Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00196768
Status:
UNKNOWN
Last Update Posted:
2007-10-23
First Post:
2005-09-12
Brief Title:
Treatment Protocol for Relapsed Acute Promyelocytic Leukemia APL With Arsenic
Sponsor:
German AML Cooperative Group
Organization:
German AML Cooperative Group
Study Overview
Official Title:
Treatment of Relapsed Acute Promyelocytic Leukemia With Arsenic Trioxide Phase IV Study
Status:
UNKNOWN
Status Verified Date:
2007-10
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Summary
Acute promyelocytic leukemia is defined by a characteristic morphology AML FAB M3M3v by the specific translocation t1517 and its molecular correlates PMLRARa and RARaPML 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 PMLRARa 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
In the present protocol ATO is given for remission induction
1 in patients with hematological or molecular first or subsequent relapse of APL and
2 in patients who do not reach a hematological or molecular remission after first line therapy
Induction therapy with ATO is the mandatory part of the protocol
After remission induction there are several options for postremission therapy Factors which have influence on the treatment decision in the individual case are
1 the eligibility for allogeneic transplantation
2 the eligibility for autologous transplantation
3 the presence or absence of contraindications against intensive chemotherapy
4 the PCR status after induction and during follow up RT-PCR of PMLRARa sensitivity 10-4
A mandatory form of post-remission therapy is not defined in the protocol Data and outcomes of any post-remission therapy should be documented in order to collect data of treatment after ATO
The following stratification of post-remission therapy can be performed according to the decision of the treating physician
Patients with a HLA-compatible donor who are suitable for allogeneic stem cell transplantation should be transplanted In patients with a positive PCR one cycle of intensive chemotherapy HAM before transplantation should be considered and patients with a negative result are immediately transplanted without preceding chemotherapy In patients who do not qualify for allogeneic but for autologous transplantation the intensity of the chemotherapy Ara-C dose of the HAM cycle is scheduled according to the PCR status after ATO and to the patients age In patients under 60 years the recommended single Ara-C dose is scheduled to 3 gm² in case of a positive PCR result and to 1 gm² in case of a negative PCR result after ATO In all patients aged over 60 years the Ara-C dose should be uniformly reduced to 1 gm² independent of the PCR status Patients who are not eligible for allogeneic or autologous transplantation too old no stem cells collected PCR positive stem cell transplant contraindications against intensive chemotherapy receive three further cycles with ATO and ATRA The group of patients not qualifying for autologous transplantation but without contraindications against intensive chemotherapy should receive an age adapted HAM whenever a positive PCR persists or reappears after the three maintenance cycles of ATO A close monitoring of the PCR of PMLRARa after each treatment cycle is part of the protocol
The main objective of the protocol is to take advantage of the expected low toxicity of ATO and to keep the part of chemotherapy as low as possible
Acute promyelocytic leukemia is defined by a characteristic morphology AML FAB M3M3v by the specific translocation t1517 and its molecular correlates PMLRARa and RARaPML 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 PMLRARa 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
In the present protocol ATO is given for remission induction
1 in patients with hematological or molecular first or subsequent relapse of APL and
2 in patients who do not reach a hematological or molecular remission after first line therapy
Induction therapy with ATO is the mandatory part of the protocol
After remission induction there are several options for postremission therapy Factors which have influence on the treatment decision in the individual case are
1 the eligibility for allogeneic transplantation
2 the eligibility for autologous transplantation
3 the presence or absence of contraindications against intensive chemotherapy
4 the PCR status after induction and during follow up RT-PCR of PMLRARa sensitivity 10-4
A mandatory form of post-remission therapy is not defined in the protocol Data and outcomes of any post-remission therapy should be documented in order to collect data of treatment after ATO
