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

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Brief Title

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

Official Title

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

Brief Summary

      The study will include newly-diagnosed AML patients, not suffering acute promyelocytic
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven
      after completion of induction, a bone marrow aspiration with MRD will be performed for an
      early evaluation of response to treatment. Patients without bone marrow blast reduction below
      10% at day seven after induction will be given a second early induction course. Patients who
      do not achieve CR after two induction courses will be randomized to one of the standard
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.
      Until transplantation, consolidation with HiDAC will be continued.
    

Detailed Description

      The successful treatment of acute myeloid leukemia (AML) depends on the ability to achieve
      complete remission (CR) and to prevent relapse. Both may be affected by the efficacy of
      induction chemotherapy. The gold standard for treatment since 1982 has been DA, a regimen of
      three days of daunorubicin (DNR) and seven days of cytarabine (Ara-C) which results in
      complete remission in 50 to 75% of patients; this is typically administered intravenously,
      with daunorubicin administered at a dose of 45 mg per square meter of body-surface area daily
      for three days, and cytarabine given at a dose of 100 mg per square meter daily for seven
      days. Neither substituting DNR with another anthracycline nor the addition of thioguanine or
      etoposide has been demonstrated to improve outcome. Recently it has been proved that
      high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of complete
      remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7
      months; P = 0.003) without any increase in serious adverse events, compared with the standard
      dose of the drug.

      An alternative method to intensify induction treatment is by the addition of the purine
      analog cladribine. Cladribine was demonstrated to increase cellular uptake of Ara-C and
      accumulation of Ara-CTP in leukemic blasts by 50% to 65% and to have direct antileukemic
      activity based on incorporation of metabolites into the DNA of proliferating cells. In two
      randomized trials by the Polish Adult Leukemia Group (PALG), the investigators demonstrated
      that the combination of cladribine with DNR (60 mg/m2) and Ara-C (DAC) resulted in a
      significantly increased CR rate after a single induction course compared with the standard
      two-drug induction (DA-60). The DAC arm was found to have a survival advantage over the DA-60
      arm for patients aged 50 years or older (P =. 005), those with an initial leukocyte count
      above 50G /L (P < .03), and those with an unfavorable karyotype (P < .03). Both induction
      protocols have the same level of recommendation by the National Cancer Comprehensive Network
      (NCCN) for routine use (level I), and are commonly used for the treatment of newly diagnosed
      AML in Poland.

      As no randomized comparison of these two standard protocols has yet been performed, the aim
      of the proposed study is to compare the efficacy of these two standard induction protocols in
      terms of achievement of CR, early leukemia elimination (at day seven, post induction) and
      quality of remission measured by minimal residual disease level. Additionally, overall
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed. It
      is also intended to compare the hematological and non-hematological toxicity of both
      regimens.

      However, in younger adults with AML treated with standard induction chemotherapy, 20-35% do
      not achieve CR and 50-70% with CR may be expected to relapse within three years. Patients
      with primary refractory disease and with relapses following CR1 have a significantly poorer
      outcome. The optimum strategy at the time of relapse or for patients with refractory disease
      remains uncertain. Allogeneic transplantation can be curative for the minority of patients
      who achieve second CR (2CR) and for whom a suitable donor is available. For the majority of
      patients, additional chemotherapy is given in the hope of achieving remission. Most salvage
      therapies utilize high or intermediate doses of arabinoside cytosine (Ara-C) in combination
      with other agents to overcome resistance in leukemic cells. Previous studies have shown that
      a combination of the purine analog fludarabine (FA) and cytosine arabinoside (Ara-C)
      increases the accumulation of Ara-C-5' triphosphate (Ara-CTP) responsible for the cytotoxic
      effect in leukemic blasts. This combination of FA plus Ara-C was initially explored in
      refractory and relapsed AML patients with satisfactory results. It is also likely that these
      results can be improved by the addition of granulocyte-colony stimulating factor (G-CSF).
      Such a combination of FA, Ara-C, idarubicin and G-CSF (the FLAG-IDA regimen) has been used in
      the treatment of refractory and relapsed AML and poor prognosis myelodysplastic syndromes
      (MDS), with CR rates of between 30-80% being reported. Recent studies have shown that another
      purine analog, cladribine (2-CdA), is also able to enhance Ara-CTP accumulation in leukemic
      blasts and that the combination of 2-Cda with Ara-C exhibited synergistic effect on
      inhibition of myeloid leukemic cell proliferation, induction of apoptosis, and on disruption
      of mitochondrial membrane potential.

      Two previous PALG studies have confirmed that the CLAG-M regimen (a combination of
      cladribine, Ara-C, G-CSF and mitoxantrone) has high efficacy and low toxicity in
      refractory/relapsed AML patients. This salvage regimen was particularly effective in a very
      poor-risk subgroup with primary refractoriness, early relapse or relapse after stem cell
      transplantation. Both salvage protocols, CLAG-M and FLAG-Ida, are wildly used in the
      treatment of relapsed/refractory AML and both have the highest level of NCCN recommendation.
      However, these two standard salvage protocols have yet to be examined as part of any
      randomized study. Therefore, the aim of this study is to compare the efficacy of these two
      standard reinduction protocols (CLAG-M vs FLAG-IDA) in terms of achievement of CR, and
      quality of remission measured by minimal residual disease level. Additionally, the overall
      survival (OS), event-free survival (EFS) and disease-free survival (DFS) will be analyzed.
      The study will also compare the hematological and non-hematological toxicity of both
      regimens.

