorca
Spain	Clínica Universitaria de Navarra	Pamplona	Navarra
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 Marqués de Valdecilla	Santander
Spain	Complejo Hospitalario Universitario de Santiago	Santiago de Compostela	La Coruña
Spain	Hospital General de Segovia	Segovia
Spain	H.U. Virgen del Rocio	Sevilla
Spain	Hospital Joan XXIII	Tarragona
Spain	Hospital Universitario de Canarias	Tenerife
Spain	Hospital Nuestra Señora del Prado	Toledo
Spain	Hospital Verge de la Cinta	Tortosa	Tarragona
Spain	Fundación Instituto Valenciano de Oncología	Valencia
Spain	Hospital Clínic	Valencia
Spain	Hospital Dr. Peset	Valencia
Spain	Hospital Francesc de Borja	Valencia
Spain	Hospital General Universitario	Valencia
Spain	Hospital La Fe	Valencia
Spain	Hospital Clínico de Valladolid	Valladolid
Spain	Hospital Comarcal Pius de Valls	Valls
Spain	Complejo Hospitalario Xeral-Cies	Vigo
Spain	Comarcal de Vinaros	Vinaros
Spain	Hospital Txagorritxu	Vitoria
Spain	Hospital de Galdakao	Vizcaya
Spain	Hospital Clínico Lozano Blesa	Zaragoza
Spain	Hospital Miguel Servet	Zaragoza

Sponsors (1)

Lead Sponsor	Collaborator
PETHEMA Foundation

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate the hematological and molecular remission rate after induction and consolidation with ATO		1 year	No
Primary	Evaluate the induction mortality with ATO in monotherapy		1 year	Yes
Primary	Evaluate the hematological and molecular relapse rate in patients treated with autologous transplantation, allogenic transplantation or ATO + ATRA +/- Mylotarg		1 year	No
Secondary	Evaluate kinetics of the MDR of PML/RARa during and after ATO		2 years	No
Secondary	Evaluate the mortality related with postremission treatment		1 year	Yes
Secondary	Side effects of ATO and the different treatments post-consolidation		2 years	Yes
Secondary	Overall survival		2 years	No

External Links

•   Pethema Foundation web
•   Spanish association of Haematology