The following stratification of post-remission therapy can be performed according to the decision of the treating physician
Patients with a HLA-compatible donor who are suitable for allogeneic stem cell transplantation should be transplanted In patients with a positive PCR one cycle of intensive chemotherapy HAM before transplantation should be considered and patients with a negative result are immediately transplanted without preceding chemotherapy In patients who do not qualify for allogeneic but for autologous transplantation the intensity of the chemotherapy Ara-C dose of the HAM cycle is scheduled according to the PCR status after ATO and to the patients age In patients under 60 years the recommended single Ara-C dose is scheduled to 3 gm² in case of a positive PCR result and to 1 gm² in case of a negative PCR result after ATO In all patients aged over 60 years the Ara-C dose should be uniformly reduced to 1 gm² independent of the PCR status Patients who are not eligible for allogeneic or autologous transplantation too old no stem cells collected PCR positive stem cell transplant contraindications against intensive chemotherapy receive three further cycles with ATO and ATRA The group of patients not qualifying for autologous transplantation but without contraindications against intensive chemotherapy should receive an age adapted HAM whenever a positive PCR persists or reappears after the three maintenance cycles of ATO A close monitoring of the PCR of PMLRARa after each treatment cycle is part of the protocol
The main objective of the protocol is to take advantage of the expected low toxicity of ATO and to keep the part of chemotherapy as low as possible
Detailed Description:
Synopsis
Title of study
Treatment of acute promyelocytic leukemia APL with arsenic trioxide ATO A phase-IV study to assess the effectiveness and toxicity of ATO as well as the kinetics of minimal residual disease MRD in patients with first and subsequent hematological or molecular relapse of APL
Study coordination Priv-Doz Dr Eva Lengfelder
Protocol committee German AMLCG and German AML-Intergroup open for other participating groups
Study duration Time of recruitment 3 years individual follow up scheduled for 3 years
Objectives of the study
Primary objectives
Assessment of
1 the rate of hematological remission
2 the rate of molecular remission
3 the kinetics of the MRD of PMLRARa during and after ATO
Secondary objectives
Assessment of
1 the side effects of ATO
2 percentage of transplantable patients in comparison to the historical results after chemotherapy
3 the overall survival
4 duration of the hematological and molecular remission
Study characteristics Open-label multicenter controlled phase-IV study
Number of patients 30 patients
Inclusion criteria
Patients in first or subsequent hematological or molecular relapse of APL
Persistence of a positive PCR or no hematological CR after first line therapy
No complete hematological remission after first line therapy
Age over 18 years
No upper age limit
Informed consent of the patient
Exclusion criteria
Absolute QTc-interval prolonged over 460 msec before therapy normal electrolytes no other drugs prolonging the QT-interval
Heart failure NYHA grade III and IV
Renal or hepatic failure WHO grade III
Pneumonia with hypoxemia
Uncontrolled sepsis
Pregnancy and lactation period
Secondary malignancy which will have major influence on the prognosis
Expected noncompliance
No informed consent of the patient
Diagnostic measures
Confirmation of relapse by RT-PCR of PMLRARa and by cytogenetics Follow up PCRs with quantitative nested RT-PCR and qualitative REAL-time PCR of PMLRARa
Treatment plan
Induction therapy
- 3 cycles of ATO with the aim to induce a hematological or a molecular remission
Options for postremission therapy
Allogeneic transplantation PBSCT in suitable patients with a related or unrelated donor
The administration of chemotherapy preceding allogeneic transplantation is stratified according to the PCR status after ATO Chemotherapy HAM should be considered in PCR positive patients according to the individual situation
No chemotherapy is given in PCR negative patients
Autologous PBSCT in patients without a donor qualifying for autologous transplantation
The intensity of chemotherapy HAM with either 3 or 1 gm² is proposed according to the PCR status of PMLRARa sensitivity 10-4 after ATO and to patients age
3 maintenance cycles of ATO This is followed by HAM in patients with persistence or reappearance of a positive PCR
