Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic

Related Clinical Trial
Total Marrow Irradiation for Refractory Acute Leukemia Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia Therapeutic Allogeneic Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Symptom-Adapted Physical Activity Intervention in Minimizing Physical Function Decline in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS) Radiolabeled BC8 Antibody, Busulfan, Cyclophosphamide Followed by Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia in First Remission 3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia Vaccine Therapy and Basiliximab in Treating Patients With Acute Myeloid Leukemia in Complete Remission Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia PXD101 in Treating Patients With Acute Myeloid Leukemia Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Rasburicase and Allopurinol in Treating Patients With Hematologic Malignancies Lenalidomide and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS Clofarabine and Cytarabine in Treating Patients With Acute Myeloid Leukemia With Minimal Residual Disease Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome SJG-136 in Treating Patients With Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndromes, Blastic Phase Chronic Myelogenous Leukemia, or Chronic Lymphocytic Leukemia Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia Connect® MDS/AML Disease Registry Combined PD1 Inhibitor and Decitabine in Elderly Patients With Relapse and Refractory Acute Myeloid Leukemia Vorinostat in Treating Patients With Acute Myeloid Leukemia Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bortezomib in Treating Patients With High-Risk Acute Myeloid Leukemia in Remission Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia Economic Analysis of Blood Product Transfusions According to the Treatment of Acute Myeloid Leukaemia in the Elderly Comparison of Diagnostic Yield Among M-FISH, FISH Probe Panel and Conventional Cytogenetic Analysis in AML Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia Red Cell Transfusion Goals in Patients With Acute Leukemias A PALG Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in AML Patients ≤ 60 Years Old An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia Fludarabine and Cytarabine as Continuous Infusion Plus G-CSF Priming for Elderly Patients With Resistant AML Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible Prognostic Values of Next Generation Sequencing (NGS) in Acute Myeloid Leukemia Patients With Allo-HSCT PET/MRI, 18F-FDG PET/CT and Whole Body MRI in Finding Extramedullary Myeloid Leukemia in Patients With Newly Diagnosed Acute Myeloid Leukemia Pilot Clinical Trial of Pazopanib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or at Initial Diagnosis When no Intensive Treatment is Possible A Safety Study of SGN-CD33A in AML Patients FLAG+Ida With G-CSF Priming for Patients Younger Than 60 Years With Resistant AML Study on Number and Outcome of Pregnancy in Acute Promielocitic Leukaemia (APL) Patients Treated With Chemotherapy Biomarkers in Bone Marrow Samples From Patients With Acute Promyelocytic Leukemia Treatment Study for Children and Adolescents With Acute Promyelocitic Leukemia A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia ASCT for Relapsed APL After Molecular Remission Diagnostic Study of Patients With Acute Lymphoblastic Leukemia or Acute Promyelocytic Leukemia National Acute Promyelocytic Leukemia (APL) Observational Study NAPOLEON-Registry of the German AML Intergroup All-trans Retinoic Acid, and Arsenic +/- Idarubicin Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia AIDA 2000 Guidelines Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia The Acute Promyelocytic Leukaemia Asian Consortium (APL-AC) Project Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL French Registry of First-line Treatment of Acute Promyelocytic Leukemia New Retinoid Agent Combined With Arsenic Trioxide for Untreated Acute Promyelocytic Leukemia Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO) Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005) Long-Term Quality of Life in Patients With Acute Promyelocytic Leukemia Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia Long-term QoL in Acute Promyelocytic Leukemia Treated With ATO or Standard Chemotherapy Treatment of Non-high-risk Acute Promyelocytic Leukemia (APL) With Realgar-Indigo Naturalis Formula (RIF) Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA) Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia Proteasome Inhibition in Acute Promyelocytic Leukemia

Brief Title

Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic

Official Title

Treatment of Relapsed Acute Promyelocytic Leukemia With Arsenic Trioxide (Phase IV Study)

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.

      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 PML/RARa, 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 patient's age. In patients under 60 years, the recommended single Ara-C dose is
      scheduled to 3 g/m² in case of a positive PCR result and to 1 g/m² 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 g/m² 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 PML/RARa 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 PML/RARa 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 PML/RARa and by cytogenetics. Follow up PCRs with
           quantitative nested RT-PCR and qualitative REAL-time PCR of PML/RARa.

           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 g/m²) is proposed according to the
           PCR status of PML/RARa (sensitivity 10-4) after ATO and to patient's 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 2.2).

           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 Phase

Phase 4

Study Type

Interventional


Primary Outcome

the rate of hematological remission

Secondary Outcome

 the side effects of ATO

Condition

Relapsed Acute Promyelocytic Leukemia

Intervention

Arsenic trioxide


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

January 2005

Completion Date

December 2010


Eligibility Criteria

        Inclusion Criteria:

          -  Patients in first or subsequent hematological or molecular relapse of APL

          -  Persistence of a positive PCR or no hematological complete remission (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 New York Health Association grade III and IV

          -  Renal or hepatic failure World Health Organization 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Eva Lengfelder, MD, PhD, 0049 621 3834110, [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT00196768

Organization ID

30052004



Study Sponsor

German AML Cooperative Group


Study Sponsor

Eva Lengfelder, MD, PhD, Principal Investigator, German AMLCG


Verification Date

October 2007