      The study will include newly-diagnosed AML patients, not suffering acute promyelocytic
      leukemia; aged 18-60 years, who are eligible for standard induction chemotherapy. The
      patients will be randomized to one standard induction regimen (DAC or DA-90). At day seven
      after completion of induction, a bone marrow aspiration with MRD will be performed for an
      early evaluation of response to treatment. Patients without bone marrow blast reduction below
      10% at day seven after induction will be given a second early induction course. Patients who
      do not achieve CR after two induction courses will be randomized to one of the standard
      salvage regimens (FLAG-IDA or CLAG-M). Postremission treatment intensity will be adjusted to
      risk group based on cytogenetic and molecular risk factors at diagnosis and AML biology
      (secondary AML, therapy related AML). Patients with a low risk of relapse will be allocated
      to consolidation, with three courses of high doses of Ara-C (HiDAC), or two courses of HiDAC
      with subsequent autologous stem cell transplantation. Intermediate- or high-risk patients
      will be referred for allogeneic stem cell transplantation, if they have a matched donor.
      Until transplantation, consolidation with HiDAC will be continued.

      The primary end point of the study is CR rate after one and two induction courses. The
      secondary end-points are the quality of CR (MRD), OS, DFS, PFS, CR rate after salvage
      regimen.

      It is planned to include 582 patients with newly-diagnosed AML. This will allow a 10%
      difference in CR rate between DAC and DA-90 induction regimens to be confirmed with a power
      of 80% and level of significance 0.05.

      The study includes neither any experimental drug nor procedures that are not of the standard
      of treatment for AML.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Induction regimen efficacy (DA-90 vs DAC) - I induction


Condition

Acute Myeloid Leukemia

Intervention

A arm (DA-90)

Study Arms / Comparison Groups

 A arm (DA-90)
Description:  Induction I:
DNR 90 mg/m2 D 1-3 in 30-60 min i.v. infusion
Ara-C 100 mg/m2 D 1-7 in 24 h i.v. infusion

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

582

Start Date

July 3, 2017

Completion Date

December 31, 2020

Primary Completion Date

April 1, 2018

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of acute myeloid leukemia (≥20% of blasts in the bone marrow)

          2. Previously untreated AML

               -  AML de novo

               -  AML secondary to the myelodysplastic syndromes (MDS)

               -  AML secondary towards used therapies or agents, which can induce leukemia (e.g.,
                  irradiation, alkylating drugs, topoisomerase II inhibitors) with a primary tumor
                  in remission for at least 2 years.

          3. Age ≥ 18 years and ≤60 years while signing a written consent form

          4. A clinical condition allowing induction treatment to be performed

               -  General state according to the ECOG ≤ 2 scale (Annex 1)

               -  Index of comorbidities, HCT-CI ≤ 3, according to Sorror et al. (43) (Annex 2)

          5. Normal function of the liver and kidneys defined as:

               -  Bilirubin of ≤1.5 of the upper limit of the normal range

               -  ALT ≤2.5 x of the upper limit of the normal range

               -  AST ≤2.5 x of the upper limit of the normal range

               -  Creatinine ≤1.5 of the upper limit of the normal range

          6. A negative pregnancy test result in women of reproductive age, or women after
             menopause

          7. The patient has understood and signed an informed consent form (Annex 3)

          8. The patient has given consent to adhere to scheduled appointments in the study and the
             remaining protocol requirements.

        Exclusion Criteria:

          1. Diagnosis or suspicion of acute promyelocytic leukemia (APL)

          2. Lack of consent for participation in the study

          3. Active cancerous disease other than AML (with the exception of carcinoma basocellulare
             cutis)

          4. Diagnosis of unstable angina pectoris, significant cardiac arrhythmia or class III or
             IV congestive heart failure according to the New York Heart Association (NYHA)
             functional classification

          5. Pregnancy

          6. Uncontrolled mycotic, bacterial or viral systemic infection

          7. Active HIV, or hepatitis B or C virus infection

          8. The use of another form of experimental therapy within 28 days of the commencement of
             treatment

          9. The presence of another comorbidity or improper study results which could expose the
             patient to excessive hazard (HCT-CI>3)

         10. Any other serious health disorders, abnormal results of laboratory tests or mental
             disorders which would interfere with participation in the study

         11. The presence of other comorbidities which would disturb the interpretation of the data
             obtained in the study.
      

Gender

All

Ages

18 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Sebastian Giebel, Prof., +48426895191, [email protected]

Location Countries

Poland

Location Countries

Poland

Administrative Informations


NCT ID

NCT03257241

Organization ID

PALG-AML1/2016


Responsible Party

Principal Investigator

Study Sponsor

Polish Adult Leukemia Group


Study Sponsor

Sebastian Giebel, Prof., Principal Investigator, PALG


Verification Date

August 2017