Patients not eligible for allogeneic or autologous transplantation but without contraindications against intensive chemotherapy 3 maintenance cycles of ATO in patients not eligible for allogeneic or autologous transplantation no suitable donor too old no stem cells collected positive stem cell transplant and with contraindications against intensive chemotherapy
Monitoring of MRD is mandatory after each ATO cycle and further treatment step Details of the treatment plan are shown in the overview of the study design Paragraph 22
Criteria for evaluation
The effectiveness of the therapy is assessed by the evaluation of the rate of hematological and molecular remission and of the duration of remission according to the commonly used definitions
The safety of the therapy is assessed by a close study monitoring using the criteria of toxicity according to WHO
Title of study
Treatment of acute promyelocytic leukemia APL with arsenic trioxide ATO A phase-IV study to assess the effectiveness and toxicity of ATO as well as the kinetics of minimal residual disease MRD in patients with first and subsequent hematological or molecular relapse of APL
Study coordination Priv-Doz Dr Eva Lengfelder
Protocol committee German AMLCG and German AML-Intergroup open for other participating groups
Study duration Time of recruitment 3 years individual follow up scheduled for 3 years
Objectives of the study
Primary objectives
Assessment of
1 the rate of hematological remission
2 the rate of molecular remission
3 the kinetics of the MRD of PMLRARa during and after ATO
Secondary objectives
Assessment of
1 the side effects of ATO
2 percentage of transplantable patients in comparison to the historical results after chemotherapy
3 the overall survival
4 duration of the hematological and molecular remission
Study characteristics Open-label multicenter controlled phase-IV study
Number of patients 30 patients
Inclusion criteria
Patients in first or subsequent hematological or molecular relapse of APL
Persistence of a positive PCR or no hematological CR after first line therapy
No complete hematological remission after first line therapy
Age over 18 years
No upper age limit
Informed consent of the patient
Exclusion criteria
Absolute QTc-interval prolonged over 460 msec before therapy normal electrolytes no other drugs prolonging the QT-interval
Heart failure NYHA grade III and IV
Renal or hepatic failure WHO grade III
Pneumonia with hypoxemia
Uncontrolled sepsis
Pregnancy and lactation period
Secondary malignancy which will have major influence on the prognosis
Expected noncompliance
No informed consent of the patient
Diagnostic measures
Confirmation of relapse by RT-PCR of PMLRARa and by cytogenetics Follow up PCRs with quantitative nested RT-PCR and qualitative REAL-time PCR of PMLRARa
Treatment plan
Induction therapy
- 3 cycles of ATO with the aim to induce a hematological or a molecular remission
Options for postremission therapy
Allogeneic transplantation PBSCT in suitable patients with a related or unrelated donor
The administration of chemotherapy preceding allogeneic transplantation is stratified according to the PCR status after ATO Chemotherapy HAM should be considered in PCR positive patients according to the individual situation
No chemotherapy is given in PCR negative patients
Autologous PBSCT in patients without a donor qualifying for autologous transplantation
The intensity of chemotherapy HAM with either 3 or 1 gm² is proposed according to the PCR status of PMLRARa sensitivity 10-4 after ATO and to patients age
3 maintenance cycles of ATO This is followed by HAM in patients with persistence or reappearance of a positive PCR
Patients not eligible for allogeneic or autologous transplantation but without contraindications against intensive chemotherapy 3 maintenance cycles of ATO in patients not eligible for allogeneic or autologous transplantation no suitable donor too old no stem cells collected positive stem cell transplant and with contraindications against intensive chemotherapy
Monitoring of MRD is mandatory after each ATO cycle and further treatment step Details of the treatment plan are shown in the overview of the study design Paragraph 22
Criteria for evaluation
The effectiveness of the therapy is assessed by the evaluation of the rate of hematological and molecular remission and of the duration of remission according to the commonly used definitions
The safety of the therapy is assessed by a close study monitoring using the criteria of toxicity according to WHO
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None